WO2019043373A1 - Cyclyl-sulfonamides substitués utilisés en tant que modulateurs de la voie de signalisation du hedgehog (hh) - Google Patents

Cyclyl-sulfonamides substitués utilisés en tant que modulateurs de la voie de signalisation du hedgehog (hh) Download PDF

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WO2019043373A1
WO2019043373A1 PCT/GB2018/052430 GB2018052430W WO2019043373A1 WO 2019043373 A1 WO2019043373 A1 WO 2019043373A1 GB 2018052430 W GB2018052430 W GB 2018052430W WO 2019043373 A1 WO2019043373 A1 WO 2019043373A1
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alkyl
pyridin
optionally substituted
trans
membered
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Filip KOLUNDŽIC
Mateja MILEK
Tanja Poljak
Maja ROŠCIC
Colin STUBBERFIELD
Srinivasamurthy VADLAMUDI
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E-Therapeutics Plc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the present invention relates to compounds that are modulators of the hedgehog (Hh) signalling pathway, and their use in the treatment of diseases and/or conditions associated with the abnormal activation and/or malfunction of this pathway.
  • Hh hedgehog
  • compounds of the invention are modulators of the Hh signalling pathway.
  • the present invention also relates to methods for the preparation of the compounds of the invention, to intermediates for their preparation, to pharmaceutical compositions comprising a compound of the invention, to the use of a compound of the invention as therapeutic agents, and to methods for the treatment of diseases and/or conditions associated with the abnormal activation and/or malfunction of Hh signalling pathway by administering a compound of the invention.
  • Hh signalling pathway plays an important role in tissue development and is a major regulator of cell differentiation, cell proliferation and tissue polarity (Ingham & McMahon, 2001). Disruption of this pathway underlies a variety of developmental disorders affecting multiple organ systems and improper activation of the pathway can lead to malignancy (Pak & Segal, 2016), fibrosis (Fabian et al, 2012), GVHD (Zerr et al, 2012) and amongst other indications, angiogenic disorders.
  • the Hh signalling pathway is named after a gene first identified in Drosophila melanogaster. Mutations of this gene were found to result in a continuous lawn of denticles (spiky processes) covering the anterior half of the larval cuticle, rather than the posterior half where they are usually found (Nusslein-Volhard & Wieschaus, 1980). This unusual phenotype led to the gene name hedgehog (Hh).
  • Hh gene product was later identified as a secreted glycoprotein ligand that triggers an intracellular signalling cascade critical for segment polarity (Mohler & Vani, 1992).
  • SHH Sonic
  • IHH Indian
  • DHH Desert
  • Hh pathway maintains normal tissue homeostasis and plays a regulatory role in stem cells (Lai et al, 2002; Levy et al, 2005).
  • Hh proteins are initially synthesized as an inactive precursor protein with an amino- terminal signalling domain and a carboxy-terminal intein-like domain which is later removed by autocatalytic cleavage (Perler, 1998).
  • the Hh signalling pathway is initiated when the Hh protein binds to its receptor, a 12-transmembrane domain (TMD) protein called Patchedl (PTCHl) (Stone et al, 1996).
  • TMD 12-transmembrane domain
  • PTCHl Patchedl
  • SMO Smoothened
  • Activated SMO results in nuclear localization and accumulation of the glioma-associated transcription factors (GLi) which are the terminal effectors of the Hh signalling cascade.
  • GLi glioma-associated transcription factors
  • mammals there are 3 GLi transcription factors (GLil, GLi2 and GLi3)(Ruiz i Altaba, 1999).
  • Glil and Gli2 function as transcriptional activators of Hh signalling, whereas Gli3 functions primarily as a repressor.
  • Gli3 functions primarily as a repressor.
  • Hh signalling pathway Uncontrolled activation of the Hh signalling pathway has been implicated in a wide range of tumours with an estimated 25% of human cancer deaths resulting from cancers with hyperactivated Hh signalling (Berman et al, 2002; Tojo et al, 2002; Thayer et al, 2003; Watkins et al, 2003; Kubo et al, 2004; Sanchez et al, 2004; Dierks et al, 2008).
  • Aberrant activation of the SHH pathway has been shown in a variety of human cancers, including, basal cell carcinoma, malignant gliomas, medulloblastoma, leukaemias, and cancers of the breast, lung, pancreas, and prostate.
  • Hh pathway has been shown to regulate cell proliferation in adults by activation of genes involved in cell cycle progression such as cyclin D which is involved in Gl-S transition. Also, SHH blocks cell-cycle arrest mediated by p21, an inhibitor of cyclin dependent kinases. Hh signalling is further implicated in cancer by inducing components in the EGFR pathway (EGF, Her2) involved in proliferation as well as components in the PDGF (PDGFa) and VEGF pathways involved in angiogenesis.
  • EGF epidermal growth factor
  • PDGFa vascular endothelial growth factor
  • Nuclear accumulation of GLi activates target genes that promote several oncogenic properties to tumour cells, including, genes involved in proliferation (cyclin Dl, MYC), resistance to apoptosis (BCL-2), angiogenesis (ANG1/2), epithelial to mesenchymal transition (SNAIL) and stem cell self-renewal (NANOG, SOX2) (Hui & Angers, 2011).
  • Improper activation of the Hh pathway can occur due to somatic mutations in upstream pathway elements such as SMO and PTCH1 (Epstein, 2008; Kool et al, 2008) or due to enhanced SHH ligand signalling (Varnat et al, 2009).
  • Hh pathway Improper activation of the Hh pathway has been studied in detail in two tumour types in particular - basal cell carcinoma and medulloblastoma. Both of these cancers are prevalent in patients with basal cell nevus syndrome, an autosomal dominant disorder that presents itself with craniofacial and skeletal abnormalities. The cause of this syndrome has been found to be due to a loss of function mutation in the PTCH1 gene resulting in dysregulated Hh signalling (Kimonis et al, 1997). The SHH pathway has also been implicated in the regulation and maintenance of cancer stem cells.
  • SMO inhibition prevents the downstream activation of the GLi transcription factors leading to suppression of the genes associated with cancer progression.
  • SMO inhibition was first observed during binding studies with the natural steroidal alkaloid cyclopamine. Cyclopamine binds to the heptahelical TMD of SMO and prevents the conformational change that is required to activate SMO (Chen et al, 2002; Zhao et al, 2007). Whilst treatment with cyclopamine was shown to effectively reduce tumour growth in vivo, its efficacy was undermined by many potent side effects (Mimeault et al., 2010).
  • Vismodegib was developed as a second generation cyclopamine derivative. It also binds to SMO and was the first in class drug approved for treating cancer by targeting of the hedgehog pathway (Robarge et al, 2009). Vismodegib is currently used in the clinic to treat basal cell carcinoma (BCC) (Sekulic et al., 2012). Sonidegib (LDE225, erismodegib) was the second SMO antagonist approved for the treatment of BCC and its mechanism of action has been determined as cell cycle arrest and apoptosis (Pan et al, 2010).
  • BCC basal cell carcinoma
  • Sonidegib LDE225, erismodegib
  • SMO antagonists There are also several other SMO antagonists currently in clinical trials including saridegib (Phase I), BMS-833923 (Phase I & II), glasdegib (Phase II) and taladegib (Phase I & II) (Rimkus et al, 2016).
  • saridegib Phase I
  • BMS-833923 Phase I & II
  • glasdegib Phase II
  • taladegib Phase I & II
  • a major setback to the targeting of SMO in the Hh signalling cascade has been the observation of spontaneous mutations that develop as a response to SMO inhibitors (Sharpe et al, 2015). For example, despite initial tumour regression, after 3 months treatment with vismodegib, resistance was observed with the appearance of novel SMO mutations (Metcalfe & de Sauvage, 2011).
  • the GLi transcription factors have also been singled out as potential therapeutic targets due to their role as the terminal effectors of the hedgehog pathway.
  • GANTS GLi antagonists
  • ATO arsenic trioxide
  • GANTs were discovered at the National Cancer Institute in a GLI-luciferase reporter assay screen in HEK293 cells.
  • GANT-58 and GANT-61 were both discovered to inhibit GLI-mediated gene activation, though GANT-61 showed more specificity towards GLI proteins and more effectively reduced GLI1 and GLI2 DNA-binding ability.
  • GANT- 61 has shown potent inhibition of GLI1 and GLI2 in many cancer cell lines, including rhabdomyosarcoma, osteosarcoma, neuroblastoma, and ovarian cancer (Rimkus et al, 2016).
  • GANT-61 reduced tumour growth and proliferation and strongly reduced expression of PTCH1 mRNA (Rimkus et al, 2016). No clinical trials are currently ongoing using GANT-61 to treat any type of cancer.
  • tissue parenchyma cell necrosis is caused by sustained inflammatory stimulation and is a pathologic process with enhanced production and excessive deposition of extracellular matrix (ECM).
  • ECM extracellular matrix
  • Fibrosis is a repairing process and also induces sclerosis and tissue hypofunction when the injury is persistent or the repair process is not sufficient.
  • Tissue fibrosis is the common final outcome of a wide variety of chronic diseases, regardless of the initial causes (Liu, 2006; Boor et al, 2010; Zeisberg and Neilson, 2010).
  • Hh signalling has also been found to be activated in human and murine chronic graft- versus-host disease (cGVHD) with increased expression of SHH and accumulation of the transcription factors GLi-1 and GLi-2.
  • cGVHD chronic graft- versus-host disease
  • the hedgehog pathway is therefore implicated in numerous conditions where there is unmet clinical need and current hedgehog inhibitors are limited by resistance due to mutations.
  • the compounds of the present invention have been identified as hedgehog modulators useful as a medicament in the treatment of diseases and/or conditions associated with the abnormal activation and/or malfunction of the hedgehog signalling pathway.
  • the present invention is based on the identification that a compound of the invention may be useful as a medicament in the treatment of diseases and/or conditions associated with the abnormal activation and/or malfunction of the hedgehog (Hh) signalling pathway.
  • a compound of the invention is a modulator of Hh signalling pathway. More particularly, a compound of the invention is useful in the treatment of conditions associated with the abnormal activation of the hedgehog pathway.
  • the present invention also relates to methods for the preparation of the compounds of the invention, to intermediates for their preparation, to pharmaceutical compositions comprising a compound of the invention, to the use of a compound of the invention as therapeutic agents, and to methods for the treatment of diseases and/or conditions associated with the abnormal activation and/or malfunction of Hh signalling pathway by administering a compound of the invention.
  • the invention relates to a compound of Formula (I):
  • R 2 is selected from: a fused 9-10 membered bicyclic heteroaryl, a 5-6 membered heteroaryl; each of which is optionally substituted by one or more S0 2 -phenyl, wherein the phenyl is optionally substituted by one or more Ci- 6 alkyl;
  • R 3 is hydrogen or together R 3 and R 4 represent a bond
  • R 4 is hydrogen or together R 4 and R 3 represent a bond
  • R 5 is hydrogen or Ci- 6 alkyl
  • R 6 and R 7 which may be the same or different, are each hydrogen, Ci- 6 alkyl, haloCi. 6 alkyl or phenyl (wherein phenyl is optionally substituted by Ci- 6 alkyl);
  • R 1 is selected from:
  • a 5-6 membered heteroaryl which is optionally substituted by one or more groups independently selected from: - Ci- 6 alkyl and Co- 6 alkyl-phenyl;
  • R 2 is selected from:
  • R 3 is hydrogen or together R 3 and R 4 represent a bond
  • R 4 is hydrogen or together R 4 and R 3 represent a bond
  • R 5 is hydrogen or Ci- 6 alkyl
  • R 6 and R 7 which may be the same or different, are each hydrogen, Ci- 6 alkyl, haloCi. 6 alkyl or phenyl (wherein phenyl is optionally substituted by Ci- 6 alkyl);
  • R 1 is a 5-6 membered heteroaryl
  • a preferred heteroaryl is selected from the group:
  • R 1 is a 4-6 membered carbocyclyl, a preferred carbocyclyl
  • R 1 is a 4-6 membered heterocyclyl
  • a preferred heterocyclyl is
  • R 1 is a 6-10 membered aryl
  • a preferred aryl is
  • the phenyl is preferably substituted in the 4-position.
  • the present invention also relates to pharmaceutical compositions comprising a compound of the invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutical carrier, excipient or diluent.
  • a pharmaceutical composition comprising a compound of the invention for use in the treatment of conditions involving abnormal activation and/or malfunction of the of the hedgehog pathway whereby the condition involving abnormal activation of the hedgehog pathway is one or more of cancer, fibrosis and chronic graft-versus-host disease (cGVHD).
  • cGVHD chronic graft-versus-host disease
  • a pharmaceutical composition comprising a compound of the invention for use in the treatment of conditions involving abnormal activation and/or malfunction of the of the hedgehog pathway whereby the condition involving abnormal activation of the hedgehog pathway is cancer, as herein defined.
  • a pharmaceutical composition comprising a compound of the invention for use in the treatment of conditions involving abnormal activation of the hedgehog pathway whereby the condition involving abnormal activation of the hedgehog pathway is fibrosis, as herein defined.
  • a pharmaceutical composition comprising a compound of the invention for use in the treatment of conditions involving abnormal activation of the hedgehog pathway whereby the condition involving abnormal activation of the hedgehog pathway is Chronic graft-versus-host disease (cGVHD), as herein defined.
  • the pharmaceutical composition may additionally comprise a second therapeutically active ingredient suitable for use in combination with compounds of the invention.
  • the compounds of the invention useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.
  • the invention in another aspect, relates to a compound of the invention for use in therapy.
  • the invention relates to a compound of Formula I for use in the manufacture of a medicament for the treatment of diseases and/or conditions associated with the abnormal activation and/or malfunction of the hedgehog (Hh) signalling pathway.
  • Hh hedgehog
  • the invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of diseases and/or conditions associated with the abnormal activation and/or malfunction of the hedgehog (Hh) signalling pathway.
  • Hh hedgehog
  • the disease or condition associated with the abnormal activation or malfunction of the Hh signalling pathway is one or more of cancer, fibrosis and chronic graft-versus-host disease (cGVHD).
  • cGVHD chronic graft-versus-host disease
  • a compound of Formula I for use in the treatment of conditions involving abnormal activation and/or malfunction of the of the hedgehog pathway whereby the condition involving abnormal activation of the hedgehog pathway is cancer, as herein defined.
  • a compound of Formula I for use in the treatment of conditions involving abnormal activation of the hedgehog pathway whereby the condition involving abnormal activation of the hedgehog pathway is fibrosis, as herein defined.
  • a compound of Formula I for use in the treatment of conditions involving abnormal activation of the hedgehog pathway whereby the condition involving abnormal activation of the hedgehog pathway is Chronic graft-versus-host disease (cGVHD), as herein defined.
  • cGVHD Chronic graft-versus-host disease
  • the invention relates to methods of the treatment of diseases and/or conditions associated with the abnormal activation and/or malfunction of the hedgehog (Hh) signalling pathway by administering of an effective amount of a compound of the invention or one or more pharmaceutical compositions of the invention.
  • Hh hedgehog
  • this invention provides methods of treatment of a subject, in particular humans, susceptible to or afflicted with diseases and/or conditions associated with the abnormal activation and/or malfunction of the hedgehog (Hh) signalling pathway selected from among those listed herein, and particularly proliferative diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more pharmaceutical compositions of the invention.
  • Hh hedgehog
  • this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.
  • analogue means one analogue or more than one analogue.
  • Co- 6 alkyl the citation of a range should be considered a representation of each member of said range.
  • Coalkyl means that alkyl group is absent.
  • selected member Coalkyl-aryl of a range Co- 6 alkyl-aryl means that aryl group is directly attached without an alkyl spacer.
  • acyl includes residues derived from acids, including but not limited to carboxylic acids, carbamic acids, carbonic acids, sulfonic acids, and phosphorous acids. Examples include aliphatic carbonyls, aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphatic sulfinyls, aromatic phosphates and aliphatic phosphates. Examples of aliphatic carbonyls include, but are not limited to, acetyl, propionyl, 2-fluoroacetyl, butyryl, 2-hydroxylacetyl, and the like.
  • alkyl refers to a straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 18 carbon atoms; more particular alkyl groups have 1 to 6 carbon atoms, and even more particular alkyl groups have 1 to 4 carbon atoms. Suitably alkyl groups have 1 or 2 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain. Exemplary branched chain groups include isopropyl, iso-butyl, t-butyl and isoamyl.
  • alkyl groups as used herein include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, n- hexyl, 1,2-dimethylbutyl, octyl, decyl, undecyl, dodecyl tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl and octadecyl.
  • alkyloxy refers to a straight or branched chain alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom containing the specified number of carbon atoms.
  • Particular alkoxy groups have between 1 and 6 carbon atoms. More particular alkoxy groups have between 1 and 4 carbon atoms.
  • Ci- 4 alkoxy means a straight or branched alkoxy containing at least 1, and at most 4, carbon atoms.
  • alkoxy examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
  • alkenyl as used herein as a group or a part of a group refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms and containing at least one double bond.
  • C 2 - 6 alkenyl means a straight or branched alkenyl containing at least 2, and at most 6, carbon atoms and containing at least one double bond.
  • Particular "alkenyl” groups have 2 to 4 carbon atoms and containing at least one double bond.
  • alkenyl examples include ethenyl, 2- propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3 -methyl but- 2-enyl, 3-hexenyl and l, l-dimethylbut-2-enyl.
  • alkynyl as used herein as a group or a part of a group refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms and containing at least one triple bond.
  • C 2 - 6 alkynyl means a straight or branched alkynyl containing at least 2, and at most 6, carbon atoms and containing at least one triple bond.
  • alkynyl as used herein include, but are not limited to, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl and 3 -methyl- 1-butynyl.
  • alkylene refers to a branched or straight chained alkyl group containing from 1 to 6 carbon atoms, having single bonds for attachment to other groups at two different carbon atoms.
  • alkylene groups include methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, pentylene, and hexylene.
  • Particular alkylene groups have between 1 and 4 carbon atoms. More particular it is methylene (-CH 2 -) or ethylene (-CH 2 -CH 2 -).
  • amino refers to the radical - H 2 .
  • amino protecting group refers to a substituent on a functional amino group which prevent undesired reactions and degradations during synthetic procedures are carried out on other functional groups on the compound, and which may be selectively removed after certain synthetic step.
  • acyl type protecting groups e.g. formyl, trifluoroacetyl and acetyl
  • aromatic urethane type protecting groups e.g. benzyloxycarbonyl (Cbz) and substituted Cbz and 9- fluorenylmethoxycarbonyl (Fmoc)
  • aliphatic urethane protecting groups e.g.
  • alkyl type protecting groups e.g. benzyl, trityl, chlorotrityl
  • aryl refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • aryl refers to a mono-, bicyclic or tricyclic carbocyclic ring system having at least one aromatic ring that includes the number of ring members specified.
  • the term includes groups that have from 6 to 10 ring members.
  • the aryl group is a monocyclic ring system it preferentially contains 6 carbon atoms and is phenyl.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, tetrahydronaphthalene and trinaphthalene. Particularly
  • compound(s) of the invention or “compound(s) according to the invention”, and equivalent expressions refers to compounds of Formula (I) (whether in solvated or unsolvated form), as herein described, including any subset or embodiment of compounds of Formula (I), or their pharmaceutically acceptable salts (whether in solvated or unsolvated form).
  • said expression includes the pharmaceutically acceptable salts, and solvates (e.g. hydrates) thereof.
  • the compound(s) of the invention may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof. Where stereochemistry is not defined in the relevant Formula(e), then the term compound(s) of the invention includes enantiomers and diastereoisomers of these compounds.
  • cycloalkyl refers to a monocyclic or poly cyclic saturated hydrocarbon ring containing the stated number of carbon atoms, for example, 3 to 10 carbon atoms.
  • Particular “cycloalkyl” groups are monocyclic or four connected cyclohexane ring like in case of adamantane.
  • Examples of “cycloalkyl” groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, cyclooctyl, cyclononyl, cyclodecycl, and adamantly.
  • Particular cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl.
  • cycloalkenyl refers to a monocyclic hydrocarbon ring containing the stated number of carbon atoms, for example, 3 to 7 carbon atoms, and at least one double bond.
  • Examples of “cycloalkenyl” groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • Particular cycloalkenyl groups include cyclopentenyl and cyclohexenyl. More particular cycloalkenyl group is cyclohexenyl.
  • halogen or “halo” or “Hal” refers to fluoro (F), chloro (CI), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro. More particular halo group is chloro.
  • hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. For example, having from 1 to 4 heteroatoms, particularly from 1 to 3 heteroatoms, and more typically 1 or 2 heteroatoms, for example a single heteroatom.
  • heteroaryl or heteroaromatic refers to a 5-6 membered monocyclic aromatic ring or a fused 9-10 membered bicyclic aromatic ring containing up to four heteroatoms independently selected from nitrogen, sulphur and oxygen and the number of ring members specified.
  • Monocyclic heteroaryl ring may contain up to three heteroatoms. Typically, monocyclic heteroaryl will contain up to 3 heteroatoms, usually up to 2, for example a single heteroatom.
  • the bicyclic heteroaryl may contain up to four heteroatoms. Typically, bicyclic heteroaryl will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one or two nitrogen atoms.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of a pyrrole nitrogen.
  • the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl and tetrazolyl groups.
  • Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl and tetrazinyl. Particular monocyclic heteroaryl groups are those derived from imidazole, pyrazole and pyridine.
  • fused heteroaryl rings examples include pyrrolopyridine, pyrrolopyrimidine, pyrazolopyridine, thienopyridine, furopyridine, azaindole, diazaindole, imidazopyridine, benzothiazole, quinoline, isoquinoline, quinazoline, quinoxaline, pteridine, cinnoline, phthalazine, naphthyridine, indole, isoindole, indazole, purine, benzofurane, isobenzofurane, benzoimidazole, benzoxazole, benzoisoxazole, benzoisothiazole, benzoxadiazole, benzothiadiazole, and the like.
  • fused heteroaryl groups are derived from pyrrolopyridine, pyrrolopyrimidine, pyrazolopyridine, thienopyridine, furopyridine, indole, azaindole, diazaindole, imidazopyridine, benzothiazole, quinoline, in particular pyrrolopyridine.
  • Heterocyclic group “heterocyclic”, “heterocycle”, “heterocyclyl”, or “heterocyclo” alone and when used as a moiety in a complex group such as a heterocycloalkyl group, are used interchangeably and refer to any mono-, bi-, or tricyclic, saturated or unsaturated, aromatic (heteroaryl) or non-aromatic ring having the number of atoms designated, generally from 5 to about 14 ring atoms, where the ring atoms are carbon and at least one heteroatom (nitrogen, sulfur or oxygen) and preferably 1 to 4 heteroatoms.
  • heterocyclic refers to a stable non-aromatic 3-, 4-, 5-, 6- or 7- membered monocyclic ring or a 7-, 8-, 9-, 10-, 11- or 12- membered bicyclic ring or a 10-, 11-, 12-, 13-, 14- or 15- membered tricyclic ring; each of which may be saturated or partially unsaturated containing at least one, e.g. 1 to 3, heteroatoms selected from oxygen, nitrogen or sulphur, where in a 8-12 membered bicyclic heterocycle one ring may be aromatic but the other one has to be fully saturated and one ring may be carbocyclic and need to include one heterocyclic ring.
  • Monocyclic heterocycle ring may contain up to three heteroatoms. Typically, monocyclic heterocycle will contain up to 3 heteroatoms, usually up to 2, for example a single heteroatom.
  • the bicyclic heterocycle may contain up to four heteroatoms. Typically, bicyclic heterocycle will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heterocycle ring contains at least one or two heteroatoms.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • Examples of monocyclic rings include azetidine, pyrrolidine, pyrazolidine, oxazolidine, piperidine, piperazine, pyrane, morpholine, thiomorpholine, thiazolidine, oxirane, oxetane, dioxolane, dioxane, oxathiolane, oxathiane, dithiane, dihydrofurane, tetrahydrofurane, dihydropyrane, tetrahydropyrane, tetrahydropyridine, tetrahydropyrimidine, tetrahydrothiophene, tetrahydrothiopyrane and the like.
  • Particular monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl and azetidinyl.
  • bicyclic rings include 6,8-dihydro-5H-imidazo[l,2-a]pyrazine, 6,7-dihydro-5H-pyrrolo[l,2-a]imidazole, 5,6,7,8-tetrahydro-imidazo[l,2-a]pyridine, 2,3-dihydro-furo[3,2-b]pyridine, indoline, isoindoline, benzodioxole, tetrahydroisoquinoline and the like.
  • heterocycloalkyl refers to a stable non-aromatic ring structure, mono-cyclic or polycyclic, containing one or more heteroatoms, particularly one or two heteroatoms independently selected from N, O and S and the number of ring atoms specified.
  • the heterocycloalkyl ring structure may have from 3 to 7 ring members.
  • a fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring. Examples of heterocyclic rings include morpholine, piperidine (e.g. 1- piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.
  • Still further examples include azetidine, piperidone, piperazone, and N-alkyl piperidines such as N-methyl piperidine.
  • Particular "heterocycloalkyl” groups are monocyclic.
  • Particular heterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl and azetidinyl.
  • heterocycloalkenyl refers to a stable non-aromatic ring structure, mono-cyclic or polycyclic, containing one or more heteroatoms, particularly one or two heteroatoms independently selected from N, O and S, and the number of ring atoms specified, and further containing at least one carbon-carbon double bonds or carbon- heteroatom double bonds in the ring as long as the ring is not rendered aromatic by their presence.
  • the heterocycloalkenyl structure may have from 3 to 7 ring members.
  • a fused heterocycloalkenyl ring system may include carbocyclic rings and need only include one heterocycloalkenyl ring.
  • heterocyclic rings examples include pyran (2H-pyran or 4H- pyran), dihydrothiophene, dihydropyran, dihydrofuran (2,3-dihydrofuran or 2,5- dihydrofuran), dihydrothiopyran, dihydrothiazole, imidazoline (2-imidazoline, 3- imidazoline, and 4-imidazoline), oxazoline, thiazoline, 2-pyrazoline, tetrahydropyridine, and the like. Still further examples include N-alkyl tetrahydropyridine such as N-methyl tetrahydropyridine.
  • heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
  • hydroxy or "hydroxyl” refers to the radical -OH.
  • hydroxy protecting group refers to a substituent on an functional hydroxyl group which prevent undesired reactions and degradations during synthetic procedures, and which may be selectively removed after certain synthetic step.
  • 'hydroxy protecting group' include: ester and ether hydroxyl protecting group.
  • ester hydroxyl protecting group examples include: formyl, -OC(0)Ci- 4 alkyl such as acetyl (Ac or - C(0)CH 3 ), methoxyacetyl, chloroacetyl, dichloroacetyl, trichloroacety, trifluoroacetyl, triphenylmethoxyacetyl, phenoxyacetyl, benzoylformyl, benzoyl (Bz or -0(0)0 6 ⁇ 5 ), benzyloxycarbonyl (Cbz or -C(0)-0-CH 2 C 6 H 5 ) ; methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl or 2-(trimethylsilyl)ethoxycarbonyl and the like.
  • ether hydroxyl protecting group examples include: alkyl silyl groups such as trimethylsilyl (TMS), tert-butyldimethylsilyl, triethylsilyl, triisopropylsilyl and the like.
  • suitable "hydroxy protecting group” include; -OC(0)Ci. 4 alkyl such as acetyl (Ac or -C(0)CH 3 ), benzoyl (Bz), benzyloxycarbonyl (Cbz) and trimethylsilyl (TMS).
  • hydroxy protecting group is: triethylsilyl or acetyl (Ac or -C(0)CH 3 ).
  • “hydroxy protecting group” is: Ac or Cbz.
  • sulfonamide refers to the - R-S0 2 -R wherein each R is independently H, alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl), a carbocycle or a heterocycle.
  • Particular sulfonamide groups are alkylsulfonamide (e.g. - H-S0 2 -alkyl), for example methylsulfonamide; arylsulfonamdie (i.e. - H-S0 2 -aryl) for example phenylsulfonamide; aralkylsulfonamide, for example benzylsulfonamide.
  • sulfonyl means a -S0 2 -R group wherein R is alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl.
  • Particular sulfonyl groups are alkylsulfonyl (i.e. -S0 2 - alkyl), for example methylsulfonyl; arylsulfonyl, for example phenylsulfonyl; aralkylsulfonyl, for example benzylsulfonyl.
  • nitro refers to the radical -N0 2 .
  • cyano refers to the radical -CN.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond between ring atoms but is not aromatic.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties. Only in case of fused 8-9 membered heterocycle one of the ring moieties may be aromatic but in that case the other ring of such fused 8-9- memberd heterocycle has to be saturated.
  • intermediate(s) of the invention refers to compounds of formulae (II), (III), (IV) and (V) (whether in solvated or unsolvated form), as herein described, including any subset or embodiment of compounds of formulae (II), (III), (IV) and (V), or their salts (whether in solvated or unsolvated form).
  • said expression includes the salts, and solvates (e.g. hydrates) thereof.
  • the intermediate(s) of the invention may possess one or more asymmetric centres; such intermediate(s) can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof. Where stereochemistry is not defined in the relevant Formula(e), then the term intermediate(s) of the invention includes enantiomers and diastereoisomers of these compounds.
  • inert solvent refers to a solvent that cannot react with the dissolved compounds including non-polar solvent such as hexane, toluene, diethyl ether, diisopropylether, chloroform, ethyl acetate, THF, dichloromethane; polar aprotic solvents such as acetonitrile, acetone, N,N- dimethylformamide, ⁇ , ⁇ -dimethylacetamide, dimethyl sulfoxide, pyridine, and polar protic solvents such as lower alcohol, acetic acid, formic acid and water.
  • non-polar solvent such as hexane, toluene, diethyl ether, diisopropylether, chloroform, ethyl acetate, THF, dichloromethane
  • polar aprotic solvents such as acetonitrile, acetone, N,N- dimethylformamide, ⁇ , ⁇ -dimethylacetamide, dimethyl
  • lower alcohol refers to a Ci- 4 alcohol, such as for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • substituted refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • substituted with one or more refers to one to four substituents. In one embodiment it refers to one to three substituents. In further embodiment it refers to one or two substituents. In a yet further embodiment it refers to one substituent.
  • pharmaceutically acceptable refers to salts, molecular entities and other ingredients of compositions that are generally physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human).
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in mammals, and more particularly in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulf
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • the term 'pharmaceutically acceptable cation' refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
  • ester refers to esters which hydrolyse in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • carrier refers to a diluent, excipient, and/or vehicle with which an active compound is administered.
  • the pharmaceutical compositions of the invention may contain combinations of more than one carrier.
  • Such pharmaceutical carriers can be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W.
  • compositions may comprise as, in addition to, the carrier any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilizing agent(s).
  • prodrug or “pharmaceutically acceptable prodrug” as used herein refers to compounds, including derivatives of the compounds of the invention, which have metabolically cleavable groups and are converted within the body e.g. by solvolysis or under physiological conditions into the compounds of the invention which are pharmaceutically active in vivo.
  • Pharmaceutically acceptable prodrugs are described in: Bundgard, H. Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985, T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems", Vol. 14 of the A.C. S. Symposium Series; Edward B. Roche, ed., "Bioreversible Carriers in Drug Design", American Pharmaceutical Association and Pergamon Press, 1987; and in D.
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particularly useful are the Ci-C 8 alkyl, C 2 -C 8 alkenyl, aryl and arylalkyl esters of the compounds of the invention.
  • solvate refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • solvents include water, ethanol, acetic acid and the like.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solvate' encompasses both solution-phase and isolable solvates.
  • solvates include hydrates, ethanolates and methanolates.
  • isotopic variant refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound
  • an 'isotopic variant' of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium ( 2 H or D), carbon- 13 ( 13 C), nitrogen- 15 ( 15 N), or the like.
  • the following atoms, where present, may vary, so that for example, any hydrogen may be 2 H/D, any carbon may be 13 C, or any nitrogen may be 15 N, and that the presence and placement of such atoms may be determined within the skill of the art.
  • the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • compounds may be prepared that are substituted with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. All isotopic variants of the compounds provided herein, radioactive or not, are intended to be encompassed within the scope of the invention.
  • isomers refers to compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers”.
  • Diastereomers are stereoisomers that are not mirror images of one another and those that are non-superimposable mirror images of each other are termed 'enantiomers'.
  • a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a "racemic mixture”.
  • Teautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H).
  • enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
  • Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, which are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • subject refers to an animal, in particular a mammal and more particular to a human or a domestic animal serving as a model for a disease (for example guinea pigs, mice, rats, gerbils, fish, birds, cats, rabbits, dogs, horses, cows, monkeys, chimpanzees or like). Specifically, the subject is a human.
  • the terms "patient” and “subject” are used interchangeably herein.
  • Effective amount means the amount of a compound that, when administered to a subject for the prophylaxis or treatment of a disease and/or condition, is sufficient to effect such prophylaxis or such treatment for the disease and/or condition.
  • the “effective amount” can vary depending on the compound, the disease and/or condition and its severity, and the age, weight, etc., of the subject.
  • Preventing refers to a reduction in risk of acquiring or developing a disease and/or condition (i.e., causing at least one of the clinical symptoms of the disease and/or condition not to develop in a subject that may be exposed to a disease and/or condition-causing agent, or predisposed to the disease and/or condition in advance of disease and/or condition onset).
  • prophylaxis is related to "prevention”, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
  • Treating” or “treatment” of any disease and/or condition refers, in one embodiment, to ameliorating the disease and/or condition (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof).
  • “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • “treating” or “treatment” refers to modulating the disease and/or condition, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • “treating” or “treatment” relates to slowing the progression of the disease and/or condition.
  • "Maintenance therapy” refers to a preventive therapy that follows successful initial treatment of the acute phase of the illness where regular (usually smaller) doses of the drug are delivered to the patient to prevent recurrence and worsening of the disease.
  • Modulators of the Hh signalling pathway include modulators of a pathway which is a target of the Hh signalling pathway; and includes Hh signalling pathway inhibitors, in which the inhibition may be complete or partial.
  • Hedgehog includes three Hedgehog homologues, Desert (DHH) (Protein accession 043323), Indian (IHH) (Protein accession Q14623), and Sonic (SHH) (Protein accession Q 15465).
  • Hh modulators as used herein may be SMO inhibitors, GLI inhibitors, SHH inhibitors, or inhibitors of any other proteins within the Hh signalling cascade.
  • Hh modulators as used herein may differentially regulate the activity of SMO, GLI, SHH, or any other proteins within the Hh signalling cascade.
  • Hh modulators as used herein may differentially regulate the expression of SMO, GLI, SHH, or any other proteins within the Hh signalling cascade.
  • diseases and/or conditions associated with the abnormal activation and/or malfunction of Hh signalling pathway refers to group of diseases and conditions including proliferative diseases, such as cancers; , fibrosis and GVHD, etc. as herein defined.
  • abnormal activation refers to aberrant activation, reduced inhibition, increased expression, increased signalling or inappropriate activation.
  • amidation used herein refers to a chemical process of formal union of carboxylic acids and amines and formation of amide functionality. It is necessary to first activate the carboxylic acid, in a process that usually takes place by converting the -OH of the acid into a good leaving group prior to treatment with the amine in the presence of a base. Suitable methods for activation of carboxylic groups are, but not limited to, formation of acyl halides, acyl azides, mixed anhydrides, activated esters and the like.
  • Acyl halides may be prepared in non-protic solvents treating the carboxylic acid with halide sources like, but not limited to, thionyl chloride, oxalyl chloride, phosphorus pentachloride, triphosgene, cyanuric fluoride, cyanuric chloride, BoP-Cl, PyBroP and the like.
  • Mixed anhydrides may be prepared in non-protic solvents with reagents like, but not limited to, pivalyl chloride, EEDQ and the like.
  • Suitable coupling reagents used in the process of amidation via active esters are, but not limited to, carbodiimides like DCC, DIC, EDAC, uronium salts like HATU, TATU, HBTU, TBTU, TDBTU, phosphonium salts like PyBoP, BoP, DEPBT. These coupling reagents can be used as stand-alone activators or in the presence of additives like, but not limited to, HOAt, HOBt and the like.
  • Other suitable amidation coupling reagents that operate on different mechanism of carboxylic group activation are, but not limited to, DPP A, T3P®, CDI, Mukaiyama reagent and the like.
  • Activation can also be performed by using solid supported versions of the abovementioned coupling reagents like, but not limited to, PS-CDI, PS-EDC, PS-BoP and the like.
  • Suitable bases used in amidation process are, but not limited to, sodium hydrocarbonate, potassium hydrocarbonate, sodium carbonate, potassium carbonate, TEA, DIPEA, DBU, DBN, DABCO and the like. A more thorough discussion of amidation can be found in Valeur, E., et al. Chem.Soc.Rev. (2009), 38, 606.
  • estersification refers to a chemical process of formal union of carboxylic acids and alcohols and formation of ester functionality. Suitable methods for synthesis of esters are Fisher, Mitsunobu, Steglich conditions, transesterification, acylation with appropriate acyl halides, decarboxylative esterification, oxidative esterification and redox esterification.
  • Acyl halides may be prepared in non-protic solvents treating the carboxylic acid with halide sources like, but not limited to, thionyl chloride, oxalyl chloride, phosphorus pentachloride, triphosgene, fluoride, cyanuric chloride and the like.
  • Suitable coupling reagents used in the process of esterification are, but not limited to, p- nitrophenylchloroformate, thiopyridyl chloroformate, 2,2'- (4-t-Bu-N- alkylimidazolyl)disulfide, Mukaiyama salts, 2,4,6-trichlorobenzoyl chloride, DEAD/PPh3, TFFH, DCC, TBTU, TATU, COMU and the like.
  • Suitable bases used in esterification process are, but not limited to, sodium hydrocarbonate, potassium hydrocarbonate, sodium carbonate, potassium carbonate, TEA, DIPEA, DBU, DBN, DABCO and the like.
  • reductive animation refers to chemical process of conversion of a carbonyl group and an amine to higher substituted amine via an intermediate imine.
  • the carbonyl group is most commonly a ketone or an aldehyde.
  • the imine intermediate is reduced to the amine by various reducing agents including, but not limited to, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, zinc and hydrochloric acid, hydrogen and transition metal catalyst, formic acid and its organic or inorganic salts, iron pentacarbonyl.
  • reducing agents including, but not limited to, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, zinc and hydrochloric acid, hydrogen and transition metal catalyst, formic acid and its organic or inorganic salts, iron pentacarbonyl.
  • alcoholic solvents are used.
  • Preferred conditions are sodium cyanoborohydride in methanolic media in the presence of acetic acid.
  • the present invention is based on the identification that a compound of the invention may be useful as a medicament in the treatment of diseases and/or conditions associated with the abnormal activation and/or malfunction of the hedgehog (Hh) signalling pathway.
  • a compound of the invention is an inhibitor of Hh signalling pathway.
  • a compound of the invention is useful in the treatment of proliferative diseases.
  • the present invention also relates to methods for the preparation of the compounds of the invention, to intermediates for their preparation, to pharmaceutical compositions comprising a compound of the invention, to the use of a compound of the invention as therapeutic agents, and to methods for the treatment of diseases and/or conditions associated with the abnormal activation and/or malfunction of Hh signalling pathway by administering a compound of the invention.
  • the present invention relates to a compound of Formula (I):
  • R 2 is selected from: a fused 9-10 membered bicyclic heteroaryl, a 5-6 membered heteroaryl; each of which is optionally substituted by one or more S0 2 -phenyl, wherein the phenyl is optionally substituted by one or more Ci- 6 alkyl;
  • R 3 is hydrogen or together R 3 and R 4 represent a bond
  • R 4 is hydrogen or together R 4 and R 3 represent a bond
  • R 5 is hydrogen or Ci- 6 alkyl
  • R 6 and R 7 which may be the same or different, are each hydrogen, Ci- 6 alkyl, haloCi.
  • R 1 is selected from:
  • a 5-6 membered heteroaryl which is optionally substituted by one or more groups independently selected from: - Ci- 6 alkyl and Co- 6 alkyl-phenyl;
  • R 2 is selected from: (i) a fused 9-10 membered bicyclic heteroaryl, which is optionally substituted by one or more S0 2 -phenyl, wherein the phenyl is optionally substituted by one or more Ci-ealkyl;
  • R 3 is hydrogen or together R 3 and R 4 represent a bond
  • R 4 is hydrogen or together R 4 and R 3 represent a bond
  • R 5 is hydrogen or Ci- 6 alkyl
  • R 6 and R 7 which may be the same or different, are each hydrogen, Ci- 6 alkyl, haloCi. 6 alkyl or phenyl (wherein phenyl is optionally substituted by Ci- 6 alkyl).
  • R 1 is a 5-6 membered heteroaryl
  • a preferred heteroaryl is selected from the group:
  • R 1 is a 4-6 membered carbocyclyl, a preferred carbocyclyl
  • R 1 is a 4-6 membered heterocyclyl
  • a preferred heterocyclyl is NH which is optionally substituted as herein defined.
  • R 1 is a 6-10 membered aryl
  • a preferred aryl is
  • the phenyl is preferably substituted in the 4-position.
  • trans-N-(4-furo[3,2-b]pyridin-3-ylcyclohexyl)-lH-pyrrole-3-sulfonamide [34] trans-N-(4-furo[3,2-b]pyridin-3-ylcyclohexyl)-lH-imidazole-4-sulfonamide; [35] trans-N-(4-furo[3,2-b]pyridin-3-ylcyclohexyl)-lH-imidazole-2-sulfonamide; [36] and trans-N-(4-furo[3,2-b]pyridin-3-ylcyclohexyl)-3-methyl-isoxazole-4-sulfonamide; [37] or a pharmaceutically acceptable salt or a solvate thereof.
  • trans-tert-butyl 3 [(4-pyridin-4-ylcyclohexyl) sulfamoyl] azetidine- 1 -carboxylate; 18 trans, cis-N-tert-butyl-3 - [ [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)cyclohexyl] sulfamoyl] cyclobutane-1 -carboxamide; [22]
  • the compound and intermediate of the invention is not an isotopic variant.
  • a compound and intermediate of the invention according to any one of the embodiments herein described is a free base.
  • a compound and intermediate of the invention according to any one of the embodiments herein described is a salt.
  • a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.
  • a compound and intermediate of the invention according to any one of the embodiments herein described is a solvate of the compound.
  • a compound of the invention according to any one of the embodiments herein described is a solvate of a salt of a compound, in particular a solvate of a pharmaceutically acceptable salt.
  • substituents on the compounds and intermediates of the invention may also have one or more asymmetric carbon atoms.
  • the compounds and intermediates of the invention may occur as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof.
  • a compound and intermediate of the invention contains an alkenyl group
  • cis (Z) and trans (E) isomerism may also occur.
  • the present invention includes the individual stereoisomers of the compound and, where appropriate, the individual tautomeric forms thereof, together with mixtures thereof.
  • Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or HPLC.
  • a stereoisomeric mixture of the agent may also be prepared from a corresponding optically pure intermediate or by resolution, such as by HPLC, of the corresponding mixture using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding mixture with a suitable optically active acid or base, as appropriate.
  • a compound and intermediate of the invention may be one for which one or more variables (R groups and/or integers) is selected from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.
  • the present invention provides prodrugs and derivatives of the compounds of the invention according to the formulae above.
  • Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo.
  • Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particularly useful are the Ci to C 8 alkyl, C 2 -C 8 alkenyl, aryl, substituted aryl, and arylalkyl esters of the compounds of the invention.
  • a compound of the invention may be administered as the bulk substance, it is preferable to present the active ingredient in a pharmaceutical formulation as a pharmaceutical composition.
  • a compound of the invention when employed as a pharmaceutical, is typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • a compound of this invention is administered in a therapeutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • compositions of the invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal.
  • routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal.
  • a compound of this invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
  • the compounds of the invention can be administered for immediate-, delayed-, modified-, sustained-, pulsed-or controlled-release applications.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier.
  • Typical unit dosage forms include prefilled, premeasured ampoules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • oral compositions are slow, delayed or positioned release (e.g., enteric especially colonic release) tablets or capsules.
  • This release profile can be achieved for example, by use of a coating resistant to conditions within the stomach but releasing the contents in the colon or other portion of the GI tract wherein a lesion or inflammation site has been identified.
  • a delayed release can be achieved by a coating that is simply slow to disintegrate.
  • compositions for delayed or positioned release and/or enteric coated oral formulations include tablet formulations film coated with materials that are water resistant, pH sensitive, digested or emulsified by intestinal juices or sloughed off at a slow but regular rate when moistened.
  • Suitable coating materials include, but are not limited to, hydroxypropyl methylcellulose, ethyl cellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, polymers of methacrylic acid and its esters, and combinations thereof.
  • Plasticizers such as, but not limited to polyethylene glycol, dibutylphthalate, triacetin and castor oil may be used.
  • a pigment may also be used to colour the film.
  • Suppositories are be prepared by using carriers like cocoa butter, suppository bases such as Suppocire C, and Suppocire NA50 (supplied by Gattefosse GmbH, D-Weil am Rhein, Germany) and other Suppocire type excipients obtained by interesterification of hydrogenated palm oil and palm kernel oil (C 8 - C 18 triglycerides), esterification of glycerol and specific fatty acids, or polyglycosylated glycerides, and witepsol (hydrogenated plant oils derivatives with additives).
  • Enemas are formulated by using the appropriate active compound according to the present invention and solvents or excipients for suspensions.
  • Suspensions are produced by using micronized compounds, and appropriate vehicle containing suspension stabilizing agents, thickeners and emulsifiers like carboxymethylcellulose and salts thereof, polyacrylic acid and salts thereof, carboxyvinyl polymers and salts thereof, alginic acid and salts thereof, propylene glycol alginate, chitosan, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxy ethylcellulose, ethylcellulose, methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, N-vinylacetamide polymer, polyvinyl methacrylate, polyethylene glycol, pluronic, gelatin, methyl vinyl ether-maleic anhydride copolymer, soluble starch, pullulan and a copolymer of methyl acrylate and 2-ethylhexyl acrylate lecithin, lecithin derivatives, propylene glycol fatty acid esters, glycerin fatty acid est
  • materials may be incorporated into the matrix of the tablet e.g. hydroxypropyl methylcellulose, ethyl cellulose or polymers of acrylic and methacrylic acid esters. These latter materials may also be applied to tablets by compression coating.
  • compositions can be prepared by mixing a therapeutically effective amount of the active substance with a pharmaceutically acceptable carrier that can have different forms, depending on the way of administration.
  • Pharmaceutical compositions can be prepared by using conventional pharmaceutical excipients and methods of preparation.
  • the forms for oral administration can be capsules, powders or tablets where usual solid vehicles including lactose, starch, glucose, methylcellulose, magnesium stearate, di- calcium phosphate, mannitol may be added, as well as usual liquid oral excipients including, but not limited to, ethanol, glycerol, and water. All excipients may be mixed with disintegrating agents, solvents, granulating agents, moisturizers and binders.
  • compositions e.g., starch, sugar, kaolin, binders disintegrating agents
  • preparation can be in the form of powder, capsules containing granules or coated particles, tablets, hard gelatin capsules, or granules without limitation, and the amount of the solid carrier can vary (between 1 mg to lg). Tablets and capsules are the preferred oral composition forms.
  • compositions containing compounds of the present invention may be in any form suitable for the intended method of administration, including, for example, a solution, a suspension, or an emulsion.
  • Liquid carriers are typically used in preparing solutions, suspensions, and emulsions.
  • Liquid carriers contemplated for use in the practice of the present invention include, for example, water, saline, pharmaceutically acceptable organic solvent(s), pharmaceutically acceptable oils or fats, and the like, as well as mixtures of two or more thereof.
  • the liquid carrier may contain other suitable pharmaceutically acceptable additives such as solubilisers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like.
  • Suitable organic solvents include, for example, monohydric alcohols, such as ethanol, and polyhydric alcohols, such as glycols.
  • Suitable oils include, for example, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and the like.
  • the carrier can also be an oily ester such as ethyl oleate, isopropyl myristate, and the like.
  • Compositions of the present invention may also be in the form of microparticles, microcapsules, liposomal encapsulates, and the like, as well as combinations of any two or more thereof.
  • Examples of pharmaceutically acceptable disintegrants for oral compositions useful in the present invention include, but are not limited to, starch, pre-gelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, croscarmellose sodium, microcrystalline cellulose, alginates, resins, surfactants, effervescent compositions, aqueous aluminium silicates and crosslinked polyvinylpyrrolidone.
  • binders for oral compositions useful herein include, but are not limited to, acacia; cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose; gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth, xanthane resin, alginates, magnesium-aluminium silicate, polyethylene glycol or bentonite.
  • acacia cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose
  • gelatin glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth, xanthane
  • Examples of pharmaceutically acceptable fillers for oral compositions include, but are not limited to, lactose, anhydrolactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (particularly microcrystalline cellulose), dihydro- or anhydro- calcium phosphate, calcium carbonate and calcium sulfate.
  • Examples of pharmaceutically acceptable lubricants useful in the compositions of the invention include, but are not limited to, magnesium stearate, talc, polyethylene glycol, polymers of ethylene oxide, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, and colloidal silicon dioxide.
  • suitable pharmaceutically acceptable flavourings for the oral compositions include, but are not limited to, synthetic aromas and natural aromatic oils such as extracts of oils, flowers, fruits (e.g., banana, apple, sour cherry, peach) and combinations thereof, and similar aromas. Their use depends on many factors, the most important being the organoleptic acceptability for the population that will be taking the pharmaceutical compositions.
  • suitable pharmaceutically acceptable dyes for the oral compositions include, but are not limited to, synthetic and natural dyes such as titanium dioxide, beta-carotene and extracts of grapefruit peel.
  • Suitable examples of pharmaceutically acceptable sweeteners for the oral compositions include, but are not limited to, aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose and sucrose.
  • Suitable examples of pharmaceutically acceptable buffers include, but are not limited to, citric acid, sodium citrate, sodium bicarbonate, dibasic sodium phosphate, magnesium oxide, calcium carbonate and magnesium hydroxide.
  • Suitable examples of pharmaceutically acceptable surfactants include, but are not limited to, sodium lauryl sulfate and polysorbates.
  • Suitable examples of pharmaceutically acceptable preservatives include, but are not limited to, various antibacterial and antifungal agents such as solvents, for example ethanol, propylene glycol, benzyl alcohol, chlorobutanol, quaternary ammonium salts, and parabens (such as methyl paraben, ethyl paraben, propyl paraben, etc.).
  • Suitable examples of pharmaceutically acceptable stabilizers and antioxidants include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), thiourea, tocopherol and butyl hydroxyanisole.
  • the compounds of the invention may also, for example, be formulated as suppositories e.g., containing conventional suppository bases for use in human or veterinary medicine or as pessaries e.g., containing conventional pessary bases.
  • the compounds according to the invention may be formulated for topical administration, for use in human and veterinary medicine, in the form of ointments, creams, gels, hydrogels, lotions, solutions, shampoos, powders (including spray or dusting powders), pessaries, tampons, sprays, dips, aerosols, drops (e.g., eye ear or nose drops) or pour-ons.
  • the compound of the present invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • Such compositions may also contain other pharmaceutically acceptable excipients, such as polymers, oils, liquid carriers, surfactants, buffers, preservatives, stabilizers, antioxidants, moisturizers, emollients, colorants, and flavourings.
  • Examples of pharmaceutically acceptable polymers suitable for such topical compositions include, but are not limited to, acrylic polymers; cellulose derivatives, such as carboxymethylcellulose sodium, methylcellulose or hydroxypropylcellulose; natural polymers, such as alginates, tragacanth, pectin, xanthan and cytosan.
  • the compound of the present invention can be administered intranasally or by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, spray or nebulizer with the use of a suitable propellant, e.g., a hydro fluoroalkane such as 1, 1, 1,2-tetrafluoroethane (HFA 134AT) or 1, 1, 1,2,3,3,3-heptafluoropropane (FIFA 227EA), or a mixture thereof.
  • a suitable propellant e.g., a hydro fluoroalkane such as 1, 1, 1,2-tetrafluoroethane (HFA 134AT) or 1, 1, 1,2,3,3,3-heptafluoropropane (FIFA 227EA), or a mixture thereof.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e.g., using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g., sorbitan trioleate.
  • a lubricant e.g., sorbitan trioleate.
  • Capsules and cartridges made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds according to the invention may be delivered for use in human or veterinary medicine via a nebulizer.
  • compositions of the invention may contain from 0.01 to 99% weight per volume of the active material.
  • the composition will generally contain from 0.01-10% w/w, more preferably 0.01-1%) w/w of the active compound.
  • a therapeutically effective amount of the compound of the present invention can be determined by methods known in the art.
  • the therapeutically effective quantities may vary and will depend on the severity of the disease, the age and the general physiological condition of the subject, the potency of the compound, the route of administration and the pharmaceutical formulation used.
  • the therapeutic doses will generally be from about 10 to 2000 mg/day and suitably from about 30 to 1500 mg/day. Other ranges may be used, including, for example, 50-500 mg/day, 50-300 mg/day, 100-200 mg/day.
  • the therapeutic dose may be about 10 mg/day, about 10 mg/day, about 50 mg/day, about 100 mg/day, about 150 mg/day, about 200 mg/day, about 250 mg/day, about 300 mg/day, about 350 mg/day, about 400 mg/day, about 450 mg/day, about 500 mg/day, about 550 mg/day, about 600 mg/day, about 650 mg/day, about 700 mg/day, about 750 mg/day, about 800 mg/day, about 850 mg/day, about 900 mg/day, about 950 mg/day, about 1,000 mg/day, about 1,050 mg/day, about 1, 100 mg/day, about 1, 150 mg/day, about 1,200 mg/day, about 1,250 mg/day, about 1,300 mg/day, about 1,350 mg/day, about 1,400 mg/day, about 1,450 mg/day, about 1,500 mg/day, about 1,550 mg/day, about 1,600 mg/day, about 1,650 mg/day, about 1,700 mg/day, about 1,750 mg/day, about 1,800
  • the daily dose as employed for acute human treatment will range from 0.01 to 40 mg/kg body weight, suitably 2 to 20 mg/kg body weight, or suitably 5 to 10 mg/kg body weight, which may be administered in one to four daily doses, for example, depending on the route of administration and the condition of the subject.
  • each unit may contain 10 mg to 2 g of active ingredient, suitably 200 mg to 1 g of active ingredient.
  • Administration may be once a day, twice a day, or more often, and may be decreased during a maintenance phase of treatment of the disease, e.g. once every second or third day instead of every day or twice a day.
  • the dose and the administration frequency will depend on the clinical signs with the reduction or absence of at least one or more, preferably more than one, clinical signs of the acute phase known to the person skilled in the art.
  • administration is once daily oral dosing.
  • the present invention is related to a pharmaceutical composition
  • a pharmaceutical composition comprising from about 10 to 2000 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, e.g. from about 0.1 to 2 g of one or more pharmaceutically acceptable excipients.
  • compounds of the invention modulate the Hh signalling pathway and are useful for the treatment of diseases and/or conditions associated with abnormal activation and/or malfunction of the Hh signalling pathway.
  • diseases and conditions include proliferative diseases, such as cancers; fibrosis and GVHD, etc. as herein defined.
  • the present invention provides novel compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use as a medicament.
  • the present invention provides novel compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the treatment of conditions involving abnormal activation of the hedgehog pathway.
  • a method of treatment of a disease or condition associated with abnormal activation and/or malfunction of the of the hedgehog pathway which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient suffering from such a disease or condition:
  • R 2 is selected from: a fused 9-10 membered bicyclic heteroaryl, a 5-6 membered heteroaryl; each of which is optionally substituted by one or more S0 2 -phenyl, wherein the phenyl is optionally substituted by one or more Ci- 6 alkyl;
  • R 3 is hydrogen or together R 3 and R 4 represent a bond
  • R 4 is hydrogen or together R 4 and R 3 represent a bond
  • R 5 is hydrogen or Ci- 6 alkyl
  • R 6 and R 7 which may be the same or different, are each hydrogen, Ci- 6 alkyl, haloCi. 6 alkyl or phenyl (wherein phenyl is optionally substituted by Ci- 6 alkyl);
  • the invention provides a method of treatment as herein described which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient suffering from such a disease or condition:
  • R 1 is selected from:
  • a 5-6 membered heteroaryl which is optionally substituted by one or more groups independently selected from: - Ci- 6 alkyl and Co- 6 alkyl-phenyl;
  • R 2 is selected from:
  • R 3 is hydrogen or together R 3 and R 4 represent a bond
  • R 4 is hydrogen or together R 4 and R 3 represent a bond
  • R 5 is hydrogen or Ci- 6 alkyl
  • R 6 and R 7 which may be the same or different, are each hydrogen, Ci- 6 alkyl, haloCi. 6 alkyl or phenyl (wherein phenyl is optionally substituted by Ci- 6 alkyl);
  • R 1 is a 5-6 membered heteroaryl
  • a preferred heteroaryl is selected from the group:
  • R 1 is a 4-6 membered carbocyclyl, a preferred carbocyclyl
  • R 1 is a 4-6 membered heterocyclyl
  • a preferred heterocyclyl is
  • R 1 is a 6-10 membered aryl
  • a preferred aryl is
  • the phenyl is preferably substituted in the 4-position.
  • the disease or condition associated with the abnormal activation or malfunction of the Hh signalling pathway is one or more of cancer, fibrosis and chronic graft-versus-host disease (cGVHD).
  • cGVHD chronic graft-versus-host disease
  • a method of treatment of cancer by modulating the Hh signalling pathway, which comprises the administration of a therapeutically effective amount of a novel compound of the invention.
  • cancer is selected from one or more of basal cell carcinoma, neuroectodermal tumours such as medullablastoma, meningioma, hemangioma, glioblastoma, pancreatic adenocarcinoma, squamous lung carcinoma, small-cell lung carcinoma, non-small cell lung carcinoma, chondrosarcoma, breast carcinoma, rhabdomyosarcoma, oesophageal cancer, stomach cancer, biliary tract cancer, renal carcinoma, thyroid carcinoma, primary cancer, breast cancer, colon cancer, prostate cancer, non-small cell lung cancer, glioblastoma, lymphoma, melanoma, mesothelioma, liver cancer, intrahepatic bile duct cancer, oesophageal cancer, pancreatic cancer, stomach cancer, laryngeal cancer, brain cancer, ovarian cancer, testi
  • neuroectodermal tumours such as medullablastoma, meningio
  • cancer in one preferred embodiment of the invention there is provided a method of treating cancer as hereinbefore described wherein the cancer is selected from one or more of basal cell carcinoma, neuroectodermal tumours such as medullablastoma, meningioma, hemangioma, glioblastoma, pancreatic adenocarcinoma, squamous lung carcinoma, small-cell lung carcinoma, non-small cell lung carcinoma, chondrosarcoma, breast carcinoma, rhabdomyosarcoma, oesophageal cancer, stomach cancer, biliary tract cancer, renal carcinoma and thyroid carcinoma.
  • neuroectodermal tumours such as medullablastoma, meningioma, hemangioma, glioblastoma, pancreatic adenocarcinoma, squamous lung carcinoma, small-cell lung carcinoma, non-small cell lung carcinoma, chondrosarcoma, breast carcinoma, rhabdomyosar
  • the cancer is selected from one or more of basal cell carcinoma, metastatic colorectal cancer, small-cell lung cancer, advanced stomach cancer, pancreatic cancer, medulloblastoma and chondrosarcoma.
  • fibrosis is cell necrosis caused by sustained inflammatory stimulation.
  • fibrosis is selected from one or more of pulmonary fibrosis, cystic fibrosis, cirrhosis, atrial fibrosis, endomyocardial fibrosis, myocardial infarction scaring, glial scar, arthrofibrosis, Crohn's disease, Dupuytren's contracture, keloid, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma/systemic sclerosis and adhesive capsulitis.
  • fibrosis is selected from one or more of liver, kidney, bile duct, pancreas, cardiac, systemic sclerosis/scleroderma and myelofibrosis.
  • liver fibrosis is selected from one or more of cirrhosis, chronic liver diseases, obesity-related liver disease or chronic viral hepatitis.
  • pulmonary fibrosis includes, but is not limited to, idiopathic or usual interstitial pneumonia, autoimmune lung diseases, chronic obstructive pulmonary disease (COPD), inflammatory pulmonary fibrosis, fibrosis secondary to asthma; adult respiratory distress syndrome; pulmonary sarcosis; fibrosis secondary to lung cancer, fibrosis secondary to graft-versus-host reaction; fibrosis secondary to viral diseases, including influenza virus, or Severe Acute Respiratory Syndrome (SARS).
  • COPD chronic obstructive pulmonary disease
  • cGVHD chronic graft-versus-host disease
  • GVHD is as a result of transplantation.
  • a compound of the invention can be administered as the sole active agent or it can be administered in combination with a second therapeutic agent, including other compounds that demonstrate the same or a similar therapeutic activity and that are determined to safe and efficacious for such combined administration.
  • coadministration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof, as herein described, in combination with a second therapeutically active ingredient in one embodiment, a compound of the invention or a pharmaceutical composition comprising the compound of the invention is administered as a medicament. In a specific embodiment, said pharmaceutical composition additionally comprises a further active ingredient.
  • a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutically active ingredient, optionally in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment of conditions and/or diseases involving abnormal activation of the hedgehog pathway.
  • the second therapeutic agent may act as a hedgehog modulator.
  • the second therapeutic agent may act as a hedgehog modulator via downstream effectors including, but not limited to, SMO, GLI, SHH or tGLIl (truncated, gain-of- function isoform of the GLI1 transcription factor).
  • SMO inhibitors include cyclopamine, vismodegib, erismodegib, saridegib, CUR61414, BMS-833923/XL139, glasdegib, PF-5274857, TAK-441, taladegib MRT-92 and jervine.
  • GLI inhibitors include Arsenic Trioxide (ATO) and GANTs (GLI antagonists) as described herein.
  • SHH inhibitors include RU-SKI 43 and SHH Monoclonal Antibodies.
  • tGLIl target gene inhibitors examples include, CD24, VEGF-A, VEGFR2, HPA1 and TEM7.
  • particular agents include, but are not limited to: other anticancer treatments such a chemotherapeutic agent, an immunotherapeutic agent, a gene therapy agent, and a radiotherapeutic agent.
  • the second therapy is selected from the group consisting of one or more of a chemotherapeutic agent; an alkylating agent, such as carmustine or temozolamide; a mitotic inhibitor, such as taxanes, (e.g. paclitaxol or docetaxol) or vinca alkaloids (e.g. vinblastine, vincristine, vindestine or vinorelbine); platinum derived compounds (e.g. carboplatin, cisplatin, nedaplatin, oxaliplatin, triplatin tetranitrate or satraplatin); dihydrofolate reductase inhibitors (e.g.
  • a DNA polymerase inhibitor e.g. cytarabine
  • a ribonucleotide reductase inhibitor e.g. gemcitabine
  • the second therapeutic agent may comprise: alemtuzumab, ipilimumab, nivolumab, ofatumumab, rituximab, actinomycin, azacitidine, azathioprin, carboplatin, capecitabin, cisplatin, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, imiquimod, irinotecan, mechlorethamine, mercaptopurin, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, sorafenib, temozolomide, teniposide, tioguanine, topotecan,
  • the additional therapeutic agent may be an immunotherapeutic agent.
  • the immunotherapeutic agent may consist of one or more of CAR-T cells, vectors, vaccines, armed antibodies; an agent capable of enhancing use of the immune system to treat cancer; an agent of the monoclonal antibody class capable of enhancing use of the immune system to treat cancer; an agent of the interferon class capable of enhancing use of the immune system to treat cancer.
  • the immunotherapeutic agent consists of one or more of CAR-T cells, vectors, vaccines, and armed antibodies.
  • the immunotherapeutic agent consists of any agent capable of enhancing use of the immune system to treat cancer.
  • the immunotherapeutic agent consists of any agent of the monoclonal antibody class capable of enhancing use of the immune system to treat cancer. In another aspect of the invention the immunotherapeutic agent consists of any agent of the interferon class capable of enhancing use of the immune system to treat cancer.
  • the immunotherapeutic agent consists of any agent of the interleukin class capable of enhancing use of the immune system to treat cancer.
  • Such an immunotherapeutic agent may be checkpoint inhibitor as herein described, e.g. an agent which targets immune checkpoints, wherein immune checkpoints are those pathways within the system for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses.
  • the checkpoint inhibitor may be an agent which targets, i.e. inhibits, one or more of CTLA4, PD1, PDL1, PDL2, CD80, CD86, CD28, B7RP1, ICOS, B7-H3, B7-H4, HVEM, BTLA, MHC-Class 1, MHC-Class 2, KIR,TCR, LAG3, CD137L, CD 137, OX40L, OX40, CD70, CD27, CD40, CD40L, GAL9, TIM3, A2aR, CD52, CD20, CD274 and CD279.
  • checkpoint inhibitor is one or more of a CTLA4, PD1 or PDLl inhibitor.
  • CTLA4 inhibitor include, but shall not be limited to,, one or more of ipilimumab, nivolumab, rituximab, pembrolizumab, ofatumumab, BMS-936559, Medl- 4736, MPDL-3280A, MSB0010718C, pidilizumab and MK-3475.
  • a particular CTLA4 inhibitor which may be mentioned is ipilimumab.
  • PD1 inhibitor include, but shall not be limited to,, one or more of nivolumab, pidilizumab and MK-3475.
  • PDL1 inhibitor examples include, but shall not be limited to, one or more of BMS- 936559, MedI-4736, MPDL-3280A and MSB0010718C.
  • particular agents include, but are not limited to: Inhibitors of SMO, ALK kinase, Notch, Wnt, Jak kinase or Bcl2.
  • examples include, pirfenidone, nintedanib, gamma secretase inhibitors, RO4929097, MRK-003, MK-0752 and PF03084014.
  • particular examples include bevacizumab (Avastin), itraconazole, carboxyamidotriazole, TNP-470, CM101, IFN-a, IL-12, platelet factor-4, suramin, SU5416, thrombospondin, VEGFR antagonists, angiostatic steroids with heparin, Cartilage-Derived Angiogenesis Inhibitory Factor, matrix metalloproteinase inhibitors, angiostatin, endostatin, 2-methoxyestradiol, tecogalan tetrathiomolybdate, thalidomide, thrombospondin, prolactin, ⁇ 3.
  • inhibitors linomide, tasquinimod, ranibizumab, sorafenib (Nexavar®), sunitinib (Sutent®), pazopanib (Votrient®) and everolimus (Afinitor®).
  • the compounds of the invention may be administered prior to, during or post-surgery, whereby surgery may be palliative or curative.
  • Co-administration includes any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation, i.e. as a single pharmaceutical composition, this is not essential. The agents may be administered in different formulations and at different times.
  • a compound of the invention as well as intermediate compounds of the invention, can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • the choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • a compound of the invention as well as intermediate of the invention can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • Column chromatography is performed on silica gel 60 (70-200 ⁇ ). Flash chromatography is carried out using prepacked columns with 15 or 50 ⁇ particle size silica gel.
  • Preparative thin-layer chromatography is carried out using pre-coated silica gel 2000 micron UV254 nm plates (thickness 2.0 mm).
  • Thin-layer chromatography is performed using pre-coated silica gel 60F-254 plates (thickness 0.25 mm).
  • MR spectra are recorded on Bruker DPX 300 MHz equipped with a 5 mm BBI probe, Bruker AV400 MHz equipped with a 5 mm PABBO probe, Bruker DRX 500 MHz equipped with a 5 mm PABBI probe and Bruker Avance III 600 spectrometer equipped with a 5 mm RT BBI probe.
  • the samples are recorded at 25 °C using DMSO-d 6 or CDC1 3 as a solvent, unless otherwise stated.
  • Chemical shifts ( ⁇ ) for 1H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane ( ⁇ 0.00) as internal reference.
  • Electrospray MS spectra are obtained on Waters Acquity UPLC with Waters Acquity PDA detector and SQD mass spectrometer. Columns used: UPLC BEH C18 1.7 ⁇ , 2.1x5mm VanGuard Pre-column with Acquity UPLC BEH C18 1.7 ⁇ , 2.1x50mm Column or Acquity UPLC CSH C18 1.7 ⁇ , 2.1x50mm Column. All the methods are using MeCN/H 2 0 gradients. MeCN and H 2 0 contains either 0.1% Formic Acid or lOmM
  • HPLC Waters Mass Directed Autopurification System
  • the system is composed of Waters Sample Manager 2767, Waters System Fluid Organizer, Waters Binary Gradient Module 2545, Waters 515 HPLC Pump, Waters Photodiode Array Detector 2998 and Waters Micromass ZQ MS detector.
  • Software used FractionLynx and MassLynx v4.1.
  • PDA detector settings wavelength: 210-400 nm, resolution: 1.2 nm, sampling rate: 1.0 points/sec, filter response: 1.
  • Microwave heating is performed with a Biotage Initiator.
  • Pharmaceutically acceptable acid addition salts which also represent an object of the present invention, may be obtained by reaction of a compound of Formula (I) with an at least equimolar amount of the corresponding inorganic or organic acid such as hydrochloric acid, hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, benzenesulfonic acid, methane sulfonic acid, laurylsulfonic acid, stearic acid, palmitic acid, succinic acid, ethylsuccinic acid, lactobionic acid, oxalic acid, salicylic acid and similar acid, in a solvent inert to the reaction.
  • a compound of Formula (I) such as hydrochloric acid, hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, benzenesulfonic acid, methane
  • Addition salts are isolated by evaporating the solvent or, alternatively, by filtration after a spontaneous precipitation or a precipitation by the addition of a non-polar co-solvent.
  • the following abbreviations listed in Table 1 are used in the Examples and other parts of the description.
  • Pd-PEPPSI-IPr [l,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(II) dichloride
  • RuPhos Pd Gl Chloro-(2-Dicyclohexylphosphino-2',6'-diisopropoxy-l, 1 '- MTBE adduct; biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) - methyl-t- RuPhos pre- butyl ether adduct
  • a compound of the invention as well as intermediate of the invention can be produced according to the following procedures.
  • the reaction is typically performed by combining an appropriate aryl or heteroaryl halide of formula R ⁇ -Hal (1 equiv.) and [4-(tert-butoxycarbonylamino)cyclohexen-l-yl]boronic acid pinacol ester of formula (Ila) (1 equiv.) in the presence of a palladium catalyst (0.05- 0.2 equiv.), such as Pd(PPh 3 ) 4 or any other suitable catalyst, and a base (1-5 equiv.), such as sodium carbonate or potassium carbonate, in a suitable solvent or mixture of solvents (typically, a mixture of dioxane and water) under inert atmosphere.
  • a suitable solvent or mixture of solvents typically, a mixture of dioxane and water
  • the expected Intermediate of formula (Ilia) may be isolated and, if desired, further purified by methods known to one skilled in the art.
  • the reaction is typically performed by adding an appropriate heteroaryl of formula R ⁇ -H (1-1.2 equiv.) and KOtBu or KOH (3 equiv.) to a solution of fert-butyl N-(4- oxocyclohexyl)carbamate derivative of formula (lib) (1 equiv.) in methanol.
  • the resulting mixture is stirred at room temperature to reflux for 3-48 h.
  • the expected intermediate of formulae (Ilia) may be isolated and, if desired, further purified by methods known to one skilled in the art.
  • the reaction is typically performed by adding ammonium formate (5-10 equiv.) and 10 wt% Pd/C (0.08-0.5 equiv.) to a solution of an appropriate compound containing cyclohexene moiety (1 equiv.) in MeOH or any other suitable solvent.
  • the resulting mixture is heated typically at 90°C for 30 min to 30 h to afford the expected cyclohexane compound, which may be isolated and, if desired, further purified by methods known to one skilled in the art.
  • the reaction is typically performed by adding KOtBu (1 equiv.) to a mixture of an appropriate Mi-functionality-containing heteroaryl, for example to a heteroaryl halide intermediate of formula R ⁇ Hal (1 equiv.) in THF or DMF, followed by TsCl (1 equiv.) and the resulting mixture is stirred at RT for 10 minutes to 18 hours.
  • the expected Ts- protected product for example Ts protected R ⁇ Hal, may be isolated and, if desired, further purified by methods known to one skilled in the art.
  • heteroaryl intermediate of formula R 1 -!! (1 equiv.) in DMF at 0 °C an appropriate heteroaryl derivative
  • BS (1 equiv.) is added under inert atmosphere, and the resulting solution is stirred at 0 °C for 20 min.
  • the reaction mixture is allowed to reach room temperature and stirring is continued for a suitable period of time.
  • the expected brominated heteroaryl analogue for example brominated R 1 heteroaryl ring analogue, may be isolated and, if desired, further purified by methods known to one skilled in the art.
  • a suitable solvent or mixture of solvents typically, a THF/MeOH mixture
  • caesium carbonate 4-6 equiv.
  • the expected product may be isolated and, if desired, further purified by methods known to one skilled in the art.
  • the reaction is typically performed by adding 1 equiv. of isocyanate to a solution of an appropriate compound of formula (1-2) (1 equiv.) in a suitable solvent (such as THF) or a solvent mixture (such as a DCM/DMF mixture), with 2.8 equiv. of base, such as TEA, or without an addition of the base.
  • a suitable solvent such as THF
  • a solvent mixture such as a DCM/DMF mixture
  • base such as TEA
  • the reaction is typically performed by adding an appropriate amine (1 equiv.) and base (6- 10 equiv.) (such as TEA) to a solution of triphosgene (0.7-1.0 equiv.) in a suitable solvent, such as TFIF, at 0 °C to room temperature.
  • a suitable solvent such as TFIF
  • the resulting mixture is stirred for 20 min to 24 h at 0 °C to room temperature, then mixed with a THF solution (or suspension) of an appropriate compound of formula (1-2) (0.5-1 equiv.) to which, if required, additional amount of base, such as TEA, may be added.
  • the reaction mixture is stirred at room temperature for 1-2 h.
  • the expected product of formula (1-3) may be isolated and, if desired, further purified by methods known to one skilled in the art.
  • Triphosgene (19.9 mg, 1 equiv.) was dissolved in dry DCM (1 mL). Then, (2R)-1, 1, 1- trifluoropropan-2-amine (10 mg, 1 equiv.) and TEA (73 ⁇ ., 8 equiv.) were added. The resulting slurry was stirred at RT for 2 hours. tram V-(4-Furo[3,2-£]pyridin-3- ylcyclohexyl)azetidine-3-sulfonamide (33.5 mg, 1.5 equiv.) and TEA (18 ⁇ ., 2 equiv.) were added, and the mixture was stirred at RT for two hours.
  • the reaction is typically performed by adding an appropriate alcohol (1 equiv.) and a base (5.2 equiv.), such as D/ ' PEA, to a solution of triphosgene (0.4 equiv.) in a suitable solvent, such as THF, at 0 °C to RT.
  • a suitable solvent such as THF
  • THF a suitable solvent
  • the resulting mixture is stirred for 2 h at 0 °C to RT.
  • the resulting mixture is stirred at RT for 5 min.
  • the expected product of formula (1-4) may be isolated and, if desired, further purified by methods known to one skilled in the art.
  • a base (2-3 equiv.), such as TEA or potassium carbonate, and alkyl halide (1.5 equiv.) are added.
  • the resulting mixture is stirred at RT for 2 hours or at 100-150 °C for 30 min by using microwave irradiation.
  • the expected product of formula (1-6 or XIV-6) may be isolated and, if desired, further purified by methods known to one skilled in the art.
  • C3H10T1/2 cells are seeded into a black 384-well plate and cultured for 24-hours until they have reached confluency. The media is replaced with a reduced serum media and the cells are then stimulated with mSHH for 72 hours at 37°C in the presence or absence of test compound.
  • the Cell Titer-Blue® reagent is then removed and alkaline phosphatase activity is measured using the phosphatase substrate 4-methylumbelliferyl phosphate.
  • the cells are incubated in the dark in the presence of the substrate for 1 1 ⁇ 2-2 hours at room temperature and substrate conversion is determined by detecting fluorescence at
  • IC50 ranges for compounds of the invention are presented in Table 2, whereby the IC50 ranges are as follows:
  • the assay measures the ability of the test compounds to compete with a fluorescently- labelled version of the known ligand, cyclopamine, for binding to SMO.
  • the fluorescent tag used is BODIPY (boron dipyrromethene).
  • An aliquot of a membrane preparation from a SMO-over-expressing HEK293 cell line is diluted to protein concentration of 0.117mg/ml in assay buffer (25mM HEPES, 2mM EDTA, 0.05% ⁇ -globulin, 0.01% pluronic acid pH7.4, plus protease Inhibitor cocktail). 8.5 ⁇ 1 of the membrane suspension is added to each well of a black, low volume 384 well microtitre plate.
  • Test compounds are added in a seven point dilution range to the wells containing the membrane preparation.
  • the final DMSO solvent concentration in the wells is maintained at 0.3%.
  • 6.5 ⁇ 1 of a 6.9nM BODIPY-cyclopamine solution is added to each of the wells (final assay concentration 3nM).
  • Table 4 details the ratio of SMO binding compared to the potency in the C3H10T1/2 cellular assay.
  • the small ratio between SMO binding and potency for vismodegib is considered to be reflective of the fact vismodegib acts mainly through inhibition of the SMO protein.
  • the larger ratios for the compound of the invention are considered to be reflective of alternate actions outside of direct SMO inhibition.
  • the objective of this study is to assess the pharmacodynamic (PD) effect of three novel inhibitors of the hedgehog pathway (of Formula I) and Sonidegib, on a subcutaneous Calu-6 xenograft model.
  • Hedgehog Signaling Pathway is a New Therapeutic Target for Patients with Breast Cancer. Cancer Res.
  • Trisenox® arsenic trioxide
  • GDC-0449 A potent inhibitor of the hedgehog pathway .
  • tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 384, 129-134.
  • Patched acts catalytically to suppress the activity of Smoothened. Nature 418, 892-896.
  • Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425, 851.
  • Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion.
  • Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458, 776.

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Abstract

L'invention concerne des composés de formule (I) dans laquelle R1, R2, R3, R4 et R5 sont tels que définis dans la description ; et leur utilisation en tant que médicament dans le traitement d'états pathologiques impliquant une activation et/ou un dysfonctionnement anormal de la voie hedgehog, tels que le cancer, la fibrose et la maladie du greffon contre l'hôte chronique (c GVHD).
PCT/GB2018/052430 2017-08-29 2018-08-29 Cyclyl-sulfonamides substitués utilisés en tant que modulateurs de la voie de signalisation du hedgehog (hh) WO2019043373A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006028958A2 (fr) * 2004-09-02 2006-03-16 Genentech, Inc. Inhibiteurs pyridyles de la signalisation hedgehog
WO2018078360A1 (fr) * 2016-10-26 2018-05-03 E-Therapeutics Plc Modulateurs de la voie de signalisation hedgehog (hh)

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006028958A2 (fr) * 2004-09-02 2006-03-16 Genentech, Inc. Inhibiteurs pyridyles de la signalisation hedgehog
WO2018078360A1 (fr) * 2016-10-26 2018-05-03 E-Therapeutics Plc Modulateurs de la voie de signalisation hedgehog (hh)

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