WO2014043608A2 - Smoothened modulators and methods of use thereof - Google Patents

Smoothened modulators and methods of use thereof Download PDF

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WO2014043608A2
WO2014043608A2 PCT/US2013/059905 US2013059905W WO2014043608A2 WO 2014043608 A2 WO2014043608 A2 WO 2014043608A2 US 2013059905 W US2013059905 W US 2013059905W WO 2014043608 A2 WO2014043608 A2 WO 2014043608A2
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compound
amino
group
alkyl
halo
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PCT/US2013/059905
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French (fr)
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WO2014043608A3 (en
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Wei Chen
Jiangbo Wang
Robert A. Mook, Jr.
Lawrence S. Barak
H. Kim Lyerly
Anthony Angelo RIBEIRO
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Duke University
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Priority to CA2878082A priority Critical patent/CA2878082A1/en
Priority to US14/405,614 priority patent/US9512106B2/en
Priority to EP13837339.4A priority patent/EP2895474B1/en
Publication of WO2014043608A2 publication Critical patent/WO2014043608A2/en
Publication of WO2014043608A3 publication Critical patent/WO2014043608A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0618—Cells of the nervous system
    • C12N5/0619—Neurons
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2500/00—Specific components of cell culture medium
    • C12N2500/30—Organic components
    • C12N2500/46—Amines, e.g. putrescine

Definitions

  • Hh signaling pathway The evolutionarily conserved Hedgehog (Hh) signaling pathway is essential for embryonic development, tissue homeostasis, and maintenance of self-renewal potential in adult stem cells 1 '3 .
  • Hh protein Hh protein
  • Ptc receptor Patched
  • Smo effector receptor Smoothened
  • dysregulation of Hh signaling resulting from mutations in components of the pathway has been directly implicated in the development of basal cell carcinoma and medulloblastoma 6"10
  • High levels of pathway activity are observed in cancers of the pancreas, proximal gastrointestinal tract, and prostate 1 1"13 .
  • mice In mice, about 14-30% of Ptc heterozygous knockout mice develop medulloblastoma and the homozygous deletion of Ptc in GFAP-positive progenitor cells resulted in the development of medulloblastoma in 100% of genetically engineered mice 14"15'
  • GDC-0449 (Vismodegib) was recently approved by the FDA to treat patients with advanced basal cell carcinoma22-24.
  • D473H Asp to His point mutation
  • the Smo-D473H mutant receptor is refractory to inhibition by GDC-0449 due to loss of interaction between the drug and receptor 17,25 .
  • Hh signaling pathway A mechanistic understanding of the Hh signaling pathway has evolved over the past decade 26 .
  • the Hedgehog family of growth factor proteins is comprised of 3 members: Sonic Desert, and Indian Hedgehog, each known to bind the transmembrane receptor Ptc.
  • the unoccupied transmembrane receptor Ptc inhibits the activity of the transmembrane protein Smo.
  • Smo Upon binding of Hh ligand to its receptor Ptc, Smo becomes activated and transduces signaling by activating Gli transcription factors that results in the modulation of Hh responsive genes such as Myc and Ptc.
  • Afirst aspect of the present invention is compounds (sometimes also referred to as "active
  • Y is C or N
  • Z is C or N
  • ring C is, with the associated N, aheterocyclo group
  • R, R 3 R , R , R , R each R , each R , and each R are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyi, aryl, arylalkyl, arylalkenyl, arylalkynyi, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroaryialkynyl, alkoxy, halo, mercapto, azido, cyano, formyl, carboxylic acid, hydroxyl, nitro, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino,
  • Q is heteroaryl, preferably pyridyl
  • n, m , and m are each integers of zero, 1, 2 or 3;
  • n is an integer of from zero or 1 to 7, preferably 2;
  • n 1 is an integer of from one to six, preferably 2;
  • n is an integer of 1 ,2 or 3;
  • a further aspect of the present invention is a composition comprising an active compound as described herein in a pharmaceutically acceptable carrier.
  • a further aspect of the present invention is a method of inhibiting the hedgehog pathway in a cell, comprising contacting the cell with an active compound as described herein
  • a further aspect of the present invention is a method for inhibiting unwanted proliferation of a cell, comprising contacting the cell with an active compound as described herein..
  • FIG. 1 Identification of novel Smo inhibitors in U20S cells. Inhibitors are detected by the homogenous distribution of the green punctate pattern that results when the intracellular association of Parr2-GFP with Smo is inhibited. Confocal images of U20S cells stably expressing (A) parr2-GFP alone, or (B-D) parr2-GFP co-expressed with Smo-633. Cells were treated for 6 hours with DMSO (B); 5 ⁇ cyclopamine (Cyc) (C); or 5 ⁇ compound A8 (D). Scale bar: 10 ⁇ .
  • FIG. 3 Compound A8 competitively displaces [3H] -cyclopamine binding to wild- type Smo and mutant Smo-D473H.
  • Competitive binding of [3 H] -cyclopamine with Smo antagonists was performed in fixed U20S cells overexpressing wild-type Smo (A) and Smo- D473H (B). Data were normalized to the maximal binding of [3H] -cyclopamine over baseline. The displacement data were analyzed by fitting to a one-site competition curve using Graphpad Prism. Data were acquired in triplicates from three independent experiments and are presented as the mean ⁇ SEM.
  • FIG. 4 Compound A8 inhibits Gli-reporter activity and GCP proliferation.
  • A Gli- luciferase response in Shh-LIGHT2 cells treated for 30 hours with Shh in the absence or presence of increasing concentrations of cyclopamine (Cyc), GDC-0449, or A8.
  • B GCP cells were treated for 48 hours with Shh in the absence or presence of increasing concentrations of Cyc, GDC-0449, or A8. Cells were then exposed to [3 H] -thymidine for 16 h and [3H]-thymidine incorporation was measured. Data were fit using Graphpad Prism (mean ⁇ SEM, n - 3).
  • Alkyl refers to a straight or branched chain hydrocarbon containing from I to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
  • Lower alkyl as used herein, is a subset of alkyl, in some embodiments preferred, and refers to a straight or branched chain hydrocarbon group containing from 1 to 4 carbon atoms.
  • Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like.
  • akyl or “Ioweralkyi” is intended to include both substituted and unsubstituted alkyl or Ioweralkyi unless otherwise indicated and these groups may be substituted with groups selected from halo (e.g., haloalkyl), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl lkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy (thereby creating a polyalkoxy such as polyethylene glycol), alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkyialkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(0) m , haloalkyl-S(0) m , alkenyl-S(0)
  • Alkylene bridge refers to a straight or branched chain hydrocarbon bridging species containing from 1 to 10 carbon atoms. Representative examples include, but are not limited to, C 1-C5 bridges such as -(CH 2 ) n - where n is 1 or 2 to 3, 4 or 5.
  • alkylene bridge is intended to include both substituted and unsubstituted unless otherwise indicated and may be substituted with groups selected from halo (e.g., haloalkyl), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxy!, alkoxy (thereby creating a polyalkoxy such as polyethylene glycol), alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkyialkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(0) m , haloalkyl- S(0) m , alkenyl-S(0) m , alkynyl-S(0) m , cycloal
  • alkyl is specifically intended to include haloalkyl such as fluoroalkyl (e.g.,-CH 2 F, -CHF 2j -CH2CF3, etc.), and specifically intended to include perhaloalkyl such as perfluoroalkyl (e.g., -CF 3 , -CF 2 CF 3 , etc.).
  • fluoroalkyl e.g.,-CH 2 F, -CHF 2j -CH2CF3, etc.
  • perhaloalkyl such as perfluoroalkyl (e.g., -CF 3 , -CF 2 CF 3 , etc.).
  • alkenyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms (or in loweralkenyl 1 to 4 carbon atoms) which include 1 to 4 double bonds in the normal chain.
  • alkenyl include, but are not limited to, vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4- pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2,4-heptadiene, and the like.
  • alkenyl or “loweralkenyl” is intended to include both substituted and unsubstituted alkenyl or loweralkenyl unless otherwise indicated and these groups may be substituted with groups as described in connection with alkyl and loweralkyl above.
  • Alkynyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms (or in loweralkynyl 1 to 4 carbon atoms) which include 1 triple bond in the normal chain.
  • Representative examples of alkynyl include, but are not limited to, 2-propynyl, 3-butynyl, 2- butynyl, 4-pentynyl, 3- pentynyl, and the like.
  • alkynyl or “loweralkynyl” is intended to include both substituted and unsubstituted alkynyl or Ioweralknynyl unless otherwise indicated and these groups may be substituted with the same groups as set forth in connection with alkyl and loweralkyl above.
  • Cycloalkyl refers to a saturated or partially unsaturated cyclic hydrocarbon group containing from 3, 4 or 5 to 6, 7 or 8 carbons (which carbons may be replaced in a heterocyclic group as discussed below).
  • Representative examples of cycloalkyl include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyi, cycloheptyl, and cyclooctyl.
  • Bicyclic and tricyclic ring systems are also included. These rings may be optionally substituted with additional substituents as described herein such as halo or loweralkyl.
  • the term “cycloalkyl” is generic and intended to include heterocyclic groups as discussed below unless specified otherwise.
  • Heterocyclo refers to an aliphatic (e.g., fully or partially saturated heterocyclo) or aromatic (e.g., heteroaryl) monocyclic- or a bicyclic-ring system.
  • Monocyclic ring systems are exemplified by any 5 or 6 membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, The 5 membered ring has from 0-2 double bonds and the 6 membered ring has from 0-3 double bonds.
  • monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine,
  • Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein.
  • Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3-benzodioxole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, purine, pyranopyridine, quinoiine, quinoliz
  • These rings include quaternized derivatives thereof and may be optionally substituted with groups selected from halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(0) m , halo alkyl- S(0) m , alkenyl- S(0) m , alkynyl-S(0) m , cycloalkyl-S(0) m , cycloalkylalkyl-S(0) m , aryl-S(0) m , arylalky
  • Aryl refers to a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused ring system having one or more aromatic rings.
  • Representative examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like.
  • aryl contains a "hetero” atom and is also a "heterocyclo" group as described above.
  • aryl is intended to include both substituted and unsubstituted aryl unless otherwise indicated and these groups may be substituted with the same groups as set forth in connection with alkyl and loweralkyl above. More specifically, "aryl" groups as used herein may be substituted 1, 2, 3, or 4 or more times with independently selected halo (e.g., haloaryl), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy (thereby creating a polyalkoxy such as polyethylene glycol), alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, aIkyl
  • Arylalkyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.
  • Arylaryl refers to a monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a ring system in which two or more identical or non-identical parent aromatic ring systems are joined directly together by a single bond, where the number of such direct ring junctions is one less than the number of parent aromatic ring systems involved. Any “aryl” may be used, substituted or unsubstituted, and optionally containing a heteroatom, as described above.
  • Typical arylaryl groups include, but are not limited to, biphenyl, tnphenyl, phenyl-naphthyl, binaphthyi, biphenyl-naphthyl, and the like, which may be substituted or unsubstituted as described in connection with aryl above. Where the number of carbon atoms in an arylaryl group are specified, the numbers refer to the carbon atoms comprising each parent aromatic ring.
  • (C 5 -C ⁇ ) arylaryl is an arylaryl group in which each aromatic ring comprises from 5 to 14 carbons, e.g., biphenyl, triphenyl, binaphthyi, phenylnaphthyl, etc.
  • each parent aromatic ring system of an arylaryl group is independently a (C 5 -C 14 ) aromatic, more preferably a (C$ -C 10 ) aromatic.
  • Heteroaryl as used herein is as described in connection with heterocyclo above.
  • Alkoxy refers to an alkyl or loweralkyl group, as defined herein (and thus including substituted versions such as polyalkoxy), appended to the parent molecular moiety through an oxy group, -0-.
  • alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
  • alkoxy is specifically intended to include haloalkoxy such as fluoroalkoxy (e.g.,-OCH 2 F, -OCHF 2 , - OCH 2 CF 3 , etc.), and specifically intended to include perhaloalkoxy such as perfluoroalkoxy (e.g., -OCF 3 , -OCF 2 CF 3) etc.).
  • fluoroalkoxy e.g.,-OCH 2 F, -OCHF 2 , - OCH 2 CF 3 , etc.
  • perhaloalkoxy such as perfluoroalkoxy (e.g., -OCF 3 , -OCF 2 CF 3) etc.).
  • Halo refers to any suitable halogen, including -F, -CI, -Br, and -I.
  • Forml refers to a ⁇ C(0)H group.
  • Carboxylic acid as used herein refers to a -C(0)OH group.
  • Hydrophill refers to an -OH group.
  • Diol as used herein refers to a chemical compound containing two hydroxyl groups.
  • Niro as used herein refers to an -N0 2 group.
  • Acyl as used herein alone or as part of another group refers to a -C(0)R radical, where R is any suitable substituent such as aryl, alkyl, alkenyi, alkynyl, cycloalkyl or other suitable substituent as described herein.
  • Alkylthio refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein.
  • Representative examples of alkylthio include, but are not limited, methylthio, ethylthio, tert-butylthio, hexylthio, and the like.
  • Amino as used herein means the radical -N3 ⁇ 4.
  • Alkylamino as used herein alone or as part of another group means the radical - NHR, where R is an alkyl group.
  • Arylalkylamino as used herein alone or as part of another group means the radical ⁇ NHR, where R is an arylalkyl group.
  • Disubstituted-amino as used herein alone or as part of another group means the radical ⁇ NR a R b , where R a and R 3 ⁇ 4 are independently selected from the groups alkyl, haloalkyl, alkenyi, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl.
  • Acylamino as used herein alone or as part of another group means the radical - NR a R b , where R a is an acyl group as defined herein and R b is selected from the groups hydrogen, alkyl, haloalkyl, alkenyi, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl.
  • Acyloxy as used herein alone or as part of another group means the radical -OR, where R is an acyl group as defined herein.
  • Ester as used herein alone or as part of another group refers to a ⁇ C(0)OR radical, where R is any suitable substituent such as alkyl, cycloalkyl, alkenyi, alkynyl or aryl.
  • Amide as used herein alone or as part of another group refers to a -C(0)NR a R b radical, where R a and R b are any suitable substituent such as alkyl, cycloalkyl, alkenyi, alkynyl or aryl.
  • Sulfoxyl refers to a compound of the formula -S(0)R, where R is any suitable substituent such as alkyl, cycloalkyl, alkenyi, alkynyl or aryl.
  • Sulfonyl refers to a compound of the formula -S(0)(0)R, where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
  • Sulfonate refers to a compound of the formula -S(0)(0)OR, where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
  • Sulfonamide as used herein alone or as part of another group refers to a - S(0) 2 NR a R b radical, where R a and b are any suitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
  • Re as used herein alone or as part of another group refers to an - N(R c )C(0)NR a R b radical, where R a , Rb and Re are any suitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
  • Alkoxyacylamino as used herein alone or as part of another group refers to an - N(R a )C(0)OR b radical, where R a , R b are any suitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
  • aminoacyloxy as used herein alone or as part of another group refers to an - OC(0)NR a Rb radical, where R a and are any suitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
  • Treat refers to any type of treatment that imparts a benefit to a patient afflicted with a disease or disorder, including improvement in the condition of the patient (e.g., in one or more symptoms), delay in the progression of the disease, etc.
  • “Pharmaceutically acceptable” as used herein means that the compound or composition is suitable for administration to a subject to achieve the treatments described herein, without unduly deleterious side effects in light of the severity of the disease and necessity of the treatment.
  • Treat refers to any type of treatment that imparts a benefit to a patient afflicted with a disease or disorder, including improvement in the condition of the patient (e.g., in one or more symptoms), delay in the progression of the disease, etc.
  • Cancer as used herein may be any type of cancer, including but not limited to lung cancer, colon cancer, colorectal cancer, breast cancer, prostate cancer, ovarian cancer, liver cancer, leukemia, lymphoma, etc.
  • “Pharmaceutically acceptable” as used herein means that the compound or composition is suitable for administration to a subject to achieve the treatments described herein, without unduly deleterious side effects in light of the severity of the disease and necessity of the treatment.
  • the present invention is primarily concerned with the treatment of human subjects, but the invention may also be carried out on animal subjects, particularly mammalian subjects such as mice, rats, dogs, cats, livestock and horses for veterinary purposes, and for drug screening and drug development purposes.
  • ring c is, with the associated N, a heterocyclo group (e.g., ring c is selected from the group consisting of piperidinyl, piperazinyl, pyrrolidinyl, pyrrolinyl; imidazolidinyl, pyrazolidinyi, morpholinyl; thiomorpholinyl, etc.)
  • R, R 1 , R 2 , R 3 , R 4 , R 5 each R 6 , each R 7 , and each R 8 are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, arylalkyl, aryialkenyi, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, halo, mercapto, azido, cyano, formyl, carboxylic acid, hydroxyl, nitro, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino,
  • Q is heteroaryl, preferably pyridyl
  • n, m 1 , and m 2 are each integers of zero, 1, 2 or 3;
  • n is an integer of from zero or 1 to 7, preferably 2;
  • n 1 is an integer of from one to six, preferably 2;
  • n is an integer of 1 ,2 or 3;
  • X is C, Y is C, and Z is N; or X is C, Y is N, and Z is C; or X is N, Y is C, and Z is C.
  • X is N, Y is N, and Z is C; or X is N, Y is C, and Z is N; or X is C, Y is N, and Z is N.
  • the compound has the structure of Formula IB and R is heterocyclo.
  • R is selected from the group consisting of:
  • n 3 and m 4 are each independently an integer of zero, 1, 2 or 3;
  • R 9 and each R' is each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, heterocyclo alkynyl, aryl, aryialkyl, arylalkenyl, arylalkynyi, heteroaryl, heteroaryialkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, halo, mercapto, azido, cyano, formyl, carboxylic acid, hydroxyl, nitro, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sul
  • the compound has the structure of Formula IIA or Formula
  • m 3 is an integer of zero, 1, 2 or 3; and each R 9 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocyclo alkenyl, heterocycloalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroaryialkyi, heteroarylalkenyl, heteroarylalkynyl, aikoxy, halo, mercapto, azido, cyano, formyl, carboxylic acid, hydroxyl, nitro, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino,
  • R is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, heterocycloalkenylaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroaryialkyi, heteroarylalkenyl, aikoxy, halo, cyano, hydroxyl, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylammo, acyloxy, ester, amide, suifoxyi, sulfonyl, sulfonamide, urea, alkoxylacylamino, and aminoacyloxy.
  • R is selected from the group consisting of H, alkyl, heterocyclo, heterocycloalkyl, heterocycloalkenylaryl, arylalkyl, heteroaryl, heteroaryialkyi, alkoxyacyl, aryloxy, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, suifoxyi, sulfonyl, sulfonamide, urea, alkoxylacylamino, and aminoacyloxy.
  • R 1 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclo, heterocycloalkyl, heterocyclo alkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroaryialkyi, heteroarylalkenyl, aikoxy, halo, cyano, hydroxyl, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, suifoxyi, sulfonyl, sulfonamide, alkoxylacylamino, and aminoacyloxy.
  • R 1 is selected from the group consisting of H, alkyl, aikoxy, halo, hydroxyl, acyl, amino, alkylamino, disubstituted amino, suifoxyi, sulfonyl, sulfonamide, alkoxylacylamino, and aminoacyloxy.
  • R is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, alkoxy, halo, azido, cyano, hydroxyl, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfoxyl, sulfonyl, sulfonamide, alkoxy lacylamino, and aminoacyloxy.
  • R 2 is selected from the group consisting of H, alkyl, alkoxy, halo, hydroxyl, amino, alkylamino, disubstituted amino, sulfoxyl, sulfonyl, sulfonamide, alkoxylacylamino, and aminoacyloxy.
  • R 3 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, halo, cyano, hydroxyl, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfoxyl, sulfonyl, sulfonamide, alkoxylacylamino, and aminoacyloxy.
  • R 4 is selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, alkoxy, halo, cyano, hydroxyl, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfoxyl, sulfonyl, sulfonamide, alkoxylacylamino, and aminoacyloxy.
  • R 4 is selected from the group consisting of H, alkyl, alkoxy, halo, cyano, hydroxyl, alkylthio, amino, alkylamino, disubstituted amino, sulfoxyl, and sulfonyl.
  • R 5 is selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, heterocyclo alkynyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, alkoxy, halo, cyano, hydroxyl, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfoxyl, sulfonyl, sulfonamide, alkoxylacylamino, and aminoacyloxy.
  • R 5 is selected from the group consisting of H, alkyl, alkoxy, halo, cyano, hydroxyl, alkylthio, amino, alkylamino, disubstituted amino, sulfoxyl, and sulfonyl.
  • each 6 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloaikylalkyl, cycloalkylalkenyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, alkoxy, halo, cyano, hydroxyl, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfoxyl, sulfonyl, sulfonamide, alkoxylacylamino, and aminoacyloxy.
  • each R 6 is independently selected from the group consisting of H, alkyl halo, and
  • each R is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloaikylalkyl, cycloalkylalkenyl heterocyclo, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, alkoxy, halo, cyano, hydroxyl, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfoxyl, sulfonyl, sulfonamide, alkoxylacylamino, and aminoacyloxy.
  • each R 7 is independently selected from the group consisting of H, alkyl, alkoxy, halo, cyano, hydroxyl, amino, alkylamino, disubstituted amino sulfoxyl, and sulfonyl.
  • each R 8 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloaikylalkyl, cycloalkylalkenyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, alkoxy, halo, cyano, hydroxyl, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfoxyl, sulfonyl, sulfonamide, alkoxylacylamino, and aminoacyloxy.
  • each R is independently selected from the group consisting of H, alkyl, halo, and hydroxyl.
  • Examples of compounds of the present invention include, but are not limited to, those set forth in Schemes A to C, and 1 to 15, as follows:
  • the active compounds disclosed herein can, as noted above, be prepared in the form of their pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects. Examples of such salts are (a) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; and salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfo ic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid,
  • the active compounds described above may be formulated for administration in a pharmaceutical carrier in accordance with known techniques. See, e.g., Remington, The Science And Practice of Pharmacy (9 th Ed. 1995).
  • the active compound (including the physiologically acceptable salts thereof) is typically admixed with, inter alia, an acceptable carrier.
  • the earner must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient.
  • the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose formulation, for example, a tablet, which may contain from 0.01 or 0.5% to 95% or 99% by weight of the active compound.
  • One or more active compounds may be incorporated in the formulations of the invention, which may be prepared by any of the well known techniques of pharmacy comprising admixing the components, optionally including one or more accessory ingredients.
  • formulations of the invention include those suitable for oral, rectal, topical, buccal (e.g., sub-lingual), vaginal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), topical ⁇ i.e., both skin and mucosal surfaces, including airway surfaces) and transdermal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular active compound which is being used.
  • Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients as noted above).
  • the formulations of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture.
  • a tablet may be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s).
  • Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
  • Formulations suitable for buccal (sub- lingual) administration include lozenges comprising the active compound in a flavoured base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations of the present invention suitable for parenteral administration comprise sterile aqueous and non-aqueous injection solutions of the active compound, which preparations are preferably isotonic with the blood of the intended recipient. These preparations may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient.
  • Aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents.
  • the formulations may be presented in unit ⁇ dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (Iyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water-for-injection immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • an injectable, stable, sterile composition comprising a compound of Formula (I), or a salt thereof, in a unit dosage form in a sealed container.
  • the compound or salt is provided in the form of a lyophiUzate which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid composition suitable for injection thereof into a subject.
  • the unit dosage form typically comprises from about 10 mg to about 10 grams of the compound or salt.
  • emulsifying agent which is physiologically acceptable may be employed in sufficient quantity to emulsify the compound or salt in an aqueous carrier.
  • emulsifying agent is phosphatidyl choline.
  • Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
  • Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
  • Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. Suitable formulations comprise citrate or bisVtris buffer (pH 6) or ethanol/water and contain from 0.1 to 0.2M active ingredient.
  • the present invention provides liposomal formulations of the compounds disclosed herein and salts thereof.
  • the technology for forming liposomal suspensions is well known in the art.
  • the compound or salt thereof is an aqueous-soluble salt, using conventional liposome technology, the same may be incorporated into lipid vesicles. In such an instance, due to the water solubility of the compound or salt, the compound or salt will be substantially entrained within the hydrophilic center or core of the liposomes.
  • the lipid layer employed may be of any conventional composition and may either contain cholesterol or may be cholesterol -free.
  • the salt may be substantially entrained within the hydrophobic lipid bilayer which forms the structure of the liposome.
  • the liposomes which are produced may be reduced in size, as through the use of standard sonication and homogenization techniques.
  • the liposomal formulations containing the compounds disclosed herein or salts thereof may be lyophilized to produce a iyophihzate which may be reconstituted with a pharmaceutically acceptable carrier, such as water, to regenerate a liposomal suspension.
  • compositions may be prepared from the water-insoluble compounds disclosed herein, or salts thereof, such as aqueous base emulsions.
  • the composition will contain a sufficient amount of pharmaceutically acceptable emulsifying agent to emulsify the desired amount of the compound or salt thereof.
  • Particularly useful emulsifying agents include phosphatidyl cholines, and lecithin.
  • the pharmaceutical compositions may contain other additives, such as pH-adjusting additives.
  • useful pH- adj sting agents include acids, such as hydrochloric acid, bases or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate.
  • the compositions may contain microbial preservatives.
  • Useful microbial preservatives include methylparaben, propylparaben, and benzyl alcohol. The microbial preservative is typically employed when the formulation is placed in a vial designed for multidose use.
  • the pharmaceutical compositions of the present invention may be lyophilized using techniques well known in the art.
  • the compounds of the present invention can be used in like manner as those described in US Patent No. 8, 178,563 to Gao et al, the disclosure of which is incorporated herein by reference.
  • the present invention makes available methods and compounds for inhibiting activation of the hedgehog signaling pathway, e.g., to inhibit aberrant growth states resulting from phenotypes such as Ptc loss-of-function, hedgehog gain-of-function, smoothened gain- of-function or Gli 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 Gli activity e.g., to reverse or control the aberrant growth state.
  • phenotypes such as Ptc loss-of-function, hedgehog gain-of-function, smoothened gain- of-function or Gli gain-of-function
  • Pattern formation is the activity by which embryonic cells form ordered spatial arrangements of differentiated tissues.
  • the physical complexity of higher organisms arises during embryogenesis through the interplay of cell-intrinsic lineage and cell-extrinsic signaling.
  • Inductive interactions are essential to embryonic patterning in vertebrate development from the earliest establishment of the body plan, to the patterning of the organ systems, to the generation of diverse cell types during tissue differentiation.
  • the effects of developmental cell interactions are varied: responding cells are diverted from one route of cell differentiation to another by inducing cells that differ from both the uninduced and induced states of the responding cells (inductions).
  • cells induce their neighbors to differentiate like themselves (homeogenetic induction); in other cases a cell inhibits its neighbors from differentiating like itself.
  • Cell interactions in early development may be sequential, such that an initial induction between two cell types leads to a progressive amplification of diversity.
  • inductive interactions occur not only in embryos, but in adult cells as well, and can act to establish and maintain morphogenetic patterns as well as induce differentiation.
  • the vertebrate family of hedgehog genes includes three members that exist in mammals, known as Desert (Dhh), Sonic (Shh) and Indian (Ihh) hedgehogs, all of which encode secreted proteins. These various Hedgehog proteins consist of a signal peptide, a highly conserved N-terminal region, and a more divergent C-terminal domain. Biochemical studies have shown that autoproteolytic cleavage of the Hh precursor protein proceeds through an internal thio ester intermediate which subsequently is cleaved in a nucleophilic substitution. It is likely that the nucleophile is a small lipophilic molecule which becomes covalently bound to the C-terminal end of the N-peptide, tethering it to the cell surface. The biological implications are profound.
  • N-terminal Hedgehog peptide As a result of the tethering, a high local concentration of N-terminal Hedgehog peptide is generated on the surface of the Hedgehog producing cells. It is this N-terminal peptide which is both necessary and sufficient for short- and long-range Hedgehog signaling activities.
  • An inactive Hedgehog signaling pathway is where the transmembrane protein receptor Patched (Ptc) inhibits the activity of Smoothened (Smo), a seven transmembrane protein.
  • the transcription factor Gli a downstream component of Hh signaling, is prevented from entering the nucleus through interactions with cytoplasmic proteins, including Fused and Suppressor of fused (Sufu).
  • cytoplasmic proteins including Fused and Suppressor of fused (Sufu).
  • Activation of the pathway is initiated through binding of any of the three mammalian ligands (Dhh, Shh or Ihh) to Ptc.
  • Ligand binding results in a reversal of the repression of Smo, thereby activating a cascade that leads to the translocation of the active form of the transcription factor Gli to the nucleus.
  • Nuclear Gli activates target gene expression, including Ptc and Gli itself.
  • Hedgehog signalling in prostate regeneration, neoplasia and metastasis are sufficient to initiate cancer formation and are required for tumor survival.
  • cancers include, but are not limited to, prostate cancer ("Hedgehog signalling in prostate regeneration, neoplasia and metastasis", Karhadkar S S, Boa G S, Abdallah N, Dhara S, Gardner D, Maitra A, Isaacs J T, Berman D M, Beachy P A., Nature. 2004 Oct.
  • medulloblastoma (Medulloblastoma growth inhibition by hedgehog pathway blockade", Berman D M, Karhadkar S S, Hallahan A R, Pritchard J ⁇ , Eberhart C G, Watkins D N, Chen J K, Cooper M K, Taipale J, Olson J M, Beachy P A., Science. 2002 Aug.
  • basal cell carcinoma (Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions", Williams J A, Guicherit O M, Zaharian B I, Xu Y, Chai L, Wichterle H, on C, Gatchalian C, Porter J A, Rubin L L, Wang F Ypen Proc Natl Acad Sci USA. 2003 Apr.
  • pancreatic cancer (“Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis", Thayer S P, di Magliano M P s Heiser P W, Nielsen C M, Roberts D J, Lauwers G Y, Qi Y P, Gysin S, Fernandez-del Castillo C, Yajnik V, Antoniu B, McMahon M, Warshaw A L, Hebrok M remember Nature. 2003 Oct.
  • the present invention further provides a method for preventing or treating any of the diseases or disorders described above in a subject in need of such treatment, which method comprises administering to said subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof for any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.
  • the present invention provides pharmaceutical formulations comprising the active compounds (including the pharmaceutically acceptable salts thereof), in pharmaceutically acceptable carriers for oral, rectal, topical, buccal, parenteral, intramuscular, intradermal, or intravenous, and transdermal administration.
  • the therapeutically effective dosage of any one active agent will vary somewhat from compound to compound, and patient to patient, and will depend upon factors such as the age and condition of the patient and the route of delivery. Such dosages can be determined in accordance with routine pharmacological procedures known to those skilled in the art. In some embodiments, a dosage from about 0.1 or 1.0 to about 250 or 500 mg kg is used, with all weights being calculated based upon the weight of the active compound, including the cases where a salt is employed.
  • the dosage may be administed one any suitable schedule, including but not limited to once, twice, or three times a day.
  • the duration daily dosage may be from one or two days, or one or two weeks, to two, three, or four months, or more, depending on the condition being treated.
  • prodrugs may be administered directly, or as prodrugs thereof.
  • Pharmaceutically acceptable prodrugs as used herein refers to those prodrugs of the active compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable risk/benefit ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood.
  • Examples include a prodrug that is metabolized in vivo by a subject to an active drug having an activity of active compounds as described herein, wherein the prodrug is an ester of an alcohol or carboxylic acid group, if such a group is present in the compound; an acetal or ketal of an alcohol group, if such a group is present in the compound; an N-Mannich base or an imine of an amine group, if such a group is present in the compound; or a Schiff base, oxime, acetal, enol ester, oxazolidine, or thiazolidine of a carbonyl group, if such a group is present in the compound, such as described in US Patent No.
  • GPCRs canonical G protein-coupled receptors
  • arr2 P ⁇ arrestin2
  • compound A8 binds the Smo mutant D473H recently associated with medulloblastoma disease progression and resistance to GDC- 0449 17,25,33 , thereby providing the basis of a strategy to treat resistant disease.
  • a library of 5740 compounds were used for high-throughput screening.
  • p-arrestin2 green fluorescent protein parr2-GFP
  • wild-type Smo wild-type Smo
  • Smo-663 mutant wild-type Smo
  • Gli-luciferase reporter have been previously described ' .
  • the Smo-D473H mutant construct was generated using the QuikChange site-directed mutagenesis kit (Stratagene). Purified Sonic Hedgehog was obtained from Stem D. Cyclopamine was purchased from Toronto Research Chemicals. [3H] -cyclopamine was purchased from American Radiolabeled Chemicals.
  • GDC-0449 Vismodegib
  • LDE-225 LDE-225
  • Erismodegib select hits identified from screening were synthesized by the Small Molecule Synthesis Facility at Duke University.
  • Smo receptor binding For competitive binding assays, U20S cells overexpressing wild-type Smo or Smo-D473H mutant receptors were grown in 24-well plates and fixed with 4%(v/v) formaldehyde/PBS for 20 min at room temperature (RT). Cells were subsequently incubated for 2 h at RT in binding buffer (Hanks Balanced Salt Solution (HBSS) without Ca2+ and Mg2+) containing 25 nM of [sHJ-cyclopamine and a range of different concentrations of cyclopamine, GDC-0449, LDE-225 or A8 (from 0— 10 ⁇ ).
  • binding buffer Hanks Balanced Salt Solution (HBSS) without Ca2+ and Mg2+
  • Gli-luciferase reporter assay The Gli-luciferase assay was conducted in Shh- LIGHT2 cells, a clonal NIH3T3 cell line stably incorporating Gli-dependent firefly luciferase and constitutive Renilla luciferase reportersss. Cells were treated with purified Sonic Hedgehog protein (50ng/mL) together with the corresponding compounds for 2 days. The reporter activity was determined by using the Dual-Luciferase Reporter Assay System (Promega).
  • Cell proliferation Primary neuronal granular cell precursor (GCP) cells were obtained from the cerebellum of 7-day postnatal C57BL/6 mice and labeled with [3H]- thymidine. Proliferation assays were performed as previously described2s.
  • GCP Primary neuronal granular cell precursor
  • mice Eight- week-old C57BL/6 female mice were shaved on the dorsal surface and depilated with Nair® (Carter-Wallace, New York, New York). Briefly, the bottom half of the shaved area was treated with Nair for 2 min, and the depilated area rinsed with water to remove residual Nair. Compound A8 was dissolved in a vehicle of 95% acetone/5% DMSO at a concentration of 0.5 mM, and 30 ⁇ of A8 solution or the vehicle were applied topically to the depilated area of mice daily for two weeks. Mice were anesthetized briefly using 3% isoflurane anesthetic inhalant during all procedures. Five mice were included in each treatment group. All animals were treated in accordance with protocols approved by Institutional Animal Care and Use Committee at Duke University.
  • Tripos 3910 (Fig. 2A) synthesized at Duke based on the structure assigned to the material by Tripos, had substantially reduced Smo antagonist activity compared to the previous test samples. Reduced activity associated with this structure was confirmed upon subsequent purification of the Tripos sample in which the major component in the library sample agreed for structure and was less active. Instead, the active substance was found to be a small impurity isolated from the library sample. Storage of the active impurity at room temperature in a DMSO or methanolic solution for 1 week retained activity. Subsequent characterization of this impurity by high-resolution mass spectrometry (HRMS) and by extensive NMR analysis allowed assignment of structure to the impurity as shown for Compound A8 (Fig. 2A).
  • HRMS high-resolution mass spectrometry
  • Compound AS is a competitive antagonist of Smo.
  • Compound A8 inhibits Gli activity and proliferation of mouse cerebellar Granular Cell Precursor (GCP) cells.
  • GCP Granular Cell Precursor
  • Compound A8 inhibits hair regrowth in mouse. Hedgehog signaling plays a key role in regulating hair follicle growths.
  • Hedgehog signaling plays a key role in regulating hair follicle growths.
  • the Smo/pArr2-GFP high throughput assay platform exploited here is based on our discovery that activated wild-type Smo or Smo-633 binds parr2-GFP and changes its cellular distribution27,28. Addition of a Smo antagonist, such as cyclopamine inhibits the aggregation of Smo-633 with Parr2-GFP. Upon screening small molecule chemical libraries at a concentration of 5 ⁇ , hits were identified by the disappearance of parr2-GFP intra- vesicular aggregates in cells, similar to the disappearance of aggregates observed with cyclopamine.
  • V2R vasopressin receptor
  • arginine vasopressin a different seven- transmembrane receptor.
  • Stimulation causes arr2-GFP to aggregate and produces a punctuate pattern in cells. Aggregation of V2R and parr2-GFP is not inhibited by the Smo antagonist cyclopamine29.
  • This control assay helps ensure the mechanism of inhibition is Smo receptor specific and allows molecules with non-specific mechanisms of inhibition to be ruled-out. Only compounds that inhibited aggregation of Smo and did not inhibit aggregation of V2R were evaluated in confirmatory assays.
  • the Smo/pArr2-GFP assay is a versatile assay platform that provides the ability to screen for antagonists or agonists by a small change in the screening protocol. Screening in the antagonist mode is as described above. Screening in the agonist mode is accomplished by the addition of 0.1 ⁇ of cyclopamine to the cells prior to screening test libraries2s. In the agonist mode, active compounds are identified by the appearance of a green punctate pattern in the cells. The ability to screen cells in an agonist or antagonist mode provides significant advantages to chemical genetic screening approaches while also providing a cellular context to identify molecules with unique mechanisms of action. The follow-up assays used here clearly demonstrate the ability of this innovative assay format to identify authentic inhibitors of Smo that inhibit hedgehog signaling.
  • a novel high-throughput, cell-based assay platform based on a fundamental finding that activated Smo causes the translocation of ⁇ 2 was capable of identifying Smo antagonists in chemical screening libraries.
  • the assay identified a potent inhibitor of hedgehog signaling and is capable of binding both wild-type and a mutated form of Smo associated with clinically resistance in rnedulloblastoma.
  • the solid was purified on a column of 220g Si02 packed in 2%MeOH/CH2C12 by eluting with a gradient of 2-9% MeOH/CH2C12 .
  • the desired fractions were concentrated and dried under high- vacuum overnight to give 6.2 g (65%) of the amine-pyridylester adduct.
  • the EtOAc solution was filtered, and to this solution was added a total of 13-15 mL of Si02, and the resultant suspension was concentrated to dryness.
  • the solids were purified by eluting them from a column of lOOmL Si02 packed in 5% MeOH/CH2C12, with a gradient of 5-10% MeOH/CH2C12. The desired fractions were combined, heptane was added, and the solution concentrated to give 0.44g (46%) of the benzylic alcohol intermediate.
  • the CH2C12 layer was separated and the aqueous layer was washed 3 times with CH2C12.
  • the CH2C12 layers were combined and washed 3 times with water (pH-9-10), dried with Na2S04, and filtered.
  • Heptane was added to the filtrate and the solution was concentrated to a residue that was placed under high vacuum to remove residual pyridine.
  • the residue was then chromatographed on Si02 with a gradient of 3-5% MeOH/CH2C12. The desired fractions were combined, heptane was added and the solution concentrated to give 0.190 g (68%) of the aldehyde C as a white foam.
  • N-ethyl-N-methylamine (3 mL, 35 mmol, 5.5 eq.) was added dropwise at room temperature to a suspension of 2-chloronicotinic acid (1.0 g, 6.4 mmol), EDC (1.58 g, 8.3 mmol, 1.3 eq.), and HOBt (1.1 g, 8.3 mmol, 1.3 eq.) in anhydrous CH2C12 (50 mL). The mixture was stirred 2 hours at room temperature. Silica gel ( ⁇ 2g) was added and the mixture was concentrated to dryness under reduced pressure.

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