WO2007084413A2 - Procedes de traitement de l’hepatite c - Google Patents

Procedes de traitement de l’hepatite c Download PDF

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Publication number
WO2007084413A2
WO2007084413A2 PCT/US2007/000923 US2007000923W WO2007084413A2 WO 2007084413 A2 WO2007084413 A2 WO 2007084413A2 US 2007000923 W US2007000923 W US 2007000923W WO 2007084413 A2 WO2007084413 A2 WO 2007084413A2
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optionally substituted
alkyl
independently selected
substituents independently
substituted
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PCT/US2007/000923
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WO2007084413A3 (fr
WO2007084413B1 (fr
Inventor
Gary Mitchell Karp
Alexander Arefolov
Hongyu Ren
Anthony Allan Turpoff
Richard Gerald Wilde
James Jan Takasugi
Peter Seongwoo Hwang
Guangming Chen
Jeffrey Allen Campbell
Chunshi Li
Steven Paget
Nanjing Zhang
Xiaoyan Zhang
Jin Zhu
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PTC Therapeutics Inc
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PTC Therapeutics Inc
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Priority claimed from PCT/US2005/024881 external-priority patent/WO2006019831A1/fr
Priority claimed from US11/331,180 external-priority patent/US7868037B2/en
Application filed by PTC Therapeutics Inc filed Critical PTC Therapeutics Inc
Priority to JP2008550442A priority Critical patent/JP2009523729A/ja
Priority to EP07718004A priority patent/EP1984332A2/fr
Priority to MX2008009061A priority patent/MX2008009061A/es
Priority to CA002636905A priority patent/CA2636905A1/fr
Publication of WO2007084413A2 publication Critical patent/WO2007084413A2/fr
Publication of WO2007084413A3 publication Critical patent/WO2007084413A3/fr
Publication of WO2007084413B1 publication Critical patent/WO2007084413B1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions for treating infection by a virus, or for affecting viral IRES activity.
  • HCV hepatitis C virus
  • hepatitis C virus the causative agent of hepatitis C. Seventy to eighty percent of HCV infections lead to chronic liver infection, which in turn may result in severe liver disease, including liver fibrosis, cirrhosis, and hepatocellular carcinoma (115).
  • HCV constitutes the Hepacivirus genus of the family Flaviviridae (106), and contains a positive-stranded 9.6 kb RNA genome.
  • the features of the HCV genome include a 5'- untranslated region (UTR) that encodes an internal ribosome entry site (IRES) that directs the translation of a single long open reading frame (ORF) encoding a polyprotein of 3,010 amino acids.
  • the HCV ORF is followed by a 3'-UTR of variable length, depending on the HCV variant, that encodes the sequences required for the initiation of antigenomic strand synthesis (79).
  • the HCV IRES and 3'-UTR both encode regions of RNA structures that are required for genome translation and replication.
  • the HCV polyprotein is posttranslationally processed into at least 10 mature viral proteins, including the structural proteins core (putative nucleocapsid), El and E2 and the nonstructural (NS) proteins NS2 to NS5B.
  • structural proteins core putative nucleocapsid
  • El and E2 the structural proteins core
  • NS proteins NS2 to NS5B Three distinct elements have been shown to be involved in HCV IRES-mediated translation: (1) integrity of the global structure of HCV IRES, (2) the 3'-terminal region of the HCV genome; and (3) trans-acting cellular factors that interact with the HCV IRES element and assist in translation initiation (35).
  • the initiation of protein synthesis in eukaryotic cells predominantly follows the 5' cap- dependent, first AUG rule (61).
  • a bicistronic expression system can be used to define and evaluate the function of IRES elements.
  • This test system harbors two different reporter genes in which the 5 '-proximal reporter gene is expressed by a cap dependent translation mechanism while the second reporter is expressed only if an upstream sequence inserted in the intergenic space contains an IRES sequence element.
  • a putative IRES in the HCV 5' UTR was unambiguously demonstrated to function as an IRES involved in translational control of viral proteins (133).
  • IRES element 23, 41, 42, 108, 129, 132, 133, 134.
  • HCV IRES guides cellular translation initiation factors to an internal site of the viral RNA (56, 58, 120), thus functionally demonstrating the HCV IRES activity.
  • HCV 5'-UTR contains an IRES element that plays an active and crucial role in the mechanism of internal initiation for HCV protein translation.
  • the IRES is one of the most conserved regions of the HCV genome, reflecting its essential nature for viral replication and protein synthesis (13, 118, 122). Although both 5' and y sequences of the IRES appear to play a role in the control of initiation of translation (42, 109, 110, 113, 136), the minimal sequence requirement for HCV IRES function has been mapped to a region between nucleotides 44-354 (40).
  • domains II and III consist of multiple stems, loops, and bulges and are important for ERES activity (23, 40, 51, 52, 54, 56, 64, 74, 75, 93, 107, 108, 110, 124, 127, 131, 139, 141, 142).
  • Domain II can induce conformational changes on the ribosome that have been implicated in the decoding process (124).
  • Domain III has the highest degree of structural conservation among the different HCV strains. It comprises the core of the flavivirus IRES and has 6 subdomains (40).
  • subdomain HId forms complex secondary/tertiary structures and is critical for initiation activity (55, 56, 57, 124, 129).
  • Domain IV has one stem- loop that spans the initiation codon and is specific for the HCV IRES (41, 122), but the precise role of domain IV in IRES activity remains controversial (41, 112).
  • the role of the HCV IRES is to position the translational machinery near an internal initiator codon in the viral mRNA.
  • the translation initiation mechanism of the HCV and other viral IRES differs significantly from that of 5 '-cap-dependent translation initiation (7, 21, 31, 35, 61, 71, 72, 81, 88, 96, 114, 123).
  • Most cellular capped mRNAs utilize a number of initiation factors (elFs) that are required for the translation initiation process.
  • the initial steps of the process require proteins that interact with the 5 ' cap structure and recruit the 4OS ribosomal subunit to the cap-proximal region of mRNA. This complex then scans 3' of the cap, until reaching an AUG codon at which translation will initiate (21, 114).
  • the IRES functionally replaces the 5' cap structure, allowing the 40S ribosomal subunit and eIF3 to bind directly to the RNA.
  • Subdomain HId of the HCV IRES harbors the binding site for the 4OS ribosomal subunit and the only initiation factors required for translation initiation are eIF2, e ⁇ F3, and eIF4E (15, 58, 94, 100, 120, 124).
  • the polypyrimidine track-binding protein (PTB) and La autoantigen are noncanor ⁇ cal translation initiation factors that bind to and enhance HCV IRES activity (1, 2, 3, 4, 5, 30, 48, 49, 53).
  • PTB 5 a 57-kDa protein involved in RNA splicing is also necessary for efficient IRES- mediated translation initiation of picornavirus mRNA, and some cellular mRNAs (10, 11, 36, 53, 59, 89, 92).
  • the La autoantigen a 52 kDa double-stranded RNA unwinding protein, also increases the activity of polio virus and cellular IRES (38, 85, 86).
  • HCV IRES-mediated translation initiation Other cellular factors involved in HCV IRES-mediated translation initiation include proteasome ⁇ -subunit PSMA7 (62), ribosomal protein S5 (26), ribosomal protein S9 (24, 25, 100), and hnRNPL (33).
  • proteasome ⁇ -subunit PSMA7 62
  • ribosomal protein S5 26
  • ribosomal protein S9 24, 25, 100
  • hnRNPL hnRNPL
  • IFN ⁇ and the nucleoside analogue ribavirin are marketed for the treatment of HCV infection.
  • these two agents are immunomodulators and have limited efficacy, relatively high toxicity, and high cost (80, 83, 84, 138).
  • the treatment outcome is variable among the six major HCV genotypes, only about one-half of all treated patients respond to therapy, suggesting that the virus encodes protein products that may directly or indirectly attenuate the. antiviral action of IFN.
  • IFNs are naturally produced in response to virus infection, and cellular exposure to IFN leads to the induced expression of a variety of IFN -stimulated genes (ISGs), many of which have an antiviral function. ISG action can limit virus replication at multiple points within the replicative cycle.
  • ISGs IFN -stimulated genes
  • the present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions for treating infection by a virus, or for affecting viral IRES activity.
  • the present invention includes a compound of Formula (I)
  • X is:
  • R x is a Ci to C O alkyl
  • -an alkyne optionally substituted with a Ci to C 6 alkyl optionally substituted with one or more independently selected halo or cyano groups; -an oxime;
  • R b is a hydrogen or a Ci to C ⁇ alkyl, and n is 0 or 1 ;
  • R c is a hydrogen, a -CONHR x , where R x is a Ci to C 6 alkyl, or an -SOaR x , where R x is a C 1 to C 6 alkyl; or
  • Rd is a Ci to Ce alkyl or a C 6 to Cg aryl; -a -NHCOR e group, where Re is: -a Ci to C 6 alkyl;
  • -a C 6 to Cs aryl optionally substituted with: -a Ci to C 6 alkyl, -an alkoxy, -a cyano group, -a nitro group, or
  • R x is a Ci to C 6 alkyl
  • R g is a C] to C 6 alkyl or a hydrogen and R h is a hydrogen, Ci to C 6 alkyl, or C 6 to Cs aryl, the Ci to C 6 alkyl or C 6 to C 8 aryl optionally substituted with an alkoxy; -a Ci to C 6 alkyl;
  • -a 5 or 6 membered heteroaryl optionally substituted with one or more of the following: -a Ci to C 6 alkyl, optionally substituted with one or more halos or a C 6 to CR aryl, -a C 6 to Cs aryl, optionally substituted with -COOR x , where R x is a Ci to C 6 alkyl, -an amino group, or -a substituent from Group A;
  • -a 5 or 6 membered heterocycle optionally substituted with: -a -COOR x group, where R x is as defined above, or -a -NHCOOR x group, where R x is as defined above; -a C 6 to C 8 aryl, optionally substituted with one or more of the following: -an alkoxy, optionally substituted with:
  • R x is a Ci to Ce alkyl and R,- is: -a hydrogen, -a Ci to C 6 alkyl,
  • R k is: -a C 1 to C 6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more Cj to C 6 alkyls, and R j is:
  • R x is a Ci to Ce alkyl, -a haloalkyl, or
  • Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino
  • Ci to Cg alkyl group optionally substituted with:
  • Rab is a 5 or 6 membered heterocycle group, -a -COOR x group, where R x is a Ci to Ce alkyl, -a -COR n , group, where R 1n is: -an amino optionally substituted with one or more Ci to Ce alkyls, where the Cj to Ce alkyls are optionally substituted with: -a hydroxy
  • Ci to C O alkyl optionally substituted with: -a halo, -an alkoxy, or -a Ce to Cg aryl, -a 5 or 6 membered heterocycle, optionally substituted with one or more Ci to
  • R 0 is:
  • R x is a Ci to C 6 alkyl
  • Ci to C ⁇ alkyl optionally and independently substituted with one or more Ce to C 8 aryl, halo and/or C 1 to Cg alkoxy groups, -a Ci to C 6 alkoxy, -a Ci to C ⁇ haloalkoxy, -a -OR S group, where R s is a C O to C 8 aryl, or -a -COOR x group, where R x is as defined above, -a Ci to Ce alkyl optionally substituted with one or more of the following:
  • -a 5 or 6 membered heterocycle optionally substituted with one or more halo, Ci to C 6 alkyl, C t to C 6 haloalkyl, Ci to C 6 alkoxy, Ci to C 6 haloalkoxy,
  • Ci to C 6 alkyl Ci to C 6 haloalkyl
  • Ci to C 6 alkoxy Ci to C 6 haloalkoxy
  • -an alkylene -an alkoxy
  • -an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Ci to Ce alkyl, -halo, or -a 5 or 6 membered heterocycle,
  • -a C 6 to Cg aryl optionally substituted with: -an alkoxy, -a halo, or -a C 1 to C 6 alkyl, or -a 5 or 6 membered heterocycle,
  • R x is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NR v SO 2 R w group, where Rv is:
  • R x is as defined above, or -a Ci to C O alkyl, optionally substituted with:
  • R x is as defined above, -a hydroxyl, or -an alkoxy, and where R w is: -a C) to C 6 alkyl optionally substituted with:
  • Ci Ci to C 6 alkyl, -Ci to C 6 haloalkyl, -C] to Cg alkoxy, - Ci to Ce haloalkoxy, -a 5 or 6 membered heterocycle, or
  • R y is a hydrogen, Ci to Ce alkyl optionally substituted with a Ci to Ce alkoxy, Ci to Ce haloalkyl, Ce to Cs aryl, 5 or 6 membered heteroaryl, or 5 or 6 membered heterocycle, where the Ce to Cg aryl, 5 or 6 membered heteroaryl, and 5 or 6 membered heterocycle are each optionally and independently substituted with one or more halo, Ci to C 6 alkyl, Cj to C 6 alkoxy, Ci to Cg haloalkyl,
  • R y is as described above and R 2 is hydrogen or a Ci to
  • R y is as described above, -a -SR x group, where R x is as defined above,
  • -an alkyl- or dialkyl-amino group optionally substituted with a hydroxy, a 5 or 6 membered heterocycle, a 5 or 6 membered heteroaryl, or a -COOR x group, where R x is as defined above, -a 5 or 6 membered heteroaryl,
  • -a 5 or 6 heterocycle optionally substituted with hydroxy, a Ci to Ce alkoxy, or a a Ci to Ce alkyl, where the alkyl is optionally substituted with one or more hydroxy, -a Ce to Cs aryl, or
  • Ci to C 6 alkyl optionally substituted with a cyano group, -an amino optionally substituted with one or more Ci to Ce alkyls, -a -NHPOR x R x , where R x is as defined above, -a -NReeCONR ff Rff group, where R 03 is a hydrogen or a Ci to C 6 alkyl, optionally substituted with a halo, and R ⁇ is: -a hydrogen, -a haloalkyl, -a haloalkoxy, -a Ci to C 6 alkyl, or
  • Ci to CO alkyl optionally substituted with: -an alkoxy
  • Ci to Ce alkyl optionally substituted with: -an alkoxy, -one or more halos, - a 5 or 6 membered heterocycle, or
  • R is a hydrogen, a halo or an alkoxy
  • Ci to C 6 alkyl Ci to C 6 alkoxy, Ci to C 6 haloalkyl, Cj to Cg haloalkoxy, Cj to Ce hydroxy, and/or SO ⁇ R X groups,
  • -a 5 or 6 membered heterocycle optionally substituted with one or more halo, Cj to Cg alkyl, C 1 to C 6 alkoxy, Ci to Ce haloalkyl, Ci to C 6 haloalkoxy, Ci to C 6 hydroxy, and/or SO 2 R x groups,
  • R 2 is:
  • Ci to Ce alkyl group optionally substituted with one or more of the following:
  • -5 or 6 membered heteroaryl group is optionally substituted with one or more halo, Ci to CO alkyl, Ci to Ce alkoxy, Ci to C 6 haloalkyl, Ci to Ce haloalkoxy, Ci to Cg hydroxy, and/or SO 2 R x groups,
  • -C ⁇ to C 8 aryl group is optionally substituted with one or more halo, Ci to C ⁇ alkyl, Ci to C 6 alkoxy, Ci to Ce haloalkyl, Ci to C O haloalkoxy, Ci to Ce hydroxy, and/or SO 2 R x groups, -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an amino group optionally substituted with one or more C] to Ce alkyl groups;
  • -an alkoxy group optionally substituted with one or more groups independently selected from the following: -halos,
  • -an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following: -a 5 or 6 membered heterocycle, or - an amino optionally substituted with one or more alkyl groups; -a dialkyl-amino optionally substituted with an alkoxy, -a 4 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ci to C 6 alkyl group, the Ci to Ce alkyl group optionally substituted with one or more independently selected Ci to C 6 alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more independently selected halo, Ci to C O alkyl, Ci to C O alkoxy, Cj to C O haloalkyl, Ci to C 6 haloalkoxy, Ci to Ce hydroxy, and/or SO 2 R x groups, or -a C 6 to Cg aryl group
  • -Ci to C 6 alkyl groups optionally substituted with one or more independently selected halo, Ci to C 6 alkoxy, Cj to C 6 hydroxy, a 5 or 6 membered heterocycle and/or a 5 or 6 membered heteroaryl, -hydroxy groups, or -C 6 to Cs aryl groups;
  • -a 5 or 6 membered heterocycle optionally substituted with one or more of the following: -Ci to C 6 alkyl,
  • -a -OCOR x group where R x is as defined above; -a -NHCOR jj group, where RJJ is: -an alkyl, -a C 6 to C 8 aryl, -an alkoxy, or
  • Ci to Ce alkyl optionally substituted with one or more independently selected halo, Ci to Ce alkyl, Ci to Ce alkoxy, Ci to C O haloalkyl, Ci to Ce haloalkoxy, Ci to C O hydroxy, and/or SO 2 R x groups,
  • R3 is:
  • Ci to C 6 alkyl optionally substituted with:
  • R 0 is:
  • R x is a Ci to Ce alkyl
  • Ci to Ce alkyl optionally and independently substituted with one or more Ce to C 8 aryl, halo and/or Ci to C O alkoxy groups, -a Ci to C ⁇ alkoxy,
  • R s is a C 6 to Cs aryl
  • R x is as defined above, -a C 2 to C 6 alkylene group, -a Ci to C 6 alkoxy group,
  • -a 5 or 6 membered heterocycle group optionally substituted with with one or more halo, Ci to C 6 alkyl, Ci to C 6 haloalkyl, Ci to C 6 alkoxy, Ci to C 6 haloalkoxy,
  • Ci to C 6 alkyl Ci to C 6 haloalkyl
  • Ci to C 6 alkoxy Ci to C 6 haloalkoxy
  • -an alkylene a C 6 to Cs aryl optionally substituted with one or more halo, Ci to C 6 alkyl, Ci to C 6 haloalkyl, Ci to C 6 alkoxy, Ci to C 6 haloalkoxy, -an alkylene,
  • R t is:
  • R x is as defined above, or -a Ci to C 6 alkyl, optionally substituted with: -a halo,
  • Ci to Ce alkyl optionally substituted with: -a halo, -a haloalkyl, -a C ⁇ to Cs aryl, or -a 5 or 6 membered heterocycle,
  • Raa is: -a Ci to C 6 alkyl, -an amino group
  • Ci to Ce alkyls optionally substituted with: -a hydroxy
  • R n is: -a -CH 2 CONH 2 , or
  • L is a direct bond, Cj to Q 2 alkylene, C 2 to C 12 alkenylene or C 2 to Ci 2 alkynylene, wherein one or more — CH 2 — group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with — O — , — S — , — SO 2 — and/or — NR mm — , and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s), halos, and/or hydroxy(s), where R mm is hydrogen or Ci to Ce alkyl; or a pharmaceutical salt thereof.
  • the present invention includes compounds of Formula I, with the proviso that at least one of Y, Z, R t and R 2 is selected from the following: Y is:
  • -an amino optionally substituted with one or more of the following: -SO 2 R x , or
  • R a b is a 5 or 6 membered heterocycle group, -a -NR 0 COR p group, where R p is:
  • Ci to Ce alkyl groups optionally substituted with one or more Ci to Ce alkyl groups where the Ci to C ⁇ alkyl groups are optionally and independently substituted with one or more Ce to Cs aryl groups and/or alkoxy groups, or -a 5 or 6 membered heterocycle, substituted with one or more Ci to C 6 alkyl or C ⁇ to C 8 aryl groups, -a -NRqCONRqR r group, where R r is:
  • Ci to C 6 alkyl substituted with one or more of the following: -a hydroxyl,
  • Ci to C12 alkyl substituted with one or more of the following: -an alkoxy group substituted with one or more alkoxy groups,
  • Ci Ci to Cg alkyl substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle;
  • Ri is an alkoxy substituted with an amino, where the amino is optionally substituted with a heterocycle; R 2 is:
  • Ci to C ⁇ alkyl group substituted with one or more of the following: -5 or 6 membered heterocycle groups, or
  • -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an alkoxy group substituted with one or more groups independently selected from the following: -a hydroxy group,
  • Ce alkyl groups substituted with Ci to Ce alkoxy, or
  • a compound of Formula I is included, with the proviso that at least one of X, Y, Z, Ri, and R 2 is selected from the following: X is:
  • -an alkyl optionally substituted with one or more halo
  • -an alkyne optionally substituted with a Cj to Ce alkyl optionally substituted with one or more halo or cyano groups
  • -a Ce to Cs aryl group substituted with one or more of the following: -Ci to Ce alkyl optionally substituted with one or more halos,
  • Y is:
  • -an amino optionally substituted with one or more of the following: -SO 2 R x , or -Ci to C 6 alkyl substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHR x , -OC(O)NH(OR x ), -OC(O)NR x (OR x ),
  • R a b is a 5 or 6 membered heterocycle group, -a -NR 0 CORp group, where R p is:
  • R 1 is: -a Ci to Cu alkyl, substituted with one or more groups independently selected from the following:
  • -an alkoxy group substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Ci to C$ alkyl, or -a 5 or 6 membered heteroaryl, -a C2 to Ce alkylene, or
  • Ci -a Ci to Ce alkyl substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle;
  • Ri is: -a Ci to Ce alkyl substituted with:
  • -an amide optionally substituted with a Ci to C 6 alkyl, or -a 5 or 6 membered heteroaryl; -a Ci to C 6 alkoxy substituted with:
  • R 2 is:
  • Ci to C ⁇ alkyl group substituted with one or more of the following: -5 or 6 membered heterocycle groups,
  • -an alkylthio group optionally substituted with a C 6 to C 8 aryl group
  • -an alkylthio group optionally substituted with a C] to C 6 alkyl group
  • -an SO2R* group optionally substituted with a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to C 6 alkyl groups
  • -an SO 2 R X group optionally substituted with a 5 or 6 membered heterocycle group; -an SO2R.
  • X group optionally substituted with a C O to Cg aryl group; -an SC ⁇ Rx group optionally substituted with a Ci to C 6 alkyl group; -an S(O)R x group optionally substituted with a 5 or 6 membered heteroaryl group; -an S(O)R x group optionally substituted with a 5 or 6 membered heterocycle group; -an S(O)R x group optionally substituted with a Ce to Cs aryl group; -an S(O)R x group optionally substituted with a Ci to C 6 alkyl group; -an alkoxy group substituted with an alkoxy group,
  • -an amino group substituted with one or more 5 or 6 membered heteroaryl, 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following: -a 5 or 6 membered heterocycle, or
  • -S-5 or 6 membered heteroaryl optionally substituted with a Ci to Ce alkyl, -S-Ci to C 6 alkyl,
  • -sulfonyl-5 or 6 membered heteroaryl optionally substituted with a Ci to C(, alkyl, -sulfonyl- Ci to Ce alkyl, -sulfonyl- C 6 to C 8 aryl, -a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected Ci to C ⁇ alkyl groups substituted with Ci to Ce alkoxy, or
  • the present invention includes compounds of Formula I, with the proviso that with the proviso that at least one of Y, Z, and R 2 is selected from the following: Y is: -a benzothiazole substituted with an amino group optionally substituted with one or more Ci to C 6 alkyls;
  • -an amino optionally substituted with one or more of the following: -SO 2 R x , or
  • R a b is a 5 or 6 membered heterocycle group, -a -NR 0 COR p group, where R p is: -an amino group optionally substituted with one or more Cj to C 6 alkyl groups where the C) to C ⁇ alkyl groups are optionally and independently substituted with one or more Ce to Cs aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, substituted with one or more Ci to Ce alkyl or Ce to Cg aryl groups, -a -NR q CONRqR r group, where R 1 - is:
  • Ci to Ce alkyl substituted with one or more of the following: -a hydroxyl, -an alkoxy,
  • Ci to Ci 2 alkyl substituted with one or more groups independently selected from the following:
  • R 2 is: -a C 1 to C O alkyl group, substituted with one or more of the following: -5 or 6 membered heterocycle groups,
  • -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an alkoxy group substituted with one or more groups independently selected from the following:
  • -an amino optionally substituted with one or more alkyl groups; -a 7 membered heterocycle group; -a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected Ci to C 6 alkyl groups substituted with Ci to Ce alkoxy, or
  • -an amide group substituted with one or more Ci to Ce alkyl groups; -a 5 or 6 membered heterocycle, optionally substituted with one or more of the following: -Ci to C 6 alkyl,
  • R x group -C(O)-C 6 to C 8 aryl, or -C(O)OR x groups
  • -an -ORkk group where R kk is: -a 5 to 6 membered heterocycle, optionally substituted with a Ci to C 6 alkyl, optionally substituted with a C$ to Cs aryl group, or -an -Si(Rx) 3 ; or a pharmaceutically acceptable salt thereof.
  • alkyl generally refers to saturated hydrocarbyl radicals of straight, branched or cyclic configuration, or combinations of cyclic and branched or straight, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n- hexyl, cyclohexyl, n-heptyl, octyl, n-octyl, and the like.
  • alkyl substituents may be Ci to Cn, or Ci to C 8 or Ci to C 6 alkyl groups.
  • alkylene generally refers to straight, branched or cyclic alkene radicals having one or more carbon-carbon double bonds, such as C 2 to Q alkylene groups including 3-pro ⁇ enyl.
  • aryl refers to a carbocyclic aromatic ring structure. Included in the scope of aryl groups are aromatic rings having from five to twenty carbon atoms.
  • Aryl ring structures include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds. Examples of aryl groups that include phenyl, tolyl, anthracenyl, fiuorenyl, indenyl, azulenyl, phenanthrenyl ⁇ i.e., phenanthrene), and napthyl (i.e., napthalene) ring structures. In certain embodiments, the aryl group may be optionally substituted.
  • heteroaryl refers to cyclic aromatic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon. Heteroatoms are typically O, S or N atoms. Included within the scope of heteroaryl, and independently selectable, are O, N, and S heteroaryl ring structures.
  • the ring structure may include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds.
  • the heteroaryl groups may be selected from heteroaryl groups that contain two or more heteroatoms, three or more heteroatoms, or four or more heteroatoms.
  • Heteroaryl ring structures may be selected from those that contain five or more atoms, six or more atoms, or eight or more atoms.
  • heteroaryl ring structures include: acridine, benzimidazole, benzoxazole, benzodioxole, benzofuran, 1,3-diazine, 1,2-diazine, 1,2-diazole, 1,4-diazanaphthalene, furan, furazan, imidazole, indole, isoxazole, isoquinoline, isothiazole, oxazole, purine, pyridazine, pyrazole, pyridine, pyrazine, pyrimidine, pyrrole, quinoline, quinoxaline, thiazole, thiophene, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, tetrazole and quinazoline.
  • heterocycle refers to cyclic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon. Heteroatoms are typically O, S or N atoms. Included within the scope of heterocycle, and independently selectable, are O, N, and S heterocycle ring structures.
  • the ring structure may include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds.
  • heterocyclo groups include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl or tetrahydrothiopyranyl and the like.
  • the heterocycle may optionally be substituted.
  • alkoxy generally refers to a group with the structure -O-R, where R is an alkyl group as defined above.
  • halo substituents may be independently selected from the halogens such as fluorine, chlorine, bromine, iodine, and astatine.
  • a haloalkyl is an alkyl group, as defined above, substituted with one or more halogens.
  • a haloalkoxy is an alkoxy group, as defined above, substituted with one or more halogens.
  • each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently substituted.
  • a more generic substituent is set forth for any position in the molecules of the present invention, it is understood that the generic substituent may be replaced with more specific substituents, and the resulting molecules are within the scope of the molecules of the present invention.
  • substituted or “optionally substituted” it is meant that the particular substituent may be substituted with a chemical group known to one of skill in the art to be appropriate for the referred-to substituent, unless a chemical group is specifically mentioned.
  • the present invention includes compounds of Formula (I-X)
  • Y is:
  • Rb is a hydrogen or a Cj to Ce alkyl, and n is 0 or 1 ;
  • R 0 is a hydrogen, a -CONHR x , where R x is a Ci to Ce alkyl, or an -S ⁇ 2R x , where R x is a Ci to C 6 alkyl; or where Ra is a Ci to C 6 alkyl or a C 6 to Cg aryl; -a -NHCOR e group, where R 6 is: -a C 1 to C 6 alkyl;
  • R 8 is a Ci to Ce alkyl or a hydrogen and R h is a C 6 to Cg aryl optionally substituted with an alkoxy; -a Ci to C 6 alkyl; -a 5 or 6 membered heteroaryl, optionally substituted with:
  • -a 5 or 6 membered heterocycle optionally substituted with: -a C i to C 6 alkyl, or -a hydroxy, -an amino optionally substituted with one or more Ci to C 6 alkyls, -a -NRiSO 2 R x group, where R x is a Ci to Ce alkyl and R 1 - is: -a hydrogen, -a Ci to C 6 alkyl,
  • Rk is: -a Ci to C 6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more Q to Cg alkyls, and Rj is:
  • R x is a Cj to Ce alkyl, -a haloalkyl, or
  • Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more of the following:
  • Cj to Ce alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, -a nitro group, -a Ci to Ce alkyl group, optionally substituted with:
  • R ab is a 5 or 6 membered heterocycle group, -a -COOR x group, where R x is a Ci to Ce alkyl, -a -COR m group, where R m is: -an amino optionally substituted with one or more Ci to C 6 alkyls, where the Ci to Ce alkyls are optionally substituted with: -a hydroxy,
  • Ci to Ce alkyl optionally substituted with: -a halo, -an alkoxy, or -a Cg to C 8 aryl, -an amino group optionally substituted with one or more Ci to Cg alkyl groups where the Ci to Ce alkyl groups are optionally and independently substituted with one or more C 6 to Cs aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more Cj to Ce alkyl or C ⁇ to Cg aryl groups, -a Ce to C 8 aryl, optionally substituted with a halo,
  • R 0 is:
  • R x is a Ci to C O alkyl
  • -a Ci to Ce alkyl optionally substituted with one or more of the following: -a halo, -a hydroxyl, -an alkoxy, -an alkylene, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, -a C 6 to Cg aryl optionally substituted with a halo, or -a -COOR x group, where R x is as defined above, -a C 2 to C 6 alkylene group, -a Ci to C ⁇ alkoxy group,
  • Ci to Ci 2 alkyl optionally substituted with one or more groups independently selected from the following:
  • -a Ce to Cs aryl optionally substituted with: -an alkoxy, -a halo, or -a Ci to C 6 alkyl, or
  • R v is: -a hydrogen, -a -COR x , where R x is as defined above, or -a Ci to Cg alkyl, optionally substituted with:
  • Ci to C O alkyl optionally substituted with a Ci to C O alkyl, where R y is a C 1 to C 6 alkyl or hydrogen,
  • R 2 is hydrogen or a Ci to Cs alkyl, optionally substituted with a Ce to Cs aryl,
  • R x is as defined above, or -a 5 or 6 membered heteroaryl, -a Ce to Cg aryl, or -a -NHRbb group, where R b b is:
  • Ci to C O alkyl optionally substituted with a cyano group, . -an amino optionally substituted with one or more Ci to Ce alkyls,
  • R ⁇ is a hydrogen or a Ci to C ⁇ alkyl. optionally substituted with a halo, and Rn- is:
  • Ci to Ce alkyl optionally substituted with: -an alkoxy, -a halo, or
  • R gg is:
  • Ci to C 6 alkyl optionally substituted with: -an alkoxy, -one or more halos, -a 5 or 6 membered heterocycle, or
  • R is a hydrogen, a halo or an. alkoxy
  • -an alkoxy optionally substituted with: -one or more halos, -a C ⁇ to Cs aryl,
  • R 2 is:
  • -an alkoxy group optionally substituted with one or more groups independently selected from the following: -halos, -a hydroxy group,
  • -an amino optionally substituted with one or more alkyl groups
  • dialkyl-amino optionally substituted with an alkoxy, -a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ci to C ⁇ alkyl group
  • the Ci to Ce alkyl group optionally substituted with one or more independently selected Ci to Ce alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more Ci to C 6 alkyl groups, or -a C ⁇ to Cg aryl group
  • -a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more Cg to C 8 aryl groups
  • -a -COOR x group where R x is as defined above; -a haloalkyl; -an amide group optionally substituted with one or more of the following: -Ci to C 6 alkyl groups, -hydroxy groups, or -C 6 to Cg aryl groups; -a 5 or 6 membered heterocycle, optionally substituted with one or more of the following: -Ci to C 6 alkyl,
  • R 3 is:
  • R x is as defined above; or a pharmaceutically acceptable salt thereof.
  • the present invention includes compounds of Formula (I-Xa)
  • Y is:
  • R b is a hydrogen or a Ci to C 6 alkyl, and n is 0 or 1;
  • R 0 is a hydrogen, a -CONHR x , where R x is a Ci to Ce alkyl, or an -SO 2 R x , where R x is a Ci to C O alkyl; or where Rd is a Ci to C 6 alkyl or a C 6 to Cs aryl; -a -NHCORe group, where R e is: -a C] to C 6 alkyl;
  • R g is a Ci to Ce alkyl or a hydrogen and Rh is a C 6 to Cs aryl optionally substituted with an alkoxy; -a Ci to Ce alkyl; -a 5 or 6 membered heteroaryl, optionally substituted with:
  • Ci to C 6 alkyl optionally substituted with a C 6 to C 8 aryl
  • -a 5 or 6 membered heterocycle optionally substituted with: -a Ci to C 6 alkyl, or -a hydroxy, -an amino optionally substituted with one or more Ci to C 6 alkyls, -a -NRiSO 2 R x group, where R x is a Ci to C 6 alkyl and Rj is: -a hydrogen, -a C 1 to C 6 alkyl,
  • R k is: -a Ci to C 6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more Ci to Ce alkyls, and R j is:
  • R x is a Ci to C 6 alkyl, -a haloalkyl, or
  • Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more of the following:
  • Ci to C 6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, -a nitro group, -a Ci to C 6 alkyl group, optionally substituted with:
  • R ab is a 5 or 6 membered heterocycle group, -a -COOR x group, where R x is a Ci to C 6 alkyl, -a -COR m group, where R m is: -an amino optionally substituted with one or more Ci to Ce alkyls, where the Ci to Ce alkyls are optionally substituted with: -a hydroxy
  • Ci to C O alkyl optionally substituted with: -a halo, -an alkoxy, or -a C ⁇ to Cg aryl, -an amino group optionally substituted with one or more Ci to C f , alkyl groups where the Cj to C& alkyl groups are optionally and independently substituted with one or more Ce to Cs aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more Ci to Ce alkyl or Ce to Cs aryl groups, -a Ce to Cs aryl, optionally substituted with a halo,
  • R 0 is:
  • R x is a Ci to Ce alkyl
  • -a Ci to Ce alkyl optionally substituted with one or more of the following: -a halo, -a hydroxyl, -an alkoxy, -an alkylene, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, -a C 6 to C 8 aryl optionally substituted with a halo, or -a -COOR x group, where R x is as defined above, -a C 2 to C ⁇ alkylene group, -a Ci to C O alkoxy group,
  • Ci to C 12 alkyl optionally substituted with one or more of the following: -a C ⁇ to Cs aryl optionally substituted with halo, Ci to Ce alkyl, or alkoxy,
  • -a Ce to Cs aryl optionally substituted with: -an alkoxy, -a halo, or -a C) to C 6 alkyl, or -a 5 or 6 membered heterocycle,
  • R v is: -a hydrogen, -a -COR x , where R x is as defined above, or -a Ci to C ⁇ alkyl, optionally substituted with:
  • R y is a C 1 to Ce alkyl or hydrogen
  • R x is hydrogen or a Ci to C O alkyl, optionally substituted with a C O to C 8 aryl,
  • R aa is:
  • R x is as defined above, or -a 5 or 6 membered heteroaryl, -a Ce to Cs aryl, or -a -NHRbb group, where Rbb is:
  • -a Ce to Cg aryl optionally substituted with one or more of the following: -an alkoxy, -a hydroxy, -a halo,
  • Ci to Ce alkyl optionally substituted with a cyano group, -an amino optionally substituted with one or more Ci to C ⁇ alkyls, -a -NHPOR x R x , where R x is as defined above,
  • R 00 is a hydrogen or a Ci to Ce alkyl, optionally substituted with a halo, and Rn- is:
  • R x is as defined above, -a -NRggCORhh group, where Rhh is: -a hydrogen, -a C] to C ⁇ alkyl optionally substituted with:
  • R x is as defined above, and R U is: -a hydrogen, -a Ci to C 6 alkyl, -a haloalkyl, -a haloalkoxy., or
  • Ci to C 6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle;
  • R 2 is:
  • -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an amino group; -an alkoxy group optionally substituted with one or more of the following: -halos,
  • -an alkoxy group optionally substituted with an alkoxy group, -an -OCOR x group, where R x is as defined above, -an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
  • Ci to C& alkyl group optionally substituted with one or more independently selected hydroxy group or Ci to C& alkyl group
  • the Ci to C ⁇ alkyl group optionally substituted with one or more independently selected Ci to Ce alkoxy group
  • -a 5 or 6 membered heteroaryl group optionally substituted with one or more Ci to C 6 alkyl groups
  • -an amide group optionally substituted with one or more of the following: -Ci to Ce alkyl groups, -hydroxy groups, or -C 6 to C 8 aryl groups; -a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
  • -C(O)OR x groups ; -a 5 or 6 membered heteroaryl; -a -OCOR x group, where R x is as defined above; -a -NHCORjj group, where Rjj is: -an alkoxy, or
  • R 3 is:
  • Y 5 Z, Ri and R 2 is selected from the following:
  • Y is: -a benzothiazole substituted with an amino group optionally substituted with one or more Ci to
  • -an amino optionally substituted with one or more of the following: -SO 2 R x , or -Ci to C(, alkyl substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHR x , -OC(O)N(R X ) 2> -OC(O)NH(OR x ), -OC(O)NR x (OR x ),
  • Rab is a 5 or 6 membered heterocycle group, -a -NR 0 COR p group, where R p is:
  • Ci to Ce alkyl groups are optionally and independently substituted with one or more C 6 to Cs aryl groups and/or alkoxy groups, or -a 5 or 6 membered heterocycle, substituted with one or more Ci to Ce alkyl or Ce to Cg aryl groups, -a -NR q CONRqRr group, where R r is: -a Ci to Ce alkyl substituted with one or more of the following:
  • R u is: -a Ci to C 12 alkyl, substituted with one or more of the following:
  • Ci to C 6 alkyl substituted with a 5 or 6 membered heterocycle or
  • Ri is an alkoxy substituted with an amino, where the amino is optionally substituted with a heterocycle
  • R 2 is:
  • Ci to C 6 alkyl group substituted with one or more of the following: -5 or 6 membered heterocycle groups, or
  • alkoxy group optionally substituted with an alkoxy group, -an amino group substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
  • -an amide group substituted with one or more Ci to C 6 alkyl groups; -a 5 or 6 membered heterocycle, optionally substituted with one or more of the following: -Cj to C 6 alkyl, -SO 2 R x ,
  • R is selected from the R substituents of compounds 1330-2128 and 2600-3348.
  • R is selected from the following non-limiting substituents:
  • R is hydrogen
  • Ri is selected from the following non-limiting substituents:
  • R 2 is selected from the following non-limiting substituents:
  • R 3 is selected from the R 3 substituents of compounds 1330- 2128, and 2600-3348. In some embodiments of the invention, compounds are provided wherein R 3 is selected from the following non-limiting subsituents:
  • the present invention includes a compound of Formula (I-XI)
  • -an alkyne optionally substituted with a Ci to Cg alkyl optionally substituted with one or more independently selected halo or cyano groups; -an oxime; -SO 2 R x ; -SO 2 NH 2 ; -SO 2 NH(R x ); -SO 2 N(Rx) 2 ;
  • -an indole optionally substituted on the nitrogen with an -SO 2 R x group; or -a Ce to Cg aryl, optionally substituted with one or more of the following: -halo;
  • R ab is a 5 or 6 membered heterocycle group, -a -NR 0 COR p group, where R p is:
  • Ci to Ce alkyl groups optionally substituted with one or more Ci to Ce alkyl groups where the Ci to C 6 alkyl groups are optionally and independently substituted with one or more C ⁇ to Cs aryl groups and/or alkoxy groups, or -a 5 or 6 membered heterocycle, optionally substituted with one or more Ci to
  • Ce alkyl optionally substituted with one or more of the following: -halo, -hydroxyl, -an alkoxy,
  • Ci to Ci 2 alkyl optionally substituted with one or more groups independently selected from the following: -a C 6 to C 8 aryl optionally substituted with halo,
  • -an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more C] to C 6 alkyl, -halo, or -a 5 or 6 membered heteroaryl, -a C 2 to Ce alkylene, or
  • Ci Ci to C ⁇ s alkyl optionally substituted with a 5 or 6 membered heterocycle, or
  • R is a hydrogen
  • Ri is:
  • -an amino optionally substituted with a heterocycle
  • -an amide optionally substituted with a Ci to Ce alkyl
  • -a 5 or 6 membered heterocycle optionally substituted with a Ci to Ce alkyl
  • -a 5 or 6 membered heterocycle optionally substituted with a Ci to C ⁇ alkyl, -a 5 or 6 membered heteroaryl, or
  • R 2 is:
  • Ci to Ce alkyl group optionally substituted with one or more of the following: -5 or 6 membered heterocycle groups,
  • -an alkylthio group optionally substituted with a 5 or 6 membered heterocycle group; -an alkylthio group optionally substituted with a C 6 to C 8 aryl group; -an alkylthio group optionally substituted with a Ci to C ⁇ alkyl group;
  • -an SO 2 R x group optionally substituted with a 5 or 6 membered heterocycle group; -an SO 2 R x group optionally substituted with a Ce to Cs aryl group; -an SO 2 R x group optionally substituted with a Ci to Ce alkyl group;
  • -an S(O)R x group optionally substituted with a 5 or 6 membered heteroaryl group; -an S(O)R x group optionally substituted with a 5 or 6 membered heterocycle group; -an S(O)R x group optionally substituted with a Ce to C 8 aryl group; -an S(O)R x group optionally substituted with a Ci to C 6 alkyl group; -an alkoxy group optionally substituted with one or more groups independently selected from the following: -halo,
  • -an amino group optionally substituted with one or more 5 or 6 mernbered heteroaryl groups, 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
  • -S-5 or 6 membered heteroaryl optionally substituted with a Ci to C 6 alkyl, -S-Ci to C 6 alkyl, -S-C 6 to C 8 aryl,
  • -sulfonyl-5 or 6 membered heteroaryl optionally substituted with a Ci to C 6 alkyl, -sulfonyl- Ci to Ce alkyl, -sulfonyl- C 6 to Cs aryl,
  • -a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ci to C 6 alkyl group
  • the Cj to C 6 alkyl group optionally substituted with one or more independently selected Ci to C 6 alkoxy group
  • -a 5 or 6 membered heteroaryl group optionally substituted with one or more Ci to Ce alkyl groups, -a C 6 to Cs aryl group; -a C 6 to C 8 aryl group;
  • -an (O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected Cj to C 6 alkyl groups
  • -a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more Ce to Cg aryl groups
  • R3 is a hydrogen; or a pharmaceutically acceptable salt thereof.
  • compounds of the present invention include compounds of Formula (I-XIa)
  • X is: -hydrogen; -a cyano group; -a nitro group; -a formyl group; -a -COOH group;
  • R x is a Ci to C 6 alkyl
  • -an amino optionally substituted with one or more Cj to C 6 alkyl groups or C(O)- Ci to Cg alkyl groups;
  • -an amide group optionally substituted with one or more independently selected Cj to Cg alkyl group;
  • -a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to C 6 alkyl groups optionally substituted with one or more halos
  • -a Ce to C 8 aryl group optionally substituted with one or more of the following: -Ci to Ce alkyl optionally substituted with one or more halos, -halo, or -cyano;
  • Y is: -a benzothiazole optionally substituted with an amino group optionally substituted with one or more Ci to Ce alkyls;
  • -an indole optionally substituted on the nitrogen with a -SO 2 R x group
  • -a CO to Cg aryl optionally substituted with one or more of the following: -halo;
  • -SO 2 R x groups -Ci to C ⁇ alkyl, the C] to C 6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, or -PO 2 R x groups, -OC(O)NHR x , -OC(O)N(R X ) 2 , -OC(O)NH(OR x ),
  • R 30 is a 5 or 6 membered heterocycle group, -a -NR 0 COR p group, where R p is: -a Ci to C 6 alkyl,
  • Ci to Ce alkyl groups are optionally and independently substituted with one or more C O to C 8 aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more Ci to Ce alkyl or C ⁇ to Cg aryl groups, and where R 0 is:
  • Ci to Ce alkyl optionally substituted with one or more of the following: -halo, -hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a Cg to C 8 aryl optionally substituted with a halo, -a C 2 to Ce atkylene group optionally substituted with one or more halo, -a C i to C O alkoxy group, or
  • Ci to Cu alkyl optionally substituted with one or more groups independently selected from the following: -a Ce to Ci aryl optionally substituted with halo,
  • Z is: -a C J to C 6 alkyl optionally substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle; R is a hydrogen;
  • Ri is:
  • Ci to Q alkyl optionally substituted with: -an amino optionally substituted with a heterocycle
  • -an amide optionally substituted with a Cj to C 6 alkyl, -a 5 or 6 membered heterocycle optionally substituted with a Ci to C ⁇ alkyl, -a 5 or 6 membered heteroaryl, or -a Ce to C 8 aryl; -a C] to C(, alkoxy optionally substituted with:
  • -an amino optionally substituted with a heterocycle
  • -an amide optionally substituted with a Ci to C 6 alkyl, -a 5 or 6 membered heterocycle optionally substituted with a Ci to Ce alkyl, -a 5 or 6 membered heteroaryl, or -a C 6 to C 8 aryl;
  • -a 5 or 6 membered heteroaryl or -alkylthio optionally substituted with the following: -a 5 or 6 membered heterocycle, -a Cs to C 8 aryl, -a 5 or 6 membered heteroaryl;
  • -amino groups optionally substituted with one or more heteocycle, alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups;
  • -an alkylthio group optionally substituted with a 5 or 6 membered heteroaryl group optionally substituted with an alkyl group;
  • -an alkylthio group optionally substituted with a 5 or 6 membered heterocycle group; -an alkylthio group optionally substituted with a C 6 to Cs aryl group; -an alkylthio group optionally substituted with a Cj to C 6 alkyl group;
  • -an SO 2 R x group optionally substituted with a 5 or 6 membered heterocycle group; -an SO 2 R x group optionally substituted with a C 6 to Cg aryl group; -an SO 2 R x group optionally substituted with a Ci to Cg alkyl group;
  • -an S(O)R x group optionally substituted with a 5 or 6 membered heteroaryl group; -an S(O)R x group optionally substituted with a 5 or 6 membered heterocycle group; -an S(O)R x group optionally substituted with a Cg to Cs aryl group; -an S(O)R x group optionally substituted with a Ci to C O alkyl group; -an alkoxy group optionally substituted with one or more groups independently selected from the following: -halo,
  • -an alkoxy group optionally substituted with an alkoxy group
  • -an amino group optionally substituted with one or more 5 or 6 membered heteroaryl groups, 5 or 6 membered heterocycle groups or alkyl groups
  • the alkyl groups optionally and independently substituted with one or more of the following: -a 5 or 6 membered heterocycle, or
  • -S-5 or 6 membered heteroaryl optionally substituted with a C 1 to C6 alkyl, -S-Ci to C 6 alkyl, -S-C 6 to C 8 aryl, -sulfinyl-5 or 6 membered heterocycle,
  • -sulfinyl-5 or 6 membered heteroaryl -sulfinyl-Ci to C 6 alkyl, -sulfinyl-C ⁇ to Cg aryl, -sulfonyl-5 or 6 membered heterocycle, -sulfonyl-5 or 6 membered heteroaryl optionally substituted with a Ci to Cg alkyl,
  • Ci to C 6 alkyl group optionally substituted with one or more independently selected Ci to C 6 alkoxy group
  • -an amide group optionally substituted with one or more of the following: -Ci to C O alkyl groups optionally substituted with one or more C] to C 6 alkoxy,
  • R 3 is a hydrogen; with the proviso that at least one of X, Y, Z, Ri, and R 2 is selected from the following: X is:
  • N amino optionally substituted with one or more C ⁇ to C ⁇ alkyl _ a groups ; -a halo;
  • Y is:
  • Rab is a 5 or 6 membered heterocycle group, -a -NR 0 CORp group, where R p is:
  • Ci to Ce alkyl groups optionally substituted with one or more Ci to Ce alkyl groups where the Ci to C 6 alkyl groups are optionally and independently substituted with one or more Ce to Ce aryl groups and/or alkoxy groups, or -a 5 or 6 membered heterocycle, substituted with one or more Ci to Ce alkyl or Ce to C 8 aryl groups,
  • Ci to C O alkyl substituted with one or more of the following: -a hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle,
  • Ci to Ci 2 alkyl substituted with one or more groups independently selected from the following:
  • R 2 is: —a Ci to C ⁇ alkyl group, substituted with one or more of the following: -5 or 6 membered heterocycle groups, -5 or 6 membered heteroaryl groups, -Ce to Cg aryl groups, -an amide optionally substituted with a Ci to C 6 alkyl, or -amino groups optionally substituted with one or more heteocycle, alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups;
  • -an alkylthio group optionally substituted with a 5 or 6 membered heteroaryl group optionally substituted with an alkyl group; -an alkylthio group optionally substituted with a 5 or 6 membered heterocycle group; -an alkylthio group optionally substituted with a C ⁇ to Ce aryl group; -an alkylthio group optionally substituted with a C] to CO alkyl group; -an SOaR x group optionally substituted with a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to C 6 alkyl groups; -an SO 2 R x group optionally substituted with a 5 or 6 membered heterocycle group; -an SOaR x group optionally substituted with a Ce to Cg aryl group; -an SOaR x group optionally substituted with a Ci to C$ alkyl group; -an S(O)R x group optionally substituted with a 5 or 6 member
  • -an amino optionally substituted with one or more alkyl groups
  • -an amide optionally substituted with a Ci to Ce alkyl, -S-5 or 6 membered heterocycle, -S-5 or 6 membered heteroaryl optionally substituted with a Ci to Ce alkyl
  • -sulfonyl-5 or 6 membered heteroaryl optionally substituted with a Cj to Cg alkyl, -sulfonyl- Ci to Ce alkyl, -sulfonyl- C 6 to C 8 aryl,
  • Formula I-XIb a compound is provided wherein all substituents except X are as stated for Formula I-XI, and X is an electron withdrawing group.
  • Formula I-XIc a compound is provided wherein all substituents except X are as stated for Formula I-XIa, and X is an electron withdrawing group.
  • an electron withdrawing group includes any electronegative element, which may be attached to or adjacent to an aromatic ring.
  • an electron withdrawing group can include a cyano group, an alkynyl group, a nitro group, an oxime, a halo, a halosubstituted alkyl, a carbonyl group, a sulfonyl group, and a heterooycle.
  • X is a cyano group.
  • Formulas I, I-XI, I-XIa, I-XIb, I-XIc, Ha, lib, Hc, Hd, or lie X is a halo.
  • X is a fluorine, chlorine, bromine or iodine.
  • I-XI, I-XIa, I-XIb, I-XIc, Ha, lib, Hc, Hd, or He X is a fluorine, bromine or iodine.
  • I-XI, I-XIa, I-XIb, I-XIc, Ha, lib, lie, Hd, or lie X is a fluorine or chlorine.
  • X is a fluorine. In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, Ha, Hb, Hc, Hd, or He, X is a chlorine. In an embodiment of Formulas I, I-XI, I-XIa, I- XIb, I-XIc, Ha, Hb 3 He, Hd, or He, X is bromine.
  • X is iodine.
  • I-XI, 1-XIa 5 I-XIb, I-XIc, Ha 3 Hb, He, Hd, or He X is an alkyl substituted with one or more halos.
  • X is a trifluoromethyl group.
  • X is selected from the X substituents of compounds 1330-2128, and 2600-3348.
  • X is selected from the group consisting of:
  • X is selected from the group consisting of
  • Ri is selected from the Ri substituents of compounds 1330- 2128, and 2600-3348.
  • Ri is selected from the group consisting of
  • the present invention includes compounds of Formula (I-XII)
  • -an indole optionally substituted on the nitrogen with an SO 2 R x group
  • -a CO to Cs aryl optionally substituted with one or more of the following: -an alkoxy,
  • -an amino optionally substituted with one or more of the following: -SCbR x group, or
  • Rab is a 5 or 6 membered heterocycle group, -a -NR 0 CORp group, where R p is: -a Ci to C 6 alkyl,
  • Ci to Cg alkyl groups are optionally and independently substituted with one or more C 6 to C 8 aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more Cj to C 6 alkyl or C 6 to C 8 aryl groups, and where R 0 is: -a hydrogen,
  • Ci to C 6 alkyl optionally substituted with one or more of the following: -a hydroxyl,
  • Ci to Ci2 alkyl optionally substituted with one or more groups independently selected from the following:

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Abstract

La présente invention concerne des composés, des compositions pharmaceutiques et des procédés d’utilisation desdits composés pour traiter une infection virale ou agir sur l’activité IRES virale.
PCT/US2007/000923 2004-07-14 2007-01-16 Procedes de traitement de l’hepatite c Ceased WO2007084413A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2008550442A JP2009523729A (ja) 2006-01-13 2007-01-16 Ｃ型肝炎の治療方法
EP07718004A EP1984332A2 (fr) 2006-01-13 2007-01-16 Procedes de traitement de l hepatite c
MX2008009061A MX2008009061A (es) 2006-01-13 2007-01-16 Metodos para tratar hepatitis c.
CA002636905A CA2636905A1 (fr) 2006-01-13 2007-01-16 Procedes de traitement de l'hepatite c

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US58748704P 2004-07-14 2004-07-14
US63497904P 2004-12-13 2004-12-13
US64558605P 2005-01-24 2005-01-24
US66534905P 2005-03-28 2005-03-28
US67544005P 2005-04-28 2005-04-28
PCT/US2005/024881 WO2006019831A1 (fr) 2004-07-14 2005-07-14 Procedes pour le traitement de l'hepatite c
US11/180,961 US8013006B2 (en) 2004-07-14 2005-07-14 Methods for treating hepatitis C
US75852706P 2006-01-13 2006-01-13
US60/758,527 2006-01-13
US11/331,180 2006-01-13
US11/331,180 US7868037B2 (en) 2004-07-14 2006-01-13 Methods for treating hepatitis C
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US11/653,436 2007-01-13

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