WO2010082044A1 - Dérivés hétérocycliques bicycliques insaturés utilisés comme antagonistes de smo - Google Patents

Dérivés hétérocycliques bicycliques insaturés utilisés comme antagonistes de smo Download PDF

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WO2010082044A1
WO2010082044A1 PCT/GB2010/050034 GB2010050034W WO2010082044A1 WO 2010082044 A1 WO2010082044 A1 WO 2010082044A1 GB 2010050034 W GB2010050034 W GB 2010050034W WO 2010082044 A1 WO2010082044 A1 WO 2010082044A1
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compound
pharmaceutically acceptable
cancer
stereoisomer
tautomer
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Danila Branca
Gabriella Dessole
Federica Ferrigno
Philip Jones
Olaf Kinzel
Ester Muraglia
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Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A.
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/10—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 carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to unsaturated bicyclic heterocyclic derivatives which are inhibitors of the Sonic Hedgehog pathway, in particular Smo antagonists.
  • the compounds of this invention are useful for the treatment of diseases associated with abnormal hedgehog pathway activation, including cancer, for example basal cell carcinoma, medulloblastoma, prostate, pancreatic, breast, colon, bone and small cell lung cancers, and cancers of the upper GI tract.
  • Hedgehog proteins are secreted signaling proteins first discovered in Drosophila. They are highly hydrophobic proteins which after secretion can diffuse and establish gradients in tissues that have a paramount role in the proper development of the embryo. Three Hh homologues with different spatial and temporal distribution patterns have been identified in humans: Sonic hedgehog (SHH), Indian hedgehog (IHH) and Desert hedgehog (DHH).
  • Hh signaling cascade is initiated upon binding of Hh to its receptor Patched (Ptch).
  • Ptch receptor Patched
  • Ptch inhibits the activity of another membrane spanning protein
  • Smo Smoothened
  • GPCR G-protein-coupled receptor
  • Ci Upon Hh signaling the cleavage of Ci is prevented and Ci becomes an activator of target gene transcription.
  • embryonic loss of SHH signaling can result in cyclopia and other developmental defects (Chiang C et al. Nature 383:407-413 (1996))
  • inappropriate activation of the SHH pathway is believed to lead to increased cell proliferation and tumor formation and is associated with many different types of malignancies, including basal cell carcinoma (BCC), medulloblastoma, pancreatic cancer, small lung cancer, prostate cancer (PC), breast cancer, digestive tract tumors and skin cancer (Kiselyov AS Anti-cancer Agents in Medicinal Chemistry 6:445-449 (2006) and Sidransky D Nature Genet. 14:7-8 (1996)).
  • BCC basal cell carcinoma
  • medulloblastoma pancreatic cancer
  • small lung cancer small lung cancer
  • prostate cancer PC
  • breast cancer digestive tract tumors
  • skin cancer Korean cancer
  • Hh pathways in cancer Aberrant activation of the Hh pathways in cancer are considered to be caused either by mutations in the pathway (ligand independent) or through Hh overexpression (ligand dependent).
  • Ptch 1 has been connected to syndrome (also called Gorlin syndrome), a condition characterized by a number of development defects and a predisposition for developing numerous basal cell carcinomas (BCC), medulloblastoma, rhabdomyosarcoma and several other neoplasms. Mutations which inactivate Ptch and activate Smo have also been found in sporadic BCC and medulloblastoma, and a number of other sporadic tumors (Reifenberger J et al. Cancer Res. 58:1798-1803 (1998) and Xie J et al. Nature 391 :90-92 (1998)).
  • Plant-derived teratogenic alkaloids cyclopamine and jervine have been proven to cause holoprosencephaly by direct inhibition of SHH signaling (Cooper MK et al. Science 280:1603- 1607 (1998) and Incardona JP et al. Development 125:3553-3562 (1998)) by binding to Smo (Chen JK et al. Genes Dev. 16:2743-2748 (2002)).
  • Synthetic Hh antagonists have been identified in SHH responsive cell models, some targeting Smo (Chen JK et al. Proc. Natl. Acad. Sci. USA 99:14071-14076 (2002), Frank-Kamenetsky M et al. J. Biol. 1 :10 (2002) and Williams JA et al. Proc. Natl. Acad. Sci. USA 100:4616-4621 (2003)) and others an unknown target downstream of Smo (Chen JK et al. Proc. Natl. Acad. Sci. USA 99:14071-14076 (2002)).
  • Hh overexpression is detected in a broad spectrum of human tumor biopsies and cell lines, including small cell lung carcinoma, pancreatic adenocarcinoma, oesophageal, stomach and biliary tract cancers, prostate cancer, breast cancer, colon cancer and liver cancer (Rubin LL et al. Nature Reviews Drug Discovery 5:1026-33 (2006)).
  • the compounds of the present invention are inhibitors of the Hh pathway, in particular Smo antagonists.
  • the present invention provides a compound of structural formula I:
  • each of X and Y is independently N or CR 9 Z is CR 10 or N;
  • A is a ring selected from: C ⁇ -ioaryl, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing one, two or three N atoms; or a 7- 15 membered saturated, partially saturated or unsaturated heterocyclic ring containing one, two, three or four heteroatoms independently selected from N, O and S; any of which rings being optionally substituted by one, two, three or four groups independently selected from L-R 11 ;
  • L is a direct bond or O; each of R 1 , R 2 , R 3 and R 9 is independently hydrogen, Ci_ 6 alkyl, C 2 -ioalkenyl, haloCi_ 6 alkyl, hydroxyCi_ 6 alkyl, carboxy, CO 2 R a , CONR a R b , S(O) r R a or S(O) r NR a R b ; each of R 4 and R 5 is independently hydrogen, Ci_ 6 alkyl or haloCi- ⁇ alkyl;
  • R 6 is hydrogen or Ci_ 6 alkyl; each of R 7 , R 8 and R 10 is independently halogen, Ci_ 6 alkyl, Ci_ 6 alkylcarbonyl, C 2 - l oalkenyl, C 2-10 alkynyl, haloCi- ⁇ alkyl, hydroxyCi- ⁇ alkyl or a ring which is: C 3 -iocycloalkyl, C ⁇ -ioaryl, C ⁇ -ioaryloxy, C ⁇ -ioarylCi- ⁇ alkoxy, azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing one, two or three heteroatoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S or a 6 membered heteroaromatic ring containing one, two or three N atoms; any
  • X is N and Y is N or CR 9 , or each of X and Y is CR 9 .
  • X is N and Y is CR 9 , for example CH. In an embodiment each of X and Y is N.
  • each of X and Y is CR > 9 , for example CH.
  • R 9 is hydrogen
  • Z is N. In an embodiment Z is CR 10 , for example CH or C-Ci_ 6 alkyl.
  • R 1 is hydrogen
  • R 2 is hydrogen
  • R 3 is hydrogen
  • R 4 is hydrogen. In an embodiment R 5 is hydrogen.
  • R 6 is hydrogen or Ci_ 4 alkyl, for example methyl. In another embodiment R 6 is hydrogen.
  • each of R 7 and R 8 is independently halogen, Ci_ 6 alkyl or haloCi- ⁇ alkyl.
  • R 7 groups are propyl, ethyl, methyl, fluorine, trifluoroethyl and butyl.
  • Specific R 7 groups are propyl, ethyl, methyl, fluorine, 2,2,2-trifluoroethyl and tert-butyl.
  • R 8 groups are propyl, ethyl, methyl and fluorine.
  • R 10 is hydrogen or Ci_ 6 alkyl. In another embodiment R 10 is hydrogen.
  • R 10 groups are hydrogen, methyl and ethyl.
  • A is a ring selected from pyridinyl, phenyl, thienyl, pyrimidinyl, tetrahydronaphthalenyl, imidazopyridinyl, thienopyridinyl, quinolinyl and isoquinolinyl, optionally substituted by one, two or three groups independently selected from L-R 11 .
  • A is unsubstituted or substituted by one or two groups independently selected from L-R 11 .
  • L is a direct bond. In another embodiment L is O. In an embodiment R 11 is halogen, Ci_ 6 alkyl, Ci_ 6 alkoxy, haloCi- ⁇ alkyl, haloCi- ⁇ alkoxy,
  • Ci_ 6 alkylcarbonyl Ci_ 6 alkoxycarbonyl, amino, aminosulfonyl or a ring which is: pyrimidinyl, morpholinyl, piperazinyl or imidazolidinyl, any of which rings being optionally substituted by one, two or three groups independently selected from oxo, hydroxy or Ci_6alkyl.
  • R 11 groups are methyl, fluoro, trifluoromethyl, butoxycarbonyl, pyrimidinyl, chloro, difluoromethyl, acetyl, amino, morpholinyl, piperazinyl, methyloxo imidazolidinyl and aminosulfonyl.
  • R 11 groups are methyl, fluoro, trifluoromethyl, tert-butoxycarbonyl, pyrimidin-2- yl, chloro, difluoromethyl, acetyl, amino, morpholin-4-yl, piperazin-1-yl, 3-methyl-2- oxoimidazolidin-1-yl and aminosulfonyl.
  • Particular A groups are pyridinyl, methylphenyl, fluorophenyl, phenyl, methoxyphenyl, methylpyridinyl, thienyl, fluoropyridinyl, (trifluoromethyl)phenyl, dimethylpyrimidinyl, tetrahydronaphthalenyl, dimethylphenyl, (butoxycarbonyl)phenyl, pyrimidinyloxyphenyl, imidazopyridinyl, chlorophenyl, (difluoromethoxy)phenyl, acetylphenyl, methoxypyridinyl, aminopyridinyl, morpholinylpyridinyl, piperazinylpyridinyl, thienopyridinyl, chlorothienopyridinyl, (methyloxoimidazolidinyl)phenyl, difluorophenyl, quinolinyl, (aminosulfonyl)
  • a groups are pyridin-3-yl, 4-methylphenyl, 4-fluorophenyl, phenyl, A- methoxyphenyl, pyridin-2-yl, 2-methoxyphenyl, 3-methylpyridin-2-yl, 3-methoxyphenyl, 3- methylphenyl, 2-thienyl, 2-fluoropyridin-4-yl, 4-(trifluoromethyl)phenyl, 4,6-dimethylpyrimidin- 2-yl, 5,6,7,8-tetrahydronaphthalen-l-yl, 3-(trifluoromethyl)phenyl, 2-methylphenyl, 2,4- dimethylphenyl, 4-(tert-butoxycarbonyl)phenyl, 4-(pyrimidin-2-yloxy)phenyl, pyridin-4-yl, imidazo[l,2-a]pyridin-6-yl, 4-chlorophenyl, 4-(difluoromethoxy)phenyl, 4-acet
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and Z are as defined above, or a pharmaceutically acceptable salt, stereoisomer or tautomer.
  • the present invention also provides compounds of formula III:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and Z are as defined above, or a pharmaceutically acceptable salt, stereoisomer or tautomer.
  • the present invention also provides compounds of formula IV:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and Z are as defined above, or a pharmaceutically acceptable salt, stereoisomer or tautomer.
  • the present invention also provides compounds of formula V:
  • the present invention also provides compounds of formula VI:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , X and Y are as defined above, or a pharmaceutically acceptable salt, stereoisomer or tautomer.
  • the present invention also includes within its scope N-oxides of the compounds of formula I above.
  • N-oxides may be formed on any available nitrogen atom.
  • the N-oxides may be formed by conventional means, such as reacting the compound of formula I with oxone in the presence of wet alumina.
  • the present invention includes within its scope prodrugs of the compounds of formula I above.
  • prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • a prodrug may be a pharmacologically inactive derivative of a biologically active substance (the "parent drug” or “parent molecule”) that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule.
  • the transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
  • the present invention includes within its scope solvates of the compounds of formula I and salts thereof, for example, hydrates.
  • the compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E.L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, all such stereoisomers being included in the present invention.
  • the compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted.
  • the compounds may exist in different isomeric forms, all of which are encompassed by the present invention.
  • Compounds of structural formula I may be separated into their individual diastereoisomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof, or via chiral chromatography using an optically active stationary phase.
  • Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
  • any stereoisomer of a compound of the general structural formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration.
  • the compounds may exist in a number of different polymorphic forms. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • the phrase "optionally substituted” should be taken to be equivalent to the phrase "unsubstituted or substituted with one or more substituents" and in such cases the preferred embodiment will have from zero to three substituents. More particularly, there are zero to two substituents.
  • a substituent on a saturated, partially saturated or unsaturated heterocycle can be attached at any substitutable position.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C 1- ⁇ alkyl is defined to include groups having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement.
  • Ci_ 6 alkyl specifically includes methyl, ethyl, n-propyl, i-propyl, n- butyl, t-butyl, i-butyl, pentyl and hexyl and so on.
  • Preferred alkyl groups are methyl and ethyl.
  • cycloalkyl means a monocyclic, bicyclic or polycyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • C 3 _ 7 Cycloalkyl includes cyclopropyl, methyl- cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, eye Io hexyl, and so on.
  • cycloalkyl includes the groups described immediately above and further includes monocyclic unsaturated aliphatic hydrocarbon groups.
  • cycloalkyl as defined in this embodiment includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclo hexyl, cyclopentenyl, cyclo butenyl, 7,7-dimethylbicyclo[2.2.1]heptyl and so on.
  • Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C 2 -ioalkenyl refers to a non-aromatic hydrocarbon radical, straight or branched, containing from 2 to 10, including 2 to 6, carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present.
  • Alkenyl groups include ethenyl, propenyl, butenyl and 2-methylbutenyl.
  • Preferred alkenyl groups include ethenyl and propenyl.
  • C 2 -ioalkynyl refers to a hydrocarbon radical straight or branched, containing from containing from 2 to 10, including 2 to 6 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present.
  • Alkynyl groups include ethynyl, propynyl, butynyl, 3-methylbutynyl and so on.
  • Preferred alkynyl groups include ethynyl and propynyl.
  • Alkoxy represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. “Alkoxy” therefore encompasses the definitions of alkyl above.
  • alkoxy groups examples include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, cyclopropyloxy, cyclobutyloxy and cyclopentyloxy.
  • the preferred alkoxy groups are methoxy and ethoxy.
  • the term 'C ⁇ -ioaryloxy' can be construed analogously, and an example of this group is phenoxy.
  • haloCi- ⁇ alkyl and "haloCi- ⁇ alkoxy” mean a Ci_6alkyl or Ci_6alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms.
  • fluoroCi- ⁇ alkyl and fluoroCi- ⁇ alkoxy groups in particular fluoroCi_3alkyl and fluoroCi_3alkoxy groups, for example, CF3, CHF 2 , CH 2 F, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CH 2 F, OCH 2 CHF 2 or OCH 2 CF 3 , and most especially CF 3 , OCF 3 and OCHF 2 .
  • hydroxyCi- ⁇ alkyl means a Ci_ 6 alkyl group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by hydroxy groups. Preferred are CH 2 OH, CH 2 CHOH and CHOHCH 3 .
  • An example of hydroxyC2-ioalkynyr is (hydroxy)(methyl)butynyl.
  • Suitable examples of Ci_ 6 alkylcarbonyl groups include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl and te/t-butylcarbonyl.
  • Ci_ 6 alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and te/t-butoxycarbonyl.
  • Ci- ⁇ alkylmercaptoCi-ealkyl represents an alkyl group of indicated number linked via an S atom.
  • suitable alkylmercaptoalkyl groups include CH 3 SCH 2 , CH 3 SCH 2 CH 2 and CH 3 SCH 2 CH 2 CH 2 and CH 3 CH 2 SCH 2 .
  • the rings present in the compounds of this invention may be monocyclic or multicyclic, particularly bicyclic.
  • the multicyclic rings may be fused, bridged or spiro linked.
  • C ⁇ -ioaryl is intended to mean any stable monocyclic or bicyclic carbon ring of 6 to 10 atoms, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl and tetrahydrobenzo[7]annulene.
  • the preferred aryl group is phenyl, naphthyl or tetrahydronaphthyl, especially phenyl.
  • heterocycles include 7, 8, 9, 10, 11, 12, 13, 14 and 15 membered heterocycles.
  • 7-10 membered rings include 7, 8, 9 and 10 membered rings.
  • Heteroaryl denotes an unsaturated heterocycle ring.
  • Examples of particular heterocycles of this invention are benzimidazolyl, benzofurandionyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, benzoxazolonyl, benzothiazolyl, benzothiadiazolyl, benzodioxolyl, benzoxadiazolyl, benzoisoxazolyl, benzoisothiazolyl, chromenyl, chromanyl, isochromanyl, carbazolyl, carbolinyl, cinnolinyl, epoxidyl, furyl, furazanyl, imidazolyl, indolinyl
  • Preferred 5 or 6 membered saturated or partially saturated heterocycles are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuran, thiomorpholinyl, azoniabicyclohexanyl, azoniabicycloheptanyl, tetrahydropyranyl and tetrahydrothiopyranyl.
  • Preferred 5 membered heteroaromatic rings are thienyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, furyl and pyrrolyl.
  • Preferred 6 membered heteraromatic rings are pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl.
  • Preferred 7-15 membered saturated, partially saturated or unsaturated heterocyclic rings are diazepanyl, azepanyl, tetrahydroquinolinyl, quinolinyl, indolyl, imidazopyridinyl, benzothiazolyl, quinoxalinyl, benzothiadiazolyl, benzoxazolyl, dihydrobenzodioxinyl, benzotriazolyl, benzodioxolyl, dihydroisoindolyl, dihydroindolyl, tetrahydroisoquinolinyl, isoquinolinyl, benzoisothiazolyl, dihydroimidazopyrazinyl, benzothienyl, benzoxadiazolyl, thiazolotriazolyl, dihydrothiazolopyrimidinyl, dihydrobenzoxazinyl, dihydrobenzofuranyl, benzimidazolyl,
  • Particular compounds within the scope of the present invention are compounds of the Examples, and pharmaceutically acceptable salts, free bases, stereoisomers and tautomers thereof.
  • the free base of compounds of Formula I can be protonated at the N atom(s) of an amine and/or N containing heterocycle moiety to form a salt.
  • the term "free base" refers to the amine compounds in non-salt form.
  • the encompassed pharmaceutically acceptable salts not only include the salts exemplified for the specific compounds described herein, but also all the typical pharmaceutically acceptable salts of the free form of compounds of Formula I.
  • the free form of the specific salt compounds described may be isolated using techniques known in the art.
  • the free form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • the free forms may differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for purposes of the invention.
  • the pharmaceutically acceptable salts of the instant compounds can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods.
  • the salts of the basic compounds are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
  • pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed by reacting a basic instant compound with an inorganic, organic acid or polymeric acid.
  • non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, sulfamic, phosphoric, phosphorous, nitric and the like, as well as salts prepared from organic acids such as maleic, pamoic, hydroxymaleic, glutamic, salicylic, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, aspartic, ethanesulfonic, ethane, disulfonic, trifluoroacetic and the like.
  • suitable polymeric salts include those derived from the polymeric acids such as tannic acid, carboxymethyl cellulose.
  • a pharmaceutically acceptable salt of this invention contains 1 equivalent of a compound of formula (I) and 1, 2 or 3 equivalent of an inorganic or organic acid.
  • pharmaceutically acceptable salts of this invention are the trifluoroacetate or the chloride salts. In an embodiment the salt is trifluoroacetate. In another embodiment the salt is chloride.
  • the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al (1977) J. Pharm. ScL, "Pharmaceutical Salts ', 66:1-19.
  • the compounds of the present invention are potentially internal salts or zwitterions, since under physiological conditions a deprotonated acidic moiety in the compound, such as a carboxyl group, may be anionic, and this electronic charge might then be balanced off internally against the cationic charge of a protonated or alkylated basic moiety, such as a quaternary nitrogen atom.
  • the compounds of this invention may be administered to mammals, preferably humans, either alone or in combination with pharmaceutically acceptable carriers, excipients, diluents, adjuvants, fillers, buffers, stabilisers, preservatives, lubricants, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds of this invention may be administered to a subject by any convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to, oral (e.g. by ingestion); topical (including e.g. transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e.g. by inhalation or insufflation therapy using, e.g. an aerosol, e.g. through mouth or nose); rectal; vaginal; parenteral, (e.g.
  • a depot e.g. subcutaneous Iy or intramuscularly.
  • the subject may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), murine (e.g. a mouse), canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a horse), a primate, simian (e.g. a monkey or ape), a monkey (e.g. marmoset, baboon), an ape (e.g. gorilla, chimpanzee, orangutang, gibbon), or a human.
  • a rodent e.g. a guinea pig, a hamster, a rat, a mouse
  • murine e.g. a mouse
  • canine e.g. a dog
  • feline e.g. a cat
  • compositions comprising one or more compounds of this invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid
  • binding agents for example starch, gelatin, polyvinyl-pyrrolidon
  • the tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropyl-methylcellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate butyrate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as poly ethylenegly col or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water soluble carrier such as poly ethylenegly col or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoo
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous solutions.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may also be a sterile injectable oil- in- water microemulsion where the active ingredient is dissolved in the oily phase.
  • the active ingredient may be first dissolved in a mixture of soybean oil and lecithin.
  • the oil solution then introduced into a water and glycerol mixture and processed to form a microemulation.
  • the injectable solutions or microemulsions may be introduced into a patient's blood stream by local bolus injection.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Compounds of Formula I may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non- irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • topical use creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the severity of the individuals symptoms, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient.
  • the amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • Administration in vivo can be effected in one dose, continuously or intermittently (e.g. in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.
  • a suitable dose of the active compound is in the range of about 100 ⁇ g to about 250 mg per kilogram body weight of the subject per day. Where the active compound is a salt, an ester, prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
  • the present invention provides methods of inhibiting activation of the hedgehog signaling pathway, e.g., to inhibit aberrant growth states resulting from phenotypes such as Ptch loss-of-function, hedgehog gain of-function, smoothened gain-of- function or GIi gain-of- function, comprising contacting the cell with a compound of Formula I, in a sufficient amount to agonize a normal Ptc activity, antagonize a normal hedgehog activity, antagonize smoothened activity, or antagonize GIi activity e.g., to reverse or control the aberrant growth state.
  • the present invention further provides methods for treating, ameliorating one or more of the symptoms of, and reducing the severity of hyperproliferative disorders, i.e. cancer, as well as other hedgehog pathway mediated disorders or conditions.
  • the compounds of the present invention can be used for treating or preventing conditions which can be ameliorated by Smo antagonism.
  • the compounds of the invention are also useful for the manufacture of a medicament for treating or preventing the diseases described herein.
  • the present invention provides the use of a compound of formula I for the manufacture of a medicament for treating or preventing conditions which can be ameliorated by Smo antagonism.
  • the present invention also provides a method for the treatment or prevention of conditions which can be ameliorated by Smo antagonism, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.
  • Cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinom
  • cancer includes a cell afflicted by any one of the above-identified conditions.
  • the compounds of this invention can be used for treating or preventing cancers selected from basal cell carcinoma, medulloblastoma, prostate, pancreatic, breast, colon, small cell lung cancers, sarcoma, lymphomas, leukemia, gastrointestinal cancer, multiple myeloma, glioma and heptacellular.
  • Further cancers that can be treated or prevented by the compounds of the present invention include sporadic and familial basal cell carcinomas, sporadic medulloblastoma, meningiomas, breast carcinoma, esophageal squamous cell carcinoma and bladder cancer.
  • the present invention also provides the use of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment or prevention of cancer.
  • the present invention also provides a method for the treatment or prevention of cancer, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.
  • Inhibition of the hedgehog pathway has been shown to ameliorate the symptoms of psoriasis (Tas, et al, Dermatology 2Oq: 126-131 (2004) and US 2004/0072913).
  • the present invention provides the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of psoriasis.
  • the present invention also provides a method for the treatment or prevention of psoriasis, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I
  • Hedgehog activation has been shown to stimulate angiogenesis (PoIa et al. Nature Medicine 7(6):706-711 (2001) and Nagase et al. Genes to Cells 10(6):595-604 (2005)) and thus compounds which act as hedgehog antagonists may be useful as angiogenesis antagonists.
  • the present invention provides the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of angiogenesis.
  • the present invention also provides a method for the treatment or prevention of angiogenesis, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.
  • Diseases caused by, supported by or associated with angiogenesis which can be treated or prevented by the compounds of formula I include cancer, ocular neovascular disease, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, epidemic keratoconjunctivitis, vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, Sjogren's, acne rosacea, phylectenulosis, syphilis, Mycobacteria infections, lipid degeneration, chemical bums, bacterial ulcers, fungal ulcers
  • the compounds of the present invention are useful for treating and preventing cancers associated with smoothened gain-of function.
  • the compounds of formula I are also useful as chemo- and radiosensitizers for cancer treatment. They are useful for the treatment of mammals who have previously undergone or are presently undergoing or will be undergoing treatment for cancer. Such other treatments include chemotherapy, radiation therapy, surgery or immunotherapy, such as cancer vaccines.
  • the instant compounds are particularly useful in combination with therapeutic, anti- cancer and/or radiotherapeutic agents.
  • the present invention provides a combination of the presently compounds of formula I with therapeutic, anti-cancer and/or radiotherapeutic agents for simultaneous, separate or sequential administration.
  • the compounds of this invention and the other anticancer agent can act additively or synergistically.
  • a synergistic combination of the present compounds and another anticancer agent might allow the use of lower dosages of one or both of these agents and/or less frequent dosages of one or both of the instant compounds and other anticancer agents and/or to administer the agents less frequently can reduce any toxicity associated with the administration of the agents to a subject without reducing the efficacy of the agents in the treatment of cancer.
  • a synergistic effect might result in the improved efficacy of these agents in the treatment of cancer and/or the reduction of any adverse or unwanted side effects associated with the use of either agent alone.
  • the therapeutic agent, anti-cancer agent and/or radiation therapy can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the therapeutic agent, anti-cancer agent and/or radiation therapy can be varied depending on the disease being treated and the known effects of the anti-cancer agent and/or radiation therapy on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents (i.e., antineoplastic agent or radiation) on the patient, and in view of the observed responses of the disease to the administered therapeutic agents, and observed adverse affects.
  • the administered therapeutic agents i.e., antineoplastic agent or radiation
  • the compounds of formula I can be administered in combination with one or more agent selected from an anti- inflammatory agent, antihistamine, anti-cancer agent, imununomodulator, therapeutic antibody and a protein kinase inhibitor, e.g., a tyrosine kinase inhibitor.
  • an anti- inflammatory agent e.g., antihistamine, anti-cancer agent, imununomodulator, therapeutic antibody and a protein kinase inhibitor, e.g., a tyrosine kinase inhibitor.
  • a combination of a compound of formula I and an anti-cancer agent for simultaneous, separate or sequential administration.
  • cancer agents or chemotherapeutic agents for use in combination with the compounds of the present invention can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers and WO 2006/061638. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • Such agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapeutics, ⁇ -secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs) and agents that interfere with cell cycle checkpoints. Examples of such agents are provided in WO 2006/061638.
  • Anticancer agents suitable for use in the combination therapy of the present invention include, but are not limited to: 1) alkaloids, including, microtubule inhibitors (e.g., Vincristine, Vinblastine, and Vindesine, etc.), microtubule stabilizers (e.g., Paclitaxel [Taxol], and Docetaxel, Taxotere, etc.), and chromatin function inhibitors, including, topoisomerase inhibitors, such as, epipodophyllotoxins (e.g., Etoposide [VP-161, and Teniposide [VM-261, etc.), and agents that target topoisomerase I (e.g., Camptothecin and Isirinotecan [CPT-I 11, etc.); 2) covalent DNA- binding agents [alkylating agents], including, nitrogen mustards (e.g., Mechloretharnine, Chlorambucil, Cyclophosphamide, Ifosphamide, and Busulfan [Myleran
  • alpha., etc.] and interleukins [e.g., IL-2, etc.], etc.); 10) adoptive immunotherapy; 1 1) hematopoietic growth factors; 12) agents that induce tumor cell differentiation (e.g., alltrans-retinoic acid, etc.); 13) gene therapy techniques; 14) antisense therapy techniques; 15) tumor vaccines; 16) therapies directed against tumor metastases (e.g., Batimistat, etc.); 17) inhibitors of angiogenesis and kinase inhibitors.
  • tumor metastases e.g., Batimistat, etc.
  • the angiogenesis inhibitor to be used as the second compound is selected from a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of f ⁇ brob last-derived growth factor, an inhibitor of platelet derived growth factor, an MMP (matrix metalloprotease) inhibitor, an integrin blocker, interferon- ⁇ , interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, ⁇ -O-chloroacetyl-carbonyFj-fumagillol, thalidomide, angiostatin, troponin- 1, or an antibody to VEGF.
  • the estrogen receptor modulator is tamoxifen or raloxifene.
  • Suitable therapeutic antibodies for use in the combination therapy of the present invention include antibodies directed against the HER2 protein, such as trastuzuinab; antibodies directed against growth factors or growth factor receptors, such as bevacizurnab, which targets vascular endothelial growth factor, and OSI-774, which targets epidermal growth factor; antibodies targeting integrin receptors, such as Vitaxin (also known as MEDI-522), and the like.
  • HER2 protein such as trastuzuinab
  • growth factors or growth factor receptors such as bevacizurnab, which targets vascular endothelial growth factor, and OSI-774, which targets epidermal growth factor
  • antibodies targeting integrin receptors such as Vitaxin (also known as MEDI-522), and the like.
  • a method of treating or preventing basal cell carcinoma, pancreatic cancer, prostate cancer, sarcoma, lymphomas, leukemia, gastrointestinal cancer, multiple myeloma, small cell lung cancer, glioma, breast cancer, heptacellular, or medulloblastoma comprises administration to a patient in need thereof of an effective amount of a compound of formula I in combination with another anti-cancer agent.
  • a method of treating or preventing psoriasis comprises administration to a patient in need thereof of an effective amount of a compound of formula I in combination with one or more other anti-psoriasis agents including, but not limited to, corticosteroids, tar, calcipotriene, tazarotene, calcineurin inhibitors, ultraviolet irradiation, methotrexate, retinoids, cyclosporine, immunomodulatory drugs, etanercept, alefacept, efalizumab, and infliximab.
  • anti-psoriasis agents including, but not limited to, corticosteroids, tar, calcipotriene, tazarotene, calcineurin inhibitors, ultraviolet irradiation, methotrexate, retinoids, cyclosporine, immunomodulatory drugs, etanercept, alefacept, efalizumab, and infliximab.
  • the compounds of the formula can be used in combination with radiation therapy.
  • radiation therapy refers to the use of electromagnetic or particulate radiation in the treatment of neoplasia and includes the use of ionizing and non- ionizing radiation.
  • a compound of the present invention may be employed in conjunction with anti-emetic agents to treat nausea or emesis, including acute, delayed, late-phase, and anticipatory emesis, which may result from the use of a compound of the present invention, alone or with radiation therapy.
  • a compound of the present invention may be used in conjunction with other anti-emetic agents, especially neurokinin- 1 receptor antagonists, 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S.Patent Nos.
  • neurokinin- 1 receptor antagonists especially 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S.Patent No
  • an antidopaminergic such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol.
  • conjunctive therapy with an anti-emesis agent selected from a neurokinin- 1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is disclosed for the treatment or prevention of emesis that may result upon administration of the instant compounds.
  • a compound of the instant invention may also be administered with an agent useful in the treatment of anemia.
  • anemia treatment agent is, for example, a continuous eythropoiesis receptor activator (such as epoetin alfa).
  • a compound of the instant invention may also be administered with an agent useful in the treatment of neutropenia.
  • a neutropenia treatment agent is, for example, a hematopoietic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF).
  • G-CSF human granulocyte colony stimulating factor
  • Examples of a G-CSF include filgrastim.
  • a compound of the instant invention may also be useful for treating or preventing cancer in combination with siRNA therapeutics.
  • a compound of the instant invention may also be useful for treating cancer in combination with the following therapeutic agents: abarelix (Plenaxis depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®); bortezomib
  • administration means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.)
  • administration and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating cancer refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis of the cancer.
  • DCM dichloromethane
  • DIPEA N,N'-Diisopropylethylamine
  • DMF dimethylformamide
  • DMSO dimethyl sulfoxide
  • eq. equivalent
  • EtOAc ethyl acetate
  • HBTU O-Benzotriazole- N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate
  • NaH sodium hydride
  • NMR nuclear magnetic resonance
  • RP-HPLC reverse phase high performance liquid chromatography
  • RT room temperature
  • TBTU saturated aqueous
  • TBTU saturated aqueous
  • TBTU saturated aqueous
  • TBTU saturated aqueous
  • TBTU 0-(lH-benzotriazol-l-yl)-jV,iV,jV',jV'- tetramethyluronium tetrafluoroborate
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • T ⁇ F tetrahydrofuran
  • L is a halogen such as chlorine or bromine, or hydroxy and all other variables are as defined above.
  • the reaction can generally be carried out in the presence of a base such as TEA in a solvent such as DMF at about RT.
  • a base such as TEA
  • a solvent such as DMF
  • coupling reagents such as TBTU or HATU are generally used, in the presence of a base such as DIPEA in a solvent such as DMF at about RT.
  • the reaction can generally be carried out in the presence of a catalyst such as CuI or CuBr; a ligand such as rac-trans-N ⁇ 1 - dimethylcyclohexane 1,2-diamine; a base such as K2CO3 or K3PO4; and a solvent such as dioxane.
  • a catalyst such as CuI or CuBr
  • a ligand such as rac-trans-N ⁇ 1 - dimethylcyclohexane 1,2-diamine
  • a base such as K2CO3 or K3PO4
  • a solvent such as dioxane
  • Standard reductive conditions can be used, such as the presence of a reducing agent such as LAH in a solvent such as THF at about O 0 C to reflux.
  • Catalytic hydrogenation can also be carried out using for example palladium on carbon, under a hydrogen atmosphere in a solvent such as methanol.
  • Compounds of formula I wherein Z is N and R 8 is hydrogen can be prepared by reacting a compound of formula IA with a compound of formula R 7 -NCO, wherein R 7 is as defined above.
  • Compounds of formula I can be prepared by reacting a compound of formula IF with a compound of formula ID:
  • Compounds of formula IF can be prepared by reacting a compound of formula IC with a compound of formula IB.
  • the conditions described above for the reaction between a compound of formula IA and a compound of formula IB may also be used for this reaction.
  • the indazoles of the present invention can be prepared by various routes, as shown in Scheme 1.
  • 4-fluoro-3-formylbenzonitriles II reacted with hydrazine hydrate under heating (preferably under microwave irradiation) yields the indazole nitrile III.
  • Reduction of the indazole nitrile III provides the aminomethyl moiety in IV.
  • Arylation or heteroarylation of the indazole nitrogen can then be performed using aryl/heteroaryl halides (bromide or chloride) in metal catalyzed coupling conditions (Cu species, eg. CuBr or CuI) to yield the indazoles of the invention I.
  • Another route to the indazoles of the invention include the reaction of the 4-fluoro-3- formylbenzonitrile II with an appropriate aryl/heteroaryl hydrazine under heating (preferably under microwave irradiation).
  • Aryl/heteroaryl indazole nitrile VI can be then reduced to VII (with metal hydrides, such as lithium aluminum hydride, or by hydrogenation using a catalyst, such as palladium on charcoal) and reacted with appropriate acyl chlorides, carbamoyl chlorides, carboxylic acids, isocyanates, as described above, to yield the indazoles of the invention..
  • Another route to the indazoles of the invention is the arylation or heteroarylation of the indazole nitrogen of IV, using metal catalyzed coupling conditions (Cu species, eg. CuBr or CuI), followed by functionalization to indazoles I as described above.
  • Cu species eg. CuBr or CuI
  • R is H or C 1-6 alkyl
  • R 6 is C
  • Aryl/heteroaryl indazole methanamine VIII prepared using any of the routes described in Scheme 1, is N-formylated (preferably with 2,2,2-trifluoroethylformate), and then reduced (preferably borane-methyl sulfide complex in THF), to provide the methylamine derivatives X, which can be functionalized by reacting with appropriate acyl chlorides (Z is CR 10 ) or carbamoyl chlorides (Y is N) in the presence of a base (TEA or DIPEA), or by reaction with appropriate carboxylic acids (Z is CR 10 ) in the presence of coupling reagents (TBTU, HATU), or by reaction with isocyanates R 7 -NCO, to produce the indazoles I.
  • Aza- derivatives of the present invention can be obtained using the procedures in Scheme 3, starting from 6-bromo-3-fluoropyridine-2-carbaldehyde XI and reacting with an appropriate aryl/heteroaryl hydrazine under heating (preferably under microwave irradiation).
  • the bromine group can then be substituted with a cyano group (e.g. using CuCN in DMSO with microwave irradiation), and the resulting compound reduced (by usual methods, as metal hydrides, such as lithium aluminum hydride, or hydrogenation using a catalyst, such as palladium on charcoal), and then functionalized as described in Scheme 1, to give the desired indazoles I.
  • Indoles of the present invention can also be prepared as shown in Scheme 4.Arylation or heteroarylation of the indole nitrogen of l-(lH-indol-5-yl)methanamine XV can be performed using aryl/heteroaryl halides (bromide or chloride) in metal catalyzed coupling conditions (Cu species, eg. CuBr/copper bronze, as described in J. Med. Chem. 1992, 55, 1092) to yield indolyl methanamine XVI. Functionalization as described in Scheme 1, gives the desired compounds. Where the synthesis of intermediates and starting materials is not described, these compounds are commercially available or can be made from commercially available compounds by standard methods or by extension of the synthesis above, schemes and Examples herein.
  • aryl/heteroaryl halides bromide or chloride
  • Cu species eg. CuBr/copper bronze
  • Compounds of formula I may be converted to other compounds of formula I by known methods or by methods described in the Examples herein.
  • any of the synthetic sequences described herein it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protecting Groups in Organic Synthesis, 3rd Edition, Greene, T. W. and Wuts, P. G. M.; Wiley Interscience, 1999 and Kocienski, P. J. Protecting Groups, Thieme, 1994.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • Boc te/t-butoxycarbonyl
  • solvents such as TFA, DCM and/or MeCN
  • a benzylcarbonyl protecting group present, the compound may be hydrogenated using standard methods, such as treating with a catalyst such as Pd/C, in a solvent such as methanol under a hydrogen atmosphere.
  • EtOAc in the presence of HCl and 1,4-dioxane may also be added to remove the Boc protecting group, at about room temperature.
  • the enantiomers may be separated from the racemic mixtures by standard separating methods such as using SFC.
  • Shh-Light II Reporter Assay Assay designed to measure firefly and Renilla luciferase, in the same well.
  • Shh-Light II cells Prior to assay the Shh-Light II cells (ATCC Catalog No. CRL-2795) were cultured in growth media Assay protocol: Day -1: seed 60,000 Shh-Light II cells in assay medium 75 uL/well, in presence of DMSO/inhibitor.
  • DMEM Dulbecco's Mod Eagle Medium with 0.11G/L Pyr, with Pyridoxine.
  • the medium has complemented with 10% FCS (fetal bovine serum), 1% Penicillin- Streptomycin (lOmg/ml) (GIBCO, 15140-114) and 1% L-Glutamine 200MM(IOOx) (GIBCO, 3042190) and 0.4mg/ml of G418 (Roche) and 0.15mg/ml Zeocyne (Invitrogen R-250-01).
  • FCS fetal bovine serum
  • Penicillin- Streptomycin lOmg/ml
  • L-Glutamine 200MM(IOOx) GIBCO, 3042190
  • DMEM Dulbecco's Mod Eagle Medium with 0.11G/L Pyr, with Pyridoxine. (GIBCO Cat No: 21063-045), without Phenol Red. The medium has complemented with 2% FCS (fetal bovine serum), 1% Penicillin-Streptomycin (10mg/ml) (GIBCO, 15140-114) and 1% L-Glutamine 200MM(IOOx) (GIBCO, 3042190). Cells cultured at 10 % CO 2 . DMSO 0.25%.
  • Assay protocol Day -1: Seed 3,500,000 Cos7 cells in Petri dish 10 cm.
  • Day 0 Transfect cells with Lipofectamine2000 (Invitrogen) and plasmid pSMO-Myc. After 5 hrs seed the cells in 96 well plate in growth DMEM (10 % FCS); 15,000 cells per lOOul well. Day 1: 24 hrs after trans fection, change the medium with assay DMEM (without Phenol Red 2
  • DMEM GIBCO Dulbecco's Mod Eagle Medium with 0.11G/L Pyr, with Pyridoxine (GIBCO, 41966-029). The medium has complemented with 10 % FCS (GIBCO, 10106- 169), 1 %
  • Penicillin-Streptomycin (10 mg/ml) (GIBCO, 15140-114) and 1 % L-Glutamine 200MM(IOOx)
  • DMEM GIBCO Dulbecco's Mod Eagle Medium with 0.11G/L Pyr, with Pyridoxine (GIBCO, 21063-045) without Phenol Red.
  • the medium has complemented with 2 % FCS (GIBCO,
  • Glutamine 200MM(IOOx) (GIBCO, 3042190). Cells cultured at 5 % CO 2 . DMSO 0.5 %.
  • A3 (1 eq), CuI (0.05 eq) and K 3 PO 4 (2 eq) were introduced in a sealed tube filled with N 2 .
  • 3- iodopyridine (1.2 eq), rac-tra/?5-N,N'-dimethylcyclohexane-l,2-diamine (0.2 eq) and dioxane (to obtain a 0.3 M solution of A3) were added sequentially under a nitrogen stream.
  • the mixture was stirred at 110 0 C (oil bath) for 18 h.
  • the solid was filtered over a celite pad and washed with DMF.
  • Step 1 l-f4-methylphenyl)-lH-indazole-5-carbonitrile (Bl)
  • Step 2 l-ri-(4-methylphenylMH-indazol-5-vllmethanamine (B2)
  • Step 1 7V- ⁇ [l-(4-fluorophenyl)-lH-indazol-5-yl]methyl ⁇ formamide (Dl)
  • Step 2 l-[l-f4-fluorophenyl)-lH-indazol-5-yll-7V-methylmethanamine (D2)
  • Step 3 7V- ⁇ ri-(4-fluorophenvl)-lH-indazol-5-vllmethvll-7V-methyl-7VJV-dipropvlurea (D3)
  • Step 1 l-(4-fluorophenyl)-lH-pyrazolo [4,3-b] pyridine-5-bromide (Fl)
  • MeOH 0.1 M
  • 6M HCl 1.5 eq
  • catalytic Pd/C 15% w/w
  • Reaction mixture was filtered on a SolcaFloc® 200 FCC pad, washing with 1.25M HCl in MeOH. Volatiles were evaporated under reduced pressure to afford the title compounds as a yellow solid.
  • Step 4 7V- ⁇ [l-(4-fluorophenyl)-lH-pyrazolo[4,3-6]pyridin-5-yl]methyl ⁇ -2- propylpentanamide (F4)

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Abstract

La présente invention porte sur des composés de formule (I); et sur des sels ou tautomères pharmaceutiquement acceptables de ceux-ci, qui sont des inhibiteurs de la voie de signalisation Sonic Hedgehog, en particulier des antagonistes de Smo. Ainsi, les composés de la présente invention sont utiles pour le traitement de maladies associées à une activation anormale de la voie de signalisation des protéines hedgehog, dont un cancer, par exemple un carcinome basocellulaire, un médulloblastome, les cancers de la prostate, du pancréas, du sein, du côlon, des os et du poumon à petites cellules, ainsi que les cancers du tractus gastro-intestinal supérieur.
PCT/GB2010/050034 2009-01-13 2010-01-12 Dérivés hétérocycliques bicycliques insaturés utilisés comme antagonistes de smo WO2010082044A1 (fr)

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Cited By (5)

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US8907089B2 (en) 2009-08-26 2014-12-09 Takeda Pharmaceutical Company Limited Fused heterocyclic ring derivative and use thereof
WO2014169882A3 (fr) * 2013-04-20 2014-12-11 复旦大学 Composé de type benzimidazole manifestant une activité antitumorale, son procédé de préparation et utilisation
EP3124482A4 (fr) * 2014-03-24 2017-03-22 Guangdong Zhongsheng Pharmaceutical Co., Ltd Dérivés de quinoléine comme inhibiteurs de smo
WO2018170517A1 (fr) * 2017-03-17 2018-09-20 Regents Of The University Of Colorado, A Body Corporate Inhibiteurs d'indazole de la fructokinase (khk) et méthodes d'utilisation dans le traitement de troubles ou de maladies à médiation par khk
US10301292B2 (en) 2014-11-26 2019-05-28 Takeda Pharmaceutical Company Limited Bicyclic compound

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8907089B2 (en) 2009-08-26 2014-12-09 Takeda Pharmaceutical Company Limited Fused heterocyclic ring derivative and use thereof
WO2014169882A3 (fr) * 2013-04-20 2014-12-11 复旦大学 Composé de type benzimidazole manifestant une activité antitumorale, son procédé de préparation et utilisation
EP3124482A4 (fr) * 2014-03-24 2017-03-22 Guangdong Zhongsheng Pharmaceutical Co., Ltd Dérivés de quinoléine comme inhibiteurs de smo
US9938292B2 (en) 2014-03-24 2018-04-10 Guangdong Zhongsheng Pharmaceutical Co., Ltd Quinoline derivatives as SMO inhibitors
US10301292B2 (en) 2014-11-26 2019-05-28 Takeda Pharmaceutical Company Limited Bicyclic compound
WO2018170517A1 (fr) * 2017-03-17 2018-09-20 Regents Of The University Of Colorado, A Body Corporate Inhibiteurs d'indazole de la fructokinase (khk) et méthodes d'utilisation dans le traitement de troubles ou de maladies à médiation par khk
US11083720B2 (en) 2017-03-17 2021-08-10 Regents Of The University Of Colorado, A Body Corporate Indazole inhibitors of fructokinase (KHK) and methods of use in treating KHK-mediated disorders or diseases

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