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WO2009032123A2 - Dérivés d'indole tétracycliques et procédés pour les utiliser - Google Patents

Dérivés d'indole tétracycliques et procédés pour les utiliser Download PDF

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Publication number
WO2009032123A2
WO2009032123A2 PCT/US2008/010147 US2008010147W WO2009032123A2 WO 2009032123 A2 WO2009032123 A2 WO 2009032123A2 US 2008010147 W US2008010147 W US 2008010147W WO 2009032123 A2 WO2009032123 A2 WO 2009032123A2
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Prior art keywords
alkyl
cycloalkyl
compound
mmol
heteroaryl
Prior art date
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PCT/US2008/010147
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English (en)
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WO2009032123A3 (fr
Inventor
Frank Bennett
Qingbei Zeng
Srikanth Venkatraman
Mousumi Sannigrahi
Kevin X. Chen
Gopinadhan N. Anilkumar
Stuart B. Rosenblum
Joseph A. Kozlowski
F. George Njoroge
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Merck Sharp and Dohme LLC
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Schering Corp
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Priority to JP2010522933A priority Critical patent/JP5179585B2/ja
Priority to AU2008295483A priority patent/AU2008295483B2/en
Priority to CA2697451A priority patent/CA2697451A1/fr
Priority to CN200880113543A priority patent/CN101842376A/zh
Priority to MX2010002316A priority patent/MX2010002316A/es
Priority to US12/675,277 priority patent/US20110104109A1/en
Application filed by Schering Corp filed Critical Schering Corp
Priority to EP08795628A priority patent/EP2197884A2/fr
Publication of WO2009032123A2 publication Critical patent/WO2009032123A2/fr
Publication of WO2009032123A3 publication Critical patent/WO2009032123A3/fr
Priority to ZA2010/01391A priority patent/ZA201001391B/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Definitions

  • the present invention relates to Tetracyclic Indole Derivatives, compositions comprising at least one Tetracyclic Indole Derivative, and methods of using the Tetracyclic Indole Derivatives for treating or preventing a viral infection or a virus-related disorder in a patient.
  • HCV is a (+)-sense single-stranded RNA virus that has been implicated as the major causative agent in non-A, non-B hepatitis (NANBH).
  • NANBH is distinguished from other types of viral-induced liver disease, such as hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis delta virus (HDV), as well as from other forms of liver disease such as alcoholism and primary biliary cirrhosis.
  • HAV hepatitis A virus
  • HBV hepatitis B virus
  • HDV hepatitis delta virus
  • Hepatitis C virus is a member of the hepacivirus genus in the family Flaviviridae. It is the major causative agent of non-A, non-B viral hepatitis and is the major cause of transfusion- associated hepatitis and accounts for a significant proportion of hepatitis cases worldwide.
  • acute HCV infection is often asymptomatic, nearly 80% of cases resolve to chronic hepatitis.
  • About 60% of patients develop liver disease with various clinical outcomes ranging from an asymptomatic carrier state to chronic active hepatitis and liver cirrhosis (occurring in about 20% of patients), which is strongly associated with the development of hepatocellular carcinoma (occurring in about 1-5% of patients).
  • the World Health Organization estimates that 170 million people are chronically infected with HCV, with an estimated 4 million living in the United States.
  • HCV has been implicated in cirrhosis of the liver and in induction of hepatocellular carcinoma.
  • the prognosis for patients suffering from HCV infection remains poor as HCV infection is more difficult to treat than other forms of hepatitis.
  • Current data indicates a four- year survival rate of below 50% for patients suffering from cirrhosis and a five-year survival rate of below 30% for patients diagnosed with localized resectable hepatocellular carcinoma. Patients diagnosed with localized unresectable hepatocellular carcinoma fare even worse, having a five-year survival rate of less than 1%.
  • HCV is an enveloped RNA virus containing a single-stranded positive-sense RNA genome approximately 9.5 kb in length.
  • RNA genome contains a 5'-nontranslated region (5 * NTR) of 341 nucleotides, a large open reading frame (ORF) encoding a single polypeptide of 3,010 to 3,040 amino acids, and a 3'-nontranslated region (3'-NTR) of variable length of about 230 nucleotides.
  • 5 * NTR 5'-nontranslated region
  • ORF open reading frame
  • 3'-NTR 3'-nontranslated region of variable length of about 230 nucleotides.
  • HCV is similar in amino acid sequence and genome organization to flaviviruses and pestiviruses, and therefore HCV has been classified as a third genus of the family Flaviviridae.
  • the 5' NTR contains an internal ribosome entry site (IRES) which plays a pivotal role in the initiation of translation of the viral polyprotein.
  • IRS internal ribosome entry site
  • a single long open reading frame encodes a polyprotein, which is co- or post-translationally processed into structural (core, El, E2 and p7) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) viral proteins by either cellular or viral proteinases.
  • the 3' NTR consists of three distinct regions: a variable region of about 38 nucleotides following the stop codon of the polyprotein, a polyuridine tract of variable length with interspersed substitutions of cytidines, and 98 nucleotides (nt) at the very 3' end which are highly conserved among various HCV isolates.
  • the 3'-NTR is thought to play an important role in viral RNA synthesis.
  • the order of the genes within the genome is: NH 2 -C-El -E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COOH.
  • the HCV polyprotein is first cleaved by a host signal peptidase generating the structural proteins C/El, E1/E2, E2/p7, and p7/NS2.
  • the NS2-3 proteinase which is a metalloprotease, then cleaves at the NS2/NS3 junction.
  • NS3/4A proteinase complex (NS3 being a serine protease and NS4A acting as a cofactor of the NS3 protease), is then responsible for processing all the remaining cleavage junctions.
  • RNA helicase and NTPase activities have also been identified in the NS3 protein.
  • One-third of the NS3 protein functions as a protease, and the remaining two-thirds of the molecule acts as the helicase/ ATPase that is thought to be involved in HCV replication.
  • NS5A may be phosphorylated and acts as a putative cofactor of NS5B.
  • the fourth viral enzyme, NS5B is a membrane-associated RNA-dependent RNA polymerase (RdRp) and a key component responsible for replication of the viral RNA genome.
  • NS5B contains the "GDD" sequence motif, which is highly conserved among all RdRps characterized to date. Replication of HCV is thought to occur in membrane-associated replication complexes.
  • the genomic plus-strand RNA is transcribed into minus-strand RNA, which in turn can be used as a template for synthesis of progeny genomic plus-strands.
  • At least two viral enzymes appear to be involved in this reaction: the NS3 helicase/NTPase, and the NS5B RNA-dependent RNA polymerase.
  • NS5B is the key enzyme responsible for synthesis of progeny RNA strands.
  • a primer- dependent RdRp a primer- dependent RdRp
  • TNTase terminal transferase
  • NS5B has been shown to catalyze RNA synthesis via a de novo initiation mechanism, which has been postulated to be the mode of viral replication in vivo. Templates with single-stranded 3' termini, especially those containing a 3 '-terminal cytidylate moiety, have been found to direct de novo synthesis efficiently. There has also been evidence for NS5B to utilize di- or trinucleotides as short primers to initiate replication.
  • HCV replication inhibitors that are useful for the treatment and prevention of HCV related disorders.
  • New approaches currently under investigation include the development of prophylactic and therapeutic vaccines, the identification of interferons with improved pharmacokinetic characteristics, and the discovery of agents designed to inhibit the function of three major viral proteins: protease, helicase and polymerase, hi addition, the HCV RNA genome itself, particularly the IRES element, is being actively exploited as an antiviral target using antisense molecules and catalytic ribozymes.
  • Particular therapies for HCV infection include ⁇ -interferon monotherapy and combination therapy comprising ⁇ -interferon and ribavirin. These therapies have been shown to be effective in some patients with chronic HCV infection.
  • the use of antisense oligonucleotides for treatment of HCV infection has also been proposed as has the use of free bile acids, such as ursodeoxycholic acid and chenodeoxycholic acid, and conjugated bile acids, such as tauroursodeoxycholic acid.
  • Phosphonoformic acid esters have also been proposed as potentially 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.
  • NS5B the RNA-dependent RNA polymerase
  • VP32947 (3-[((2-dipropylamino)ethyl)thio]-5H-l,2,4-triazino[5,6-b]indole) is a potent inhibitor of pesti virus replication and most likely inhibits the NS5B enzyme since resistant strains are mutated in this gene.
  • the present invention provides compounds of formula (I):
  • X is -O-, -S-, -NH-, -N(R 9 )-, -OC(R 8 ) 2 O- or -OC(R 8 ) 2 N(R 9 )-;
  • Z is -N- or-C(R 31 )-;
  • R 4 , R 5 , R 6 and R 7 are each, independently, H, alkyl, alkenyl, alkynyl, aryl, -[C(R 12 ) 2 ] q - cycloalkyl, -[C(R 12 ) 2 ] q -cycloalkenyl, -[C(R 12 ) 2 ] q -heterocycloalkyl, -[C(R 12 ) 2 ] q - heterocycloalkenyl, -[C(R 12 ) 2 ] q -heteroaryl, -[C(R 12 ) 2 ] q -haloalkyl, -[C(R 12 ) 2 ] q -hydroxyalkyl, halo, hydroxy, -OR 9 , -CN, -[C(R 12 ) 2 ] q -C(O)R 8 , -[C(R 12 ) 2 ] q
  • R 31 is H, alkyl, alkenyl, alkynyl, aryl, -[C(R 12 ) 2 ] q -cycloalkyl, -[C(R 12 ) 2 ] q -cycloalkenyl, - [C ⁇ ' ⁇ q -heterocycloalkyl, -[C(R l2 ) 2 ] q -heterocycloalkenyl, -[C(R l2 ) 2 ] q -heteroaryl, -[C(R 12 ) 2 ] q - haloalkyl, -[C(R I2 ) 2 ] q -hydroxyalkyl, halo, hydroxy, -OR 9 or -CN; each occurrence of p is independently 0, 1 or 2; each occurrence of q is independently an integer ranging from 0 to 4; and each occurrence of r is independently an integer ranging from 1 to 4.
  • the compounds of formula (I) (the "Tetracyclic Indole Derivatives") and pharmaceutically acceptable salts, solvates, esters and prodrugs thereof can be useful for treating or preventing a viral infection or a virus-related disorder in a patient.
  • Also provided by the invention are methods for treating or preventing a viral infection or a virus-related disorder in a patient, comprising administering to the patient an effective amount of at least one Tetracyclic Indole Derivative.
  • the present invention further provides pharmaceutical compositions comprising an effective amount of at least one Tetracyclic Indole Derivative or a pharmaceutically acceptable salt, solvate thereof, and a pharmaceutically acceptable carrier.
  • the compositions can be useful for treating or preventing a viral infection or a virus-related disorder in a patient.
  • the details of the invention are set forth in the accompanying detailed description below.
  • the present invention provides Tetracyclic Indole Derivatives, pharmaceutical compositions comprising at least one Tetracyclic Indole Derivative, and methods of using the Tetracyclic Indole Derivatives for treating or preventing a viral infection in a patient.
  • a "patient” is a human or non-human mammal.
  • a patient is a human.
  • a patient is a non-human mammal, including, but not limited to, a monkey, dog, baboon, rhesus, mouse, rat, horse, cat or rabbit.
  • a patient is a companion animal, including but not limited to a dog, cat, rabbit, horse or ferret.
  • a patient is a dog.
  • a patient is a cat.
  • alkyl refers to an aliphatic hydrocarbon group, wherein one of the aliphatic hydrocarbon group's hydrogen atoms is replaced with a single bond.
  • An alkyl group can be straight or branched and can 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 another embodiment, an alkyl group contains from about 1 to about 6 carbon atoms.
  • 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 optionally 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, -O-aryl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, cyano, hydroxy, - O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, alkylthio, -NH 2 , -NH(alkyl), -N(alkyl) 2 , -NH-aryl, - NH-heteroaryl, -NHC(O)-alkyl, -NHC(O)NH-alkyl, -NHSO 2 -alkyl, -NHSO 2 -aryl, -NHSO 2 - heteroaryl, -NH(cycloalkyl), -OC(O)-alkyl,
  • an alkyl group is unsubstituted.
  • an alkyl group is a straight chain alkyl group.
  • an alkyl group is a branched alkyl group.
  • alkenyl refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond, wherein one of the aliphatic hydrocarbon group's hydrogen atoms is replaced with a single bond.
  • An alkenyl group can be straight or branched and can contain from about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 10 carbon atoms. In another embodiment, an alkenyl group contains from about 2 to about 6 carbon atoms.
  • Non-limiting examples of illustrative alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
  • An alkenyl group may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, alkynyl, -O-aryl, aryl, cycloalkyl, cycloalkenyl, cyano, hydroxy, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, alkylthio, -NH 2 , -NH(alkyl), - N(alkyl) 2 , -NH-aryl, -NH-heteroaryl, -NHC(O)-alkyl, -NHC(O)NH-alkyl, -NHSO 2 -alkyl, - NHSO 2 -aryl, -NHSO 2 -heteroaryl, -NH(cycloalkyl), -OC(O)-alkyl, -OC
  • alkynyl refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond, wherein one of the aliphatic hydrocarbon group's hydrogen atoms is replaced with a single bond.
  • An alkynyl group can be straight or branched and can contain from about 2 to about 15 carbon atoms. In one embodiment, an alkynyl group contains from about 2 to about 10 carbon atoms. In another embodiment, an alkynyl group contains from about 2 to about 6 carbon atoms.
  • Non-limiting examples of illustrative alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl.
  • An alkynyl group may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, alkenyl, -O-aryl, aryl, cycloalkyl, cycloalkenyl, cyano, hydroxy, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, alkylthio, -NH 2 , -NH(alkyl), -N(alkyl) 2 , -NH-aryl, -NH-heteroaryl, - NHC(O)-alkyl, -NHC(O)NH-alkyl, -NHSO 2 -alkyl, -NHSO 2 -aryl, -NHSO 2 -heteroaryl, - NH(cycloalkyl), -OC(O)-alkyl, -
  • an alkynyl group is unsubstituted. In another embodiment, an alkynyl group is a straight chain alkynyl group. In another embodiment, an alkynyl group is a branched alkynyl group.
  • alkylene refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms is replaced with a bond.
  • alkylene include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, - CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 - and -CH 2 CH 2 CH(CH 3 )-.
  • an alkylene group is a straight chain alkylene group.
  • an alkylene group is a branched alkylene group.
  • Aryl means an aromatic monocyclic or multicyclic ring system having from about 6 to about 14 ring carbon atoms. In one embodiment, an aryl group has from about 6 to about 10 ring 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. Non- limiting examples of illustrative aryl groups include phenyl and naphthyl. In one embodiment, an aryl group is unsubstituted. In another embodiment, an aryl group is a phenyl group.
  • cycloalkyl refers to a non-aromatic mono- or multicyclic ring system having from about 3 to about 10 ring carbon atoms. In one embodiment, a cycloalkyl has from about 5 to about 10 ring carbon atoms. In another embodiment, a cycloalkyl has from about 5 to about 7 ring carbon atoms.
  • Non-limiting examples of illustrative monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Non-limiting examples of illustrative multicyclic cycloalkyls include 1-decalinyl, norbomyl, adamantyl and the like.
  • 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.
  • cycloalkenyl refers to a non-aromatic mono- or multicyclic ring system comprising from about 3 to about 10 ring carbon atoms and containing at least one endocyclic double bond. In one embodiment, a cycloalkenyl contains from about 5 to about 10 ring carbon atoms. In another embodiment, a cycloalkenyl contains 5 or 6 ring carbon atoms.
  • Non-limiting examples of illustrative 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. In one embodiment, a cycloalkenyl group is unsubstituted.
  • halo means -F, -Cl, -Br or -I. In one embodiment, halo refers to -Cl or -F.
  • haloalkyl refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a halogen.
  • a haloalkyl group has from 1 to 6 carbon atoms.
  • a haloalkyl group is substituted with from 1 to 3 F atoms.
  • Non-limiting examples of illustrative haloalkyl groups include -CH 2 F, -CHF 2 , -CF 3 , -CH 2 Cl and -CCl 3 .
  • 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.
  • a hydroxyalkyl group has from 1 to 6 carbon atoms.
  • Non-limiting examples of illustrative hydroxyalkyl groups include hydroxymethyl, 2-hydroxyethyl, 3- hydroxypropyl, 4-hydroxybutyl and -CH(OH)CH 2 CH 3 .
  • 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 monocyclic and has 5 or 6 ring atoms and at least one nitrogen ring atom.
  • 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 has been fused to a benzene ring.
  • Non-limiting examples of illustrative heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[l,2-a]pyridinyl, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl
  • heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
  • a heteroaryl group is a 6-membered heteroaryl group.
  • a heteroaryl group is a 5-membered heteroaryl group.
  • heterocycloalkyl refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to about 10 ring atoms, wherein from 1 to 4 of the ring atoms are independently O, S or N and the remainder of the ring atoms are carbon atoms.
  • a heterocycloalkyl group has from about 5 to about 10 ring atoms.
  • a heterocycloalkyl group has 5 or 6 ring atoms. 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.
  • 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 heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Non-limiting examples of illustrative monocyclic heterocycloalkyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
  • a ring carbon atom of a heterocycloalkyl group may be functionalized as a carbonyl group.
  • An illustrative example of such a heterocycloalkyl group is is pyrrolidonyl:
  • a heterocycloalkyl group is a 6-membered heterocycloalkyl group. In another embodiment, a heterocycloalkyl group is a 5-membered heterocycloalkyl group.
  • heterocycloalkenyl refers to a heterocycloalkyl group, as defined above, wherein the heterocycloalkyl group contains from 3 to 10 ring atoms, and at least one endocyclic carbon-carbon or carbon-nitrogen double bond.
  • a heterocycloalkenyl group has from 5 to 10 ring atoms.
  • a heterocycloalkenyl group is monocyclic and has 5 or 6 ring atoms.
  • a heterocycloalkenyl group can optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above.
  • heterocycloalkenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • illustrative 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, pyridonyl (including N-sbustituted pyridone), dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydr
  • a heterocycloalkenyl group is a 6-membered heterocycloalkenyl group. In another embodiment, a heterocycloalkenyl group is a 5-membered heterocycloalkenyl group.
  • 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, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, aralkoxy, acyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulf
  • Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogens on the same carbon atom (such as to to form a carbonyl group) or replaces two available hydrogen atome on two adjacent carbon atoms (one H on each carbon) on a ring system.
  • substituted me ⁇ ans that on-e 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.
  • purified in purified form or “in isolated and purified form” for a compound refers to the physical state of said compound after being 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.
  • variable e.g., aryl, heterocycle, R 1 ', etc.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.
  • the transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • mechanisms e.g., by metabolic or chemical processes
  • prodrugs are provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • 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-Cg)alkyl, (C 2 -Ci 2 )alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Q-Cejalkanoyloxymethyl, 1-((C 1 -C 6 )alkanoyloxy)ethyl, 1- methyl-l-((Ci-C6)alkanoyloxy)ethyl, (Ci-QOalkoxycarbonyloxymethyl, N-(Cj- C 6 )alkoxycarbonylaminomethyl, succinoyl, (Ci-C 6 )alkanoyl, ⁇ -amino(C 1 -C 4 )alkanyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L- amino acids, P(O)(OH) 2 ,
  • 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 where R and R' are each independently (Ci-C 10 )alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ - aminoacyl or natural ⁇ -aminoacyl, — C(OH)C(O)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
  • 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 illustrative solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceutical Sci., 93(3). 601 -611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 50), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001).
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • an effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention that is effective to treat or prevent a viral infection or a virus-related disorder.
  • Metabolic conjugates such as glucuronides and sulfates which can undergo reversible conversion to the Tetracyclic Indole Derivatives are contemplated in the present invention.
  • Tetracyclic Indole Derivatives may form salts, and all such salts are contemplated within the scope of this invention.
  • Reference to a Tetracyclic Indole Derivative 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.
  • Tetracyclic Indole Derivative 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
  • Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful.
  • Salts of the compounds of the Formula I may be formed, for example, by reacting a Tetracyclic Indole Derivative 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.
  • 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 dicyclohexylamines, t-butyl amines, choline, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
  • esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, Ci- 4 alkyl, or or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and
  • the Tetracyclic Indole Derivatives may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the Tetracyclic Indole Derivatives as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a Tetracyclic Indole Derivative 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.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • converting e.g., hydrolyzing
  • some of the Tetracyclic Indole Derivatives maybe atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • the straight line as a bond generally indicates a mixture of, or either of, the possible isomers, non-limiting example(s) include, containing (R)- and (S)- stereochemistry.
  • the possible isomers include, containing (R)- and (S)- stereochemistry.
  • a dashed line ( ) represents an optional bond.
  • the indicated line (bond) may be attached to any of the substitutable ring atoms, non limiting examples include carbon, nitrogen and sulfur ring atoms.
  • 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 equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, positional isomers, racemates or prodrugs of the inventive compounds.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Such compounds are useful as therapeutic, diagnostic or research reagents.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 U, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Tetracyclic Indole Derivatives are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 4 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labelled Tetracyclic Indole Derivatives can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
  • Tetracyclic Indole Derivatives Polymorphic forms of the Tetracyclic Indole Derivatives, and of the salts, solvates, hydrates, esters and prodrugs of the Tetracyclic Indole Derivatives, are intended to be included in the present invention.
  • ATP is adenosine-5 '-triphosphate
  • BSA bovine serum albumin
  • CDCl 3 deuterated chloroform
  • CTP is cytidine-5 '-triphosphate
  • DABCO is l,4-diazabicyclo[2.2.2]octane
  • dba is dibenzylideneacetone
  • DME is dimethoxyethane
  • DMF is N ⁇ V-dimethylformamide
  • DMSO dimethylsulfoxide
  • dppf is l,r-bis(diphenylphosphino)ferrocene
  • DTT is 1,4-dithio-threitol
  • EDCI is l-(3-dimethylaminopropyl)-3- ethylcarbodiimide
  • EDTA is ethylenediaminetetraacetic acid
  • Et 3 N is triethylamine
  • EtOAc is ethyl
  • the present invention provides Tetracyclic Indole Derivatives having the formula:
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-.
  • X is -O-.
  • X is -S-.
  • X is -NH-.
  • X is -N(R 9 )-.
  • X is -OC(R 8 ) 2 O-.
  • X is -OC(R 8 ) 2 N(R 9 )-.
  • Y O.
  • Y NH.
  • Y NR 9 .
  • Y NSOR n .
  • Y NSO 2 R n .
  • Y NSO 2 N(R n ) 2 .
  • Z is -N-.
  • Z is -C(R 3 ')- hi another embodiment, Z is -CH-.
  • Z is -C(R 31 ) and R 31 is halo.
  • Z is -CF-.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • R 11 is alkyl, cycloalkyl, haloalkyl or heterocycloalkyl.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • R 11 is methyl, ethyl, isopropyl, cyclopropyl or phenyl.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Y is -O- or ⁇ N ⁇ R ⁇ SOR 1 ' ;
  • Z is -C(R 3 V, and R 9 is H, methyl, ethyl or cyclopropyl.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-; and Z is -C(R 31 )-.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-; and
  • R 1 is - [C(R 12 ) 2 ] r -.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-; and
  • R 1 is -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )- or
  • X is -O-, -OCH 2 O-,. -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-;
  • R 1 is - [C(R 12 ) 2 ] r -; and
  • R 4 and R 7 are each independently H, halo or hydroxy.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-;
  • R 1 is - [C(R 12 ) 2 ] r -; and
  • R 5 is H, alkyl, -O-alkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, - NH 2 Or -CN.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-;
  • R 1 is -[C(R 12 ) 2 ] r -; and
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-;
  • R 1 is - [C(R 12 )2]rS and R 5 and R 6 groups, together with the common carbon atom to which they are attached, , join to form a 3- to 7-membered cyclic group, selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-;
  • R 1 is - [C(R 12 ) 2 ] ⁇ -; and
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-;
  • R 1 is - [C(R 12 ) 2 ] r -; and
  • R 6 is H, alkyl, -O-alkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, - NH 2 Or -CN.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-;
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-;
  • R 1 is
  • R 10 is phenyl, naphthyl, pyridyl, quinolinyl or quinoxalinyl.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-;
  • R 1 is -
  • R 13 is H, F, Br or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, - NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyl, -S-alkyl, -CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-;
  • R 1 is -
  • R 6 is H, alkyl, -O-alkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NH 2 or -CN; and R 10 is:
  • R 13 is H, F, Br or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, - NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyl, -S-alkyl, -CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-;
  • R 1 is -
  • R is methyl, ethyl or cyclopropyl; R is H, Cl, F or
  • R 10 is: wherein R 13 is H, F, Br or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, - NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -S0 2 alkyl, -SO 2 NHalkyl, -S-alkyl, -CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • X and Y are each O; R 1 is -CH 2 -; and R 10 is:
  • R 13 is H, F, Br or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, - NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -S0 2 alkyl, -SO 2 NHalkyl, -S-alkyl, -CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • X and Y are each O; Z is -CH-; R 1 is -CH 2 -; and R 10 is:
  • R 13 is H, F, Br or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, - NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyl, -S-alkyl, -CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • X is O and Y is O.
  • X is O
  • Y is O
  • Z is -C(R 31 )-.
  • X is O, Y is O, Z is -C(R 31 )- and R 31 is H or halo.
  • X is O, Y is O, Z is -C(R 31 )- and R 31 is H or F.
  • X is O, Y is O and Z is -CH-.
  • X is O, Y is O and Z is -C(F)-.
  • X is O, Y is O and Z is -C(Cl)-.
  • X is O, Y is O, Z is -C(R 31 )-, each occurrence of R 30 is H, and R 31 is H or halo.
  • X is O, Y is O, Z is -C(F)-, and each occurrence of R 30 is H.
  • X is O, Y is O, Z is -CH-, and each occurrence of R 30 is H.
  • X is O, Y is O, Z is -CH-, one occurrence of R 30 is alkyl and the other occurrence of R 30 is H.
  • X is O, Y is O, Z is -CH-, one occurrence of R 30 is methyl and the other occurrence of R 30 is H.
  • X is O, Y is O, Z is -CH-, one occurrence of R 30 is -O- alkylene-C(O)O-H, and the other occurrence of R 30 is H.
  • X is O
  • Y is O
  • Z is -CH-
  • one occurrence of R 30 is -O- alkylene-C(O)O-alkyl
  • the other occurrence of R 30 is H.
  • X is O
  • Y is O
  • Z is -C(R 31 )-
  • R 31 is halo
  • each occurrence of R 30 is H.
  • R 1 is a bond or -[C(R 12 ) 2 ] r -. In another embodiment, R 1 is a bond In another embodiment, R 1 is -[C(R I2 ) 2 ] r -.
  • R 1 is -[C(R 12 ) 2 ] r -O-[C(R 12 ) 2 ] q -.
  • R 1 is -[C(R I2 ) 2 ]r-N(R 9 )-[C(R 12 ) 2 ] q -.
  • R 1 is -[C(R 12 ) 2 ] q -C ⁇ C-[C(R 12 ) 2 ] q -.
  • R 1 is -[C(R 12 ) 2 ] q -SO 2 -[C(R 12 ) 2 ] q -.
  • R 1 is -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )- or
  • R 1 is -CH 2 -. In another embodiment, R 1 is -CH 2 CH 2 -. In still another embodiment, R 1 is -CH(CH 3 )-
  • R 1 is:
  • R 1 is H.
  • R 10 is aryl. In another embodiment, R 10 is cycloalkyl.
  • R 10 is cycloalkenyl
  • R 10 is heterocycloalkenyl.
  • R 10 is heteroaryl
  • R 10 is heterocycloalkyl. In another embodiment, R 10 is phenyl.
  • R 10 is pyridyl
  • R 10 is quinolinyl
  • R 10 is aryl or heteroaryl, either of which can be optionally substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -S(O) 2 -haloalkyl, -C(O)NH 2 , -C(O)NH-alkyl, -OH, NHS(O) 2 -alkyl, -NHS(O) 2 - cycloalkyl, -O-alkyl, -C(O)NH-alkylene-cycloalkyl, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or - NHS(O) 2 -alkyl.
  • 1-4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 , -CN, -NO 2 , -S(O) 2 NH 2
  • R 10 is aryl, which can be optionally substituted with from 1-4 groups independently selected from: halo, alkyl, -CN, -NO 2 , -N(R 9 ) 2 , -S(O) 2 NH 2 , -C(O)NH 2 , - S(O) 2 -haloalkyl, -C(O)NH-alkyl, -NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, -C(O)NH- alkylene-cycloalkyl, -OH, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 10 is heteroaryl, which is substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -S(O) 2 -haloalkyl, - C(O)NH 2 , -C(O)NH-alkyl, -OH, NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, -C(O)NH- alkylene-cycloalkyl, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 10 is heteroaryl, which is substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 or -O-alkyl.
  • R 10 is
  • R 13 is F or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyl, -S-alkyl, - CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycioalkyl and heteroaryl.
  • R 10 is
  • R 1 is F or Cl and R 4 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyl, -S-alkyl, - CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • R 10 is
  • R 13 is F or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyl, -S-alkyl, - CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • R 10 is pyridyl or quinolinyl, which is substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R ⁇ 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -S(O) 2 - haloalkyl, -C(O)NH 2 , -C(O)NH-alkyl, -OH, NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, - C(O)NH-alkylene-cycloalkyl, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 10 is pyridyl or quinolinyl, which is substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R ⁇ 2 or -O-alkyl.
  • R 10 is pyridyl, which is substituted with from 1 -4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -S(O) 2 -haloalkyl, - C(O)NH 2 , -C(O)NH-alkyl, -OH, NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, -C(O)NH- alkylene-cycloalkyl, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 10 is pyridyl, which is substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 or -O-alkyl. In one embodiment, R 10 is pyridyl, which is substituted with an -N(R 9 ) 2 group.
  • R 10 is pyridyl, which is substituted with an -NH 2 group. In another embodiment, R 10 is:
  • R 1 is quinolinyl, which is substituted with from 1-3 groups independently selected from Cl and F. In another embodiment, R 1 is:
  • R 10 is phenyl, which can be optionally substituted with from 1-4 groups independently selected from: halo, alkyl, -CN, -NO 2 , -N(R ⁇ 2 , -S(O) 2 NH 2 , -C(O)NH 2 , - S(O) 2 -haloalkyl, -C(O)NH-alkyl, -NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, -C(O)NH- alkylene-cycloalkyl, -OH, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 10 is phenyl, which is substituted with one F atom and can be further and optionally substituted with from 1-3 groups independently selected from: halo, alkyl, -CN, -NO 2 , -N(R 9 ) 2 , -S(O) 2 NH 2 , -C(O)NH 2 , -S(O) 2 -haloalkyl, -C(O)NH-alkyl, - NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, -C(O)NH-alkylene-cycloalkyl, -OH, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 10 is phenyl, which is substituted with two F atoms and can be further and optionally substituted with from 1-2 groups independently selected from: halo, alkyl, -CN, -NO 2 , -N(R 9 ) 2 , -S(O) 2 NH 2 , -C(O)NH 2 , -S(O) 2 -haloalkyl, -C(O)NH-alkyl, - NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, -C(O)NH-alkylene-cycloalkyl, -OH, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 10 is phenyl, which is substituted with from 1-2 groups independently selected from halo and -NO 2 .
  • R 10 is phenyl, which is substituted with from 1-2 groups independently selected from F and -NO 2 .
  • -R 10 is:
  • R represents up to 2 optional and additional phenyl substituents, each independently selected from halo, -O-alkyl, alkyl, -CF 3 , -CN, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)OH, - NH 2 , -SO 2 -alkyl, -SO 2 NH-alkyl, -S-alkyl, -CH 2 NH 2 , -SO 2 NH 2 , -NHC(O)- alkyl, -C(O)O-alkyl, -C(0)-heterocycloalkyl and heteroaryl.
  • R 10 is
  • R 1 is -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )- or
  • R 10 is aryl or heteroaryl, either of which can be optionally substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -S(O) 2 - haloalkyl, -C(O)NH 2 , -C(O)NH-alkyl, -OH, NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, - C(O)NH-alkylene-cycloalkyl, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 1 is -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )- or
  • R 10 is aryl, which can be optionally substituted with from 1-4 groups independently selected from: halo, alkyl, -CN, -NO 2 , -N(R 9 ) 2 , -S(O) 2 NH 2 , -C(O)NH 2 , -S(O) 2 - haloalkyl, -C(O)NH-alkyl, -NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, -C(O)NH- alkylene-cycloalkyl, -OH, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 1 is -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )- or
  • R 10 is heteroaryl, which is substituted with from 1 -4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -S(O) 2 -haloalkyl, -C(O)NH 2 , - C(O)NH-alkyl, -OH, NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, -C(O)NH-alkylene- cycloalkyl, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 1 is -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )- or
  • R 10 is heteroaryl, which is substituted with from 1 -4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 or -O-alkyl.
  • R 1 is -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )- or wherein R 13 is F or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -S0 2 alkyl, -SO 2 NHalkyl, -S-alkyl, - CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • R 1 is -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )- or
  • R 10 is phenyl, which can be optionally substituted with from 1-4 groups independently selected from: halo, alkyl, -CN, -NO 2 , -N(R 9 ) 2 , -S(O) 2 NH 2 , -C(O)NH 2 , -S(O) 2 - haloalkyl, -C(O)NH-alkyl, -NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, -C(O)NH- alkylene-cycloalkyl, -OH, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 1 is -CH 2 - and R 1 is aryl or heteroaryl, either of which can be optionally substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 , - CN, -NO 2 , -S(O) 2 NH 2 , -S(O) 2 -haloalkyl, -C(O)NH 2 , -C(O)NH-alkyl, -OH, NHS(O) 2 -alkyl, - NHS(O) 2 -cycloalkyl, -O-alkyl, -C(O)NH-alkylene-cycloalkyl, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 1 is -CH 2 - and R 10 is aryl, which can be optionally substituted with from 1-4 groups independently selected from: halo, alkyl, -CN, -NO 2 , -N(R 9 ) 2 , - S(O) 2 NH 2 , -C(O)NH 2 , -S(O) 2 -haloalkyl, -C(O)NH-alkyl, -NHS(O) 2 -alkyl, -NHS(O) 2 - cycloalkyl, -O-alkyl, -C(O)NH-alkylene-cycloalkyl, -OH, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or - NHS(O) 2 -alkyl.
  • 1-4 groups independently selected from: halo, alkyl, -CN, -NO 2 , -N(R 9 ) 2 , - S
  • R 1 is -CH 2 - and R .1 ⁇ 0 ⁇ is heteroaryl, which is substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R ⁇ 2 , -CN, -NO 2 , -S(O) 2 NH 2 , - S(O) 2 -haloalkyl, -C(O)NH 2 , -C(O)NH-alkyl, -OH, NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O- alkyl, -C(O)NH-alkylene-cycloalkyl, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 1 is -CH 2 - and R 1 is heteroaryl, which is substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R ⁇ 2 or -O-alkyl.
  • R 1 is -CH 2 - and R 10 is
  • R 13 is F or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -S0 2 alkyl, -SO 2 NHalkyl, -S-alkyl, - CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • R 1 is -CH 2 - and R 10 is
  • R 13 is F or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -S0 2 alkyl, -SO 2 NHalkyl, -S-alkyl, - CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • R i i •s -CH 2 - and R , 10 is
  • R 13 is F or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyl, -S-alkyl, - CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(0)-heterocycloalkyl and heteroaryl.
  • R 1 is -CH 2 - and R 10 is pyridyl or quinolinyl, which is substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -S(O) 2 -haloalkyl, -C(O)NH 2 , -C(O)NH-alkyl, -OH, NHS(O) 2 -alkyl, -NHS(O) 2 - cycloalkyl, -O-alkyl, -C(O)NH-alkylene-cycloalkyl, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or - NHS(O) 2 -alkyl.
  • R 1 is -CH 2 - and R 10 is pyridyl or quinolinyl, which is substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 or -O-alkyl.
  • R 1 is -CH 2 - and R 10 is pyridyl, which is substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -S(O) 2 - haloalkyl, -C(O)NH 2 , -C(O)NH-alkyl, -OH, NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, - C(O)NH-alkylene-cycloalkyl, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 1 is -CH 2 - and R 10 is pyridyl, which is substituted with from 1-4 groups independently selected from: halo, alkyl,
  • R 1 is -CH 2 - and R 10 is pyridyl, which is substituted with an - N(R 9 ) 2 group.
  • R 1 is -CH 2 - and R 10 is pyridyl, which is substituted with an - NH 2 group.
  • R 1 is -CH 2 - and R 10 is:
  • R 1 is -CH 2 - and R 10 is quinolinyl, which is substituted with from 1-3 groups independently selected from Cl and F.
  • R 1 is -CH 2 - and R 10 is:
  • R 1 is -CH 2 - and R 10 is phenyl, which can be optionally substituted with from 1-4 groups independently selected from: halo, alkyl, -CN, -NO 2 , -N(R 9 ) ⁇ - S(O) 2 NH 2 , -C(O)NH 2 , -S(O) 2 -haloalkyl, -C(O)NH-alkyl, -NHS(O) 2 -alkyl, -NHS(O) 2 - cycloalkyl, -O-alkyl, -C(O)NH-alkylene-cycloalkyl, -OH, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or - NHS(O) 2 -alkyl.
  • 1-4 groups independently selected from: halo, alkyl, -CN, -NO 2 , -N(R 9 ) ⁇ - S(O)
  • R 1 is -CH 2 - and R 10 is phenyl, which is substituted with one F atom and can be further and optionally substituted with from 1 -3 groups independently selected from: halo, alkyl, -CN, -NO 2 , -N(R 9 ) 2 , -S(O) 2 NH 2 , -C(O)NH 2 , -S(O) 2 -haloalkyl, - C(O)NH-alkyl, -NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, -C(O)NH-alkylene- cycloalkyl, -OH, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 1 is -CH 2 - and R 10 is phenyl, which is substituted with two F atoms and can be further and optionally substituted with from 1-2 groups independently selected from: halo, alkyl, -CN, -NO 2 , -N(R 9 ) 2 , -S(O) 2 NH 2 , -C(O)NH 2 , -S(O) 2 -haloalkyl, - C(O)NH-alkyl, -NHS(O) 2 -alkyl, -NHS(0) 2 -cycloalkyl, -O-alkyl, -C(O)NH-alkylene- cycloalkyl, -OH, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • 1-2 groups independently selected from: halo, alkyl, -CN, -NO 2 , -
  • R 1 is -CH 2 - and R 10 is phenyl, which is substituted with from 1-2 groups independently selected from halo and -NO 2 .
  • R 1 is -CH 2 - and R 10 is phenyl, which is substituted with from 1-2 groups independently selected from F and -NO 2 .
  • R 1 is -CH 2 - and R 10 is:
  • R represents up to 2 optional and additional phenyl substituents, each independently selected from halo, -O-alkyl, alkyl, -CF 3 , -CN, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)OH, - NH 2 , -SO 2 -alkyl, -SO 2 NH-alkyl, -S-alkyl, -CH 2 NH 2 , -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • R 1 is -CH 2 - and R 10 is
  • -R 1 -R 10 is alkyl. In another embodiment, -R 1 -R 10 is haloalkyl.
  • -R'-R 10 is -R 1 -R 10 is benzyl, wherein the phenyl moiety of the benzyl group is substituted with 1 or 2 fluorine atoms.
  • -R 1 -R 10 is -R'-R 10 is benzyl, wherein the phenyl moiety of the benzyl group is substituted with one fluorine atom and one nitro group.
  • -R'-R 10 is -CH 2 -cycloalkyl.
  • R 4 , R 5 , R 6 and R 7 are each independently selected from H, halo, - O-alkyl, alkyl or haloalkyl.
  • R 4 , R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, -O-methyl, methyl, ethyl or -CF 3 .
  • R 4 is H.
  • R 4 is F.
  • R 5 is halo, alkyl or haloalkyl.
  • R 5 is F, Cl, Br, -O-methyl, methyl, ethyl or -CF 3 In another embodiment, R 5 is H.
  • R 5 is alkyl
  • R 5 is methyl
  • R 5 is ethyl
  • R 5 is halo. In another embodiment, R 5 is F.
  • R 5 is haloalkyl
  • R 5 is -CF 3 .
  • R 6 is H.
  • R 6 is H, halo or -O-alkyl. In another embodiment, R 6 is F.
  • R 6 is methoxy
  • R 7 is H.
  • R 4 and R 7 are each H.
  • R 4 , R 6 and R 7 are each H. In another embodiment, R 4 , R 5 , R 6 and R 7 are each H.
  • R 4 , R 6 and R 7 are each H and R 5 is other than H.
  • R 5 is selected from H, halo, -O-alkyl, alkyl or haloalkyl and R 4 , R 6 and R 7 are each H. In one embodiment, R 5 is selected from F 3 Cl, Br, -O-methyl, methyl, ethyl or -CF 3 and R 4 , R 6 and R 7 are each H.
  • R 5 is selected from F, methyl, ethyl or -CF 3 , and R 4 , R 6 and R 7 are each H. In another embodiment, R 5 is alkyl and R 4 , R 6 and R 7 are each H.
  • R 5 is methyl and R 4 , R 6 and R 7 are each H.
  • R 5 is ethyl and R 4 , R 6 and R 7 are each H.
  • R 5 is -CF 3 and R 4 , R and R are each H.
  • R 5 is halo and R 4 , R 6 and R 7 are each H. In another embodiment, R 5 is F and R 4 , R 6 and R 7 are each H.
  • R 5 is alkyl
  • R 6 is H, halo or -O-alkyl
  • R 6 and R 7 are each H.
  • R 5 is ethyl
  • R 6 is H, halo or -O-alkyl
  • R 6 and R 7 are each H.
  • R 5 is ethyl
  • R 6 is H, F or methoxy
  • R 6 and R 7 are each H.
  • R 10 is aryl or heteroaryl, either of which can be optionally substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -S(O) 2 - haloalkyl, -C(O)NH 2 , -C(O)NH-alkyl, -OH, NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, - C(O)NH-alkylene-cycloalkyl, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R , 10 is aryl, which can be optionally substituted with from 1-4 groups independently selected from: halo, alkyl, -CN, -NO 2 , -N(R 9 ) 2 , -S(O) 2 NH 2 , -C(O)NH 2 , -S(O) 2 - haloalkyl, -C(O)NH-alkyl, -NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, -C(O)NH- alkylene-cycloalkyl, -OH, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • X is O; Y is O; R 1 is -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )- or ; and R 10 is heteroaryl, which is substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R 9 K -CN, -NO 2 , -S(O) 2 NH 2 , -S(O) 2 -haloalkyl, -C(O)NH 2 , - C(O)NH-alkyl, -OH, NHS(O) 2 -alkyl 5 -NHS(O) 2 -cycloalkyl, -O-alkyl, -C(O)NH-alkylene- cycloalkyl, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 10 is heteroaryl, which is substituted with from 1-4 groups independently 1 from: halo, alkyl, -N(R 9 ) 2 or -O-alkyl.
  • X is O;
  • Y is O;
  • R 1 is -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )- or
  • R 13 is F or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyl, -S-alkyl, - CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • R 10 is phenyl, which can be optionally substituted with from 1-4 groups independently selected from: halo, alkyl, -CN, -NO 2 , -N(R 9 ) 2 , -S(O) 2 NH 2 , -C(O)NH 2 , -S(O) 2 - haloalkyl, -C(O)NH-alkyl, -NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, -C(O)NH- alkylene-cycloalkyl, -OH, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • X is O; Y is O; R 1 is -CH 2 -; and R 10 is heteroaryl, which is substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 or -O-alkyl.
  • R 13 is F or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyl, -S-alkyl, - CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • R 13 is F or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -S0 2 alkyl, -SO 2 NHalkyl, -S-alkyl, - CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • R 13 is F or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -NO 2 ,
  • X is O; Y is O; R 1 is -CH 2 -; and R 1 is pyridyl or quinolinyl, which is substituted with from 1-4 groups independently selected from: halo, alkyl,
  • X is O; Y is O; R 1 is -CH 2 -; and R 10 is pyridyl or quinolinyl, which is substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 or
  • X is O; Y is O; R 1 is -CH 2 -; and R 10 is pyridyl, which is substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 or -O-alkyl.
  • X is O; Y is O; R 1 is -CH 2 -; and R 10 is pyridyl, which is substituted with an -N(R ⁇ 2 group.
  • X is O; Y is O; R 1 is -CH 2 -; and R 10 is quinolinyl, which is substituted with from 1-3 groups independently selected from Cl and F.
  • X is O; Y is O; R 1 is -CH 2 -; and R 10 is:
  • R represents up to 2 optional an "d additional phenyl substituents, each independently selected from halo, -O-alkyl, alkyl, -CF 3 , -CN, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)OH, - NH 2 , -SO 2 -alkyl, -SO 2 NH-alkyl, -S-alkyl, -CH 2 NH 2 , -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • R >5 i -s alkyl; and R i IO is aryl or heteroaryl, either of which can be optionally substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -S(O) 2 -haloalkyl, -C(O)NH 2 , -C(O)NH-alkyl, -OH, NHS(O) 2 -alkyl, -NHS(O) 2 - cycloalkyl, -O-alkyl, -C(O)NH-alkylene-cycloalkyl, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or - NHS(O) 2 -alkyl.
  • R 5 is alkyl; and R 1 is aryl, which can be optionally substituted with from 1-4 groups independently selected from: halo, alkyl, -CN, -NO 2 , -N(R 9 ) 2 , -S(O) 2 NH 2 , -C(O)NH 2 , - S(O) 2 -haloalkyl, -C(O)NH-alkyl, -NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, -C(O)NH- alkylene-cycloalkyl, -OH, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 5 is alkyl; and R 1 is heteroaryl, which is substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -S(O) 2 -haloalkyl, - C(O)NH 2 , -C(O)NH-alkyl, -OH, NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, -C(O)NH- alkylene-cycloalkyl, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 13 is F or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyl, -S-alkyl, - CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • R represents up to 2 optional and additional phenyl substituents, each independently selected from halo, -O-alkyl, alkyl, -CF 3 , -CN, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)OH, - NH 2 , -SO 2 -alkyl, -SO 2 NH-alkyl, -S-alkyl, -CH 2 NH 2 , -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(0)-heterocycloalkyl and heteroaryl.
  • R 13 is F or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyl, -S-alkyl, - CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • R represents up to 2 optional and additional phenyl substituents, each independently selected from halo, -O-alkyl, alkyl, -CF 3 , -CN, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)OH, - NH 2 , -SO 2 -alkyl, -SO 2 NH-alkyl, -S-alkyl, -CH 2 NH 2 , -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • R 5 is alkyl
  • R 10 is aryl or heteroaryl, either of which can be optionally substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -S(O) 2 -haloalkyl, -C(O)NH 2 , -C(O)NH-alkyl, -OH, NHS(O) 2 -alkyl, -NHS(O) 2 - cycloalkyl, -O-alkyl, -C(O)NH-alkylene-cycloalkyl, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or - NHS(O) 2 -alkyl.
  • R is alkyl; and R is aryl, which can be optionally substituted with from 1-4 groups independently selected from: halo, alkyl, -CN, -NO 2 , -N(R 9 ) 2 , -S(O) 2 NH 2 , -C(O)NH 2 , - S(O) 2 -haloalkyl, -C(O)NH-alkyl, -NHS(O) 2 -alkyl, -NHS(0) 2 -cycloalkyl, -O-alkyl, -C(O)NH- alkylene-cycloalkyl, -OH, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 5 is alkyl; and R 1 is heteroaryl, which is substituted with from 1-4 groups independently selected from: halo, alkyl, -N(R 9 ) 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -S(O) 2 -haloalkyl, - C(O)NH 2 , -C(O)NH-alkyl, -OH, NHS(O) 2 -alkyl, -NHS(O) 2 -cycloalkyl, -O-alkyl, -C(O)NH- alkylene-cycloalkyl, haloalkyl, -S(O) 2 -alkyl, -S-alkyl or -NHS(O) 2 -alkyl.
  • R 13 is F or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -S0 2 alkyl, -SO 2 NHalkyl, -S-alkyl, - CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • R represents up to 2 optional and additional phenyl substiruents, each independently selected from
  • R represents up to 2 optional and additional phenyl substituents, each independently selected from halo, -O-alkyl, alkyl, -CF 3 , -CN, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)OH, - NH 2 , -SO 2 -alkyl, -SO 2 NH-alkyl, -S-alkyl, -CH 2 NH 2 , -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-; Z is -C(R 31 )-; R 1 is - [C(R 12 ) 2 ] r -; and R 4 and R 7 are each independently H, halo or hydroxy.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-; Z is -C(R 31 )-; R 1 is -
  • R 5 is H, alkyl, -O-alkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, - NH 2 Or-CN.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-;
  • R 1 is -[C(R l2 ) 2 ] r -; and R 4 and R 5 groups, together with the common carbon atom to which they are attached, join to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-;
  • R 1 is - [C(R 12 ) 2 ] r S and R 5 and R 6 groups, together with the common carbon atom to which they are attached, join to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-;
  • R 1 is - [C(R 12 ) 2 ] r -; and
  • R 6 is H, alkyl, -O-alkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, - NH 2 Or -CN.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-;
  • R 10 is aryl or heteroaryl.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-;
  • R 1 is
  • R 10 is phenyl, naphthyl, pyridyl, quinolinyl or quinoxalinyl.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 3 ')-;
  • R 1 is -
  • R 13 is H, F, Br or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, - NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyl, -S-alkyl, -CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 3
  • R 5 is H, alkyl, -O-alkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NH 2 or -CN
  • R 6 is H, alkyl, -O-alkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NH 2 or -CN
  • R 10 is:
  • R 13 is H, F, Br or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, - NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyl, -S-alkyl, -CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • X is -O-, -OCH 2 O-, -NH- or -OCH 2 NH-;
  • Z is -C(R 31 )-;
  • R 1 is -
  • R 5 is methyl, ethyl or cyclopropyl
  • R 6 is H, Cl, F or
  • R 10 is: wherein R 13 is H, F, Br or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -
  • X and Y are each O; R 1 is -CH 2 -; and R 10 is:
  • R 13 is H, F, Br or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, - NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyl, -S-alkyl, -CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • X and Y are each O; Z is -CH-; R 1 is -CH 2 -; and R 10 is:
  • R 13 is H, F, Br or Cl and R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, - NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyl, -S-alkyl, -CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl.
  • L — ⁇ ; and R 4 and R 7 are each independently H, alkyl, halo or hydroxy.
  • R 5 is H, alkyl, -O-haloalkyl, -O-alkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NH 2 or -CN; and R 6 is H, alkyl, -O-alkyl, -O-haloalkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NH 2 , -NH-alkyl or -CN.
  • R 4 and R 5 together with the common carbon atom to which they are attached, join to form a -3- to 7-membered cyclic group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
  • R 5 and R 5 together with the common carbon atom to which they are attached, join to form a -3- to 7-membered cyclic group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
  • R 13 is H, F, Br or Cl
  • R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyl, -S-alkyl, - CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl; and
  • R 5 is H, alkyl, -O-alkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NH 2 or -CN;
  • R 6 is H, alkyl, -O-alkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NH 2 or -CN; and
  • R 10 is:
  • R 13 is H, F, Br or Cl
  • R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyl, -S-alkyl, CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl; and
  • R 13 is H, F, Br or Cl
  • R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyI, -S-alkyl, - CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl; and
  • R 13 is H, F, Br or Cl
  • R 14 represents up to 4 optional and additional substiruents, each independently selected from alkyl, cycloalkyl, CF 3 , -CN, halo, -O-alkyl, -NHSO 2 -alkyl, -NO 2 , -C(O)NH 2 , -C(O)NH-alkyl, -C(O)OH, hydroxy, -NH 2 , -SO 2 alkyl, -SO 2 NHalkyl, -S-alkyl, - CH 2 NH 2 , -CH 2 OH, -SO 2 NH 2 , -NHC(O)-alkyl, -C(O)O-alkyl, -C(O)-heterocycloalkyl and heteroaryl; and represents a pyridyl group, wherein the ring nitrogen atom can be at any of the five unsubstituted ring atom positions.
  • the compound of formula (I) has the formula (Ia):
  • R 1 is a bond or an alkylene group
  • R 4 is H or or R 4 and R 5 , together with the carbon atoms to which they are attached, join to form a 5-membered cyclic group, selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
  • R 5 and R 6 are each independently H, halo, alkyl, -O-alkyl, haloalkyl, -O-haloalkyl, heterocycloalkenyl or cycloalkyl, or R 5 and R 6 , together with the carbon atoms to which they are attached, join to form a 5-membered cyclic group, selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
  • R 7 is H or or R 6 and R 7 , together with the carbon atoms to which they are attached, join to form a 5-membered cyclic group, selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
  • R 10 is H, halo, aryl, heterocycloalkenyl or heteroaryl, wherein an aryl or heteroaryl group can be optionally and independently substituted with up to 4 substituents, which are each independently selected from H, alkyl, halo, -NH 2 , -OH, , -CN, -NO 2 , -O-alkyl, -C(O)NH 2 , heteroaryl, -SO 2 NH 2 , -SO 2 NH-alkyl, -SO 2 -alkyl, phenyl, -NHC(O)OH, -S-alkyl, -NHSO 2 - alkyl, -NHSOa-cycloalkyl, -O-benzyl, -C(O)NH-alkyl, -S-haloalkyl or -S(O)-haloalkyl, such that when R 1 is a bond, R 10 is other than H; each occurrence of R 1
  • R 31 is H or halo.
  • a Tetracyclic Indole Derivative is in purified form.
  • Tetracyclic Indole Derivatives are set forth below in Tables 1 and 2 and in the Examples section below herein.
  • Scheme 1 shows one method for preparing compounds of formula A4, which are useful intermediates for making of the Tetracyclic Indole Derivatives.
  • R 4 -R 7 are defined above for the compounds of formula (I) and R is H, alkyl or aryl.
  • An aniline compound of formula i can be converted to an indole compound of formula iv using various indole syntheses that are well-known to those skilled in the art of organic synthesis, including but not limited to, a Fischer indole synthesis through intermediates of type ⁇ and ⁇ i, the method set forth in Nazare et al., Angew. Chem.. 116:4626-4629 (2004).
  • the compounds of formula iv can be further elaborated to provide the Tetracyclic Indole Derivatives using the method described below in Scheme 4.
  • Scheme 2 shows methods useful for making compounds vi ⁇ and x, which are useful intermediates for making of the Tetracyclic Indole Derivatives.
  • R 4 -R 7 are defined above for the compounds of formula (I) and R is H, alkyl or aryl.
  • a benzene derivative of formula v, wherein R 7 is H can be di-brominated to provide compound vi.
  • Selective de-bromination provides the corresponding monobromo analog vii, which under palladium catalyzed cyclization conditions provides the desired intermediate viii, wherein R 7 is H.
  • a compound of formula v, wherein R 7 is other than H can be monobrominated to provide compound ix.
  • a compound of formula ix can then undergo under palladium catalyzed cyclization conditions provides the desired intermediate x, wherein R 7 is other than H.
  • Scheme 3 illustrates methods by which intermediate compounds of formula xi can be further derivatized to provide the Tetracyclic Indole Derivatives, which are intermediates to the title Tetracyclic Indole derivatives.
  • R 1 , R 3 , R 4 -R 7 and R 10 are defined above for the compounds of formula (I);
  • PG is a carboxy protecting group; and
  • X is halo, -O-triflate, -B(OH) 2 , -Si(alkyl) 2 ⁇ H, -Sn(alkyl) 3 , - MgBr, -MgCl, -ZnBr, or -ZnCl; and M is any metal which can participate in an organometallic cross-coupling reaction.
  • An intermediate compound of formula xi can be converted to a 3-substituted indole of formula xii using methods well-known to one skilled in the art of organic synthesis.
  • a compound of formula xii, wherein X is halo or -O-triflate can then be coupled with an appropriate compound of formula R 3 -M (wherein M is -B(OH) 2 , -Si(alkyl) 2 ⁇ H, -Sn(alkyl) 3 , - MgBr, -MgCl, -ZnBr, -ZnCl, or any metal which can participate in an organometallic cross- coupling reaction) using an organometallic cross-coupling method.
  • a compound of formula xii wherein X is -B(OH) 2 , -Si(alkyl) 2 OH, -Sn(alkyl) 3 , -MgBr, -MgCl, -ZnBr, - ZnCl, or any metal which can participate in an organometallic cross-coupling reaction, can then be coupled with an appropriate compound of formula R 3 -M (wherein M is halo or -O- triflate) using an organometallic cross-coupling method.
  • Suitable cross-coupling methods include, but not limited to, a Stille coupling (see Choshi et al., J. Org.
  • Indole Derivatives and Q is a halo group.
  • a 3-haloindole compound of formula xvi can be coupled with a boronic acid of formula xvii using a Suzuki coupling reaction to provide the R 3 -substituted indole compounds of formula xvi ⁇ .
  • a compound of formula xvi ⁇ can be further elaborated using methods set forth above to provide the compounds of formula xix.
  • a compound of formula N can be converted to a compound of formula xx using strong acid, such as HCl.
  • a compound of formula xx can than be reacted with a base or dehydrating agent to provide the Tetracyclic Indole Derivatives.
  • Tetracyclic Indole Derivatives may require the need for the 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 the Tetracyclic Indole Derivatives and methods for their installation and removal may be found in Greene et al., Protective Groups in Organic Synthesis, Wiley-Interscience, New York, (1999).
  • the starting materials and the intermediates prepared using the methods set forth in Schemes 1-4 may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.
  • reaction mixture was diluted with dichloromethane (300 mL) and washed with water (2 x 100 mL) and brine (100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to provide compound 5B (9.20 g; 98 %) as a white solid.
  • indole derivative 5D (6.5 g, 15.237 mmol) in 50 mL of dry THF was added to an ice-cooled suspension of sodium hydride (1.3 eq, 792 mg of 60% suspension in mineral oil) in 50 mL of dry THF. The resulting solution was stirred for 10 min followed by addition of 2,5-difluorobenzyl bromide (1.3 eq, 2.54 mL, d 1.613). A catalytic amount of tetrabutylammonium iodide (0.2 eq, 1.12 g) was added to the reaction mixture and stirring was continued for 18 h (temperature from 0 to 25 0 C).
  • the reaction was quenched by addition of water (10 mL) and the mixture was diluted with ethyl acetate (500 mL). The organic layer was washed with water (2 x 100 mL) and brine (80 mL), dried over magnesium sulfate, filtered and concentrated to afford the crude product 5E as a colorless foam contaminated with undesired bis-N,O-difluorobenzyl product. The crude mixture was used for next reaction without further any further purification.
  • the reaction mixture was heated to 70 °C and stirred overnight. TLC (10% ethyl acetate in hexanes) and MS analyses showed complete conversion of starting material.
  • the mixture was diluted with ethyl acetate (80 mL) and washed successively with water (10 mL), 10% aq ammonium hydroxide (10 mL), water (10 mL), and brine (10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.
  • reaction mixture was diluted with dichloromethane (300 mL) and washed with water (2 x 200 mL) and brine (200 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to provide compound 7B (15.75 g) as a white solid.
  • the 2-methoxy-3-pyridine boronic acid (1.05 eq, 6.99 g) was added to a solution of 7C (19.4 g; 43.55 mmol) in 500 mL of 1 ,2-dimethoxyethane.
  • the mixture was degassed (vaccum/argon flush) and PdCl2(dppf) 2 (5 mol%, 1.78 g) was added and the resulting orange solution was stirred for 30 min at room temp.
  • a solution of potassium carbonate (4.0 eq, 174 mL of aq IM solution) was added and the resulting brown solution was stirred at 90 °C for 2 h.
  • the reaction mixture was cooled to room temperature and concentrated.
  • indole derivative 7D (4.0 g, 9.376 mmol) in 90 mL of dry DMF was ice- cooled and treated with 2,5-difluorobenzyl bromide (1.1 eq, 1.32 mL, d 1.613) and cesium carbonate (3.0 eq, 9.16 g). The mixture turned yellow in color and the ice- water bath was removed. A catalytic amount of tetrabutyl ammonium iodide (approx 20 mg) was added. The reaction mixture was stirred for 30 min where it became green in color and TLC (20% ethyl acetate in hexanes) showed no more starting materials left.
  • the reaction was quenched by addition of water (10 mL) and the mixture was diluted with ethyl acetate (400 mL). The organic layer was washed with water (3 x 80 mL) and brine (80 mL), dried over magnesium sulfate, filtered and concentrated to afford the crude product 7E. The crude mixture was used for next reaction without further any further purification.
  • reaction mixture was then diluted with EtOAc (200 mL) and the resulting solution was concentrated in vacuo to provide a crude residue which was purified using flash column chromatography (EtOAc/Hexanes, 0 to 30% EtOAc) to provide the product 1OD as a solid (820.0 mg).
  • reaction materials HC 200 mg, 0.59 mmol
  • 2-fluorobenzylchloride 170 mg, 1.76 mmol
  • cesium carbonate 700 mg, 2.16 mmol
  • DMF 3 ml
  • the resulting suspension was stirred at room temperature for 16 hours, diluted with ethyl acetate (100 ml), and washed with water (3X40 ml).
  • the organic solution was dried over sodium sulfate and concentrated.
  • the residue was purified by Combiflash chromatography on silica gel using 0-10% ethyl acetate in hexanes as the eluent to deliver the product HD as a gel (205 mg, 78%).
  • the starting materials 12A (15.0 g, 69.04 mmol) and THF (100 ml) were added to a 1000 ml round-bottomed flask. The resulting solution was cooled with a water bath. To this stirring solution, N-iodosuccinimide (15.30 g, 68.80 mmol) was added slowly. The resulting solution was allowed to stir at room temperature for 5 hours before 700 ml of water was added. The resulting mixture was continued to stir at room temperature for 30 min and then filtered. The cake was washed with water (2 X 40 ml), dried by air and then on house vacuum to provide compound 12B as an off-white solid (23.0 g, 97%). MS found 344.2 for Ci 3 H] 4 INO 2 + H + .
  • 2-methoxy-3 -pyridine boronic acid (2.94 g, 19.23 mmol) was added to a solution of 6- Fluoro-3-iodo-5-methyl-lH-indole-2-carboxylic acid methyl ester 13E (5.34 g, 16.03 mmol) in 1, 2 dimethoxyethane (105 mL).
  • the mixture was degassed and PdCl 2 (dppf) 2 (1.3g, l. ⁇ Ommol) was added to the reaction mixture. After the resulting orange solution was stirred at room temperature for 30 min., a solution OfK 2 CO 3 (8.86g in 64mL OfH 2 O) was added.
  • 14D 14E A solution of 4-ethyl-5-fiuoro-2-iodo-phenylamine (14D) (7.29 g; 27.50 mmol) in 60 mL of dry DMF was treated with pyruvic acid (3.0 eq, 7.26 g, d 1.267) and DABCO (3.0 eq, 9.24 g). The mixture was degassed (vacuum/nitrogen flush) and palladium(II) acetate (0.05 eq, 308 mg) was added. The resulting solution was heated to 105 0 C for 3 h.
  • the mixture was adsorbed on silica gel and purified on a Biotage 65-M column (gradient: 10 to 50% dichloromethane in hexanes) to provide compound 14F (3.0 g; 50 % for two steps) as a white solid.
  • the N,N-bis-Boc protected aminoisothiazole HA (480 mg; 0.730 mmol) was treated with 4 M HCl in dioxane (15 mL). The resulting slurry was stirred for 3 h at which point no more starting material remained according to TLC (50 % ethyl acetate in hexanes). The mixture was concentrated to dryness in vacuo to give the crude product HB (ca 99 %; 333 mg) as a slightly yellow solid which was used without further purification.
  • Lactone 19A (380 mg; 0.631 mmol) was diluted with 5 mL methylene dichloride to which 5 mL difluoro acetic acid was added. The reaction was stirred for 3 h. The reaction mixture was dried under reduced pressure and set to dry further under vacuum for 48 h. to afford dry 224.
  • the purified solid was dissolved in CH 2 Cl 2 (40 mL) and TFA (40 mL) and stirred at rt. for 1 h.
  • the reaction mixture was concentrated and treated with ether and the resulting solid 153 was filtered and dried.
  • N,N-Dimethylformamide (53.7 mL, 694 mmol) was charged into a three necked flask and cooled to 0 °C and treated with phosphoryl chloride (177.7 mL, 1906 mmol) dropwise.
  • the reaction was stirred at that temperature for 10 min and treated with 3-Chloro-N- phenylpropanamide 25A (50.00 g, 272.3 mmol) and stirred at room temperature, for 30 min.
  • the reaction mixture was heated at 80 0 C for 3 h and slowly poured into ice.
  • the solid separating out was filtered and washed extensively with water (2x1000 mL), aq. saturated sodium bicarbonate (500 mL), and taken in EtOAc (IL),
  • the solution was dried (MgSO 4 ) filtered concentrated in vacuo and the residue obtained was recrystallized from boiling hexanes to provide compound 25B (20 g).

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Abstract

La présente invention concerne des dérivés d'indole tétracycliques, des compositions comprenant au moins un dérivé d'indole tétracyclique, et des procédés d'utilisation des dérivés d'indole tétracycliques pour traiter ou prévenir une infection virale ou une affection liée à un virus chez un patient.
PCT/US2008/010147 2005-07-13 2008-08-27 Dérivés d'indole tétracycliques et procédés pour les utiliser Ceased WO2009032123A2 (fr)

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CN200880113543A CN101842376A (zh) 2007-08-29 2008-08-27 四环吲哚衍生物及其用于治疗或预防病毒感染
MX2010002316A MX2010002316A (es) 2007-08-29 2008-08-27 Derivados tetraciclicos de indol y su uso para el tratamiento o prevencion de infecciones virales.
US12/675,277 US20110104109A1 (en) 2005-07-13 2008-08-27 Tetracyclic indole derivatives and their use for treating or preventing viral infections
JP2010522933A JP5179585B2 (ja) 2007-08-29 2008-08-27 四環系インドール誘導体およびその使用法
EP08795628A EP2197884A2 (fr) 2007-08-29 2008-08-27 Dérivés d'indole tétracycliques et procédés pour les utiliser
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US8697700B2 (en) 2010-12-21 2014-04-15 Albany Molecular Research, Inc. Piperazinone-substituted tetrahydro-carboline MCH-1 antagonists, methods of making, and uses thereof
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EP2753325A4 (fr) * 2011-09-08 2015-01-21 Merck Sharp & Dohme Composés hétérocycliques tétracycliques et leurs procédés d'utilisation pour le traitement de maladies virales
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US9573939B2 (en) 2011-09-08 2017-02-21 Merck Sharp & Dohme Corp. Substituted benzofuran compounds and methods of use thereof for the treatment of viral diseases
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WO2013039876A1 (fr) 2011-09-14 2013-03-21 Merck Sharp & Dohme Corp. Composés hétérocycliques contenant un silyle et méthodes d'utilisation desdits composés pour traiter les maladies virales
US9242988B2 (en) 2012-10-17 2016-01-26 Merck Sharp & Dohme Corp. 2′-cyano substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
WO2014062596A1 (fr) 2012-10-17 2014-04-24 Merck Sharp & Dohme Corp. Dérivés de nucléosides 2'-méthyle substitués et leurs procédés d'utilisation dans le traitement de maladies virales
WO2014059901A1 (fr) 2012-10-17 2014-04-24 Merck Sharp & Dohme Corp. Dérivés nucléosides à substitution 2'-cyano et leurs méthodes d'utilisation pour le traitement de maladies virales
US9457039B2 (en) 2012-10-17 2016-10-04 Merck Sharp & Dohme Corp. 2′-disubstituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
WO2014078463A1 (fr) 2012-11-19 2014-05-22 Merck Sharp & Dohme Corp. Dérivés de nucléoside à substitution alkynyle en position 2 pour le traitement de maladies virales
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US9364482B2 (en) 2013-06-24 2016-06-14 Merck Sharp & Dohme Corp. Substituted benzofuran compounds and methods of use thereof for the treatment of viral diseases
US10167298B2 (en) 2013-10-30 2019-01-01 Merck Sharp & Dohme Corp. Pseudopolymorphs of an HCV NS5A inhibitor and uses thereof
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JP2010537980A (ja) 2010-12-09
JP5179585B2 (ja) 2013-04-10
AU2008295483A1 (en) 2009-03-12
CN101842376A (zh) 2010-09-22
WO2009032123A3 (fr) 2009-06-11
AR068109A1 (es) 2009-11-04
MX2010002316A (es) 2010-03-22
KR20100061819A (ko) 2010-06-09
TW200918536A (en) 2009-05-01
ZA201001391B (en) 2010-11-24
EP2197884A2 (fr) 2010-06-23
CA2697451A1 (fr) 2009-03-12
AU2008295483B2 (en) 2013-11-21

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