WO2010023480A1 - Saturated bicyclic heterocyclic derivatives as smo antagonists - Google Patents

Saturated bicyclic heterocyclic derivatives as smo antagonists Download PDF

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Publication number
WO2010023480A1
WO2010023480A1 PCT/GB2009/051079 GB2009051079W WO2010023480A1 WO 2010023480 A1 WO2010023480 A1 WO 2010023480A1 GB 2009051079 W GB2009051079 W GB 2009051079W WO 2010023480 A1 WO2010023480 A1 WO 2010023480A1
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Prior art keywords
compound
independently selected
alkyl
βalkyl
haloci
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PCT/GB2009/051079
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French (fr)
Inventor
Danila Branca
Federica Ferrigno
Jose Ignacio Martin Hernando
Philip Jones
Olaf Kinzel
Savina Malancona
Ester Muraglia
Maria Cecilia Palumbi
Giovanna Pescatore
Rita Scarpelli
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Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A.
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Priority claimed from GB0815700A external-priority patent/GB0815700D0/en
Priority claimed from GB0821817A external-priority patent/GB0821817D0/en
Application filed by Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. filed Critical Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A.
Priority to CA2735177A priority Critical patent/CA2735177C/en
Priority to AU2009286528A priority patent/AU2009286528B2/en
Priority to JP2011524457A priority patent/JP5816087B2/en
Priority to EP09785541.5A priority patent/EP2334683B1/en
Priority to US13/060,718 priority patent/US8470823B2/en
Publication of WO2010023480A1 publication Critical patent/WO2010023480A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to saturated bicyclic heterocyclic derivatives which are inhibitors of the Sonic Hedgehog pathway, in particular they function as Smoothened (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. ScL 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 m and n is independently 1 or 2; each of w, y and z is independently 0, 1 or 2; x is 0 or 1 ;
  • A is C 3 _ 7 Cycloalkyl or fluoroCs.ycycloalkyl
  • R 1 is d- ⁇ alkyl, haloCi- ⁇ alkyl or a ring which is: C ⁇ -ioaryl; C 3 -iocycloalkyl; oxetanyl; 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; a 6 membered heteroaromatic ring containing one, two or three N atoms; or a 7-15 membered unsaturated, partially saturated or saturated 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 or three groups independently selected from R 10 ;
  • R 2 is a Ci_ioalkyl, haloCi_ioalkyl, Ci_ 6 alkylmercaptoCi_ 6 alkyl, C 2 -ioalkenyl or a ring which is: C 3 -iocycloalkyl; C ⁇ -ioaryl; oxetanyl; 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; 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
  • R 7 is hydrogen or Ci_ 6 alkyl; each of R 8 and R 9 is independently hydrogen, Ci_ 6 alkyl, Ci_ 6 alkoxy, Ci_ 6 alkoxycarbonyl or haloCi- ⁇ alkyl; each R 10 is independently hydroxy, cyano, halogen, Ci_ 6 alkyl, haloCi- ⁇ alkyl, OR a or NR a R b ; each R 11 is independently hydroxy, oxo, cyano, halogen, Ci_ 6 alkyl, Ci_ 6 alkylcarbonyl, C 2 - loalkenyl, C 2 -i 0 alkynyl, haloCi_ 6 alkyl, hydroxy C i_ 6 alky 1, carboxy, nitro, OR a , NR a R b , NR a COR b , NR a S(O) r R b , NR a S(O) r NR a R b , CO 2 R
  • each of R 3 , R 4 , R 5 and R 6 is independently C h alky!, C 2 -ioalkenyl, haloCi- ⁇ 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 R 11 is independently hydroxy, oxo, cyano, halogen, Ci_ 6 alkyl, Ci_ 6 alkylcarbonyl, C 2 - l oalkenyl, C 2 -i 0 alkynyl, haloCi_ 6 alkyl, hydroxyCi_ 6 alkyl, carboxy, nitro, OR a , NR a R b , NR a COR b , NR a S(O) r R b , NR a S(O) r NR a R b , CO 2
  • R 2 is a Ci_ioalkyl, haloCi_ioalkyl, Ci-ealkylmercaptoCi- ⁇ alkyl or a ring which is: C 3 _iocycloalkyl, C ⁇ -ioaryl, 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 R 11 ; and each R 11 is independently hydroxy, oxo, cyano, halogen, C ⁇ alkyl, C 2-10 alkenyl, haloCi_ 6 alkyl, hydroxyCi_
  • x is 0. In another embodiment x is 1. In an embodiment R 4 is Ci_ 6 alkyl, for example methyl. In another embodiment, x is 1 and R 4 is Ci_ 6 alkyl, for example methyl. In an embodiment y is 0.
  • z is 0.
  • each of w, y and z is 0 and x is 0 or 1.
  • each of w, x, y and z is 0. In another embodiment each of w, y and z is 0 and x is 1. In an embodiment each of R 3 , R 4 , R 5 and R 6 is independently Ci_ 6 alkyl, for example methyl.
  • R 4 is Ci_ 6 alkyl or Ci_ 6 alkoxyCi_ 6 alkyl. Particular R 4 groups are methyl, ethyl or methoxymethyl. In an embodiment A is C 3 _ 6 Cycloalkyl or fluoroCs- ⁇ cycloalkyl. Particular A groups are cyclopropyl, fluorocyclopropyl and cyclobutyl.
  • A is cyclopropyl
  • a is 1. In an embodiment b is 1.
  • c is 0. In an embodiment d is 0 or 1. In an embodiment e is 0.
  • R 7 is hydrogen or Ci_ 6 alkyl.
  • Particular R 7 groups are hydrogen and butyl, especially hydrogen.
  • each of R 8 and R 9 is independently hydrogen, Ci_ 6 alkyl and
  • one of R 8 and R 9 is hydrogen or methyl and the other hydrogen, methyl or ethoxycarbonyl.
  • one of R 8 and R 9 is hydrogen or methyl and the other methyl or ethoxycarbonyl.
  • n is 1. In another embodiment m is 2.
  • n is 1. In another embodiment n is 2.
  • each of m and n is 1.
  • R 1 is C ⁇ -ioaryl, optionally substituted by one, two or three groups independently selected from R 10 .
  • R 1 is an optionally substituted phenyl.
  • R 1 when R 1 is a ring it is unsubstituted or monosubstituted.
  • R 1 is C ⁇ -ioaryl; C 3 _iocycloalkyl; oxetanyl; 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; a 6 membered heteroaromatic ring containing one, two or three N atoms; or a 7-15 membered unsaturated, partially saturated or saturated 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 or three groups independently selected from
  • R , 10 is cyano, halogen or OR a .
  • R 10 is halogen or OR a .
  • R a is Ci_ 6 alkyl.
  • Particular R 10 groups are chlorine, fluorine and methoxy.
  • a further particular R 10 group is cyano.
  • a further R 10 group is bromine.
  • R 1 groups are phenyl, chlorophenyl, fluorophenyl and methoxyphenyl. Further particular R 1 groups are difluorophenyl and cyanophenyl. A further particular R 10 group is dibromophenyl. Specific R 1 groups are phenyl, 4-chlorophenyl, 4-fluorophenyl and A- methoxyphenyl. Further specific R 1 groups are 2-methoxyphenyl, 3,4-difluorophenyl, 3- methoxyphenyl, 2,4-difluorophenyl, 4-cyanophenyl and 3-cyanophenyl. A further specific R 10 group is 3,5-dibromophenyl.
  • R 2 is Ci_ioalkyl, Ci-ealkylmercaptoCi- ⁇ alkyl or a ring which is: C 3 _iocycloalkyl, 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 8-10 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 or three groups independently selected from R 11 .
  • R 2 is C 3 _iocycloalkyl, 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 8-10 membered 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 or three groups independently selected from R 11 .
  • R 2 is Ci_salkyl, Ci-ealkylmercaptoCi- ⁇ alkyl, C 2 - 6 alkenyl or a ring which is: phenyl, cyclohexyl, pyrazolyl, pyridinyl, benzodioxolyl, isoxazolyl, pyrrolidinyl, cyclopropyl, piperidinyl, tetrahydrothiopyranyl, oxazolyl, tetrahydronaphthalenyl, tetrahydroquinolinyl or tetrahydropyranyl; any of which rings being optionally substituted by one, two or three groups independently selected from R 1 ⁇ . Further optionally substituted rings include cyclopentyl and bicycloheptyl.
  • R 2 is 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, optionally substituted by one, two or three groups independently selected from halogen, Ci_ 6 alkyl, haloCi- ⁇ alkyl or C ⁇ -ioaryl optionally substituted by one, two or three groups independently selected from halogen, Ci_ 6 alkyl or haloCi- ⁇ alkyl.
  • R 2 is Ci_salkyl, Ci-ealkylmercaptoCi- ⁇ alkyl or a ring which is: phenyl, cyclohexyl, pyrazolyl, pyridinyl or benzodioxolyl; any of which rings being optionally substituted by one, two or three groups independently selected from R 11 .
  • R 2 is phenyl, cyclohexyl, pyrazolyl, pyridinyl or benzodioxolyl; optionally substituted by one, two or three groups independently selected from R 11 .
  • R 2 is phenyl, optionally substituted by one, two or three groups independently selected from R 11 .
  • R 2 when R 2 is a ring it is unsubstituted or optionally substituted by one, two or three groups independently selected from R 11 .
  • R 11 is oxo, cyano, halogen, C ⁇ alkyl, C 2-10 alkenyl, haloCi- ⁇ alkyl, Ci_ ealkylcarbonyl, OR a , NR a R b , CO 2 R a , S(O) r R a NR a S(O) r R b or a ring which is: C 3 -i 0 cycloalkyl, C 6 - loaryl, C6-ioarylCi_6alkoxy, C6-ioarylCi_6alkyl or 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; any of which rings being optionally substituted by one, two or three groups
  • R 11 is cyano, halogen, Ci_ 6 alkyl, C 2 -ioalkenyl, haloCi- ⁇ alkyl, OR a , NR a R b , CO 2 R a , S(O) r R a or a ring which is: C 6 -i 0 aryl, C 6 -i 0 arylCi_ 6 alkoxy, or 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; any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, d- ⁇ alkyl, haloCi- ⁇ alkyl, Ci_6alkoxy and haloCi- ⁇ alkoxy.
  • each of R a and R b is independently hydrogen, Ci_ 6 alkyl or C ⁇ -io
  • R a groups are hydrogen, methyl and phenyl.
  • R b groups are hydrogen, methyl, phenyl and methylphenyl, for example A- methylphenyl
  • each R a is independently Ci_ 6 alkyl or haloCi- ⁇ alkyl, for example methyl or trifluoromethyl.
  • r is 2.
  • R b is Ci_ 6 alkyl, for example methyl.
  • each of R a and R b is independently hydrogen or Ci_ 6 alkyl.
  • R 11 is cyano, oxo, halogen, Ci_ 6 alkyl, Ci_ 6 alkylcarbonyl, C 2 - 6 alkenyl,
  • R 11 is cyano, halogen, Ci_ 6 alkyl, C 2 - 6 alkenyl, haloCi- ⁇ alkyl, Ci_ 6 alkoxy, haloCi- ⁇ alkoxy, Ci_6alkoxycarbonyl, amino, Ci_6alkylamino, di(Ci_6alkyl)amino, Ci_ 6 alkylsulfonyl or a ring which is: phenyl, benzyloxy, thienyl or oxazolyl; any of which rings being optionally substituted by one, two or three groups independently selected from halogen, Ci_ 6 alkyl, haloCi- ⁇ alkyl and Ci_ 6 alkoxy.
  • R 1 ⁇ when R 1 ⁇ is a ring it is unsubstituted or monosubstituted.
  • the optional substituents on the R 11 ring are independently selected from halogen, Ci_ 6 alkyl, haloCi- ⁇ alkyl and Ci_ 6 alkoxy. Further optional substituents on the R 11 ring are cyano and Ci_ 6 alkylsulfonyl. Particular optional substituents on the R 11 ring are independently selected from chloro, trifluoromethyl and methoxy . Further particular optional substituents on the R 11 ring are methylsulfonyl, fluoro, cyano and methyl.
  • R 11 groups are phenyl, chloro, chlorophenyl, propenyl, benzyloxy, dimethylamino, trifluoromethyl, methoxy, propyl, fluoro, thienyl, methylsulfonyl, cyano, methyl, oxazolyl, trifluoromethoxy, methoxycarbonyl, (trifluoromethyl)phenyl and methoxyphenyl.
  • R 11 groups are cyclopropyl, acetyl, oxo, (methylsulfonyl)phenyl, (dimethylamino)carbonyl, ethyl, fluorophenyl, dichlorophenyl, pyridinyl, cyanophenyl, methylpyrazolyl and ethynyl.
  • R 11 groups are butyl, cyclohexyl, propanyl,
  • R 11 groups are phenyl, chloro, 3 -chlorophenyl, isopropenyl, benzyloxy, dimethylamino, trifluoromethyl, methoxy, isopropyl, fluoro, 3-thienyl, methylsulfonyl, cyano, methyl, l,3-oxazol-5-yl, trifluoromethoxy, methoxycarbonyl, 3-(trifluoromethyl)phenyl, 2-chlorophenyl, 4-chlorophenyl, 2-methoxyphenyl, 3 -methoxyphenyl and 4-methoxyphenyl.
  • R 11 groups are cyclopropyl, acetyl, oxo, 3-(methylsulfonyl)phenyl, (dimethylamino)carbonyl, ethyl, 3-fluorophenyl, 3, 5 -dichlorophenyl, 4-fluorophenyl, pyridin-3- yl, 3 -cyanophenyl, 1 -methyl- lH-pyrazol-4-yl and ethynyl.
  • R 11 groups are tertbutyl, cyclohexyl, propan-2-yl, [(4- methylphenyl)sulfonyl]amino, benzyl and phenylsulfonyl.
  • R 2 groups are biphenyl, dichlorophenyl, cyclohexyl, phenylpyrazolyl, (chlorophenyl)pyridinyl, isopropenylphenyl, butyl, benzodioxolyl, methylmercaptoethyl, (benzyloxy)phenyl, hexyl, (dimethylamino)phenyl, (trifluoromethyl)phenyl, methoxyphenyl, isopropylphenyl, dichlorofluorophenyl, phenyl, chlorofluorophenyl, chloropyridinyl, thienylpyridinyl, thienylphenyl, chloro(methylsulfonyl)phenyl, (chloro)(cyano)(methyl)phenyl, dichlorocyanophenyl, (chloro)(methyl)phenyl, oxazolylphenyl, dichloro(
  • R 2 groups are phenylisoxazolyl, (chloro)(cyclopropyl)pyridinyl, (acetyl)(phenyl)pyrrolidinyl, methylcyclopropyl, (acetyl)(phenyl)piperidinyl, dioxidotetrahydrothiopyranyl, [(methylsulfonyl)phenyl]pyridinyl, (chlorophenyl)pyrazolyl, phenyloxazolyl, phenylcyclohexyl, tetrahydronaphthalenyl, dichloro [(dimethylamino)carbonyl]phenyl, (chloro)dimethylphenyl, (chloro)(methoxy)pyridinyl, (chloro)(methyl)pyridinyl, (chloro)(ethyl)pyridinyl, (fluorophenyl)pyrazolyl,
  • R 2 groups are (fluorophenyl)(methyl)pyrazolyl, (acetyl)(methyl)piperidinyl, cyclopentyl, dimethylcyclohexyl, phenylcyclohexyl, butylcyclohexyl, trimethylbicyclo[2.2.1]heptyl, bi(cyclohexyl), tetrahydropyranyl, methyl(propanyl)cyclohexyl,
  • R 2 groups are biphenyl-2-yl, 2,3-dichlorophenyl, cyclohexyl, 1-phenyl-lH- pyrazol-5-yl, 2-(3-chlorophenyl)pyridin-3-yl, 3-isopropenylphenyl, 2,6-dichlorophenyl, butyl, l,3-benzodioxol-5-yl, methylmercaptoethyl, 4-(benzyloxy)phenyl, biphenyl-4-yl, hexyl, 4- (dimethylamino)phenyl, 2-(trifluoromethyl)phenyl, 2-methoxyphenyl, 2-isopropylphenyl, 2,6- dichloro-4-fluorophenyl, phenyl, 2-chloro-4-fluorophenyl, 2-chloropyridin-3-yl, 2-(3- thienyl)pyridin-3-yl,
  • R 2 groups are 4-phenylisoxazol-5-yl, 4-chloro-2-cyclopropylpyridin-3-yl, (E)-l-acetyl- 4-phenylpyrrolidin-3-yl, 1-methylcyclopropyl, tert-butyl, l-acetyl-3-phenylpiperidin-4-yl, 1,1- dioxidotetrahydro-2H-thiopyran-4-yl, 2-[3-(methylsulfonyl)phenyl]pyridin-3-yl, l-(3- chlorophenyl)-lH-pyrazol-5-yl, 5-phenyl-l,3-oxazol-2-yl, (lR,2S)-2-phenylcyclo hexyl, 1,2,3,4- tetrahydronaphthalen- 1 -yl, 2,6-dichloro-4-[(dimethylamino)carbonyl]phenyl
  • R 2 groups are 4-(4-fluorophenyl)-l- methyl- 1 H-pyrazol-5-yl, 3 -(3 -fluorophenyl)- 1 -methyl- lH-pyrazol-4-yl, 1 -acetyl-4- methylpiperidin-4-yl, cyclopentyl, 4,4-dimethylcyclohexyl, 1-phenylcyclohexyl, 2- methylcyclohexyl, 3-methylcyclohexyl, trans-4-methylcyclohexyl, trans-2-phenylcyclohexyl, 4- tert-butylcyclohexyl, 4-phenylcyclohexyl, (IS, 2R)-l,7,7-trimethylbicyclo[2.2.1]hept-2-yl, (lR,2S)-l,7,7-trimethylbicyclo[2.2.1]hept-2-yl, cis-bicyclohex-2-
  • each of w, x, y and z is 0;
  • R 1 is C ⁇ -ioaryl, optionally substituted by one, two or three groups independently selected from R 10 .
  • each of w, x, y and z is 0;
  • R 2 is C 3 _iocycloalkyl, 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 ⁇ membered heteroaromatic ring containing one, two or three N atoms, or a 8-10 membered 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 or three groups independently selected from R 1 ! .
  • each of w, y and z is 0 and x is 1;
  • R 4 is Ci_ 6 alkyl; d is O;
  • R 7 is hydrogen;
  • R 2 is 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, optionally substituted by one, two or three groups independently selected from halogen, Ci_ 6 alkyl, haloCi- ⁇ alkyl or C ⁇ -ioaryl optionally substituted by one, two or three groups independently selected from halogen, Ci_ 6 alkyl or haloCi- ⁇ alkyl.
  • each of w, y and z is 0 and x is 1; each of m and n is 1;
  • R 1 is C ⁇ -ioaryl, optionally substituted by one, two or three groups independently selected from R 10 .
  • the present invention also provides a compound of formula II:
  • 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.
  • 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, cyclohexyl, cyclopentenyl, cyclobutenyl, 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. Examples of suitable alkoxy groups 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_6alkyl and fluoroCi_6alkoxy groups in particular fluoroCi_3alkyl and fluoroCi_3alkoxy groups, for example, CF 3 , 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 .
  • the term 'hydroxyC 2 -ioalkenyl' and 'hydroxyC 2 -ioalkynyl' can be construed analogously.
  • An example of 'hydroxyC 2 -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.
  • the term 'C ⁇ -ioarylcarbonyl' can be construed analogously, and an example of this group is benzoyl.
  • 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.
  • aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl and tetrahydrobenzo[7]annulene.
  • the preferred aryl group is phenyl or naphthyl, 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 and tetrahydropyranyl.
  • a further ring is 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, thiazo Io triazolyl, dihydrothiazolopyrimidinyl, dihydrobenzoxazinyl, dihydrobenzofuranyl, benzimidazolyl,
  • halogen refers to fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.
  • Particular compounds within the scope of the present invention are the specific compounds named in the representative 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.
  • conventional 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 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 polyoxy ethylene 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 mono
  • 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.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous solutions. Among the 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. For example, 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.
  • phenotypes such as Ptch loss-of-function, hedgehog gain of-function, smoothened gain-of- function or GIi gain-of- function
  • 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
  • nephroblastoma lymphoma, leukemia
  • bladder and urethra squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, mal
  • 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.
  • 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, Herpes simplex infections, Herpes zoster infections, protozoan infections, Kaposi sarcoma, Mooren ulcer, Terrien's marginal degeneration, marginal keratolysis, rheuma
  • the compounds of the present invention are useful for treating and preventing cancers selected from basal cell carcinoma, medulloblastoma, prostate, pancreatic, breast, colon, small cell lung cancers, sarcoma, lymphomas, leukemia, gastrointestinal cancer, multiple myeloma, glioma, heptacellular, sporadic and familial basal cell carcinomas, sporadic medulloblastoma, meningiomas, breast carcinoma, esophageal squamous cell carcinoma and bladder cancer.
  • cancers selected from basal cell carcinoma, medulloblastoma, prostate, pancreatic, breast, colon, small cell lung cancers, sarcoma, lymphomas, leukemia, gastrointestinal cancer, multiple myeloma, glioma, heptacellular, sporadic and familial basal cell carcinomas, sporadic medulloblastoma, meningiomas, breast carcinoma, esophageal s
  • the compounds of the present invention are useful for treating and preventing cancers associated with patched loss-of function.
  • 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, anticancer 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., anti-neoplastic 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., anti-neoplastic 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,
  • nitrosoureas e.g., Carmustine, Lomustine, and Semustine, etc.
  • other alkylating agents e.g., dacarbazine, Hydroxymethylmelamine, Thiotepa, and Mitocycin, etc.
  • 3) noncovalent DNA- binding agents [antitumor antibiotics], including, nucleic acid inhibitors (e.g., Dactinomycin [Actinomycin Dl, etc.), anthracyclines (e.g., Daunorubicin [Daunomycin, and Cerubidine], Doxorubicin [Adrianycin], and Idarubicin [Idamycin], etc.), anthracenediones (e.g., anthracycline analogues, such as, [Mitoxantrone], etc.), bleomycin
  • nucleic acid inhibitors e.g., Dactinomycin [Actinomycin Dl, etc.
  • 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 fibrob 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.
  • 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 or “treatment of 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.
  • the compounds of this invention can be prepared according to the following procedures. All variables within the formulae are defined above.
  • reaction is generally carried out in the presence of a base such as DIPEA or TEA, in a solvent such as DCM or MeCN at about RT.
  • a base such as DIPEA or TEA
  • a solvent such as DCM or MeCN
  • the solvent DCE may also be used.
  • Compounds of formula IA can be prepared in situ by reacting the corresponding amine of formula IC with an agent such as CDI:
  • R x is Ci_ 6 alkyl, for example methyl
  • P is a protecting group such as tert-butoxycarbonyl and all other variables are as defined above.
  • the cyclization can generally be carried out in the presence of a base such as DIPEA, a solvent such a toluene at reflux.
  • the cyclization can be carried out under acidic conditions, such as in the presence of an acid such as
  • the protecting group can be removed according to standard procedures. For example, when P is tert-butoxycarbonyl it can be removed by the addition of an acid such as TFA in a solvent such as DCM at about RT.
  • Compounds of formula IB wherein x is 1 can be prepared by reacting a compound of formula IB wherein x is 0 with a compound of formula wherein L 1 is a leaving group such as halogen, for example iodine.
  • the reaction can generally be carried out in the presence of a strong base such as LDA and a solvent such as THF at about -78 0 C to RT.
  • a strong base such as LDA
  • a solvent such as THF at about -78 0 C to RT.
  • compounds may be protected by protecting groups such as tert-butoxycarbonyl.
  • reaction can be carried out in the presence of a base such as DIPEA or Et 3 N in a solvent such as DCM at about RT.
  • a base such as DIPEA or Et 3 N
  • a solvent such as DCM
  • L 2 is hydroxy and the reaction can be carried out in the presence of a coupling reagent such as TBTU.
  • compounds of formula I wherein a is 1 and X is C can be prepared by reacting a compound of formula IB with a compound of formula IJ:
  • reaction is generally carried out in the presence of a base such as TEA in a solvent such as DCM at about RT.
  • the compound of formula IJ wherein b is 1 and R 7 is hydrogen can be prepared by reacting a compound of formula IC with phenyl chloro formate, generally in a solvent such as DCE at about RT.
  • a solvent such as DCE
  • Compounds from this invention can be prepared from suitably protected rings such as piperazine-2-carboxylic acid derivatives. Reaction of these piperazines with isocyanates gives an intermediate urea that can be cyclised to the required bicyclic hydantoin at reflux in toluene, in the presence of a tertiary amine base such as di-iso-propylethylamine. Alternatively, the urea can also be cyclised under acidic conditions at room temperature, such as 4M HCl solution in dioxane, to give the required bicyclic framework. Under these latter conditions, acid labile protecting groups such as Boc-groups can be removed during the cyclisation reaction.
  • Derivitization of the other nitrogen atom can be accomplished by reaction with an isocyanate group, to yield the desired ureas.
  • isocyanates can be prepared in situ from an amine and triphosgene in a solvent such as DCM.
  • the bicyclic system can also be reacted with an acyl imidazole intermediate obtained from the reaction of an amine with carbonyl diimidazole in MeCN at 8O 0 C, condensation with the bicyclic hydantoin then yields the requisite urea.
  • amines can be preactivated with phenyl chloroformate in solvents such as DCE to yield the corresponding phenyl carbonate, which can in turn be reacted with the bicyclic framework to yield the desired ureas as Smo antagonists.
  • This latter reaction is typically conducted in a solvent such as DCM, at room temperature, in the presence of a trialkylamine base such as triethylamine.
  • Coupling of the bicyclic framework with carboxylic acids using a coupling agent such as TBTU, in solvents like DMF allows the formation of the corresponding amides which are themselves Smo antagonists.
  • Similar compounds can be prepared by coupling of acyl chlorides with the scaffold in the presence of a trialkylamine base in a solvent such as DCM.
  • An alternative synthetic strategy which allows variation of the right-hand side of the compounds of this invention involves the formation of the bicyclic hydantoin core by reaction of a ring such as a piperazine-2-carboxylic acid derivative with potassium cyanate in water and dioxane, in the presence of 1 equivalent of HCl (Scheme 2).
  • the resulting bicyclic framework can then be reacted with neat vinyl acetate in the presence of catalytic Na 2 PdCl 4 at reflux as described in Eur. J. Org. Chem. 2000, 1507.
  • P protecting group, e.g. Boc Pd(OAc) 2 , LiBr, NaOAc
  • a suitable projected core scaffold can be deprotonated using a strong
  • the resulting anion can be quenched with an alkylating agent, such as methyl iodide, warming the reaction from -78 0 C to room temperature to ensure successful alkylation.
  • an alkylating agent such as methyl iodide
  • 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. For example, when the Boc (te/t-butoxycarbonyl) or benzylcarbonyl protecting group is present, it may be removed by the addition of solvents such as TFA, DCM and/or MeCN at about room temperature.
  • the compound may also 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 benzylcarbonyl protecting group, at about room temperature.
  • the enantiomers may be separated from the racemic mixtures by standard separating methods such as using SFC.
  • SFC standard separating methods
  • Day -1 seed 60,000 Shh-Light II cells in assay medium 75 uL/well, in presence of
  • 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 % FCS) and add compound/DMSO 0.5%. Incubate at 37 0 C 5 % CO2. Day 2: After 16 hrs, add Cyclopamine-Bodipy (Toronto Research Chemical, B674800) at the final concentration of 5OnM. Incubate for 4 hrs at 37 0 C 5 % CO 2 . Then cells are fixed 10 minutes with 3.5% Formaldehyde lOOul/well. Cells are washed 3 times with PBS and nuclei are stained with 1.5 uM Propidium Iodide. Read at Acumen Explorer.
  • 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) (GIBCO, 3042190). Cells cultured at 5 % CO 2 For assay:
  • 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, 10106-169), 1 % Penicillin-Streptomycin (10 mg/ml) (GIBCO, 15140-114) and 1 % L- Glutamine 200MM(IOOx) (GIBCO, 3042190). Cells cultured at 5 % CO 2 . DMSO 0.5 %.
  • Step 1 (261-l-[(Benzyloxy)carbonyll-4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid
  • Step 3 ⁇ -tert-Butyl 3-methyl QffHJ-piperazinedicarboxylate (AA3) 10% Pd-C (0.2 eq.) was added to a stirred solution of AA2 in MeOH (0.1 M) at RT and the mixture was stirred under H 2 atmosphere at RT for 3 h. The mixture was filtered, washing with MeOH, and the filtrate was evaporated under reduced pressure to give the title compound in 89 % yield.
  • AA3 ⁇ -tert-Butyl 3-methyl QffHJ-piperazinedicarboxylate
  • reaction mixture was then irradiated for 1 h at 120 0 C, using an irradiation power of 100 W. After completion of the reaction, the vial was cooled to 50 0 C with air jet cooling before it was opened. The reaction mixture was diluted with EtOAc and filtered on a pad of Solca Floc®200FCC. The crude product was purified by flash chromatography eluting with 5-100% EtO Ac/petroleum ether affording the titled compound as violet oil. MS (ES) C 6 H 7 ClN 2 requires: 142, found: 143, 145 (M+H) + .
  • Step 1 l-[(benzyloxy)carbonyll-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (Al)
  • a 0.68 M solution of Boc-ON (1.1 eq) in dioxane was added dropwise at RT to the above mixture and the reaction mixture was stirred at RT overnight.
  • the mixture was extracted with Et 2 O (x3) and acidified with cone. HCl to pH 2.
  • the aqueous layer was extracted with EtOAc (x3).
  • Step 4 tert-butyi l,3-dioxo-2-[tr ⁇ /?5-2-phenylcyclopropyllhexahydroimidazo[l,5- ⁇ lpyrazine- 7(lH)-carboxylate (A4)
  • the mixture was stirred O/N at rt.
  • DIPEA 1.5 eq.
  • the organic phase was washed with phosphate buffer (2 x 200 mL, 0.75 M NaH 2 PO 4 , pH ⁇ 4.5) and the solvent removed under reduced pressure.
  • Step 5 2-[tr ⁇ /?5-2-phenylcyclopropylltetrahydroimidazo[l,5- ⁇ lpyrazine-l,3(2H,5H)-dione (A5)
  • a solution of A4 in DCM (0.5 M) was cooled to 0°C (ice bath) and TFA (9 eq.) was added and the reaction was stirred at RT overnight. The solvent was removed under reduced pressure.
  • Step 6 ⁇ /-Biphenyl-2-yl-l,3-dioxo-2-[tr ⁇ /?5-2-phenylcyclopropyllhexahydroimidazo[l,5- a "
  • l,l'-Biphenyl]-2-yl-isocyanate (1.1 eq) was added to a stirred solution of A5 and DIPEA (3.0 eq) in DCM (0.09 M), and the mixture was stirred at RT for 1 h.
  • Step 2 (8aSV2-IYl S.2R)-2-Phenylcvclopropyl1tetrahvdroimidazor 1 ,5-alpyrazine- 1 ,3(2H.5HV dione HCl salt (D2) 4N HCl solution in dioxane (44 eq.) was added at RT to Dl. The resulting 0.1 M solution obtained was stirred for Ih at RT, then the solvent was removed under reduced pressure. The residue was co-evaporated with toluene (x3) and it was used as such in next step without further purification. MS (ES + ) Ci 5 Hi 7 N 3 O 2 requires 271, found: 272 (M+H) + .
  • Step 3 (8a ⁇ -N-(2.3-Dichlorophenvn-1.3-dioxo-2-r(l t S'.2i?)-2-phenylcvclopropyllhexahvdro imidazo[l ,5- ⁇ lpyrazine-7(lH)-carboxamide (D3)
  • 2,3-Dichlorophenyl isocyanate (1.1 eq.) was added to a stirred solution of D2 and DIPEA (3.0 eq.) in DCM (0.09 M) and the mixture was stirred at RT for 1 h. The solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 10-80% EtO Ac/petroleum ether to give the title compound in 67 % yield, 92% de by SFC.
  • the title compound was prepared, as described in example 4. After workup the crude product was purified by preparative RP- ⁇ PLC using H 2 O (0.1% TFA) and MeCN (0.1% TFA) as eluents. The desired fractions were lyophilized to afford the title compound in 44% yield.
  • Example 4 D2 (1 eq) was dissolved in DCM (0.1M), F3 (1.5 eq) and TEA (1.5 eq) were added and the reaction was stirred at RT 6h. The reaction was diluted with DCM and washed with water and brine, dried and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 10-100% EtO Ac/petroleum ether to afford the title compound in 85% yield.
  • Step 3 N-r2-(3-chlorophenvnpyridin-3-yll-1.3-dioxo-2-r(lR.2SV2- phenylcyclopropyl]hexahydro imidazo[l,5-alpyrazine-7(lH)-carboxamide (G3)
  • Step 2 ferf-Butyl (8a61-l,3-dioxo-2-vinylhexahydroimidazo[l,5- ⁇ lpyrazine-7(lH)-carboxylate
  • Step 3 tert-Butyl (8a61-2-[(E)-2-(4-chlorophenyl)vinyll-l,3-dioxohexahydroimidazo[l,5- ⁇ lpyrazine-7(lH)-carboxylate ( ⁇ 3)
  • Step 4 (8a61-2-[tr ⁇ /?5-2-(4-chlorophenyl)cyclopropylltetrahydroimidazo[l,5- ⁇ lpyrazine- U(2H.5H)-dione ( ⁇ 4)
  • Step 5 (8aS)-N-biphenyl-2-yl-2-rtraw5-2-(4-chlorophenvncvclopropyll- 1.3- dioxohexahydroimidazo[l ,5- ⁇ lpyrazine-7(lH)-carboxamide ( ⁇ 5)
  • Step 2 8a-Methyl-2-[(16',2i?)-2-phenylcyclopropylltetrahydroimidazo[l,5- ⁇ lpyrazine- 1.3(2/f.5H)-dione (12) and corresponding diastereomers: (8aS)-8a-meth ⁇ l-2- ⁇ ( ⁇ S,2R)-2- phenylcyclopropylltetrahydroimidazo[ 1 ,5- ⁇ ]pyrazine- 1 ,3(2H,5H)-dione and (8ai?)-8a-methyl-2- [(16',2i?)-2-phenylcyclopropylltetrahydroimidazo[l,5- ⁇ lpyrazine-l,3(2/f,5H)-dione (I2a and I2b) 12 was prepared following the procedure reported in Example 1 step 5 and the crude was purified using 1ST ISOLUTE ® SPE column SCX (loading in MeOH; eluti
  • the diastereoisomers of 12 were separated by chiral SFC purification (column: Chiralpak AD-H (1x25 cm), flow: 10 ml/min, T co i: 35°C, P co i: 100 bar, modifier: 25% 1 PrOH + 0.4% Et 2 NH, using CO 2 as supercritic eluent).
  • Step 3 iV-(Biphenyl-2-yl)-8a-methyl- 13-dioxo-2-r ⁇ £2i?V2-phenylcvclopropyll-hexahvdro imidazo-[l,5- ⁇ lpyrazine-7(lH)-carboxamide (13) and corresponding diastereomers: (8a61-N- biphenyl-2-yl-8a-methyl-l,3-dioxo-2-[(16',2i?)-2-phenylcyclopropyllhexahydroimidazo[l,5- ⁇ lpyrazine-7(lH)-carboxamide and (8ai?)- ⁇ /-biphenyl-2-yl-8a-methyl-l,3-dioxo-2-[(16',2i?)-2- phenylcyclopropyllhexahydroimidazo[l,5- ⁇ lpyrazine-7(lH)-carboxamide (I3
  • the reaction vessel was fitted with a rubber septum, was evacuated and back-filled with argon and sealed with an aluminum/Teflon crimp top.
  • the reaction mixture was then irradiated for 1 h at 120 0 C, using an irradiation power of 100 W.
  • the vial was cooled to 50 0 C with air jet cooling before it was opened.
  • the reaction mixture was diluted with EtOAc and filtered on a pad of Solca Floc®200FCC.
  • the crude product was purified by flash chromatography eluting with 5-100% EtO Ac/petroleum ether affording the titled compound as yellow oil.
  • Step 2 (8a ⁇ -N-(4-Chloro-2-cvclopropylpyridin-3-yl)-1.3-dioxo-2-r(l&2i?)-2-phenylcvclo propyllhexahydroimidazo[l ,5- ⁇ lpyrazine-7(lH)-carboxamide (L2)
  • Step 1 tert-butyi (l-acetyl-4-phenylpyrrolidin-3-yl)carbamate (Ml)
  • Step 3 (8aS)-N- ⁇ (E)- 1 -AcetyM-phenylpyrrolidin-S-yll- 1.3-dioxo-2-r(l t S'.2i?)-2-phenylcvclo propyl "
  • M2 1.0 eq.
  • reaction mixture was stirred 30 min at RT and slowly added to a solution of Example 4, D2 (0.5 eq) and DIPEA (0.5 eq) in DCE (0.1M).
  • the reaction mixture was stirred 3h at RT, volatiles were removed under reduced pressure and the crude product was purified by flash chromatography eluting with 5-100% EtO Ac/petroleum ether, then 0-10% MeOH/EtOAc affording the titled compound as a white powder.
  • Example 4 To a stirred solution of Example 4, D2 (1 eq) and TEA (1.1 eq) in DCM (0.08M) was added pivaloyl chloride (2.1 eq) and the reaction mixture was stirred at 25 0 C for 2h.
  • the crude product was purified by preparative RP- ⁇ PLC using H 2 O (0.1 % TFA) and MeCN (0.1 % TFA) as eluents, affording the title compound.
  • the title compound was prepared, as described in Example 4 starting from tert-butyi 4-amino-3- phenylpiperidine-1-carboxylate. After workup the crude product was treated with a mixture of DCM:TFA (1 :1, 0.1M) and the reaction mixture was stirred for 30 min at RT. Volatiles were removed under reduced pressure and the crude product was purified by preparative RP-HPLC using H 2 O (0.1 % TFA) and MeCN (0.1 % TFA) as eluents. The desired fractions were lyophilized to afford the title compound in 33% yield.
  • Step 2 (8aS)-N-(l-Acetyl-3-phenylpiperidin-4-yl)-1.3-dioxo-2-r(lS.2R)-2-phenylcvclopropyll hexahydroimidazori,5-alpyrazine-7(lH)-carboxamide (P2).
  • Pl (1 eq) and DIPEA (2 eq) in DCM (0.1M) were added acetyl chloride (4 eq) and DIPEA (4 eq). After 30 min stirring at RT, the reaction was diluted with DCM, washed with sat. aq. NaHCOs solution (2x) and water.

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Abstract

The present invention relates to compounds of formula I: and pharmaceutically acceptable salts or tautomers thereof which are inhibitors of the Sonic Hedgehog pathway, in particular Smoantagonists. Thus 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.

Description

SATURATED BICYCLIC HETEROCYCLIC DERIVATIVES AS SMO ANTAGONISTS
The present invention relates to saturated bicyclic heterocyclic derivatives which are inhibitors of the Sonic Hedgehog pathway, in particular they function as Smoothened (Smo) antagonists. Thus 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 (Hh) 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).
The Hh signaling cascade is initiated upon binding of Hh to its receptor Patched (Ptch). In the absence of Hh, Ptch inhibits the activity of another membrane spanning protein,
Smoothened (Smo) which is a key mediator of Hh signaling. Smo has a structure reminiscent of the G-protein-coupled receptor (GPCR) superfamily, but is not involved in the binding of any Hhs. When Hh is present it binds to Ptch to form an inactive complex, relieving Ptch's inhibition of Smo and activating the Hh response pathway. The Hh signal is then transmitted via a protein complex to the transcription factor cubitus interrupts (Ci) in Drosophila and GLI transcription factors in mammals. In the absence of Hh signaling Ci is cleaved and the amino terminal fragment acts as an inhibitor of Hh target gene transcription. Upon Hh signaling the cleavage of Ci is prevented and Ci becomes an activator of target gene transcription. Whereas 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)). Thus, the Hh pathway is an important pharmacological target for a variety of conditions.
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).
Mutations in Ptch 1 have been connected to nevoid basal cell carcinomas 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)). In vitro tests have shown that the teratogen cyclopamine can inhibit the abnormal cell growth of fibroblast cells from Ptch"7" mice, several glioblastoma/glioma cell lines, medulloblastoma cell lines, squamous cell carcinoma cell lines and SCLC cell lines (Bak M et al. Pharmacogenomics 4(4) :411-429 (2003)). Cyclopamine has also displayed efficacy in vivo in the models of medulloblastoma (Dahmane N et al. Development 128:5201-5212 (2001) and Berman CM et al. Science 297:1559-1561 (2002)). Synthetic Hh antagonists have been identified in SHH responsive cell models, some targeting Smo (Chen JK et al. Proc. Natl. Acad. ScL 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)).
Reports have shown that Hh overexpression, sometimes accompanied by increased expression of Hh target genes, 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:
Figure imgf000003_0001
(i)
wherein: each of m and n is independently 1 or 2; each of w, y and z is independently 0, 1 or 2; x is 0 or 1 ;
A is C3_7Cycloalkyl or fluoroCs.ycycloalkyl;
L is -(X=O)a(NR7)b(O)c(CR8R9)d(NR7)e-; a is 0 or 1 ; b is 0 or 1 ; c is 0 or 1 ; d is O, 1, 2, 3, 4, 5 or 6; e is 0 or 1 ;
R1 is d-βalkyl, haloCi-βalkyl or a ring which is: Cβ-ioaryl; C3-iocycloalkyl; oxetanyl; 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; a 6 membered heteroaromatic ring containing one, two or three N atoms; or a 7-15 membered unsaturated, partially saturated or saturated 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 or three groups independently selected from R10;
R2 is a Ci_ioalkyl, haloCi_ioalkyl, Ci_6alkylmercaptoCi_6alkyl, C2-ioalkenyl or a ring which is: C3-iocycloalkyl; Cβ-ioaryl; oxetanyl; 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; 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 R11; each of R3, R4, R5 and R6 is independently Chalky!, C2-ioalkenyl, haloCi-βalkyl, hydroxyCi_6alkyl, Ci_6alkoxy, Ci_6alkoxyCi_6alkyl, carboxy, CO2Ra, CONRaRb, S(O)rRa or S(O)rNRaRb; r is 0, 1 or 2;
R7 is hydrogen or Ci_6alkyl; each of R8 and R9 is independently hydrogen, Ci_6alkyl, Ci_6alkoxy, Ci_6alkoxycarbonyl or haloCi-βalkyl; each R10 is independently hydroxy, cyano, halogen, Ci_6alkyl, haloCi-βalkyl, ORa or NRaRb; each R11 is independently hydroxy, oxo, cyano, halogen, Ci_6alkyl, Ci_6alkylcarbonyl, C2- loalkenyl, C2-i0alkynyl, haloCi_6alkyl, hydroxy C i_6 alky 1, carboxy, nitro, ORa, NRaRb, NRaCORb, NRaS(O)rRb, NRaS(O)rNRaRb, CO2Ra, CONRaRb, S(O)rRa, S(O)rNRaRb or a ring which is: C3-iocycloalkyl, Cβ-ioaryl, Cβ-ioaryloxy, Cβ-ioarylCi-βalkoxy, C6-ioarylCi_6alkyl, 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 of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, Ci_6alkyl, Ci_6alkylsulfonyl, haloCi_ βalkyl, Ci_6alkoxy and haloCi-βalkoxy; X is C or S=O; each of Ra and Rb is independently hydrogen, Ci_6alkyl, Ci_6alkylcarbonyl, haloCi-βalkyl, hydroxyCi-βalkyl, C3-iocycloalkyl or Cβ-ioaryl, any of which rings being optionally substituted by one, two or three groups independently selected from halogen and Ci_6alkyl; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. In an embodiment: each of R3, R4, R5 and R6 is independently Chalky!, C2-ioalkenyl, haloCi-βalkyl, hydroxyCi_6alkyl, carboxy, CO2Ra, CONRaRb, S(O)rRa or S(O)rNRaRb; each R11 is independently hydroxy, oxo, cyano, halogen, Ci_6alkyl, Ci_6alkylcarbonyl, C2- loalkenyl, C2-i0alkynyl, haloCi_6alkyl, hydroxyCi_6alkyl, carboxy, nitro, ORa, NRaRb, NRaCORb, NRaS(O)rRb, NRaS(O)rNRaRb, CO2Ra, CONRaRb, S(O)rRa, S(O)rNRaRb or a ring which is: C3_iocycloalkyl, Cβ-ioaryl, Cβ-ioaryloxy, C6-ioarylCi_6alkoxy, 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 of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, Ci_6alkyl, Ci_6alkylsulfonyl, haloCi-βalkyl, Ci_6alkoxy and haloCi_ 6alkoxy; each of Ra and Rb is independently hydrogen, Ci_6alkyl, Ci_6alkylcarbonyl, haloCi-βalkyl, hydroxyCi-βalkyl or C3-iocycloalkyl; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. In an embodiment of each previous embodiment:
R2 is a Ci_ioalkyl, haloCi_ioalkyl, Ci-ealkylmercaptoCi-βalkyl or a ring which is: C3_iocycloalkyl, Cβ-ioaryl, 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 R11; and each R11 is independently hydroxy, oxo, cyano, halogen, C^alkyl, C2-10alkenyl, haloCi_6alkyl, hydroxyCi_6alkyl, carboxy, nitro, ORa, NRaRb, NRaCORb, NRaS(O)rRb, NRaS(O)rNRaRb, CO2Ra, CONRaRb, S(O)rRa, S(O)rNRaRb or a ring which is: C3-i0cycloalkyl, Cβ-ioaryl, Cβ-ioaryloxy, Cβ-ioarylCi-βalkoxy, 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 of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, Ci_6alkyl, haloCi-βalkyl, Ci_6alkoxy and haloCi-βalkoxy. In an embodiment w is 0.
In an embodiment x is 0. In another embodiment x is 1. In an embodiment R4 is Ci_6alkyl, for example methyl. In another embodiment, x is 1 and R4 is Ci_6alkyl, for example methyl. In an embodiment y is 0.
In an embodiment z is 0.
In an embodiment each of w, y and z is 0 and x is 0 or 1.
In an embodiment each of w, x, y and z is 0. In another embodiment each of w, y and z is 0 and x is 1. In an embodiment each of R3, R4, R5 and R6 is independently Ci_6alkyl, for example methyl.
In an embodiment R4 is Ci_6alkyl or Ci_6alkoxyCi_6alkyl. Particular R4 groups are methyl, ethyl or methoxymethyl. In an embodiment A is C3_6Cycloalkyl or fluoroCs-βcycloalkyl. Particular A groups are cyclopropyl, fluorocyclopropyl and cyclobutyl.
In an embodiment A is cyclopropyl.
For the avoidance of doubt, -LR2 is -(X=O)a(NR7)b(O)c(CR8R9)d(NR7)eR2. It will be apparent that when each of a, b, c, d and e is 0 then R2 is attached directly to the core ring.
In an embodiment a is 1. In an embodiment b is 1.
In an embodiment c is 0. In an embodiment d is 0 or 1. In an embodiment e is 0.
In an embodiment L is -(X=O)(NR7)b(CR8R9)d-. In an embodiment L is -(X=O)(NR7)(CR8R9)d-.
In an embodiment X is C. In another embodiment X is S=O.
In an embodiment L is -(C=O)(NR7)-, -(C=O)(CR8R9)d- or -(C=O)(NR7)(CR8R9)-. In another embodiment L is -(C=O)(NR7)-. In another embodiment L is - (C=O)(CR8R9)d-. In another embodiment L is -(C=O)(NR7)(CR8R9)-.
In an embodiment R7 is hydrogen or Ci_6alkyl. Particular R7 groups are hydrogen and butyl, especially hydrogen. In an embodiment each of R8 and R9 is independently hydrogen, Ci_6alkyl and
C i .βalkoxy carbonyl .
In an embodiment one of R8 and R9 is hydrogen or methyl and the other hydrogen, methyl or ethoxycarbonyl.
In an embodiment one of R8 and R9 is hydrogen or methyl and the other methyl or ethoxycarbonyl.
In an embodiment L is -(C=O)(NH)-. In another embodiment L is -(C=O).
In an embodiment m is 1. In another embodiment m is 2.
In an embodiment n is 1. In another embodiment n is 2.
In an embodiment each of m and n is 1. In an embodiment R1 is Cβ-ioaryl, optionally substituted by one, two or three groups independently selected from R10. In another embodiment R1 is an optionally substituted phenyl.
In an embodiment when R1 is a ring it is unsubstituted or monosubstituted.
In another embodiment R1 is Cβ-ioaryl; C3_iocycloalkyl; oxetanyl; 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; a 6 membered heteroaromatic ring containing one, two or three N atoms; or a 7-15 membered unsaturated, partially saturated or saturated 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 or three groups independently selected from
R 10
In an embodiment R , 10 is cyano, halogen or ORa.
In an embodiment R 10 is halogen or ORa.
In an embodiment Ra is Ci_6alkyl. Particular R10 groups are chlorine, fluorine and methoxy. A further particular R10 group is cyano. A further R10 group is bromine.
Particular R1 groups are phenyl, chlorophenyl, fluorophenyl and methoxyphenyl. Further particular R1 groups are difluorophenyl and cyanophenyl. A further particular R10 group is dibromophenyl. Specific R1 groups are phenyl, 4-chlorophenyl, 4-fluorophenyl and A- methoxyphenyl. Further specific R1 groups are 2-methoxyphenyl, 3,4-difluorophenyl, 3- methoxyphenyl, 2,4-difluorophenyl, 4-cyanophenyl and 3-cyanophenyl. A further specific R10 group is 3,5-dibromophenyl. In an embodiment R2 is Ci_ioalkyl, Ci-ealkylmercaptoCi-βalkyl or a ring which is: C3_iocycloalkyl, Cβ-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 8-10 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 or three groups independently selected from R11.
In an embodiment R2 is C3_iocycloalkyl, Cβ-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 8-10 membered 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 or three groups independently selected from R11. In an embodiment R2 is Ci_salkyl, Ci-ealkylmercaptoCi-βalkyl, C2-6alkenyl or a ring which is: phenyl, cyclohexyl, pyrazolyl, pyridinyl, benzodioxolyl, isoxazolyl, pyrrolidinyl, cyclopropyl, piperidinyl, tetrahydrothiopyranyl, oxazolyl, tetrahydronaphthalenyl, tetrahydroquinolinyl or tetrahydropyranyl; any of which rings being optionally substituted by one, two or three groups independently selected from R1 λ . Further optionally substituted rings include cyclopentyl and bicycloheptyl.
In an embodiment R2 is 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, optionally substituted by one, two or three groups independently selected from halogen, Ci_6alkyl, haloCi-βalkyl or Cβ-ioaryl optionally substituted by one, two or three groups independently selected from halogen, Ci_6alkyl or haloCi-βalkyl.
In an embodiment R2 is Ci_salkyl, Ci-ealkylmercaptoCi-βalkyl or a ring which is: phenyl, cyclohexyl, pyrazolyl, pyridinyl or benzodioxolyl; any of which rings being optionally substituted by one, two or three groups independently selected from R11.
In an embodiment R2 is phenyl, cyclohexyl, pyrazolyl, pyridinyl or benzodioxolyl; optionally substituted by one, two or three groups independently selected from R11.
In an embodiment R2 is phenyl, optionally substituted by one, two or three groups independently selected from R11.
In an embodiment, when R2 is a ring it is unsubstituted or optionally substituted by one, two or three groups independently selected from R11. In an embodiment R11 is oxo, cyano, halogen, C^alkyl, C2-10alkenyl, haloCi-βalkyl, Ci_ ealkylcarbonyl, ORa, NRaRb, CO2Ra, S(O)rRa NRaS(O)rRb or a ring which is: C3-i0cycloalkyl, C6- loaryl, C6-ioarylCi_6alkoxy, C6-ioarylCi_6alkyl or 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; any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, d-βalkyl, haloCi-βalkyl, Ci_6alkoxy and haloCi-βalkoxy.
In an embodiment R11 is cyano, halogen, Ci_6alkyl, C2-ioalkenyl, haloCi-βalkyl, ORa, NRaRb, CO2Ra, S(O)rRa or a ring which is: C6-i0aryl, C6-i0arylCi_6alkoxy, or 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; any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, d-βalkyl, haloCi-βalkyl, Ci_6alkoxy and haloCi-βalkoxy. In an embodiment each of Ra and Rb is independently hydrogen, Ci_6alkyl or Cβ-ioaryl optionally substituted by one, two or three Ci_6alkyl groups.
Particular Ra groups are hydrogen, methyl and phenyl.
Particular Rb groups are hydrogen, methyl, phenyl and methylphenyl, for example A- methylphenyl In an embodiment each Ra is independently Ci_6alkyl or haloCi-βalkyl, for example methyl or trifluoromethyl.
In an embodiment r is 2.
In an embodiment Rb is Ci_6alkyl, for example methyl.
In an embodiment each of Ra and Rb is independently hydrogen or Ci_6alkyl. In an embodiment R11 is cyano, oxo, halogen, Ci_6alkyl, Ci_6alkylcarbonyl, C2-6alkenyl,
C2-6alkynyl, halod-βalkyl, Ci_6alkoxy, haloCi-βalkoxy, d-βalkoxycarbonyl, amino, Ci_ βalkylamino, di(Ci_6alkyl)amino, [di(C1-6alkyl)amino]carbonyl,C1-6alkylsulfonyl or a ring which is: cyclopropyl, phenyl, benzyloxy, thienyl, oxazolyl, pyridinyl or pyrazolyl; any of which rings being optionally substituted by one, two or three groups independently selected from halogen, cyano, Ci_6alkyl, Ci_6alkylsulfonyl, haloCi-βalkyl and Ci_6alkoxy. Further R11 groups include
[(C i_6alkylphenyl)sulfonyl] amino, phenylsulfonyl and optionally substituted rings selected from cyclohexyl and benzyl.
In an embodiment R11 is cyano, halogen, Ci_6alkyl, C2-6alkenyl, haloCi-βalkyl, Ci_6alkoxy, haloCi-βalkoxy, Ci_6alkoxycarbonyl, amino, Ci_6alkylamino, di(Ci_6alkyl)amino, Ci_6alkylsulfonyl or a ring which is: phenyl, benzyloxy, thienyl or oxazolyl; any of which rings being optionally substituted by one, two or three groups independently selected from halogen, Ci_6alkyl, haloCi-βalkyl and Ci_6alkoxy.
In an embodiment, when R1 λ is a ring it is unsubstituted or monosubstituted.
In an embodiment the optional substituents on the R11 ring are independently selected from halogen, Ci_6alkyl, haloCi-βalkyl and Ci_6alkoxy. Further optional substituents on the R11 ring are cyano and Ci_6alkylsulfonyl. Particular optional substituents on the R11 ring are independently selected from chloro, trifluoromethyl and methoxy . Further particular optional substituents on the R11 ring are methylsulfonyl, fluoro, cyano and methyl.
Particular R11 groups are phenyl, chloro, chlorophenyl, propenyl, benzyloxy, dimethylamino, trifluoromethyl, methoxy, propyl, fluoro, thienyl, methylsulfonyl, cyano, methyl, oxazolyl, trifluoromethoxy, methoxycarbonyl, (trifluoromethyl)phenyl and methoxyphenyl. Further particular R11 groups are cyclopropyl, acetyl, oxo, (methylsulfonyl)phenyl, (dimethylamino)carbonyl, ethyl, fluorophenyl, dichlorophenyl, pyridinyl, cyanophenyl, methylpyrazolyl and ethynyl. Further particular R11 groups are butyl, cyclohexyl, propanyl,
[(methylphenyl)sulfonyl]amino, benzyl and phenylsulfonyl.
Specific R11 groups are phenyl, chloro, 3 -chlorophenyl, isopropenyl, benzyloxy, dimethylamino, trifluoromethyl, methoxy, isopropyl, fluoro, 3-thienyl, methylsulfonyl, cyano, methyl, l,3-oxazol-5-yl, trifluoromethoxy, methoxycarbonyl, 3-(trifluoromethyl)phenyl, 2-chlorophenyl, 4-chlorophenyl, 2-methoxyphenyl, 3 -methoxyphenyl and 4-methoxyphenyl. Further specific R11 groups are cyclopropyl, acetyl, oxo, 3-(methylsulfonyl)phenyl, (dimethylamino)carbonyl, ethyl, 3-fluorophenyl, 3, 5 -dichlorophenyl, 4-fluorophenyl, pyridin-3- yl, 3 -cyanophenyl, 1 -methyl- lH-pyrazol-4-yl and ethynyl.
Further specific R11 groups are tertbutyl, cyclohexyl, propan-2-yl, [(4- methylphenyl)sulfonyl]amino, benzyl and phenylsulfonyl.
Particular R2 groups are biphenyl, dichlorophenyl, cyclohexyl, phenylpyrazolyl, (chlorophenyl)pyridinyl, isopropenylphenyl, butyl, benzodioxolyl, methylmercaptoethyl, (benzyloxy)phenyl, hexyl, (dimethylamino)phenyl, (trifluoromethyl)phenyl, methoxyphenyl, isopropylphenyl, dichlorofluorophenyl, phenyl, chlorofluorophenyl, chloropyridinyl, thienylpyridinyl, thienylphenyl, chloro(methylsulfonyl)phenyl, (chloro)(cyano)(methyl)phenyl, dichlorocyanophenyl, (chloro)(methyl)phenyl, oxazolylphenyl, dichloro(trifluoromethoxy)phenyl, dichloro(trifluoromethyl)phenyl, (chloro)(methoxycarbonyl)phenyl, [(trifluoromethyl)phenyl]pyridinyl, (methoxycarbonyl)(methyl)phenyl, dichloropyridinyl, (methoxyphenyl)pyridinyl and dichloro(methylsulfonyl)phenyl. Further particular R2 groups are phenylisoxazolyl, (chloro)(cyclopropyl)pyridinyl, (acetyl)(phenyl)pyrrolidinyl, methylcyclopropyl, (acetyl)(phenyl)piperidinyl, dioxidotetrahydrothiopyranyl, [(methylsulfonyl)phenyl]pyridinyl, (chlorophenyl)pyrazolyl, phenyloxazolyl, phenylcyclohexyl, tetrahydronaphthalenyl, dichloro [(dimethylamino)carbonyl]phenyl, (chloro)dimethylphenyl, (chloro)(methoxy)pyridinyl, (chloro)(methyl)pyridinyl, (chloro)(ethyl)pyridinyl, (fluorophenyl)pyrazolyl,
(dichlorophenyl)pyrazolyl, oxotetrahydroquino linyl, (fluoro)(oxo)tetrahydroquino linyl, dimethylpyridinyl, methylcyclohexyl, (fluorophenyl)pyridinyl, bipyridinyl, (cyanophenyl)pyridinyl, (methylpyrazolyl)pyridinyl, phenylpyridinyl, (cyclopropyl)(methyl)pyridinyl, ethyl, propyl, ethenyl, (methylsulfonyl)(phenyl)piperidinyl, (methyl)(phenyl)piperidinyl, methyltetrahydropyranyl and ethynylcyclohexyl. Further particular R2 groups are (fluorophenyl)(methyl)pyrazolyl, (acetyl)(methyl)piperidinyl, cyclopentyl, dimethylcyclohexyl, phenylcyclohexyl, butylcyclohexyl, trimethylbicyclo[2.2.1]heptyl, bi(cyclohexyl), tetrahydropyranyl, methyl(propanyl)cyclohexyl,
{[(methylphenyl)sulfonyl] amino} cyclohexyl, difluorocyclohexyl, phenylpiperidinyl, benzylmethylpiperidinyl, fluoropiperidinyl, (methylsulfonyl)piperidinyl, (acetyl)(fluoro)piperidinyl, (fluoro)(methylsulfonyl)piperidinyl, (fluoro)(phenylsulfonyl)piperidinyl and acetylpiperidinyl. Specific R2 groups are biphenyl-2-yl, 2,3-dichlorophenyl, cyclohexyl, 1-phenyl-lH- pyrazol-5-yl, 2-(3-chlorophenyl)pyridin-3-yl, 3-isopropenylphenyl, 2,6-dichlorophenyl, butyl, l,3-benzodioxol-5-yl, methylmercaptoethyl, 4-(benzyloxy)phenyl, biphenyl-4-yl, hexyl, 4- (dimethylamino)phenyl, 2-(trifluoromethyl)phenyl, 2-methoxyphenyl, 2-isopropylphenyl, 2,6- dichloro-4-fluorophenyl, phenyl, 2-chloro-4-fluorophenyl, 2-chloropyridin-3-yl, 2-(3- thienyl)pyridin-3-yl, 2,3-dichloro-4-fluorophenyl, 2-(3-thienyl)phenyl, 2-chloro-4-
(methylsulfonyl)phenyl, 2-chloro-4-cyano-6-methylphenyl, 2,6-dichloro-4-cyanophenyl, 3-chloro-2-methylphenyl, 2-chloro-6-methylphenyl, 3,5-dichlorophenyl, 2-(l,3-oxazol-5- yl)phenyl, 2,6-dichloro-4-(trifluoromethoxy)phenyl, 2,6-dichloro-4-(trifluoromethyl)phenyl, 2-chloro-3 -methoxycarbonylphenyl, 2- [3 -(trifluoromethyl)phenyl]pyridin-3 -yl, 3-methoxycarbonyl-2-methylphenyl, 3,5-dichloropyridin-4-yl, 2-(2-chlorophenyl)pyridin-3-yl, 2-(4-chlorophenyl)pyridin-3 -yl, 2-(2-methoxyphenyl)pyridin-3 -yl, 2-(3 -methoxyphenyl)pyridin- 3-yl, 2-(4-methoxyphenyl)pyridin-3-yl and 2,6-dichloro-4-(methylsulfonyl)phenyl. Further specific R2 groups are 4-phenylisoxazol-5-yl, 4-chloro-2-cyclopropylpyridin-3-yl, (E)-l-acetyl- 4-phenylpyrrolidin-3-yl, 1-methylcyclopropyl, tert-butyl, l-acetyl-3-phenylpiperidin-4-yl, 1,1- dioxidotetrahydro-2H-thiopyran-4-yl, 2-[3-(methylsulfonyl)phenyl]pyridin-3-yl, l-(3- chlorophenyl)-lH-pyrazol-5-yl, 5-phenyl-l,3-oxazol-2-yl, (lR,2S)-2-phenylcyclo hexyl, 1,2,3,4- tetrahydronaphthalen- 1 -yl, 2,6-dichloro-4-[(dimethylamino)carbonyl]phenyl, 2-chloro-4,6- dimethylphenyl, 4-chloro-2-methoxypyridin-3-yl, 4-chloro-2-methylpyridin-3-yl, 4-chloro-2- ethylpyridin-3-yl, l-(3-fluorophenyl)-lH-pyrazol-5-yl, l-(3,5-dichlorophenyl)-lH-pyrazol-5-yl, 2-oxo-l,2,3,4-tetrahydroquinolin-4-yl, 6-fluoro-2-oxo-l,2,3,4-tetrahydroquinolin-4-yl, 2,4- dimethylpyridin-3-yl, 1-methylcyclo hexyl, 2-(4-fluorophenyl)pyridin-3-yl, 2,3'-bipyridin-3-yl, 2- (3-cyanophenyl)pyridin-3-yl, 2-(l -methyl- lH-pyrazol-4-yl)pyridin-3-yl, 2-phenylpyridin-3-yl, 2- cyclopropyl-4-methylpyridin-3-yl, 3-phenylpyridin-4-yl, ethyl, propyl, ethenyl, 1- (methylsulfonyl)-3-phenylpiperidin-4-yl, 1 -methyl-3-phenylpiperidin-4-yl, 4-methyltetrahydro- 2H-pyran-4-yl, 1 -ethynylcyclohexyl, trans- l-acetyl-3-phenylpiperidin-4-yl, cis-l-acetyl-3- phenylpiperidin-4-yl, trans- l-(methylsulfonyl)-3-phenylpiperidin-4-yl and cis-1- (methylsulfonyl)-3-phenylpiperidin-4-yl. Further specific R2 groups are 4-(4-fluorophenyl)-l- methyl- 1 H-pyrazol-5-yl, 3 -(3 -fluorophenyl)- 1 -methyl- lH-pyrazol-4-yl, 1 -acetyl-4- methylpiperidin-4-yl, cyclopentyl, 4,4-dimethylcyclohexyl, 1-phenylcyclohexyl, 2- methylcyclohexyl, 3-methylcyclohexyl, trans-4-methylcyclohexyl, trans-2-phenylcyclohexyl, 4- tert-butylcyclohexyl, 4-phenylcyclohexyl, (IS, 2R)-l,7,7-trimethylbicyclo[2.2.1]hept-2-yl, (lR,2S)-l,7,7-trimethylbicyclo[2.2.1]hept-2-yl, cis-bicyclohex-2-yl, trans-bicyclohex-2-yl, tetrahydro-2H-pyran-4-yl, (lR,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl, (1 S,2S)-2- {[(4- methylphenyl)sulfonyl] amino } cyclohexyl, ( 1 R,2R)-2- { [(4- methylphenyl)sulfonyl]amino}cyclohexyl, 4,4-difluoro-cyclohexyl, 1-phenylpiperidinyl, cis-3- benzyl-1 -methylpiperidin-4-yl, 3-fluoropiperidin-4-yl, l-(methylsulfonyl)piperidin-4-yl, (trans)- l-acetyl-3-fluoropiperidin-4-yl, (trans)-3-fluoro-l-methylsulfonylpiperidin-4-yl, (trans)-3-fluoro- 1 -(phenylsulfonyl)piperidin-4-yl, (cis)-3-fluoro- 1 -(methylsulfonyl)piperidin-4-yl, (cis)- 1 -acetyl- 3-fluoropiperidin-4-yl and l-acetylpiperidin-4-yl.
In an embodiment: each of w, x, y and z is 0;
L is -(C=O)(NR7); m is 1 or 2; n is 1 or 2; and
R1 is Cβ-ioaryl, optionally substituted by one, two or three groups independently selected from R10.
In another embodiment: each of w, x, y and z is 0;
L is -(C=O)(NR7); m is 1 or 2; n is 1 or 2; and
R2 is C3_iocycloalkyl, Cβ-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 βmembered heteroaromatic ring containing one, two or three N atoms, or a 8-10 membered 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 or three groups independently selected from R1 ! . In an embodiment: each of w, y and z is 0 and x is 1;
R4 is Ci_6alkyl; d is O;
R7 is hydrogen; R2 is 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, optionally substituted by one, two or three groups independently selected from halogen, Ci_ 6alkyl, haloCi-βalkyl or Cβ-ioaryl optionally substituted by one, two or three groups independently selected from halogen, Ci_6alkyl or haloCi-βalkyl.
In an embodiment: each of w, y and z is 0 and x is 1; each of m and n is 1;
R1 is Cβ-ioaryl, optionally substituted by one, two or three groups independently selected from R10.
The present invention also provides a compound of formula II:
Figure imgf000013_0001
(H) wherein m, n, d, w, x, y, z, A, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined above; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. The present invention also provides a compound of formula III:
Figure imgf000013_0002
(HI) wherein: q is 0, 1, 2 or 3; m, n, d, w, x, y, z, A, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are as defined above; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. The present invention also provides a compound of formula IV:
Figure imgf000014_0001
(IV) wherein: m, n, d, w, x, y, z, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined above; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. The present invention also provides a compound of formula V:
Figure imgf000014_0002
(V) wherein: d, w, x, y, z, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined above; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. The present invention also provides a compound of formula VI:
Figure imgf000014_0003
(VI) wherein: d, w, x, y, z, R i l1, τ R") 44, 7 R) 60, τ R-) 9
Figure imgf000014_0004
Figure imgf000014_0005
Figure imgf000014_0006
y are as defined above; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. The present invention also provides a compound of formula VII:
Figure imgf000015_0001
wherein: d, q, w, x, y, z, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are as defined above; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. The present invention also provides a compound of formula VIII:
Figure imgf000015_0002
wherein: d, q, w, y, z, R2, R3, R5, R6, R7, R8, R9 and R10 are as defined above; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. The present invention also provides a compound of formula IX:
Figure imgf000016_0001
(IX) wherein: m, n, d, w, x, y, z, R1, R2, R3, R4, R5, R6, R8 and R9 are as defined above; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. The preferred identities with reference to compounds of formulae II, III, IV, V, VI, VII,
VIII and IX are as defined previously for formula I mutatis mutandis. In an embodiment q is 0 or 1.
The present invention also includes within its scope N-oxides of the compounds of formula I above. In general, such 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. In general, such 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. In addition, 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.
Alternatively, 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. As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1- βalkyl" is defined to include groups having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement. For example, "Ci_6alkyl" 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. The term "cycloalkyl" means a monocyclic, bicyclic or polycyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "C3_7Cycloalkyl" includes cyclopropyl, methyl- cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, eye Io hexyl, and so on. In an embodiment of the invention the term "cycloalkyl" includes the groups described immediately above and further includes monocyclic unsaturated aliphatic hydrocarbon groups. For example, "cycloalkyl" as defined in this embodiment includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl, 7,7-dimethylbicyclo[2.2.1]heptyl and so on. Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. As used herein, the term "C2-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.
As used herein, the term "C2-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. Examples of suitable alkoxy groups 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 'Cβ-ioaryloxy' can be construed analogously, and an example of this group is phenoxy.
The terms "haloCi-βalkyl" and "haloCi-βalkoxy" 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. Preferred are fluoroCi_6alkyl and fluoroCi_6alkoxy groups, in particular fluoroCi_3alkyl and fluoroCi_3alkoxy groups, for example, CF3, CHF2, CH2F, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCHF2.
As used herein, the term "hydroxyCi-βalkyl" means a Ci_6alkyl group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by hydroxy groups. Preferred are CH2OH, CH2CHOH and CHOHCH3. The term 'hydroxyC2-ioalkenyl' and 'hydroxyC2-ioalkynyl' can be construed analogously. An example of 'hydroxyC2-ioalkynyr is (hydroxy)(methyl)butynyl.
As used herein, the term "Ci_6alkylcarbonyl" or "Ci_6alkoxycarbonyl" denotes a Ci_6alkyl or Ci_6alkoxy radical, respectively, attached via a carbonyl (C=O) radical. Suitable examples of Ci_6alkylcarbonyl groups include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl and te/t-butylcarbonyl. Examples of Ci_6alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and te/t-butoxycarbonyl. The term 'Cβ-ioarylcarbonyl' can be construed analogously, and an example of this group is benzoyl.
As used herein, the term "Ci-βalkylmercaptoCi-ealkyl" represents an alkyl group of indicated number linked via an S atom. Examples of suitable alkylmercaptoalkyl groups include CH3SCH2, CH3SCH2CH2 and CH3SCH2CH2CH2 and CH3CH2SCH2. 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.
As used herein, "Cβ-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 or naphthyl, especially phenyl.
7-15 membered heterocycles include 7, 8, 9, 10, 11, 12, 13, 14 and 15 membered heterocycles. Similarly, 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, indolyl, indolizinyl, indolinyl, isoindolinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazolinyl, isoxazolinyl, oxetanyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridinyl, pyrimidinyl, triazinyl, tetrazinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinolizinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1 ,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidyl, pyridin-2-onyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrrolinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydroiso quinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, dihydroisochromenyl, dihydrochromenyl, dihydroimidazolonyl, dihydrotriazolonyl, dihydrobenzodioxinyl, dihydrothiazolopyrimidinyl, dihydroimidazopyrazinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, thiazolidinonyl, imidazolonyl, isoindolinonyl, octahydroquinolizinyl, octahydroisoindolyl, imidazopyridinyl, azabicycloheptanyl, chromenonyl, triazolopyrimidinyl, dihydrobenzoxazinyl, thiazo Io triazolyl, azoniabicycloheptanyl, azoniabicyclooctanyl, phthalazinyl, naphthyridinyl, pteridinyl, dihydroquinazolinyl, dihydrophthalazinyl, benzisoxazolyl, tetrahydronaphthyridinyl, dibenzo[δ,<i]furanyl, dihydrobenzothiazolyl, imidazothiazolyl, tetrahydroindazolyl, tetrahydrobenzothienyl, hexahydronaphthyridinyl, tetrahydroimidazopyridinyl, tetrahydroimidazopyrazinyl, pyrrolopyridinyl, diazepanyl, azoniabicyclohexanyl, azoniabicycloheptanyl, azepanyl, octahydropyridopyrazinyl, diazabicycloheptanyl diazoniaspirodecanyl, diazoniaspirononanyl, octahydropyrrolopyrrolyl and tetrahydrotriazolopyrazinyl and N-oxides thereof. Attachment of a heterocyclyl substituent can occur via a carbon atom or via a heteroatom.
Preferred 5 or 6 membered saturated or partially saturated heterocycles are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuran, thiomorpholinyl, azoniabicyclohexanyl, azoniabicycloheptanyl and tetrahydropyranyl. A further ring is 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, thiazo Io triazolyl, dihydrothiazolopyrimidinyl, dihydrobenzoxazinyl, dihydrobenzofuranyl, benzimidazolyl, benzofuranyl, dihydrobenzoxazolyl, dihydroquinazolinyl, dihydrophthalazinyl, indazolyl, benzisoxazolyl, tetrahydronaphthyridinyl, triazolopyrimidinyl, dibenzo[δ,<i]furanyl, naphthyridinyl, dihydroquinolinyl, dihydroisochromenyl, dihydrochromenyl, dihydrobenzothiazolyl, imidazothiazolyl, tetrahydroindazolyl, tetrahydrobenzothienyl, hexahydronaphthyridinyl, tetrahydroimidazopyridinyl, tetrahydroimidazopyrazinyl, pyrrolopyridinyl, quinazolinyl, indolizinyl, octahydropyridopyrazinyl, diazabicycloheptanyl, diazoniaspirodecanyl, diazoniaspirononanyl, octahydropyrrolopyrrolyl and tetrahydrotriazolopyrazinyl.
As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.
Particular compounds within the scope of the present invention are the specific compounds named in the representative Examples, and pharmaceutically acceptable salts, free bases, stereoisomers and tautomers thereof.
Included in the instant invention is the free base of compounds of Formula I, as well as the pharmaceutically acceptable salts and stereoisomers thereof. The compounds of the present invention 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. For example, 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. 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. Generally, 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.
Thus, 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. For example, conventional 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. Examples of suitable polymeric salts include those derived from the polymeric acids such as tannic acid, carboxymethyl cellulose. Preferably, 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. More particularly, 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.
It will also be noted that 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. by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal); and by implant of 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.
The invention also provides pharmaceutical 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. These 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. 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. For example, 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.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such 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 polyoxy ethylene 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 monooleate. 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. The pharmaceutical compositions may be in the form of a sterile injectable aqueous solutions. Among the 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. For example, 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. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS™ 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. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, 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. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
For 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. To be administered in the form of a transdermal delivery system, 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.
When a compound according to this invention is administered into a subject, 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. In general, a suitable dose of the active compound is in the range of about 100 μg 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.
Many tumors and proliferative conditions have been shown to depend on the hedgehog pathway. The growth of such cells and survival can be affected by treatment with the compounds of the present invention. For example, small molecule inhibition of the hedgehog pathway has been shown to inhibit the growth of basal cell carcinoma (Williams et al.
PNAS 100: 4616-21 (2003)), medulloblastoma (Berman et al. Science 297:1559-61 (2002)), pancreatic cancer, gastrointestinal cancers and esophageal cancer (Berman et al. Nature 425:846- 51 (2003) and WO 05/013800), lung cancer (Watkins et al. Nature 422:313-7 (2003)), and prostate cancer (Karhadkar et al. Nature 431 : 707-12 (2004)). In addition, it has been shown that many cancer types have uncontrolled activation of the hedgehog pathway, for example, breast cancer (Kubo et al. Cancer Research 64:6071-4 (2004)), heptacellular cancer (Patil et al. (2005) 96th Annual AACR conference, abstract #2942 and Sicklick et al. (2005) ASCO annual meeting, abstract #9610), hematological malignancies (Watkins and Matsui, unpublished results), basal carcinoma (Bale et al Human Molec. Genet. B:757-762 (2001), Xie et al Nature 391 : 90-92 (1998)), medulloblastoma (Pietsch et al Cancer Res. 57: 2085-88 (1997)), and gastric cancer (Ma et al Carcinogenesis May 19, (2005) (EPub)).
Expression of a dysfunctional mutated patched gene has been reported in sporadic and familial BCCs. Patched gene mutations or deletions have also been found in sporadic medulloblastoma, meningiomas, breast carcinoma, esophageal squamous cell carcinoma and bladder tumors (Oncogene (1998) 17, 1167-1172).
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.
The compounds, compositions and methods provided herein are particularly deemed useful for the treatment of cancer. 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 (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectal, rectal; Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor
[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondro myxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. Thus, the term "cancerous cell" as provided herein, includes a cell afflicted by any one of the above-identified conditions. In an embodiment 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, Herpes simplex infections, Herpes zoster infections, protozoan infections, Kaposi sarcoma, Mooren ulcer, Terrien's marginal degeneration, marginal keratolysis, rheumatoid arthritis, systemic lupus, polyarteritis, trauma, Wegeners sarcoidosis, Scleritis, Stevens Johnson disease, periphigoid radial keratotomy, corneal graph rejection, rheumatoid 15 arthritis, osteoarthritis chronic inflammation (eg., ulcerative colitis or Crohn's disease), hemangioma, Osier- Weber-Rendu disease, and hereditary hemorrhagic telangiectasia. In an embodiment the compounds of the present invention are useful for treating and preventing cancers selected from basal cell carcinoma, medulloblastoma, prostate, pancreatic, breast, colon, small cell lung cancers, sarcoma, lymphomas, leukemia, gastrointestinal cancer, multiple myeloma, glioma, heptacellular, sporadic and familial basal cell carcinomas, sporadic medulloblastoma, meningiomas, breast carcinoma, esophageal squamous cell carcinoma and bladder cancer.
In an embodiment the compounds of the present invention are useful for treating and preventing cancers associated with patched loss-of function.
In another embodiment 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, anticancer and/or radiotherapeutic agents. Thus, 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. In addition, 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., anti-neoplastic 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.
In one embodiment, 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.
In another embodiment is provided a combination of a compound of formula I and an anti-cancer agent for simultaneous, separate or sequential administration.
Examples of 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), 6th 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, γ-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], etc.), nitrosoureas (e.g., Carmustine, Lomustine, and Semustine, etc.), and other alkylating agents (e.g., Dacarbazine, Hydroxymethylmelamine, Thiotepa, and Mitocycin, etc.); 3) noncovalent DNA- binding agents [antitumor antibiotics], including, nucleic acid inhibitors (e.g., Dactinomycin [Actinomycin Dl, etc.), anthracyclines (e.g., Daunorubicin [Daunomycin, and Cerubidine], Doxorubicin [Adrianycin], and Idarubicin [Idamycin], etc.), anthracenediones (e.g., anthracycline analogues, such as, [Mitoxantrone], etc.), bleomycins (Blenoxane), etc., and plicamycin (Mithramycin), etc.; 4) antimetabolites, including, antifolates (e.g., Methotrexate, Folex, and Mexate, etc.), purine antimetabolites (e.g., 6-Mercaptopurine [6-MP, Purinethol], 6- Thioguanine [6-TG], Azathioprine, Acyclovir, Ganciclovir, Chlorodeoxyadenosine, 2- Chlorodeoxyadenosine [CdA], and 2'-Deoxycoformycin [Pentostatin], etc.), pyrimidine antagonists (e.g., fluoropyrimidines [e.g., 5-fluorouracil (Adrucil), 5-fluorodeoxyuridine (FdUrd) (Floxuridine)] etc.), and cytosine arabinosides (e.g., Cytosar [ara-C] and Fludarabine, etc.); 5) enzymes, including, L-asparaginase; 6) hormones, including, glucocorticoids, such as, antiestrogens (e.g., Tamoxifen, etc.), nonsteroidal antiandrogens (e.g., Flutamide, etc.), and aromatase inhibitors (e.g., anastrozole [Arimidex], etc.); 7) platinum compounds (e.g., Cisplatin and Carboplatin, etc.); 8) monoclonal antibodies conjugated with anticancer drugs, toxins, and/or radionuclides, etc.; 9) biological response modifiers (e.g., interferons [e.g., IFN-. 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.
In an embodiment, 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 fibrob last-derived growth factor, an inhibitor of platelet derived growth factor, an MMP (matrix metalloprotease) inhibitor, an integrin blocker, interferon-α, interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, ό-O-chloroacetyl-carbonyFj-fumagillol, thalidomide, angiostatin, troponin- 1, or an antibody to VEGF. In an embodiment, 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. In an embodiment is provided 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, which method 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.
In an embodiment is provided a method of treating or preventing psoriasis, which method 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. The compounds of the formula can be used in combination with radiation therapy. The phrase "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. For the prevention or treatment of emesis, 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. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, an antidopaminergic, such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol. In another embodiment, 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. Such an 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. Such 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). 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 (Velcade®); busulfan intravenous (Busulfex®); busulfan oral (Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine (Gliadel®); carmustine with Polifeprosan 20 Implant (Gliadel Wafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®); cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine (CIo lar®); cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide (Cytoxan Injection®); cyclophosphamide (Cytoxan Tablet®); cytarabine (Cytosar-U®); cytarabine liposomal (DepoCyt®); dacarbazine (DTIC-Dome®); dactinomycin, actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®); daunorubicin liposomal (DanuoXome®); daunorubicin, daunomycin (Daunorubicin®); daunorubicin, daunomycin (Cerubidine®); Denileukin diftitox (Ontak®); dexrazoxane (Zinecard®); docetaxel (Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®); doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®); doxorubicin liposomal (Doxil®); dromostanolone propionate (Dromostanolone ®); dromostanolone propionate (Masterone Injection®); Elliott's B Solution (Elliott's B Solution®); epirubicin (Ellence®); Epoetin alfa (epogen®); erlotinib (Tarceva®); estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide, VP- 16 (Vepesid®); exemestane (Aromasin®); Filgrastim (Neupogen®); floxuridine (intraarterial) (FUDR®); fludarabine (Fludara®); fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®); histrelin acetate (Histrelin implant®); hydroxyurea (Hydrea®); Ibritumomab Tiuxetan (Zevalin®); idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®); Interferon alfa-2b (Intron A®); irinotecan (Camptosar®); lenalidomide (Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®); meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (Mesnex tabs®); methotrexate (Methotrexate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolone phenpropionate (Durabolin-50®); nelarabine (Arranon®); Nofetumomab (Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®); pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®); porfimer sodium (Photofrin®); procarbazine (Matulane®); quinacrine (Atabrine®); Rasburicase (Elitek®); Rituximab (Rituxan®); sargramostim (Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®); sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®); temozolomide (Temodar®); teniposide, VM-26 (Vumon®); testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab (Bexxar®); Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); vorinostat (Zolinza®); zoledronate (Zometa®), nilotinib (Tasigna®); and dasatinib (Sprycel®).
The term "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When 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.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. The term "treating cancer" or "treatment of 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. The compounds of this invention can be prepared according to the following procedures. All variables within the formulae are defined above.
Abbreviations used in the description of the chemistry and in the Examples that follow are: eq.: equivalents; RT: room temperature; h.: hours; min.: minutes; aq.: aqueous; sol: solution; RP-HPLC: reverse phase HPLC; EtOAc: ethyl acetate; HCl: hydrochloric acid; KOCN: potassium cyanate; DMF: dimethylformamide; DCE: dichloroethane; MeOH: methanol; DCM: dichloromethane; MeCN: acetonitrile; TFA: trifluoroacetic acid; DMSO-dβ: deuterated dimethylsulfoxyde; NaOAc: sodium acetate; Et3N: triethylamine; DIPEA: Di-iso- propylethylamine; CDI: l,l'-carbonyldiimidazole; LDA: lithium diisopropylamide; LiHMDS: lithium bis(trimethylsilyl)amide; TBTU: O-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate.
Compounds of formula I wherein L is -(C=O)(NH)(O)c(CR8R9)d(NR7)e- can be prepared by reacting a compound of fomula IA with a compound of formula IB:
O=C=N(O)c(CR8R9)d(NR7)eR2
(IA)
Figure imgf000034_0001
(IB)
wherein all variables are as defined above. The reaction is generally carried out in the presence of a base such as DIPEA or TEA, in a solvent such as DCM or MeCN at about RT. The solvent DCE may also be used.
Compounds of formula IA can be prepared in situ by reacting the corresponding amine of formula IC with an agent such as CDI:
H2N(O)c(CR8R9)d(NR7)eR2 (IC) wherein all variables are as defined above, generally by reacting at about 800C, in a solvent such as MeCN. A base such as LiHMDS may also be used in a solvent such as THF. The reaction can also be carried out utilizing triphosgene, generally in the presence of a base such as DIPEA, in a solvent such as DCM at about RT.
Compounds of formula IB can be prepared by cyclization of a compound of formula ID:
Figure imgf000035_0001
(ID)
wherein Rx is Ci_6alkyl, for example methyl, P is a protecting group such as tert-butoxycarbonyl and all other variables are as defined above. The cyclization can generally be carried out in the presence of a base such as DIPEA, a solvent such a toluene at reflux. Alternatively, the cyclization can be carried out under acidic conditions, such as in the presence of an acid such as
HCl, in a solvent such as dioxane at about RT.
The protecting group can be removed according to standard procedures. For example, when P is tert-butoxycarbonyl it can be removed by the addition of an acid such as TFA in a solvent such as DCM at about RT.
Compounds of formula ID can be prepared by reacting a compound of formula IE with a compound of formula IF:
Figure imgf000035_0002
(IE) wherein all the variables are as defined above. The reaction is generally carried out in a solvent such as toluene or DCM at about RT. Compounds of formula IF can be prepared by reacting a compound of formula IG with an agent such as CDI:
Figure imgf000036_0001
(IG) wherein all variables are as defined above, generally in a solvent such as MeCN at about 800C. The reaction can also be carried out utilizing triphosgene, in a solvent such as DCM at about RT.
Compounds of formula IB wherein x is 1 can be prepared by reacting a compound of formula IB wherein x is 0 with a compound of formula
Figure imgf000036_0002
wherein L1 is a leaving group such as halogen, for example iodine. The reaction can generally be carried out in the presence of a strong base such as LDA and a solvent such as THF at about -780C to RT. During the reaction, compounds may be protected by protecting groups such as tert-butoxycarbonyl.
Compounds of formula I wherein a is 1 and X is C can be prepared by reacting a compound of formula IB with a compound of formula IH:
L2-(C=O)(NR7)b(O)c(CR8R9)d(NR7)eR2
(IH) wherein L2 is a leaving group such as halogen, for example chlorine, and all other variables are as defined above. The reaction can be carried out in the presence of a base such as DIPEA or Et3N in a solvent such as DCM at about RT. Alternatively, L2 is hydroxy and the reaction can be carried out in the presence of a coupling reagent such as TBTU.
Alternatively, compounds of formula I wherein a is 1 and X is C can be prepared by reacting a compound of formula IB with a compound of formula IJ:
PhO-(C=O)(NR7)b(O)c(CR8R9)d(NR7)eR2
(IJ) wherein all variables are as defined above. The reaction is generally carried out in the presence of a base such as TEA in a solvent such as DCM at about RT.
The compound of formula IJ wherein b is 1 and R7 is hydrogen can be prepared by reacting a compound of formula IC with phenyl chloro formate, generally in a solvent such as DCE at about RT. The compounds of this invention were prepared according to the following schemes.
Other methods known in the art can also be used to synthesise the present compounds.
Scheme 1
Compounds from this invention can be prepared from suitably protected rings such as piperazine-2-carboxylic acid derivatives. Reaction of these piperazines with isocyanates gives an intermediate urea that can be cyclised to the required bicyclic hydantoin at reflux in toluene, in the presence of a tertiary amine base such as di-iso-propylethylamine. Alternatively, the urea can also be cyclised under acidic conditions at room temperature, such as 4M HCl solution in dioxane, to give the required bicyclic framework. Under these latter conditions, acid labile protecting groups such as Boc-groups can be removed during the cyclisation reaction. Derivitization of the other nitrogen atom can be accomplished by reaction with an isocyanate group, to yield the desired ureas. Alternatively, when not commercially available, isocyanates can be prepared in situ from an amine and triphosgene in a solvent such as DCM. The bicyclic system can also be reacted with an acyl imidazole intermediate obtained from the reaction of an amine with carbonyl diimidazole in MeCN at 8O0C, condensation with the bicyclic hydantoin then yields the requisite urea. Alternatively, amines can be preactivated with phenyl chloroformate in solvents such as DCE to yield the corresponding phenyl carbonate, which can in turn be reacted with the bicyclic framework to yield the desired ureas as Smo antagonists. This latter reaction is typically conducted in a solvent such as DCM, at room temperature, in the presence of a trialkylamine base such as triethylamine. These compounds can be prepared chirally starting from enantiomerically pure piperazine-2-carboxylic acid derivatives, or alternatively can be separated using chiral SFC, or other separation techniques.
Coupling of the bicyclic framework with carboxylic acids, using a coupling agent such as TBTU, in solvents like DMF allows the formation of the corresponding amides which are themselves Smo antagonists. Similar compounds can be prepared by coupling of acyl chlorides with the scaffold in the presence of a trialkylamine base in a solvent such as DCM.
Figure imgf000038_0001
bicycle
Figure imgf000038_0002
Scheme 1
Scheme 2
An alternative synthetic strategy which allows variation of the right-hand side of the compounds of this invention involves the formation of the bicyclic hydantoin core by reaction of a ring such as a piperazine-2-carboxylic acid derivative with potassium cyanate in water and dioxane, in the presence of 1 equivalent of HCl (Scheme 2). The resulting bicyclic framework can then be reacted with neat vinyl acetate in the presence of catalytic Na2PdCl4 at reflux as described in Eur. J. Org. Chem. 2000, 1507. Palladium catalyzed Heck reaction, using Pd(OAc)2 in the presence of LiBr and NaOAc at 9O0C in water and DMF, then yields the JV-(2-aryl)vinyl derivatives as described in J. Org. Chem. 2006, 71, 8610. Simmons-Smith cyclopropanation of these enamides as described in Angew. Chem. Int. Ed. Engl. 2007, 46, 4069 using chloroiodomethane and diethylzinc in dichloroethane, then furnishes the trans-cyclopropane, with contemporary deprotection of the secondary amine, which is then ready to be functionalised to yield the desired Smo antagonists.
KOCN Vinyl acetate Dioxane/H2O Na2PdCl2 l eq. HCl, RT Reflux, O/N
Figure imgf000039_0001
Figure imgf000039_0002
Figure imgf000039_0003
Heck Reaction e.g. Aryl iodide
P = protecting group, e.g. Boc Pd(OAc)2, LiBr, NaOAc
DMF/H20, 900C
Figure imgf000039_0004
Scheme 2
Scheme 3
Once the bicyclic framework has been prepared it too can undergo further synthetic modifications. For instance, a suitable projected core scaffold can be deprotonated using a strong
10 base such as LDA at -780C in solvent like THF. The resulting anion can be quenched with an alkylating agent, such as methyl iodide, warming the reaction from -780C to room temperature to ensure successful alkylation. The resulting functionalised core can then be manipulated as previous described.
Alkylation
RT
Figure imgf000039_0005
Figure imgf000039_0006
P=Protecting group, e.g. Boc i c L1=Leaving group, e.g. I or Br
Scheme 3 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.
Compounds of formula I may be converted to other compounds of formula I by known methods or by methods described in the Examples herein.
During 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. For example, when the Boc (te/t-butoxycarbonyl) or benzylcarbonyl protecting group is present, it may be removed by the addition of solvents such as TFA, DCM and/or MeCN at about room temperature. The compound may also 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 benzylcarbonyl protecting group, at about room temperature.
When the compounds of the present invention have chiral centres, the enantiomers may be separated from the racemic mixtures by standard separating methods such as using SFC. The exemplified compounds described herein and tested by the assays described below were found to have an IC50 value of less than 5 uM.
Shh-Light II Reporter Assay
Assay designed to measure firefly and Renilla luciferase, in the same well. 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. Day 0: after overnight incubation at 370C 10 % CO2 add 3uM of Purmorphamine (Calbiochem
540220) in water.
Day 1: After 30 hrs at 370C 10 % CO2 of incubation develop the assay, directly to cells in growth medium.
- Add 75μl of DualGlow Luciferase Reagent (Promega, E2940) - Incubate 10 min. in the dark
- Read plate at Luminometer: TopCount, by PerkinElmer
- Add 75ul of DualGlow Stop & Glow
- Incubate lOmin. in the dark - Read plate at Luminometer: TopCount, by PerkinElmer.
- Output is the ratio between FireFly/Renilla counts Growth Media: For growth: DMEM: Dulbecco's Mod Eagle Medium with 0.11G/L Pyr, with Pyridoxine. (GIBCO Cat No: 41966-029). 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). Cells cultured at 10% CO2. For assay:
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 % CO2. DMSO 0.25%.
SHH Smo Binding assay
In transfected Cos7 cells we are able to measure the binding of SMO ligand Cyclopamine- bodipy.
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 % FCS) and add compound/DMSO 0.5%. Incubate at 370C 5 % CO2. Day 2: After 16 hrs, add Cyclopamine-Bodipy (Toronto Research Chemical, B674800) at the final concentration of 5OnM. Incubate for 4 hrs at 370C 5 % CO2. Then cells are fixed 10 minutes with 3.5% Formaldehyde lOOul/well. Cells are washed 3 times with PBS and nuclei are stained with 1.5 uM Propidium Iodide. Read at Acumen Explorer.
- Growth Media: For growth:
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) (GIBCO, 3042190). Cells cultured at 5 % CO2 For assay:
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, 10106-169), 1 % Penicillin-Streptomycin (10 mg/ml) (GIBCO, 15140-114) and 1 % L- Glutamine 200MM(IOOx) (GIBCO, 3042190). Cells cultured at 5 % CO2. DMSO 0.5 %.
PREPARATIVE EXAMPLE 1 (1-tert-Butyl 3-methyl (3S)-l,3-piperazinedicarboxylate (AA3)
Step 1 : (261-l-[(Benzyloxy)carbonyll-4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid
(AAl)
It was prepared from (25)-2-piperazinecarboxylic acid dihydrochloride with slight modifications as described in Molecular Discovery 1998, 4, 221-232. A solution of (25)-2-piperazinecarboxylic acid dihydrochloride in a dioxane-water mixture (1 :1, 0.164 M) was made basic (pH 11) with 50% aqueous NaOH. A 0.68 M solution of BOC-ON (1.1 eq.) in dioxane was added dropwise at RT to the above mixture and the reaction mixture was stirred at RT overnight. The mixture was extracted with Et2O (x3) and acidified with cone. HCl to pH 2. The aqueous layer was extracted with EtOAc (x3). The aqueous solution was basified to pH 10 with 50% NaOH. A solution Λ/-(benzyloxycarbonyloxy)succinimide in dioxane (0.59 M) was added to the mixture at 00C. The reaction mixture was stirred 3 h at RT. Dioxane was removed under reduced pressure. The basic solution was extracted with Et2O (x2) then acidified to pH 1 with cone. HCl, and extracted with EtOAc (x3). The combined organic layers were dried and evaporated. The residue was used as such in next step. Step 2: 1 -Benzyl 4-fert-butyl 2-methyl (2,SV1.2.4-piperazinetricarboxylate (AA2)
A solution of TMS-diazomethane (2.0 M in Et2O, 4.0 eq.) was added to a stirred 0.16 M solution of AAl in a toluene-MeOH mixture (2:1). The reaction mixture was stirred overnight at RT. Solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 20 to 100% EtO Ac/petroleum ether to give the title compound in 92 % yield. 97% ee by SFC. [CC]D20 -10.6 (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl3, 300K) δ 7.37 (5H, m), 5.18 (2H, m), 4.79-4.57 (2H, m), 4.10-3.90 (2H, m), 3.75 (1.5H, s), 3.70 (1.5H, s), 3.34-3.30 (IH, m), 3.10 (IH, dd, J = 13.6, 4.4 Hz), 2.86 (IH, m), 1.45 (9H, s). MS (ES+) Ci9H26N2O6 requires 378, found: 401 (M+Na)+. Step 3: \-tert-Butyl 3-methyl QffHJ-piperazinedicarboxylate (AA3) 10% Pd-C (0.2 eq.) was added to a stirred solution of AA2 in MeOH (0.1 M) at RT and the mixture was stirred under H2 atmosphere at RT for 3 h. The mixture was filtered, washing with MeOH, and the filtrate was evaporated under reduced pressure to give the title compound in 89 % yield. 1H NMR (400 MHz, CDCl3, 300K) δ 4.05 (IH, m), 3.76 (3H, s), 3.74-3.68 (IH, m), 3.44 (IH, dd, J = 8.6, 3.5 Hz), 3.30-3.12 (IH, m), 3.10-3.00 (2H, m), 2.75 (IH, m), 2.17-1.74 (IH, m), 1.47 (9H, s). MS (ES+) Ci 1H20N2O4 requires 244, found: 267 (M+Na)+.
PREPARATIVE EXAMPLE 2 [QR.,2S)-2-Isocyanatocyclopropyllbenzene (BBl) Triphosgene (0.33 eq.) was added to a stirred, cooled 0 0C, 0.053 M mixture of (25,35)-2,3- dihydroxysuccinic acid and (15,2i?)-2-phenylcyclopropanamine (1 :1) (prepared according to: Newman in "Optical resolution procedures for chemical compounds" Chapter 1 Amines and related com. Pages 120-122) in a 1 :1 mixture of DCM and sat. aq. NaHCOs solution, and the reaction mixture was stirred at 0 0C for 1 h. The reaction was poured into a separatory funnel and layers were separated. Aqueous layer was extracted with DCM (x3). Combined organic layers were dried and evaporated to give the title compound as colorless oil in quantitative yield. 1H NMR (300 MHz, CDCl3, 300K) δ 7.30 (2H, t, J = 7.0 Hz), 7.21 (IH, t, J = 7.0 Hz), 7.05 (2H, d, J = 7.0 Hz), 2.92 (IH, ddd, J = 7.4, 4.3, 3.3 Hz), 2.20 (IH, ddd, J = 9.8, 6.8, 3.3 Hz), 1.33-1.20 (2H, m).
PREPARATIVE EXAMPLE 3 4-Chloro-2-methoxypyridin-3-amine (CCl)
To a stirred solution of 2-bromo-4-chloropyridin-3 -amine (prepared as described in £752002/0119982) (1.0 eq.) in dry MeOH (0.25M) under argon was added a solution of NaOMe (25% wt in MeOH, 1.5 eq.) and the reaction mixture was refluxed for Ih, more NaOMe (25% wt in MeOH, 1.5 eq) was added and the reaction mixture was refluxed for an additional 2h. The volatiles were removed under reduced pressure and the crude product was purified by flash chromatography eluting with 2-10% EtO Ac/petroleum ether affording the titled compound as yellow oil. 1H-NMR (300 MHz, DMSO-d6, 300K) δ 7.33 (IH, d, J = 5.5 Hz), 6.88 (IH, d, J = 5.5 Hz), 5.13 (2H, bs), 3.89 (3H, s). MS (ES) C6H7C1N2O requires: 158, found: 159, 161 (M+H)+.
PREPARATIVE EXAMPLE 4 4-Chloro-2-methylpyridin-3-amine (DPI)
Following a modified synthetic procedure reported in WO 2005/016892, a mixture of 2-bromo-4- chloropyridin-3 -amine (prepared as described in £752002/0119982) (1.0 eq.), trimethylboroxine (1.05 eq.), K2CO3 (3.5 eq.) and PdCl2(dppf)-CH2Cl2 adduct (0.1 eq.) in 10:1 solution 1,4- dioxane:H2O (0.28M) was put in a 10-mL glass vial equipped with a small magnetic stirring bar. The reaction vessel was fitted with a rubber septum, was evacuated and back-filled with argon and sealed with an aluminum/Teflon crimp top. The reaction mixture was then irradiated for 1 h at 120 0C, using an irradiation power of 100 W. After completion of the reaction, the vial was cooled to 50 0C with air jet cooling before it was opened. The reaction mixture was diluted with EtOAc and filtered on a pad of Solca Floc®200FCC. The crude product was purified by flash chromatography eluting with 5-100% EtO Ac/petroleum ether affording the titled compound as violet oil. MS (ES) C6H7ClN2 requires: 142, found: 143, 145 (M+H)+.
PREPARATIVE EXAMPLE 5 4-Chloro-2-ethylpyridin-3-amine (EEl)
Following a modified synthetic procedure reported in J. Org. Chem. 2006, 71, 7322, a to a stirred solution of 2-bromo-4-chloropyridin-3-amine (prepared as described in {75*2002/0119982) (1.0 eq.), and Pd(Ph3P)4 (0.05 eq.) in dry THF (0.05M) under argon was added dropwise Me3Al (1.0M in hexane, 2.0 eq.) and the reaction mixture was refluxed for O/N. The volatiles were removed under reduced pressure and the crude product was purified by flash chromatography eluting with 5-100% EtO Ac/petroleum ether affording the titled compound as orange oil. 1H NMR (300 MHz, DMSO-d6, 300K) δ 7.67 (IH, d, J = 5.2 Hz), 7.11 (IH, d, J = 5.2 Hz), 5.26 (2H, br. s), 2.69 (2H, q, J = 7.3 Hz), 1.73 (3H, t, J = 7.3 Hz). MS (ES) C7H9ClN2 requires: 156, found: 157, 159 (M+H)+.
PREPARATIVE EXAMPLE 6 2-Cvclopropyl-4-methylpyridin-3-amine (FFl)
Following a modified synthetic procedure reported in J. Org. Chem. 2003, 68, 5534, a mixture of 2-bromo-4-methylpyridin-3-amine (1.0 eq.), potassium cyclopropyltrifluoroborate (2.0 eq.), Cs2CO3 (3.0 eq.) and PdCl2(dppf)-CH2Cl2 adduct (0.1 eq.) in 10:1 solution THF:H2O (0.14M) was put in a 10-mL glass vial equipped with a small magnetic stirring bar. The reaction vessel was fitted with a rubber septum, was evacuated and back-filled with argon and sealed with an aluminum/Teflon crimp top. The reaction mixture was then heated for O/N at 80 0C. After completion of the reaction, the vial was cooled to RT before it was opened. The reaction mixture was diluted with EtOAc and filtered on a pad of Solca Floc®200FCC. The crude product was purified by flash chromatography eluting with 10-100% EtO Ac/petroleum ether affording the titled compound as brown oil. 1H-NMR (400 MHz, DMSO-d6, 300K) δ 7.55 (IH, d, J = 4.7 Hz), 6.75 (IH, d, J = 4.7 Hz), 4.89 (2H, br. s), 2.13-2.04 (4H, m), 0.85-0.68 (4H, m). MS (ES) C9Hi2N2 requires: 148, found: 149 (M+H)+.
REPRESENTATIVE EXAMPLES
EXAMPLE 1 7V-Biphenyl-2-yl- 1 ,3-dioxo-2- [^røws-2-phenylcyclopr opyll hexahydr oimidazo [ 1 ,5-al pyrazine- 7qH)-carboxamide (A6)
Step 1 : l-[(benzyloxy)carbonyll-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (Al) A solution 0.164 M of 2-piperazinecarboxylic acid dihydrochloride in a 1 :1 dioxane-water mixture was made basic (pH 11) with 50% aqueous NaOH. A 0.68 M solution of Boc-ON (1.1 eq) in dioxane was added dropwise at RT to the above mixture and the reaction mixture was stirred at RT overnight. The mixture was extracted with Et2O (x3) and acidified with cone. HCl to pH 2. The aqueous layer was extracted with EtOAc (x3). The aqueous solution was basified to pH 10 with 50% NaOH. A 0.59 M solution Λ/-(benzyloxycarbonyloxy)succinimide (1.1 eq.) in dioxane was added to the mixture at 00C. The reaction mixture was stirred 3 h at RT. Dioxane was removed under reduced pressure. The basic solution was extracted with Et2O (x2) then acidified to pH 1 with cone. HCl, and extracted with EtOAc (x3). The combined organic layers were dried and evaporated. The residue was used as such in next step. Step 2: 1 -benzyl 4-tert-butγ\ 2-methyl piperazine-l,2,4-tricarboxylate (A2)
This step was carried out using the procedure described in Tetrahedron Letters 30 (39), 1989, 5193-5196. A 0.5 M solution of Al in acetone was treated with K2CO3 (1.3 eq.) and Me2SO4 (1.2 eq.) and the mixture was refluxed 6h. The reaction mixture was filtered and filtrate was concentrated under reduced pressure. The residue was dissolved in Et2O and washed with sat. aq. NaHCO3 solution, and brine, then dried and evaporated. The residue was purified by column chromatography on silica gel, eluting with 20-100% EtO Ac/petroleum ether to give the title compound in 90 % yield. 1H NMR (300 MHz, CDCl3, 300K) δ 7.35 (5H, m), 5.17 (2H, m), 4.77-4.50 (2H, m), 4.10-3.85 (lH,m), 3.74 (1.5H, s), 3.64 (1.5H, s), 3.30 (IH, m), 3.10 (IH, dd, J 13.6, 4.4), 2.86 (IH, m), 1.45 (9H, s). MS (ES+) Ci9H26N2O6 requires 378, found: 401 (M+Na)+. Step 3: 1-ferf-butyl 3-methyl piperazine-l,3-dicarboxylate (A3)
10% Pd-C (0.2 eq) was added to a stirred RT 0.1 M solution of A2 in MeOH and the mixture was stirred under an H2 atmosphere at RT for 3 h. The mixture was filtered, washing with MeOH, and the filtrate was evaporated under reduced pressure to give the title compound in 95 % yield. 1H NMR (400 MHz, CDCl3, 300K) δ 4.02 (IH, m), 3.74 (3H, s), 3.70 (IH, m), 3.43 (IH, m), 3.20 (IH, m), 3.04 (2H, m), 2.75 (IH, m), 2.14 (IH, m), 1.47 (9H, s). MS (ES+) CnH20N2O4 requires 244, found: 267 (M+Na)+.
Step 4: tert-butyi l,3-dioxo-2-[trα/?5-2-phenylcyclopropyllhexahydroimidazo[l,5-αlpyrazine- 7(lH)-carboxylate (A4) To A3 in toluene (0.4M) was added dropwise trans-2-phenylcyclopropyl isocyanate (1.05 eq.). The mixture was stirred O/N at rt. DIPEA (1.5 eq.) was added and the mixture refluxed for 20 h. The organic phase was washed with phosphate buffer (2 x 200 mL, 0.75 M NaH2PO4, pH ~ 4.5) and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 20-100% EtO Ac/petroleum ether to give the title compound in 60 % yield. MS (ES+) C20H25N3O4 requires 371, found: 394 (M+Na)+. Step 5: 2-[trα/?5-2-phenylcyclopropylltetrahydroimidazo[l,5-αlpyrazine-l,3(2H,5H)-dione (A5) A solution of A4 in DCM (0.5 M) was cooled to 0°C (ice bath) and TFA (9 eq.) was added and the reaction was stirred at RT overnight. The solvent was removed under reduced pressure. The crude material was treated with Et2O (20 mL) and HCl (IN, 12 mL). The two layers were separated, and organic phase washed with water (2x15 mL). To the combined organic extracts was added solid K2CO3 in small portion until pΗ 9-10. The mixture was extracted with DCM and combined extracts were dried and evaporated under reduced pressure to yield (100 %) the desired compound that was used crude in the next step. 1H NMR (400 MHz, DMSO-d6, 300K) δ 7.29-7.20 (5H, m), 3.90 (IH, m), 3.78 (lH,m ), 3.15 (IH, m), 2.85 (3H, m), 2.65 (IH, m), 2.50- 2.30 (3H, m), 1.5 (IH, m), 1.35 (IH, m). MS (ES+) Ci5HnN3O2 requires 271, found: 272 (M+H)+.
Step 6: Λ/-Biphenyl-2-yl-l,3-dioxo-2-[trα/?5-2-phenylcyclopropyllhexahydroimidazo[l,5- a"|pyrazine-7(lH)-carboxamide (A6) [l,l'-Biphenyl]-2-yl-isocyanate (1.1 eq) was added to a stirred solution of A5 and DIPEA (3.0 eq) in DCM (0.09 M), and the mixture was stirred at RT for 1 h. The solvents were removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with 10-80% EtO Ac/petroleum ether to give the title compound in 76 % yield. 1H NMR (400 MHz, DMSO-de, 300K) δ 8.36 (IH, s), 7.43-7.38 (4H, m), 7.33-7.27 (7H, m), 7.20 (3H, m), 4.19 (IH, m), 3.93 (IH, m), 3.85-3.77 (2H, m), 2.86 (IH, m), 2.74 (2H, d, J = 9.3 Hz), 2.67 (IH, m), 2.40-2.30 (IH, m), 1.58-1.48 (IH, m), 1.43-1.37 (IH, m). MS (ES+) C28H26N4O3 requires 466, found: 467 (M+H)+.
EXAMPLE 2 N-( 2,3-Dichlorophenyl)- 1.,3-dioxo-2- [;m«s-2-phenylcyclopr opyll hexahydr oimidazo [ 1 ,5- alpyrazine-7(lH)-carboxamide (Bl)
Compound Bl was prepared according to procedure reported in Example 1. Yield 860Zo-1H NMR (400 MHz, DMSO-de, 300K) δ 8.80 (IH, s), 7.43 (2H, m), 7.35-7.28 (3H, m), 7.23-7.18 (3H, m), 4.35 (IH, m), 4.14-4.09 (2H, m), 3.93 (IH, m), 3.04-2.92 (3H, m), 2.69 (IH, m), 2.42-2.35 (IH, m), 1.64-1.50 (IH, m), 1.41 (IH, m). MS (ES+) C22H20Cl2N4O3 requires 458, 460, found: 459, 461 (M+H)+.
EXAMPLE 3 N-Biphenyl-2-yl- 1 ,3-dioxo-2- [^røws-2-phenylcyclopr opyll hexahydr oimidazo [ 1 ,5-al pyrazine- 7(lH)-carboxamide (Diastereomer 1), (8aS)-N-Biphenyl-2-yl-l,3-dioxo-2-r(lS,2R)-2- phenylcyclopropyllhexahydroimidazorLS-alpyrazine^lHVcarboxamide, N-Biphenyl-2-yl- l.,3-dioxo-2-[^rø«s-2-phenylcyclopropyllhexahydroimidazo[l,5-alpyrazine-7flH)- carboxamide ( Diastereomer 2) and N-Biphenyl-2-yl- l,3-dioxo-2- \trans-2- phenylcyclopropyllhexahydroimidazo[l,5-alpyrazine-7flH)-carboxamide (Diastereomer 3) (Cl, C2, C3 and C4)
The diasteromers of (A6) (Example 1) were separated with two sequential separations using a SFC system.
First purification -Column: Chiralpak IB (1x25 cm); flow: 10 mL/min; modifier: 30% (MeOH 0.2% DEA); Tcol: 35°C; Pcol: 100 bar- gave two pairs of isomers that were purified separately - Column: Chiralcel OJ (1x25 cm); flow: 10 mL/min; modifier: 60% (MeOH 0.2% DEA); Tcoi: 35°C; Pcol: 100 bar- to obtain the four diastereomers classified in ordered of elution on column OJ-METH, gradient 20-60% MeOH + 0.2% DEA: First compound eluted: Retention time = 8.39 min. yield 10% 1H NMR (400 MHz, DMSO-de, 300K) δ 8.36 (IH, s), 7.43-7.38 (4H, m), 7.33-7.27 (7H, m), 7.20 (3H, app. d, J = 7 Hz), 4.20 (IH, dd, J = 12.9, 4.1 Hz), 3.93 (IH, d, J = 9.5 Hz), 3.82 (IH, dd, J = 11.3, 4.8 Hz), 3.79 (IH, d, J = 10.8 Hz), 2.87 (IH, dd, J = 12.1, 12.1 Hz), 2.74 (IH, d, J=9.4 Hz), 2.66 (IH, m), 2.33 (IH, m), 1.55 (IH, ddd, J = 9.5, 5.6, 4.9 Hz), 1.39 (IH, dd, J = 13.5, 6.8 Hz). MS (ES+) C28H26N4O3 requires 466, found: 467 (M+ H)+.
Second compound eluted: Retention time = 10.15 min yield 10% . 1H NMR (400 MHz, DMSO- d6, 300K) δ 8.36 (IH, s), 7.43-7.38 (4H, m), 7.33-7.27 (7H, m), 7.20 (3H, app. d, J = 7 Hz), 4.19 (IH, dd, J = 13.0, 4.1 Hz), 3.92 (IH, d, J = 9.8 Hz), 3.82 (IH, dd, J = 11.3, 4.9 Hz), 3.78 (IH, d, J = 10.4 Hz), 2.86 (IH, dd, J = 13.0, 11.3 Hz), 2.79-2.70 (2H, m), 2.66 (IH, m), 2.37 (IH, ddd, J = 9.8, 6.7, 3.3 Hz), 1.51 (IH, ddd, J = 9.9, 5.7, 4.4 Hz), 1.39 (IH, dd, J = 13.6, 6.8 Hz). MS (ES+) C28H26N4O3 requires 466, found: 467 (M+ H+).
Third compound eluted: Retention time = 10.76 min yield 10% . 1H NMR (400 MHz, DMSO-de, 300K) δ 8.36 (IH, s), 7.43-7.38 (4H, m), 7.33-7.27 (7H, m), 7.20 (3H, app. d, J = 7 Hz), 4.19 (IH, dd, J = 13.0, 4.1 Hz), 3.92 (IH, d, J = 9.8 Hz), 3.82 (IH, dd, J = 11.3, 4.9 Hz), 3.78 (IH, d, J = 10.4 Hz), 2.86 (IH, dd, J = 13.0, 11.3 Hz), 2.79-2.70 (2H, m), 2.66 (IH, m), 2.37 (IH, ddd, J = 9.8, 6.7, 3.3 Hz), 1.51 (IH, ddd, J = 9.9, 5.7, 4.4 Hz), 1.39 (IH, dd, J = 13.6, 6.8 Hz). MS (ES+) C28H26N4O3 requires 466, found: 467 (M+ H+). Fourth compound eluted: Retention time = 11.49 min yield 10% 1H NMR (400 MHz, DMSO-d6, 300K) δ 8.36 (IH, s), 7.43-7.38 (4H, m), 7.33-7.27 (7H, m), 7.20 (3H, app. d, J = 7 Hz), 4.20
(IH, dd, J = 12.9, 4.1 Hz), 3.93 (IH, d, J = 9.5 Hz), 3.82 (IH, dd, J = 11.3, 4.8 Hz), 3.79 (IH, d, J = 10.8 Hz), 2.87 (IH, dd, J = 12.1, 12.1 Hz), 2.74 (IH, d, J=9.4 Hz), 2.66 (IH, m), 2.33 (IH, m), 1.55 (IH, ddd, J = 9.5, 5.6, 4.9 Hz), 1.39 (IH, dd, J = 13.5, 6.8 Hz). MS (ES+) C28H26N4O3 requires 466, found: 467 (M+ H+).
EXAMPLE 4
(8aS)-N-q,3-Dichlorophenyl)-l,3-dioxo-2-rαS,2R)-2- phenylcyclopropyllhexahydroimidazorLS-alpyrazine-TflHVcarboxamide (D3) Step 1 : 1-tert-Butyl 3-methyl (3S)-4-((r(lS.2R)-2-phenylcvclopropyllaminolcarbonvn-1.3- piperazinedicarboxylate (Dl)
A solution of l-tert-buty\ 3-methyl (35)-l,3-piperazinedicarboxylate (AA3) in DCM (0.17 M) was added to a stirred solution of [(li?,25)-2-isocyanatocyclopropyl]benzene (1.0 eq.) in DCM (0.17 M) and the mixture was stirred at RT for 1 h. Solvents were evaporated under reduced pressure to give the title compound that was used as such in next step. MS (ES+) C2iH2gN3θ5 requires 403, found: 404 (M+H)+.
Step 2: (8aSV2-IYl S.2R)-2-Phenylcvclopropyl1tetrahvdroimidazor 1 ,5-alpyrazine- 1 ,3(2H.5HV dione HCl salt (D2) 4N HCl solution in dioxane (44 eq.) was added at RT to Dl. The resulting 0.1 M solution obtained was stirred for Ih at RT, then the solvent was removed under reduced pressure. The residue was co-evaporated with toluene (x3) and it was used as such in next step without further purification. MS (ES+) Ci5Hi7N3O2 requires 271, found: 272 (M+H)+. Step 3: (8a^-N-(2.3-Dichlorophenvn-1.3-dioxo-2-r(ltS'.2i?)-2-phenylcvclopropyllhexahvdro imidazo[l ,5-αlpyrazine-7(lH)-carboxamide (D3)
2,3-Dichlorophenyl isocyanate (1.1 eq.) was added to a stirred solution of D2 and DIPEA (3.0 eq.) in DCM (0.09 M) and the mixture was stirred at RT for 1 h. The solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 10-80% EtO Ac/petroleum ether to give the title compound in 67 % yield, 92% de by SFC. 1H NMR (400 MHz, DMSO-d6, 300K) δ 8.80 (IH, s), 7.45-7.42 (2H, m), 7.34-7.28 (3H, m), 7.23-7.18 (3H, m), 4.35 (IH, dd, J = 12.9, 4.2 Hz), 4.14-4.09 (2H, m), 3.92 (IH, dd, J = 13.0,
2.7 Hz), 3.07-2.99 (2H, m), 2.91 (IH, td, J = 12.6, 3.0 Hz), 2.68 (IH, m), 2.39 (IH, ddd, J = 9.8, 6.8, 3.2 Hz), 1.51 (IH, ddd, J = 9.5, 5.7, 4.3 Hz), 1.41 (IH, dd, J = 14.0, 7.1 Hz). MS (ES+) C22H20Cl2N4O3 requires 458, 460, found: 459, 461 (M+H+).
EXAMPLE 5
( 8aS)-N-2-biphenylyl- 1.,3-dioxo-2- [(I S,2R)-2-phenylcyclopr opyll hexahydr oimidazo [ 1 ,5- al pyrazine-7( lH)-carboxamide ( C2) The title compound was prepared, as described in example 4, using [l,l'-biphenyl]-2-yl- isocyanate (1.1 eq.) to give the desired compound in 67% yield, 92% de by SFC. 1H NMR (400 MHz, DMSO-de, 300K) δ 8.36 (IH, s), 7.43-7.38 (4H, m), 7.33-7.27 (7H, m), 7.20 (3H, app. d, J = 7 Hz), 4.19 (IH, dd, J = 13.0, 4.1 Hz), 3.92 (IH, d, J = 9.8 Hz), 3.82 (IH, dd, J = 11.3, 4.9 Hz), 3.78 (IH, d, J = 10.4 Hz), 2.86 (IH, dd, J = 13.0, 11.3 Hz), 2.79-2.70 (2H, m), 2.66 (IH, m), 2.37 (IH, ddd, J = 9.8, 6.7, 3.3 Hz), 1.51 (IH, ddd, J = 9.9, 5.7, 4.4 Hz), 1.39 (IH, dd, J = 13.6,
6.8 Hz). MS (ES+) C28H26N4O3 requires 466, found: 467 (M+H+).
EXAMPLE 6
TV-Cyclohexyl- 1.,3-dioxo-2- [ftγms-2-phenylcyclopr opyll hexahydr oimidazo [ 1 ,5-al pyrazine- 7qH)-carboxamide (El)
The title compound was prepared, as described in example 4. After workup the crude product was purified by preparative RP-ΗPLC using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents. The desired fractions were lyophilized to afford the title compound in 44% yield. 1H NMR (400 MHz, DMSO-d6, 300K) δ 7.31-7.18 (5H, m), 6.51 (IH, bs), 4-28-4.24 (IH, m), 4.02- 3.95 (2H, m), 3.83 (IH, m), 3.41 (IH, m), 2.80 (IH, m), 2.77 (IH, m), 2.67 (2H, m), 2.40-2.29 (IH, m), 1.79-1.65 (4H, m), 1.61-1.47 (2H, m), 1.38(1H, m), 1.25-1.15 (4H, m), 1.09 (IH, m). MS (ES+) C22H28N4O3 requires 396, found: 397 (M+H)+. EXAMPLE 7
(SaS^-l^-Dioxo-l-rαSJRVl-phenylcvclopropyll-TV-q-phenyl-lH-pyrazol-S- yl)hexahvdroimidazori,5-fllpyrazine-7(lH)-carboxamide (F2)
Synthesis A Step 1 :_ l-Phenyl-lΗ-pyrazol-5-amine (Fl)
5-Amino-4-carbethoxy-l-phenylpyrazole (leq.) was dissolved in 36% HCl solution (30 eq.) and the reaction mixture was stirred under reflux for overnight. The mixture was cooled, poured onto ice and made basic with NH4OH. The mixture was extracted with DCM (x3). The combined organic fractions were washed with brine, dried (Na2SO4), and the solvent was evaporated under reduced pressure to obtain the product as pale yellow oil in 94 % yield. MS (ES+) C9H9N3 requires 159, found: 160 (M+H)+.
Step l^Sa^-lJ-dioxo-l-rd^lffl-l-phenylcvclopropyll-N-d-phenyl-l/f-pyrazol-S- yl)hexahydroimidazo[l ,5-αlpyrazine-7(lH)-carboxamide (F2) Fl (1.0 eq.) was dissolved in MeCN (0.1M) and CDI (1.0 eq.) was added. The reaction was stirred at 8O0C for 5h. After cooling at RT a solution of (D2) (0.5 eq.) and TEA (0.6 eq.) in MeCN (0.2M) was added dropwise. The mixture was stirred overnight. The solvents were removed under reduced pressure. Crude product was purified by preparative RP-HPLC using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents. The desired fractions were lyophilized to afford the title compound in 33% yield. 1H NMR (400 MHz, DMSO-d6, 300K) δ 8.91 (IH, s), 7.62 (IH, d, J=I .7 Hz), 7.54-7.47 (4H, m), 7.37 (IH, m), 7.30 (2H, m), 7.22-7.20 (3H, m), 6.31 (IH, d, J=I.7 Hz), 4.24 (IH, m), 4.02-3.96 (2H, m), 3.87 (IH, m), 2.97 (lH,m), 2.84 (2H, m), 2.67 (IH, m), 2.38 (IH, m), 1.52-1.48 (IH, m), 1.40 (IH, m). MS (ES+) C25H24N6O3 requires 456, found: 457 (M+ H+). Synthesis B Step 1 : Phenyl (1 -phenyl- lH-pyrazol-5-yl)carbamate (F3)
1 -Phenyl- lH-pyrazol-5-amine (1 eq) was dissolved in DCE (0.1M), phenylchloroformate (1.1 eq) was added. The reaction was stirred Ih, then diluted with DCM and washed with water and brine, dried and concentrated under reduced pressure to afford the product in quantitave yield. Step 2: ^α6')-1.3-Dioxo-2-r^tS'.2i?)-2-phenylcvclopropyll-N-(l-phenyl-lH-pyrazol-5- yl)hexahydroimidazo[l ,5-a"|pyrazine-7(lH)-carboxamide (F2)
Example 4, D2 (1 eq) was dissolved in DCM (0.1M), F3 (1.5 eq) and TEA (1.5 eq) were added and the reaction was stirred at RT 6h. The reaction was diluted with DCM and washed with water and brine, dried and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 10-100% EtO Ac/petroleum ether to afford the title compound in 85% yield. 1H NMR (400 MHz, DMSO-d6, 300K) δ 8.91 (IH, s), 7.62 (IH, d, J=I.7 Hz), 7.54-7.47 (4H, m), 7.37 (IH, m), 7.30 (2H, m), 7.22-7.20 (3H, m), 6.31 (IH, d, J=I.7 Hz), 4.24 (IH, m), 4.02-3.96 (2H, m), 3.87 (IH, m), 2.97 (lH,m), 2.84 (2H, m), 2.67 (IH, m), 2.38 (IH, m), 1.52-1.48 (IH, m), 1.40 (IH, m). MS (ES+) C25H24N6O3 requires 456, found: 457 (M+ H+).
EXAMPLE 8 (8aS)-7V-r2-(3-Chlorophenyl)pyridin-3-yll-l,3-dioxo-2-rαS,2R)-2- phenylcvclopropyllhexahydroimidazorLS-fllpyrazine-TQHVcarboxamide (G3)
Step 1 : 2-(3-Chlorophenyl)pyridin-3-amine (Gl)
To the solution of 2-bromopyridin-3 -amine in DME (0.1M) were added 2M aqueous Na2CO3 solution (2 eq.) and (3-chlorophenyl)boronic acid (1.1 eq). The mixture was degassed and placed under an argon atmosphere. PdCl2(dppf) (0.02 eq) were added and the reaction was heated at reflux overnight under argon. After cooling the reaction was diluted with EtOAc and washed with water and brine, then dried and evaporated under reduced pressure to afford the titled compound which was used as such in the next step. MS (ES+) CnH9ClN2 requires 204, 206, found: 205, 207 (M+H)+. Step 2: 2-(3-Chlorophenyl)-3-isocyanatopyridine (G2)
Gl (1 eq.) was dissolved in DCM (0.1M) and DIPEA was added (4 eq.). This solution was slowly added to a solution of triphosgene (0.33 eq.) in DCM (IM). The reaction was stirred 30 min and used as such in the next step. Step 3: N-r2-(3-chlorophenvnpyridin-3-yll-1.3-dioxo-2-r(lR.2SV2- phenylcyclopropyl]hexahydro imidazo[l,5-alpyrazine-7(lH)-carboxamide (G3)
The solution of G2 (2 eq.) in DCM was added dropwise to the solution D2 (1.0 eq.) and DIPEA (1.1 eq.) in DCE (0.1 M). The reaction was stirred for 4h. Then the solvent was evaporated under vacuum and residue was purified by preparative RP-HPLC using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents. The desired fractions were lyophilized to afford the title compound in 40% yield. 1H NMR (400 MHz, DMSO-d6, 300K) δ 8.75 (IH, s), 8.49 (IH, d, J=3.5 Hz), 7.77 (IH, d, J=7.88), 7.66 (IH, bs), 7.61 (IH, d, J=7.08), 7.49-7.38 (3H, m), 7.32- 7.28 (2H, m), 7.21 (3H, m), 4.26 (IH, dd, J=12.7, 3.9 Hz)), 3.96-3.86 (3H, m), 2.96 (IH, m), 2.83 (2H,m), 2.68 (IH, m), 2.39 (IH, m), 1.52 (IH, m), 1.41 (IH, m). MS (ES+) C27H24ClN5O3 requires 501, 503 found: 502, 504 (M+ H+).
EXAMPLE 9 f8aS)-7V-Biphenyl-2-yl-2-[^rø«s-2-f4-chlorophenyl)cvclopropyll-l,3- dioxohexahydroimidazo [ 1 ,5-al pyrazine-7( lHVcarboxamide ( Η5) Step 1 : ferf-Butyl (8a61-l,3-dioxohexahydroimidazo[l,5-αlpyrazine-7(lH)-carboxylate (Hl) To a stirred solution of l-tert-buty\ 3-methyl (35)-piperazine-l,3-dicarboxylate (AA3) (1.0 eq.) and 6 N aq. HCl sol. (1.0 eq.) in 1,4-dioxane (1 M) was added a sol. of KOCN (2.0 eq.) in H2O (2 M). The reaction mixture was stirred at RT for 2 h, then the organic solvent was removed under reduced pressure. The desired product precipitated from H2O: it was filtered off, washed with cold water and dried at the high vacuum pump. Mother liquors were extracted with EtOAc, the organic phase was washed with brine, dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 10-100% EtO Ac/petroleum ether to afford the desired product (Hl) as a white powder which was combined with the previously isolated precipitate. 1H-NMR (300 MHz, DMSO-de, 300K) δ
10.95 (IH, bs), 4.15-4.00 (2H, m), 3.97-3.75 (2H, m), 2.97-2.67 (3H, m), 1.42 (9H, s). MS (ES)
CnHi7N3O4 requires: 255, found: 256 (M+H)+.
Step 2: ferf-Butyl (8a61-l,3-dioxo-2-vinylhexahydroimidazo[l,5-αlpyrazine-7(lH)-carboxylate
(Η2) A solution of (Hl) (1.0 eq.) in vinyl acetate (60 eq.) was degassed under argon, then Na2PdCl4 (0.2 eq.) was added and the reaction mixture was heated to reflux for 18 h. The reaction mixture was diluted with EtOAc and filtered on a pad of SolcaFloc® 200 FCC. The solvent was removed under reduced pressure giving an orange sticky solid which was purified by flash chromatography on silica gel eluting with 10-100% EtO Ac/petroleum ether to afford the title compound (H2) as a white powder. 1H-NMR (300 MHz, DMSO-d6, 300K) δ 6.60 (IH, dd, J = 9.7 and 16.3 Hz), 5.84 (IH, d, J = 16.3 Hz), 4.96 (IH, d, J = 9.7 Hz), 4.22-4.07 (2H, m), 4.00- 3.83 (2H, m), 3.13-2.75 (3H, m), 1.43 (9H, s). MS (ES) Ci3Hi9N3O4 requires: 281, found: 304 (M+Na)+. Step 3: tert-Butyl (8a61-2-[(E)-2-(4-chlorophenyl)vinyll-l,3-dioxohexahydroimidazo[l,5- αlpyrazine-7(lH)-carboxylate (Η3)
A mixture of (H2) (1.0 eq.), l-chloro-4-iodobenzene (2.0 eq.), Pd(OAc)2 (0.05 eq.), NaOAc (3.0 eq.) and LiBr (6.0 eq.) in DMF:H2O sol. (10:1, 0.078 M) was placed in a sealed vial and stirred at 900C for 18 h under argon. The reaction mixture was diluted with EtOAc, washed with water, brine, dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 10-100% EtO Ac/petroleum ether to afford the title compound (H3) as a yellow powder. 1H-NMR (300 MHz, DMSO-d6, 300K) δ 1.51-1 Al (2H, m), 7.46-7.33 (3H, m), 7.10 (IH, d, J = 15.2 Hz), 4.30-4.10 (2H, m), 4.05-3.85 (2H, m), 3.15-2.75 (3H, m), 1.44 (9H, s). MS (ES) Ci9H22ClN3O4 requires: 391, 393, found: 414, 416 (M+Na)+. Step 4: (8a61-2-[trα/?5-2-(4-chlorophenyl)cyclopropylltetrahydroimidazo[l,5-αlpyrazine- U(2H.5H)-dione (Η4)
Molecular sieves (4 A) and CH2ClI (10.0 eq.) were added to a solution of (H3) (1.0 eq.) in anhydrous DCE (0.1 M), and the resulting mixture was stirred at RT for 30 min. Diethylzinc (1.0 M in hexanes, 5.0 eq.) was then added carefully dropwise. Stirring was continued at RT for 18 h. The reaction mixture was diluted with MeOH and the crude product was purified by Isolute® SCX cartridge to yield the title compound as a mixture of diastereomers which was used in the next step without further purification. MS (ES) Ci5Hi6ClN3O2 requires: 291, 293 found: 292, 294 (M+H)+. Step 5 : (8aS)-N-biphenyl-2-yl-2-rtraw5-2-(4-chlorophenvncvclopropyll- 1.3- dioxohexahydroimidazo[l ,5-αlpyrazine-7(lH)-carboxamide (Η5)
To a stirred solution of (H4) (1.0 eq.) in anhydrous DCE (0.25 M) were added Et3N (1.1 eq.) and [l,l'-biphen]-2-yl isocyanate (1.1 eq.). The reaction mixture was stirred at RT for 2 h, then diluted with DCM, washed with water, brine, dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified by preparative RP-HPLC using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents. The desired fractions were lyophilized to afford the title compound (H5) as a mixture of diastereomers as a pale yellow powder. 1H-NMR (400 MHz, DMSO-d6, 300K) δ 8.36 (IH, bs), 7.42-7.20 (13H, m), 4.25-4.15 (IH, m), 3.99-3.87 (IH, m), 3.84-3.72 (2H, m), 2.89-2.78 (IH, m), 2.78-2.67 (2H, m), 2.67-2.61 (IH, m), 2.40-2.28 (IH, m), 1.60-1.46 (IH, m), 1.43-1.34 (IH, m). MS (ES) C28H25ClN4O3 requires: 500, 502 found: 501, 503 (M+H)+.
The compounds in the following table were made according to the procedure described above.
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
EXAMPLE 59
7V-fBiphenyl-2-yl)-8a-methyl-l,3-dioxo-2-[flS,2R)-2-phenylcvclopropyll-hexahvdro imidazo-[l,5-alpyrazine-7flH)-carboxamide (13) and corresponding diastereomers: (8SLS)- 7V-biphenyl-2-yl-8a-methyl-l,3-dioxo-2-[flS,2R)-2-phenylcvclopropyllhexahydroimidazo [1,5-al pyrazine-7(lH)-carboxamide and (8a/?)-7V-biphenyl-2-yl-8a-methyl-l.,3-dioxo-2- [flS.,2R)-2-phenylcvclopropyllhexahvdroimidazo[l,5-alpyrazine-7flH)-carboxamide (I3a and I3b) Step 1 : tert-Butyl 8a-methyl-l,3-dioxo-2-[(16',2i?)-2-phenylcyclopropyllhexahydroimidazo- [l,5α]-pyrazine-7(lH)-carboxylate (II)
(A4) (Example 1) was dissolved in TΗF (0.1 M) and cooled at -780C. LDA (3.0 eq, 2.0 M in TΗF) was then slowly added. After 1 h, MeI (5.0 eq) was added and the reaction was slowly warmed to RT. The reaction was then quenched with sat. aq. NH4Cl solution and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column on silica using 10-30% EtO Ac/Petroleum ether to yield in 48% the desired (II) as a foam. 1H NMR (400 MHz, CDCl3, 300K) δ 7.32-7.24 (4H, m), 7.23-7.18 (IH, m), 4.30-4.10 (2H, m), 4.03 (IH, dd, J = 13.6, 3.6 Hz), 3.10-3.00 (IH, m), 2.80-2.70 (3H, m), 2.60-2.50 (IH, m), 1.65-1.60 (IH, m), 1.48 (9H, s), 1.48-1.40 (IH, m), 1.44 (3H, s). MS (ES+) C2IH27N3O4 requires 385, found: 408 (M+Na)+.
Step 2: 8a-Methyl-2-[(16',2i?)-2-phenylcyclopropylltetrahydroimidazo[l,5-αlpyrazine- 1.3(2/f.5H)-dione (12) and corresponding diastereomers: (8aS)-8a-methγl-2-\(\S,2R)-2- phenylcyclopropylltetrahydroimidazo[ 1 ,5-α]pyrazine- 1 ,3(2H,5H)-dione and (8ai?)-8a-methyl-2- [(16',2i?)-2-phenylcyclopropylltetrahydroimidazo[l,5-αlpyrazine-l,3(2/f,5H)-dione (I2a and I2b) 12 was prepared following the procedure reported in Example 1 step 5 and the crude was purified using 1ST ISOLUTE® SPE column SCX (loading in MeOH; eluting with 3N NH3 in MeOH). Yield = 100%. 1H NMR (400 MHz, CD3OD, 300K) δ 7.32-7.24 (4H, m), 7.22-7.16 (IH, m), 3.90 (IH, dd, J = 13.6, 3.6 Hz), 3.10-2.90 (3H, m), 2.72-2.62 (2H, m), 2.60-2.50 (IH, m), 2.50- 2.40 (IH, m), 1.60-1.50 (IH, m), 1.49 (3H, s), 1.43-1.40 (IH, m). MS (ES+) Ci6Hi9N3O2 requires 285, found: 286 (M+H)+.
The diastereoisomers of 12 were separated by chiral SFC purification (column: Chiralpak AD-H (1x25 cm), flow: 10 ml/min, Tcoi: 35°C, Pcoi: 100 bar, modifier: 25% 1PrOH + 0.4% Et2NH, using CO2 as supercritic eluent). Evaporation of the solvent followed by lyophilization gave as oils: First eluted diastereoisomer (12a): tret = 3.24 min; yield 31% : 1H NMR (400MHz, CD3CN, 300K) δ 7.35-7.30 (2H, m), 7.27-7.22 (3H, m), 3.83 (IH, dd, J = 13.6, 3.6 Hz), 2.97 (IH, td, J= 12.6, 3.6 Hz), 2.92-2.86 (2H, m), 2.70-2.65 (IH, m), 2.62 (IH, d, J = 12.4 Hz), 2.50 (IH, td, J= 12.4, 3.8 Hz), 2.41 (IH, ddd, J= 10.0, 6.6, 3.6 Hz), 1.59 (IH, ddd, J = 10.4, 6.0, 4.4 Hz), 1.47 (3H, s), 1.40 (IH, dd, J = 13.8, 6.9 Hz). MS (ES+) Ci6Hi9N3O2 requires 285, found: 286 (M+H)+. Second eluted diastereoisomer 02b) tret = 5.33 min; yield 37%: 1H NMR (400MHz, CD3CN, 300K) δ 7.33-7.30 (2H, m), 7.24-7.20 (3H, m), 3.81 (IH, dd, J = 13.2, 3.6 Hz), 2.97 (IH, td, J= 12.4, 3.6 Hz), 2.95-2.85 (2H, m), 2.70-2.60 (2H, m), 2.49 (IH, td, J= 12.4, 3.6 Hz), 2.38 (IH, ddd, J= 10.3, 6.8, 3.5 Hz), 1.59 (IH, ddd, J = 10.4, 6.0, 4.4 Hz), 1.46 (3H, s), 1.41 (IH, dd, J = 13.7, 6.8 Hz). MS (ES+) Ci6Hi9N3O2 requires 285, found: 286 (M+H)+.
Step 3 : iV-(Biphenyl-2-yl)-8a-methyl- 13-dioxo-2-rα£2i?V2-phenylcvclopropyll-hexahvdro imidazo-[l,5-αlpyrazine-7(lH)-carboxamide (13) and corresponding diastereomers: (8a61-N- biphenyl-2-yl-8a-methyl-l,3-dioxo-2-[(16',2i?)-2-phenylcyclopropyllhexahydroimidazo[l,5- αlpyrazine-7(lH)-carboxamide and (8ai?)-Λ/-biphenyl-2-yl-8a-methyl-l,3-dioxo-2-[(16',2i?)-2- phenylcyclopropyllhexahydroimidazo[l,5-αlpyrazine-7(lH)-carboxamide (I3a and I3b).
Compound 13 was prepared following the procedure reported in Example 1 step 6 and the crude was purified by flash column on SiO2 using 50% EtO Ac/Petroleum ether to yield in 77% the desired (13) as a white powder. 1H NMR (400MΗz, OMSO-d6, 300K) δ 8.25 (IH, s), 7.43-7.38 (4H, m), 7.35-7.26 (7H, m), 7.20 (3H, d, J = 7.3 Hz), 4.02-3.90 (IH, m), 3.96-3.90 (IH, d, J = 13.6 Hz), 3.80 (IH, d, J= 13.6 Hz), 2.92-2.80 (2H, m), 2.78-2.73 (IH, m), 2.70-2.65 (IH, m), 2.38-2.30 (IH, m), 1.54 (IH, ddd, J = 10.4, 6.0, 4.4 Hz), 1.38 (IH, dd, J = 14.0, 6.8 Hz), 1.09 (3H, s). MS (ES+) C29H28N4O3 requires 480, found: 481 (M+H)+.
The diasteromers of (13) were separated by chiral SFC purification (column: ChiralCel OJ-H (1x25 cm), flow: 10 ml/min, Tcoi: 35°C, Pcoi: 100 bar, modifier: 40% 1PrOH + 0.4% Et2NH, using CO2 as supercritic eluent). Evaporation of the solvent followed by lyophilization gave as white powders:
First eluted diastereoisomer: tret = 7.40 min; yield 36% 1H NMR (400MHz, OMSO-d6, 300K) δ 8.25 (IH, s), 7.42-7.38 (4H, m), 7.34-7.26 (7H, m), 7.20 (3H, d, J = 7.6 Hz), 4.00 (IH, d, J= 13.2 Hz), 3.95 (IH, d, J= 13.2 Hz), 3.80 (IH, dd, J = 12.9, 2.6 Hz), 2.90 (IH, d, J = 13.0 Hz), 2.83 (IH, dd, , J= 12.9, 3.1 Hz), 2.75 (IH, dd, , J= 12.8, 3.0 Hz), 2.72-2.65 (IH, m), 2.40-2.30 (IH, m), 1.52 (IH, ddd, J = 10.4, 6.0, 4.4 Hz), 1.38 (IH, dd, J = 13.6, 6.8 Hz), 1.10 (3H, s). MS (ES+) C29H28N4O3 requires 480, found: 481 (M+H)+.
Second eluted diastereoisomer: tret = 8.93 min; yield 41% 1U NMR (400MHz, OMSO-d6, 300K) δ 8.25 (IH, s), 7.42-7.38 (4H, m), 7.34-7.25 (7H, m), 7.20 (3H, d, J = 7.4 Hz), 4.00 (IH, d, J = 12.4 Hz), 3.95 (IH, d, J = 13.0 Hz), 3.80 (IH, dd, J= 12.8, 2.4 Hz), 2.89 (IH, d, J= 12.4 Hz), 2.84 (IH, dd, J = 13.0, 3.0 Hz), 2.76 (IH, dd, J = 12.6, 2.8 Hz), 2.72-2.65 (IH, m), 2.40-2.30 (IH, m), 1.54-1.46 (IH, m), 1.38 (IH, dd, J = 13.6, 7.0 Hz), 1.09 (3H, s). MS (ES+) C29H28N4O3 requires 480, found: 481 (M+H)+. EXAMPLE 60
8a-methyl-l,3-dioxo-2-[flS,2R)-2-phenylcvclopropyll-7V-fl-phenyl-lH-pyrazol-5- yl)hexahvdroimidazo[l,5-alpyrazine-7flH)-carboxamide ( Jl) and the corresponding diastereomers: f8aS)-8a-methyl-l,3-dioxo-2-[flS,2R)-2-phenylcvclopropyll-7V-fl-phenyl- lH-pyrazol-5-yl)hexahvdroimidazo[l,5-alpyrazine-7flH)-carboxamide and (8a/?)-8a- methyl-l,3-dioxo-2-[flS,2R)-2-phenylcvclopropyll-7V-fl-phenyl-lH-pyrazol-5- yl)hexahvdroimidazo[l,5-alpyrazine-7flH)-carboxamide ( JIa and JIb)
Compound Jl was prepared from 12 following the procedure reported in Example 7 step 2 and the crude was purified by flash column on SiO2 using 30-80% EtO Ac/Petroleum ether to yield in 79% the desired (Jl) as a white powder. 1H NMR (300MΗz, OMSO-d6, 300K) δ 8.75 (IH, s), 7.61 (IH, d, J = 2.2 Hz), 7.56-7.44 (4H, m), 7.40-7.32 (lH,m), 7.30-7.25 (2H, m), 7.25-7.18 (3H, m), 6.27 (IH, d, J = 2.2 Hz), 4.10-3.93 (2H, m), 3.84 (IH, d, J = 12.6 Hz), 3.03 (IH, d, J = 13.4 Hz), 2.96-2.90 (IH, m), 2.83 (IH, d, J= 12.3 Hz) 2.74-2.66 (IH, m), 2.40-2.30 (IH, m), 1.58- 1.48 (IH, m), 1.40 (IH, dd, J = 13.5, 6.9 Hz), 1.18 (3H, s). MS (ES+) C26H26N6O3 requires 470, found: 471 (M+H)+.
The diasteromers of (Jl) were separated by chiral SFC purification (column: Chiralpak IA (1 x 25 cm), flow: 10 ml/min, T∞i: 35°C, Pcoi: 100 bar, modifier: 28% MeOH+ 0.2% Et2NH, using CO2 as supercritic eluent). Evaporation of the solvent followed by lyophilization gave as white powders:
First eluted diastereoisomer: tret = 5.11 min; yield 43%. 1H NMR (400MHz, OMSO-d6, 300K) δ 8.78 (IH, s), 7.62 (IH, d, J = 1.8 Hz), 7.56-7.44 (4H, m ), 7.40-7.32 (IH, m), 7.32-7.26 (2H, m), 7.23-7.16 (3H, m), 6.27 (IH, d, J = 1.8 Hz), 4.08-4.02 (IH, m), 3.97 (IH, d, J = 13.2 Hz), 3.85 (IH, dd, J = 13.2, 2.8 Hz), 3.04-3.00 (IH, d, J = 13.2 Hz), 3.00-2.90 (IH, m) 2.84-2.74 (IH, m), 2.72-2.66 (IH, m), 2.40-2.30 (IH, m), 1.55-1.47 (IH, m), 1.44-1.36 (IH, dd, J = 14.2, 7.2 Hz), 1.19 (3H, s). MS (ES+) C26H26N6O3 requires 470, found: 471 (M+H)+.
Second eluted diastereoisomer: tret = 6.47 min; yield 36%. 1H NMR (400MHz, OMSO-d6, 300K) δ 8.66 (IH, s), 7.59 (IH, d, J = 1.8 Hz), 7.56-7.54 (2H, m ), 7.50-7.45 (2H, m ), 7.36-7.35 (IH, m), 7.30-7.26 (2H, m), 7.25-7.16 (3H, d, J = 13.3 Hz), 6.27 (IH, d, J = 1.8 Hz), 4.08-3.96 (2H, m), 3.86 (IH, d, J = 13.6Hz), 3.04-3.00 (IH, d, J = 13.3 Hz), 2.98-2.92 (IH, m) 2.84-2.74 (IH, m), 2.76-2.70 (IH, m), 2.42-2.36 (IH, m), 1.60-1.54 (IH, m), 1.42-1.36 (IH, m), 1.19 (3H, s). MS (ES+) C26H26N6O3 requires 470, found: 471 (M+H)+.
EXAMPLE 61 l,3-Dioxo-2-[flS,2/?)-2-phenylcvclopropyll-7V-f4-phenylisoxazol-5-yl)hexahvdroimidazo ri-,5-fllpyrazine-7(lH)-carboxamide (Kl) 4-Phenylisoxazol-5-amine (2 eq) was dissolved in THF (0.1M) and treated with LiHMDS (O. IN, 2 eq), after stirring for Ih CDI (leq) was added. The suspension was stirred for a further 2 h and then A5 (1 eq, 0.1 M) was added and the reaction stirred 5h. The reaction was quenched with sat. aq. NH4Cl solution and then extracted with EtOAc. Organic layers were washed with brine, dried and concentrated under reduced pressure. The crude material was purified by preparative RP- HPLC using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents. The desired fractions were lyophilized to afford the title compound in 30% yield. 1H NMR (400 MHz, DMSO, 300K) δ 9.68 (IH, s), 9.00 (IH, s), 7.54 (2H, m), 7.43 (2H, m), 7.30 (3H, m), 7.23 (3H, m), 4.35 (IH, m), 4.16-4.06 (2H, m), 3.17-2.88 (3H, m), 2.69 (IH, m), 2.42-2.31 (IH, m), 1.61-1.49 (IH, m), 1.45- 1.39 (IH, m). MS (ES+) C25H23N5O4 requires 457, found: 458 (M+H)+.
EXAMPLE 62
(SaSri-N-M-CMoro-l-CYtioOroOYiOYridm^-YYi-ia-dioxo-l-UlSJR)-!- phenylcvclopropyllhexahydroimidazorLS-fllpyrazine-TflHVcarboxamide (L2) Step 1 : 4-Chloro-2-cyclopropylpyridin-3 -amine (Ll)
Following a modified synthetic procedure reported in J. Org. Chem. 2003, 68, 5534 a mixture of 2-bromo-4-chloropyridin-3-amine (prepared as described in £752002/0119982) (1.0 eq.), cyclopropylboronic acid (2.0 eq.), Cs2CO3 (3.0 eq.) and PdCl2(dppf)-CΗ2Cl2 adduct (0.1 eq.) in 10:1 solution THF:H2O (0.14 M) was put in a 10-mL glass vial equipped with a small magnetic stirring bar. The reaction vessel was fitted with a rubber septum, was evacuated and back-filled with argon and sealed with an aluminum/Teflon crimp top. The reaction mixture was then irradiated for 1 h at 120 0C, using an irradiation power of 100 W. After completion of the reaction, the vial was cooled to 50 0C with air jet cooling before it was opened. The reaction mixture was diluted with EtOAc and filtered on a pad of Solca Floc®200FCC. The crude product was purified by flash chromatography eluting with 5-100% EtO Ac/petroleum ether affording the titled compound as yellow oil. 1H-NMR (400 MHz, DMSO-d6, 300K) δ 7.59 (IH, d, J = 5.1 Hz), 7.04 (IH, d, J = 5.1 Hz), 5.42 (2H, br. s), 2.24-2.15 (IH, m), 0.92-0.82 (4H, m). MS (ES) C8H9ClN2 requires: 168, found: 169, 171 (M+H)+. Step 2: (8a^-N-(4-Chloro-2-cvclopropylpyridin-3-yl)-1.3-dioxo-2-r(l&2i?)-2-phenylcvclo propyllhexahydroimidazo[l ,5-αlpyrazine-7(lH)-carboxamide (L2)
Ll (1.0 eq.) and DIPEA (5.0 eq.) in DCM (0.1M) was slowly added to an ice cooled solution of triphosgene (0.33 eq.) in DCM (0.1M). The reaction mixture was stirred 30 min at RT and slowly added to a solution of Example 4, D2 (0.5 eq) and DIPEA (0.5 eq) in DCE (0.1M). The reaction mixture was stirred 3h at RT, volatiles were removed under reduced pressure and the crude product was purified by preparative RP-HPLC using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents. The desired fractions were lyophilized to afford the title compound as a white powder. 1H-NMR (400 MHz, DMSO-de, 300K) δ 8.80 (IH, br. s), 8.24 (IH, d, J = 5.1 Hz), 7.34 (IH, d, J = 5.1 Hz), 7.32-7.26 (2H, m), 7.25-7.17 (3H, m), 4.39 (IH, dd, J = 4.1 and 13.0 Hz), 4.17-4.06 (2H, m), 3.97-3.90 (IH, m), 3.12-2.88 (3H, m), 2.72-2.65 (IH, m), 2.43-2.35 (IH, m), 2.30-2.20 (IH, m), 1.55-1.47 (IH, m), 1.45-1.38 (IH, m), 0.98-0.90 (4H, m). MS (ES) C24H24ClN5O3 requires: 465, found: 466, 468 (M+H)+.
EXAMPLE 63
(8aS)-7V-r^-l-Acetyl-4-phenylpyrrolidin-3-yll-l,3-dioxo-2-rαS,2R)-2- phenylcyclopropyllhexahydroimidazori.,5-fllpyrazine-7(lH)-carboxamide (M3)
Step 1 : tert-butyi (l-acetyl-4-phenylpyrrolidin-3-yl)carbamate (Ml)
To an ice cooled stirred solution of tert-butyl (4-phenylpyrrolidin-3-yl)carbamate (prepared as described in J. Med. Chem. 1993, 36, 4139 starting from (2£)-3-phenylprop-2-enoic acid) (1.0 eq.) in dry DCM (0.1M) were slowly added acetyl chloride (4.0 eq.) and DIPEA (4.0 eq.). The reaction mixture was stirred for Ih at RT, then diluted with DCM, washed with sat. aq. NaHCO3 sol, water and brine. The solution was dried (Na2SO4), filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography eluting with 5- 100% EtO Ac/petroleum ether, then eluting with 0- 10% MeOH/EtOAc affording the titled compound as yellow oil. MS (ES) CnH24N2O3 requires: 304, found: 305 (M+H)+. Step 2: l-Acetyl-4-phenylpyrrolidin-3 -amine (M2)
A stirred solution of Ml (1.0 eq.) in 10%TFA/DCM (0.1M) was stirred for Ih at RT. The volatiles were removed under reduced pressure and the crude product was purified by SCX Isolute® cartridge affording the titled compound as yellow oil. MS (ES) Ci2Hi6N2O requires: 204, found: 205 (M+H)+.
Step 3 : (8aS)-N-\(E)- 1 -AcetyM-phenylpyrrolidin-S-yll- 1.3-dioxo-2-r(ltS'.2i?)-2-phenylcvclo propyl"|hexahydroimidazo|"l ,5-α1pyrazine-7(lH)-carboxamide (M3) A solution of M2 (1.0 eq.) and DIPEA (3.0 eq.) in DCM (0.1M) was slowly added to an ice cooled solution of triphosgene (0.33 eq.) in DCM (0.1M). The reaction mixture was stirred 30 min at RT and slowly added to a solution of Example 4, D2 (0.5 eq) and DIPEA (0.5 eq) in DCE (0.1M). The reaction mixture was stirred 3h at RT, volatiles were removed under reduced pressure and the crude product was purified by flash chromatography eluting with 5-100% EtO Ac/petroleum ether, then 0-10% MeOH/EtOAc affording the titled compound as a white powder. 1H-NMR (300 MHz, DMSO-de, 300K) δ 7.38-7.15 (1OH, m), 7.06-6.90 (IH, m), 4.45- 4.12 (2H, m), 4.02-3.68 (4.5H, m), 3.62-3.20 (3H, m overlapped to the water signal), 3.14-3.03 (0.5H, m), 2.91-2.60 (4H, m), 2.42-2.30 (IH, m), 1.96 (3H, s), 1.56-1.44 (IH, m), 1.44-1.32 (IH, m). MS (ES) C28H3IN5O4 requires: 501, found: 502 (M+H)+.
EXAMPLE 64 f8aS)-7-[fl-Methylcyclopropyl)carbonyll-2-[flS,2R)-2-phenylcyclopropylltetrahydro imidazori,5-fllpyrazine-l,3(2H,5H)-dione (Nl) To a 0.2 M solution of Example 4, D2 (1 eq) in DMF were added 1- methylcyclopropanecarboxylic acid (1.1 eq), DIPEA (2.5 eq) and TBTU (1.5 eq). The reaction mixture was stirred at RT for 12 h. The crude product was purified by preparative RP-HPLC using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents, affording the title compound. IH NMR (300 MHz, DMSO-d6, 300K) δ: 7.27-7.09 (5H, m), 4.42-4.32 (IH, m), 4.19 (IH, d, J= 9.3 Hz), 4.05-3.95 (IH, m), 3.91-3.82 (IH, m), 2.97-2.81 (3H, m), 2.65-2.57 (IH, m), 2.36-2.26 (IH, m), 1.49-1.40 (IH, m), 1.39-1.30 (IH, m), 1.18 (3H, s), 0.83-0.76 (2H, m), 0.54-0.48 (2H, m). MS (ES) C20H23N3O3 requires: 353, found: 354 (M+H)+.
EXAMPLE 65
(8aS)-7-α,2-Dimethylpropyl)-2-rαS,2R)-2-phenylcvclopropylltetrahvdro imidazo fl,5- alpyrazine-l,3(2H,5H)-dione (Ql)
To a stirred solution of Example 4, D2 (1 eq) and TEA (1.1 eq) in DCM (0.08M) was added pivaloyl chloride (2.1 eq) and the reaction mixture was stirred at 25 0C for 2h. The crude product was purified by preparative RP-ΗPLC using H2O (0.1 % TFA) and MeCN (0.1 % TFA) as eluents, affording the title compound. IH NMR (400 MHz, DMSO-d6, 300K) 7.48-7.18 (5H, m), 4.75-4.63 (IH, m), 4.42-4.33 (IH, m), 4.05-3.93 (2H, m), 3.15-2.80 (3H, m), 2.72-2.63 (IH, m), 2.50-2.38 (IH, m), 1.58-1.51 (IH, m), 1.48-1.38 (IH, m), 1.35 (9H, s). MS (ES) C20H25N3O3 requires: 354 found: 355 (M+H)+.
EXAMPLE 66 f8aS)-N-fl-Acetyl-3-phenylpiperidin-4-yl)-l,3-dioxo-2-[flS.,2R)-2-phenylcvclopropyllhexa hydroimidazo[l,5-alpyrazine-7flH)-carboxamide (P2) Step 1 : 4-({[(8a61-l,3-Dioxo-2-[(16',2i?)-2-phenylcyclopropyllhexahydroimidazo[l,5-αlpyrazin- 7(lH)-yllcarbonyl|amino)-3-phenylpiperidinium trifluoroacetate. (Pl)
The title compound was prepared, as described in Example 4 starting from tert-butyi 4-amino-3- phenylpiperidine-1-carboxylate. After workup the crude product was treated with a mixture of DCM:TFA (1 :1, 0.1M) and the reaction mixture was stirred for 30 min at RT. Volatiles were removed under reduced pressure and the crude product was purified by preparative RP-HPLC using H2O (0.1 % TFA) and MeCN (0.1 % TFA) as eluents. The desired fractions were lyophilized to afford the title compound in 33% yield. 1H NMR (300 MHz, DMSO-de, 300K) (mixture of conformers) δ 9.08-8.75 (IH, m), 8.58-8.35 (IH, m), 7.30-7.07 (1OH, m), 6.68 (0.5H, d, J = 8.7 Hz), 6.48 (0.5H, t, J = 8.6 Hz), 4.25 (0.5H, m), 4.15-3.88 (1.5H, m), 3.86-3.50 (3.5H, m), 3.30-2.88 (5.5H, partially under water, m), 2J8-.249 (2.5H, m), 2.34-2.14 (1.5H, m), 2.05- 1.90 (IH, m), 1.80-1.57 (IH, m), 1.39 (IH, m), 1.30 (IH, m). MS (ES+) C27H31N5O3 requires 473, found: 474 (M+H)+.
Step 2: (8aS)-N-(l-Acetyl-3-phenylpiperidin-4-yl)-1.3-dioxo-2-r(lS.2R)-2-phenylcvclopropyll hexahydroimidazori,5-alpyrazine-7(lH)-carboxamide (P2). To a solution of Pl (1 eq) and DIPEA (2 eq) in DCM (0.1M) at 0° C were added acetyl chloride (4 eq) and DIPEA (4 eq). After 30 min stirring at RT, the reaction was diluted with DCM, washed with sat. aq. NaHCOs solution (2x) and water. The organic layer was concentrated under reduced pressure. The compound was lyophilized from a 1 :1 mixture CH3CN/H2O to afford the title compound in 68% yield. 1H NMR (400 MHz, DMSO-d6, 300K) (mixture of conformers) δ 7.38-7.28 (5H, m), 7.27-7.19 (5H, m), 6.63 (0.5H, d, J = 8.7 Hz), 6.40-6.49 (0.5H, m), 4.51 (0.25H, d, J = 12.8 Hz), 4.41 (0.25H, d, J = 11.4 Hz), 4.28-3.40 (7H, m), 3.36-3.24 (m, IH), 3.23-3.18 (m, 0.25H), 3.08-3.00 (m, 0.25H), 2.85-2.56 (5H, partially under solvent, m), 2.43- 2.28 (1.3H, m), 2.10 (2.3H, m), 2.00 (0.7H, s), 1.96-1.84 (0.7H, m), 1.83-1.62 (IH, m), 1.52 (IH, m), 1.42 (IH, m). MS (ES+) C29H33N5O4 requires 515, found: 516 (M+H)+.
The compounds in the following table were made according to the procedures described above.
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
The compounds in the following table were made according to the procedures described above:
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001

Claims

1. A compound of structural formula I:
Figure imgf000074_0001
(I)
wherein: each of m and n is independently 1 or 2; each of w, y and z is independently 0, 1 or 2; x is 0 or 1 ;
A is C3-7cycloalkyl or fluoroC3-7cycloalkyl;
L is -(X=O)a(NR7)b(O)c(CR8R9)d(NR7)e-; a is 0 or 1 ; b is 0 or 1 ; c is 0 or 1 ; d is O, 1, 2, 3, 4, 5 or 6; e is 0 or 1 ;
R1 is Ci_6alkyl, haloCi-βalkyl or a ring which is: Cβ-ioaryl; C3_iocycloalkyl; oxetanyl; 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; a 6 membered heteroaromatic ring containing one, two or three N atoms; or a 7-15 membered unsaturated, partially saturated or saturated 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 or three groups independently selected from
R 10
R2 is a C1-10alkyl, haloCi_ioalkyl, Ci-ealkylmercaptoCi-βalkyl, C2-ioalkenyl or a ring which is: C3_iocycloalkyl; Cβ-ioaryl; oxetanyl; 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; 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 R11; each of R3, R4, R5 and R6 is independently Ci_6alkyl, C2-ioalkenyl, haloCi-βalkyl, hydroxyCi_6alkyl, Ci_6alkoxy, Ci_6alkoxyCi_6alkyl, carboxy, CO2Ra, CONRaRb, S(O)rRa or S(O)rNRaRb; r is 0, 1 or 2; R7 is hydrogen or Ci_6alkyl; each of R8 and R9 is independently hydrogen, d-βalkyl, Ci_6alkoxy, Ci_6alkoxycarbonyl or haloCi-βalkyl; each R10 is independently hydroxy, cyano, halogen, Chalky!, haloCi-βalkyl, ORa or
NRaRb each R , 11 is independently hydroxy, oxo, cyano, halogen, d-βalkyl, d-βalkylcarbonyl, C2- loalkenyl, C2-i0alkynyl, haloCi_6alkyl, hydroxyd_6alkyl, carboxy, nitro, ORa, NRaRb, NRaCORb, NRaS(O)rRb, NRaS(O)rNRaRb, CO2Ra, CONRaRb, S(O)rRa, S(O)rNRaRb or a ring which is: C3_iocycloalkyl, Cβ-ioaryl, Cβ-ioaryloxy, Cβ-ioarylCi-βalkoxy, C6-ioarylCi_6alkyl, 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 of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, Ci_6alkyl, Ci_6alkylsulfonyl, haloCi_ βalkyl, Ci_6alkoxy and haloCi-βalkoxy; X is C or S=O; each of Ra and Rb is independently hydrogen, d-βalkyl, Ci_6alkylcarbonyl, haloCi-βalkyl, hydroxyCi-βalkyl, C3_iocycloalkyl or Cβ-ioaryl, any of which rings being optionally substituted by one, two or three groups independently selected from halogen and Ci_6alkyl; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
2. A compound of claim 1 of formula II:
Figure imgf000076_0001
(H) wherein m, n, d, w, x, y, z, A, R . 1 , τ R-> 2 , τ R-> 33, τ R-> 44, τ R-> 5D, τ R-> 60, τ R-> 7', R8 and R are as defined in claim i; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
3. A compound of claim 1 of formula IV:
Figure imgf000076_0002
(IV) wherein: m, n, d, w, x, y, z, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined in claim 1; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
4. A compound of claim 1 of formula V:
Figure imgf000076_0003
(V) wherein: d, w, x, y, z, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined in claim 1; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
5. A compound of claim 1 of formula VII:
Figure imgf000077_0001
wherein: dd,, qq,, ww,, x, y, z, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are as defined in claim 1; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
6. A compound of any previous claim wherein R2 is d-salkyl, Ci-ealkylmercaptoCi-βalkyl, C2-6alkenyl or a ring which is: phenyl, cyclohexyl, pyrazolyl, pyridinyl, benzodioxolyl, isoxazolyl, pyrrolidinyl, cyclopropyl, piperidinyl, tetrahydrothiopyranyl, oxazolyl, tetrahydronaphthalenyl, tetrahydroquinolinyl, tetrahydropyranyl, cyclopentyl or bicycloheptyl; any of which rings being optionally substituted by one, two or three groups independently selected from R11.
7. A compound of any previous claim wherein R11 is cyano, halogen, Ci_6alkyl, C2- loalkenyl, haloCi_6alkyl, ORa, NRaRb, CO2Ra, S(O)rRa or a ring which is: C6-i0aryl, C6-i0arylCi_ βalkoxy, or 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; any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, C^aUcyl, haloCi-βalkyl, Ci_6alkoxy and haloCi-βalkoxy.
8. A pharmaceutical composition comprising a compound of any previous claim, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof in association with a pharmaceutically acceptable carrier.
9. A combination of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof and an anti-cancer agent for simultaneous, separate or sequential administration.
10. A compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof for use in therapy.
11. A compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof for use in the treatment or prevention of conditions which can be ameliorated by Smo antagonism.
12. A compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof for use in the treatment or prevention of cancer.
13. A compound as defined in claim 12 wherein the cancer is selected from basal cell carcinoma, medulloblastoma, prostate, pancreatic, breast, colon, small cell lung cancers, sarcoma, lymphomas, leukemia, gastrointestinal cancer, multiple myeloma, glioma, heptacellular, sporadic and familial basal cell carcinomas, sporadic medulloblastoma, meningiomas, breast carcinoma, esophageal squamous cell carcinoma and bladder cancer.
14. The use of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof for the manufacture of a medicament for the treatment or prevention of cancer.
15. A method of treating or preventing cancer, which method comprises administration to a patient in need thereof of an effective amount of a compound of claim 1 or a composition comprising a compound of claim 1.
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