EP2621932A1 - Tetracyclic heterocycle compounds for treating hepatitis c viral infection - Google Patents

Tetracyclic heterocycle compounds for treating hepatitis c viral infection

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Publication number
EP2621932A1
EP2621932A1 EP11828123.7A EP11828123A EP2621932A1 EP 2621932 A1 EP2621932 A1 EP 2621932A1 EP 11828123 A EP11828123 A EP 11828123A EP 2621932 A1 EP2621932 A1 EP 2621932A1
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EP
European Patent Office
Prior art keywords
alkyl
group
membered
occurrence
int
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP11828123.7A
Other languages
German (de)
French (fr)
Other versions
EP2621932A4 (en
Inventor
Michael P Dwyer
Kartik M Keertikar
Craig A Coburn
Hao Wu
Bin Hu
Bin Zhong
Chengren Zhang
Zhigang Dan
Ling Tong
Wensheng Yu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Organon Pharma UK Ltd
Merck Sharp and Dohme LLC
Original Assignee
Merck Sharp and Dohme Ltd
Merck Sharp and Dohme LLC
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Publication date
Priority claimed from PCT/CN2010/077498 external-priority patent/WO2012040924A1/en
Application filed by Merck Sharp and Dohme Ltd, Merck Sharp and Dohme LLC filed Critical Merck Sharp and Dohme Ltd
Publication of EP2621932A1 publication Critical patent/EP2621932A1/en
Publication of EP2621932A4 publication Critical patent/EP2621932A4/en
Withdrawn legal-status Critical Current

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    • 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
    • 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
    • A61K31/4985—Pyrazines or piperazines 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
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
    • 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
    • C07D498/02—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
    • 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 Fused Tetracyclic Heterocycle
  • compositions comprising at least one Fused Tetracyclic Heterocycle Compound, and methods of using the Fused Tetracyclic Heterocycle Compounds for treating or preventing HCV infection in a patient.
  • HCV Hepatitis C virus
  • BB-NANBH blood-associated NANBH
  • NANBH is to be distinguished from other types of viral- induced liver disease, such as hepatitis A virus (HAV), hepatitis B virus (HBV), delta hepatitis virus (HDV),
  • HAV hepatitis A virus
  • HBV hepatitis B virus
  • HDV delta hepatitis virus
  • CMV cytomegalovirus
  • EBV Epstein-Barr virus
  • HCV replication inhibition is a viable strategy for the prevention of hepatocellular carcinoma.
  • Current therapies for HCV infection include a-interferon monotherapy and combination therapy comprising a-interferon and ribavirin. These therapies have been shown to be effective in some patients with chronic HCV infection, but suffer from poor efficacy and unfavorable side-effects and there are currently efforts directed to the discovery of HCV replication inhibitors that are useful for the treatment and prevention of HCV related disorders.
  • chenodeoxycholic acid and conjugated bile acids (such as tauroursodeoxycholic acid).
  • Phosphono formic acid esters have also been proposed as potentially useful for the treatment of various viral infections, including HCV.
  • Vaccine development has been hampered by the high degree of viral strain heterogeneity and immune evasion and the lack of protection against reinfection, even with the same inoculum.
  • HCV NS5A is a 447 amino acid phosphoprotein which lacks a defined enzymatic function. It runs as 56kd and 58kd bands on gels depending on phosphorylation state (Tanji, et al. J. Virol. 69:3980-3986 (1995)). HCV NS5A resides in replication complex and may be responsible for the switch from replication of RNA to production of infectious virus (Huang, Y, et al, Virology 364: 1-9 (2007)).
  • HCV NS5A inhibitors having fused tricyclic moieties are disclosed in International Patent Publication Nos. WO 10/065681, WO 10/065668, and WO 10/065674.
  • HCV NS5A inhibitors and their use for reducing viral load in HCV infected humans have been described in U.S. Patent Publication No. US20060276511.
  • a and A' are each independently selected from a 5 or 6-membered monocyclic heterocycloalkyl, wherein said 5 or 6-membered monocyclic heterocycloalkyl group can be optionally fused to an aryl group; and wherein said 5 or 6-membered monocyclic
  • heterocycloalkyl group can be optionally and independently substituted on one or more ring carbon atoms with R 13 , such that any two R 13 groups on the same ring, together with the carbon atoms to which they are attached, can join to form a fused, bridged or spirocyclic 3 to 6-membered cycloalkyl group or a fused, bridged or spirocyclic 4 to 6-membered
  • heterocycloalkyl group wherein said 5 or 6-membered monocyclic heterocycloalkyl contains from 1 to 2 ring heteroatoms, each independently selected from N(R 4 ), S, O and Si(R 16 ) 2 ;
  • U is selected from N(R 2 ), O, S and S0 2 ;
  • V and V are each independently selected from N and C(R 15 );
  • W and W are each independently selected from N and C(R J );
  • X and X' are each independently selected from N and C(R 10 );
  • Y and Y' are each independently selected from N and C(R 10 );
  • R 1 is selected from H, Ci-C 6 alkyl, 3 to 6 membered cycloalkyl, halo, -OH, -O- (Ci-C 6 alkyl), Ci-C 6 haloalkyl and -0-(Ci-C 6 haloalkyl);
  • R 2 is selected from H, Ci-C 6 alkyl, 3 to 6-membered cycloalkyl, aryl, 5 or 6- membered heteroaryl and benzyl, wherein said aryl group, said 5 or 6-membered heteroaryl group or the phenyl moiety of said benzyl group can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from Ci-C 6 alkyl, Ci-C 6
  • haloalkyl -0-(d-C 6 alkyl), -0-(d-C 6 haloalkyl), halo, -(Ci-C 6 alkylene)-0-(Ci-C 6 alkyl) and -CN;
  • each occurrence of R 3 is independently selected from H, Ci-C 6 alkyl, Ci-C 6 haloalkyl, -(Ci-C 6 alkylene)-0-(Ci-C 6 alkyl), 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl, 5 or 6-membered heteroaryl, -CH 2 -(5 or 6 membered heteroaryl) and benzyl, wherein said aryl group, said 5 or 6-membered heteroaryl group or the phenyl moiety of said benzyl group can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from Ci-C 6 alkyl, Ci-C 6 haloalkyl, -0-(Ci-C 6 alkyl), -0(Ci-C 6 haloalkyl), halo, -(Ci-C 6 alkylene)-0-(Ci-C 6 alkyl) and
  • each occurrence of R 4 is independently selected from -[C(R 7 ) 2 ] q N(R 6 ) 2 , - C(0)R n , -C(0)-[C(R 7 ) 2 ] q N(R 6 ) 2 , -C(0)-[C(R 7 ) 2 ] q -R n , -C(0)-[C(R 7 ) 2 ] q N(R 6 )C(0)-R n , - -C(0)-[C(R 7 ) 2 ] q N(R 6 )C(0)0-R 11 , -C(0)-[C(R 7 ) 2 ] q C(0)0-R 11 and -alkylene-N(R 6 )-[C(R 7 ) 2 ] q -N(R 6 )-C(0)0-R 11 ;
  • each occurrence of R 5 is independently selected from H, Ci-C 6 alkyl, -(Ci-C 6 alkylene)-0-(Ci-C 6 alkyl), 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl, 5 or 6-membered heteroaryl and benzyl, wherein said aryl group, said 5 or 6-membered heteroaryl group or the phenyl moiety of said benzyl group can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from Ci-C 6 alkyl, Ci-C 6 haloalkyl, -0-(d-C 6 alkyl), -0-(d-C 6 haloalkyl), halo, -(Ci-C 6 alkylene)-0-(Ci-C 6 alkyl) and -CN;
  • each occurrence of R 6 is independently selected from H, Ci-C 6 alkyl, 3 to 6- membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl and 5 or 6-membered heteroaryl, wherein said 3 to 6-membered cycloalkyl group, said 4 to 6-membered heterocycloalkyl group, said aryl group and said 5 or 6-membered heteroaryl group can be optionally and independently substituted with up to two R 8 groups, and wherein two R 6 groups that are attached to the same nitrogen atom, together with the common nitrogen atom to which they are attached, can join to form a 4 to 6-membered heterocycloalkyl group;
  • each occurrence of R 7 is independently selected from H, Ci-C 6 alkyl, Ci-C 6 haloalkyl, silylalkyl, -alkylene-0-(Ci-C 6 alkyl), 3 to 6-membered cycloalkyl, 4 to 6- membered heterocycloalkyl, aryl and 5 or 6-membered heteroaryl, wherein said 3 to 6- membered cycloalkyl group, said 4 to 6-membered heterocycloalkyl group, said aryl group and said 5 or 6-membered heteroaryl group can be optionally substituted with up to three R 8 groups;
  • each occurrence of R 8 is independently selected from H, Ci-C 6 alkyl, halo, - Ci-C 6 haloalkyl, Ci-C 6 hydroxyalkyl, -OH, -C(0)NH-(Ci-C 6 alkyl), -C(0)N(Ci-C 6 alkyl) 2 , - 0-(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 and -NHC(0)-(Ci-C 6 alkyl);
  • each occurrence of R 9 is independently selected from H, Ci-C 6 alkyl, Ci-C 6 haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl and 5 or 6- membered heteroaryl;
  • each occurrence of R 10 is independently selected from H, Ci-C 6 alkyl, Ci-C 6 haloalkyl, halo, -OH, -0-(Ci-C 6 alkyl) and -CN;
  • each occurrence of R 11 is independently selected from H, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 hydro xyalkyl, 3 to 6-membered cycloalkyl and 4 to 6-membered hetero cyclo alkyl; each occurrence of R 12 is independently selected from Ci-C 6 alkyl, Ci-C 6 haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl and 5 or 6- membered heteroaryl;
  • each occurrence of R 13 is independently selected from H, halo, Ci-C 6 alkyl, Ci-C 6 haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, -CN, -OR 9 , -N(R 9 ) 2 , -C(0)R 12 , -C(0)OR 9 , -C(0)N(R 9 ) 2 , -NHC(0)R 12 , -NHC(0)NHR 9 , -NHC(0)OR 9 , - OC(0)R 12 , -SR 9 and -S(0) 2 R 12 , wherein two R 13 groups that attached to the same ring, together with the carbon atom(s) to which they are attached, can optionally join to form a 3 to 6-membered cycloalkyl group or 4 to 6-membered heterocycloalkyl group;
  • each occurrence of R 14 is independently selected from H, halo, Ci-C 6 alkyl,
  • each occurrence of R 15 is independently selected from H, Ci-C 6 alkyl, 3 to 6- membered cycloalkyl, halo, -OH, -0-(Ci-C 6 alkyl), Ci-C 6 haloalkyl and -0-(Ci-C 6 haloalkyl);
  • each occurrence of R 16 is independently selected from H, halo, Ci-C 6 alkyl and 3 to 6-membered cycloalkyl, wherein two R 16 groups that are attached to a common silicon atom can join to form a -(CH 2 ) 4 - or a -(CH 2 )s- group; and
  • each occurrence of q is independently an integer ranging from 0 to 4.
  • 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 Fused Tetracyclic Heterocycle Compounds inhibit HCV viral replication by inhibiting HCV NS5A.
  • the present invention provides methods for treating or preventing
  • HCV infection in a patient comprising administering to the patient an effective amount of at least one Fused Tetracyclic Heterocycle Compound.
  • the present invention relates to novel Fused Tetracyclic Heterocycle
  • a "patient” is a human or non-human mammal. In one embodiment, a patient is a human. In another embodiment, a patient is a chimpanzee.
  • an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.
  • preventing refers to reducing the likelihood of HCV infection.
  • alkyl refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond.
  • An alkyl group may be straight or branched and contain from about 1 to about 20 carbon atoms. In one embodiment, an alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, an alkyl group contains from 1 to 6 carbon atoms (Ci-C 6 alkyl) or from about 1 to about 4 carbon atoms (C 1 -C4 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-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.
  • 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, -O-C(O)- cycloalkyl, -C(0)OH and -C(0)0-alkyl.
  • C 2 -C 6 alkenyl refers to an alkenyl group having from 2 to 6 carbon atoms. Unless otherwise indicated, an alkenyl group is unsubstituted.
  • alkynyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and having one of its hydrogen atoms replaced with a bond. An alkynyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkynyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkynyl group contains from about 2 to about 6 carbon atoms.
  • 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), -0-C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(0)OH and -C(0)0- alkyl.
  • C 2 -C 6 alkynyl refers to an alkyn
  • 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 -, - CH2CH2CH2CH2-, -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.
  • arylene refers to a bivalent group derived from an aryl group, as defined above, by removal of a hydrogen atom from a ring carbon of an aryl group.
  • An arylene group can be derived from a monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an arylene group contains from about 6 to about 10 carbon atoms. In another embodiment, an arylene group is a naphthylene group. In another embodiment, an arylene group is a phenylene group.
  • An arylene group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • An arylene group is divalent and either available bond on an arylene group can connect to either group flanking the arylene group. For example, the group "A-arylene-B,” wherein the arylene group is:
  • an arylene group can be optionally fused to a cycloalkyl or cycloalkanoyl group.
  • arylene groups include phenylene and naphthalene.
  • an arylene group is unsubstituted.
  • an arylene group is:
  • cycloalkyl refers to a non-aromatic mono- or multicyclic ring system comprising from about 3 to about 10 ring carbon atoms. In one embodiment, a cycloalkyl contains from about 5 to about 10 ring carbon atoms. In another embodiment, a cycloalkyl contains from about 3 to about 7 ring atoms. In another embodiment, a cycloalkyl contains from about 5 to about 6 ring atoms.
  • cycloalkyl also encompasses a cycloalkyl group, as defined above, which is fused to an aryl (e.g., benzene) or heteroaryl ring.
  • aryl e.g., benzene
  • 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.
  • a cycloalkyl group is unsubstituted.
  • the term "3 to 6-membered cycloalkyl” refers to a cycloalkyl group having from 3 to 6 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
  • a cycloalkenyl group is
  • a cycloalkenyl group is cyclohexenyl.
  • the term "4 to 6-membered cycloalkenyl” refers to a cycloalkenyl group having from 4 to 6 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-Cg 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.
  • 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.
  • heteroaryl also
  • 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, benzo furazanyl, indolyl, azaindolyl, benzimidazolyl,
  • heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
  • a heteroaryl group is a 5-membered heteroaryl.
  • a heteroaryl group is a 6-membered heteroaryl.
  • a heteroaryl group comprises a 5- to 6-membered heteroaryl group fused to a benzene ring. Unless otherwise indicated, a heteroaryl group is unsubstituted.
  • heteroarylene refers to a bivalent group derived from an heteroaryl group, as defined above, by removal of a hydrogen atom from a ring carbon or ring heteroatom of a heteroaryl group.
  • a heteroarylene group can be derived from a monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of the ring atoms are each independently O, N or S and the remaining ring atoms are carbon atoms.
  • a heteroarylene group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • heteroarylene group is joined via a ring carbon atom or by a nitrogen atom with an open valence, and any nitrogen atom of a heteroarylene can be optionally oxidized to the corresponding N-oxide.
  • heteroarylene also encompasses a heteroarylene group, as defined above, which is fused to a benzene ring.
  • heteroarylenes include pyridylene, pyrazinylene, furanylene, thienylene, pyrimidinylene, pyridonylene (including those derived from N-substituted pyridonyls), isoxazolylene, isothiazolylene, oxazolylene, oxadiazolylene, thiazolylene, pyrazolylene, thiophenylene, furazanylene, pyrrolylene, triazolylene, 1,2,4-thiadiazolylene, pyrazinylene, pyridazinylene,
  • quinoxalinylene phthalazinylene, oxindolylene, imidazo[l,2-a]pyridinylene, imidazo[2,l- b]thiazolylene, benzo furazanylene, indolylene, azaindolylene, benzimidazolylene,
  • heteroarylene also refers to partially saturated heteroarylene moieties such as, for example, tetrahydroisoqumolylene, tetrahydroqumolylene, and the like.
  • a heteroarylene group is divalent and either available bond on a heteroarylene ring can connect to either group flanking the heteroarylene group.
  • a heteroarylene group is a monocyclic heteroarylene group or a bicyclic heteroarylene group. In another embodiment, a heteroarylene group is a monocyclic heteroarylene group. In another embodiment, a heteroarylene group is a bicyclic heteroarylene group. In still another embodiment, a heteroarylene group has from about 5 to about 10 ring atoms. In another embodiment, a heteroarylene group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heteroarylene group is bicyclic and has 9 or 10 ring atoms. In another embodiment, a heteroarylene group is a 5-membered monocyclic heteroarylene.
  • a heteroarylene group is a 6-membered monocyclic heteroarylene.
  • a bicyclic heteroarylene group comprises a 5 or 6- membered monocyclic heteroarylene group fused to a benzene ring. Unless otherwise indicated, a heteroarylene group is unsubstituted.
  • heterocycloalkyl refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to about 11 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 4 to about 7 ring atoms.
  • 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:
  • a ring carbon atom of a heterocycloalkyl group may be functionalized as a carbonyl group.
  • An illustrative example of such a heterocycloalkyl group is:
  • a heterocycloalkyl group is a 5-membered monocyclic heterocycloalkyl. In another embodiment, a heterocycloalkyl group is a 6-membered monocyclic heterocycloalkyl.
  • the term "3 to 6-membered monocyclic cycloalkyl” refers to a monocyclic heterocycloalkyl group having from 3 to 6 ring atoms.
  • the term "4 to 6- membered monocyclic cycloalkyl” refers to a monocyclic heterocycloalkyl group having from 4 to 6 ring atoms.
  • 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.
  • heterocycloalkenyl group can be joined via a ring carbon or ring nitrogen atom.
  • a heterocycloalkenyl group has from 4 to 6 ring atoms.
  • a heterocycloalkenyl group is monocyclic and has 5 or 6 ring atoms.
  • a heterocycloalkenyl group is bicyclic.
  • a heterocycloalkenyl group can optionally
  • 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,
  • 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 6-membered heterocycloalkenyl" refers to a heterocycloalkenyl group having from 4 to 6 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,
  • 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, and formulation into an efficacious therapeutic agent.
  • substantially purified form refers to the physical state of a compound after the compound is isolated from a synthetic process (e.g., from a reaction mixture), a natural source, or a combination thereof.
  • substantially purified form also refers to the physical state of a compound after the compound is obtained from a purification process or processes described herein or well-known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well-known to the skilled artisan.
  • protecting groups When a functional group in a compound is termed "protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.
  • any substituent or variable e.g., alkyl, R 6 , R a , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • 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, Prodrugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in
  • prodrug means a compound (e.g., a drug precursor) that is transformed in vivo to provide a Fused 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-C8)alkyl, (C 2 - Ci 2 )alkanoyloxymethyl, l-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- 1- (alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, l-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1- methyl- l-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon
  • 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, l-methyl-l-((Ci-C 6 )alkanoyloxy)ethyl, (Ci- C 6 )alkoxycarbonyloxymethyl, N-(Ci-C 6 )alkoxycarbonylamino methyl, succinoyl, (Ci-C 6 )alkanoyloxymethyl, l-((Ci- C 6 )alkanoyloxy)ethyl, l-methyl-l-((Ci-C 6 )alkanoyloxy)ethyl, (Ci- C 6 )alkoxycarbonyloxymethyl, N-(Ci-C 6 )alkoxycarbonylamino methyl, succinoyl, (C
  • each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, -P(0)(OH) 2 , -P(0)(0(Ci-C 6 )alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl-, RO-carbonyl-, NRR'-carbonyl- wherein R and R' are each independently (Ci-Cio)alkyl, (C 3 -C7) cycloalkyl, benzyl, a natural ⁇ -aminoacyl, -C(OH)C(0)OY 1 wherein Y 1 is H, (Ci-C 6 )alkyl or benzyl, -C(OY 2 )Y 3 wherein Y 2 is (C 1 -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
  • 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), 601-61 1 (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
  • 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 Fused Tetracyclic Heterocycle Compounds can form salts which are also within the scope of this invention.
  • Reference to a Fused 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.
  • zwitterions may be formed and are included within the term "salt(s)" as used herein.
  • the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt.
  • the salt is other than a pharmaceutically acceptable salt.
  • Salts of the Compounds of Formula (I) may be formed, for example, by reacting a Fused 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,
  • 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
  • Basic nitrogen-containing groups may be quartemized 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., hydro lyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • Stero chemically pure compounds may also be prepared by using chiral starting materials or by employing salt resolution techniques. Also, some of the Fused 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.
  • Fused Tetracyclic Heterocycle Compounds may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention.
  • all keto-enol and imine-enamine forms of the compounds are included in the invention.
  • All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts, solvates, hydrates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. If a Fused 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, positional isomers, 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.
  • Compound of Formula (I) has one or more of its hydrogen atoms replaced with deuterium.
  • Polymorphic forms of the Fused Tetracyclic Heterocycle Compounds, and of the salts, solvates, hydrates, esters and prodrugs of the Fused Tetracyclic Heterocycle Compounds, are intended to be included in the present invention.
  • Ac is acyl; AcCl is acetyl chloride; AcOH or HO Ac is acetic acid; Amphos is (4-(N,N)- dimethylaminophenyl)-di-tertbutylphosphine; Aq is aqueous; BF 3 » OEt 2 is boron trifluoride etherate; BOC or Boc is ie/t-butyloxycarbonyl; Boc 2 0 is Boc anhydride; Boc-Pro-OH is Boc protected proline; L-Boc-Val-OH is Boc protected L-valine; n-BuLi is n-butyllithium; CBZ or Cbz is carbobenzoxy; DCM is dichloromethane; DDQ is 2,3-dichloro-5,6-dicyano-l,4- benzoquinone; Dess-Martin reagent is ,l,l-Triacetoxy-l,l-dihydro-l,2-benziodoxo
  • LiHMDS lithium hexamethyldisilazide
  • LRMS low resolution mass spectrometry
  • Mel is iodomethane
  • MeOH is methanol
  • NBS is N- bromosuccinimide
  • ⁇ 4 ⁇ is ammonium acetate
  • NMM is N-methylmorpholine
  • Pd/C palladium on carbon
  • Pd(PPh 3 ) 4 is tetrakis (triphenylphosphine)palladium(O)
  • PdC ⁇ dppfh is [l,l '-Bis(diphenylphosphino) ferrocene] dichloro palladium(II);
  • PdCl 2 (dppf) 2 » CH 2 Cl 2 is [l,l '-Bis(diphenylphosphino)ferrocene] dichloro palladium(II) complex with
  • the present invention provides Fused Tetracyclic Heterocycle Compounds of Formula (I):
  • a and A' are each a 5-membered heterocycloalkyl group. In another embodiment, A and A' are each a 6-membered heterocycloalkyl group.
  • a and A' are each independently selected from:
  • a and A' are each independently selected from:
  • a and A' are each independently selected from:
  • a and A' are each independently selected from:
  • a and A' are each:
  • a and A' are each:
  • R 13 is independently H, CH 3 or F.
  • each occurrence of R 4 is independently -C(O)- [C(R 7 ) 2 ] q N(R 6 )C(0)0-R n
  • each occurrence of R 4 is independently -C(O)- CH(R 7 )NHC(0)0-R n .
  • each occurrence of R 4 is independently: , wherein R is H, alkyl, haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl or heteroaryl and R a is alkyl, haloalkyl, silylalkyl, 3 to 6-membered cycloalkyl or 4 to 6-membered heterocycloalkyl, aryl or heteroaryl.
  • each occurrence of R 4 is independently: , wherein R a is H, methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, -CH 2 CH 2 Si(CH 3 )3, -CH 2 CH 2 CF 3 , pyranyl, benzyl or phenyl, and R b is methyl, ethyl or isopropyl.
  • each occurrence of R 4 is independently - C(0)CH(R 7 )NHC(0)0-R n , wherein each occurrence of R 7 is independently Ci-C 6 alkyl or phenyl and each occurrence of R 11 is independently Ci-C 6 alkyl.
  • each occurrence ofR 4 is independently -C(0)CH(Ci- C 6 alkyl)-NHC(0)0-(Ci-C 6 alkyl).
  • each occurrence of R 4 is independently:
  • a and A' are each independently selected from:
  • R 4 is: , wherein R is H, alkyl, haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl or heteroaryl and R a is alkyl, haloalkyl, silylalkyl, 3 to 6-membered cycloalkyl or 4 to 6-membered heterocycloalkyl, aryl or heteroaryl.
  • a and A' are each independently selected from:
  • a and A' are each:
  • R 13 is independently H, CH 3 or F;
  • G is -C(R 3 ) 2 -0-.
  • G is -CHR 3 -0-.
  • G is -C(R 3 ) 2 -0- and each occurrence ofR 3 is
  • H Ci-C 6 alkyl, cycloalkyl, heterocycloakyl, heteroaryl and phenyl, wherein said heteroaryl and phenyl groups can be optionally substituted with up to 2 groups, which can be the same or different, and are selected from halo, -CN, Ci-C 6 alkyl, Ci- C 6 haloalkyl, -0-Ci-C 6 alkyl, -(Ci-C 6 alkylene)-0-Ci-C 6 alkyl and -0-Ci-C 6 haloalkyl.
  • G is -C(R 3 ) 2 -0- and each occurrence ofR 3 is independently selected from H, methyl, ethyl, isopropyl, cyclopropyl, l'-methylcyclopropyl, methylenecyclopropyl, phenyl, pyridyl, and pyrimidyl wherein said phenyl, pyridyl and pyrimidinyl group can be optionally substituted with up to 2 groups, which can be the same or different, and are selected from F, CI, -CN, CH 3 , CF 3 , OCF 3 , OCH 2 CH 2 OCH 3 .
  • G is -C(R 3 ) 2 -0- and each occurrence ofR 3 is independently selected from H and Ci-C 6 alkyl.
  • G is -C(R 3 ) 2 -0- and both R 3 groups, together with the common carbon atom to which they are attached, join to form a carbonyl group, a 3 to 6-membered spirocyclic cycloalkyl group or a 3 to 6-membered spirocyclic
  • G is -CHR 3 -0-, wherein R 3 is selected from Ci-C 6 alkyl, -0-(Ci-C 6 alkylene)-Ci-C6 alkyl, benzyl, phenyl, cycloalkyl and 5 or 6-membered heteroaryl, wherein said phenyl group can be optionally substituted with a group selected from: Ci-C 6 alkyl, halo and -O-alkyl.
  • G is -CHR 3 -0-, wherein R 3 is selected from ethyl, isopropyl, t-butyl, sec-butyl, -CH 2 OCH 3 , benzyl, phenyl, cyclopentyl, cyclohexyl, furanyl or pyridyl, wherein said phenyl group can be optionally substituted with a group selected from: Ci-C 6 alkyl, halo and -O-alkyl.
  • U is -N(R 2 )- or -0-.
  • U is -NH- or -N(CH 3 )-.
  • U is O.
  • V is C(R 15 ).
  • V is CH.
  • V is N.
  • V * is C(R 15 ).
  • V is CH.
  • V is N.
  • V and V are each CH.
  • W is C(R 15 ).
  • W is CH.
  • W is N.
  • W * is C(R 15 ).
  • W ' is CH.
  • W is N.
  • W and W are each CH.
  • V, V W and W are each CH.
  • R 1 is absent.
  • R 1 represents one F substituent.
  • each occurrence of R 10 is independently H or F In another embodiment, each occurrence of R 10 is H. In one embodiment the group:
  • each occurrence of R 3 is independently selected from H and Ci-C 6 alkyl and R 2 is H or Ci-C 6 alkyl.
  • R 2 is H or Ci-C 6 alkyl
  • R 3 is ethyl, isopropyl, t-butyl, sec-butyl, -CH 2 OCH 3 , benzyl, phenyl, cyclopentyl, cyclohexyl, furanyl or pyridyl, wherein said phenyl group can be optionally substituted with a group selected from: Ci-C 6 alkyl, halo and -O-alkyl.
  • variables A, A', G, R 1 , R 15 , U, V, V, W, W, X, X * , Y and Y' for the Compounds of Formula (I) are selected independently of each other.
  • the Compounds of Formula (I) are in substantially purified form.
  • a and A' are each independently a 5-membered monocyclic heterocycloalkyl, wherein said 5-membered monocyclic heterocycloalkyl group can be optionally and independently substituted on one or more ring carbon atoms with R 13 , such that any two R 13 groups on the same ring, together with the carbon atoms to which they are attached, can join to form a fused, bridged or spirocyclic 3 to 6-membered cycloalkyl group or a fused, bridged or spirocyclic 4 to 6-membered heterocycloalkyl group, wherein said 5-membered
  • monocyclic heterocycloalkyl contains from 1 to 2 ring heteroatoms, each independently selected from N(R 4 ) and Si(R 16 ) 2 ;
  • U is selected from -N(R 2 )- and -0-;
  • V and V are each independently selected from N and C(R 15 );
  • R 1 represents from 0 to 2 ring substituents on the phenyl ring to which R 1 is attached, wherein said substituents are each independently selected from Ci-C 6 alkyl and halo;
  • each occurrence of R 3 is independently selected from H, Ci-C 6 alkyl, -(Ci-C 6 alkylene)-0-Ci-C6 alkyl, 3 to 6-membered cycloalkyl, Ci-C 6 haloalkyl, aryl, 5 or 6- membered heteroaryl and benzyl, wherein said aryl group, said 5 or 6-membered heteroaryl group or the phenyl group of said benzyl group can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from halo, -CN, Ci-C 6 alkyl, Ci- Ce haloalkyl, -0-Ci-C 6 alkyl, -(Ci-C 6 alkylene)-0-Ci-C 6 alkyl and -0-Ci-C 6 haloalkyl;
  • each occurrence of R 4 is independently -C(0)-[C(R 7 ) 2 ]N(R 6 )C(0)0-R n ; each occurrence of R 6 is independently selected from H and Ci-C 6 alkyl;
  • each occurrence of R 7 is independently selected from Ci-C 6 alkyl, 3 to 6- membered cycloalkyl and aryl;
  • each occurrence of R 10 is independently selected from H and halo;
  • each occurrence of R 1 1 is independently Ci-C 6 alkyl
  • each occurrence of R 13 is independently selected from H, Ci-C 6 alkyl and halo, wherein two R 13 groups, together with the carbon atom(s) to which they are attached, can optionally join to form a 3 to 6-membered cycloalkyl group or 4 to 6-membered
  • R 14 is selected from H, halo, Ci-C 6 alkyl, -(Ci-C 6 alkylene)-0-Ci-C 6 alkyl, 3 to 6-membered cycloalkyl, Ci-C 6 haloalkyl, aryl, 5 or 6-membered heteroaryl and benzyl, wherein said aryl group, said 5 or 6-membered heteroaryl group or the phenyl group of said benzyl group can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from halo, -CN, Ci-C 6 alkyl, Ci-C 6 haloalkyl, -0-Ci-C 6 alkyl, - (Ci-C 6 alkylene)-0-Ci-C 6 alkyl and -0-Ci-C 6 haloalkyl; and
  • each occurrence of R 15 is independently selected from H and halo; and each occurrence of R 16 is independently selected from Ci-C 6 alkyl.
  • a and A' are each independentl selected from:
  • a and A' are each inde endently selected from:
  • a and A' are each:
  • R 13 is independently H, CH 3 or F.
  • each occurrence of R 4 is independently -C(0)-[C(R 7 ) 2 ] q N(R 6 )C(0)0-R n .
  • each occurrence of R 4 is independently -C(0)CH(R 7 )NHC(0)0-R 1 1 .
  • each occurrence of R 4 is independently: , wherein R b is Ci-C 6 alkyl and R a is Ci-C 6 alkyl, 3 to 6- membered cycloalkyl or aryl.
  • each occurrence of R 4 is independently: , wherein R a is methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, or phenyl, and R b is methyl, ethyl or isopropyl.
  • each occurrence of R 4 is independently - C(0)CH(R 7 )NHC(0)0-R n , wherein each occurrence of R 7 is independently Ci-C 6 alkyl or phenyl and each occurrence of R 1 1 is independently Ci-C 6 alkyl.
  • each occurrence of R 4 is independently -C(0)CH(Ci-C 6 alkyl)-NHC(0)0-(Ci-C 6 alkyl).
  • each occurrence of R 4 is independently:
  • a and A' are each independently selected from:
  • R is: , wherein R b is Ci-C 6 alkyl and R a is Ci-C 6 alkyl, 3 to 6- membered cycloalkyl or aryl.
  • a and A' are each inde endently selected from:
  • a and A' are each:
  • R 13 is independently H, CH 3 or F;
  • G is -C(R 3 ) 2 -0-.
  • G is -CHR 3 -0-.
  • G is -C(R 3 ) 2 -0- and each occurrence of R 3 is independently selected from H and Ci-C 6 alkyl.
  • G is -CHR 3 -O-, wherein R 3 is selected from ethyl, isopropyl, t-butyl, sec-butyl, -CH 2 OCH 3 , benzyl, phenyl, cyclopentyl, cyclohexyl, furanyl or pyridyl, wherein said phenyl group can be optionally substituted with a group selected from: Ci-C 6 alkyl, halo and -O-alkyl.
  • U is -N(R 2 )- or -0-. In another embodiment, for the Compounds of Formula (la), U is -NH- or -
  • V is C(R 15 ).
  • V is CH.
  • V is N.
  • V is C(R 15 ).
  • V is CH.
  • V is N.
  • V and V are each CH.
  • W is C(R 15 ).
  • W is CH.
  • W is N.
  • W ' is C(R 15 ).
  • W ' is CH.
  • W is N.
  • W and W are each CH.
  • V, V W and W are each CH.
  • R 1 is absent.
  • R 1 represents one
  • each occurrence of R 10 is independently H or F. In another embodiment, for the Compounds of Formula (la), each occurrence of R IU is H.
  • each occurrence of R 3 is independently selected from H and Ci-C 6 alkyl and R 2 is H or Ci-C 6 alkyl.
  • R 2 is H or Ci-C 6 alkyl
  • R 3 is ethyl, isopropyl, t-butyl, sec-butyl, -CH 2 OCH 3 , benzyl, phenyl, cyclopentyl, cyclohexyl, furanyl or pyridyl, wherein said phenyl group can be optionally substituted with a group selected from: Ci-C 6 alkyl, halo and -O-alkyl.
  • variables A, A * , G, R 1 , R 2 , R 10 , R 15 , U, V and V for the Compounds of Formula (la) are selected independently of each other.
  • the Compounds of Formula (la) are in substantially purified form.
  • the Compounds of Formula (I) have the formula (lb):
  • R 2 is selected from H and Ci-C 6 alkyl
  • each occurrence of R 3 is independently selected from H, Ci-C 6 alkyl, -(Ci-C 6 alkylene)-0-(Ci-C6 alkyl), benzyl, phenyl, cycloalkyl and 5 or 6-membered heteroaryl, wherein said phenyl group can be optionally substituted with a group selected from: Ci-C 6 alkyl, halo and -O-alkyl; and
  • each occurrence of R 13 is independently selected from H, Ci-C 6 alkyl and halo.
  • R 2 is H. In another embodiment, for the Compounds of Formula (lb), R 2 is Ci-C 6 alkyl. In one embodiment, for the Compounds of Formula (lb), each occurrence of R 3 is independently selected from H and Ci-C 6 alkyl.
  • one occurrence of R 3 is H and the other occurrence of R 3 is selected from ethyl, isopropyl, t-butyl, sec-butyl, benzyl, phenyl, cyclopentyl, cyclohexyl, furanyl or pyridyl, wherein said phenyl group can be optionally substituted with a group selected from Ci-C 6 alkyl, halo and -O-alkyl.
  • R 13 is independently selected from H, CH 3 and F.
  • R 2 is H or methyl and each occurrence of R 13 is independently selected from H, CH 3 and F.
  • R 2 is H or methyl; each occurrence of R 13 is independently selected from H, CH 3 and F; one occurrence ofR 3 is H; and the other occurrence of R 3 is selected from ethyl, isopropyl, t-butyl, sec-butyl, benzyl, phenyl, cyclopentyl, cyclohexyl, furanyl or pyridyl, wherein said phenyl group can be optionally substituted with a group selected from: Ci-C 6 alkyl, halo and -O-alkyl.
  • the Compounds of Formula (lb) are in substantially purified form.
  • composition comprising an effective amount of a Compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a
  • HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
  • a pharmaceutical combination that is (i) a Compound of Formula (I) and (ii) a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti- infective agents; wherein the Compound of Formula (I) and the second therapeutic agent are each employed in an amount that renders the combination effective for inhibiting HCV replication, or for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.
  • HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
  • a method of inhibiting HCV replication in a subject in need thereof hich comprises administering to the subject an effective amount of a Compound of Formula
  • At least one second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.
  • HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
  • (j) A method of inhibiting HCV replication in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b) or (c) or the combination of (d) or (e).
  • (k) A method of treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b) or (c) or the
  • 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) medicine, (b) inhibiting HCV replication or (c) treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.
  • the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents selected from HCV antiviral agents, anti- infective agents, and
  • Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(k) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, 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.
  • compositions and methods provided as (a) through (k) above are understood to include all embodiments of the compounds, including such embodiments as result from combinations of embodiments.
  • the Compounds of Formula (I) may be referred to herein by chemical structure and/or by chemical name. In the instance that both the structure and the name of a Compound of Formula (I) are provided and a discrepancy is found to exist between the chemical structure and the corresponding chemical name, it is understood that the chemical structure will predominate.
  • Non- limiting examples of the Compounds of Formula (I) include compounds 1-36 as set forth in the Examples below, and pharmaceutically acceptable salts thereof.
  • the Compounds of Formula (I) may be prepared from known or readily prepared starting materials, following methods known to one skilled in the art of organic synthesis. Methods useful for making the Compounds of Formula (I) are set forth in the Examples below and generalized in Schemes 1-5 below. Alternative synthetic pathways and analogous structures will be apparent to those skilled in the art of organic synthesis.
  • Scheme 1 shows methods useful for making the tetracyclic compounds of formula G9, which are useful intermediates for making the Compounds of Formula (I), wherein U is -N(R 2 )-; W and W are each -QR 1 )-; and V and V * are each -C(R 15 )-.
  • K' and Y represent coupling partners which can form a bridging group G;
  • M, M' and M" are each independently halo, hydroxy, or a protected hydroxy, triflate, boronic acid or boronic ester;
  • Q and Q' are each independently halo, methoxy or benzyloxy;
  • M and M' are each independently halo, triflate, boronic acid or boronic ester;
  • PG is a secondary amino protecting group, such as Boc or 4-methoxybenzyl;
  • R 4 is -C(0)R n , -C(O)- [C(R 7 ) 2 ] q N(R 6 ) 2 , -C(0)-[C(R 7 ) 2 ] q -R n , -C(0)-[C(R 7 ) 2 ] q N(R 6 )C(0)-R n , - C(0)[C(R 7 ) 2 ] q N(R 6
  • K' and Y represent coupling partners which can form a bridge G.
  • G is a two atom bridge
  • K' and Y can each contain one atom of the latent bridge, or that each of either K' or Y can contain both atoms.
  • Tetracyclic compounds of formula G8 can be prepared from suitably substituted indole derivatives of formulas G4 and G7.
  • Indole derivatives of general formula G4 and G7 may be obtained commercially or prepared by using methods known to those skilled in the art of organic synthesis.
  • the compounds of formula G4 can be made via dehydration of a hydrazide of formula Gl with a ketone of formula G2 to provide hydrazones of formula G3, which can then be cyclized in the presence of a strong acid such as PPA or a Lewis acid such as aluminum chloride, to provide the hydroxyl- substituted indole compounds of formula G4.
  • a compound of formula G4 can then be reacted with an aldehyde of formula R 3 -CHO to provide the cyclized compounds of formula G8, wherein G is -CHR 3 -0-.
  • Compounds of formula G7 can be made, for example, via the arylation of the 2-position of an indole of formula G5 with a coupling partner of formula G6.
  • a compound of formula G7 can then be cyclized by reacting Y and K' to provide the compounds of formula G8.
  • the Q and Q' groups of a compound of formula G8 can be converted to the M and M' groups of the compounds of formula G9 using methods well-known to those skilled in the art of organic synthesis.
  • Scheme 2 shows a method useful for making the compounds of formula G12, which correspond to the Compounds of Formula (I), wherein U is -N(R 2 )-; W and W are each -QR 1 )-; V and V are each -C(R 15 )-; X and X' are each -CH- and Y and Y' are each - N-.
  • D and D' are each independently C(R 13 ) 2 , N(R 4 ), S, O or Si(R 16 ) 2 ;
  • M and M' are each independently halo, triflate, boronic acid or boronic ester;
  • PG is a protecting group, such as Boc or 4-methoxybenzyl;
  • R 4 is -C(0)R n , -C(0)-[C(R 7 ) 2 ] q N(R 6 ) 2 , -C(O)- [C(R 7 ) 2 ] q -R n , -C(0)-[C(R 7 ) 2 ] q N(R 6 )C(0)-R n , -C(0)[C(R 7 ) 2 ] q N(R 6 )S0 2 -R n , -C(O)-
  • the compounds of formula G9 can be coupled with a coupling partner of formula G22 (preparation of compounds of formula G22 is described below in Scheme 5) to provide the compounds of formula G10.
  • Removal of the protecting groups of the compounds of formula G10 provides the diamino compounds of formula Gil, which can then be reacted with an appropriately substituted carboxylic acid to form the R 4 groups of the di-amide compounds of formula G12, which which correspond the the Compounds of Formula (I), wherein U is -N(R 2 )-; W and W are each -C(R 1 )-; V and V are each -C(R 15 )-; X and X * are each -CH- and Y and Y' are each -N-.
  • Scheme 3 shows a method useful for making the compounds of formula G15, which correspond to the Compounds of Formula (I), wherein intermediates for making the Compounds of Formula (I), wherein U is -0-; W and W are each -QR 1 )-; V and V are each -C(R 15 )-; X and X' are each -CH- and Y and Y' are each -N-.
  • D and D' are each independently C(R 13 ) 2 , N(R 4 ), S, O or Si(R 16 ) 2 ;
  • M and M' are each independently halo, triflate, boronic acid or boronic ester;
  • R 4 is -C(0)R n , - C(0)-[C(R 7 ) 2 ] q N(R 6 ) 2 , -C(0)-[C(R 7 ) 2 ] q -R n , -C(0)-[C(R 7 ) 2 ] q N(R 6 )C(0)-R n , - C(0)[C(R 7 ) 2 ] q N(R 6 )S0 2 -R n , -C(0)-[C(R 7 ) 2 ] q N(R 6 )C(0)0-R n or -C(0)-[C(R 7 ) 2 ] q C(0)0-R n ; and G, R 2 and R 15 are
  • a substituted benzoxazole of formula G13 can be arylated at the 2-position with coupling partner of formula G6 using methods analogous to those described in Scheme 1 for the formation of G8 from G5 and G6, to provide the 2-aryl benzoxazoles of formula G14.
  • a compound of formula G14 can then be carried forth to the compounds of G15 using methods analogous to those described in Scheme 2 for the conversion of G9 to G12.
  • Scheme 4 shows a method useful for making the compounds of formula G12, which correspond the the Compounds of Formula (I), wherein U is -N(R 2 )-; W and W are each -QR 1 )-; V is -CH-; V * is -N-; X and X * are each -CH- and Y and Y * are each -N-.
  • D and D' are each independently C(R 13 ) 2 , N(R 4 ), S, O or Si(R 16 ) 2 ;
  • M and M' are each independently halo, triflate, boronic acid or boronic ester;
  • R 4 is -C(0)R n , - C(0)-[C(R 7 ) 2 ] q N(R 6 ) 2 , -C(0)-[C(R 7 ) 2 ] q -R n , -C(0)-[C(R 7 ) 2 ] q N(R 6 )C(0)-R n , - C(0)[C(R 7 ) 2 ] q N(R 6 )S0 2 -R n , -C(0)-[C(R 7 ) 2 ] q N(R 6 )C(0)0-R n or -C(0)-[C(R 7 ) 2 ] q C(0)0-R n ; and G, R 1 and R 2 are
  • a pyridyl hydrazone of formula G16 can be converted to the tetracyclic compounds of formula G17 using methods analogous to those described in Scheme 1 for the formation of G8 from G3.
  • a compound of formula G17 can then be carried forth to the compounds of G18 using methods analogous to those described in Scheme 2 for the conversion of G9 to G12.
  • Scheme 5 shows methods useful for making the compounds of formula G22, which are useful intermediates for making the Compounds of Formula (I) wherein X and X' are each CH and Y and Y' are each N.
  • D is C(R 13 ) 2 , N(R 4 ), S, O or Si(R 16 ) 2 ;
  • X is halo or triflate; and
  • PG is a amino protecting group, such as Boc or 4-methoxybenzyl.
  • An appropriately functionalized aldehyde of formula G19 can be reacted with glyoxal and ammonia.to provide a substituted imidazole of formula G20.
  • a compound of formula G20 can subsequently be selectively mono-halogenated to provide a mono- halogenated imidazole compound of formula G22.
  • a compound of formula G22 can subsequently be di-halogenated to provide a compound of formula G21, which is then selectively reduced to provide a mono-halogenated imidazole compound of formula G22.
  • amino acids such as, but not limited to proline, 4-(R)-fluoroproline, 4-(S)-fluoroproline, 4,4- difluoroproline, 4,4-dimethylsilylproline, aza-bicyclo[2.2.1]heptane carboxylic acid, aza- bicyclo[2.2.2]octane carboxylic acid, (S)-2-piperidine carboxylic acid, valine, alanine, norvaline, etc.) are incorporated as part of the structures.
  • amide bonds include but are not limited to, the use of a reactive carboxy derivative ⁇ e.g., an acid halide, or ester at elevated temperatures) or the use of an acid with a coupling reagent ⁇ e.g., HOBt, EDCI, DCC, HATU, PyBrop) with an amine.
  • a reactive carboxy derivative e.g., an acid halide, or ester at elevated temperatures
  • a coupling reagent e.g., HOBt, EDCI, DCC, HATU, PyBrop
  • the Compounds Formula (I) may contain one or more silicon atoms.
  • the compounds contemplated in this invention in general can be prepared using the carba-analog methodology unless otherwise noted.
  • a recent review of the synthesis of silicon containing compounds can be found in "Silicon Chemistry: from Atom to Extended Systems", Ed P. Jutzi & U. Schubet; ISBN 978-3-527-30647-3.
  • Preparation of silyl containing amino acids has been described. See Bolm et al., Angew. Chem. Int Ed., 39:2289 (2000). Descriptions of improved cellular update ( Giralt, J. Am. Chem. Soc, 128:8479 (2006)) and reduced metabolic processing of silyl containing compounds have been described ( Johansson et al., Drug Metabolism & Disposition, 38:73 (2009)).
  • the starting materials used and the intermediates prepared using the methods set forth 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 Fused Tetracyclic Heterocycle Compounds are useful in human and veterinary medicine for treating or preventing a viral infection in a patient.
  • the Fused Tetracyclic Heterocycle Compounds are useful in human and veterinary medicine for treating or preventing a viral infection in a patient.
  • the Fused Tetracyclic Heterocycle Compounds can be inhibitors of viral replication.
  • the Fused Tetracyclic Heterocycle Compounds can be inhibitors of HCV replication. Accordingly, the Fused Tetracyclic Heterocycle Compounds are useful for treating viral infections, such as HCV.
  • the Fused Tetracyclic Heterocycle Compounds can be administered to a patient in need of treatment or prevention of a viral infection.
  • the invention provides methods for treating a viral infection in a patient comprising administering to the patient an effective amount of at least one Fused Tetracyclic Heterocycle Compound or a pharmaceutically acceptable salt thereof. Treatment or Prevention of a Flaviviridae Virus
  • the Fused Tetracyclic Heterocycle Compounds can be useful for treating or preventing a viral infection caused by the Flaviviridae family of viruses.
  • Flaviviridae infections that can be treated or prevented using the present methods include but are not limited to, dengue fever, Japanese encephalitis, Kyasanur Forest disease, Murray Valley encephalitis, St. Louis encephalitis, Tick-borne encephalitis, West Nile encephalitis, yellow fever and Hepatitis C Virus (HCV) infection.
  • dengue fever Japanese encephalitis
  • Kyasanur Forest disease Murray Valley encephalitis
  • St. Louis encephalitis St. Louis encephalitis
  • Tick-borne encephalitis West Nile encephalitis
  • West Nile encephalitis yellow fever
  • HCV Hepatitis C Virus
  • the Flaviviridae infection being treated is hepatitis C virus infection.
  • the Fused Tetracyclic Heterocycle Compounds are useful in the inhibition of HCV (e.g., HCV NS5A), the treatment of HCV infection and/or reduction of the likelihood or severity of symptoms of HCV infection and the inhibition of HCV viral replication and/or HCV viral production in a cell-based system.
  • HCV e.g., HCV NS5A
  • 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.
  • the hepatitis C infection is acute hepatitis C. In another embodiment, the hepatitis C infection is chronic hepatitis C.
  • the invention provides methods for treating HCV infection in a patient, the methods comprising administering to the patient an effective amount of at least one Fused Tetracyclic Heterocycle Compound or a pharmaceutically acceptable salt thereof.
  • the amount administered is effective to treat or prevent infection by HCV in the patient.
  • the amount administered is effective to inhibit HCV viral replication and/or viral production in the patient.
  • the Fused Tetracyclic Heterocycle Compounds are also useful in the preparation and execution of screening assays for antiviral compounds.
  • the Fused Tetracyclic Heterocycle Compounds are useful for identifying resistant HCV replicon cell lines harboring mutations within NS5 A, which are excellent screening tools for more powerful antiviral compounds.
  • the Fused Tetracyclic Heterocycle Compounds are useful in establishing or determining the binding site of other antivirals to the HCV replicase.
  • compositions and combinations of the present invention can be useful for treating a patient suffering from infection related to any HCV genotype.
  • HCV types and subtypes may differ in their antigenicity, level of viremia, severity of disease produced, and response to interferon therapy as described in Holland et al., Pathology, 30(2): 192- 195 (1998).
  • the nomenclature set forth in Simmonds et al, J Gen Virol, 74(Ptl l):2391-2399 (1993) is widely used and classifies isolates into six major genotypes, 1 through 6, with two or more related subtypes, e.g., la and lb.
  • the present methods for treating or preventing HCV infection can further comprise the administration of one or more additional therapeutic agents which are not Fused Tetracyclic Heterocycle Compounds.
  • the additional therapeutic agent is an antiviral agent. In another embodiment, the additional therapeutic agent is an antiviral agent. In another embodiment, the additional therapeutic agent is an antiviral agent. In another embodiment, the additional therapeutic agent is an antiviral agent. In another embodiment, the additional therapeutic agent is an antiviral agent. In another embodiment, the additional therapeutic agent is an antiviral agent.
  • immunomodulatory agent such as an immunosuppressive agent.
  • the present invention provides methods for treating a viral infection in a patient, the method comprising administering to the patient: (i) at least one Fused Tetracyclic Heterocycle Compound, or a pharmaceutically acceptable salt thereof, and (ii) at least one additional therapeutic agent that is other than a Fused Tetracyclic Heterocycle Compound, wherein the amounts administered are together effective to treat or prevent a viral infection.
  • therapeutic agents in the combination may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like.
  • the amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts).
  • a Fused 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).
  • the at least one Fused Tetracyclic Heterocycle Compound is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.
  • the at least one Fused 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.
  • the at least one Fused 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.
  • the at least one Fused 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.
  • the at least one Fused Tetracyclic Heterocycle Compound and the additional therapeutic agent(s) are present in the same composition. In one embodiment, the at least one Fused Tetracyclic Heterocycle Compound and the additional therapeutic agent(s) are present in the same composition. In one
  • 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.
  • the viral infection is HCV infection.
  • the at least one Fused 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.
  • the administration of at least one Fused 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.
  • the additional therapeutic agent is a viral protease inhibitor.
  • the additional therapeutic agent is a viral replication inhibitor. In another embodiment, the additional therapeutic agent is an HCV NS3 protease inhibitor.
  • the additional therapeutic agent is an HCV NS5B polymerase inhibitor.
  • the additional therapeutic agent is a nucleoside inhibitor.
  • the additional therapeutic agent is an interferon.
  • the additional therapeutic agent is an HCV replicase inhibitor.
  • the additional therapeutic agent is an antisense agent.
  • the additional therapeutic agent is a therapeutic vaccine.
  • the additional therapeutic agent is a virion production inhibitor.
  • the additional therapeutic agent is an antibody therapy.
  • the additional therapeutic agent is an HCV NS2 inhibitor.
  • the additional therapeutic agent is an HCV NS4A inhibitor.
  • the additional therapeutic agent is an HCV NS4B inhibitor.
  • the additional therapeutic agent is an HCV NS5A inhibitor
  • the additional therapeutic agent is an HCV NS3 helicase inhibitor.
  • the additional therapeutic agent is an HCV IRES inhibitor.
  • the additional therapeutic agent is an HCV p7 inhibitor.
  • the additional therapeutic agent is an HCV entry inhibitor.
  • the additional therapeutic agent is an HCV assembly inhibitor.
  • the additional therapeutic agents comprise a viral protease inhibitor and a viral polymerase inhibitor.
  • the additional therapeutic agents comprise a viral protease inhibitor and an immunomodulatory agent.
  • the additional therapeutic agents comprise a polymerase inhibitor and an immunomodulatory agent.
  • the additional therapeutic agents comprise a viral protease inhibitor and a nucleoside.
  • the additional therapeutic agents comprise an immunomodulatory agent and a nucleoside.
  • the additional therapeutic agents comprise an HCV protease inhibitor and an HCV polymerase inhibitor.
  • the additional therapeutic agents comprise a nucleoside and an HCV NS5 A inhibitor.
  • the additional therapeutic agents comprise a viral protease inhibitor, an immunomodulatory agent and a nucleoside.
  • the additional therapeutic agents comprise a viral protease inhibitor, a viral polymerase inhibitor and an immunomodulatory agent.
  • the additional therapeutic agent is ribavirin.
  • HCV polymerase inhibitors useful in the present compositions and methods include, but are not limited to, VP- 19744 (Wyeth/ViroPharma), PSI-7851 (Pharmasset), R7128 (Roche/Pharmasset), PF-868554/filibuvir (Pfizer), VCH-759 (ViroChem Pharma), HCV-796 (Wyeth/ViroPharma), IDX-184 (Idenix), IDX-375 (Idenix), NM-283
  • 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 09/0321 16, WO
  • Interferons useful in the present compositions and methods include, but are not limited to, interferon alfa-2a, interferon alfa-2b, interferon alfacon-1 and PEG-interferon alpha conjugates.
  • PEG-interferon alpha conjugates are interferon alpha molecules covalently attached to a PEG molecule.
  • Illustrative PEG-interferon alpha conjugates include interferon alpha-2a (RoferonTM, Hoffman La-Roche, Nutley, New Jersey) in the form of pegylated interferon alpha-2a (e.g., as sold under the trade name PegasysTM), interferon alpha-2b (IntronTM, from Schering-Plough Corporation) in the form of pegylated interferon alpha-2b (e.g. , as sold under the trade name PEG-IntronTM from Schering-Plough
  • interferon alpha-2b-XL e.g. , as sold under the trade name PEG-IntronTM
  • interferon alpha-2c Boehringer Ingelheim, Ingelheim, Germany
  • PEG- interferon lambda Bristol-Myers Squibb and ZymoGenetics
  • interferon alfa-2b alpha fusion polypeptides interferon fused with the human blood protein albumin (AlbuferonTM, Human Genome Sciences), Omega Interferon (Intarcia), Locteron controlled release interferon (Biolex/OctoPlus), Biomed-510 (omega interferon), Peg-IL-29 (ZymoGenetics), Locteron CR (Octoplus), IFN-a-2b-XL (Flamel Technologies), and consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (InfergenTM, 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).
  • ATCC American Type Culture Collection
  • 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.
  • HCV protease inhibitors useful in the present compositions and methods include, but are not limited to, SCH503034 (Boceprevir, Schering-Plough),
  • SCH900518 (Schering-Plough), VX-950 (Telaprevir, Vertex), VX-500 (Vertex), VX-813 (Vertex), VBY-376 (Virobay), BI-201335 (Boehringer Ingelheim), TMC-435
  • 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); Ingallmella 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, 3703): 11459-11468 (1998); Dimasi et al, J Virol, 71(10 ⁇ :7461-7469 (1997); Martin et al, Protein Eng, 10(5 ⁇ :607-614 (1997); Elzouki et al, J Hepat, 27( ⁇ :42-48 (1997); BioWorld Today, 9(217 ⁇ :4 (November 10, 1998); U.S. Patent Publication Nos.
  • HCV protease inhibitors useful in the present compositions and methods include, but are not limited to, the following compounds:
  • Viral replication inhibitors useful in the present compositions and methods include, but are not limited to, HCV replicase inhibitors, IRES inhibitors, NS4A inhibitors, NS3 helicase inhibitors, NS5A inhibitors, NS5B inhibitors, ribavirin, AZD-2836 (Astra Zeneca), BMS-790052 (Bristol-Myers Squibb, see Gao et al, Nature, 465:96-100 (2010)), viramidine, A-831 (Arrow Therapeutics); an antisense agent or a therapeutic vaccine.
  • HCV NS4A inhibitors 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
  • HCV NS4A inhibitors useful in the present compositions and methods include, but are not limited to, AZD2836 (Astra Zeneca) and ACH-806 (Achillon Pharmaceuticals, New Haven, CT).
  • HCV replicase inhibitors useful in the present compositions and methods include, but are not limited to, those disclosed in U.S. Patent Publication No.
  • compositions and methods examples include, but are not limited to, Ritonavir (Abbott), TT033 (Benitec/Tacere Bio/Pfizer), Sirna-034 (Sirna Therapeutics), GNI-104 (GENimmune), GI- 5005 (Globelmmune), IDX-102 (Idenix), LevovirinTM (ICN Pharmaceuticals, Costa Mesa,
  • Humax (Genmab), ITX-2155 (Ithrex/Novartis), PRO 206 (Progenies), HepaCide- I (NanoVirocides), MX3235 (Migenix), SCY-635 (Scynexis); KPE02003002 (Kemin Pharma), Lenocta (Vio Quest Pharmaceuticals), IET - Interferon Enhancing Therapy
  • the doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of HCV infection can be determined by the attending clinician, taking into consideration the approved doses and dosage regimen in the package insert; the age, sex and general health of the patient; and the type and severity of the viral infection or related disease or disorder.
  • the Fused 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.
  • kits comprising the separate dosage forms is therefore advantageous.
  • 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.
  • the dosage is from about 10 to about 1000 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 500 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 100 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 50 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 500 to about 1500 mg/day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 500 to about 1000 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 100 to about 500 mg/day, administered in a single dose or in 2-4 divided doses.
  • the additional therapeutic agent is INTRON-A interferon alpha 2b (commercially available from 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.
  • the additional therapeutic agent is PEG- 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.
  • 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.
  • PEGASUS interferon alpha 2a pegylated (commercially available from Hoffmann-La Roche), this agent is administered by subcutaneous injection at 180 mcg/lmL or 180 mcg/0.5mL, once a week for at least 24 weeks.
  • INFERGEN interferon alphacon-1 (commercially available from Amgen), this agent is administered by subcutaneous injection at 9 mcg/TIW is 24 weeks for first time treatment and up to 15 mcg/TIW for 24 weeks for non-responsive or relapse treatment.
  • the additional therapeutic agent is Ribavirin (commercially available as REBETOL ribavirin from 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.
  • one or more compounds of the present invention are administered with one or more additional therapeutic agents selected from: an interferon, an immunomodulator, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a viral polymerase inhibitor, a nucleoside inhibitor, a viral protease inhibitor, a viral helicase inhibitor, a viral polymerase inhibitor a virion production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, an antibody therapy (monoclonal or polyclonal), and any agent useful for treating an RNA-dependent polymerase-related disorder.
  • additional therapeutic agents selected from: an interferon, an immunomodulator, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a viral polymerase inhibitor, a nucleoside inhibitor, a viral protease inhibitor, a viral helicase inhibitor, a viral polymerase inhibitor a virion production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, an antibody therapy (monoclonal or polyclonal), and any agent useful for treating
  • one or more compounds of the present invention are administered with one or more additional therapeutic agents selected from an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV replication inhibitor, a nucleoside, an interferon, a pegylated interferon and ribavirin.
  • the combination therapies can include any combination of these additional therapeutic agents.
  • one or more compounds of the present invention are administered with one additional therapeutic agent selected from an HCV protease inhibitor, an interferon, a pegylated interferon and ribavirin.
  • one or more compounds of the present invention are administered with two additional therapeutic agents selected from an HCV protease inhibitor, an HCV replication inhibitor, a nucleoside, an interferon, a pegylated interferon and ribavirin.
  • one or more compounds of the present invention are administered with an HCV protease inhibitor and ribavirin. In another specific embodiment, one or more compounds of the present invention are administered with a pegylated interferon and ribavirin.
  • one or more compounds of the present invention are administered with three additional therapeutic agents selected from an HCV protease inhibitor, an HCV replication inhibitor, a nucleoside, an interferon, a pegylated interferon and ribavirin.
  • one or more compounds of the present invention are administered with one or more additional therapeutic agents selected from an HCV
  • 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.
  • one or more additional therapeutic agents selected from an HCV polymerase inhibitor, a viral protease inhibitor, an interferon, and a viral replication inhibitor.
  • one or more compounds of the present invention are administered with one or more additional therapeutic agents selected from an HCV polymerase inhibitor, a viral protease inhibitor, an interferon, and ribavirin.
  • one or more compounds of the present invention are administered with one additional therapeutic agent selected from an HCV polymerase inhibitor, a viral protease inhibitor, an interferon, and a viral replication inhibitor. In another embodiment, one or more compounds of the present invention are 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.
  • one or more compounds of the present invention are administered with ribavirin, interferon and another therapeutic agent.
  • one or more compounds of the present invention are administered with ribavirin, interferon and another therapeutic agent, wherein the additional therapeutic agent is selected from an HCV polymerase inhibitor, a viral protease inhibitor, and a viral replication inhibitor.
  • one or more compounds of the present invention are administered with ribavirin, interferon and a viral protease inhibitor.
  • one or more compounds of the present invention are administered with ribavirin, interferon and an HCV protease inhibitor.
  • one or more compounds of the present invention are administered with ribavirin, interferon and boceprevir or telaprevir.
  • one or more compounds of the present invention are administered with ribavirin, interferon and an HCV polymerase inhibitor.
  • one or more compounds of the present invention are administered with pegylated- interferon alpha and ribavirin.
  • the Fused Tetracyclic Heterocycle Compounds are useful in veterinary and human medicine. As described above, the Fused Tetracyclic Heterocycle Compounds are useful for treating or preventing HCV infection in a patient in need thereof.
  • Compounds can be administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle.
  • the present invention provides
  • Tetracyclic Heterocycle Compound and a pharmaceutically acceptable carrier.
  • 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 so lid- filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like.
  • 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.
  • preparations include powders, tablets, dispersible granules, capsules, cachets and
  • Powders and tablets may be comprised of from about 0.5 to about 95 percent inventive composition. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
  • suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
  • lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate.
  • Liquid form preparations include solutions, suspensions and emulsions and may include water or water-propylene glycol solutions for parenteral injection.
  • Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.
  • a pharmaceutically acceptable carrier such as an inert compressed gas.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed
  • compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize therapeutic effects, i.e., antiviral activity and the like.
  • Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • the one or more Fused Tetracyclic Heterocycle is one or more Fused Tetracyclic Heterocycle
  • Compounds are administered orally.
  • the one or more Fused Tetracyclic Heterocycle Compounds are administered intravenously.
  • the one or more Fused Tetracyclic Heterocycle Compounds are administered topically.
  • the one or more Fused Tetracyclic Heterocycle Compounds are administered sublingually.
  • a pharmaceutical preparation comprising at least one Fused Tetracyclic Heterocycle Compound is in unit dosage form.
  • the preparation is subdivided into unit doses containing effective amounts of the active components.
  • compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present compositions can contain, in one embodiment, from about 0.1% to about 99% of the Fused Tetracyclic Heterocycle
  • compositions can contain, in one embodiment, from about 1% to about 70% or from about 5% to about 60% of the Fused Tetracyclic Heterocycle Compound(s) by weight or volume.
  • the quantity of Fused 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.
  • 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.
  • a total daily dosage of the Fused 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.
  • the dosage is from about 1 to about 200 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 10 to about 2000 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 100 to about 2000 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 500 to about 2000 mg/day, administered in a single dose or in 2-4 divided doses.
  • compositions of the invention can further comprise one or more additional therapeutic agents, selected from those listed above herein. Accordingly, in one embodiment, the present invention provides compositions comprising: (i) at least one Fused Tetracyclic Heterocycle Compound or a pharmaceutically acceptable salt thereof; (ii) one or more additional therapeutic agents that are not a Fused Tetracyclic Heterocycle Compound; and (iii) a pharmaceutically acceptable carrier, wherein the amounts in the composition are together effective to treat HCV infection.
  • the present invention provides compositions comprising a Compound of Formula (I) and a pharmaceutically acceptable carrier.
  • 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,
  • 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.
  • the present invention provides a kit comprising a therapeutically effective amount of at least one Fused Tetracyclic Heterocycle Compound, or a
  • the present invention provides a kit comprising an amount of at least one Fused 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.
  • the one or more Fused Tetracyclic Heterocycle Compounds and the one or more additional therapeutic agents are provided in the same container.
  • the one or more Fused Tetracyclic Heterocycle Compounds and the one or more additional therapeutic agents are provided in separate containers.
  • N-Bromosuccinimide (838.4 mg, 4.71 mmol) was added in portions over 15 minutes to a cooled (ice/water) CH 2 CI 2 (20 mL) solution of imidazole Int-7c (1.06 g, 4.50 mmol). The reaction mixture was allowed to stir for 75 minutes and concentrated in vacuo to oil. The crude product was purified using silica-gel RPLC (Acetonitrile/ water/ 0.1% TFA) to separate the mono bromide from its dibromo analog (over bromination) and the starting material. The RPLC elute was neutralized with excess NHs/MeOH, and the volatile component was removed in vacuo.
  • Int-7g (3.01g, 6.78 mmol, 1.0 eq) and Int-la (1.202 g, 6.86 mmol, 1.01 eq) were added to a 250 mL round-bottomed flask equipped with a stir bar. DMF was added, and the flask was connected to a vacuum line. The flask was cycled between vacuum and N 2 twice, then cooled in an ice-methanol bath for 10 minutes. HATU (2.75 g, 7.23 mmol, 1.07 eq) was added, followed by diisopropylethyl amine (2.80 mL).
  • the reaction mixture was allowed to stir at -15 °C for 20 minutes. Additional diisopropylethyl amine (2.0 mL) was added. The reaction mixture was allowed to stir for 40 minutes, then quenched with water (1.5 mL). The resulting solution was diluted with EtOAc (100 mL) and Et 2 0 (100 mL), then washed with water (6 x 15 mL) and brine (2 x 25 mL). The organic layer was dried with MgS0 4 , filtered, and concentrated in vacuo to dryness yielding 2.23 g of a clear oil.
  • the crude product was purified via chromatography using an 80 g Isco Gold Si0 2 cartridge with a 0.5%-2.5% MeOH/ CH 2 C1 2 gradient as the mobile phase.
  • the major peak was collected to provide 1.28 g Int-7h as a white foam.
  • This material was further purified via sgc on an 80 g Isco Gold Si0 2 cartridge using a 45%-65% gradient of (5% methanol in EtOAc)/hexanes. Triethylamine 1% by volume was added to the MeOH/EtOAc solution.
  • the fractions were assayed via TLC using Hanessian's stain. (See Example 13 below for more information on Hanessian's stain.)
  • the major peak was collected as product to provide 1.18 g of Int-7h as a white foam.
  • Int-8b (7.5 g, 21.3 mmol) was dissolved in 100 mL of dichloromethane and cooled to 0 °C. TFA (100 mL) was added and the reaction was allowed to stir to room temperature over 2h. The solvent was removed and the residue obtained was redissolved in EtOAc then washed with saturated bicarbonate solution then brine. The extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to provide Compound Int-8c as an oil, which was used without further purification.
  • the aldehyde Int-lla was prepared from the commercially available alcohol using the method described in Example 10.
  • Int-llc was prepared from Int-llb using the method described in Example 10.
  • Intermediate compounds Int-lld, Int-lle and Int-llf can be prepared using the methods described in Example 10 and Example 1 1.
  • n-Butyllithium (Aldrich 2.5 M in hexanes , 478 mL, 1.19 mol, 1.09 eq) was added via a dropping funnel over 1 hour while maintaining the internal reaction temperature between -67 °C and -76 °C. The resulting orange-red solution was allowed to gradually warm to room temperature for about 15 hours. The reaction mixture was then re-cooled to 0 °C and quenched with 500 mL of water.
  • the resulting crude product was dried under house vacuum for about 15 hours.
  • the crude product was then dissolved in CH 2 C1 2 (750 mL) and Et 2 0 (1250 mL) and sodium iodide (96.4 g, 0.643 mol, 1.0 eq) was added.
  • Diisopropylethylamine (336 mL, 1.929 mol, 3.0 eq) was added slowly over 25 minutes with stirring, causing the temperature to increase to 35 °C then decrease to room temperature again.
  • the reaction mixture was allowed to stir at room temperature for 2 hours, after which time the MS of an aliquot indicated consumption of the starting material.
  • the reaction mixture was allowed to stir for an additional 2 hours and then Boc-anhydride (281 g, 1.286 mol, 2.0 eq) was added. The reaction mixture was then allowed to stir at room temperature. After two days, the reaction mixture was diluted with EtOAc (2 L) and water (1 L), and he layers were separated. The aqueous phase was extracted with 500 mL of EtOAc. The combined organic layers were washed with water (500 mL), and brine (500 mL), dried with MgS0 4 , filtered, and concentrated in vacuo to a yellow oil (380 g). The crude product was split into two 180 g portions for convenience and each portion was purified via flash silica gel chromatography.
  • the mixture was allowed to stir for 30 minutes at - 78 °C, warmed to 0 °C, and allowed to stir for an additional 1.5 hours.
  • the mixture was diluted with CH 2 C1 2 (400 mL) and was transferred to a separatory funnel.
  • the organic layer was washed with sat. aq NH 4 C1 (2 x 100 mL) and brine (2 x 100 mL).
  • the organic layer was dried (Na 2 S0 4 ), filtered, and concentrated in vacuo to provide Int-14b,18 g (99%) as a clear oil, which was used without further purification.
  • Step C Preparation of Compound Int-15c
  • MeOH MeOH
  • 10% aqueous HCl 3 mL
  • the mixture was allowed to stir at 25 °C for 18 hours.
  • the mixture was concentrated in vacuo and the residue obtained was
  • Step D Preparation of Compound Int-16e
  • Compound Int-16d (7.9 g, 26.4 mmol) was dissolved in MeOH (100 mL) and cooled to 0 °C.
  • KOH (1M in water, 39.6 mL, 39.6 mmol) was added.
  • the solution was allowed to stir at 0 °C for 2 hours, and then at room temperature for 3 hours.
  • HCl (2 N, 20 mL) was added, then additional HCl was added slowly to adjust the solution to pH 4.
  • the acidified solution was concentrated in vacuo and to the residue obtained was added water (150 mL) and EtOAc (200 mL).
  • the organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 100 mL).
  • Int-19c and Int-19c' were made using the method described in Example 18, step B (Int-19c, 390 mg, 64 % yield; Int-19c ⁇ 420 mg, 61 % yield ).
  • Int-20c was treated with 50 % NaOH (30 mL, CH 3 OH /H 2 0) and stirred at room temperature until TLC indicated the hydrolysis was complete.
  • the basic solution was neutralized with 2N HCl and the solvent was removed in vacuo to provide Int-20d (15 g) which was used directly in the next step.
  • Int-20d (3 g) was treated with py-HCl and heated at 120 °C until TLC indicated that the reaction was complete. The reaction mixture was allowed to cool to room temperature and was partitioning between ethyl acetate and 2N HCl. The organic phase was concentrated in vacuo and the residue obtained was purified using silica gel chromatography to provide Int-20e (15 g). MS (ESI) m/e (M+H) + : 253.
  • Int-20g was prepared from In-20f using the method described in Example 17, step B (1.8 g). MS (ESI) m/e (M+H) + : 473.
  • Int-20h was prepared from Int-20g using the method described in Example 18, step C (0.8 g). MS (ESI) m/e (M+H) + : 691.
  • Int-20i was prepared from Int-20h using the method described in Example 18, Step D. MS (ESI) m e (M+H) + : 691.
  • Int-21b was prepared from Int-21a using the method described in Example 18, step D (0.2 g). MS (ESI) m/e (M+H) + : 489.
  • Compound 17 was prepared from Compound Int-21b using the method described in Example 18 (50 mg, 50 %).
  • a pressure tube charged with a stir bar was charged with Int-22e (2.3 g, 4.1 mmol), bis(pinacolato)diboron (2.2 g, 8.9 mmol), PdCl 2 (dppf) (0.15 g, 0.20 mmol), dppf (0.11 g, 0.20 mmol), KOAc (1.6 g, 16 mmol), and dioxane (18 mL).
  • the resulting solution was degassed under house vacuum and filled with N 2 six times, then capped, and heated to 80 °C. The reaction was allowed to stir for 16 hours at 80 °C, then was cooled to room temperature, and concentrated in vacuo.

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Abstract

Tetracyclic heterocycle compounds of formula (I) and pharmaceutically acceptable salts thereof are provided, wherein A, A', G, R1, R15, U, V, V', W, W, X, X', Y and Y' are as defined in the invention. The pharmaceutical compositions comprising these compounds and the use of the compounds for treating hepatitis C virus (HCV) infection are also provided.

Description

TETRACYCLIC HETEROCYCLE COMPOUNDS FOR TREATING
HEPATITIS C VIRAL INFECTION
FIELD OF THE INVENTION
The present invention relates to novel Fused Tetracyclic Heterocycle
Compounds, compositions comprising at least one Fused Tetracyclic Heterocycle Compound, and methods of using the Fused Tetracyclic Heterocycle Compounds for treating or preventing HCV infection in a patient.
BACKGROUND OF THE INVENTION
Hepatitis C virus (HCV) is a major human pathogen. A substantial fraction of these HCV-infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma, which are often fatal. HCV is a (+)-sense single-stranded enveloped R A virus that has been implicated as the major causative agent in non-A, non-B hepatitis (NANBH), particularly in blood-associated NANBH (BB-NANBH) (see,
International Publication No. WO 89/04669 and European Patent Publication No. EP 381 216). NANBH is to be distinguished from other types of viral- induced liver disease, such as hepatitis A virus (HAV), hepatitis B virus (HBV), delta hepatitis virus (HDV),
cytomegalovirus (CMV) and Epstein-Barr virus (EBV), as well as from other forms of liver disease such as alcoholism and primary biliar cirrhosis.
It is well-established that persistent infection of HCV is related to chronic hepatitis, and as such, inhibition of HCV replication is a viable strategy for the prevention of hepatocellular carcinoma. Current therapies for HCV infection include a-interferon monotherapy and combination therapy comprising a-interferon and ribavirin. These therapies have been shown to be effective in some patients with chronic HCV infection, but suffer from poor efficacy and unfavorable side-effects and there are currently efforts directed to the discovery of HCV replication inhibitors that are useful for the treatment and prevention of HCV related disorders.
Current research efforts directed toward the treatment of HCV includes the use of antisense oligonucleotides, free bile acids (such as ursodeoxycholic acid and
chenodeoxycholic acid) and conjugated bile acids (such as tauroursodeoxycholic acid).
Phosphono formic acid esters have also been proposed as potentially useful for the treatment of various viral infections, including HCV. Vaccine development, however, has been hampered by the high degree of viral strain heterogeneity and immune evasion and the lack of protection against reinfection, even with the same inoculum.
In light of these treatment hurdles, the development of small-molecule inhibitors directed against specific viral targets has become a major focus of anti-HCV research. The determination of crystal structures for NS3 protease, NS3 R A helicase, NS5A, and NS5B polymerase, with and without bound ligands, has provided important structural insights useful for the rational design of specific inhibitors.
Recent attention has been focused toward the identification of inhibitors of HCV NS5A. HCV NS5A is a 447 amino acid phosphoprotein which lacks a defined enzymatic function. It runs as 56kd and 58kd bands on gels depending on phosphorylation state (Tanji, et al. J. Virol. 69:3980-3986 (1995)). HCV NS5A resides in replication complex and may be responsible for the switch from replication of RNA to production of infectious virus (Huang, Y, et al, Virology 364: 1-9 (2007)).
Multicyclic HCV NS5A inhibitors have been reported. See U.S. Patent
Publication Nos. US20080311075, US20080044379, US20080050336, US20080044380,
US20090202483 and US2009020478. HCV NS5A inhibitors having fused tricyclic moieties are disclosed in International Patent Publication Nos. WO 10/065681, WO 10/065668, and WO 10/065674.
Other HCV NS5A inhibitors and their use for reducing viral load in HCV infected humans have been described in U.S. Patent Publication No. US20060276511.
SUMMARY OF THE INVENTION
as ect, the present invention provides Compounds of Formula (I)
(I)
and pharmaceutically acceptable salts thereof, wherein:
A and A' are each independently selected from a 5 or 6-membered monocyclic heterocycloalkyl, wherein said 5 or 6-membered monocyclic heterocycloalkyl group can be optionally fused to an aryl group; and wherein said 5 or 6-membered monocyclic
heterocycloalkyl group can be optionally and independently substituted on one or more ring carbon atoms with R13, such that any two R13 groups on the same ring, together with the carbon atoms to which they are attached, can join to form a fused, bridged or spirocyclic 3 to 6-membered cycloalkyl group or a fused, bridged or spirocyclic 4 to 6-membered
heterocycloalkyl group, wherein said 5 or 6-membered monocyclic heterocycloalkyl contains from 1 to 2 ring heteroatoms, each independently selected from N(R4), S, O and Si(R16)2;
G is selected from -C(R3)2-0-, -0-C(R3)2-, -C(R3)2-N(R5)-, -C(0)-0-, -C(O)- N(R5)-, -C(R3)2-C(0)-, -C(=NR5)-N(R5)-, -C(R3)2-S02-, -S02-C(R3)2-, -S02N(R5)-,
-C(R3)2-C(R3)2-, -C(R14)=C(R14)- and -C(R14)=N-;
U is selected from N(R2), O, S and S02;
V and V are each independently selected from N and C(R15);
W and W are each independently selected from N and C(RJ);
X and X' are each independently selected from N and C(R10);
Y and Y' are each independently selected from N and C(R10);
R1 is selected from H, Ci-C6 alkyl, 3 to 6 membered cycloalkyl, halo, -OH, -O- (Ci-C6 alkyl), Ci-C6 haloalkyl and -0-(Ci-C6 haloalkyl);
R2 is selected from H, Ci-C6 alkyl, 3 to 6-membered cycloalkyl, aryl, 5 or 6- membered heteroaryl and benzyl, wherein said aryl group, said 5 or 6-membered heteroaryl group or the phenyl moiety of said benzyl group can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from Ci-C6 alkyl, Ci-C6
haloalkyl, -0-(d-C6 alkyl), -0-(d-C6 haloalkyl), halo, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl) and -CN;
each occurrence of R3 is independently selected from H, Ci-C6 alkyl, Ci-C6 haloalkyl, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl, 5 or 6-membered heteroaryl, -CH2-(5 or 6 membered heteroaryl) and benzyl, wherein said aryl group, said 5 or 6-membered heteroaryl group or the phenyl moiety of said benzyl group can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from Ci-C6 alkyl, Ci-C6 haloalkyl, -0-(Ci-C6 alkyl), -0(Ci-C6 haloalkyl), halo, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl) and -CN and wherein two R3 groups attached to the same carbon atom, together with the common carbon atom to which they are attached, can join to form a carbonyl group, a 3 to 6-membered spirocyclic cycloalkyl group or a 3 to 6-membered spirocyclic heterocycloalkyl group;
each occurrence of R4 is independently selected from -[C(R7)2]qN(R6)2, - C(0)Rn, -C(0)-[C(R7)2]qN(R6)2, -C(0)-[C(R7)2]q-Rn, -C(0)-[C(R7)2]qN(R6)C(0)-Rn, - -C(0)-[C(R7)2]qN(R6)C(0)0-R11, -C(0)-[C(R7)2]qC(0)0-R11 and -alkylene-N(R6)-[C(R7)2]q-N(R6)-C(0)0-R11 ;
each occurrence of R5 is independently selected from H, Ci-C6 alkyl, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl, 5 or 6-membered heteroaryl and benzyl, wherein said aryl group, said 5 or 6-membered heteroaryl group or the phenyl moiety of said benzyl group can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from Ci-C6 alkyl, Ci-C6 haloalkyl, -0-(d-C6 alkyl), -0-(d-C6 haloalkyl), halo, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl) and -CN;
each occurrence of R6 is independently selected from H, Ci-C6 alkyl, 3 to 6- membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl and 5 or 6-membered heteroaryl, wherein said 3 to 6-membered cycloalkyl group, said 4 to 6-membered heterocycloalkyl group, said aryl group and said 5 or 6-membered heteroaryl group can be optionally and independently substituted with up to two R8 groups, and wherein two R6 groups that are attached to the same nitrogen atom, together with the common nitrogen atom to which they are attached, can join to form a 4 to 6-membered heterocycloalkyl group;
each occurrence of R7 is independently selected from H, Ci-C6 alkyl, Ci-C6 haloalkyl, silylalkyl, -alkylene-0-(Ci-C6 alkyl), 3 to 6-membered cycloalkyl, 4 to 6- membered heterocycloalkyl, aryl and 5 or 6-membered heteroaryl, wherein said 3 to 6- membered cycloalkyl group, said 4 to 6-membered heterocycloalkyl group, said aryl group and said 5 or 6-membered heteroaryl group can be optionally substituted with up to three R8 groups;
each occurrence of R8 is independently selected from H, Ci-C6 alkyl, halo, - Ci-C6 haloalkyl, Ci-C6 hydroxyalkyl, -OH, -C(0)NH-(Ci-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, - 0-(Ci-C6 alkyl), -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2 and -NHC(0)-(Ci-C6 alkyl);
each occurrence of R9 is independently selected from H, Ci-C6 alkyl, Ci-C6 haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl and 5 or 6- membered heteroaryl;
each occurrence of R10 is independently selected from H, Ci-C6 alkyl, Ci-C6 haloalkyl, halo, -OH, -0-(Ci-C6 alkyl) and -CN;
each occurrence of R11 is independently selected from H, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 hydro xyalkyl, 3 to 6-membered cycloalkyl and 4 to 6-membered hetero cyclo alkyl; each occurrence of R12 is independently selected from Ci-C6 alkyl, Ci-C6 haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl and 5 or 6- membered heteroaryl;
each occurrence of R13 is independently selected from H, halo, Ci-C6 alkyl, Ci-C6 haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, -CN, -OR9, -N(R9)2, -C(0)R12, -C(0)OR9, -C(0)N(R9)2, -NHC(0)R12, -NHC(0)NHR9, -NHC(0)OR9, - OC(0)R12, -SR9 and -S(0)2R12, wherein two R13 groups that attached to the same ring, together with the carbon atom(s) to which they are attached, can optionally join to form a 3 to 6-membered cycloalkyl group or 4 to 6-membered heterocycloalkyl group;
each occurrence of R14 is independently selected from H, halo, Ci-C6 alkyl,
Ci-C6 haloalkyl, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), 3 to 6-membered cycloalkyl, 4 to 6 membered heterocycloalkyl, aryl, 5 or 6-membered heteroaryl, CH2-(5 or 6 membered heteroaryl) and benzyl, wherein said aryl group, said 5 or 6-membered heteroaryl group or the phenyl moiety of said benzyl group can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from halo, -CN, Ci-C6 alkyl, Ci-C6 haloalkyl, -0-(d-C6 alkyl), -(Ci-C6 alkylene)-0-(d-C6 alkyl) and -0-(Ci-C6 haloalkyl);
each occurrence of R15 is independently selected from H, Ci-C6 alkyl, 3 to 6- membered cycloalkyl, halo, -OH, -0-(Ci-C6 alkyl), Ci-C6 haloalkyl and -0-(Ci-C6 haloalkyl);
each occurrence of R16 is independently selected from H, halo, Ci-C6 alkyl and 3 to 6-membered cycloalkyl, wherein two R16 groups that are attached to a common silicon atom can join to form a -(CH2)4- or a -(CH2)s- group; and
each occurrence of q is independently an integer ranging from 0 to 4.
The Compounds of Formula (I) (also referred to herein as the "Fused
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 Fused Tetracyclic Heterocycle Compounds inhibit HCV viral replication by inhibiting HCV NS5A.
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 Fused 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 Fused Tetracyclic Heterocycle
Compounds, compositions comprising at least one Fused Tetracyclic Heterocycle Compound, and methods of using the Fused 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 predominates. 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 "hydro xyalkyl," "haloalkyl," "-0- 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, refers to an amount of Fused
Tetracyclic Heterocycle Compound and/or an additional therapeutic agent, or a composition thereof that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a patient suffering from a viral infection or virus- related disorder. In the combination therapies of the present invention, an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.
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 (Ci-C6 alkyl) or from about 1 to about 4 carbon atoms (C1-C4 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-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. 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, -O-C(O)- 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), -0-C(0)-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 "arylene," as used herein, refers to a bivalent group derived from an aryl group, as defined above, by removal of a hydrogen atom from a ring carbon of an aryl group. An arylene group can be derived from a monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an arylene group contains from about 6 to about 10 carbon atoms. In another embodiment, an arylene group is a naphthylene group. In another embodiment, an arylene group is a phenylene group. An arylene group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. An arylene group is divalent and either available bond on an arylene group can connect to either group flanking the arylene group. For example, the group "A-arylene-B," wherein the arylene group is:
is understood to represent both:
In one embodiment, an arylene group can be optionally fused to a cycloalkyl or cycloalkanoyl group. Non-limiting examples of arylene groups include phenylene and naphthalene. In one embodiment, an arylene group is unsubstituted. In another embodiment, an arylene group is:
Unless otherwise indicated, an arylene 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 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 6-membered cycloalkyl" refers to a cycloalkyl group having from 3 to 6 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:
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 6-membered cycloalkenyl" refers to a cycloalkenyl group having from 4 to 6 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-Cg 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. 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. 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, benzo furazanyl, indolyl, azaindolyl, benzimidazolyl, benzo thienyl, quinolinyl, imidazolyl, benzimidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, iso quinolinyl, benzo azaindolyl, 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 "heteroarylene," as used herein, refers to a bivalent group derived from an heteroaryl group, as defined above, by removal of a hydrogen atom from a ring carbon or ring heteroatom of a heteroaryl group. A heteroarylene group can be derived from a monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of the ring atoms are each independently O, N or S and the remaining ring atoms are carbon atoms. A heteroarylene group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below. A heteroarylene group is joined via a ring carbon atom or by a nitrogen atom with an open valence, and any nitrogen atom of a heteroarylene can be optionally oxidized to the corresponding N-oxide. The term "heteroarylene" also encompasses a heteroarylene group, as defined above, which is fused to a benzene ring. Non- limiting examples of heteroarylenes include pyridylene, pyrazinylene, furanylene, thienylene, pyrimidinylene, pyridonylene (including those derived from N-substituted pyridonyls), isoxazolylene, isothiazolylene, oxazolylene, oxadiazolylene, thiazolylene, pyrazolylene, thiophenylene, furazanylene, pyrrolylene, triazolylene, 1,2,4-thiadiazolylene, pyrazinylene, pyridazinylene,
quinoxalinylene, phthalazinylene, oxindolylene, imidazo[l,2-a]pyridinylene, imidazo[2,l- b]thiazolylene, benzo furazanylene, indolylene, azaindolylene, benzimidazolylene,
benzothienylene, quinolinylene, imidazolylene, benzimidazolylene, thienopyridylene, quinazolinylene, thienopyrimidylene, pyrrolopyridylene, imidazopyridylene, isoquinolinylene, benzoazaindolylene, 1,2,4-triazinylene, benzo thiazolylene and the like, and all isomeric forms thereof. The term "heteroarylene" also refers to partially saturated heteroarylene moieties such as, for example, tetrahydroisoqumolylene, tetrahydroqumolylene, and the like. A heteroarylene group is divalent and either available bond on a heteroarylene ring can connect to either group flanking the heteroarylene group. For example, the group "A- heteroar lene-B," wherein the heteroarylene group is:
In one embodiment, a heteroarylene group is a monocyclic heteroarylene group or a bicyclic heteroarylene group. In another embodiment, a heteroarylene group is a monocyclic heteroarylene group. In another embodiment, a heteroarylene group is a bicyclic heteroarylene group. In still another embodiment, a heteroarylene group has from about 5 to about 10 ring atoms. In another embodiment, a heteroarylene group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heteroarylene group is bicyclic and has 9 or 10 ring atoms. In another embodiment, a heteroarylene group is a 5-membered monocyclic heteroarylene. In another embodiment, a heteroarylene group is a 6-membered monocyclic heteroarylene. In another embodiment, a bicyclic heteroarylene group comprises a 5 or 6- membered monocyclic heteroarylene group fused to a benzene ring. Unless otherwise indicated, a heteroarylene group is unsubstituted.
The term "heterocycloalkyl," as used herein, refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to about 11 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 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:
A ring carbon atom of a heterocycloalkyl group may be functionalized as a carbonyl group. An illustrative example of such a heterocycloalkyl group is:
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 6-membered monocyclic cycloalkyl" refers to a monocyclic heterocycloalkyl group having from 3 to 6 ring atoms. The term "4 to 6- membered monocyclic cycloalkyl" refers to a monocyclic heterocycloalkyl group having from 4 to 6 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 6 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 6-membered heterocycloalkenyl" refers to a heterocycloalkenyl group having from 4 to 6 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-heteroaryl, - Si(alkyl)2, -Si(aryl)2, -Si(heteroaryl)2, -Si(alkyl)(aryl), -Si(alkyl)(cycloalkyl), - Si(alkyl)(heteroaryl), cycloalkyl, heterocycloalkyl, -0-C(0)-alkyl, -0-C(0)-aryl, -O-C(O)- cycloalkyl, -C(=N-CN)-NH2, -C(=NH)-NH2, -C(=NH)-NH(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:
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, and formulation into an efficacious therapeutic agent.
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, Prodrugs 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 Fused 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 Fused 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, l-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- 1- (alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, l-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1- methyl- l-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(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 Fused 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, l-methyl-l-((Ci-C6)alkanoyloxy)ethyl, (Ci- C6)alkoxycarbonyloxymethyl, N-(Ci-C6)alkoxycarbonylamino methyl, succinoyl, (Ci-
C6)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-C6)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 Fused 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 α-aminoacyl, -C(OH)C(0)OY1 wherein Y1 is H, (Ci-C6)alkyl or benzyl, -C(OY2)Y3 wherein Y2 is (C1-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 Ci_2o 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), 601-61 1 (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 Fused Tetracyclic Heterocycle Compounds can form salts which are also within the scope of this invention. Reference to a Fused 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 Fused 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 Fused 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, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. 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 quartemized 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., hydro lyzing) the individual diastereomers to the corresponding pure enantiomers.
Stero chemically pure compounds may also be prepared by using chiral starting materials or by employing salt resolution techniques. Also, some of the Fused 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 Fused 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 Fused 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, positional isomers, 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 Fused Tetracyclic Heterocycle Compounds, and of the salts, solvates, hydrates, esters and prodrugs of the Fused 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; AcCl is acetyl chloride; AcOH or HO Ac is acetic acid; Amphos is (4-(N,N)- dimethylaminophenyl)-di-tertbutylphosphine; Aq is aqueous; BF3 »OEt2 is boron trifluoride etherate; BOC or Boc is ie/t-butyloxycarbonyl; Boc20 is Boc anhydride; Boc-Pro-OH is Boc protected proline; L-Boc-Val-OH is Boc protected L-valine; n-BuLi is n-butyllithium; CBZ or Cbz is carbobenzoxy; DCM is dichloromethane; DDQ is 2,3-dichloro-5,6-dicyano-l,4- benzoquinone; Dess-Martin reagent is ,l,l-Triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)- one; DIPEA is diisopropylethylamine; DME is dimethoxyethane; DMF is N,N- dimethylformamide; dppf is diphenylphosphinoferrocene; DMSO is dimethylsulfoxide; EtMgBr is ethylmagnesium bromide; EtOAc is ethyl acetate; Et20 is diethyl ether; Et3N or NEt3 is triethylamine; HATU is 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HPLC is high performance liquid chromatography; HRMS is high resolution mass spectrometry; KOAc is potassium acetate; LCMS is liquid
chromatography/mass spectrometry; LiHMDS is lithium hexamethyldisilazide; LRMS is low resolution mass spectrometry; Mel is iodomethane; MeOH is methanol; NBS is N- bromosuccinimide; ΝΗ4ΟΑο is ammonium acetate; NMM is N-methylmorpholine; Pd/C is palladium on carbon; Pd(PPh3)4 is tetrakis (triphenylphosphine)palladium(O); PdC^dppfh is [l,l '-Bis(diphenylphosphino) ferrocene] dichloro palladium(II); PdCl2(dppf)2 »CH2Cl2 is [l,l '-Bis(diphenylphosphino)ferrocene] dichloro palladium(II) complex with
dichloromethane; pinacol2B2 is bis(pinacolato)diboron; PPTS is pyridinium p-toluene sulfonate; RPLC is reverse-phase liquid chromatography; Select-F is l-Chloromethyl-4- Fluoro-1, 4-Diazoniabicyclo[2.2.2]Octane Bis-(Tetrafiuoroborate); SEM-C1 is 2- (trimethylsilyl)ethoxymethyl chloride; TBAF is tetrabutylammonium fluoride; TBDMSCl is ieri-butyldimethylsilyl chloride; TFA is trifiuoro acetic acid; Tf20 is triflic anhydride; THF is tetrahydrofuran; TLC is thin- layer chromatography; and TosCl is p-toluenesulfonyl chloride.
The Compounds of Formula (I)
The present invention provides Fused Tetracyclic Heterocycle Compounds of Formula (I):
(I) and pharmaceutically acceptable salts thereof, wherein A, A', G, R1, R15, U, V, V, W, W, X, X', Y and Y' are defined above for the Compounds of Formula (I).
In one embodiment, A and A' are each a 5-membered heterocycloalkyl group. In another embodiment, A and A' are each a 6-membered heterocycloalkyl group.
In another embodiment A and A' are each independently selected from:
In another embodiment A and A' are each independently selected from:
In still another embodiment, A and A' are each independently selected from:
In another embodiment A and A' are each independently selected from:
In another embodiment, A and A' are each:
In another embodiment, A and A' are each:
wherein each occurrence of R13 is independently H, CH3 or F.
In one embodiment, each occurrence of R4 is independently -C(O)- [C(R7)2]qN(R6)C(0)0-Rn
In another embodiment, each occurrence of R4 is independently -C(O)- CH(R7)NHC(0)0-Rn.
In another embodiment, each occurrence of R4 is independently: , wherein R is H, alkyl, haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl or heteroaryl and Ra is alkyl, haloalkyl, silylalkyl, 3 to 6-membered cycloalkyl or 4 to 6-membered heterocycloalkyl, aryl or heteroaryl.
In another embodiment, each occurrence of R4 is independently: , wherein Ra is H, methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, -CH2CH2Si(CH3)3, -CH2CH2CF3, pyranyl, benzyl or phenyl, and Rb is methyl, ethyl or isopropyl.
In still another embodiment, each occurrence of R4 is independently - C(0)CH(R7)NHC(0)0-Rn, wherein each occurrence of R7 is independently Ci-C6 alkyl or phenyl and each occurrence of R11 is independently Ci-C6 alkyl.
In another embodiment, each occurrence ofR4 is independently -C(0)CH(Ci- C6 alkyl)-NHC(0)0-(Ci-C6 alkyl).
In another embodiment, each occurrence of R4 is independently:
In one embodiment A and A' are each independently selected from:
and R4 is: , wherein R is H, alkyl, haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl or heteroaryl and Ra is alkyl, haloalkyl, silylalkyl, 3 to 6-membered cycloalkyl or 4 to 6-membered heterocycloalkyl, aryl or heteroaryl.
In another embodiment A and A' are each independently selected from:
and R is:
In yet another embodiment, A and A' are each:
wherein each occurrence of R13 is independently H, CH3 or F; and
R4 is
embodiment, G is -C(R3)2-0-, -C(R3)2-C(R3)2-, -C(R14)=C(R14)-
C(R14)=N-.
In another embodiment, G is -C(R3)2-0-.
In another embodiment, G is -CHR3-0-.
In one embodiment, G is -C(R3)2-0- and each occurrence ofR3 is
independently selected from H, Ci-C6 alkyl, cycloalkyl, heterocycloakyl, heteroaryl and phenyl, wherein said heteroaryl and phenyl groups can be optionally substituted with up to 2 groups, which can be the same or different, and are selected from halo, -CN, Ci-C6 alkyl, Ci- C6 haloalkyl, -0-Ci-C6 alkyl, -(Ci-C6 alkylene)-0-Ci-C6 alkyl and -0-Ci-C6 haloalkyl.
In another embodiment, G is -C(R3)2-0- and each occurrence ofR3 is independently selected from H, methyl, ethyl, isopropyl, cyclopropyl, l'-methylcyclopropyl, methylenecyclopropyl, phenyl, pyridyl, and pyrimidyl wherein said phenyl, pyridyl and pyrimidinyl group can be optionally substituted with up to 2 groups, which can be the same or different, and are selected from F, CI, -CN, CH3, CF3, OCF3, OCH2CH2OCH3.
In another embodiment, G is -C(R3)2-0- and each occurrence ofR3 is independently selected from H and Ci-C6 alkyl.
In still another embodiment, G is -C(R3)2-0- and both R3 groups, together with the common carbon atom to which they are attached, join to form a carbonyl group, a 3 to 6-membered spirocyclic cycloalkyl group or a 3 to 6-membered spirocyclic
heterocycloalkyl group.
In another embodiment, G is -CHR3-0-, wherein R3 is selected from Ci-C6 alkyl, -0-(Ci-C6 alkylene)-Ci-C6 alkyl, benzyl, phenyl, cycloalkyl and 5 or 6-membered heteroaryl, wherein said phenyl group can be optionally substituted with a group selected from: Ci-C6 alkyl, halo and -O-alkyl.
In another embodiment, G is -CHR3-0-, wherein R3 is selected from ethyl, isopropyl, t-butyl, sec-butyl, -CH2OCH3, benzyl, phenyl, cyclopentyl, cyclohexyl, furanyl or pyridyl, wherein said phenyl group can be optionally substituted with a group selected from: Ci-C6 alkyl, halo and -O-alkyl.
In another embodiment, G is -CH2CH2- or -CH=CH-.
In one embodiment, U is -N(R2)- or -0-.
In another embodiment, U is -NH- or -N(CH3)-.
In another embodiment, U is O.
In one embodiment, V is C(R15).
In another embodiment, V is CH.
In another embodiment, V is N.
In one embodiment, V* is C(R15).
In another embodiment, V is CH.
In another embodiment, V is N.
In still another embodiment, V and V are each CH.
In one embodiment, W is C(R15).
In another embodiment, W is CH.
In another embodiment, W is N.
In one embodiment, W * is C(R15).
In another embodiment, W ' is CH.
In another embodiment, W is N.
In still another embodiment, W and W are each CH. In a further embodiment, V, V W and W are each CH.
In one embodiment, R1 is absent.
In another embodiment, R1 represents one F substituent.
In one embodiment, each occurrence of R10 is independently H or F In another embodiment, each occurrence of R10 is H. In one embodiment the group:
has the structure:
In another embodiment the group:
has the structure:
In another embodiment the group:
has the structure:
wherein each occurrence of R3 is independently selected from H and Ci-C6 alkyl and R2 is H or Ci-C6 alkyl.
In still another embodiment the group:
has the structure:
R2 is H or Ci-C6 alkyl; and R3 is ethyl, isopropyl, t-butyl, sec-butyl, -CH2OCH3, benzyl, phenyl, cyclopentyl, cyclohexyl, furanyl or pyridyl, wherein said phenyl group can be optionally substituted with a group selected from: Ci-C6 alkyl, halo and -O-alkyl.
In another embodiment the group:
has the structure:
wherein the dotted line represents an optional and additional bond. In one embodiment, variables A, A', G, R1, R15, U, V, V, W, W, X, X*, Y and Y' for the Compounds of Formula (I) are selected independently of each other.
In another embodiment, the Compounds of Formula (I) are in substantially purified form.
In one embodiment the Compounds of Formula (I) have the formula (la):
(la)
and pharmaceutically acceptable salts thereof, wherein:
A and A' are each independently a 5-membered monocyclic heterocycloalkyl, wherein said 5-membered monocyclic heterocycloalkyl group can be optionally and independently substituted on one or more ring carbon atoms with R13, such that any two R13 groups on the same ring, together with the carbon atoms to which they are attached, can join to form a fused, bridged or spirocyclic 3 to 6-membered cycloalkyl group or a fused, bridged or spirocyclic 4 to 6-membered heterocycloalkyl group, wherein said 5-membered
monocyclic heterocycloalkyl contains from 1 to 2 ring heteroatoms, each independently selected from N(R4) and Si(R16)2;
G is selected from -C(R3)2-C(R3)2-, -C(R14)=C(R14)- and -C(R3)2-0-;
U is selected from -N(R2)- and -0-;
V and V are each independently selected from N and C(R15);
R1 represents from 0 to 2 ring substituents on the phenyl ring to which R1 is attached, wherein said substituents are each independently selected from Ci-C6 alkyl and halo;
each occurrence of R3 is independently selected from H, Ci-C6 alkyl, -(Ci-C6 alkylene)-0-Ci-C6 alkyl, 3 to 6-membered cycloalkyl, Ci-C6 haloalkyl, aryl, 5 or 6- membered heteroaryl and benzyl, wherein said aryl group, said 5 or 6-membered heteroaryl group or the phenyl group of said benzyl group can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from halo, -CN, Ci-C6 alkyl, Ci- Ce haloalkyl, -0-Ci-C6 alkyl, -(Ci-C6 alkylene)-0-Ci-C6 alkyl and -0-Ci-C6 haloalkyl;
each occurrence of R4 is independently -C(0)-[C(R7)2]N(R6)C(0)0-Rn; each occurrence of R6 is independently selected from H and Ci-C6 alkyl;
each occurrence of R7 is independently selected from Ci-C6 alkyl, 3 to 6- membered cycloalkyl and aryl;
each occurrence of R10 is independently selected from H and halo;
each occurrence of R1 1 is independently Ci-C6 alkyl;
each occurrence of R13 is independently selected from H, Ci-C6 alkyl and halo, wherein two R13 groups, together with the carbon atom(s) to which they are attached, can optionally join to form a 3 to 6-membered cycloalkyl group or 4 to 6-membered
heterocycloalkyl group;
R14 is selected from H, halo, Ci-C6 alkyl, -(Ci-C6 alkylene)-0-Ci-C6 alkyl, 3 to 6-membered cycloalkyl, Ci-C6 haloalkyl, aryl, 5 or 6-membered heteroaryl and benzyl, wherein said aryl group, said 5 or 6-membered heteroaryl group or the phenyl group of said benzyl group can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from halo, -CN, Ci-C6 alkyl, Ci-C6 haloalkyl, -0-Ci-C6 alkyl, - (Ci-C6 alkylene)-0-Ci-C6 alkyl and -0-Ci-C6 haloalkyl; and
each occurrence of R15 is independently selected from H and halo; and each occurrence of R16 is independently selected from Ci-C6 alkyl.
In one embodiment, for the Compounds of Formula (la), A and A' are each independentl selected from:
In another embodiment, for the Compounds of Formula (la), A and A' are each inde endently selected from:
In another embodiment, for the Compounds of Formula (la), A and A' are each:
wherein each occurrence of R13 is independently H, CH3 or F.
In one embodiment, for the Compounds of Formula (la), each occurrence of R4 is independently -C(0)-[C(R7)2]qN(R6)C(0)0-Rn .
In one embodiment, for the Compounds of Formula (la), each occurrence of R4 is independently -C(0)CH(R7)NHC(0)0-R1 1.
In another embodiment, for the Compounds of Formula (la), each occurrence of R4 is independently: , wherein Rb is Ci-C6 alkyl and Ra is Ci-C6 alkyl, 3 to 6- membered cycloalkyl or aryl.
In another embodiment, for the Compounds of Formula (la), each occurrence of R4 is independently: , wherein Ra is methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, or phenyl, and Rb is methyl, ethyl or isopropyl.
In still another embodiment, each occurrence of R4 is independently - C(0)CH(R7)NHC(0)0-Rn, wherein each occurrence of R7 is independently Ci-C6 alkyl or phenyl and each occurrence of R1 1 is independently Ci-C6 alkyl.
In another embodiment, for the Compounds of Formula (la), each occurrence of R4 is independently -C(0)CH(Ci-C6 alkyl)-NHC(0)0-(Ci-C6 alkyl).
In another embodiment, for the Compounds of Formula (la), each occurrence of R4 is independently:
In one embodiment, for the Compounds of Formula (la), A and A' are each independently selected from:
and R is: , wherein Rb is Ci-C6 alkyl and Ra is Ci-C6 alkyl, 3 to 6- membered cycloalkyl or aryl.
In another embodiment, for the Compounds of Formula (la), A and A' are each inde endently selected from:
In yet another embodiment, for the Compounds of Formula (la), A and A' are each:
wherein each occurrence of R13 is independently H, CH3 or F; and
R4 is
In one embodiment, for the Compounds of Formula (la), G is -C(R3)2-0-, - C(R3)2-C(R3)2-, -C(R14)=C(R14)- or -C(R14)=N-.
In another embodiment, for the Compounds of Formula (la), G is -C(R3)2-0-.
In another embodiment, for the Compounds of Formula (la), G is -CHR3-0-.
In one embodiment, for the Compounds of Formula (la), G is -C(R3)2-0- and each occurrence of R3 is independently selected from H and Ci-C6 alkyl. In another embodiment, for the Compounds of Formula (la), G is -CHR3-O-, wherein R3 is selected from ethyl, isopropyl, t-butyl, sec-butyl, -CH2OCH3, benzyl, phenyl, cyclopentyl, cyclohexyl, furanyl or pyridyl, wherein said phenyl group can be optionally substituted with a group selected from: Ci-C6 alkyl, halo and -O-alkyl.
In another embodiment, for the Compounds of Formula (la), G is -CH2CH2- or -CH=CH-.
In one embodiment, for the Compounds of Formula (la), U is -N(R2)- or -0-. In another embodiment, for the Compounds of Formula (la), U is -NH- or -
N(CH3)-.
In another embodiment, for the Compounds of Formula (la), U is O.
In one embodiment, for the Compounds of Formula (la), V is C(R15).
In another 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), V is C(R15).
In another embodiment, for the Compounds of Formula (la), V is CH.
In another embodiment, for the Compounds of Formula (la), V is N.
In still another embodiment, for the Compounds of Formula (la), V and V are each CH.
In one embodiment, for the Compounds of Formula (la), W is C(R15).
In another embodiment, for the Compounds of Formula (la), W is CH.
In another embodiment, for the Compounds of Formula (la), W is N.
In one embodiment, for the Compounds of Formula (la), W ' is C(R15).
In another embodiment, for the Compounds of Formula (la), W ' is CH.
In another embodiment, for the Compounds of Formula (la), W is N.
In still another embodiment, for the Compounds of Formula (la), W and W are each CH.
In a further embodiment, for the Compounds of Formula (la), V, V W and W are each CH.
In one embodiment, for the Compounds of Formula (la), R1 is absent.
In another embodiment, for the Compounds of Formula (la), R1 represents one
F substituent.
In one embodiment, for the Compounds of Formula (la), each occurrence of R10 is independently H or F. In another embodiment, for the Compounds of Formula (la), each occurrence of RIU is H.
In one embodiment for the Compounds of Formula (la), the group:
has the structure:
In another embodiment for the Compounds of Formula (la), the group:
has the structure:
In another embodiment for the Compounds of Formula (la), the group:
has the structure:
wherein each occurrence of R3 is independently selected from H and Ci-C6 alkyl and R2 is H or Ci-C6 alkyl.
In still another embodiment for the Compounds of Formula (la), the group:
has the structure:
R2 is H or Ci-C6 alkyl; and R3 is ethyl, isopropyl, t-butyl, sec-butyl, -CH2OCH3, benzyl, phenyl, cyclopentyl, cyclohexyl, furanyl or pyridyl, wherein said phenyl group can be optionally substituted with a group selected from: Ci-C6 alkyl, halo and -O-alkyl.
In another embodiment for the Compounds of Formula (la), the group:
has the structure:
wherein the dotted line represents an optional and additional bond. In one embodiment, variables A, A*, G, R1, R2, R10, R15, U, V and V for the Compounds of Formula (la) are selected independently of each other.
In another embodiment, the Compounds of Formula (la) are in substantially purified form.
In one embodiment, the Compounds of Formula (I) have the formula (lb):
(lb)
and pharmaceutically acceptable salt thereof, wherein:
R2 is selected from H and Ci-C6 alkyl;
each occurrence of R3 is independently selected from H, Ci-C6 alkyl, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), benzyl, phenyl, cycloalkyl and 5 or 6-membered heteroaryl, wherein said phenyl group can be optionally substituted with a group selected from: Ci-C6 alkyl, halo and -O-alkyl; and
each occurrence of R13 is independently selected from H, Ci-C6 alkyl and halo.
In one embodiment, for the Compounds of Formula (lb), R2 is H. In another embodiment, for the Compounds of Formula (lb), R2 is Ci-C6 alkyl. In one embodiment, for the Compounds of Formula (lb), each occurrence of R3 is independently selected from H and Ci-C6 alkyl.
In another embodiment, for the Compounds of Formula (lb), one occurrence of R3 is H and the other occurrence of R3 is selected from ethyl, isopropyl, t-butyl, sec-butyl, benzyl, phenyl, cyclopentyl, cyclohexyl, furanyl or pyridyl, wherein said phenyl group can be optionally substituted with a group selected from Ci-C6 alkyl, halo and -O-alkyl.
In one embodiment, for the Compounds of Formula (lb), each occurrence of
R13 is independently selected from H, CH3 and F.
In one embodiment, for the Compounds of Formula (lb), R2 is H or methyl and each occurrence of R13 is independently selected from H, CH3 and F.
In another embodiment, for the Compounds of Formula (lb), R2 is H or methyl; each occurrence of R13 is independently selected from H, CH3 and F; one occurrence ofR3 is H; and the other occurrence of R3 is selected from ethyl, isopropyl, t-butyl, sec-butyl, benzyl, phenyl, cyclopentyl, cyclohexyl, furanyl or pyridyl, wherein said phenyl group can be optionally substituted with a group selected from: Ci-C6 alkyl, halo and -O-alkyl.
In one embodiment, variables R2, R3 and R13 for the Compounds of Formula
(lb) are selected independently of each other.
In another embodiment, the Compounds of Formula (lb) are in substantially purified form.
Other embodiments of the present invention include the following:
(a) A pharmaceutical composition comprising an effective amount of a Compound of Formula (I) or a pharmaceutically acceptable salt thereof, 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 HCV protease 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 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 agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
(f) A method of inhibiting HCV replication in a subject in need thereof hich comprises administering to the subject an effective amount of a Compound of Formula
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). (h) The method of (g), 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.
(i) The method of (h), wherein the HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
(j) A method of inhibiting HCV replication in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b) or (c) or the combination of (d) or (e).
(k) A method of treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b) or (c) or the
combination of (d) or (e).
The present invention also includes a compound of the present invention for use (i) in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) medicine, (b) inhibiting HCV replication or (c) treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection. 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
immuno mo dulator s .
Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(k) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, 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.
It is further to be understood that the embodiments of compositions and methods provided as (a) through (k) above are understood to include all embodiments of the compounds, including such embodiments as result from combinations of embodiments.
The Compounds of Formula (I) may be referred to herein by chemical structure and/or by chemical name. In the instance that both the structure and the name of a Compound of Formula (I) are provided and a discrepancy is found to exist between the chemical structure and the corresponding chemical name, it is understood that the chemical structure will predominate.
Non- limiting examples of the Compounds of Formula (I) include compounds 1-36 as set forth in the Examples below, and pharmaceutically acceptable salts thereof.
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.
Scheme 1 shows methods useful for making the tetracyclic compounds of formula G9, which are useful intermediates for making the Compounds of Formula (I), wherein U is -N(R2)-; W and W are each -QR1)-; and V and V* are each -C(R15)-.
Scheme 1
G9
Wherein K' and Y represent coupling partners which can form a bridging group G; M, M' and M" are each independently halo, hydroxy, or a protected hydroxy, triflate, boronic acid or boronic ester; Q and Q' are each independently halo, methoxy or benzyloxy; M and M' are each independently halo, triflate, boronic acid or boronic ester; PG is a secondary amino protecting group, such as Boc or 4-methoxybenzyl; R4 is -C(0)Rn, -C(O)- [C(R7)2]qN(R6)2, -C(0)-[C(R7)2]q-Rn, -C(0)-[C(R7)2]qN(R6)C(0)-Rn, - C(0)[C(R7)2]qN(R6)S02-Rn, -C(0)-[C(R7)2]qN(R6)C(0)0-Rn or -C(0)-[C(R7)2]qC(0)0-Rn; and G, R2 and R15 are defined above for the Compounds of Formula (I). K' and Y represent coupling partners which can form a bridge G. One skilled in the art of organic synthesis will recognize that when G is a two atom bridge, K' and Y can each contain one atom of the latent bridge, or that each of either K' or Y can contain both atoms. Well known coupling patners exit in the chemical literature, including but limited to a benzylic halide and an alkoxide anion, a benzylic halide and a amine anion, an acyl chloride an aryl halide and organoboron reagent, an aryl halide and a organopalladium reagent, an aryl halide and a organostannane reagent, an acid chloride or an anion such as an alkoside, anilide or carbanion.
Tetracyclic compounds of formula G8 can be prepared from suitably substituted indole derivatives of formulas G4 and G7. Indole derivatives of general formula G4 and G7 may be obtained commercially or prepared by using methods known to those skilled in the art of organic synthesis. In an illustrative example, the compounds of formula G4 can be made via dehydration of a hydrazide of formula Gl with a ketone of formula G2 to provide hydrazones of formula G3, which can then be cyclized in the presence of a strong acid such as PPA or a Lewis acid such as aluminum chloride, to provide the hydroxyl- substituted indole compounds of formula G4. A compound of formula G4 can then be reacted with an aldehyde of formula R3-CHO to provide the cyclized compounds of formula G8, wherein G is -CHR3-0-.
Compounds of formula G7 can be made, for example, via the arylation of the 2-position of an indole of formula G5 with a coupling partner of formula G6. A compound of formula G7 can then be cyclized by reacting Y and K' to provide the compounds of formula G8. The Q and Q' groups of a compound of formula G8 can be converted to the M and M' groups of the compounds of formula G9 using methods well-known to those skilled in the art of organic synthesis.
It will be obvious to one skilled in the art of organic synthesis that the compounds of formulas G4 and G7 may undergo further functional group manipulations prior to cyclization as necessary in order to provide the full scope of the Compounds of Formula (I).
Scheme 2 shows a method useful for making the compounds of formula G12, which correspond to the Compounds of Formula (I), wherein U is -N(R2)-; W and W are each -QR1)-; V and V are each -C(R15)-; X and X' are each -CH- and Y and Y' are each - N-.
Scheme 2
Wherein D and D' are each independently C(R13)2, N(R4), S, O or Si(R16) 2; M and M' are each independently halo, triflate, boronic acid or boronic ester; PG is a protecting group, such as Boc or 4-methoxybenzyl; R4 is -C(0)Rn, -C(0)-[C(R7)2]qN(R6)2, -C(O)- [C(R7)2]q-Rn, -C(0)-[C(R7)2]qN(R6)C(0)-Rn, -C(0)[C(R7)2]qN(R6)S02-Rn, -C(O)-
[C(R7)2]qN(R6)C(0)0-Rn or -C(0)-[C(R7)2]qC(0)0-Rn; and G, R1, R2 and R15 are defined above for the Compounds of Formula (I).
Depending on the identity of M and or M', the compounds of formula G9 can be coupled with a coupling partner of formula G22 (preparation of compounds of formula G22 is described below in Scheme 5) to provide the compounds of formula G10. Removal of the protecting groups of the compounds of formula G10 provides the diamino compounds of formula Gil, which can then be reacted with an appropriately substituted carboxylic acid to form the R4 groups of the di-amide compounds of formula G12, which which correspond the the Compounds of Formula (I), wherein U is -N(R2)-; W and W are each -C(R1)-; V and V are each -C(R15)-; X and X* are each -CH- and Y and Y' are each -N-.
Scheme 3 shows a method useful for making the compounds of formula G15, which correspond to the Compounds of Formula (I), wherein intermediates for making the Compounds of Formula (I), wherein U is -0-; W and W are each -QR1)-; V and V are each -C(R15)-; X and X' are each -CH- and Y and Y' are each -N-.
Scheme 3
Wherein D and D' are each independently C(R13)2, N(R4), S, O or Si(R16) 2; M and M' are each independently halo, triflate, boronic acid or boronic ester; R4 is -C(0)Rn, - C(0)-[C(R7)2]qN(R6)2, -C(0)-[C(R7)2]q-Rn, -C(0)-[C(R7)2]qN(R6)C(0)-Rn, - C(0)[C(R7)2]qN(R6)S02-Rn, -C(0)-[C(R7)2]qN(R6)C(0)0-Rn or -C(0)-[C(R7)2]qC(0)0-Rn; and G, R2 and R15 are defined above for the Compounds of Formula (I).
A substituted benzoxazole of formula G13 can be arylated at the 2-position with coupling partner of formula G6 using methods analogous to those described in Scheme 1 for the formation of G8 from G5 and G6, to provide the 2-aryl benzoxazoles of formula G14. A compound of formula G14 can then be carried forth to the compounds of G15 using methods analogous to those described in Scheme 2 for the conversion of G9 to G12.
Scheme 4 shows a method useful for making the compounds of formula G12, which correspond the the Compounds of Formula (I), wherein U is -N(R2)-; W and W are each -QR1)-; V is -CH-; V* is -N-; X and X* are each -CH- and Y and Y* are each -N-.
Scheme 4
G18
Wherein D and D' are each independently C(R13)2, N(R4), S, O or Si(R16) 2; M and M' are each independently halo, triflate, boronic acid or boronic ester; R4 is -C(0)Rn, - C(0)-[C(R7)2]qN(R6)2, -C(0)-[C(R7)2]q-Rn, -C(0)-[C(R7)2]qN(R6)C(0)-Rn, - C(0)[C(R7)2]qN(R6)S02-Rn, -C(0)-[C(R7)2]qN(R6)C(0)0-Rn or -C(0)-[C(R7)2]qC(0)0-Rn; and G, R1 and R2 are defined above for the Compounds of Formula (I).
A pyridyl hydrazone of formula G16 can be converted to the tetracyclic compounds of formula G17 using methods analogous to those described in Scheme 1 for the formation of G8 from G3. A compound of formula G17 can then be carried forth to the compounds of G18 using methods analogous to those described in Scheme 2 for the conversion of G9 to G12.
Scheme 5 shows methods useful for making the compounds of formula G22, which are useful intermediates for making the Compounds of Formula (I) wherein X and X' are each CH and Y and Y' are each N.
Scheme 5
G21
Wherein D is C(R13)2, N(R4), S, O or Si(R16) 2; X is halo or triflate; and PG is a amino protecting group, such as Boc or 4-methoxybenzyl..
An appropriately functionalized aldehyde of formula G19 can be reacted with glyoxal and ammonia.to provide a substituted imidazole of formula G20. A compound of formula G20 can subsequently be selectively mono-halogenated to provide a mono- halogenated imidazole compound of formula G22. Alternatively, a compound of formula G22 can subsequently be di-halogenated to provide a compound of formula G21, which is then selectively reduced to provide a mono-halogenated imidazole compound of formula G22.
In some of the Compounds of Formula (I) contemplated in Schemes 1-5, amino acids (such as, but not limited to proline, 4-(R)-fluoroproline, 4-(S)-fluoroproline, 4,4- difluoroproline, 4,4-dimethylsilylproline, aza-bicyclo[2.2.1]heptane carboxylic acid, aza- bicyclo[2.2.2]octane carboxylic acid, (S)-2-piperidine carboxylic acid, valine, alanine, norvaline, etc.) are incorporated as part of the structures. Methods have been described in the organic chemistry literature as well as in Banchard US 2009/0068140 (Published March 9th 2009) for the preparation of such amino acid-derived intermediates. One skilled in the art of organic synthesis will recognize that the synthesis of fused tetracyclic cores contained in Compounds of Formula (I) 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 et ah, Protective Groups in Organic Synthesis, Wiley-Interscience, New York, (1999).
One skilled in the art of organic synthesis will also recognize that one route for the synthesis of the fused tetracyclic cores of the Compounds of Formula (I) may be more desirable depending on the choice of appendage substituents. Additionally, one skilled in the 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.
One skilled in the art of organic synthesis will recognize that the synthesis of certain fused tetracyclic cores of the Compounds of Formula (I) require the construction of an amide bond. Methods useful for making such amide bonds, include but are not limited to, the use of a reactive carboxy derivative {e.g., an acid halide, or ester at elevated temperatures) or the use of an acid with a coupling reagent {e.g., HOBt, EDCI, DCC, HATU, PyBrop) with an amine.
The preparation of multicyclic intermediates useful for making the fused tetracyclic ring systems of the Compounds of Formula (I) have been described in the literature and in compendia such as "Comprehensive Heterocyclic Chemistry" editions I, II and III, published by Elsevier and edited by A.R. Katritzky & R. JK Taylor. Manipulation of the required substitution patterns have also been described in the available chemical literature as summarized in compendia such as "Comprehensive Organic Chemistry" published by Elsevier and edited by DH R. Barton and W. D. Ollis; "Comprehensive Organic Functional Group Transformations" edited by edited by A.R. Katritzky & R. JK Taylor and
"Comprehensive Organic Transformation" published by Wily-CVH and edited by R. C. Larock.
The Compounds Formula (I) may contain one or more silicon atoms. The compounds contemplated in this invention in general can be prepared using the carba-analog methodology unless otherwise noted. A recent review of the synthesis of silicon containing compounds can be found in "Silicon Chemistry: from Atom to Extended Systems", Ed P. Jutzi & U. Schubet; ISBN 978-3-527-30647-3. Preparation of silyl containing amino acids has been described. See Bolm et al., Angew. Chem. Int Ed., 39:2289 (2000). Descriptions of improved cellular update ( Giralt, J. Am. Chem. Soc, 128:8479 (2006)) and reduced metabolic processing of silyl containing compounds have been described ( Johansson et al., Drug Metabolism & Disposition, 38:73 (2009)).
The starting materials used and the intermediates prepared using the methods set forth 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.
Uses of the Fused Tetracyclic Heterocvcle Compounds
The Fused Tetracyclic Heterocycle Compounds are useful in human and veterinary medicine for treating or preventing a viral infection in a patient. In one
embodiment, the Fused Tetracyclic Heterocycle Compounds can be inhibitors of viral replication. In another embodiment, the Fused Tetracyclic Heterocycle Compounds can be inhibitors of HCV replication. Accordingly, the Fused Tetracyclic Heterocycle Compounds are useful for treating viral infections, such as HCV. In accordance with the invention, the Fused 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 Fused Tetracyclic Heterocycle Compound or a pharmaceutically acceptable salt thereof. Treatment or Prevention of a Flaviviridae Virus
The Fused Tetracyclic Heterocycle Compounds can be useful for treating or preventing a viral infection caused by the Flaviviridae family of viruses.
Examples of Flaviviridae infections that can be treated or prevented using the present methods include but are not limited to, dengue fever, Japanese encephalitis, Kyasanur Forest disease, Murray Valley encephalitis, St. Louis encephalitis, Tick-borne encephalitis, West Nile encephalitis, yellow fever and Hepatitis C Virus (HCV) infection.
In one embodiment, the Flaviviridae infection being treated is hepatitis C virus infection.
Treatment or Prevention of HCV Infection The Fused Tetracyclic Heterocycle Compounds are useful in the inhibition of HCV (e.g., HCV NS5A), 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 Fused 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 Fused 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 Fused Tetracyclic Heterocycle Compounds are also useful in the preparation and execution of screening assays for antiviral compounds. For example the Fused Tetracyclic Heterocycle Compounds are useful for identifying resistant HCV replicon cell lines harboring mutations within NS5 A, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the Fused 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 l):2391-2399 (1993) is widely used and classifies isolates into six major genotypes, 1 through 6, with two or more related subtypes, e.g., la and lb. 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, J 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 Fused 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 Fused Tetracyclic Heterocycle Compound, or a pharmaceutically acceptable salt thereof, and (ii) at least one additional therapeutic agent that is other than a Fused 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 Fused 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 Fused 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 Fused 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 Fused 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 Fused 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 Fused 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 Fused 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 Fused 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 NS5 A 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), R7128 (Roche/Pharmasset), PF-868554/filibuvir (Pfizer), VCH-759 (ViroChem Pharma), HCV-796 (Wyeth/ViroPharma), IDX-184 (Idenix), IDX-375 (Idenix), NM-283
(Idenix/Novartis), R-1626 (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), VCH222 (ViroChem), VCH916 (ViroChem), VCH716(ViroChem), GSK-71185 (Glaxo SmithKline), ANA598 (Anadys), GSK-625433 (Glaxo SmithKline), XTL-2125 (XTL Biopharmaceuticals), and those disclosed in Ni et al., 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 09/0321 16, 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 PEG-interferon alpha conjugates. "PEG-interferon alpha conjugates" are interferon alpha molecules covalently attached to a PEG molecule. Illustrative PEG-interferon alpha conjugates include interferon alpha-2a (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 PEG-Intron™ from Schering-Plough
Corporation), interferon alpha-2b-XL (e.g. , as sold under the trade name PEG-Intron™), interferon alpha-2c (Berofor Alpha™, Boehringer Ingelheim, Ingelheim, Germany), PEG- interferon lambda (Bristol-Myers Squibb and ZymoGenetics), interferon alfa-2b alpha fusion polypeptides, interferon fused with the human blood protein albumin (Albuferon™, Human Genome Sciences), Omega Interferon (Intarcia), Locteron controlled release interferon (Biolex/OctoPlus), Biomed-510 (omega interferon), Peg-IL-29 (ZymoGenetics), Locteron CR (Octoplus), IFN-a-2b-XL (Flamel Technologies), 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, SCH503034 (Boceprevir, Schering-Plough),
SCH900518 (Schering-Plough), VX-950 (Telaprevir, Vertex), VX-500 (Vertex), VX-813 (Vertex), VBY-376 (Virobay), BI-201335 (Boehringer Ingelheim), TMC-435
(Medivir/Tibotec), ABT-450 (Abbott), TMC-435350 (Medivir), ITMN-191/R7227
(InterMune/Roche), EA-058 (Abbott/Enanta), EA-063 (Abbott/Enanta), GS-9132
(Gilead/Achillion), ACH-1095 (Gilead/Achillon), IDX-136 (Idenix), IDX-316 (Idenix), ITMN-8356 (InterMune), ITMN-8347 (InterMune), 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); Ingallmella 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, 3703): 11459-11468 (1998); Dimasi et al, J Virol, 71(10^:7461-7469 (1997); Martin et al, Protein Eng, 10(5^:607-614 (1997); Elzouki et al, J Hepat, 27(Π:42-48 (1997); BioWorld Today, 9(217^:4 (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:
53
54
Viral replication inhibitors useful in the present compositions and methods include, but are not limited to, HCV replicase inhibitors, IRES inhibitors, NS4A inhibitors, NS3 helicase inhibitors, NS5A inhibitors, NS5B inhibitors, ribavirin, AZD-2836 (Astra Zeneca), BMS-790052 (Bristol-Myers Squibb, see Gao et al, Nature, 465:96-100 (2010)), viramidine, A-831 (Arrow Therapeutics); an antisense agent or a therapeutic vaccine.
HCV NS4A inhibitors useful in the present compositions and methods include, but are not limited to, those disclosed in U.S. Patent Nos. 7,476,686 and 7,273,885; U.S. Patent Publication No. US20090022688; and International Publication Nos. WO
2006/019831 and WO 2006/019832. Additional HCV NS4A inhibitors useful in the present compositions and methods include, but are not limited to, AZD2836 (Astra Zeneca) and ACH-806 (Achillon Pharmaceuticals, New Haven, CT).
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.
Examples of further additional therapeutic agents that may be 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 (Globelmmune), 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 (Vio Quest 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); A A773 (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 Fused 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 Fused 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 PEG- 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
PEGASUS interferon alpha 2a pegylated (commercially available from Hoffmann-La Roche), this agent is administered by subcutaneous injection at 180 mcg/lmL or 180 mcg/0.5mL, once a week for at least 24 weeks.
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 Fused Tetracyclic Heterocycle Compounds are useful in veterinary and human medicine. As described above, the Fused Tetracyclic Heterocycle Compounds are useful for treating or preventing HCV infection in a patient in need thereof.
When administered to a patient, the Fused 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 Fused
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 so lid- 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.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.
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 Fused Tetracyclic Heterocycle
Compounds are administered orally.
In another embodiment, the one or more Fused Tetracyclic Heterocycle Compounds are administered intravenously.
In another embodiment, the one or more Fused Tetracyclic Heterocycle Compounds are administered topically.
In still another embodiment, the one or more Fused Tetracyclic Heterocycle Compounds are administered sublingually.
In one embodiment, a pharmaceutical preparation comprising at least one Fused 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 Fused 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 Fused Tetracyclic Heterocycle Compound(s) by weight or volume.
The quantity of Fused 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 Fused 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 Fused 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 Fused Tetracyclic Heterocycle Compound or a pharmaceutically acceptable salt thereof; (ii) one or more additional therapeutic agents that are not a Fused 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 Fused 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 Fused 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 Fused Tetracyclic Heterocycle Compounds and the one or more additional therapeutic agents are provided in the same container. In one embodiment, the one or more Fused Tetracyclic Heterocycle Compounds and the one or more additional therapeutic agents are provided in separate containers.
EXAMPLES
General Methods
Solvents, reagents, and intermediates that are commercially available were used as received. Reagents and intermediates that are not commercially available were prepared in the manner as described below. 1H NMR spectra were obtained on either a Varian VNMR System 400 (400 MHz) or a Bruker Avance 500 (500 MHz) and are reported as ppm downfield from Me4Si with number of protons, multiplicities, and coupling constants in Hertz indicated parenthetically. Where LC/MS data are presented, analyses was performed using an Agilent 6110A MSD or an Applied Biosystems API- 100 mass spectrometer and Shimadzu SCL-IOA LC column: Altech platinum CI 8, 3 micron, 33 mm x 7mm ID; gradient flow: 0 minutes - 10% CH3CN, 5 minutes - 95% CH3CN, 5-7 minutes - 95% CH3CN, 7 minutes - stop. The retention time and observed parent ion are given. Flash column chromatography was performed using pre-packed normal phase silica from Biotage, Inc. or bulk silica from Fisher Scientific. Unless otherwise indicated, column chromatography was performed using a gradient elution of hexanes/ethyl acetate, from 100% hexanes to 100% ethyl acetate.
EXAMPLE 1
Preparation of Intermediate Compound Int-la
Int-la
To a solution of L- valine (10. O g, 85.3 mmol) in 1M aqueous NaOH solution (86 mL) at room temperature was added solid sodium carbonate (4.60 g, 43.4 mmol). The reaction mixture was cooled to 0 °C (ice bath) and then methyl chloro formate (7.20 mL, 93.6 mmol) was added dropwise over 20 minutes. The reaction mixture was then allowed to warm to room temperature, and allowed to stir at room temperature for an additional 4 hours. The reaction mixture was then diluted with diethyl ether (100 mL), the resulting solution was cooled to at 0 °C, and then concentrated hydrochloric acid (18 mL, 216 mmol) was added slowly. The reaction was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgSC^, filtered and concentrated in vacuo to provide Int-la (13.5 g, 90%), which was used without further purification.
The following intermediates can be prepared by the reaction of L-valine with isopropyl chloro formate, 2-methoxyethyl chloro formate or with 1-methylcyclopropyl hydroxysuccinimide respectively as above.
Int-lb Int-lc Int-ld
EXAMPLE 2
Preparation of Intermediate Compound Int-2a
Int-2a
To a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g, 265 mmol) in water (60 mL) at 0 °C was added methyl chloroformate (10.2 mL, 133 mmol) dropwise over 20 minutes. The resulting mixture was allowed to stir at 0 °C for 1 hour, then was acidified using concentrated hydrochloric acid (25 mL, 300 mmol). The acidic solution was extracted with EtOAc (3 x 100 mL) and the combined organics were dried over MgSC^, filtered and concentrated in vacuo to provide Int-2a (12.6 g, 91%), which was used without further purification.
The following intermediates can be prepared by the reaction of glycine, L- Alanine and 4-F phenylglycine respectively with methyl chloroformate (Aldrich Inc.) using the method described above:
EXAMPLE 3
Preparation of Intermediate Compound Int-3a
Int-3a
A solution of D-phenylglycine (20.0 g, 132 mmol), 37% aqueous formaldehyde (66 mL, 814 mmol) and 5 % Pd on carbon (8.0 g, mmol) in a mixture of methanol (80 mL) and 1 N HC1 (60 mL) was placed on a hydrogenation shaker and shook under an atmosphere of 35-40 psi hydrogen for 4 hours. The reaction was then flushed with nitrogen, filtered through a celite pad and concentrated in vacuo to provide Compound Int-3a (29.7 g, quant.) as a white solid, which was used without further purification.
EXAMPLE 4
Preparation of Intermediate Compound Int-4f
1 1 lnt-4b lnt-4c
l nt-4d lnt-4e lnt-4f Step A - Preparation of Compound Int-4b
To a solution of methyl 2-(benzyloxycarbonylamino)-2-(dimethoxyphosphoryl) acetate (10.0 g, 30.2 mmol, made as decribed in Hamada et ah, Organic Letters; English, 20:4664-4667 (2009)) in THF (100 mL) at -20 °C was added tetramethylguanidine (4.20 mL, 33.2 mmol). The reaction mixture was allowed to stir at -20 °C for 1 hour then dihydro-2H- pyran-4(3H)-one (4a) was added (3.1 mL, 33.2 mmol) in THF (5 mL) and the reaction mixture was warmed to room temperature and allowed to stir for about 15 hours. EtOAc (200 mL) was added and the organic mixture was washed with water (3 >< 50 mL) and brine (50 mL). The organic layers were combined and dried with Na2S04, filtered and
concentrated in vacuo. The crude product was purified using flash chromatography on an ISCO 330 g Redi-Sep column using 0-35% EtOAc/hexanes as the eluent to provide
Compound Int-4b as a white solid (615 mg, 45%). 1H NMR (CDC13) δ 7.40-7.30 (m, 5H), 6.00 (br s, 1H), 5.12 (s, 2H), 3.80-3.65 (m, 7H), 2.92 (m, 2H), 2.52-2.48 (m, 2H).
Step B - Preparation of Compound Int-4c
To a solution of Int-4b (2.43 g, 7.96 mmol) in methanol (160 mL) previously purged with N2 was added (-)-l,2-Bis((2S,5S)-2,5-dimethylphospholano) ethane
(cyclooctadiene)rhodium(I) tetrafluoroborate (487 mg, 0.880 mmol) under N2. The mixture was shaken in a Parr shaker apparatus for 18 hours at 50 psi of H2. After evacuating the hydrogen, the suspension was filtered and the filtrate was concentrated in vacuo to provide Compound Int-4c as a white solid (1.30 g, 53%). 1H NMR (CDC13) δ 7.40-7.30 (m, 5H), 5.32 (br s, 1H), 5.12 (s, 2H), 4.40-4.30 (m, 1H), 4.00-3.95 (m, 2H), 3.75 (s, 3H), 3.40-3.25 (m, 2H), 2.10-1.95 (m, 1H), 1.50-1.45 (m, 4H).
Step C - Preparation of Compound Int-4d
To a suspension of 50%> palladium on carbon (10%> wet, 200 mg) in absolute ethanol (20 mL) under nitrogen was added Int-4c (1.06 g, 3.45 mmol). With stirring, the solution was placed in vacuo for 30 seconds and then was opened to a hydrogen gas balloon for 2 hours. After evacuating the hydrogen, the suspension was filtered through a Celite pad and the pad washed with ethanol (2 x 20 mL). The filtrate was concentrated in vacuo to provide Compound Int-4d as a colorless oil (585 mg, 98%). 1H NMR (CDC13) δ 4.06-3.96 (m, 2H), 3.73 (s, 3H), 3.48-3.28 (m, 3H), 1.92-1.78 (m, 1H), 1.61-1.47 (m, 6H). Step D - Preparation of Compound Int-4e
To the solution of compound Int-4d (585 mg, 3.37 mmol) and triethylamine (0.710 mL, 5.09 mmol) in CH2C12 (6 mL) was added methyl chloro formate (0.290 mL, 3.76 mmol). The reaction mixture was allowed to stir at room temperature for about 15 hours. Water (15 mL) was added and the aqueous mixture was extracted with CH2C12 (3 x 20 mL). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified using flash chromatography on an ISCO 24 g Redi-Sep column using 0-3% MeOH/CH2Cl2 as the eluent to provide Compound Int-4e as a colorless oil (600 mg, 77%). 1H NMR (CDC13) δ 5.27-5.18 (m, 1H), 4.38-4.28 (m, 1H), 4.06-3.96 (m, 2H), 3.75 (s, 3H), 3.69 (s, 3H), 3.39-3.30 (m, 2H), 2.09-1.94 (m, 1H), 1.59-1.48 (m, 4H).
Step E - Preparation of Compound Int-4f
To the solution of compound Int-4e (600 mg, 2.59 mmol) in THF (5 mL) was added lithium hydroxide mono hydrate (218 mg, 5.19 mmol) in water (5 mL). The reaction mixture was allowed to stir at room temperature for 2 hours then concentrated in vacuo to half volume. The aqueous mixture was then acidified with 6N HCl and extracted with EtOAc (7 x 50 mL). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to provide Compound Int-4f as an off-white solid (485 mg, 86%). 1H NMR
(CD3OD) δ 4.09-4.07 (m, 1H), 3.96-3.92 (m, 2H), 3.65 (s, 3H), 3.40-3.34 (m, 2H), 2.10- 1.99 (m, 1H), 1.56-1.47 (m, 4H).
EXAMPLE 5
Preparation of Intermediate Compound Int-5f
' lnt-5a lnt-5b lnt-5c
lnt-5d lnt-5e lnt-5f
Step A - Preparation of Compound IntSa To a solution of methyl 2-(benzyloxycarbonylamino)-2-(dimethoxyphosphoryl) acetate (1.50 g, 4.52 mmol) in THF (5 mL) at -20 °C was added tetramethylguanidine (625 μί, 4.98 mmol). The reaction mixture was allowed to stir at -20 °C for 1 hour then tert-butyl 4-oxopiperidine-l-carboxylate was added (992 mg, 4.97 mmol) in THF (2 mL) and the reaction mixture was warmed to room temperature and allowed to stir for about 15 hours. EtOAc (90 mL) was added and the organic mixture was washed with water (3 x 20 mL) and brine (25 mL). The combined organic layers were dried over Na2S04, filtered and
concentrated in vacuo. The crude product was purified using flash chromatography on an ISCO 40 g Redi-Sep column using 0-35% EtOAc/hexanes as the eluent to provide
Compound Int-5a as a white semi-solid (1.1 g, 61%). 1H NMR (CDC13) δ 7.40-7.30 (m, 5H), 6.02 (br s, 1H), 5.12 (s, 2H), 3.80-3.40 (m, 7H), 2.90-2.80 (m, 2H), 2.45-2.35 (m, 2H), 1.45 (s, 9H).
Step B - Preparation of Compound IntSb
To a solution of Int-5a (1.30 g, 3.21 mmol) in methanol (90 mL) previously purged with N2 was added (-)-l,2-Bis((2S,5S)-2,5-dimethylphospholano)
ethane(cyclooctadiene)rhodium(I) tetrafluoroborate (197 mg, 0.354 mmol) under N2. The mixture was then shaken in a Parr shaker apparatus for 18 hours at 50 psi of H2. After evacuating the hydrogen, the suspension was filtered and the filtrate was concentrated in vacuo to provide Compound Int-5b as colorless oil (1.00 g, 77%). 1H NMR (CDC13) δ 7.40- 7.30 (m, 5H), 5.35-5.25 (m, 1H), 5.10 (s, 2H), 4.40-4.35 (m, 1H), 4.20-4.10 (m, 2H), 3.70 (s, 3H), 2.70-2.55 (m, 2H), 2.00-1.90 (m, 1H), 1.65-1.40 (m, 11H), 1.30-1.20 (m, 2H).
Step C - Preparation of Compound IntSc
To a solution of 50%> palladium on carbon (10%> wet, 250 mg) in absolute ethanol (20 mL) under nitrogen was added Int-5b (1.00 g, 2.46 mmol). The reaction was evacuated, then put under an H2 atmosphere using a hydrogen- filled balloon and allowed to stir for 2 hours. The hydrogen was evacuated and the resulting suspension was filtered through a Celite pad and the pad washed with ethanol (2 x 20 mL). The filtrate and ethanol washings were combined and concentrated in vacuo to provide Compound Int-5c as a colorless oil (670 mg, quant.). 1H NMR (CDC13) δ 4.21-4.08 (m, 2H), 3.73 (s, 3H), 3.31 (d, / = 6.0 Hz, 1H), 2.75-2.57 (m, 2H), 1.84-1.70 (m, 1H), 1.68-1.56 (m, 1H), 1.45 (s, 9H), 1.45-1.20 (m, 5H). Step D - Preparation of Compound IntSd
To the solution of compound Int-5c (670 mg, 2.46 mmol) and triethylamine (0.520 mL, 3.73 mmol) in CH2CI2 (10 mL) was added methyl chloroformate (0.210 mL, 2.72 mmol). The reaction mixture was allowed to stir at room temperature for about 15 hours. Water (20 mL) was added and the aqueous mixture was extracted with CH2CI2 (2 x 15 mL). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified using flash chromatography on an ISCO 24 g Redi-Sep column using 0-3% MeOH/CH2Cl2 as the eluent to provide Compound Int-5d as an off- white solid (515 mg, 63%). 1H NMR (CDC13) δ 5.26-5.17 (m, 1H), 4.38-4.30 (m, 1H), 4.20-4.07 (m, 2H), 3.75 (s, 3H), 3.68 (s, 3H), 2.71-2.57 (m, 2H), 2.00-1.85 (m, 1H), 1.87- 1.48 (m, 2H), 1.44 (s, 9H), 1.35-1.18 (m, 2H).
Step E - Preparation of Compound IntSe
Compound Int-5d (300 mg, 0.908 mmol) was dissolved in a mixture of TFA (2 mL) and CH2CI2 (10 mL) and the solution was allowed to stir at room temperature for 1 hour, then was concentrated in vacuo. To the resulting residue was added triethylamine (0.760 mL, 5.45 mmol) in CH2C12 (10 mL), then acetic anhydride (0.086 mL, 0.915 mmol). The reaction was allowed to stir at room temperature for about 15 hours then concentrated in vacuo. The residue obtained was purified using flash chromatography on an ISCO 12 g Redi- Sep column using 0-4% MeOH/CH2Cl2 as the eluent to provide Compound Int-5e as colorless oil (247 mg, 99%). 1H NMR (CDC13) δ 5.27-5.21 (m, 1H), 4.73-4.62 (m, 1H), 4.42-4.32 (m, 1H), 3.69 (s, 3H), 3.18 (s, 3H), 3.18-3.09 (m, 1H), 3.07-2.95 (m ,1H), 2.55- 2.41 (m, 1H), 2.07 (s, 3H), 1.78-1.49 (m, 3H), 1.38-1.21 (m, 2H). Step F - Preparation of Compound IntSf
To the solution of compound Int-5e (247 mg, 2.59 mmol) in THF (3 mL) was added lithium hydroxide monohydrate (77 mg, 1.83 mmol) in water (3 mL). The reaction mixture was allowed to stir at room temperature for about 15 hours then concentrated in vacuo to 50% of its original volume. The concentrated solution was then acidified with IN HC1 to pH 4 and extracted with EtOAc (7 x 15 mL). The combined organic extracts were dried over Na2S04, filtered and concentrated in vacuo to provide Compound Int-5f as an off- white solid (106 mg, 45%). 1H NMR (CD3OD) δ 5.52-5.43 (m, 1H), 4.71-4.62 (m, 1H), 4.44-4.31 (m, 1H), 3.91-3.81 (M, 1H), 3.70 (s, 3H), 3.12-2.99 (m, 1H), 2.58-2.46 (m, 1H), 2.10 (m, 4H), 1.86-1.54 (m, 2H), 1.50-1.21 (m, 3H). EXAMPLE 6
Preparation of Intermediate Compound Int-6f
Int-6c
: endo : 1
Int-6f
- Preparation of Compound Int-6c
Int-6c
A stirred mixture of D-(+)-a-methylbenzyl amine Int-6a (50.0 g, 0.412 mol), ethyl glyoxylate (81.5 mL, 50% in toluene, 0.412 mol) and PPTS (0.50 g, 2.00 mmol) in benzene (600 mL) was heated to reflux in a Dean- Stark apparatus and allowed to remain at reflux until no further water (~8 mL) azeotroped from the reaction (~ 4 hours). The resulting mixture was concentrated in vacuo to provide Compound Int-6b, which was used without further purification: 1H NMR (300 MHz, CDC13) δ 7.72 (s, 1H), 7.36-7.24 (m, 5H), 4.61 (q, J = 6.9 Hz, lH), 4.35 (q, / = 7.2 Hz, 2H), 1.62 (d, / = 6.6 Hz, 3H), 1.34 (t, / = 7.2 Hz, 3H).
To a stirred solution of crude Int-6b in methylene chloride (600 mL) at -78 °C were added the following in 10 minute intervals: TFA (31.0 mL, 0.416 mol), boron trifluoride etherate (51.3 mL, 0.416 mol) and freshly distilled cyclopentadiene (32.7 g, 0.494 mol). After less than 2 minutes following the addition of cyclopentadiene, the reaction mixture formed a thick brown mass, which was allowed to stir for 6 hours at -78 °C. The reaction mixture was then allowed to warm to room temperature on its own and stir for an additional 15 hours. The resulting dark brown reaction mixture was quenched with sat. aq. Na2C03 (~ 900 mL) and allowed to stir for 30 minutes. The resultant suspension was filtered through a pad of Celite® and the filtrate was extracted with methylene chloride (3 x 100 mL). The combined organic extracts were washed with sat. aq. NaCl (2 x 75 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue obtained was purified using flash column chromatography (silica; 8 x 18 cm, 10% to 25% ethyl acetate/hexanes as the eluent) to provide endo Int-6c (10.9 g, 9%) as a brown oil: 1H NMR (300 MHz, CDC13) δ 7.34-7.19 (m, 5H), 6.00-5.95 (m, 1H), 4.18 (q, / = 7.1 Hz, 3H), 3.47 (s, 1H), 3.03 (s, 1H), 2.97 (q, / = 6.5 Hz, 1H), 2.41 (s, 1H), 1.86 (d, / = 8.2 Hz, 1H), 1.26 (t, / = 6.6 Hz, 3H), 1.17 (t, / = 6.6 Hz, 3H). Exo Int-6c (84.3 g, 74%) was also collected as a brown oil: 1H NMR (300 MHz, CDC13) δ 7.34-7.19 (m, 5H), 6.36-6.33 (m, 1H), 6.22-6.18 (m, 1H), 4.37 (s, 1H), 3.87 (q, / = 6.8 Hz, 2H), 3.10 (q, / = 6.5 Hz, 1H), 2.96 (s, 1H), 2.27 (s, 1H), 2.20 (d, / = 8.4 Hz, 1H), 1.48 (d, / = 6.5 Hz, 3H), 1.01 (d, / = 7.0 Hz, 3H), 1.00 (m, 1H).
Step B- Representative Example for the Preparation of Compound \nt-6d
A mixture of exo-\nt-6c (15.8 g, 0.582 mol) and 10% Pd/C (4.07 g, 50% wet) in a 1 :2 mixture of EtOH/EtOAc (150 mL) was shaken for 23 hours in a Parr hydrogenation apparatus under an atmosphere of H2 (50 psi). The reaction mixture was then filtered through Celite® and the filtrate was concentrated in vacuo. 1H NMR analysis of the residue (10.8 g) showed some aromatic resonances present. Repetition of the hydrogenation procedure using 10%) Pd/C (2.0 g) afforded Int-6d (10.0 g, quant.) as a brown oil, which was used without further purification. 1H NMR (300 MHz, CDC13) δ 4.18 (q, / = 7.2 Hz, 3H), 3.54 (s, 1H), 3.32 (s, 1H), 2.62 (s, 1H), 2.23 (s, 1H), 1.64-1.39 (m, 5H), 1.31-1.20 (m, 4H).
Step C - Preparation of Compound \nt-6e
To a solution of Int-6d (36.6 g, 0.236 mol) and sat. aq. Na2C03 (300 mL) in THF (600 mL) at 0 °C was added di-ie/t-butyl dicarbonate (59.0 g, 0.270 mol). The resulting reaction was allowed to slowly warm to room temperature with stirring over 6 hours, then was allowed to stir at room tempearature for an additional 68 hours. The reaction mixture was diluted with EtOAc (250 mL) and water (250 mL) and thhe aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with sat. aq. NaCl (2 x 75 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue obtained was purified using flash column chromatography (silica; 16 x 10 cm) using 10-20% ethyl acetate/hexanes as the eluent to provide Int-6e (49.0 g, 84%) as a pale yellow oil: 1H NMR (300 MHz, CDCls) δ 4.35 (s, 0.6H), 4.22-4.10 (m, 2.4H), 3.81 (s, 0.45H), 3.71 (s, 0.55H), 2.66 (s, 1H), 1.96-1.90 (m, 1H), 1.76-1.50 (m, 3H), 1.55-1.45 (m, 5H), 1.39 (s, 5H), 1.30- 1.23 (m, 4H).
Step D- Preparation of Compound 2.2.1 Bic die Acid Intermediate Int-6 *
To a stirred mixture of Int-6e (49.0 g, 0.182 mmol) in 1 : 1 THF/water (600 mL) was added LiOH»H20 (15.3 g, 0.364 mo 1). The reaction mixture was heated to 60 °C and allowed to stir at this temperature for 47 hours. The reaction mixture was then cooled to room temperature, concentrated in vacuo, and the residue obtained was diluted with CH2C12 (200 mL) then acidified with 2N HC1 to pH ~ 4. The acidic solution was extracted with CH2C12 (4 x 100 mL) and the combined organic extracts were washed with sat. aq. NaCl (25 mL), dried over Na2S04, filtered and concentrated in vacuo to provide Int-6f, (IR, 3S, 4S)-N-
Boc-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (41.2 g, 93%) as an off white solid, which was used without further purification: 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 4.13 (s, 0.56H), 4.06 (s, 0.47H), 3.61 (d, / = 4.0 Hz, 1H), 2.59 (s, 1H), 1.75-1.45 (m, 5H), 1.39 (s, 4H), 1.32 (s, 5H), 1.23 (t, 7 = 8.4 Hz, 1H); Optical Rotation: [a]D 25 -169.0° (c = 1.1, CHC13).
EXAMPLE 7
Preparation of Intermediate Compound Int-7h
lnt-7h
- Preparation of Compound Int-7b
lnt-7a lnt-7b
A 2 L, 3 -necked round bottomed flask equipped with an overhead stirrer and a N2 inlet was charged with a solution of oxalyl chloride (130 mL, 0.26 mol) in dichloromethane (250 mL). The solution was cooled to -78 °C, and a solution of DMSO (20 mL, 0.28 mol) in dichloromethane (30 mL) was added dropwise. After 30 minutes, a solution of (S)-N-Boc-prolinol, Int-7a (40 g, 0.20 mol) in dichloromethane (200 mL) was added dropwise. After 30 minutes, triethylamine (140 mL, 1.00 mol) was added to the solution, and the flask was transferred to an ice/water bath and allowed to stir for another 30 minutes. The reaction mixture was diluted with dichloromethane (200 mL) and washed successively with H20, 1M HC1, saturated NaHC03, and brine. The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to provide crude (S)-2-formyl-pyrrolidine-l- carboxylic acid tert-butyl ester, Int-7b (40 g) as oil, which was used without further purification.
Step B - Preparation of Compound Int-7c
lnt-7b lnt-7c
To (5)-Boc-prolinal, Int-7b (crude, 80g, 0.4 mol) was added a solution of ammonia in MeOH (prepared from 150 mL of 7 N ammonia/MeOH and 200 mL MeOH, 1.05 mol, 260 mol%). An exotherm was noted with the internal temperature rising to ~ 30 °C. The solution was allowed to stir for 0.5 hours at ambient temperature, then glyoxal (76 g, 0.52 mol, 130 mole%) was added over 5 minutes in portions, with the internal temperature rising to ~ 60 °C and then returning to room temperature after 1 hour. The reaction was allowed to stir for an additional 15 hours and the reaction mixture was concentrated in vacuo. The resulting residue was diluted with dichloromethane (1 L) and water (0.5 L) were added and the organic phase was washed with water (0.25 L), dried over MgS04, filtered and concentrated in vacuo. The residue obtained was slurried with warm ethyl acetate ( ~ 100 mL) and Hexane (100 mL), then was cooled and filtered. The solid obtained was washed with 30%ethyl acetate/Hexane to provide Int-7c (66.2g, 70% yield). - Preparation of Compound Int-7d
lnt-7c lnt-7d
N-Bromosuccinimide (838.4 mg, 4.71 mmol) was added in portions over 15 minutes to a cooled (ice/water) CH2CI2 (20 mL) solution of imidazole Int-7c (1.06 g, 4.50 mmol). The reaction mixture was allowed to stir for 75 minutes and concentrated in vacuo to oil. The crude product was purified using silica-gel RPLC (Acetonitrile/ water/ 0.1% TFA) to separate the mono bromide from its dibromo analog (over bromination) and the starting material. The RPLC elute was neutralized with excess NHs/MeOH, and the volatile component was removed in vacuo. The residue obtained was partitioned between CH2CI2 and water, and the aqueous layer was extracted with water. The combined organic phase was dried (MgSC^), filtered, and concentrated in vacuo to provide compound Int-7d as a white solid (374 mg). 1H NMR (DMSO) δ: 12.12 (br s, 1H), 7.10 (m, 1H), 4.70 (m, 1H), 3.31 (m, 1H; overlapped with water signal), 2.25-1.73 (m, 4H), 1.39/1.17 (s, 3.8H + 5.2H).
Step D - Alternative Synthesis ofInt-7d
lnt-7b lnt-7e
To a suspension of Int-7b (140 g, 0.59 mol) in THF (2000 mL) was added N- bromosuccinimide (200 g, 1.1 mol). The mixture was allowed to stir at ambient temperature under N2 gas for about 15 hours. The solvent was then removed in vacuo, and the residue obtained was purified using silica-gel chromatography (ethyl acetate eluent) to provide 230 g of the desired dibromo compound, Int-7e. MS (ESI) m/e (M+H+): 396.
To a suspension of Int-7e (230 g, 0.58 mol) in EtOH/H20 (1 : 1 ratio, 3000 mL) was added Na2S03 (733 g, 5.8 mol). The resulting mixture was allowed to stir at mild reflux for about 15 hours. After cooling to room temperature, the mixture was extracted with dichloromethane twice and the combined organic layer was concentrated in vacuo to a semisolid. The residue obtained was purified using chromatography on silica gel to provide the desired compound, Int-7d. MS (ESI) m/e (M+H+): 317.
- Preparation of Compound Int-7f
lnt-7e lnt-7f
Compound Int-7e (2.63 g, 5.0 mmol) was dissolved in THF (30 mL) and cooled to - 78 °C, n-BuLi (1M in hexane, 2.2 mL, 5.5 mmol) was added and the reaction was allowed to stir for 20 minutes. N-fluorodibenzenesulfonimide (1.6 mL, 5.0 mmol) was added at -78 °C and the reaction mixture was allowed to warm slowly to room temperature again. The reaction was quenched with aq. NH4C1 then partitioned between water and ethyl acetate. The organic layer was dried over Na2S04 and concentrated in vacuo. The residue obtained was purified using flash column chromatography (Gradient Ethyl acetate :petroleum ether from 0-20% Ethyl acetate) to provide Int-7f. (63 % yield). MS (ESI) m/z (M+H)+: 464, 466. 19 F NMR = -151.8 ppm .
- Preparation of Compound Int-7g
lnt-7d lnt-7g
Intermediate 7d (2.51 g, 7.94 mmol, 1.0 eq) was dissolved in 20 mL of CH2C12 and to the resulting solution was added trifluoro acetic acid (5 mL). The reaction mixture was allowed to stir for about 15 hours at room temperature under N2, and the reaction was diluted with hexanes (15 mL) and concentrated in vacuo to provide a yellow oil. CH2C12 and toluene were added and the solution was re-concentrated in vacuo. This step was repeated until excess TFA was removed, giving a solid which was dried under vacuum for 1 hour to provide 3.5 g of solid Int-7g. MS (ESI) m/z (M+H)+:217/ 218.1. - Preparation of Compound Int-7h
lnt-1a lnt-7g lnt-7h Int-7g (3.01g, 6.78 mmol, 1.0 eq) and Int-la (1.202 g, 6.86 mmol, 1.01 eq) were added to a 250 mL round-bottomed flask equipped with a stir bar. DMF was added, and the flask was connected to a vacuum line. The flask was cycled between vacuum and N2 twice, then cooled in an ice-methanol bath for 10 minutes. HATU (2.75 g, 7.23 mmol, 1.07 eq) was added, followed by diisopropylethyl amine (2.80 mL). The reaction mixture was allowed to stir at -15 °C for 20 minutes. Additional diisopropylethyl amine (2.0 mL) was added. The reaction mixture was allowed to stir for 40 minutes, then quenched with water (1.5 mL). The resulting solution was diluted with EtOAc (100 mL) and Et20 (100 mL), then washed with water (6 x 15 mL) and brine (2 x 25 mL). The organic layer was dried with MgS04, filtered, and concentrated in vacuo to dryness yielding 2.23 g of a clear oil. The crude product was purified via chromatography using an 80 g Isco Gold Si02 cartridge with a 0.5%-2.5% MeOH/ CH2C12 gradient as the mobile phase. The major peak was collected to provide 1.28 g Int-7h as a white foam. This material was further purified via sgc on an 80 g Isco Gold Si02 cartridge using a 45%-65% gradient of (5% methanol in EtOAc)/hexanes. Triethylamine 1% by volume was added to the MeOH/EtOAc solution. The fractions were assayed via TLC using Hanessian's stain. (See Example 13 below for more information on Hanessian's stain.) The major peak was collected as product to provide 1.18 g of Int-7h as a white foam. MS (ESI) m/z (M+H)+:373.1.
EXAMPLE 8
Preparation of Intermediate Compound Int-8h
lnt-8h
Step A - Preparation of Compound Int-8b
A solution of Int-8a (11.0 g, 42.6 mmol) in THF (50 mL) was cooled to 0 °C and to the cooled solution was added EtMgBr (82 mmol). After addition was complete, the cooling bath was removed and the resulting reaction was allowed to stir at room temperature for 6 hours. 3 N HC1 was then added and the reaction mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water, brine, dried over Na2S04, and concentrated in vacuo. The residue obtained was purified using silica gel chromatography to provide Int-8b (7.5 g, 50% yield).
Step B - Preparation of Compound Int-8c
lnt-8b lnt-8c
Int-8b (7.5 g, 21.3 mmol) was dissolved in 100 mL of dichloromethane and cooled to 0 °C. TFA (100 mL) was added and the reaction was allowed to stir to room temperature over 2h. The solvent was removed and the residue obtained was redissolved in EtOAc then washed with saturated bicarbonate solution then brine. The extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to provide Compound Int-8c as an oil, which was used without further purification.
Step C - Preparation of Compound IntSd
lnt-8c lnt-8d
To a solution of compound Int-8c(4.2 g, 33 mmol) in THF (30 mL) was added Et3N (4.1 g, 49 mmol) and then trityl chloride (8.7 g, 40 mmol). The mixture was allowed to stir at room temperature for 2 hours, then concentrated in vacuo. The residue obtained was purified using flash chromatography on silica gel to provide compound Int-8d (8.7 g, 71% yield). MS (ESI) m/z (M+H)+: 370.
- Preparation of Compound Int-8e
lnt-8d lnt-8e
To a solution of compound Int-8d (3.6 g, 10.0 mmol) in THF (30 mL) was added LiHMDS (11.0 mmol) and then NBS (1.8 g, 10 mmol) at 0 °C. The mixture was allowed to stir at room temperature for 2 hours and then 3 N HCl was added to the mixture and the resulting solution was extracted with ethyl acetate (2 x 25 mL). The combined organic extracts were concentrated in vacuo and the residue obtained was purified using chromatography to provide compound Int-8e (1.98 g, 44% yield). MS (ESI) m/z (M+H)+: 478, 480.
- Preparation of Compound Int-8f
lnt-8e lnt-8f
To a solution of compound Int-8e (3.6 g, 10.0 mmol) in THF (30 mL) was added LiHMDS (11.0 mmol) and then NBS (1.8 g, 10 mmol). The mixture was allowed to stir at room temperature for 2 hours and then 3 N HCl was added to the mixture and extracted with ethyl acetate twice. The organic layer was concentrated in vacuo. The residue obtained was purified using chromatography to provide the Int-8f (1.98 g, 44% yield). MS (ESI) m z (M+H)+: 478, 480. Step F - Preparation of Compound Int-8g
To a solution of compound Int-8f (3.9 g, 10 mmol) in chloroform (30 mL) was added NBS (1.76 g, 10 mmol) and the mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo and the residue obtained was purified using flash chromatography to provide Compound Int-8g (2.2 g, 47% yield).
- Preparation of Compound Int-8h
lnt-8g lnt-i
To a solution of compound Int-8g (1.28 g, 2.7 mmol) in dichloromethane (10 mL) was added TFA (10 mL) and the mixture was allowed to stir at room temperature for 2 hours. Then the mixture was concentrated and used in the next reaction directly. The residue obtained was dissolved in THF (20 mL) and Et3N (5 mL) and to the resulting solution was added BOC anhydride (590 mg, 2.7 mmol). The mixture was allowed to stir at room temperature for 2 hours and concentrated in vacuo. The residue obtained was purified using chromatography to provide compound Int-8h (600 mg, 67% yield).
MS (ESI) m/z (M+H)+: 331.
EXAMPLE 9
Preparation of Intermediate Compound Int-9g
lnt-9g
Step A - Preparation of Compound Int- 9b
To a solution of compound Int-9a (50 g, 0.2 mol) in THF (500 mL) and Et3N (20 mL) was added dropwise isopropyl chloroformate (25 g, 0.22 mol) at ice water bath. Then the resulting solution was allowed to warm to room temperature and allowed to stir for lh. Then a solution of CH2N2 (0.22 mol) in ether was added slowly until no N2 gas evolution was noted. Acetic acid (4 mL) was added and the reaction mixture was allowed to stir for 10 minutes. NaHC03 solution was then added and the reaction mixture extracted three times with ethyl acetate. The organic layers were combined, dried over Na2S04, and concentrated in vacuo to provide crude product. The crude product was then purified using column chromatography on silica gel (Pet Ether: E.Acetate = 3: 1) to provide Int-9b (38 g, 70% yield)
Step B - Preparation of Com ound Int-9c
lnt-9b lnt-9c
To a solution of Int-9b (38 g, 0.14 mol) in HO Ac (20 mL) was added dropwise an aqueous HBr solution (11.2 g, 0.14 mol). After 10 minutes, the mixture was poured into an aqueous NaHC03 solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, water, dried over Na2S04 and concentrated in vacuo to provide the product Int-9c (30 g, 68% yield).
Step C - Preparation o Compound Int-9e
lnt-9c 9d lnt-9e To a solution of Int-9c (10 g, 32 mmol) and compound 9d (8.4 g, 64 mmol) in DMF (70 mL) was added K2C03 (18 g, 126 mmol). The mixture was allowed to stir at 100 °C in a sealed tube for about 15 hours. The solvent was removed and the residue obtained was purified using column chromatography on silica gel (dichloro methane: MeOH = 20: 1) to provide the product Int-9e. (6 g, 59% yield).
- Preparation of Compound Int-9f
lnt-9e lnt-9f
To a solution Int-9e (4 g, 14.7 mmol) in THF (40 mL) was added NaH (6.6 g, 60 % content, 16.17 mmol) at 0 °C. The mixture was allowed to stir at room temperature for 30 minutes, and then cooled to 0 °C, and SEM-C1 (2.4 g, 14.7 mmol) added dropwise. The resulting mixture was allowed to stir at 0 °C for 2 hours. The solvent was removed in vacuo and the residue obtained was purified using column chromatography on silica gel
(dichloromethane: MeOH =20: 1) to provide the product Int-9f. (2 g, 34 % yield).
- Preparation of Compound Int-9g
lnt-9f lnt-9g To a solution of Int-9f (2 g, 5 mmol) in THF (20 mL) was added dropwise n-
BuLi (2.5 mL, 6.3 mmol) at -78 °C (bath) under N2 protection. The resulting solution was allowed to stir at this temperature for 30 minutes. Then a solution of NBS (0.89 g, 5 mmol) in THF (10 mL) was added dropwise at -78 °C. The mixture was allowed to stir at -78 °C for 1 hour and then aqueous NH4C1 solution was added. The organic layer was separated and concentrated off to provide a crude residue, which was purified using column chromatography on silica gel (petroleum ether :EA=3: 1 as the eluent) to provide Int-9g (400 mg, 16.5% yield).
EXAMPLE 10
Preparation of Intermediate Compound Int-lOf
lnt-10a lnt-10b lnt-10c lnt-10d
Step A - Preparation of Compound Int-lOb
(2lS,,4R)-l-(ieri-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (Int-
10a, 20 g, 85.75 mmol) was dissolved in anhydrous THF and cooled to 0 °C. BH3 THF (1M in THF, 171 mL, 171 mmol) was added via an addition funnel. The solution was gradually warmed up to room temperature and stirred at room temperature for about 15 hours. MeOH was added until no bubbles came out. The solution was concentrated and the product was purified using silica gel chromatography (330g, 0% to 60% of EtOAc in Hexane) to provide Int-10b (15.1 g, 80.3%)
Step B - Preparation of Compound Int- 10c
To a dry 1000 mL round bottom flask was added oxalyl chloride (7.50 mL, 88.9 mmol) and dry dichloromethane (250 mL). After the solution was cooled to -78 °C, DMSO (6.80 mL, 95.8 mmol) in dichloromethane (20 mL) was added dropwise. The solution was allowed to stir at -78 °C for 30 minutes. Int-lOb (15.0 g, 68.4 mmol) in dichloromethane (50 mL) was added via syringe. After the solution was allowed to stir at - 78 °C for 30 minutes, TEA (38.1 mL, 273.6 mmol) was added. The solution was allowed to stir at -78 °C for 30 minutes and at 0 °C for one hour. The solution was diluted with dichloromethane (300 mL) and washed with water, IN HC1, sat NaHC03, and brine. It was dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue obtained was dried in vacuo for 1 hour to provide Int- 10c which was used without further purification. Step C - Preparation of Compound Int-lOd
To a 1000 mL round bottom flask was added Int-lOc and NH3 (7N in MeOH, 150 mL). Glyoxal (15 mL, 40% in water, 131 mmol) was added slowly. The solution was allowed to stir at room temperature for about 15 hours. Additional glyoxal (5 mL, 44 mmol) was added and the reaction was allowed to stir at room temperature for another 24 hours. The solution was concentrated and the product was purified using silica gel chromatography (240g, 0% to 5% of MeOH in dichloromethane, with 0.1% NH3 H20) to provide Int-lOd (8.5 g, 48.7% from 2)
Step D - Preparation of Compound Int-lOe
To a 100 mL round bottom flask was added Int-lOd (8.5 g, 33.3 mmol) and CH3CN (250 mL). More CH3CN was added to form a clear solution. NBS (11.3 g, 63.3 mmol) was added in one portion and the solution was allowed to stir at room temperature for about 15 hours. CH3CN was removed in vacuo and dichloromethane (50 mL) was added with stirring. The solid was filtered and washed with dichloromethane twice. The filtrate was concentrated in vacuo to about 30 mL and filtered again. The filtrate was purified using silica gel chromatography (120g, 20% to 80% of EtOAc in Hexane) to provide Int-lOe
(11.88 g, 86.4%).
Step E - Preparation of Compound Int-lOf
To a 1000 mL round bottom flask was added Int-lOd (11.88 g, 28.76 mmol), sodium sulfite (Na2S03, 36.0 g, 288 mmol), EtOH (270 mL) and water (130 mL). The solution was allowed to stir at reflux for about 15 hours. More Na2S03 (10 g, 79 mmol) was added and the solution was allowed to stir at reflux for another 24 hours. After cooling down, the solid was filtered and washed with EtOAc three times. The filtrate was concentrated and the residue obtained was dissolved in a mixture of EtOAc (300 mL) and water (200 mL). The organic layer was separated and washed with brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The product was purified using silica gel
chromatography (240g, 0% to 33% of EtOAc in Hexane) to provide Int-lOf (5.12 g, 53.3%).
EXAMPLE 11
Preparation of Intermediate Compound Int-llc
- Preparation of Compound Int-llb
Int-lla Int-llb
The aldehyde Int-lla was prepared from the commercially available alcohol using the method described in Example 10.
A flask was charged with aldehyde Int-lla (82g, 0.35 mol) and a 2.33 N ammonia/MeOH solution was added with good stirring (600 mL, 4.0 eq., prepared from 200ml 7N ammonia/MeOH diluted with 400 ml MeOH). The reaction was then heated to 35 °C and allowed to stir at this temperature for 2 hours, after which time a solution of 40 wt% glyoxal in water (80 mL, 2.0 eq.) was added dropwise over about 15 minutes. After stirring for an additional 2 hours, a solution of 7N ammonia/MeOH (100 mL, 2.0 eq.) was added and the reaction was allowed to stir at 35 °C for 1 hour. Additional glyoxal (40 mL, 1.0 eq.) was then added dropwise over 5 minutes and the resulting reaction was allowed to stir at 35 °C for 1 hour. The reaction mixture was then allowed to cool room temperature and stir for about 15 hours. Additional 7N ammonia/MeOH (50 mL, 1.0 eq.) was then added and the reaction reheated to 35 °C and allowed to stir at this temperature for 1 hour. An additional amount of glyoxal (20 mL, 0.5 eq.) was then added and the resulting reaction was allowed to stir at 35 °C for 1 hour, then the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue obtained was diluted with dichloro methane and water (2 L, 1 : 1). The organic layer was separated, washed with 1L of water, then brine and dried (MgSC^), filtered and concentrated in vacuo. The brown foam residue obtained was further purified by being passed through a short silica gel column to provide Int-llb (60g, 62%).
Step B - Preparation of Compound Int-llc
Int-llc was prepared from Int-llb using the method described in Example 10. Intermediate compounds Int-lld, Int-lle and Int-llf can be prepared using the methods described in Example 10 and Example 1 1.
lnt-11e lnt-11f
EXAMPLE 12
Preparation of Intermediate Compound Int-12i
Step A - Preparation of Compound Int-llb
lnt-12a lnt-12b
To a solution of compound Int-12a (60 g, 0.24 mol) in dry THF (1 L) stirred at -78 °C was added lithium hexamethyldisilazide (82 g, 0.49 mol, 1 M in THF). After the reaction mixture had been stirred at -78 °C for 1 hour, the iodomethane (66 g, 0.46 mol) dissolved in dry THF (100 mL) was added at -78 °C and the mixture was allowed to stir for 15 minutes at this temperature and 2 hours at 25 °C. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with dichloro methane (3 x 300 mL). The combined organic phases were dried over MgSC^, filtered, and concentrated in vacuo to dryness. The products were purified using silica gel chromatography to provide compound Int-12b (18.3 g, 27% yield). 1H NMR δ: 4.38-4.34 (m, 1 H), 4.08-4.05 (m, 2 H), 2.09-2.03 (m, 1 H), 1.77-1.73 (m, 1 H), 1.35 (s, 9 H), 1.12 (t, / = 8 Hz, 3 H), 1.06 (s, 6 H).
Step B - Preparation of Compound Int-12c
lnt-12b lnt-12c
To a solution of compound Int-12b (18.3 g, 60 mmol) in dichloromethane (150 mL) was added TFA (15 mL) and the mixture stirred at room temperature for 30 minutes. The solvent was removed to provide compound Int-12c (11.2 g, 100% yield). Step C - Preparation of Compound Int-12d
lnt-12c lnt-12d
A suspension of L1AIH4 (16.2 g, 0.44 mol) and compound Int-12c (11.2 g, 54.8 mmol) in THF (200 mL) was allowed to stir under reflux for 8 hours. After successive addition of 17 mL of water, 17 mL of 10% aq NaOH, and 51 mL of water, and filtration, the filtrate was concentrated in vacuo to provide compound Int-12d (6.7 g, 94%> yield).
Step D - Preparation of Compound Int-12e
lnt-12d lnt-12e
Compound Int-12D was dissolved in THF and Et3N, (Boc)20 were added.
The mixture was allowed to stir at room temperature for 2 hours and concentrated in vacuo. The residue obtained was purified using chromatography to provide Int-12e (14 g, 100%) yield). - Preparation of Compound Int-12f
B
Int-12e lnt-12f
To a solution of compound Int-12e (14g, 65.4 mmol) in dichloromethane was added Dess-Martin reagent (41.6 g, 98.1 mol). After stirring at room temperature for about 15 hours, the solvent was removed and the residue obtained was purified using silica gel chromatography to provide compound Int-12f (7 g, 47% yield). 1H NMR δ: 9.40 (s, 1 H), 4.05-4.03 (m, 1 H), 3.14-3.11 (m, 2 H), 1.83-1.79 (m, 1 H), 1.66-1.63 (m, 1 H), 1.36 (s, 9 H), 1.02 (s, 6 H).
Step F - Preparation of Com ound Int-12g
lnt-12f lnt-12g
Glyoxal (1.75 mL of 40% in water) was added dropwise over 11 minutes to a solution of NH4OH (26 mL) and compound Int-12f (6.1 g, 28.8 mmol) in methanol and stirred at ambient temperature for 19 hours. The volatile component was removed in vacuo and the residue obtained was purified using a flash chromatography on silica gel to provide compound Int-12g (3 g, 39% yield).
MS (ESI) m/z (M+H)+: 266.
Step G - Preparation of Compound Int-12h
A mixture of compound Int-12g (2.2 g, 8.3 mmol), N-bromosuccinimide (2.66 g, 14.9 mmol) in anhydrous THF (80 mL) was heated at reflux for about 15 hours. After cooling to room temperature, the solids are removed by filtration and the filtrate was concentrated in vacuo and the residue obtained was purified using chromatography to provide compound Int-12h (2.0 g, 57% yield). 1H NMR (J000120117 H10170-003-1 CDC13 varian 400 MHz) δ: 11.03 (s, 1 H), 4.79 (t, / = 8 Hz, 1 H), 3.25 (t, J = 12 Hz, 1 H), 2.96 (t, / = 12 Hz, 1 H), 2.58-2.53 (m, 1 H), 2.95-1.90 (m, 1 H), 1.34 (s, 9 H), 1.05 (s, 3 H), 0.99 (s, 3 H). MS (ESI) m/z (M+H)+: 422.
- Preparation of Compound Int-12i
lnt-12h lnt-12i
To the solution of compound Int-12h (1.9 g, 4.5 mmol) in H20/EtOH (40 mL /20 mL) was added Na2S03 (5.6 g, 4.5 mmol) and the mixture was allowed to stir at room temperature for about 15 hours. The reaction mixture was concentrated in vacuo and the residue obtained was dissolved in ethyl acetate, washed with brine, dried over MgSC^, filtered, and concentrated in vacuo. The residue obtained was purified using chromatography on silica gel to provide compound Int-12i (0.75 g, 48% yield). 1H NMR δ: 6.92 (s, 1 H), 4.71-4.67 (m, 1 H), 3.26-3.21 (m, 2 H), 2.01-1.96 (m, 1 H), 1.78-1.72 (m, 1 H), 1.13 (s, 9 H), 1.00 (s, 3 H).
EXAMPLE 13
Preparation of Intermediate Compounds Int-13d and Int-13e
lnt-13b lnt-13c lnt-13c" lnt-13d
Step A - Preparation of Compound Int— 13c
A 5 L- 3 necked round bottomed flask, equipped with a mechanical stirrer, temperature probe, addition funnel and N2 inlet, was charged with the Schollkopf chiral auxiliary-(Int-13a, 200 g, 1.09 mol, 1.0 eq), bis(chloromethyl) dimethylsilane (Int-13b, 256 g, 1.63 mol, 1.5 eq), and THF (2 L, Aldrich anhydrous). The flask was cooled in a dry ice/ 2- propanol bath until the internal temperature reached -75 °C. n-Butyllithium (Aldrich 2.5 M in hexanes , 478 mL, 1.19 mol, 1.09 eq) was added via a dropping funnel over 1 hour while maintaining the internal reaction temperature between -67 °C and -76 °C. The resulting orange-red solution was allowed to gradually warm to room temperature for about 15 hours. The reaction mixture was then re-cooled to 0 °C and quenched with 500 mL of water.
Diethyl ether (2L) was added and the layers were separated. The aqueous layer was extracted with 1 L of diethyl ether. The combined organic layers was washed with water and brine, dried with MgSC^, filtered, and concentrated in vacuo to dryness, giving 480 g of orange oil. This material was left in vacuo for about 15 hours to provide 420 g of oil. The crude product was split into two batches and purified via silica gel chromatography on a 1.6 kg flash column. The column was eluted with gradient of 0-4% Et20 in hexanes. The product fractions were concentrated in vacuo at a bath temperature at or below 40 °C giving 190 grams of Int-13c-(60%yield).
Step B - Preparation of Compound Int-13d
A 5 L, 3 -necked round bottomed flask equipped with a mechanical stirrer, addition funnel, temperature probe, external water bath and N2 inlet was charged with compound Int-13c (196 g, 0.643 mol, 1.0 eq) and methanol (1.5 L). Aqueous HC1 (500 mL of 10% by volume) was added at room temperature over 30 minutes, with a mild exotherm observed. The temperature increased to 37 °C then dropped back down. The reaction mixture was allowed to stir at room temperature for 3 hours and was monitored by TLC and LCMS. The reaction mixture was then concentrated in vacuo to an oil. Additional methanol (3 x 200 mL) was added and the reaction mixture was concentrated in vacuo to dryness again. The resulting crude product was dried under house vacuum for about 15 hours. The crude product was then dissolved in CH2C12 (750 mL) and Et20 (1250 mL) and sodium iodide (96.4 g, 0.643 mol, 1.0 eq) was added. Diisopropylethylamine (336 mL, 1.929 mol, 3.0 eq) was added slowly over 25 minutes with stirring, causing the temperature to increase to 35 °C then decrease to room temperature again. The reaction mixture was allowed to stir at room temperature for 2 hours, after which time the MS of an aliquot indicated consumption of the starting material. The reaction mixture was allowed to stir for an additional 2 hours and then Boc-anhydride (281 g, 1.286 mol, 2.0 eq) was added. The reaction mixture was then allowed to stir at room temperature. After two days, the reaction mixture was diluted with EtOAc (2 L) and water (1 L), and he layers were separated. The aqueous phase was extracted with 500 mL of EtOAc. The combined organic layers were washed with water (500 mL), and brine (500 mL), dried with MgS04, filtered, and concentrated in vacuo to a yellow oil (380 g). The crude product was split into two 180 g portions for convenience and each portion was purified via flash silica gel chromatography. Column conditions for a 180 g portion of crude product are as follows. The 180 gram sample of crude product was loaded onto a 191 g Si02 cartridge and purified on a 1.5 kg Si02 column. The column was eluted using a 0%-20% EtOAc/hexanes gradient as the mobile phase to provide 52 grams of pure Int-13d and additional fractions of Int-13d that contained a small amount of a Boc-valine impurity. The impure fractions from the two columns were recombined and re-purified. After
chromatography, compound Int-13d was obtained as an oil which solidified to a white solid on standing (128 g, 65 % yield over the three steps.)
Step C - Preparation of Com ound Int-13e
lnt-13d lnt-13e
A solution of Int-13d (8.5 g, 31.1 mmol) in methanol (100 mL) and 1.0 M aqueous KOH solution (48 mL, 48 mmol) was allowed to stir at room temperature for about 15 hours. The reaction was then neutralized with 48 ml of 1.0 M aqueous HCl solution to pH ~5, and partially concentrated in vacuo. The aqueous layer was then extracted twice with dichloromethane (2 x 100 mL). The combined organic solutions were concentrated in vacuo to provide Int-13e as a gel (7.74 g, 96%).
Note: Because of poor UV absorbance, the above reactions were monitored by TLC using Hanessian's stain. To prepare the visualization stain, combine 450 mL of H20, 25 g ammonium molybdate, 5 g of eerie sulfate, and 50 mL of cone. HCl or cone. H2S04.
EXAMPLE 14
Preparation of Intermediate Compound Int-14d
lnt-14c ' lnt-14d
Step A - Preparation of Compound Int-14a
To a mixture of carboxylic acid Int-13e (20 g, 77 mmol) in THF (400 mL) at 0 °C was added 1M BH3 in THF ( 0.17 L) via addition funnel at 0 °C. The mixture was allowed to warm to room temperature and stir for about 15 hours. The reaction was carefully quenched by addition of MeOH (~ 75 mL) until bubbling ceased. The reaction mixture was concentrated in vacuo to dryness whereupon the residue obtained was partitioned between EtOAc and H20. The layers were separated and the aqueous layer was extracted with EtOAc (2x). The organic layers were combined, washed with brine, dried (Na2S04), and
concentrated in vacuo to provide Int-14d (18 g, 99%) as a clear oil, which was used without further purification. MS (ESI) m/e (M+H+Na) +: 268.
Step B - Preparation of Compound Int-14b
To a dry 2-necked flask equipped with a stir bar was added oxalyl chloride
(8.2 mL, 96 mmol) and CH2C12 (280 mL). The solution was cooled to -78 °C whereupon a solution of DMSO (7.4 mL, 0.10 mol) in CH2C12 (22 mL) was added and the mixture was allowed to stir for 30 minutes at -78 °C. A solution of alcohol Int-14a (18 g, 74 mmol) from Step A in CH2C12 (60 mL) was added dropwise via addition funnel over 30 minutes. The resulting solution was allowed to stir for an additional 30 minutes at -78 °C whereupon Et3N (42 mL, 0.30 mol) was added dropwise. The mixture was allowed to stir for 30 minutes at - 78 °C, warmed to 0 °C, and allowed to stir for an additional 1.5 hours. The mixture was diluted with CH2C12 (400 mL) and was transferred to a separatory funnel. The organic layer was washed with sat. aq NH4C1 (2 x 100 mL) and brine (2 x 100 mL). The organic layer was dried (Na2S04), filtered, and concentrated in vacuo to provide Int-14b,18 g (99%) as a clear oil, which was used without further purification.
Step C - Preparation of Compound Int-14c
To a round bottom flask charged with aldehyde Int-14b (18 g, 74 mmol) from Step B was added a 7N NH3 in MeOH solution (28 mL, 0.19 mol) in MeOH (37 mL) at room temperature. The mixture was allowed to stir for 30 minutes at room temperature whereupon a solution of glyoxal (14 g, 96 mmol) was added over 5 minutes. The resulting solution was allowed to stir for 12 hours at room temperature and was concentrated in vacuo. The residue obtained was purified using column chromatography using a gradient of 100% CH2CI2 to 97.5% CH2Cl2/2.5% MeOH to provide Int-14c, 9.9 g (48%) as yellow oil. MS (ESI) m/e (M+H) +: 282.
Step D - Preparation of Compound Int-14d
To a solution of imidazole Int-14c (1.0 g, 3.6 mmol) from Step C in CH2C12 (5 mL) at 0 °C, was added NBS (0.44 g, 2.5 mmol) in CH2C12 (10 mL) dropwise via addition funnel. The resulting mixture was allowed to stir for 90 minutes at 0 °C whereupon the mixture was concentrated in vacuo to dryness. The crude residue obtained was partitioned between CHCI3 (10 mL) and water (3 mL) and the layers were separated. The organic layer was washed with water (3 x 3 mL), dried (Na2S04), filtered, and concentrated in vacuo. The residue obtained was purified using column chromatography (80g) using a gradient of 100%) hexanesto 65% hexanes/35% EtOAc to provide Int-14d, (0.35 g, 27%) as a white solid. MS (ESI) m/e (M+H) +: 360/362.
EXAMPLE 15
Preparation of Intermediate Compound Int-15c
Int-15c
- Preparation of Compound Int-1
Int-15a To a solution of dichlorozirconocene (Cp2ZrCl2) (4.2 g, 14.2 mmol) in 40 mL THF at -78 °C was added n-BuLi (1.6 M in hexane, 18 mL, 28.4 mmol). The resulting reaction was allowed to stir for 1 hour, then diphenyldiallylsilane (2 g, 14.2 mmol) in 17 mL of THF was added at -78 °C . The reaction was allowed to stir for 1 hour at -78 °C and for 18 hours at 25 °C. Iodine (9 g, 35.5 mmol) in 20 mL THF was then added at -78 °C and the mixture was allowed to stir for 1 hour. The reaction was quenched with 10% aqueous H2SO4 and the organic phase was extracted by ether. The organic solution was washed with saturated aqueous NaHC03 solution, brine solution, and dried (Na2S04). After filtration, the filtrate was concentrated in vacuo and the residue obtained was purified using ISCO 120 g column (hexane) to provide Compound Int-15a, 2.75 g (49%). 1H NMR (CDC13) δ 3.44 (dd, J = 2.2, 10.0 Hz, 2H), 3.33 (dd, / = 4.7, 10.0 Hz, 2H), 1.20 (m, 2H), 0.93 (dd, / = 5.9, 14.7 Hz, 2H), 0.63 (dd, / = 11.1, 14.2 Hz, 2H), 0.19 (s, 6H).
- Preparation of Compound Int-
Int-15b
To a solution of (2R)-(-)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (0.61 g, 4.36 mmol) in THF (8 mL) was added n-BuLi (2.5 M in hexane, 1.8 mL, 4.58 mmol) at -78 °C. After allowed to stir for 0.3 hours, Compound Int-15a (2.75 g, 6.98 mmol) in 2 mL of THF was added and the mixture was allowed to stir at the temperature for 4 hours.
The reaction was quenched by saturated aqueous NH4C1 solution and the organic layers were extracted with EtOAc. The combined organic solution was washed with brine solution, dried (Na2S04), and concentrated in vacuo. The residue obtained was purified using ISCO 40 g column (gradient from 0%> to 2.5% ether in hexane) to provide Compound Int-15b, 783 mg (44%). 1H NMR (CDC13) δ 4.05 (m, 1H), 3.96 (t, / = 3.4 Hz, 1H), 3.72 (s, 3H), 3.71 (s, 3H), 3.49 (dd, J = 2,8, 0.4 Hz, 1H), 3.26 (dd, / = 6, 9.4 Hz, 1H), 2.30 (m, 1H), 1.96 (m, 1H), 1.60 (m, 2H), 1.37-1.17 (m, 3H), 1.08 (d, / = 6.9 Hz, 3H), 0.99-0.86 (m, 2H), 0.72 (d, / = 6.6 Hz, 3H), 0.49 (dd, / = 11.0, 14.4 Hz, 1H), 0.35 (dd, / = 11.0, 14.2 Hz, 1H), 0.16 (s, 6H). Step C - Preparation of Compound Int-15c To a solution of Compound Int-15b (780 mg, 1.92 mmol) in MeOH (9 mL) was added 10% aqueous HCl (3 mL) at 0 °C and the mixture was allowed to stir at 25 °C for 18 hours. The mixture was concentrated in vacuo and the residue obtained was
co concentrated in vacuo with MeOH twice. The resulting white foam was dissolved in ether (6 mL) and CH2CI2 (9 mL), and diisopropylethylamine (1 mL, 5.7 mmol) was added. After stirred at 25 °C for 18 hours, di-t-butyl dicarbonate (922 mg, 4.22 mmol) was added and the resulting mixture was allowed to stir at 25 °C for 2 days. The mixture was added to cold water and the organic layers were extracted with EtOAc. The combined organic solution was washed with brine solution, dried (Na2S04), and concentrated in vacuo. Then the residue obtained was dissolved in MeOH (8 mL) and treated with aqueous 1 M KOH solution (3.3 mL, 3.3 mmol). After stirred at 0 °C to 25 °C, the reaction mixture was acidified with 10% aqueous HCl and the organic layers were extracted with CH2C12. The combined organic solution was washed with brine solution, dried (Na2S04), and concentrated in vacuo to provide Compound Int-15c, which was used without further purification.
EXAMPLE 16
Pre aration of Intermediate Compound Int-16e
lnt-16d lnt-16e Step A - Preparation of Compound Int-16b
To a 1000 mL flame dried flask was added 1, 1-dichlorosilolane (Int-16a, 28.09 g, 181.1 mmol), bromochloromethane (23.5 mL, 362.2 mmol), and anhydrous THF (400 mL). The solution was cooled to -70 °C, then w-BuLi (2.5M in hexane, 145 mL, 362 mmol) was added slowly over a period of 1 hour. The resulting reaction was allowed to stir at -70 to -60 °C for 20 minutes, then was allowed to warm to room temperature over 1 hour. Saturated NH4C1 solution (200 mL) and Et20 (200 mL) were then added and the organic layer was separated and the aqueous layer was extracted with Et20 (100 mL) twice. The organic layers were combined, washed with brine, dried over Na2S04, filtered and
concentrated in vacuo. The residue obtained was purified using Si02 chromatography (240 g, eluted with hexane) to provide compound Int-16b (17.2 g, 51.9%). Step B - Preparation of Compound Int-16c
To a 500 mL flame dried flask was added (R)-2-isopropyl-3, 6-dimethoxy-2,5- dihydropyrazine (10.0 g, 54.3 mmol) and anhydrous THF (200 mL). The solution was cooled to -78 °C. w-BuLi (2.5M in hexane, 24.0 mL, 59.7 mmol) was added dropwise. After the solution was allowed to stir at -78 °C for 30 minutes, compound Int-16b (in 5 mL anhydrous THF) was added dropwise. After the solution was allowed to stir at -78 °C for 1 hour, it was allowed to warm up to room temperature in two hours. Water (100 mL) and Et20 (150 mL) were added. The organic layer was separated and the aqueous layer was extracted with Et20 (100 mL) twice. The organic layers were combined, washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue obtained was purified using Si02
chromatography (40 g, eluted with Et20 in Hexane: 0%> to 3%) to provide compound Int-16c (10.43 g, 58.0%).
Step C - Preparation of Compound Int-16d
To a 500 mL flask was added compound Int-16c (11.5 g, 34.8 mmol) and MeOH (80 mL). 10% HC1 (20 mL) was added. The solution was allowed to stir at room temperature for 5 hours and concentrated in vacuo. The residue obtained was dissolved in 20 mL MeOH and concentrated again to remove water and HC1. This process was repeated three times. The residue obtained was dissolved in dichloromethane (50 mL) and Et20 (70 mL). DIPEA (15.4 mL, 86.9 mmol) and Nal (5.2 g, 34.75 mmol) were added. The solution was allowed to stir at room temperature for about 15 hours. Di-tert-butyl dicarbonate (18.9 g, 86.9 mmol) was added. The solution was allowed to stir at room temperature for 4 hours. Water (100 mL) and EtOAc (100 mL) were added. The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL) twice. The organic layers were combined and washed with brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The product was purified using Si02 chromatography (220g, Hexane/EtOAC: 0% to 20%) to provide compound Int-16d (7.9 g, 75.9%).
Step D - Preparation of Compound Int-16e Compound Int-16d (7.9 g, 26.4 mmol) was dissolved in MeOH (100 mL) and cooled to 0 °C. KOH (1M in water, 39.6 mL, 39.6 mmol) was added. The solution was allowed to stir at 0 °C for 2 hours, and then at room temperature for 3 hours. HCl (2 N, 20 mL) was added, then additional HCl was added slowly to adjust the solution to pH 4. The acidified solution was concentrated in vacuo and to the residue obtained was added water (150 mL) and EtOAc (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue obtained was dried in vacuo for 48 hours to provide compound Int-16e (7.45 g, 99%), which was used without further purification.
EXAMPLE 17
Preparation of Intermediate Compound Int-17i
lnt-17i
Step A - Preparation of Compound Int-17b
lnt-17a lnt-17b
To a 500 mL flask was added Int-17a (25.0 g, 130 mmol), dry
dichloromethane (250 mL) and DIPEA (25.37 g, 195 mmol). The solution was cooled to 0 °C and acetyl chloride (13.27g, 169 mmol, in 30 mL dry dichloromethane) was added dropwise. The resulting reaction was allowed to stir at 0 °C for one hour and then at room temperature for about 15 hours. The solution was diluted with EtOAc and washed with water. The organic phase was dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The product was purified using silica gel chromatography (330g, 0% to 50% of EtOAc in Hexane) to provide Int-17b (22.58 g, 74.5%)
- Preparation of Compound lnt-17c
lnt-17b lnt-17c
To a 500 mL flask was added Int-17b (21.45 g, 92.05 mmol) and dry dichloromethane (200 mL). It was cooled to 0 °C and aluminum trichloride (A1C13, 36.82 g, 276.2 mmol) was added in portions. After the solution was allowed to stir at 0 °C for 30 minutes, it was concentrated in vacuo. The semi-solid residue obtained was heated at 140 °C for three hours. After it was cooled to 80 °C, water (10 mL) was added dropwise. It was then cooled to 0 °C and EtOAc (300 mL) and water (200 mL) were added. The suspension was allowed to stir at 0 °C until the entire solid dissolved. More EtOAc was added and the organic layer was separated. The organic layer was washed with water, dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The product was purified using silica gel chromatography (330g, 0% to 10% of EtOAc in Hexane)to provide Int-17c (18.76 g, 87%).
Step C - Pre aration of Compound Int-17h
lnt-17h
A mixture of Int-17d (prepared using the method described above for the synthesis of Compound Int-17c, 4.2 g, 20 mmol) and 4-bromophenyl hydrazine
hydrochloride (4.4 g, 20 mmol) in AcOH and EtOH (1 : 10, 100 mL) was heated to reflux for 6 hours. The solvent was removed in vacuo to provide a solid, Int-17h, which was used without further purification (9.2 g crude). MS (ESI) m / e (M+H+): 383.
Step D - Preparation of Compound Int-17i
lnt-17h lnt-17i A mixture of Int-17h (9.2 g) in PPA was heated to 80°C for 2 hours. After cooling to room temperature, the mixture was poured into ice water. The resulting solution was extracted with dichloromethane. The combined organic phases were washed with brine, dried over Na2S04, and concentrated in vacuo. The residue obtained was purified using column chromatographyto provide Int-17i (4.8 g). MS (ESI) m l e (M+H+): 368.
EXAMPLE 18
Preparation of Compound 1
A solution of Int-17i (2.02 g, 5.5 mmol) and methoxyacetaldehyde (2 g, 16.5 mmol) in 1,4-dioxane was placed in a sealed tube, heated to 140 °C and allowed to stir at this temperature for 1 hour. The reaction mixture was then cooled to room temperature, concentrated in vacuo, and the residue obtained was purified using column chromatography on silica to provide Int-18a (1.5 g, 62.3 % yield). MS (ESI) m/z (M+H)+: 423.10.
- Preparation of Compound Int-18b
A suspension of compound Int-18a (844 mg, 2 mmol), bis(pincolato)diboron (2 mmol), Pd(dppf)2Cl2 (200 mg), Na2C03 (3 mmol) and in THF/H20 (10: 1, 33 mL) was refluxed at 75 °C for about 15 hours under N2 protection. After that, the mixture was filtered, the filtrate was washed with water (50 mL) and extracted with ethyl acetate (100 mL), washed with brine and dried over anhydrous sodium sulfate. After being concentrated in vacuo, the residue obtained was purified using column chromatography (petroleum ether / ethyl acetate = 8: 1→5: 1) to provide compound Int-18b. (84.8 % yield). MS (ESI) m/z (M+H)+: 517.
- Preparation of Compound Int-18c
A suspension of Int-7d (1.58 g, 5.00 mmol), Int-18b (1.03 g, 2.00 mmol), Pd(dppf)Cl2 (146 mg, 0.2 mmol), and Na2C03 (636 mg, 6 mmol) were refluxed in THF/H20 (10: 1, 33 mL) for about 15 hours under N2 protection. The mixture was cooled, filtered, and the filtrate was washed with water (50 mL) then extracted with EtOAc (100 mL), washed with brine and dried over anhydrous sodium sulfate. The solution was concentrated and the residue obtained was purified using column chromatography (petroleum ether/ethyl acetate = 8: 1→5: 1) to provide Int-18c (61.3 % yield). MS (ESI) m/z (M+H)+: 736.
- Preparation of Compound Int-18d
lnt-18c lnt-18d
Int-18c (1.2 mmol) was diluted with 3M HCl/CH3OH (20 mL) and the resulting reaction was allowed to stir at room temperature for 2 to 3 hours. The reaction mixture was concentrated in vacuo to provide Compound Int-18d, which was used dwithout further purification. (95 % yield). MS (ESI) m e (M+H+): 536.
Step E - Preparation of Compounds 1A and IB
To a solution of compound Int-18d (536 mg, 1.0 mmol), N-Moc-L-Val-OH (350 mg, 2.0 mmol) and DIPEA/NMM (0.2 mL) in DMF (3 mL) was added HATU/BOP (2.2 mmol). The resulting reaction was allowed to stir at room temperature for 5 hours, then was concentrated in vacuo. The residue obtained was purified using chiral HPLC to provide Compounds 1A and IB.
1A: (0.052 g, 23 % yield). 1H NMR (MeOD) δ: 7.95-7.90 (m, 2 H), 7.85 (s, 1 H), 7.71 (s, 1 H), 7.59-7.55 (m, 2 H), 7.52-7.49 (m, 2 H), 5.24-5.21 (m, 2 H), 5.15-5.13 (m, 1 H), 4.22-4.20 (m, 2 H), 4.11-4.09 (m, 2 H), 3.88-3.82 (m, 2 H), 3.65 (s, 3 H), 3.64 (s, 6 H), 3.46-3.40 (m, 2 H), 2.58-2.55 (m, 2 H), 2.26-2.01 (m, 8 H), 0.92-0.87 (m, 12 H). MS (ESI) m/z (M+H)+: 850.
IB: (0.064 g, 32 % yield). 1H NMR (MeOD) δ: 7.98-7.95 (m, 2 H), 7.88 (s, 1 H), 7.76 (s, 1 H), 7.64-7.62 (m, 2 H), 7.60-7.53 (m, 2 H), 5.28-5.23 (m, 2 H), 5.19-5.16 (m, 1 H), 4.25-4.22 (m, 2 H), 4.12-4.09 (m, 2 H), 3.91-3.85 (m, 2 H), 3.69 (s, 3 H), 3.66 (s, 6 H), 3.50-3.45 (m, 2 H), 2.59-2.56 (m, 2 H), 2.30-2.04 (m, 8 H), 0.96-0.93 (m, 12 H). MS (ESI) m/z (M+H)+: 850.
The following compounds of the present invention were made using the method described above in Example 18 and substituting the appropriate reactants and reagents.
EXAMPLE 19
Preparation of Compound 15
lnt-19a To a solution of compound Int-17i (1.1 g, 3 mmol) and 4-chlorobenzaldehyde (1.0 g, 7.5 mmol) in toluene (10 mL), was added TosCl (57 g, 0.3 mmol). The reaction was then subjected to microwave radiation at 150 °C for 1 hour, and concentrated in vacuo. The residue obtained was purified using column chromatography over silica gel to provide Int- 19a (0.63 g, 43 % yield). 1H NMR (DMSO): δ 12.21 (s, 1 H), 1.69 (d, / = 8.0 Hz, 1 H), 7.44 - 7.51 (m, 5 H), 7.29 - 7.33 (m, 3 H), 7.22 (s, 1 H), 6.99 (s, 1 H). MS (ESI) m / e (M+H+): 490.
Step B - Preparation of Compound Int-19b and Int-19b '
lnt-19b'
A solution of compound Int- 19a (1.9 mmol, 3.9 mmol) in THF (10 mL) was added NaH (200 mg, 60 % in material oil, 5.0 mmol) in an ice-water bath. After strring for 15 min, Mel (720 mg, 5.0 mmol) was added dropwise. The mixture was allowed to stir at room temperature for 30 minutes. Water (2 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated in vacuo and the residue obtained was purified through a silica gel column to provide a racemate from which two isomers were separated by Chiral SFC (Int-19b, 510 mg, 26 % yield; Int-19b\ 540 mg, 27 % yield ).
Int-19b: 1H NMR (CDC13): δ 7.56 (d, / = 8.0 Hz, 1 H), 7.33 - 7.35 (m, 4 H), 7.25 - 7.29 (m, 2 H), 7.17 - 7.20 (m, 2 H), 7.14 (s, 1 H), 6.58 (s, 1 H), 4.07 (s, 3 H). MS (ESI) m / e (M+H+): 504.
Int-19b': 1H NMR (CDC13): δ 7.56 (d, / = 8.0 Hz, 1 H), 7.33 - 7.35 (m, 4 H), 7.25 - 7.29 (m, 2 H), 7.17 - 7.20 (m, 2 H), 7.14 (s, 1 H), 6.58 (s, 1 H), 4.07 (s, 3 H). MS (ESI) m / e (M+H+): 504.
Step C - Preparation of Compounds Int-19c and Int-19c '
Int-19c and Int-19c' were made using the method described in Example 18, step B (Int-19c, 390 mg, 64 % yield; Int-19c\ 420 mg, 61 % yield ).
Int-19c: 1H NMR (CDC13): δ 7.74 (s, 1 H), 7.69 (d, / = 8.0 Hz, 1 H), 7.64 (d, / = 8.0 Hz, 1 H), 7.36 - 7.42 (m, 3 H), 7.24 - 7.27 (m, 2 H), 7.18 (d, / = 8.0 Hz, 2 H), 6.68 (s, 1 H), 4.07 (s 3 H), 1.32 (s, 12 H). MS (ESI) m l e (M+H+): 598.
Int-19c': 1H NMR (CDC13): δ 7.74 (s, 1 H), 7.69 (d, / = 8.0 Hz, 1 H), 7.64 (d, / = 8.0 Hz, 1 H), 7.36 - 7.42 (m, 3 H), 7.24 - 7.27 (m, 2 H), 7.18 (d, / = 8.0 Hz, 2 H), 6.68 (s, 1 H), 4.07 (s 3 H), 1.32 (s, 12 H). MS (ESI) m l e (M+H+): 598.
Compounds Int-19d and Int-19d' were prepared from Int-19c and Int-19c' respectively, using the method described in Example 18, step C (Int-19d, 230 mg, 51 % yield; Int-19d\ 150 mg, 35 % yield ). Compounds Int-19d and Int-19d': MS (ESI) m l e (M+H+): 816.
Step E - Preparation of Compounds Int-19e and Int-19e '
Compound Int-19e and Int-19e' was prepared from Int-19d and Int-19d', using the method described in Example 18, Step D (Int-19e, 172 mg, 87 % yield; Int-19e', 160 mg, 85% yield ). Compounds Int-19e and Int-19e' : MS (ESI) m / e (M+H+): 616.
Step F- Preparation of Compounds 15 A and 15B
Compounds 15A and 15B were made using the method described in Example 18, step E (Compound 15A - 40 mg, 17 % yield; Compound 15B - 70 mg, 31 %).
15A: 1H NMR (MeOD): δ 7.89 (d, / = 8.4 Hz, 1 H), 7.82 (s, 1 H), 7.62 - 7.66 (m, 2 H), 7.53
- 7.55 (m, 2 H), 7.27 - 7.34 (m, 4 H), 6.80 (s, 1 H), 5.19 (bs, 1 H), 4.17 - 4.02 (m, 4 H), 4.06 (bs, 2 H), 3.84 (bs, 2 H), 3.63 (s, 6 H), 2.52 (bs, 2 H), 2.02 - 2.23 (m, 8 H), 0.85 - 0.90 (m, 12 H). MS (ESI) m / e (M+H+): 930.
15B: 1H NMR (MeOD): δ 7.95 (d, / = 8.4 Hz, 1 H), 7.81 (s, 1 H), 7.60 - 7.65 (m, 2 H), 7.49
- 7.53 (m, 2 H), 7.36 - 7.38 (m, 1 H), 7.26 - 7.33 (m, 4 H), 6.80 (s,l H), 5.17 - 5.19 (m, 2 H), 4.15 - 4.20 (m, 4 H), 4.06 (bs, 2 H), 3.83 (bs, 2 H), 3.63 (bs, 6 H), 2.52 (bs, 2 H), 2.00 - 2.24 (m, 8 H), 0.82 - 0.97 (m, 12 H). MS (ESI) m l e (M+H+): 930.
The following compound of the present invention was made using the method described above in Example 19 and substituting the appropriate reactants and/or reagents.
EXAMPLE 20
Preparation of Compound 16
5ί Λ - Preparation of Compound Int-20a
lnt-20a
6-Methoxy-l-tetralone (4.7 g) was dissolved in diethyl ether, and to the resulting solution was added dropwise Br2 (4.7 g, 29.3 mmol). The resulting reaction was allowed to stir for 2 hours at room temperature, then the reaction mixture was washed with 10% Na2S203, brine, dried over Na2S04, filtered and concentrated in vacuo to provide Int- 20a which was used without further purification. MS (ESI) m/e (M+H) +: 256.
Step B - Preparation of Compound Int-20b
lnt-20a lnt-20b
A solution of Int-20a (40 g, 0.163 mol) in THF (100 mL) was cooled to - 78 °C, and to the cooled solution was added LiHMDS (0.265 M in THF, 325 mL). The reaction was allowed to stir for 15 minutes at -78 °C , then a solution of acetic anhydride (50 g, 0.49 mol) in THF (100 mL) was added. The reaction was allowed to stir at 0 °C for 30 minutes, then the reaction mixture was diluted with ethyl ether. The resulting solution was washed with HCl (1 N), saturated NaHC03, water and brine, then dried over MgS04, filtered and concentrated in vacuo to provide Compound Int-20b (41.5 g) as a dark oil that eventually solidified on standing. 1H-NMR (MeOD) δ: 7.00 (d, 1 H), 6.71 - 6.88 (m, 2 H), 3.79 (s, 3 H), 3.00 - 2.84 (m, 4 H), 2.34 (s, 3 H).
- Preparation of Compound Int-20c
A suspension of Int-20b (29.7 g, 100 mmol), 2,5-dimethoxyphenylboronic acid (18.2 g, 100 mmol), Pd(PPh3)4 (5.78 g, 5 mmol), Na2C03 (15.9 g, 150 mmol) and in THF/H20 (10: 1, 1.5 L) was heated to reflux and allowed to stir at this temperature for about 15 hours under N2 atmosphere. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with water (2 x 500 mL) and extracted with EtOAc (2 x 500 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue obtained was purified using column chromatography (petroleum ether/ethyl acetate = 8: 1→5: 1) to provide Int-20c (20 g, 56%). Step D - Preparation oflnt-20d
lnt-20c n -
Int-20c was treated with 50 % NaOH (30 mL, CH3OH /H20) and stirred at room temperature until TLC indicated the hydrolysis was complete. The basic solution was neutralized with 2N HCl and the solvent was removed in vacuo to provide Int-20d (15 g) which was used directly in the next step.
- Preparation oflnt-20e
lnt-20d lnt-20e
Int-20d (3 g) was treated with py-HCl and heated at 120 °C until TLC indicated that the reaction was complete. The reaction mixture was allowed to cool to room temperature and was partitioning between ethyl acetate and 2N HCl. The organic phase was concentrated in vacuo and the residue obtained was purified using silica gel chromatography to provide Int-20e (15 g). MS (ESI) m/e (M+H) +: 253.
Step F - Preparation oflnt-20f
lnt-20e lnt-20f A solution of Int-20e (3 g) in dichloromethane (20 mL) was cooled to 0 oC, and to the cooled solution was added triflic anhydride (4.4 mL, 26.2 mmol) dropwise. The reaction was allowed to stir at room temperature until TLC indicated that Int-20e was consumed. The reaction mixture was then concentrated in vacuo and the residue obtained was purified using silica gel chromatography to provide Compound Int-20f (3.2 g). MS (ESI) m/e (M+H) +: 517. Step G - Preparation oflnt-20g
Int-20g was prepared from In-20f using the method described in Example 17, step B (1.8 g). MS (ESI) m/e (M+H) +: 473.
St - Preparation oflnt-20h
Int-20h was prepared from Int-20g using the method described in Example 18, step C (0.8 g). MS (ESI) m/e (M+H) +: 691.
- Preparation oflnt-20i
Int-20i was prepared from Int-20h using the method described in Example 18, Step D. MS (ESI) m e (M+H) +: 691.
- Preparation of Compound 16
Compound 16 was prepared from Compound Int-20i using the method described in Example 18, step E. (40 mg, 23 %) 1H-NMR: (MeOD) δ: 7.64 - 7.94 (m, 8 H), 5.23 - 5.25 (m, 2 H), 4.21 - 4.23 (m, 2 H), 4.09 (m, 2 H), 3.85 - 3.87 (m, 2 H), 3.04 - 3.09 (m, 2 H), 3.64 - 3.68 (m, 11 H), 2.56 (br, 2 H), 2.02 - 2.28 (m, 8 H). MS (ESI) m/e (M+H) +: 806.
EXAMPLE 21
Pr aration of Compound 17
- Preparation ofInt-21a
A solution of Compound Int-20h (0.8 g) in 1, 4-dioxane and dichloromethane (1 : 1, 10 mL) was cooled to 0 °C, then DDQ (310 mg) was added. . The resulting reaction was heated to reflux and allowed to stir at this temperature for 3 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, and the residue obtained was purified using preparative HPLC to provide Int-21a (0.4 g, 50 %). MS (ESI) m e (M+H) +: 689.81.
Step B - Preparation ofInt-21b
Int-21b was prepared from Int-21a using the method described in Example 18, step D (0.2 g). MS (ESI) m/e (M+H) +: 489.
- Preparation of Compound 17
Compound 17 was prepared from Compound Int-21b using the method described in Example 18 (50 mg, 50 %). 1H-NMR: (MeOD) δ: 7.38 - 8.58 (m, 22 H), 5.32 - 5.53 (m, 4 H), 4.05 - 4.07 (m, 2 H), 3.61 - 3.64 (m, 7 H), 2.20 - 2.42 (m, 2 H), 1.99 - 2.20 (m, 6 H). MS (ESI) m/e (M+H)+: 872.
EXAMPLE 22
Preparation of Compound 18
lnt-22a
Int-22a was prepared as described in J. Org. Chem., 73: 1752 (2008). Preparation of Compound Int-22b
lnt-22a lnt-22b
To a flask charged with Int-22a (4.0 g, 19 mmol) in EtOH (90 mL) was added 4-methoxyphenylhydrazine hydrochloride (4.4 g, 25 mmol) in one portion. The mixture was heated to 90 °C and allowed to stir at this temperature for 12 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo, and the residue obtained was partitioned between EtOAc (100 mL) and sat. aq. NaHC03 (25 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The organic layers were combined, washed with brine (1 x 50 mL), dried (Na2S04), filtered, and concentrated in vacuo. The residue obtained was purified using flash chromatography (gradient of 100% hexanes to 50%> hexanes/50%> EtOAc) to provide Compound Int-22b (4.1g, 70 %) as a brown solid. MS (ESI) m/e (M+H) +: 310.
- Preparation ofInt-22c
lnt-22b lnt-22c
To a solution of Int-22b (4.3 g, 14 mmol) in DMF (60 mL) at 0 °C was added NaH (1.0 g, 42 mmol) in one portion. The resulting reaction was allowed to stir at 0 °C for 15 minutes, then iodomethane (1.3 mL, 21 mmol) was added dropwise. The reaction was allowed to gradually warm to room temperature and was allowed to stir at this temperature for 12 hours. The reaction mixture was quenched with sat. aq. NaHC03 (35 mL) and diluted with EtOAc (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc ( 2 x 100 mL). The organic layers were combined and washed with brine (1 x 50 mL), dried (Na2S04), filtered, and concentrated in vacuo. The residue obtained was purified using flash chromatography using (gradient of 100% hexanes to 50% hexanes/50% EtOAc) to provide Int-22c (3.9 g, 86%) as a yellow solid. MS (ESI) m/e (M+H) +: 324.
Step D - Preparation ofInt-22d
lnt-22c lnt-22d
To a mixture of Int-22c (1.6 g, 5.0 mmol) in CH2C12 (10 mL) at 0 °C was added BBr3 (1.0M in CH2C12, 45 mL) dropwise over 10 minutes. The resulting solution was allowed to stir for 90 minutes at 0 °C, then the reaction was carefully quenched with sat. aq. NaHC03 (~ 20 mL). EtOAc (75 mL) was added and the resulting solution was allowed to stir for 30 minutes, then the layers were separated. The aqueous layer was extracted with EtOAc (2 x 75 mL) and the combined organic extracts were washed with brine (1 x 30 mL), dried (Na2S04), filtered, and concentrated in vacuo to provide Int-22d (1.2 g, 81%) as a yellow solid, which was used without further purification. MS (ESI) m/e (M+H) +: 296. Step E - Preparation ofInt-22e
lnt-22d lnt-22e
To a solution of Int-22d (1.2 g, 4.1 mmol) in CH2C12 (25 mL) at -10 °C was added triethylamine (1.6 mL, 11 mmol) followed by triflic anhydride (1.5 mL, 9.0 mmol). The resulting reaction was allowed to stir at -10 °C for 90 minutes, then 10% citric acid (~10 mL) was added to the reaction, followed by CH2C12 (25 mL). The layers were separated and the organic layer was washed sequentially with sat. aq. NaHC03 (1 x 10 mL) and brine (1 x 10 mL), then dried (Na2S04), filtered, and concentrated in vacuo to provide of Int-22e (2.3 g, 99%>) as a maroon semisolid, which was used without further purification. MS (ESI) m/e (M+H) +: 560.
Step - Preparation ofInt-22f
lnt-22e lnt-22f
A pressure tube charged with a stir bar was charged with Int-22e (2.3 g, 4.1 mmol), bis(pinacolato)diboron (2.2 g, 8.9 mmol), PdCl2(dppf) (0.15 g, 0.20 mmol), dppf (0.11 g, 0.20 mmol), KOAc (1.6 g, 16 mmol), and dioxane (18 mL). The resulting solution was degassed under house vacuum and filled with N2 six times, then capped, and heated to 80 °C. The reaction was allowed to stir for 16 hours at 80 °C, then was cooled to room temperature, and concentrated in vacuo. The residue obtained was dissolved in CH2C12 (15 mL) and was filtered through a pad of Celite. The pad was washed with CH2C12 (3 x 15 mL) and the combined filtrate and washings were concentrated in vacuo. The resulting residue was purified using flash chromatography (gradient of 100% hexanes to 60% hexanes/40% EtOAc) to provide Int-22f (0.36 g, 17%) as a light yellow solid. MS (ESI) m/e (M+H) +: 516.
Step G - Preparation of Compound Int-22g
lnt-22f nt- g
To a flask charged with Int-22f (0.36 g, 0.70 mmol) was added Int-7d (0.53 g, 1.7 mmol), PdCl2(dppf) (0.20 g, 0.28 mmol), K2C03 (0.48 g, 3.5 mmol), and DME/H20 (8 mL/2 mL). The mixture was degassed under house vacuum and filled with N2 six times, heated to 90 °C, and was allowed to stir for 12 hours. The mixture was cooled to room temperature and was partitioned between CH2C12 (15 mL) and water (4 mL). The layers were separated and the aqueous layer was extracted with CH2C12 (2 x 15 mL). The organic layers were combined and were washed with brine (1 x 7 mL). The organic layer dried (Na2S04), filtered, and concentrated in vacuo. The crude product was purified using preparative thin- layer chromatography using 6 x 1000 μΜ plates and a 20: 1 mixture of CH2Cl2/MeOH (7N NH3) as eluent to provide 0.25 g (49%) of Int-22g as a yellow solid. MS (ESI) m/e (M+H) +: 734. - Preparation of Compound Int-22h
Int-22g (0.20 g, 0.27 mmol) was taken up in 4N HC1 in dioxane (4 mL). The resulting reaction was allowed to stir at room temperature for 3 hours, then was concentrated in vacuo. The resulting residue was and placed under high vacuum for 24 hours to to provide Int-22h (0.18 g, 99%) as a yellow semisolid. MS (ESI) m/e (M+H) +: 534.
Step I - Preparation of Compound 18
To a solution of Int-22h (92 mg, 0.14 mmol) in DMF (1.5 mL) at -10 °C was added N-Moc-L-Val-OH (47 mg, 0.27 mmol), HATU (0.10 g, 0.27 mmol) and DIPEA (0.11 mL, 0.68 mmol). The reaction was allowed to stir for 45 minutes at -15 °C whereupon the mixture was diluted with water (1.5 mL) and EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic extracts were sequentially washed with water (2 x 3 mL) and brine (1 x 3 mL), then was dried (Na2S04), filtered, and concentrated in vacuo. The residue obtained was purified using reverse phase HPLC purification (C18 column, gradient of 89.95:9.95:0.1 H20:MeCN:TFA to 9.95:89.95:0.1 H20:MeCN:TFA) to provide Compound 18 (50 mg, 40%) as a tan solid as its dihydrochloride salt after treatment with HC1. 1H NMR (CD3OD) δ 7.90-8.02 (2H, m), 7.90 (1H, s), 7.83 (1H, s), 7.66 (1H, d, J = 8.7 Hz), 7.60 (1H, d, J = 8.7 Hz), 5.26 (2H, m), 4.25 (2H, m), 4.15 (3H, s), 3.89 (2H, m), 3.68 (6H, s), 2.59 (2H, m), 2.28 (2H, m), 2.00-2.15 (9H, m), 1.86 (6H, s), 0.99 (1H, m), 0.92-0.97 (12H, m); MS (ESI) m/e (M+H) +: 848.
The following compounds of the present invention were made using the method described above in Example 22 and substituting the appropriate reactants and/or reagents.
EXAMPLE 23
Preparation of Compound 31
31
Step A - Preparation ofInt-23a
lnt-23a
To a at 0°C solution of 3-methoxyphenylacetic acid (2 g, 12.05 mmol) in DCM (20 mL) was added BOP reagent (5.331 g, 12.05 mmol), DIPEA (3.133 g, 24.1 mmol) and N,0- dimethylhydroxylamine (1.181 g, 12.05 mmol). The reaction mixture was stirred at room temperature before the solution was washed with IN HCl and brine, dried over Na2S04, filtered and concentrated. The crude product was purified by chromatography with silica gel (petroleum ether / EtOAc = 5 : 1) to give compound Int-23a as a colorless oil (1.60 g). MS (ESI) m / e (M+H+): 210.0 Step B - Preparation ofInt-23b
lnt-23a lnt-23b
To a solution of Int-23a (1.6 g, 7.66 mmol) in dry THF (20 mL) was added PhMgBr (3 mL, 8.42 mmol) dropwise at 0°C under the protection of N2. After the reaction mixture was stirred at room temperature for 2 hours, the reaction was quenched by saturated NH4CI solution (20 mL) at 0°C. After removal of THF, the aqueous layer was extracted with EtOAc (20 mL) and the organic extracts were washed with brine, dried over Na2S04, filtered and concentrated. The crude product was purified by chromatography with silica gel (petroleum ether / EtOAc = 20: 1) to give compound Int-23b as colorless oil (1.5 g). 1H NMR (CDC13) δ 7.98-8.00 (d, J = 7.2 Hz, 2 H), 7.52-7.56(m, 1 H), 7.42-7.46 (m, 2 H), 7.20-7.22 (d, / = 8.0 Hz, 2 H), 6.77- 6.85 (m, 3 H), 4.24 (s, 2 H), 3.77 (s, 3 H). MS (ESI) m / e (M+H+): 227.0.
Step C - Preparation ofInt-23c
lnt-23b lnt-23c To a solution of compound Int-23c (20 g, 88.5 mmol) in AcOH/H20 (100 mL / 100 mL) was added bromine (4.5 mL, 88.50 mmol) dropwise at 0°C. After the reaction mixture was stirred at room temperature for 1 hour, the white precipitate was filtered, washed with water and dried to afford Int-23c as white solid (24.2 g). 1H NMR (CDC13) δ 8.02-8.04 (m, 1 H), 7.56- 7.59 (m, 1 H), 7.44-7.49 (m, 3 H), 6.78-6.79(d, / = 3.2 Hz, 1 H), 6.69-6.72 (dd, Ji = 8.8 Hz, h = 3.2 Hz, 1 H), 4.40 (s, 2 H), 3.75 (s, 3 H). MS (ESI) m / e (M+H+): 306.8.
Step D - Preparation ofInt-23d
To a solution of compound Int-23c (24.2 g, 79.34 mmol) in EtOH (200 mL) was added NaBH4 (4.523 g, 119.02 mmol) in small portions at 0°C. The solution was allowed to stir at room temperature for 5 hours then quenched carefully with IN HC1 (200 mL). Then the solvent was removed and the aqueous layer was extracted by EtOAc (200 mL) three times. The combined organic extracts were washed with brine, dried over Na2S04, filtered and concentrated to afford Int-23d as white solid (24 g). MS (ESI) m / e (M-OH): 290.8 Step E - Preparation ofInt-23e
lnt-23d lnt-23e
A mixture of compound Int-23d (4.747 g, 15.46 mmol), N-Boc-6-methoxyindole-2-boronic acid (4.5 g, 15.46 mmol), Pd(dppf)Cl2 (1.13 g, 1.55 mmol) and Na2C03 (4.91 g, 46.3 mmol) in THF/H20 (5/1, 120 mL) was heated to 80 °C under the protection of N2 for 2 h. The reaction mixture was cooled and concentrated to remove the THF. The aqueous layer was extracted with EtOAc (100 mL) three times, washed with brine, dried over Na2S04, filtered and concentrated. The crude was purified by chromatography with silica gel (petroleum ether/ EtOAc = 50/1 to 10/1) to give Int-23e as brown oil (5.6 g). MS (ESI) m / e (M+H+): 474.0
Step F - Preparation ofInt-23f
To a solution of compound Int-23e (3.5 g, 7.38 mmol) in DCM (40 mL) was added MsCl (1.019 g, 8.86 mmol) and TEA (2 mL, 14.77 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, quenched with water and the organic phase was separated, washed with brine, dried over Na2S04 and concentrated. The crude mixture was purified by chromatography with silica gel (petroleum ether/ EtOAc = 20/1) to give compound Int-23f as white solid (2 g). 1H NMR (CDC13) δ 7.91-7.93 (d, / = 8.8 Hz, 1 H), 7.41-7.43 (d, / = 8.8 Hz, 1 H), 7.17-7.24 (m, 5 H), 6.79-6.82(m, 2 H), 6.70-6.71 (d, / = 2.4 Hz, 1 H), 6.23-6.24 (d, / = 2.8 Hz, 1 H), 4.17-4.21 (m, 1 H), 3.80 (s, 3 H), 3.59 (s, 3 H), 3.14-3.34 (m, 2 H), 1.66 (s, 9 H). MS (ESI) m / e (M+Na+): 456.0.
A solution of Int-23f (100 mg, 0.22 mmol) in DCM (3 mL) was treated with TFA (3 mL) at 0 °C and the reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was diluted with DCM (10 mL) and water (10 mL) and separated. The organic layer was washed with saturated NaHC03, brine, dried over Na2S04 and concentrated to afford a white solid which was used in the next reaction without further purification (75 mg). MS (ESI) m / e (M+Na+): 356.0
Step H - Preparation ofInt-23h
lnt-23g lnt-23h
To a 0°C solution of compound Int-23g (75 mg, 0.21 mmol) in THF (5 mL) was added NaH (9.3 g, 0.23 mmol). After effervescence ceased, Mel (33 mg, 0.23 mmol) was added to the reaction mixture drop wise and the reaction mixture was stirred at 25 °C overnight. The reaction mixture was quenched with water and the organic layer was separated, washed with brine, dried over Na2S04 and concentrated. The crude was purified by TLC to give compound Int-23h as green solid (75 mg). 1H NMR (CDC13) δ 7.53-7.55 (d, / = 8.4 Hz, 1 H), 7.13-7.18 (m, 6 H), 6.72-6.79 (m, 3 H), 6.23-6.24 (d, / = 2.4 Hz, 1 H), 4.25-4.29 (m, 1 H), 3.95 (s, 3 H), 3.75 (s, 3 H), 3.54 (s, 3 H), 3.09-3.27 (m, 2 H). MS (ESI) m / e (M+H+): 369.
Step I - Preparation ofInt-23i
lnt-23h lnt-23i
To a solution of compound Int-23i (1.1 g, 2.98 mmol) in dry DCM (20 mL) was added BBr3 (0.89 mL, 8.94 mmol) dropwise at 0 °C under the protection of N2. The reaction mixture was allowed to warm to room temperature over 6 hours. The reaction mixture was quenched with iced water and the layers were separated and the aqueous layer was extracted by EtOAc (20 mL) three times. The combined organic extracts were washed with NaHC03, brine, dried over Na2S04, filtered and concentrated to afford Int-23i as a white solid which was used in the next step without further purification (0.8 g). MS (ESI) m / e (M+H+): 342.
Step J - Preparation ofInt-23j
To a solution of Int-23i (0.8 g, 2.35 mmol) in DCM (20 mL) was added TEA (0.7 mL, 5.16 mmol) and PhNTf^ (1.675 g, 4.69 mmol). The reaction mixture was stirred at room
temperature overnight and the solvent was removed. The crude residue was purified by preparative HPLC to give Int-23j as white solid (0.4 g). 1H NMR (DMSO-d6) δ 8.00-8.02 (d, / = 8.8 Hz, 1 H), 7.67-7.70 (d, / = 8.8 Hz, 1 H), 7.52-7.53 (d, / = 2.4 Hz, 1 H), 7.43-7.46 (dd, / i= 8.8 Hz, J 2= 2.4 Hz, 1 H), 7.17-7.23(m, 6 H), 6.75-6.76(d, / = 2.4 Hz, 1 H), 4.43-4.47 (m, 1 H), 4.09 (s, 3 H), 3.20-3.30 (m, 2 H). MS (ESI) m l e (M+H+): 608.
Step K - Preparation of Compound 31
Compound 31 was made using the method described in Example 18, steps B-E starting from Int-23j. 1H NMR (CD3OD) δ 7.97-7.99 (d, / = 8.0 Hz, 1 H), 7.78 (s, 1 H), 7.50-7.68 (m, 6 H), 7.05-7.14 (m, 5 H), 5.16-5.19 (t, / = 6.8 Hz, 1 H), 4.57-4.58 (m, 1 H), 4.10-4.20 (m, 5 H), 4.00-4.06 (m, 2 H), 3.80-3.90 (m, 2 H ), 3.63 (s, 6 H), 3.55-3.59 (m, 1 H), 3.22-3.25 (m, 1 H), 2.40-2.60 (m, 2 H), 1.99-2.22 (m, 8 H), 0.82-0.92 (m, 12 H). MS (ESI) m / e (M/2+H+): 447.8.
The following compounds of the present invention were made using the method described above in Example 23 and substituting the appropriate reactants and/or reagents.
Compound Structure MS
Proton NMR data for Compounds 19, 32 and 36 is provided below: Compound 19: 1H NMR (CD3OD) δ 7.62-7.97 (5H, m), 5.24 (2H, m), 4.84 (1H, s), 4.20 (2H, m), 4.06 (3H, s), 3.87 (2H, m), 3.62 (3H, s), 3.61 (3H, s), 3.40 (1H, m), 3.00 (2H, m), 2.55 (2H, m), 2.00-2.15 (9H, m), 0.99 (1H, m), 0.92-0.97 (12H, m).
Compound 32: 1H NMR (CD3OD) δ: 8.01 (s, 1 H), 7.87 - 7.95 (m, 2 H), 7.70 - 7.78 (m, 3 H), 7.54 - 7.62 (m, 2 H), 5.26 (m, 2 H), 4.24 - 4.25 (d, / = 7.2 Hz, 2 H), 4.13 (s, 5 H), 3.88 - 3.92 (m, 2 H), 3.67 (s, 6 H), 3.43 - 3.47 (m, 1 H), 3.17 - 3.20 (m, 1 H), 2.58 - 2.82 (m, 3 H), 2.04 - 2.48 (m, 8 H), 0.92 - 1.01 (m, 12 H), 0.91 (m, 1 H), 0.22 - 0.48 (m, 4 H).
Compound 36: 1H NMR (CD3OD) δ: 7.86 (s, 1 H), 7.81 (s, 1 H), 7.79- 7.60 (m, 4 H), 7.51- 7.43 (m, 2 H), 5.27- 5.22 (m, 2 H), 4.21- 4.18 (m, 2 H), 4.10- 4.06 (m, 2 H), 3.86- 3.82 (m, 2 H), 3.64 (s, 6 H), 3.17-3.11 (m, 2 H), 3.06-3.02 (m, 2 H), 2.56- 2.51 (m, 2 H), 2.30- 2.01 (m, 8 H), 0.93- 0.88 (m, 12 H).
EXAMPLE 24
Cell-Based HCV Replicon Assay
To measure cell-based anti-HCV activity of selected compounds of the present invention, replicon cells were seeded at 5000 cells/well in 96-well collagen I-coated Nunc plates in the presence of the test compound. Various concentrations of test compound, typically in 10 serial 2-fold dilutions, were added to the assay mixture, with the starting concentration ranging from 250 μΜ to 1 μΜ. The final concentration of DMSO was 0.5%, fetal bovine serum was 5%, in the assay media. Cells were harvested on day 3 by the addition of lx cell lysis buffer (Ambion cat #8721). The replicon RNA level was measured using real time PCR (Taqman assay). The amplicon was located in 5B. The PCR primers were: 5B.2F, ATGGACAGGCGCCCTGA (SEQ ID NO. 1); 5B.2R,
TTGATGGGCAGCTTGGTTTC (SEQ ID NO. 2); the probe sequence was FAM-labeled CACGCCATGCGCTGCGG (SEQ ID NO. 3). GAPDH RNA was used as endogenous control and was amplified in the same reaction as NS5B (multiplex PCR) using primers and VIC-labeled probe recommended by the manufacturer (PE Applied Biosystem). The realtime RT-PCR reactions were run on ABI PRISM 7900HT Sequence Detection System using the following program: 48 C for 30 minutes, 95 C for 10 minutes, 40 cycles of 95 C for 15 sec, 60 C for 1 minutes. The ACT values (CT5B-CTGAPDH) were plotted against the
concentration of test compound and fitted to the sigmoid dose-response model using XLfit4 (MDL). EC50 was defined as the concentration of inhibitor necessary to achieve ACT=1 over the projected baseline; EC90 the concentration necessary to achieve ACT=3.2 over the baseline. Alternatively, to quantitate the absolute amount of replicon RNA, a standard curve was established by including serially diluted T7 transcripts of replicon RNA in the Taqman assay. All Taqman reagents were from PE Applied Biosystems. Such an assay procedure was described in detail in e.g. Malcolm et ah, Antimicrobial Agents and Chemotherapy 50: 1013- 1020 (2006).
HCV replicon assay data was calculated for selected compounds of the present invention using this method and is provided in the table below. Replicon EC90 data for selected compounds of the present invention is provided in the table below.
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

1. A compound having the formula:
(I)
or a pharmaceutically acceptable salt thereof, wherein:
A and A' are each independently selected from a 5 or 6-membered monocyclic heterocycloalkyl, wherein said 5 or 6-membered monocyclic heterocycloalkyl group can be optionally fused to an aryl group; and wherein said 5 or 6-membered monocyclic
heterocycloalkyl group can be optionally and independently substituted on one or more ring carbon atoms with R13, such that any two R13 groups on the same ring, together with the carbon atoms to which they are attached, can join to form a fused, bridged or spirocyclic 3 to 6-membered cycloalkyl group or a fused, bridged or spirocyclic 4 to 6-membered
heterocycloalkyl group, wherein said 5 or 6-membered monocyclic heterocycloalkyl contains from 1 to 2 ring heteroatoms, each independently selected from N(R4), S, O and Si(R16)2;
G is selected from -C(R3)2-0-, -0-C(R3)2-, -C(R3)2-N(R5)-, -C(0)-0-, -C(O)- N(R5)-, -C(R3)2-C(0)-, -C(=NR5)-N(R5)-, -C(R3)2-S02-, -S02-C(R3)2-, -S02N(R5)-,
-C(R3)2-C(R3)2-, -C(R14)=C(R14)- and -C(R14)=N-;
U is selected from N(R2), O, S and S02;
V and V are each independently selected from N and C(R15);
W and W are each independently selected from N and C(RJ);
X and X' are each independently selected from N and C(R10);
Y and Y' are each independently selected from N and C(R10);
R1 is selected from H, Ci-C6 alkyl, 3 to 6 membered cycloalkyl, halo, -OH, -O- (Ci-C6 alkyl), Ci-C6 haloalkyl and -0-(d-C6 haloalkyl);
R2 is selected from H, Ci-C6 alkyl, 3 to 6-membered cycloalkyl, aryl, 5 or 6- membered heteroaryl and benzyl, wherein said aryl group, said 5 or 6-membered heteroaryl group or the phenyl moiety of said benzyl group can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from Ci-C6 alkyl, Ci-C6 haloalkyl, -0-(d-C6 alkyl), -0-(Ci-C6 haloalkyl), halo, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl) and -CN;
each occurrence of R3 is independently selected from H, Ci-C6 alkyl, Ci-C6 haloalkyl, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl, 5 or 6-membered heteroaryl, -CH2-(5 or 6 membered heteroaryl) and benzyl, wherein said aryl group, said 5 or 6-membered heteroaryl group or the phenyl moiety of said benzyl group can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from Ci-C6 alkyl, Ci-C6 haloalkyl, -0-(Ci-C6 alkyl), -0(Ci-C6 haloalkyl), halo, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl) and -CN and wherein two R3 groups attached to the same carbon atom, together with the common carbon atom to which they are attached, can join to form a carbonyl group, a 3 to 6-membered spirocyclic cycloalkyl group or a 3 to 6-membered spirocyclic heterocycloalkyl group;
each occurrence of R4 is independently selected from -[C(R7)2]qN(R6)2, - C(0)Rn, -C(0)-[C(R7)2]qN(R6)2, -C(0)-[C(R7)2]q-Rn, -C(0)-[C(R7)2]qN(R6)C(0)-Rn, - C(0)[C(R7)2]qN(R6)S02-Rn, -C(0)-[C(R7)2]qN(R6)C(0)0-Rn, -C(0)-[C(R7)2]qC(0)0-Rn and -alkylene-N(R6)-[C(R7)2]q-N(R6)-C(0)0-R11 ;
each occurrence of R5 is independently selected from H, Ci-C6 alkyl, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl, 5 or 6-membered heteroaryl and benzyl, wherein said aryl group, said 5 or 6-membered heteroaryl group or the phenyl moiety of said benzyl group can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from Ci-C6 alkyl, Ci-C6 haloalkyl, -0-(d-C6 alkyl), -0-(Ci-C6 haloalkyl), halo, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl) and -CN;
each occurrence of R6 is independently selected from H, Ci-C6 alkyl, 3 to 6- membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl and 5 or 6-membered heteroaryl, wherein said 3 to 6-membered cycloalkyl group, said 4 to 6-membered heterocycloalkyl group, said aryl group and said 5 or 6-membered heteroaryl group can be optionally and independently substituted with up to two R8 groups, and wherein two R6 groups that are attached to the same nitrogen atom, together with the common nitrogen atom to which they are attached, can join to form a 4 to 6-membered heterocycloalkyl group;
each occurrence of R7 is independently selected from H, Ci-C6 alkyl, Ci-C6 haloalkyl, silylalkyl, -alkylene-0-(Ci-C6 alkyl), 3 to 6-membered cycloalkyl, 4 to 6- membered heterocycloalkyl, aryl and 5 or 6-membered heteroaryl, wherein said 3 to 6- membered cycloalkyl group, said 4 to 6-membered heterocycloalkyl group, said aryl group and said 5 or 6-membered heteroaryl group can be optionally substituted with up to three R groups;
each occurrence of R8 is independently selected from H, Ci-C6 alkyl, halo, - Ci-C6 haloalkyl, Ci-C6 hydroxyalkyl, -OH, -C(0)NH-(Ci-C6 alkyl), -C(0)N(d-C6 alkyl)2, - 0-(Ci-C6 alkyl), -NH2, -NH(Ci-C6 alkyl), -N(d-C6 alkyl)2 and -NHC(0)-(Ci-C6 alkyl);
each occurrence of R9 is independently selected from H, Ci-C6 alkyl, Ci-C6 haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl and 5 or 6- membered heteroaryl;
each occurrence of R10 is independently selected from H, Ci-C6 alkyl, Ci-C6 haloalkyl, halo, -OH, -0-(Ci-C6 alkyl) and -CN;
each occurrence of R11 is independently selected from H, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 hydro xyalkyl, 3 to 6-membered cycloalkyl and 4 to 6-membered
hetero cyclo alkyl;
each occurrence of R12 is independently selected from Ci-C6 alkyl, Ci-C6 haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl and 5 or 6- membered heteroaryl;
each occurrence of R13 is independently selected from H, halo, Ci-C6 alkyl, Ci-C6 haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, -CN, -OR9, -N(R9)2, -C(0)R12, -C(0)OR9, -C(0)N(R9)2, -NHC(0)R12, -NHC(0)NHR9, -NHC(0)OR9, - OC(0)R12, -SR9 and -S(0)2R12, wherein two R13 groups that attached to the same ring, together with the carbon atom(s) to which they are attached, can optionally join to form a 3 to 6-membered cycloalkyl group or 4 to 6-membered heterocycloalkyl group;
each occurrence of R14 is independently selected from H, halo, Ci-C6 alkyl, Ci-C6 haloalkyl, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), 3 to 6-membered cycloalkyl, 4 to 6 membered heterocycloalkyl, aryl, 5 or 6-membered heteroaryl, CH2-(5 or 6 membered heteroaryl) and benzyl, wherein said aryl group, said 5 or 6-membered heteroaryl group or the phenyl moiety of said benzyl group can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from halo, -CN, Ci-C6 alkyl, Ci-C6 haloalkyl, -0-(Ci-C6 alkyl), -(Ci-C6 alkylene)-0-(Ci-C6 alkyl) and -0-(Ci-C6 haloalkyl);
each occurrence of R15 is independently selected from H, Ci-C6 alkyl, 3 to 6- membered cycloalkyl, halo, -OH, -0-(Ci-C6 alkyl), Ci-C6 haloalkyl and -0-(Ci-C6 haloalkyl);
each occurrence of R16 is independently selected from H, halo, Ci-C6 alkyl and 3 to 6-membered cycloalkyl, wherein two R16 groups that are attached to a common silicon atom can join to form a -(CH2)4- or a -(CH2)s- group; and each occurrence of q is independently an integer ranging from 0 to 4.
2. The com ound of claim 1 having the formula:
(la)
or a pharmaceutically acceptable salt thereof, wherein:
A and A' are each independently a 5-membered monocyclic heterocycloalkyl, wherein said 5-membered monocyclic heterocycloalkyl group can be optionally and independently substituted on one or more ring carbon atoms with R13, such that any two R13 groups on the same ring, together with the carbon atoms to which they are attached, can join to form a fused, bridged or spirocyclic 3 to 6-membered cycloalkyl group or a fused, bridged or spirocyclic 4 to 6-membered heterocycloalkyl group, wherein said 5-membered
monocyclic heterocycloalkyl contains from 1 to 2 ring heteroatoms, each independently selected from N(R4) and Si(R16)2;
G is selected from -C(R3)2-C(R3)2-, -C(R14)=C(R14)- and -C(R3)2-0-;
U is selected from -N(R2)- and -0-;
V and V are each independently selected from N and C(R15);
R1 represents from 0 to 2 ring substituents on the phenyl ring to which R1 is attached, wherein said substituents are each independently selected from Ci-C6 alkyl and halo;
each occurrence of R3 is independently selected from H, Ci-C6 alkyl, -(Ci-C6 alkylene)-0-Ci-C6 alkyl, 3 to 6-membered cycloalkyl, Ci-C6 haloalkyl, aryl, 5 or 6- membered heteroaryl and benzyl, wherein said aryl group, said 5 or 6-membered heteroaryl group or the phenyl group of said benzyl group can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from halo, -CN, Ci-C6 alkyl, Ci- C6 haloalkyl, -0-Ci-C6 alkyl, -(Ci-C6 alkylene)-0-Ci-C6 alkyl and -0-Ci-C6 haloalkyl;
each occurrence of R4 is independently -C(0)Rn or -C(O)- [C(R7)2]N(R6)C(0)0-Rn;
each occurrence of R6 is independently selected from H and Ci-C6 alkyl; each occurrence of R7 is independently selected from Ci-C6 alkyl, 3 to 6- membered cycloalkyl and aryl;
each occurrence of R10 is independently selected from H and halo; each occurrence of R11 is independently Ci-C6 alkyl;
each occurrence of R13 is independently selected from H, Ci-C6 alkyl and halo, wherein two R13 groups, together with the carbon atom(s) to which they are attached, can optionally join to form a 3 to 6-membered cycloalkyl group or 4 to 6-membered
heterocycloalkyl group;
R14 is selected from H, halo, Ci-C6 alkyl, -(Ci-C6 alkylene)-0-Ci-C6 alkyl, 3 to 6-membered cycloalkyl, Ci-C6 haloalkyl, aryl, 5 or 6-membered heteroaryl and benzyl, wherein said aryl group, said 5 or 6-membered heteroaryl group or the phenyl group of said benzyl group can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from halo, -CN, Ci-C6 alkyl, Ci-C6 haloalkyl, -0-Ci-C6 alkyl, - (Ci-C6 alkylene)-0-Ci-C6 alkyl and -0-Ci-C6 haloalkyl; and
each occurrence of R15 is independently selected from H and halo; and each occurrence of R16 is independently Ci-C6 alkyl.
3. The com ound of claim 1 or 2 wherein the group:
has the structure:
4. The compound of claim 1 or 2, wherein the group:
has the structure:
The com ound of claim 1 or 2, wherein the group:
has the structure:
wherein the dashed line represents an optional and additional bond.
6. The compound of any one of claims 1 to 5, wherein A and A' are each independently selected from:
7. The compound of an one of claims 1 to 6, wherein A and A' are each:
and each occurrence of R13 is independently H, CH3 or F.
8. The compound of any one of claims 1 to 8, wherein each occurrence of R4 is independently -C(0)CH(R7)NHC(0)0-R11 and wherein each occurrence of R7 is independently Ci-C6 alkyl or phenyl and each occurrence of R11 is independently Ci-C6 alkyl.
9. The compound of claim 1 having the formula:
or a pharmaceutically acceptable salt thereof, wherein:
R2 is selected from H and Ci-C6 alkyl;
each occurrence of R3 is independently selected from H, Ci-C6 alkyl, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), benzyl, phenyl, cycloalkyl and 5 or 6-membered heteroaryl, wherein said phenyl group can be optionally substituted with a group selected from: Ci-C6 alkyl, halo and -O-alkyl; and
each occurrence of R13 is independently selected from H, Ci-C6 alkyl and halo.
10. The compound of any one of claims 1 to 9, wherein each occurrence of
R4 is: 133
134
135
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising an effective amount of the compound of any of claims 1 to 11 and a pharmaceutically acceptable carrier.
13. The pharmaceutical composition according to claim 12 further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.
14. The pharmaceutical composition according to claim 13, further comprising a third therapeutic agent selected from the group consisting of HCV protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.
15. The use of the compound according to any of claims 1 to 11 in the preparation of a medicament for inhibiting HCV NS5A activity or for preventing and/or treating infection by HCV in a patient in need thereof.
16. A method of treating a patient infected with HCV comprising the step of administering an amount of (i) the compound according to any of claims 1 to 11 or (ii) the composition according to any of claims 12 to 14 effective to prevent and/or treat infection by HCV in said patient.
17. The method according to claim 16, further comprising the step of administering pegylated-interferon alpha and an HCV protease to said patient.
18. The method according to claim 16 or 17, further comprising the step of administering ribavirin to said patient.
EP11828123.7A 2010-09-29 2011-09-28 TETRACYCLIC HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF HEPATITIS C VIRUS INFECTION Withdrawn EP2621932A4 (en)

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