WO2019043372A1 - Substitutes sulfonyl azacycles as modulators of hedgehog (hh) signalling pathway - Google Patents

Substitutes sulfonyl azacycles as modulators of hedgehog (hh) signalling pathway Download PDF

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WO2019043372A1
WO2019043372A1 PCT/GB2018/052429 GB2018052429W WO2019043372A1 WO 2019043372 A1 WO2019043372 A1 WO 2019043372A1 GB 2018052429 W GB2018052429 W GB 2018052429W WO 2019043372 A1 WO2019043372 A1 WO 2019043372A1
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alkyl
pyrrolo
sulfonylpiperidin
tert
pyridine
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Mihaela JURKOVIC
Ivana Ozimec Landek
Tanja Poljak
Maja ROŠCIC
Colin STUBBERFIELD
Srinivasamurthy VADLAMUDI
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E-Therapeutics Plc
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    • C07D491/04—Ortho-condensed systems
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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):
  • X is R 3 or CR 3 R 4 ;
  • R 1 is hydrogen or together R 1 and R 4 represent a bond;
  • R 2 is selected from: a fused 9-10 membered bicyclic heteroaryl, a 5-6 membered heteroaryl, a 6-10 membered aryl and a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl; each of which is optionally substituted by one or more groups independently selected from - R 5 R 6 , halogen, N0 2 , phenyl, CN, -Ci- 6 alkyl-0-Ci- 6 alkyl, Ci -6 alkyl, haloCi -6 alkyl, -OCi -6 alkyl, -Ci -6 alkyl-OH, -Ci.
  • R 4 is hydrogen or together R 4 and R 1 represent a bond
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 which may be the same or different, are each hydrogen or Ci- 6 alkyl;
  • n and n which may be the same or different, are each 0 or 1 ;
  • the compound of formula I is not 4-[l-(4-tert-butylphenyl) sulfonylpiperidin-4-yl]pyridine; and is not 2-[4-(2,4-dimethylphenyl)piperazin-l-yl] sulfonyl-5 , 6, 7, 8,9, 10-hexahydrocyclohepta[b] indole.
  • X is R 3 or CR 3 R 4 ;
  • R 2 is selected from:
  • R 3 is selected from:
  • (iii) 6-10 membered aryl optionally substituted by one or more groups independently selected from halogen, -OCi- 6 alkyl( R 8 R 9 ), -OCi- 6 alkyl(C 0)amino, -OCi. ealkylnitrile, -OCi -6 alkyl(COOH), OH, Ci -6 alkyl, -OCi -6 alkyl, haloCi -6 alkyl, H 2 ;
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m and n are each as herein defined;
  • X is NR 3 .
  • X is CR 3 R 4 .
  • R 2 is a fused 9-10 membered bicyclic heteroaryl
  • a preferred bicyclic heteroaryl is selected from the group:
  • R 2 is a 5-6 membered heteroaryl
  • a preferred heteroaryl is selected from the group:
  • R 2 is a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl a preferred bicyclic or tricyclic heterocyclyl is:
  • a preferred bicyclic heteroaryl is selected from the group:
  • R is a 5-6 membered heteroaryl
  • a preferred heteroaryl is selected from the group:
  • R 3 is a fused 8-10 membered partially unsaturated bicyclic heterocyclyl
  • a preferred partially unsaturated bicyclic heterocyclyl is selected from the group:
  • R 3 is a 6-10 membered aryl, a preferred is selected from the group:
  • n is 0. In another embodiment of the present invention n is i .
  • the present invention also relates to pharmaceutical compositions comprising a compound of the invention.
  • the present invention provides 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).
  • 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, eg 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):
  • X is R 3 or CR 3 R 4 ;
  • R 1 is hydrogen or together R 1 and R 4 represent a bond
  • R 2 is selected from: a fused 9-10 membered bicyclic heteroaryl, a 5-6 membered heteroaryl, a 6-10 membered aryl and a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl; each of which is optionally substituted by one or more groups independently selected from - R 5 R 6 , halogen, N0 2 , phenyl, CN, -Ci- 6 alkyl-0-Ci- 6 alkyl, Ci -6 alkyl, haloCi -6 alkyl, -OCi -6 alkyl, -Ci -6 alkyl-OH, -Ci.
  • R 4 is hydrogen or together R 4 and R 1 represent a bond
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 which may be the same or different, are each hydrogen or Ci- 6 alkyl;
  • n and n which may be the same or different, are each 0 or 1;
  • X is R 3 or CR 3 R 4 ;
  • R 2 is selected from:
  • R 3 is selected from:
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m and n are each as herein defined.
  • the present invention provides a compound of formula (I) for use as a medicament wherein X is R 3 .
  • the present invention provides a compound of formula (I) for use as a medicament wherein X is CR 3 R 4 .
  • R 2 is a fused 9-10 membered bicyclic heteroaryl
  • a preferred bicyclic heteroaryl is selected from the group:
  • R 2 is a 5-6 membered heteroaryl a preferred heteroaryl is selected from the group:
  • R 2 is a 6-10 membered aryl
  • a preferred aryl is:
  • R 2 is a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl a preferred bicyclic or tricyclic heterocyclyl is:
  • a preferred bicyclic heteroaryl is selected from the group:
  • R is a 5-6 membered heteroaryl
  • a preferred heteroaryl is selected from the group:
  • R is a fused 8-10 membered partially unsaturated bicyclic heterocyclyl a preferred partially unsaturated bicyclic heterocyclyl is selected from the group:
  • R 3 is a 6-10 membered aryl
  • a preferred aryl is selected from the group:
  • the present invention provides a compound of formula (I) for use as a medicament wherein n is 0.
  • the present invention provides a compound of formula (I) for use as a medicament wherein n is 1.
  • specific compounds of formula I which may mentioned include those selected from the group consisting of: N,N-dimethyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyridin-2-amine;
  • 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.
  • reference to intermediates of the invention, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
  • the compounds and intermediates of the invention have more than one asymmetric carbon atom.
  • the solid wedge shaped bond indicates that the bond is above the plane of the paper.
  • the broken bond indicates that the bond is below the plane of the paper.
  • 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.
  • the term '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.
  • the compound of the invention is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • 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.
  • the two (delayed and positioned release) profiles can be combined in a single formulation by choice of one or more appropriate coatings and other excipients. Such formulations constitute a further feature of the present invention.
  • Suitable 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, hydroxyethylcellulose, 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 esters
  • micronized particles can be between 1 and 20 micrometers, or can be less than 1 micrometer.
  • Compounds can also be incorporated in the formulation by using their water-soluble salt forms. Alternatively, 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 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.
  • 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 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, eg 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 a patient suffering from such a disease or condition:
  • X is R 3 or CR 3 R 4 ;
  • R 1 is hydrogen or together R 1 and R 4 represent a bond
  • R 2 is selected from: a fused 9-10 membered bicyclic heteroaryl, a 5-6 membered heteroaryl, a 6-10 membered aryl and a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl; each of which is optionally substituted by one or more groups independently selected from - R 5 R 6 , halogen, N0 2 , phenyl, CN, -Ci- 6 alkyl-0-Ci- 6 alkyl, Ci -6 alkyl, haloCi -6 alkyl, -OCi -6 alkyl, -Ci -6 alkyl-OH, -Ci.
  • R 4 is hydrogen or together R 4 and R 1 represent a bond
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 which may be the same or different, are each hydrogen or Ci- 6 alkyl;
  • n and n which may be the same or different, are each 0 or 1 ;
  • the invention relates to 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:
  • X is R 3 or CR 3 R 4 ;
  • R 2 is selected from:
  • R 3 is selected from:
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m and n are each as herein defined;
  • X is NR 3 .
  • X is CR 3 R 4 .
  • R 2 is a fused 9-10 membered bicyclic heteroaryl
  • a preferred bicyclic heteroaryl is selected from the group :
  • R 2 is a 5-6 membered heteroaryl
  • a preferred heteroaryl is selected from the group:
  • R 2 is a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl
  • preferred bicyclic or tricyclic heterocyclyl is:
  • a preferred bicyclic heteroaryl is selected from the group:
  • R 3 is a 5-6 membered heteroar l
  • a preferred heteroaryl is selected from the group:
  • R 3 is a fused 8-10 membered partially unsaturated bicyclic heterocyclyl
  • a preferred partially unsaturated bicyclic heterocyclyl is selected from the group:
  • R 3 is a 6-10 membered aryl
  • a preferred is selected from the group:
  • n 0.
  • n is i .
  • 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).
  • 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.
  • 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, thyroid carcinoma, primary cancer, breast cancer, colon cancer, prostate cancer, non-small cell lung cancer, glioblastoma, lymphoma, melanoma, mesotheliom
  • 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
  • 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
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • 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).
  • SARS Severe Acute Respiratory Syndrome
  • 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.
  • a compound of the invention or a pharmaceutical composition comprising the compound of the invention is administered as a medicament.
  • said pharmaceutical composition additionally comprises a further active ingredient.
  • 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, SUH 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.
  • SUH inhibitors examples include RU-SKI 43 and SHH Monoclonal Antibodies.
  • tGLIl target gene inhibitors examples include, CD24, VEGF-A, VEGFR2, HPA1 and TEM7. Cancer
  • 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. In another aspect of the invention 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.
  • 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.
  • Examples of PD1 inhibitor include, but shall not be limited to,, one or more of nivolumab, pidilizumab and MK-3475.
  • Examples of PDL1 inhibitor 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.
  • bevacizumab (Avastin), itraconazole, carboxyamidotriazole, TNP-470, CMlOl, 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.
  • 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-catalyst butyl ether adduct
  • a compound of the invention as well as intermediate of the invention can be produced according to the following procedures. SYNTHETIC PREPARATION OF THE COMPOUND OF THE INVENTION
  • the reaction is typically performed by combining an appropriate aryl or heteroaryl halide of formula R ⁇ -Hal (1 equiv.) and N-Boc-l,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester of formula (Ila) or N-Cbz-l,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester of formula (He) (1-1.2 equiv.) in the presence of a palladium catalyst (0.05-0.2 equiv.), such as Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 x CH 2 Cl 2 or any other suitable catalyst, and a base (1-5 equiv.), such as sodium carbonate or potassium carbonate, in a suitable solvent or a mixture of solvents (typically, a mixture of dioxane and water) under inert atmosphere.
  • a palladium catalyst 0.05-0.2 equiv.
  • a palladium catalyst such as Pd
  • the resulting mixture was sealed in a microwave vial and heated under microwave irradiation for 30 min at 120 °C.
  • the reaction mixture was poured into water and extracted with EtOAc (2 ⁇ ). Combined organic extracts were washed with water and brine, dried, and the solvent was removed in vacuo.
  • the obtained crude product was purified by flash chromatography on silica gel (eluting with a cyclohexane/EtOAc gradient, 0-30 % of EtOAc) to afford the expected product (270 mg).
  • Method A2 General procedure for the preparation of piperidine Intermediates of formulae (Ilia), (IIIc) and (Hid) by condensation
  • the reaction is typically performed by adding an appropriate heteroaryl of formula R ⁇ -H (1-1.2 equiv.) and KOH or KOtBu (3-4 equiv.) to a solution of an appropriate Boc-4- piperidone derivative of formula (lib) or (lid) (1 equiv.) in ethanol or methanol.
  • the resulting mixture is heated at room temperature to reflux for 4-24 h.
  • the expected Intermediate of formulae (Ilia), (IIIc) and (Hid) may be isolated and, if desired, further purified by methods known to one skilled in the art.
  • Method B2 General procedure for the preparation of piperidine Intermediates of formula (IHb) or (Hie) by transfer hydrogenation with ammonium formate
  • the reaction is typically performed by adding ammonium formate (1-10 equiv.) and 10 wt% Pd/C (0.08-0.5 equiv.) to a solution of an appropriate Intermediate of formulae (Ilia) or (IIIc) and (Hid) (1 equiv.) in EtOH, MeOH, or any other suitable solvent.
  • the resulting mixture is heated typically at 50-90°C for 30 min to 30 h to afford the expected Intermediate of formula (Illb) or (Hie), which may be isolated and, if desired, further purified by methods known to one skilled in the art.
  • the reaction is typically performed under argon atmosphere by adding a 1.3 M THF solution of LiHMDS (2.5 equiv.) to a mixture of an appropriate heteroaryl halide of formula R ⁇ -Hal (1 equiv.), 1-Boc-piperazine of formula (Ilf) (1.2-1.3 equiv.), RuPhos (0.02-0.05 equiv.) and Ruphos pre-catalyst, MTBE adduct (0.02-0.05 equiv.) in THF.
  • the resulting mixture is purged with argon for 5 min, and then sealed in a vial and heated for 3 h at 70-75 °C.
  • the expected Intermediate of formula (Illg) 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 solution of an appropriate Mi-functionality-containing heteroaryl, for example to a heteroaryl halide intermediate of formula R ⁇ Hal (1 equiv.), in THF, followed by an addition of TsCl (1- 1.5 equiv.) and the resulting mixture is stirred at RT for 1-5 h.
  • an appropriate Mi-functionality-containing heteroaryl for example to a heteroaryl halide intermediate of formula R ⁇ Hal (1 equiv.)
  • TsCl (1- 1.5 equiv.
  • Method HI Amide cou ling with HATU, HBTU or TBTU
  • oxalyl chloride 8 equiv.
  • a suitable solvent such as DCM, DMF, or a mixture thereof
  • oxalyl chloride 8 equiv.
  • the reaction mixture is stirred at RT for 1.5 h, and is then diluted with toluene and concentrated in vacuo.
  • the resulting oil is taken up in THF and is added to a mixture of an appropriate aniline (1.0 equiv.) and NaH (2.1 equiv.) in THF at 0 °C.
  • the reaction mixture is stirred at 0 °C for 45 min and at RT for 18 h.
  • the expected amide 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 TEA (1 equiv.) to a mixture of an appropriate pyrazole compound (1 equiv.) in dry DMF at 0 °C, followed by TrCl (0.99 equiv.) and the resulting mixture is stirred at RT for 24 h.
  • TrCl (0.99 equiv.
  • the reaction is typically performed by adding Cul (0.1 equiv.) to the mixture of an appropriate heteroaryl iodide (1 equiv.), thiobenzoic acid (1.2 equiv.), 1, 10-phenantroline (0.2 equiv.), and a base, such as DIPEA (2 equiv.) in degassed toluene, and the resulting mixture is stirred under argon atmosphere at reflux for 16-24 h.
  • a base such as DIPEA (2 equiv.)
  • the reaction is typically performed by adding TCCA (1.2 equiv.) to the suspension of BnMesNCl (3.4 equiv.) in acetonitrile, and the resulting solution is added dropwise to a solution of an appropriate heteroaryl thiobenzoate in acetonitrile at 0 °C, followed by an addition of a base, such as Na 2 C0 3 (1 equiv.), and the resulting mixture is stirred at RT for 1 h.
  • a base such as Na 2 C0 3 (1 equiv.
  • the reaction mixture was poured into a saturated aq. solution of Na 2 C03 (60 mL) and extracted with EtOAc (2x50 mL). Combined organic extracts were washed with brine (60 mL), dried over Na 2 S0 4 , filtered, and the solvent was removed in vacuo.
  • the crude product was purified by flash chromatography on silica gel (eluting with a cyclohexane/EtOAc gradient, 0-10 % of EtOAc) to afford the expected product (385 mg).
  • TFA 2-150 equiv.
  • the expected product may be isolated and, if desired further purified by methods known to one skilled in the art.
  • borane- dimethyl sulfide complex (4-10 equiv.), and the resulting mixture is stirred under reflux for one hour and at RT for 18 h.
  • the expected product may be isolated and, if desired, further purified by methods known to one skilled in the art.
  • a heteroaryl halide (1 equiv.) in dry THF is added a base (such as TEA, 4 equiv.), followed by a primary or secondary amine (13 equiv.), and the resulting reaction mixture is heated at 100 °C in MW for 20 min to 2 h.
  • a base such as TEA, 4 equiv.
  • a primary or secondary amine 13 equiv.
  • the expected product may be isolated and, if desired, further purified by methods known to one skilled in the art.
  • a primary amine (1 equiv.) in a suitable solvent such as dry 1,2-DCE or dry MeOH
  • a suitable solvent such as dry 1,2-DCE or dry MeOH
  • an aldehyde (1-1.2 equiv.) is added, and the resulting reaction mixture is stirred at RT for 1-24 h.
  • Reducing agent such as NaBLL . or NaBH(OAc) 3 (1.6-3 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 an appropriate amine (1-8 equiv.) and base (2-10 equiv.) (such as TEA or D/ ' PEA) to a solution of triphosgene (0.3-1.5 equiv.) in a suitable solvent, such as THF, at 0 °C to room temperature.
  • a suitable solvent such as THF
  • the resulting mixture is stirred for 20 min to 24 h at 0 °C to room temperature, and then mixed with a THF solution (or suspension) of an appropriate pyrazole sulfonamide compound (0.5-1 equiv.) to which, if required, additional amount of base, such as TEA or D/ ' PEA may be added.
  • the reaction mixture is stirred at room temperature for 1-24 h.
  • the expected urea product may be isolated and, if desired, further purified by methods known to one skilled in the art.
  • Triphosgene (21.9 mg, 0.74 equiv.) was dissolved in dry THF (1 mL). Then, a solution of N-tert-butylmethylamine (57.7 ⁇ ., 4 equiv.) and TEA (40 ⁇ ⁇ , 3 equiv.) in dry THF (0.5 mL) was added dropwise.

Abstract

There are described compounds of formula (I) in which X, R1, R2 and n are each as herein defined; and their use as a medicament in the treatment of conditions involving abnormal activation and/or malfunction of the hedgehog pathway, such as cancer, fibrosis and chronic graft-versus-host disease (c GVHD).

Description

SUBSTITUTES SULFONYL AZACYCLES AS MODULATORS
OF HEDGEHOG (HH) SIGNALLING
Field of the Invention
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.
In particular, 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.
Background of the Invention
The evolutionarily conserved 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). The Hh gene product was later identified as a secreted glycoprotein ligand that triggers an intracellular signalling cascade critical for segment polarity (Mohler & Vani, 1992). Whilst flies possess one Hh gene, three are found in mammals: Sonic (SHH), Indian (IHH) and Desert (DHH) (Echelard et al, 1993). SHH is the best studied and is of fundamental importance during embryo development and post-natal homeostasis (Echelard et al, 1993; Chiang et al, 1996). There are few parts of the vertebrate body plan that are not influenced in some way by a SHH signal. The other two members of the family, IHH and DHH, have been shown to participate in bone development and spermatogenesis, respectively (Bitgood et al, 1996; St- Jacques et al, 1999). Although vertebrate Hh signalling is critical for many aspects of development, the importance of this pathway in later life appears more limited. During adulthood, the Hh pathway maintains normal tissue homeostasis and plays a regulatory role in stem cells (Lai et al, 2002; Levy et al, 2005).
All 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). In the absence of the Hh ligand, PTCHl blocks the downstream pathway by inhibiting the central positive mediator of Hh signalling, a 7-TMD G-protein-coupled-like receptor called Smoothened (SMO) (Alcedo et al, 1996; Murone et al, 1999). When the Hh ligand binds to PTCHl, repression of SMO is released due to internalization and degradation of both PTCHl and Hh (Incardona et al., 2000). The mechanism by which PTCHl inhibits SMO and how Hh releases this suppression is unknown, but it is thought that PTCHl inhibits the transport or synthesis of SMO rather than a direct inhibitory interaction (Taipale et al, 2002). Upon release of PTCHl, SMO is able to enter the primary cilium and become phosphorylated by casein kinase 1 (CK1) and the G-protein coupled receptor kinase 2 (GPRK-2) to assume its activated conformation (Chen et al, 2011). 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. In 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. Ultimately, it is the balance of the collective activator and repressor functions of the Gli transcription factors that determines the status of the Hh transcriptional program. 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. Tumorigenesis, tumour progression and therapeutic response have all been shown to be impacted by the SHH signalling pathway. An explanation for this is that 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.
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). 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. In chronic myeloid leukaemia and breast cancer, studies have shown that SHH signalling is essential for the maintenance of cancer stem cells and inhibition of the SHH pathway resulted in decreased stem cell propagation and renewal (Zhao et al, 2009). Furthermore, studies in epithelial cancers have found that tumours cells actually secrete the SHH ligand in a paracrine fashion to stimulate the production of growth factors to promote tumour progression and survival (Yauch et al, 2008).
Development of therapeutics targeting the Hh signalling pathway has primarily focused on targeting the SMO and GLil proteins. 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). 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). However, 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. However, the list of GLi antagonists (GANTS) is not as extensive as that of SMO antagonists and the only FDA- approved inhibitor of GLi is arsenic trioxide (ATO) which has been approved for the treatment of promyelocytic leukaemia (List et al, 2003). ATO binds directly to GLil and GLi2 preventing their nuclear accumulation in response to the Hh signal. This is currently in several clinical trials for a wide range of other cancer types (phase I to IV) (Rimkus et al, 2016). 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). In a human prostate cancer xenograft model in mice, 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.
Efforts have also been made to develop inhibitors directly targeting SHh as it is the most potent of the three Hh ligands (Pathi et al, 2001). These include a monoclonal antibody 5E1 (Coon et al, 2010) and an inhibitor of the enzyme SHHat which is critical to the synthesis of SHH (Petrova et al, 2013). Both are currently in pre-clinical development (Rimkus et al., 2016). Due to the prevalence of Hh signalling pathway dysregulation in multiple cancers and the resistance problems associated with current therapeutics, there is a need for potent inhibitors of the Hh signalling pathway, especially those targeting components other than SMO. Abnormal activation has also been shown to result in excessive extracellular matrix deposition, resulting in fibrosis.
In fibrosis, 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). 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). It is known that some signalling pathways have an important role in the occurrence and development of tissue fibrosis, such as Wnt/p-catenin (He et al, 2009), Notch (Bielesz et al, 2010), Ras-Raf-Mek (Grande et al, 2010), and the PI3K/Akt (phosphoinositide 3- kinase/protein kinase B) pathway (Niu et al, 2007). Recently, evidence has suggested that the Hh signalling pathway may be involved in fibrogenesis in multiple tissues (Omenetti et al, 2007; Jung et al, 2011; Fabian et al, 2012).
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 is a prognosis limiting complication of allogeneic stem cell transplantation. Treatment with a small-molecule antagonist of SMO, abrogated the activation of Hh signalling and protected against experimental cGVHD (Zerr et al, 2012).
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.
Summary of the Invention
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. In a particular aspect, 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.
In one aspect the invention relates to a compound of Formula (I):
Figure imgf000007_0001
in which:
X is R3 or CR3R4; R1 is hydrogen or together R1 and R4 represent a bond;
R2 is selected from: a fused 9-10 membered bicyclic heteroaryl, a 5-6 membered heteroaryl, a 6-10 membered aryl and a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl; each of which is optionally substituted by one or more groups independently selected from - R5R6, halogen, N02, phenyl, CN, -Ci-6alkyl-0-Ci-6alkyl, Ci-6alkyl, haloCi-6alkyl, -OCi-6alkyl, -Ci-6alkyl-OH, -Ci.6alkylC(=0)Ci-6alkyl, Ci. 6alkylC(=0)OR7, -C(=0)OCi-6alkyl,
Figure imgf000008_0001
-
Figure imgf000008_0002
-C(=0)het1 (wherein het1 is a 5-6-membered unsaturated heterocyclyl), - HC(=0)het2 (wherein het2 is a 5-6-membered heteroaryl which is optionally substituted by one or more Ci-6alkyl), -C(=0) Hhet2;
R3 is selected from: a fused 9-10 membered bicyclic heteroaryl, a 5-6 membered heteroaryl, a 6-10 membered aryl, a fused 8-10 membered partially unsaturated bicyclic heterocyclyl and - H(CH2)mhet3 (wherein het3 is a 5-6-membered heteroaryl); each of which is optionally substituted by one or more groups independently selected from: halogen, OH, H2, Ci-6alkyl, -OCi-6alkyl, haloCi-6alkyl, C2-6alkenyl, -C(=0)OCi-6alkyl, - OCi-6alkyl( R8R9), -OCi-6alkyl(C=0)amino, -OCi-6alkylnitrile, -OCi-6alkyl(COOH), - C(=O) R10Ru, -C(=0)het4, (wherein het4 is a 5-6-membered heteroaryl which is optionally substituted by Ci-6alkyl) and Ci-6alkyl-phenyl (wherein phenyl is optionally substituted by Ci-4alkyl);
R4 is hydrogen or together R4 and R1 represent a bond;
R5, R6, R7, R8, R9, R10 and R11, which may be the same or different, are each hydrogen or Ci-6alkyl; and
m and n, which may be the same or different, are each 0 or 1 ;
or a pharmaceutically acceptable salt or a solvate thereof;
provided that the compound of formula I is not 4-[l-(4-tert-butylphenyl) sulfonylpiperidin-4-yl]pyridine; and is not 2-[4-(2,4-dimethylphenyl)piperazin-l-yl] sulfonyl-5 , 6, 7, 8,9, 10-hexahydrocyclohepta[b] indole.
More specifically, the invention relates to a compound of Formula (I):
Figure imgf000008_0003
in which
X is R3 or CR3R4;
R2 is selected from:
(i) a fused 9-10 membered bicyclic heteroaryl optionally substituted by one or more groups independently selected from -Ci-6alkyl-0-Ci-6alkyl,
Figure imgf000009_0001
(ii) 5-6 membered heteroaryl optionally substituted by one or more groups independently selected from - R5R6, halogen, N02, Ci-6alkyl, haloCi-6alkyl, -OCi-6alkyl, - Ci-6alkyl-OH, -Ci-6alkyl C(=0)Ci-6alkyl, -C(=0)OCi-6alkyl, phenyl,
Figure imgf000009_0002
-
Figure imgf000009_0003
and -C(=0)het1 (wherein het1 is a 5-6- membered unsaturated heterocyclyl);
(iii) 6-10 membered aryl optionally substituted by one or more groups independently selected from halogen, H2, CN, N02, Ci-6alkyl, haloCi-6alkyl, Ci-6alkyl- OH, Ci-6alkylC(=0)OR7,
Figure imgf000009_0004
(wherein het2 is a 5-6- membered heteroaryl which is optionally substituted by one or more Ci-6alkyl), - C(=0) Hhet2, -C(=0)het1;
(iv) a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl optionally substituted by one or more groups;
R3 is selected from:
(i) a fused 9-10 membered bicyclic heteroaryl optionally substituted by one or more groups independently selected from halogen, Ci-6alkyl, C2-6alkenyl, haloCi-6alkyl, - OCi-6alkyl, -C(=0)OCi-6alkyl, -C(=O) R10Ru, -C(=0)het4, (het4 is a 5-6-membered heteroaryl which is optionally substituted by Ci-6alkyl);
(ii) 5-6 membered heteroaryl optionally substituted by one or more groups independently selected from Ci-6alkyl, -OCi-6alkyl, Ci-6alkyl-phenyl (wherein phenyl is optionally substituted by Ci-4alkyl);
(iii) 6-10 membered aryl optionally substituted by one or more groups independently selected from halogen, -OCi-6alkyl( R8R9), -OCi-6alkyl(C=0)amino, -OCi. ealkylnitrile, -OCi-6alkyl(COOH), OH, Ci-6alkyl, -OCi-6alkyl, haloCi-6alkyl, H2;
(iv) a fused 8-10 membered partially unsaturated bicyclic heterocyclyl optionally substituted by one or more groups -C(=0)OCi-6alkyl; and
(v) - H(CH2)mhet3 (wherein het3 is a 5-6-membered heteroaryl);
R1, R4, R5, R6, R7, R8, R9, R10, R11, m and n are each as herein defined;
or a pharmaceutically acceptable salt or a solvate thereof; provided that the compound of formula I is not 4-[l-(4-tert-butylphenyl) sulfonylpiperidin-4-yl]pyridine; and is not 2-[4-(2,4-dimethylphenyl)piperazin-l-yl] sulfonyl-5 , 6, 7, 8,9, 10-hexahydrocyclohepta[b] indole. In one embodiment of the present invention X is NR3.
In another embodiment of the present invention X is CR3R4.
When R2 is a fused 9-10 membered bicyclic heteroaryl a preferred bicyclic heteroaryl is selected from the group:
Figure imgf000010_0001
each of which is optionally substituted as herein defined.
When R2 is a 5-6 membered heteroaryl a preferred heteroaryl is selected from the group:
Figure imgf000010_0002
each of which is optionally substituted as herein defined.
When R is a 6-10 membered aryl a preferred aryl is:
Figure imgf000011_0001
which is optionally substituted as herein defined.
When R2 is a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl a preferred bicyclic or tricyclic heterocyclyl is:
Figure imgf000011_0002
which is optionally substituted as herein defined.
When R3 is a fused 9-10 membered bicyclic heteroaryl, a preferred bicyclic heteroaryl is selected from the group:
Figure imgf000011_0003
Figure imgf000011_0004
Figure imgf000012_0001
each of which is optionally substituted as herein defined.
When R is a 5-6 membered heteroaryl, a preferred heteroaryl is selected from the group:
Figure imgf000012_0002
Figure imgf000012_0003
each of which is optionally substituted as herein defined.
When R3 is a fused 8-10 membered partially unsaturated bicyclic heterocyclyl a preferred partially unsaturated bicyclic heterocyclyl is selected from the group:
Figure imgf000012_0004
each of which is optionally substituted as herein defined. When R3 is a 6-10 membered aryl, a preferred is selected from the group:
Figure imgf000013_0001
each of which is optionally substituted as herein defined. In one embodiment of the present invention n is 0. In another embodiment of the present invention n is i .
The present invention also relates to pharmaceutical compositions comprising a compound of the invention.
In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutical carrier, excipient or diluent. According to the invention there is further provided 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).
According to this aspect of the invention there is further provided 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.
According to a further aspect of the invention there is provided 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.
According to a further aspect of the invention there is provided 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. In a particular aspect, the pharmaceutical composition may additionally comprise a second therapeutically active ingredient suitable for use in combination with compounds of the invention.
Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.
In another aspect, the invention relates to a compound of the invention for use in therapy.
In a further aspect, 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.
In another aspect, 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.
According to this aspect of the invention the disease or condition associated with the abnormal activation or malfunction of the Hh signalling pathwayis one or more of cancer, fibrosis and chronic graft-versus-host disease (cGVHD).
According to this aspect of the invention there is further provided 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. According to a further aspect of the invention there is provided 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.
According to a further aspect of the invention there is provided 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.
In a further aspect, 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.
In another aspect of the invention, 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.
In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.
Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.
Detailed Description of the Invention
Definitions It will be understood that the present invention covers all combinations of aspects, suitable, convenient and preferred groups described herein.
When describing the invention, which may include processes, compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. Unless otherwise stated, the term "substituted" is to be defined as set out below. It should be further understood that the terms "groups" and "radicals" can be considered interchangeable when used herein.
The articles "a" and "an" may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example "an analogue" means one analogue or more than one analogue. When ranges are referred to herein, for example but without limitation, Co-6alkyl, the citation of a range should be considered a representation of each member of said range. By way of example Coalkyl means that alkyl group is absent. Thus, for example, selected member Coalkyl-aryl of a range Co-6alkyl-aryl means that aryl group is directly attached without an alkyl spacer.
The term "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.
The term "alkyl" as used herein as a group or a part of a group 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. Examples of 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. The term "alkyloxy" or "alkoxy", as used herein, 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. For example, Ci-4alkoxy means a straight or branched alkoxy containing at least 1, and at most 4, carbon atoms. Examples of "alkoxy" as used herein 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.
The term "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. For example, the term "C2-6alkenyl" 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. Examples of "alkenyl" as used herein 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.
The term "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. For example, the term "C2-6alkynyl" means a straight or branched alkynyl containing at least 2, and at most 6, carbon atoms and containing at least one triple bond. Examples of "alkynyl" as used herein include, but are not limited to, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl and 3 -methyl- 1-butynyl. The term "alkylene" as used herein as a group or a part of a group 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. Examples of such 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 (-CH2-) or ethylene (-CH2-CH2-).
The term "amino" refers to the radical - H2.
The term "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. Examples of 'amino protecting group' include: 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. methoxycarbonyl, ethoxycarbonyl, t-butyloxycarbonyl (Boc), isopropyloxycarbonyl and cyclohexyloxycarbonyl) and alkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl).
The term "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. In particular 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. Specifically, the term includes groups that have from 6 to 10 ring members. Where 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 aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. More particular aryl group is phenyl.
The term "carboxy" refers to the radical -C(0)OH.
The term "carbamoyl" or "amido" refers to the radical -C(0) H2. The term "comprise", and variations such as "comprises" and "comprising", throughout the specification and the claims which follow, unless the context requires otherwise, will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.
The term "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). Suitably, 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.
The term "cyano" to the radical -CN.
The term "cycloalkyl" as used herein, 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.
The term "cycloalkenyl" as used herein, 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. The term "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. The term "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.
The term "heteroaryl or heteroaromatic" as used herein 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. In one embodiment, 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. In general, 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.
Examples of fused heteroaryl rings 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. Particular 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.
The term "heterocyclic" as used herein, 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, eg 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. In one embodiment, 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. Examples of 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.
As used herein, the term "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. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone (2-pyrrolidone or 3-pyrrolidone), tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazolidinone, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine and the like. Further examples include thiomorpholine and its S-oxide and S,S- dioxide (particularly thiomorpholine). 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. As used herein, the term "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. Examples of heterocyclic rings 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. One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
The term "hydroxy" or "hydroxyl" refers to the radical -OH.
The term "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. Examples of 'hydroxy protecting group' include: ester and ether hydroxyl protecting group. Examples of ester hydroxyl protecting group include: formyl, -OC(0)Ci-4alkyl such as acetyl (Ac or - C(0)CH3), methoxyacetyl, chloroacetyl, dichloroacetyl, trichloroacety, trifluoroacetyl, triphenylmethoxyacetyl, phenoxyacetyl, benzoylformyl, benzoyl (Bz or -0(0)06Η5), benzyloxycarbonyl (Cbz or -C(0)-0-CH2C6H5); methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl or 2-(trimethylsilyl)ethoxycarbonyl and the like. Examples of ether hydroxyl protecting group include: alkyl silyl groups such as trimethylsilyl (TMS), tert-butyldimethylsilyl, triethylsilyl, triisopropylsilyl and the like. Examples of suitable "hydroxy protecting group" include; -OC(0)Ci.4alkyl such as acetyl (Ac or -C(0)CH3), benzoyl (Bz), benzyloxycarbonyl (Cbz) and trimethylsilyl (TMS). Suitably, "hydroxy protecting group" is: triethylsilyl or acetyl (Ac or -C(0)CH3). Conveniently, "hydroxy protecting group" is: Ac or Cbz. The term "sulfonamide" refers to the - R-S02-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-S02-alkyl), for example methylsulfonamide; arylsulfonamdie (i.e. - H-S02-aryl) for example phenylsulfonamide; aralkylsulfonamide, for example benzylsulfonamide.
The term "sulfonyl" means a -S02-R group wherein R is alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl. Particular sulfonyl groups are alkylsulfonyl (i.e. -S02- alkyl), for example methylsulfonyl; arylsulfonyl, for example phenylsulfonyl; aralkylsulfonyl, for example benzylsulfonyl. The term "nitro" refers to the radical -N02. The term "cyano" refers to the radical -CN.
The term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond between ring atoms but is not aromatic. The term "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.
The term "intermediates(s) of the invention" or "intermediate(s) according to the invention", and equivalent expressions 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). Suitably, 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.
The term "inert solvent" or "solvent inert to the reaction", as used herein, 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, Ν,Ν-dimethylacetamide, dimethyl sulfoxide, pyridine, and polar protic solvents such as lower alcohol, acetic acid, formic acid and water.
The term "lower alcohol", as used herein, refers to a Ci-4alcohol, such as for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. The term "substituted" refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
As used herein, the term "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.
The term "pharmaceutically acceptable", as used herein, 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). Suitably, as used herein, the term "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. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, 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-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminium ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. 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.
The term "pharmaceutically acceptable 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. Examples of particular 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.
The term "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. Martin, 18th Edition. The choice of pharmaceutical carrier can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical 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).
The term "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. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 1 15-130. 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. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the Ci-C8 alkyl, C2-C8 alkenyl, aryl and arylalkyl esters of the compounds of the invention.
The term "solvate" refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional 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. Representative solvates include hydrates, ethanolates and methanolates. The term "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound For example, an 'isotopic variant' of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium (2H or D), carbon- 13 (13C), nitrogen- 15 (15N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be 2H/D, any carbon may be 13C, or any nitrogen may be 15N, and that the presence and placement of such atoms may be determined within the skill of the art. Likewise, 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. 3H, and carbon- 14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Further, 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.
The term "isomer(s)" 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'. When 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". "Tautomers" 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 π electrons and an atom (usually H). For example, 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. The term "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" or "prevention" 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).
The term "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). In another embodiment "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "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. In a further embodiment, "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. As used herein the term Hedgehog (Hh) includes three Hedgehog homologues, Desert (DHH) (Protein accession 043323), Indian (IHH) (Protein accession Q14623), and Sonic (SHH) (Protein accession Q 15465).
The term Hh modulators as used herein may be SMO inhibitors, GLI inhibitors, SHH inhibitors, or inhibitors of any other proteins within the Hh signalling cascade.
The term Hh modulators as used herein may differentially regulate the activity of SMO, GLI, SHH, or any other proteins within the Hh signalling cascade. The term Hh modulators as used herein may differentially regulate the expression of SMO, GLI, SHH, or any other proteins within the Hh signalling cascade.
As used herein the term "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.
The term 'abnormal activation' used herein refers to aberrant activation, reduced inhibition, increased expression, increased signalling or inappropriate activation.
The term "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.
The term "esterification" used herein 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. The term "reductive animation" used herein 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. Generally 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. In a particular aspect, a compound of the invention is an inhibitor of Hh signalling pathway. More particularly, 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.
Accordingly, in another aspect the present invention relates to a compound of Formula (I):
Figure imgf000033_0001
or a pharmaceutically acceptable salt, or a solvate, or a solvate of the salt thereof, for use as a medicament, wherein:
X is R3 or CR3R4;
R1 is hydrogen or together R1 and R4 represent a bond;
R2 is selected from: a fused 9-10 membered bicyclic heteroaryl, a 5-6 membered heteroaryl, a 6-10 membered aryl and a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl; each of which is optionally substituted by one or more groups independently selected from - R5R6, halogen, N02, phenyl, CN, -Ci-6alkyl-0-Ci-6alkyl, Ci-6alkyl, haloCi-6alkyl, -OCi-6alkyl, -Ci-6alkyl-OH, -Ci.6alkylC(=0)Ci-6alkyl, Ci. 6alkylC(=0)OR7, -C(=0)OCi-6alkyl,
Figure imgf000033_0002
-
Figure imgf000033_0003
-C(=0)het1 (wherein het1 is a 5-6-membered unsaturated heterocyclyl), - HC(=0)het2 (wherein het2 is a 5-6-membered heteroaryl which is optionally substituted by one or more Ci-6alkyl), -C(=0) Hhet2;
R3 is selected from: a fused 9-10 membered bicyclic heteroaryl, a 5-6 membered heteroaryl, a 6-10 membered aryl, a fused 8-10 membered partially unsaturated bicyclic heterocyclyl and - H(CH2)mhet3 (wherein het3 is a 5-6-membered heteroaryl); each of which is optionally substituted by one or more groups independently selected from: halogen, OH, H2, Ci-6alkyl, -OCi-6alkyl, haloCi-6alkyl, C2-6alkenyl, -C(=0)OCi-6alkyl, - OCi-6alkyl( R8R9), -OCi-6alkyl(C=0)amino, -OCi-6alkylnitrile, -OCi-6alkyl(COOH), - C(=O) R10Ru, -C(=0)het4, (wherein het4 is a 5-6-membered heteroaryl which is optionally substituted by Ci-6alkyl) and Ci-6alkyl-phenyl (wherein phenyl is optionally substituted by Ci-4alkyl);
R4 is hydrogen or together R4 and R1 represent a bond;
R5, R6, R7, R8, R9, R10 and R11, which may be the same or different, are each hydrogen or Ci-6alkyl; and
m and n, which may be the same or different, are each 0 or 1;
or a pharmaceutically acceptable salt or a solvate thereof. More specifically, the in ntion relates to a compound of Formula (I):
Figure imgf000034_0001
or a pharmaceutically acceptable salt or a solvate thereof, for use as a medicament, in which:
X is R3 or CR3R4;
R2 is selected from:
(i) a fused 9-10 membered bicyclic heteroaryl optionally substituted by one or more groups independently selected from -Ci-6alkyl-0-Ci-6alkyl,
Figure imgf000034_0002
(ii) 5-6 membered heteroaryl optionally substituted by one or more groups independently selected from - R5R6, halogen, N02, Ci-6alkyl, haloCi-6alkyl, -OCi-6alkyl, - Ci-6alkyl-OH, -Ci-6alkyl C(=0)Ci-6alkyl, -C(=0)OCi-6alkyl, phenyl,
Figure imgf000034_0003
-
Figure imgf000034_0004
and -C(=0)het1 (wherein het1 is a 5-6- membered unsaturated heterocyclyl);
(iii) 6-10 membered aryl optionally substituted by one or more groups independently selected from halogen, H2, CN, N02, Ci-6alkyl, haloCi-6alkyl, Ci-6alkyl- OH, Ci-6alkylC(=0)OR7,
Figure imgf000034_0005
(wherein het2 is a 5-6- membered heteroaryl which is optionally substituted by one or more Ci-6alkyl), - C(=0) Hhet2, -C(=0)het1;
(iv) a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl optionally substituted by one or more groups;
R3 is selected from:
(i) a fused 9-10 membered bicyclic heteroaryl optionally substituted by one or more groups independently selected from halogen, Ci-6alkyl, C2-6alkenyl, haloCi-6alkyl, -
OCi-6alkyl, -C(=0)OCi-6alkyl, -C(=O) R10Ru, -C(=0)het4, (het4 is a 5-6-membered heteroaryl which is optionally substituted by Ci-6alkyl);
(ii) 5-6 membered heteroaryl optionally substituted by one or more groups independently selected from Ci-6alkyl, -OCi-6alkyl, Ci-6alkyl-phenyl (wherein phenyl is optionally substituted by Ci-4alkyl); (iii) 6-10 membered aryl optionally substituted by one or more groups independently selected from halogen, -OCi-6alkyl( R8R9), -OCi-6alkyl(C=0)amino, -OCi. ealkylnitrile, -OCi-6alkyl(COOH), OH, Ci-6alkyl, -OCi-6alkyl, haloCi-6alkyl, H2;
(iv) a fused 8-10 membered partially unsaturated bicyclic heterocyclyl optionally substituted by one or more groups -C(=0)OCi-6alkyl; and
(v) - H(CH2)mhet3 (wherein het3 is a 5-6-membered heteroaryl);
R1, R4, R5, R6, R7, R8, R9, R10, R11, m and n are each as herein defined.
In one aspect the present invention provides a compound of formula (I) for use as a medicament wherein X is R3.
In another aspect the present invention provides a compound of formula (I) for use as a medicament wherein X is CR3R4. When R2 is a fused 9-10 membered bicyclic heteroaryl a preferred bicyclic heteroaryl is selected from the group:
Figure imgf000035_0001
each of which is optionally substituted as herein defined. When R2 is a 5-6 membered heteroaryl a preferred heteroaryl is selected from the group:
Figure imgf000035_0002
Figure imgf000036_0001
Figure imgf000036_0002
each of which is optionally substituted as herein defined.
When R2 is a 6-10 membered aryl a preferred aryl is:
Figure imgf000036_0003
which is optionally substituted as herein defined.
When R2 is a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl a preferred bicyclic or tricyclic heterocyclyl is:
Figure imgf000036_0004
which is optionally substituted as herein defined.
When R is a fused 9-10 membered bicyclic heteroaryl, a preferred bicyclic heteroaryl is selected from the group:
Figure imgf000037_0001
Figure imgf000037_0002
Figure imgf000037_0003
each of which is optionally substituted as herein defined.
When R is a 5-6 membered heteroaryl, a preferred heteroaryl is selected from the group:
Figure imgf000037_0004
Figure imgf000037_0005
each of which is optionally substituted as herein defined. When R is a fused 8-10 membered partially unsaturated bicyclic heterocyclyl a preferred partially unsaturated bicyclic heterocyclyl is selected from the group:
Figure imgf000038_0001
each of which is optionally substituted as herein defined.
When R3 is a 6-10 membered aryl, a preferred aryl is selected from the group:
Figure imgf000038_0002
each of which is optionally substituted as herein defined. In one aspect the present invention provides a compound of formula (I) for use as a medicament wherein n is 0.
In another aspect the present invention provides a compound of formula (I) for use as a medicament wherein n is 1.
Specific compounds of formula I for use as a medicament, which may be mentioned include those selected from the group consisting of:
4- [4-( 1 -prop-2-enylpyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylaniline; [ 1 ]
N,N-dimethyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyridin-2-amine;
[2]
3 - [ 1 -(4-cyclopropylphenyl)sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine; [3 ]
2-[4-[4-(lH-pyrrolo[2,3-b]pyridin-3-yl)piperidin-l-yl]sulfonylphenyl]propan-2-ol; [4] [ 1 - [4-[4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 - yl] sulfonylphenyl] cyclopropyl] methanol; [5 ]
methyl 1 - [4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylphenyl] cyclopropane- 1-carboxylate; [6]
3 , 5 -dimethyl-N- [4- [4-( 1 -prop-2-enylpyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl phenyl]- 1 ,2-oxazole-4-carboxamide; [7]
N- [4-methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl- 1 , 3 -thiazol-2-yl] acetamide; [8]
morpholin-4-yl- [5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylfuran-2-yl] methanone; [9]
N-tert-butyl- 5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylfuran-2- carboxamide; [10]
5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl-N- [rac-(2R)- 1 -hydroxy-3 - methylbutan-2-yl]furan-2-carboxamide; [11]
[4-methoxy-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylthiophen-3 -yl] - morpholin-4-ylmethanone; [12]
[ 1 -methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyrrol-2-yl] - morpholin-4-ylmethanone; [13]
[3 - [ 1 -(4-aminophenyl)sulfonylpiperidin-4-yl]pyrrolo [2,3 -b]pyridin- 1 -yl] -(3 , 5 -dimethyl- l,2-oxazol-4-yl)methanone; [14]
N-tert-butyl-4-methoxy-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl thiophene-3-carboxamide; [15]
4-methoxy-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl-N- [rac-(2R)- 1 - hydroxy-3 -methylbutan-2-yl]thiophene-3 -carboxamide; [16]
N-tert-butyl- 1 -methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyrrole- 2-carboxamide; [17]
4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl-N- [rac- 1 -hydroxy-3 - methylbutan-2-yl]benzamide; [18]
morpholin-4-yl- [4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylphenyl] methanone; [19]
N-propan-2-yl-4-[4-(lH-pyrrolo[2,3-b]pyridin-3-yl)piperidin-l-yl]sulfonylbenzamide; [20] [cis-2, 6-dimethylmorpholin-4-yl] - [4- [4-( 1 H-pyrrolo [2, 3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylphenyl]methanone; [21] N-(3 , 5 -dimethyl- 1 ,2-oxazol-4-yl)-4- [4-( 1 H-pyrrolo [2, 3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylbenzamide; [22]
N-(oxan-4-yl)-4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylbenzamide; [23 ] 3 - [ 1 -(3 , 5 -dimethylphenyl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine; [24]
3-[l-(6-nitropyridin-3-yl)sulfonylpiperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine; [25] ethyl 3 -methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl- 1 H-pyrazole-4 carboxylate; [26]
3 - [ 1 - [[4-(trifluoromethyl)phenyl] methylsulfonyl]piperidin-4-yl] - 1 H-pyrrolo [2,3- b]pyridine; [27]
3-(l-benzylsulfonylpiperidin-4-yl)-lH-pyrrolo[2,3-b]pyridine; [28]
3 - [ 1 -(6-chloropyridin-3 -yl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine; [29]
3 - [ 1 -(2-nitrophenyl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine; [30]
methyl 2-methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylfuran-3 carboxylate; [31]
ethyl 5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylfuran-3 -carboxylate; [32] 3 - [ 1 - [3 , 5 -bis(trifluoromethyl)phenyl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine;
[33]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -5 -fluoro- 1 H-pyrrolo [2,3 -b]pyridine; [34]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]thieno[2,3-b]pyridine; [35]
3 - [ [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylmethyl]benzonitrile; [36]
3-[rac-(2S)-l-(4-tert-butylphenyl)sulfonyl-2-methyl-4-piperidyl]-lH-pyrrolo[2,3- b]pyridine; [37]
3- [l-[(2,4-dichlorophenyl)methylsulfonyl]piperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine; [38] 2-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-5-methoxypyridine; [39]
4- (3-benzylimidazol-4-yl)-l-(4-tert-butylphenyl)sulfonylpiperidine; [40]
2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] ethanamine; [41 ]
5- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-2-methoxypyridine; [42]
2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] acetonitrile; [43 ]
2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] acetamide; [44]
l-[3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazin- 7-yl]ethanone; [45]
3 - [4-(4-tert-butylphenyl)sulfonylpiperazin- 1 -yl]- 1 ,2-benzothiazole; [46]
3-[l-(lH-benzimidazol-5-ylsulfonyl)piperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine; [47] 3-[4-(4-tert-butylphenyl)sulfonylpiperazin-l-yl]-lH-pyrrolo[2,3-b]pyridine; [48] 2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] acetic acid; [49]
2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] -N,N-dimethylethanamine;
[50]
4- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]phenol; [51]
2- [4-(lH-pyrrolo[2,3-b]pyridin-3-yl)piperidin-l-yl]sulfonyl-5,6,7,8,9, 10- hexahydrocyclohepta[b]indole; [52]
3- [l-(lH-indol-5-ylsulfonyl)piperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine; [53]
tert-butyl 3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-6,8-dihydro-5H-imidazo[l,2 a] pyrazine-7-carboxylate; [54]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole;
[55]
3-[4-(4-tert-butylphenyl)sulfonylpiperazin-l-yl]furo[3,2-b]pyridine; [56]
5 - [4-(3 -methylimidazol-4-yl)piperidin- 1 -yl] sulfonyl- 1 H-indole; [57]
l-(4-tert-butylphenyl)sulfonyl-4-(2,4-dimethylphenyl)piperazine; [58]
5 - [4-(4-methoxyphenyl)piperidin- 1 -yl] sulfonyl- 1 H-indole; [59]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-lH-pyrrolo[3,2-b]pyridine; [60]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -5 -(trifluoromethyl)- 1 H-pyrrolo [2,3- b] pyridine; [61]
l-(4-tert-butylphenyl)sulfonyl-4-(2,3-dimethylimidazol-4-yl)piperidine; [62]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]imidazo[l,2-a]pyrimidine; [63]
3-[l-(4-tert-butylphenyl)sulfonyl-3,6-dihydro-2H-pyridin-4-yl]imidazo[l,2-a]pyrazine;
[64]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -5 -methoxy- 1 H-pyrrolo [2,3 -b]pyridine;
[65]
methyl 3 - [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine-5 carboxylate; [66]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]imidazo[l,2-a]pyridine; [67]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine;
[68]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]thieno[3,2-b]pyridine; [69]
3- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]furo[3,2-b]pyridine; [70]
4- [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl]pyrimidine ; [71 ]
1 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -3 H-imidazo [4, 5 -b]pyridin-2-one; [72] 3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] - 1 H-indole ; [73 ] l-(4-tert-butylphenyl)sulfonyl-4-(4-methyl-l,2,4-triazol-3-yl)piperidine; [74]
3- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine; [75]
4- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]aniline; [76]
1- (4-tert-butylphenyl)sulfonyl-4-(3-methylimidazol-4-yl)piperidine; [77]
5- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-l,3-oxazole; [78]
2- (4-pyridin-4-ylpiperazin- 1 -yl) sulfonyl-5 , 6, 7, 8, 9, 10-hexahydrocyclohepta[b] indole; [79] 1 -(4-tert-butylphenyl)sulfonyl-4-pyridin-4-ylpiperazine; [80]
N-[[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]methyl]pyridin-4-amine; [81]
1- (4-tert-butylphenyl)sulfonyl-N-(pyridin-4-ylmethyl)piperidin-4-amine; [82]
4-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]quinolone; [83]
2- (4-pyridin-4-ylpiperidin-l-yl)sulfonyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole; [84] 4-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-3-methylpyridine; [85]
2- [4-(2,4-dimethylphenyl)piperidin- 1 -yl] sulfonyl-5 , 6, 7, 8, 9, 10- hexahydrocyclohepta[b]indole; [86]
2- chloro-3-methyl-5-(4-pyridin-4-ylpiperidin-l-yl)sulfonylpyridine; [87]
4-[l-(4-bromophenyl)sulfonylpiperidin-4-yl]pyridine; [88]
4-[l-[(2,4-dichlorophenyl)methylsulfonyl]piperidin-4-yl]pyridine; [89]
4-[l-(4-chloro-2,5-dimethylphenyl)sulfonylpiperidin-4-yl]pyridine; [90]
4-[ 1 -(2,5-dichlorothiophen-3-yl)sulfonylpiperidin-4-yl]pyridine; [91 ]
3- [(4-pyridin-4-ylpiperidin-l-yl)sulfonylmethyl]benzonitrile; [92]
4- [l-[3,5-bis(trifluoromethyl)phenyl]sulfonylpiperidin-4-yl]pyridine; [93]
methyl 2-methyl-5-(4-pyridin-4-ylpiperidin-l-yl)sulfonylfuran-3-carboxylate; [94] 4-[l-[4-(trifluoromethyl)phenyl]sulfonylpiperidin-4-yl]pyridine; [95]
4- [ 1 -(3 , 5 -dimethylphenyl) sulfonylpiperidin-4-yl]pyridine; [96]
l-(4-tert-butylphenyl)sulfonyl-4-[4-(trifluoromethyl)phenyl]piperidine; [97]
1 -(4-tert-butylphenyl)sulfonyl-4-naphthalen- 1 -ylpiperidine; [98]
l-(4-tert-butylphenyl)sulfonyl-4-(4-methoxyphenyl)piperidine; [99]
4-[l-[[4-(trifluoromethyl)phenyl]methylsulfonyl]piperidin-4-yl]pyridine; [100]
4-[ 1 -(5-chlorothiophen-2-yl)sulfonylpiperidin-4-yl]pyridine; [101]
4-[ 1 -(4,5-dichlorothiophen-2-yl)sulfonylpiperidin-4-yl]pyridine; [ 102]
4-[ 1 -(2,4-dichlorophenyl)sulfonylpiperidin-4-yl]pyridine; [103]
1 -(4-tert-butylphenyl)sulfonyl-4-(2,4-dimethylphenyl)piperidine; [ 104]
2,4-diphenyl-5-(4-pyridin-4-ylpiperidin- 1 -yl)sulfonyl- 1 ,3 -thiazole; [105]
4-[ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl]pyridine; [ 106] 2- [4-(2,4-dimethylphenyl)piperazin- 1 -yl] sulfonyl- 5 , 6, 7, 8, 9, 10- hexahydrocyclohepta[b]indole; [ 107]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3- b] pyridine; [108]
3- [l-[l-(3,3,3 -trifluoro-2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H- pyrrolo[2,3-b]pyridine; [109]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3- c] pyridine; [110]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] -6-methyl- 1 H- pyrrolo[2,3-b]pyridine; [111]
N-tert-butyl-3 - [ 1 - [ 1 - [tert-butyl(methyl)carbamoyl] pyrazol-4-yl] sulfonylpiperidin-4-yl] -N- methylpyrrolo[2,3-b]pyridine-l-carboxamide; [112]
3 - [ 1 - [ 1 -(2-methoxy-2-methylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3- b]pyridine; [113]
3 - [ 1 - [ 1 -(2-methoxy-2-methylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [3 ,2- b]pyridine; [114]
3 - [ 1 -( 1 -benzylpyrazol-4-yl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine; [115]
3 - [ 1 - [ 1 - [ [ 1 -(trifluoromethyl)cyclopropyl] methyl]pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H- pyrrolo[2,3-b]pyridine; [116]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [3 ,2- b]pyridine; [117]
N-tert-butyl-N-methyl-3-[l-(lH-pyrazol-4-ylsulfonyl)piperidin-4-yl]pyrrolo[2,3- b]pyridine- 1 -carboxamide; [118]
3- [l-[l-(2,2-dimethylpropyl)pyrazol-4-yl]sulfonylpiperidin-4-yl]furo[3,2-b]pyridine; [119]
2- methyl- 1 - [4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyrazol- 1 - yl]propan-2-ol; [120]
4- [ 1 -[ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl]pyridine; [121] l-[4-(4-furo[3,2-b]pyridin-3-ylpiperidin-l-yl)sulfonylpyrazol-l-yl]-3,3-dimethylbutan-2- one; [122]
rac-(2R)- 1 -[4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyrazol- 1 - yl]propan-2-ol; [123]
5 - methyl-4- [ [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)- 1 -piperidyl] sulfonyl] isoxazole; [ 124]
3 - [ 1 -( 1 -methylpyrazol-4-yl)sulfonyl-4-piperidyl] - 1 H-pyrrolo [2,3 -b]pyridine; [125] 3 - [ 1 - [(3 , 5-dimethyl- 1 H-pyrazol-4-yl) sulfonyl] -4-piperidyl] - 1 H-pyrrolo [2,3 -b]pyridine;
[126]
3 -methyl-4- [ [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)- 1 -piperidyl] sulfonyl] isoxazole; [127] 6-methyl-3 - [ 1 -( 1 -methylpyrazol-4-yl)sulfonyl-4-piperidyl] - 1 H-pyrrolo [2,3 -b]pyridine;
[128] and
3 - [ 1 -( 1 H-imidazol-2-ylsulfonyl)-4-piperidyl] -6-methyl- 1 H-pyrrolo [2,3 -b]pyridine; [129] or a pharmaceutically acceptable salt or a solvate thereof.
Specific novel compounds of formula I which may be mentioned include those selected from the group consisting of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128 and 129.
In one aspect of the invention, specific compounds of formula I which may be mentioned include those selected from the group consisting of:
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]thieno[2,3-b]pyridine; [35]
2- [4-(lH-pyrrolo[2,3-b]pyridin-3-yl)piperidin-l-yl]sulfonyl-5,6,7,8,9, 10- hexahydrocyclohepta[b]indole; [52]
3- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]imidazo[l,2-a]pyridine; [67]
4- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]quinolone; [83]
2-(4-pyridin-4-ylpiperidin-l-yl)sulfonyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole; [84] 2- [4-(2,4-dimethylphenyl)piperidin- 1 -yl] sulfonyl- 5 , 6, 7, 8, 9, 10-hexahydro
cyclohepta[b]indole; [86]
1 -(4-tert-butylphenyl)sulfonyl-4-(2,4-dimethylphenyl)piperidine; [ 104]
4-[ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl]pyridine; [ 106]
2- [4-(2,4-dimethylphenyl)piperazin- 1 -yl] sulfonyl- 5 , 6, 7, 8, 9, 10-hexahydro
cyclohepta[b]indole; [107]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3- b]pyridine; [108] 3-[l-[l-(3,3,3 -trifluoro-2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H- pyrrolo[2,3-b]pyridine; [109]
3 - [ 1 - [ 1 -(2-methoxy-2-methylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3- b]pyridine; [113]
3 - [ 1 -( 1 -benzylpyrazol-4-yl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine; [115] or a pharmaceutically acceptable salt or a solvate thereof.
In another aspect of the invention, specific compounds of formula I which may mentioned include those selected from the group consisting of:
2- [4-[4-(lH-pyrrolo[2,3-b]pyridin-3-yl)piperidin-l-yl]sulfonylphenyl]propan-2-ol; [4] 3 , 5 -dimethyl-N- [4- [4-( 1 -prop-2-enylpyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl phenyl]- 1 ,2-oxazole-4-carboxamide; [7]
[4-methoxy-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylthiophen-3 -yl] - morpholin-4-ylmethanone; [12]
[cis-2, 6-dimethylmorpholin-4-yl] - [4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylphenyl]methanone; [21]
3 - [ 1 - [[4-(trifluoromethyl)phenyl] methylsulfonyl]piperidin-4-yl] - 1 H-pyrrolo [2,3- b]pyridine; [27]
3 - [ [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylmethyl]benzonitrile; 36 2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] acetonitrile; [43 ]
2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] acetamide; [44]
3- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]imidazo[l,2-a]pyrimidine; [63]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] - 1 H-indole ; [73 ]
l-(4-tert-butylphenyl)sulfonyl-4-(3-methylimidazol-4-yl)piperidine; [77]
2,4-diphenyl-5-(4-pyridin-4-ylpiperidin- 1 -yl)sulfonyl- 1 ,3 -thiazole; [105]
N-tert-butyl-3 - [ 1 - [ 1 - [tert-butyl(methyl)carbamoyl] pyrazol-4-yl] sulfonylpiperidin-4-yl] -N methylpyrrolo[2,3-b]pyridine-l-carboxamide; [112]
3 - [ 1 - [ 1 - [ [ 1 -(trifluoromethyl)cyclopropyl] methyl]pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H- pyrrolo[2,3-b]pyridine; [116]
or a pharmaceutically acceptable salt or a solvate thereof.
In another aspect of the invention, specific compounds of formula I which may mentioned include those selected from the group consisting of: N,N-dimethyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyridin-2-amine;
[2]
3 - [ 1 -(4-cyclopropylphenyl)sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine; [3 ]
[ 1 - [4-[4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylphenyl] cyclopropyl] methanol; [5]
methyl 1 - [4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylphenyl] cyclopropane- 1-carboxylate; [6]
N- [4-methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl- 1 , 3 -thiazol-2-yl] acetamide; [8]
morpholin-4-yl- [5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylfuran-2-yl] methanone; [9]
N-tert-butyl- 5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylfuran-2- carboxamide; [10]
5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl-N- [rac-(2R)- 1 -hydroxy-3 - methylbutan-2-yl]furan-2-carboxamide; [11]
[ 1 -methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyrrol-2-yl] - morpholin-4-ylmethanone; [13]
N-tert-butyl-4-methoxy-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl thiophene-3-carboxamide; [15]
4- methoxy-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl-N- [rac-(2R)- 1 - hydroxy-3 -methylbutan-2-yl]thiophene-3 -carboxamide; [16]
N-tert-butyl- 1 -methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyrrole-
2- carboxamide; [17]
morpholin-4-yl- [4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylphenyl] methanone; [19]
N-propan-2-yl-4-[4-(lH-pyrrolo[2,3-b]pyridin-3-yl)piperidin-l-yl]sulfonylbenzamide; [20] N-(3 , 5 -dimethyl- 1 ,2-oxazol-4-yl)-4- [4-( 1 H-pyrrolo [2, 3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylbenzamide; [22]
N-(oxan-4-yl)-4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylbenzamide; [23 ]
3 - [ 1 -(3 , 5 -dimethylphenyl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine; [24] ethyl 3 -methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl- 1 H-pyrazole-4- carboxylate; [26]
3-(l-benzylsulfonylpiperidin-4-yl)-lH-pyrrolo[2,3-b]pyridine; [28]
3 - [ 1 -(6-chloropyridin-3 -yl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine; [29] 3 - [ 1 -(2-nitrophenyl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine; [30] methyl 2-methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylfuran-3 - carboxylate; [31]
ethyl 5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylfuran-3 -carboxylate; [32] 3 - [ 1 - [3 , 5 -bis(trifluoromethyl)phenyl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine;
[33]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -5 -fluoro- 1 H-pyrrolo [2,3 -b]pyridine; [34] 3-[rac-(2S)-l-(4-tert-butylphenyl)sulfonyl-2-methyl-4-piperidyl]-lH-pyrrolo[2,3- b]pyridine; [37]
3- [l-[(2,4-dichlorophenyl)methylsulfonyl]piperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine; [38]
4- (3-benzylimidazol-4-yl)-l-(4-tert-butylphenyl)sulfonylpiperidine; [40]
2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] ethanamine; [41 ]
5- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-2-methoxypyridine; [42]
3 - [4-(4-tert-butylphenyl)sulfonylpiperazin- 1 -yl]- 1 ,2-benzothiazole; [46]
3-[l-(lH-benzimidazol-5-ylsulfonyl)piperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine; [47] 3-[4-(4-tert-butylphenyl)sulfonylpiperazin-l-yl]-lH-pyrrolo[2,3-b]pyridine; [48]
3-[l-(lH-indol-5-ylsulfonyl)piperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine; [53]
3-[4-(4-tert-butylphenyl)sulfonylpiperazin-l-yl]furo[3,2-b]pyridine; [56]
l-(4-tert-butylphenyl)sulfonyl-4-(2,4-dimethylphenyl)piperazine; [58]
5 - [4-(4-methoxyphenyl)piperidin- 1 -yl] sulfonyl- 1 H-indole; [59]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-lH-pyrrolo[3,2-b]pyridine; [60] l-(4-tert-butylphenyl)sulfonyl-4-(2,3-dimethylimidazol-4-yl)piperidine; [62]
3-[l-(4-tert-butylphenyl)sulfonyl-3,6-dihydro-2H-pyridin-4-yl]imidazo[l,2-a]pyrazine;
[64]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]thieno[3,2-b]pyridine; [69]
3- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]furo[3,2-b]pyridine; [70]
4- [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl]pyrimidine ; [71 ]
1 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -3 H-imidazo [4, 5 -b]pyridin-2-one; [72] l-(4-tert-butylphenyl)sulfonyl-4-(4-methyl-l,2,4-triazol-3-yl)piperidine; [74]
4- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]aniline; [76]
5- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-l,3-oxazole; [78]
N-[[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]methyl]pyridin-4-amine; [81]
4-[l-(4-bromophenyl)sulfonylpiperidin-4-yl]pyridine; [88]
4-[l-[(2,4-dichlorophenyl)methylsulfonyl]piperidin-4-yl]pyridine; [89] 4-[l-(4-chloro-2,5-dimethylphenyl)sulfonylpiperidin-4-yl]pyridine; [90] 4- [ 1 - [3 , 5 -bis(trifluoromethyl)phenyl] sulfonylpiperidin-4-yl]pyridine; [93 ]
4-[l-[4-(trifluoromethyl)phenyl]sulfonylpiperidin-4-yl]pyridine; [95]
l-(4-tert-butylphenyl)sulfonyl-4-[4-(trifluoromethyl)phenyl]piperidine; [97]
1 -(4-tert-butylphenyl)sulfonyl-4-naphthalen- 1 -ylpiperidine; [98]
1- (4-tert-butylphenyl)sulfonyl-4-(4-methoxyphenyl)piperidine; [99]
4-[l-[[4-(trifluoromethyl)phenyl]methylsulfonyl]piperidin-4-yl]pyridine; [100]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3- c]pyridine; [110]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] -6-methyl- 1 H- pyrrolo[2,3-b]pyridine; [111]
3 - [ 1 - [ 1 -(2-methoxy-2-methylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [3 ,2- b]pyridine; [114]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [3 ,2- b]pyridine; [117]
N-tert-butyl-N-methyl-3-[l-(lH-pyrazol-4-ylsulfonyl)piperidin-4-yl]pyrrolo[2,3-b] pyridine- 1 -carboxamide; [118]
3- [l-[l-(2,2-dimethylpropyl)pyrazol-4-yl]sulfonylpiperidin-4-yl]furo[3,2-b]pyridine; [119]
2- methyl- 1 - [4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyrazol- 1 -yl] propan-2-ol; [120]
4- [ 1 -[ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl]pyridine; [121] l-[4-(4-furo[3,2-b]pyridin-3-ylpiperidin-l-yl)sulfonylpyrazol-l-yl]-3,3-dimethylbutan-2- one; [122]
rac-(2R)- 1 -[4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyrazol- 1 - yl]propan-2-ol; [123]
or a pharmaceutically acceptable salt or a solvate thereof.
In another aspect of the invention, specific compounds of formula I which may be mentioned include those selected from the group consisting of:
4- [4-( 1 -prop-2-enylpyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylaniline; [ 1 ]
[3 - [ 1 -(4-aminophenyl)sulfonylpiperidin-4-yl]pyrrolo [2,3 -b]pyridin- 1 -yl] -(3 , 5 -dimethyl- l,2-oxazol-4-yl)methanone; [14]
4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl-N- [rac- 1 -hydroxy-3 - methylbutan-2-yl]benzamide; [18] 3- [l-(6-nitropyridin-3-yl)sulfonylpiperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine; [25]
2-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-5-methoxypyridine; [39]
1- [3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazin- 7-yl]ethanone; [45]
2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] acetic acid; [49]
2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] -N,N-dimethylethanamine;
[50]
4- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]phenol; [51]
tert-butyl 3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-6,8-dihydro-5H-imidazo[l,2- a] pyrazine-7-carboxylate; [54]
3- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole;
[55]
5 - [4-(3 -methylimidazol-4-yl)piperidin- 1 -yl] sulfonyl- 1 H-indole; [57]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -5 -(trifluoromethyl)- 1 H-pyrrolo [2,3- b] pyridine; [61]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -5 -methoxy- 1 H-pyrrolo [2,3 -b]pyridine;
[65]
methyl 3 - [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine-5 - carboxylate; [66]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine;
[68]
3- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine; [75]
2-(4-pyridin-4-ylpiperazin- 1 -yl) sulfonyl-5 , 6, 7, 8, 9, 10-hexahydrocyclohepta[b] indole; [79] 1 -(4-tert-butylphenyl)sulfonyl-4-pyridin-4-ylpiperazine; [80]
1- (4-tert-butylphenyl)sulfonyl-N-(pyridin-4-ylmethyl)piperidin-4-amine; [82]
4- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-3-methylpyridine; [85]
2- chloro-3-methyl-5-(4-pyridin-4-ylpiperidin-l-yl)sulfonylpyridine; [87]
4-[ 1 -(2,5-dichlorothiophen-3-yl)sulfonylpiperidin-4-yl]pyridine; [91 ]
3- [(4-pyridin-4-ylpiperidin-l-yl)sulfonylmethyl]benzonitrile; [92]
methyl 2-methyl-5-(4-pyridin-4-ylpiperidin-l-yl)sulfonylfuran-3-carboxylate; [94]
4- [ 1 -(3 , 5 -dimethylphenyl) sulfonylpiperidin-4-yl]pyridine; [96]
4-[ 1 -(5-chlorothiophen-2-yl)sulfonylpiperidin-4-yl]pyridine; [101]
4-[ 1 -(4,5-dichlorothiophen-2-yl)sulfonylpiperidin-4-yl]pyridine; [ 102]
4-[ 1 -(2,4-dichlorophenyl)sulfonylpiperidin-4-yl]pyridine; [103] 5 - methyl-4- [ [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)- 1 -piperidyl] sulfonyl] isoxazole; [ 124] 3 - [ 1 -( 1 -methylpyrazol-4-yl)sulfonyl-4-piperidyl] - 1 H-pyrrolo [2,3 -b]pyridine; [125]
3 - [ 1 - [(3 , 5-dimethyl- 1 H-pyrazol-4-yl) sulfonyl] -4-piperidyl] - 1 H-pyrrolo [2,3 -b]pyridine;
[126]
3 -methyl-4- [ [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)- 1 -piperidyl] sulfonyl] isoxazole; [127]
6- methyl-3 - [ 1 -( 1 -methylpyrazol-4-yl)sulfonyl-4-piperidyl] - 1 H-pyrrolo [2,3 -b]pyridine;
[128]
3 - [ 1 -( 1 H-imidazol-2-ylsulfonyl)-4-piperidyl] -6-methyl- 1 H-pyrrolo [2,3 -b]pyridine; [129] or a pharmaceutically acceptable salt or a solvate thereof.
In another aspect of the invention, specific compounds of formula I which may be mentioned include those selected from the group consisting of:
[ 1 -methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyrrol-2-yl] - morpholin-4-ylmethanone; [13]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]thieno[2,3-b]pyridine; [35]
2- [4-(lH-pyrrolo[2,3-b]pyridin-3-yl)piperidin-l-yl]sulfonyl-5,6,7,8,9, 10- hexahydrocyclohepta[b]indole; [52]
3- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]imidazo[l,2-a]pyridine; [67]
3- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine; [75]
2- [4-(2,4-dimethylphenyl)piperidin- 1 -yl] sulfonyl- 5 , 6, 7, 8, 9, 10- hexahydrocyclohepta[b]indole; [86]
1 -(4-tert-butylphenyl)sulfonyl-4-(2,4-dimethylphenyl)piperidine; [ 104]
4- [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl]pyridine; [ 106]
2- [4-(2,4-dimethylphenyl)piperazin- 1 -yl] sulfonyl- 5 , 6, 7, 8, 9, 10- hexahydrocyclohepta[b]indole; [ 107]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3- b]pyridine; [108]
3- [l-[l-(3,3,3 -trifluoro-2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H- pyrrolo[2,3-b]pyridine; [109]
3 - [ 1 - [ 1 -(2-methoxy-2-methylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3- b]pyridine; [113]
3 - [ 1 - [ 1 - [ [ 1 -(trifluoromethyl)cyclopropyl] methyl]pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H- pyrrolo[2,3-b]pyridine; [116]
3-[l-[l-(2,2-dimethylpropyl)pyrazol-4-yl]sulfonylpiperidin-4-yl]furo[3,2-b]pyridine; [119] or a pharmaceutically acceptable salt or a solvate thereof.
In another aspect of the invention, specific compounds of formula I which may be mentioned include those selected from the group consisting of:
methyl 1 - [4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylphenyl] cyclopropane-
1- carboxylate; [6]
3 , 5 -dimethyl-N- [4- [4-( 1 -prop-2-enylpyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 - yl]sulfonylphenyl]-l,2-oxazole-4-carboxamide; [7]
N- [4-methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl- 1 , 3 -thiazol-2- yl]acetamide; [8]
morpholin-4-yl- [5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylfuran-2- yl]methanone; [9]
N-tert-butyl- 5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylfuran-2- carboxamide; [10]
5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl-N- [rac-(2R)- 1 -hydroxy-3 - methylbutan-2-yl]furan-2-carboxamide; [11]
[ 1 -methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyrrol-2-yl] - morpholin-4-ylmethanone; [13]
N-tert-butyl- 1 -methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyrrole-
2- carboxamide; [17]
[cis-2, 6-dimethylmorpholin-4-yl] - [4- [4-( 1 H-pyrrolo [2, 3 -b]pyridin-3 -yl)piperidin- 1 - yl] sulfonylphenyl]methanone; [21 ]
3 - [ 1 - [[4-(trifluoromethyl)phenyl] methylsulfonyl]piperidin-4-yl] - 1 H-pyrrolo [2,3- b]pyridine; [27]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -5 -fluoro- 1 H-pyrrolo [2,3 -b]pyridine; [34] 3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]thieno[2,3-b]pyridine; [35]
3 - [ [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylmethyl]benzonitrile; [36] 3-[rac-(2S)-l-(4-tert-butylphenyl)sulfonyl-2-methyl-4-piperidyl]-lH-pyrrolo[2,3- b]pyridine; [37]
2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] acetonitrile; [43 ]
2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] acetamide; [44]
3 - [4-(4-tert-butylphenyl)sulfonylpiperazin- 1 -yl]- 1 ,2-benzothiazole; [46]
2-[4-(lH-pyrrolo[2,3-b]pyridin-3-yl)piperidin-l-yl]sulfonyl-5,6,7,8,9, 10- hexahydrocyclohepta[b]indole; [52] 3-[4-(4-tert-butylphenyl)sulfonylpiperazin-l-yl]furo[3,2-b]pyridine; [56] 3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-lH-pyrrolo[3,2-b]pyridine; [60] l-(4-tert-butylphenyl)sulfonyl-4-(2,3-dimethylimidazol-4-yl)piperidine; [62]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]imidazo[l,2-a]pyrimidine; [63]
3-[l-(4-tert-butylphenyl)sulfonyl-3,6-dihydro-2H-pyridin-4-yl]imidazo[l,2-a]pyrazine;
[64]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]imidazo[l,2-a]pyridine; [67]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine;
[68]
3- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]thieno[3,2-b]pyridine; [69]
4- [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl]pyrimidine; [71 ]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] - 1 H-indole; [73 ]
3- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine; [75]
4- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]aniline; [76]
l-(4-tert-butylphenyl)sulfonyl-4-(3-methylimidazol-4-yl)piperidine; [77]
5- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-l,3-oxazole; [78]
N-[[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]methyl]pyridin-4-amine; [81]
1- (4-tert-butylphenyl)sulfonyl-N-(pyridin-4-ylmethyl)piperidin-4-amine; [82]
4-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]quinoline; [83]
2- (4-pyridin-4-ylpiperidin-l-yl)sulfonyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole; [84] 4-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-3-methylpyridine; [85]
2- [4-(2,4-dimethylphenyl)piperidin- 1 -yl] sulfonyl- 5 , 6, 7, 8, 9, 10- hexahydrocyclohepta[b]indole; [86]
l-(4-tert-butylphenyl)sulfonyl-4-[4-(trifluoromethyl)phenyl]piperidine; [97]
1 -(4-tert-butylphenyl)sulfonyl-4-naphthalen- 1 -ylpiperidine; [98]
1- (4-tert-butylphenyl)sulfonyl-4-(4-methoxyphenyl)piperidine; [99]
1 -(4-tert-butylphenyl)sulfonyl-4-(2,4-dimethylphenyl)piperidine; [ 104]
4-[ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl]pyridine; [ 106]
2- [4-(2,4-dimethylphenyl)piperazin- 1 -yl] sulfonyl- 5 , 6, 7, 8, 9, 10- hexahydrocyclohepta[b]indole; [ 107]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3- b]pyridine; [108]
3 - [ 1 - [ 1 -(3 , 3 , 3 -trifluoro-2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H- pyrrolo[2,3-b]pyridine; [109] 3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] -6-methyl- 1 H- pyrrolo[2,3-b]pyridine; [111]
3 - [ 1 - [ 1 -(2-methoxy-2-methylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3- b]pyridine; [113]
3 - [ 1 - [ 1 -(2-methoxy-2-methylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [3 ,2- b]pyridine; [114]
3 - [ 1 -( 1 -benzylpyrazol-4-yl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine; [115] 3 - [ 1 - [ 1 - [ [ 1 -(trifluoromethyl)cyclopropyl] methyl]pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H- pyrrolo[2,3-b]pyridine; [116]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [3 ,2- b]pyridine; [117]
3-[l-[l-(2,2-dimethylpropyl)pyrazol-4-yl]sulfonylpiperidin-4-yl]furo[3,2-b]pyridine; [119] or a pharmaceutically acceptable salt or a solvate thereof.
In another aspect the present invention any one or more of the compounds or groups of compiounds herein defined, or a pharmaceutically acceptable salt or a solvate thereof, for use as a medicament. In one embodiment the compound and intermediate of the invention is not an isotopic variant.
In one aspect a compound and intermediate of the invention according to any one of the embodiments herein described is a free base.
In one aspect a compound and intermediate of the invention according to any one of the embodiments herein described is a salt.
In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.
In one aspect a compound and intermediate of the invention according to any one of the embodiments herein described is a solvate of the compound. In one aspect 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. Similarly, reference to intermediates of the invention, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
With regard to stereoisomers, the compounds and intermediates of the invention have more than one asymmetric carbon atom. In the general formula(e) as drawn, the solid wedge shaped bond indicates that the bond is above the plane of the paper. The broken bond indicates that the bond is below the plane of the paper.
It will be appreciated that the substituents on the compounds and intermediates of the invention may also have one or more asymmetric carbon atoms. Thus, 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.
Where 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.
Unless otherwise stated, in formulae disclosed herein a bond drawn without any attached group means a methyl group. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
While specified groups for each embodiment have generally been listed above separately, 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.
Alternatively, the exclusion of one or more of the specified variables from a group or an embodiment, or combinations thereof is also contemplated by the present invention. In certain aspects, 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.
Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H. Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). 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. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the Ci to C8 alkyl, C2-C8 alkenyl, aryl, substituted aryl, and arylalkyl esters of the compounds of the invention. A person of skill in the art will appreciate that when administered in vivo compounds of the invention may be metabolised and that some of these biological metabolites may be active. In one aspect, the present invention therefore provides for biologically active metabolites of compounds of the invention.
Pharmaceutical Compositions
While it is possible that, for use in the methods 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. Thus, when employed as a pharmaceutical, a compound of the invention 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. Generally, 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. The pharmaceutical compositions of the invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, 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.
The 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. The term '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. In such compositions, the compound of the invention is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
In one aspect, 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. Or a delayed release can be achieved by a coating that is simply slow to disintegrate. Or the two (delayed and positioned release) profiles can be combined in a single formulation by choice of one or more appropriate coatings and other excipients. Such formulations constitute a further feature of the present invention.
Suitable 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 Deutschland GmbH, D-Weil am Rhein, Germany) and other Suppocire type excipients obtained by interesterification of hydrogenated palm oil and palm kernel oil (C8- C18 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, hydroxyethylcellulose, 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 esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrated castor oil, polyoxyethylene alkyl ethers, and pluronic and appropriate buffer system in pH range of 6.5 to 8. The use of preservatives, masking agents is suitable. The average diameter of micronized particles can be between 1 and 20 micrometers, or can be less than 1 micrometer. Compounds can also be incorporated in the formulation by using their water-soluble salt forms. Alternatively, 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.
Pharmaceutical 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. When a solid carrier is used for preparation of oral 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.
Pharmaceutical 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. For parenteral administration, 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.
Examples of pharmaceutically acceptable 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.
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.
Examples of 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.
Examples of 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.
For application topically to the skin, 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.
As indicated, 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. In the case of a pressurized aerosol, 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.
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. For topical administration by inhalation the compounds according to the invention may be delivered for use in human or veterinary medicine via a nebulizer.
The pharmaceutical compositions of the invention may contain from 0.01 to 99% weight per volume of the active material. For topical administration, for example, 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. Thus, 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 mg/day, about 1,850 mg/day, about 1,900 mg/day, about 1,950 mg/day or about 2,000. 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. When the composition comprises dosage units, 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. In one aspect of the present invention, administration is once daily oral dosing. The present invention is related to 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, eg from about 0.1 to 2 g of one or more pharmaceutically acceptable excipients. Methods of Treatment
It has been identified that 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. Such diseases and conditions include proliferative diseases, such as cancers; fibrosis and GVHD, etc. as herein defined.
In one embodiment, the present invention provides novel compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use as a medicament. In a particular embodiment, 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.
In one embodiment of the invention we provide 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 a patient suffering from such a disease or condition:
Figure imgf000064_0001
in which:
X is R3 or CR3R4;
R1 is hydrogen or together R1 and R4 represent a bond;
R2 is selected from: a fused 9-10 membered bicyclic heteroaryl, a 5-6 membered heteroaryl, a 6-10 membered aryl and a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl; each of which is optionally substituted by one or more groups independently selected from - R5R6, halogen, N02, phenyl, CN, -Ci-6alkyl-0-Ci-6alkyl, Ci-6alkyl, haloCi-6alkyl, -OCi-6alkyl, -Ci-6alkyl-OH, -Ci.6alkylC(=0)Ci-6alkyl, Ci. 6alkylC(=0)OR7, -C(=0)OCi-6alkyl,
Figure imgf000064_0002
-
Figure imgf000064_0003
-C(=0)het1 (wherein het1 is a 5-6-membered unsaturated heterocyclyl), - HC(=0)het2 (wherein het2 is a 5-6-membered heteroaryl which is optionally substituted by one or more Ci-6alkyl), -C(=0) Hhet2;
R3 is selected from: a fused 9-10 membered bicyclic heteroaryl, a 5-6 membered heteroaryl, a 6-10 membered aryl, a fused 8-10 membered partially unsaturated bicyclic heterocyclyl and - H(CH2)mhet3 (wherein het3 is a 5-6-membered heteroaryl); each of which is optionally substituted by one or more groups independently selected from: halogen, OH, H2, Ci-6alkyl, -OCi-6alkyl, haloCi-6alkyl, C2-6alkenyl, -C(=0)OCi-6alkyl, - OCi-6alkyl( R8R9), -OCi-6alkyl(C=0)amino, -OCi-6alkylnitrile, -OCi-6alkyl(COOH), - C(=O) R10Ru, -C(=0)het4, (wherein het4 is a 5-6-membered heteroaryl which is optionally substituted by Ci-6alkyl) and Ci-6alkyl-phenyl (wherein phenyl is optionally substituted by Ci-4alkyl);
R4 is hydrogen or together R4 and R1 represent a bond;
R5, R6, R7, R8, R9, R10 and R11, which may be the same or different, are each hydrogen or Ci-6alkyl; and
m and n, which may be the same or different, are each 0 or 1 ;
or a pharmaceutically acceptable salt or a solvate thereof. More specifically, the invention relates to 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:
Figure imgf000065_0001
in which
X is R3 or CR3R4;
R2 is selected from:
(i) a fused 9-10 membered bicyclic heteroaryl optionally substituted by one or more groups independently selected from -Ci-6alkyl-0-Ci-6alkyl,
Figure imgf000065_0002
(ii) 5-6 membered heteroaryl optionally substituted by one or more groups independently selected from - R5R6, halogen, N02, Ci-6alkyl, haloCi-6alkyl, -OCi-6alkyl, - Ci-6alkyl-OH, -Ci-6alkyl C(=0)Ci-6alkyl, -C(=0)OCi-6alkyl, phenyl,
Figure imgf000065_0003
-
Figure imgf000065_0004
and -C(=0)het1 (wherein het1 is a 5-6- membered unsaturated heterocyclyl);
(iii) 6-10 membered aryl optionally substituted by one or more groups independently selected from halogen, H2, CN, N02, Ci-6alkyl, haloCi-6alkyl, Ci-6alkyl- OH, Ci-6alkylC(=0)OR7,
Figure imgf000065_0005
(wherein het2 is a 5-6- membered heteroaryl which is optionally substituted by one or more Ci-6alkyl), - C(=0) Hhet2, -C(=0)het1;
(iv) a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl optionally substituted by one or more groups;
R3 is selected from:
(i) a fused 9-10 membered bicyclic heteroaryl optionally substituted by one or more groups independently selected from halogen, Ci-6alkyl, C2-6alkenyl, haloCi-6alkyl, - OCi-6alkyl, -C(=0)OCi-6alkyl, -C(=O) R10Ru, -C(=0)het4, (het4 is a 5-6-membered heteroaryl which is optionally substituted by Ci-6alkyl);
(ii) 5-6 membered heteroaryl optionally substituted by one or more groups independently selected from Ci-6alkyl, -OCi-6alkyl, Ci-6alkyl-phenyl (wherein phenyl is optionally substituted by Ci-4alkyl); (iii) 6-10 membered aryl optionally substituted by one or more groups independently selected from halogen, -OCi-6alkyl( R8R9), -OCi-6alkyl(C=0)amino, -OCi. ealkylnitrile, -OCi-6alkyl(COOH), OH, Ci-6alkyl, -OCi-6alkyl, haloCi-6alkyl, H2;
(iv) a fused 8-10 membered partially unsaturated bicyclic heterocyclyl optionally substituted by one or more groups -C(=0)OCi-6alkyl; and
(v) - H(CH2)mhet3 (wherein het3 is a 5-6-membered heteroaryl);
R1, R4, R5, R6, R7, R8, R9, R10, R11, m and n are each as herein defined;
or a pharmaceutically acceptable salt or a solvate thereof. In one embodiment of the present invention X is NR3.
In another embodiment of the present invention X is CR3R4.
When R2 is a fused 9-10 membered bicyclic heteroaryl a preferred bicyclic heteroaryl is selected from the group :
Figure imgf000066_0001
each of which is optionally substituted as herein defined.
When R2 is a 5-6 membered heteroaryl a preferred heteroaryl is selected from the group:
Figure imgf000066_0002
Figure imgf000067_0001
each of which is optionally substituted as herein defined.
When R is a 6-10 membered aryl a preferred aryl is:
Figure imgf000067_0002
which is optionally substituted as herein defined.
When R2 is a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl preferred bicyclic or tricyclic heterocyclyl is:
Figure imgf000067_0003
which is optionally substituted as herein defined.
When R3 is a fused 9-10 membered bicyclic heteroaryl, a preferred bicyclic heteroaryl is selected from the group:
Figure imgf000067_0004
Figure imgf000068_0001
Figure imgf000068_0002
each of which is optionally substituted as herein defined.
When R3 is a 5-6 membered heteroar l, a preferred heteroaryl is selected from the group:
Figure imgf000068_0003
Figure imgf000068_0004
each of which is optionally substituted as herein defined.
When R3 is a fused 8-10 membered partially unsaturated bicyclic heterocyclyl a preferred partially unsaturated bicyclic heterocyclyl is selected from the group:
Figure imgf000069_0001
each of which is optionally substituted as herein defined.
When R3 is a 6-10 membered aryl, a preferred is selected from the group:
Figure imgf000069_0002
each of which is optionally substituted as herein defined.
In one embodiment of the present invention n is 0.
In another embodiment of the present invention n is i . In one embodiment of the invention 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).
According to a further aspect of the invention we provide a method 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.
According to a further aspect of the invention there is provided 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. According to a yet further aspect of the invention we provide 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, 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, testicular cancer, cervical cancer, oral cancer, pharyngeal cancer, renal cancer, thyroid cancer, uterine cancer, urinary bladder cancer, hepatocellular carcinoma, thyroid carcinoma, osteosarcoma, small cell lung cancer, leukaemia, myeloma, gastric carcinoma and metastatic cancers. 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.
In a further 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, metastatic colorectal cancer, small-cell lung cancer, advanced stomach cancer, pancreatic cancer, medulloblastoma and chondrosarcoma.
According to a further aspect of the invention we provide a method treatment of conditions involving abnormal activation of the hedgehog pathway whereby the condition involving abnormal activation of the hedgehog pathway is fibrosis.
Whereby fibrosis is cell necrosis caused by sustained inflammatory stimulation. Whereby 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.
Whereby fibrosis is selected from one or more of liver, kidney, bile duct, pancreas, cardiac, systemic sclerosis/scleroderma and myelofibrosis. Whereby liver fibrosis is selected from one or more of cirrhosis, chronic liver diseases, obesity-related liver disease or chronic viral hepatitis.
Whereby 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). According to a further aspect of the invention we provide a method 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). According to this aspect of the invention 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. In a specific embodiment, coadministration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen. Thus, according to this aspect of the invention there is provided 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. Thus, according to this aspect of the invention there is further provided 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.
In one embodiment, 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.
According to a further aspect of the invention the second therapeutic agent may act as a hedgehog modulator. According to this aspect of the invention the second therapeutic agent may act as a hedgehog modulator via downstream effectors including, but not limited to, SMO, GLI, SUH or tGLIl (truncated, gain-of- function isoform of the GLI1 transcription factor).
Examples of SMO inhibitors include cyclopamine, vismodegib, erismodegib, saridegib, CUR61414, BMS-833923/XL139, glasdegib, PF-5274857, TAK-441, taladegib MRT-92 and jervine.
Examples of GLI inhibitors include Arsenic Trioxide (ATO) and GANTs (GLI antagonists) as described herein.
Examples of SUH inhibitors include RU-SKI 43 and SHH Monoclonal Antibodies.
Examples of tGLIl target gene inhibitors include, CD24, VEGF-A, VEGFR2, HPA1 and TEM7. Cancer
When the condition involving abnormal activation of the hedgehog pathway is cancer 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.
According to a this aspect of the invention 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. aminopterin, methotrexate, pemetrexed or pralatrexate); a DNA polymerase inhibitor (e.g. cytarabine); a ribonucleotide reductase inhibitor (e.g. gemcitabine); a thymidylate synthase inhibitors (e.g. fluorouracil, capecitabine, tegafur, carmofur or floxuridine); aspirin; a non-steroidal anti-inflammatory agent (e.g. ibuprofen); a steroidal anti-inflammatory agent (e.g. a corticosteroid, such as, prednisolone or Cortisol); a non-drug oncology therapeutic agent; radiotherapy; tumour embolisation; surgery; and ultrasound.
More preferably 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, valrubicin vinblastine, vincristine, vindesine, vinorelbine or vismodegib.
In one aspect of the invention 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.
In one aspect of the invention the immunotherapeutic agent consists of one or more of CAR-T cells, vectors, vaccines, and armed antibodies. In another aspect of the invention the immunotherapeutic agent consists of any agent 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 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.
In another aspect of the invention 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.
According to this aspect of the invention 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.
In a preferred aspect of the invention checkpoint inhibitor is one or more of a CTLA4, PD1 or PDLl inhibitor. Examples of 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.
Examples of PD1 inhibitor, include, but shall not be limited to,, one or more of nivolumab, pidilizumab and MK-3475. Examples of PDL1 inhibitor, include, but shall not be limited to, one or more of BMS- 936559, MedI-4736, MPDL-3280A and MSB0010718C.
Fibrosis
When the condition involving abnormal activation of the hedgehog pathway is fibrosis particular agents include, but are not limited to: Inhibitors of SMO, ALK kinase, Notch, Wnt, Jak kinase or Bcl2.
According to this aspect of the invention examples include, pirfenidone, nintedanib, gamma secretase inhibitors, RO4929097, MRK-003, MK-0752 and PF03084014.
According to this aspect of the invention, particular examples include bevacizumab (Avastin), itraconazole, carboxyamidotriazole, TNP-470, CMlOl, 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, ανβ3. 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.
SYNTHETIC PROCEDURES
General
Compounds of Formula (I), and salts and solvates thereof; and intermediates of formulae (II), (III), (IV) and (V) may be prepared by the general methods outlined herein or any method known in the art, said methods constituting a further aspect of the invention. In the following description, the groups R1, R2, R3, W1, W2, W3A, W3B, W4A, W4B, n and m have the meaning defined herein for the compounds of Formula (I) as herein described, unless otherwise stated.
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.
Additionally, as will be apparent to those skilled in the art, conventional 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.
The following methods are presented with details as to the preparation of a compound of the invention as well as intermediate of the invention as defined hereinabove and the comparative examples.
Compounds of the invention, as well as intermediates of the invention, may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis, using methods known to the person skilled in the art or by methods described herein. All reagents were of commercial grade and were used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents were used for reactions conducted under inert atmosphere. Reagent grade solvents were used in all other cases, unless otherwise specified.
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 μπι). Flash chromatography is carried out using prepacked columns with 15 or 50 μπι 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-d6 or CDC13 as a solvent, unless otherwise stated. Chemical shifts (δ) for 1H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (δ 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 1.7μπι, 2.1x5mm VanGuard Pre-column with Acquity UPLC BEH C18 1.7 μπι, 2.1x50mm Column or Acquity UPLC CSH C18 1.7 μιη, 2.1x50mm Column. All the methods are using MeCN/H20 gradients. MeCN and H20 contains either 0.1% Formic Acid or lOmM
For preparative purification HPLC Waters Mass Directed Autopurification System is used. 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. General HPLC method parameters: gradient mobile phase of 0.1 % formic acid in H20 and MeCN or lOmM H4HCO3 pH=10 and MeCN. Column XBridge 30x150mm, 5μm. 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. 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.
Figure imgf000079_0001
Abbreviation Definition
BPin Boronic acid pinacol ester
br. s. broad singlet
CDI 1 , -Carbonyldiimidazole
Cpd Compound
Cpd# Compound number
d doublet
DCM Dichloromethane
1,2-DCE 1 ,2-Dichloroethane
DIPEA or DiPEA N,N-diisopropylethylamine
DMAP 4-(Dimethylamino)pyridine
DMF N,N-Dimethylformamide
DMSO Dimethylsulfoxide
DSC N,N'-Disuccinimidyl carbonate
EDCxHCl N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride
equiv. Equivalents
EtOAc Ethyl acetate
EtOH Ethanol
EWG Electron-withdrawing group
g Gram
h hour(s)
Hal Halogen
HATU 1 - [Bis(dimethylamino)methylene] - IH- 1 ,2, 3 -triazolo [4,5- £]pyridinium 3-oxid hexafluorophosphate
HBTU 0-(Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluoropho sphate
Het Heteroaryl
HOBt 1 -Hydroxybenzotriazole
HPLC High-performance liquid chromatography
Int Intermediate
zPrOH Isopropyl alcohol
KOtBu Potassium tert-butoxide Abbreviation Definition
LiHMDS Lithium bis(trimethylsilyl)amide
LCMS Liquid Chromatography-Mass Spectrometry
m multiplet
MeCN Acetonitrile
MeOH Methanol
mg milligram
min minute
mL millilitre
mmol millimoles
MTBE Methyl tert-butyl ether
Mtd Method
MW Molecular weight
BS N-bromosuccinimide
NMR Nuclear Magnetic Resonance
Pd/C Palladium on Carbon 10 wt%
Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0)
Pd(dppf)Cl2 [1, 1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
Pd-PEPPSI-IPr [l,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(II) dichloride
Ph Phenyl
RT Room temperature
RuPhos 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl
RuPhos Pd Gl, Chloro-(2-Dicyclohexylphosphino-2',6'-diisopropoxy-l, 1 '- MTBE adduct; biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) - methyl-t- RuPhos pre-catalyst butyl ether adduct
tBu tert-Butyl
s singlet
SCX Strong Cation Exchange
t triplet
TBTU O-(Benzotriazol- 1 -yl)-N,N,A^,N'-tetramethyluronium
tetrafluoroborate
TCCA Trichloroisocyanuric Acid Abbreviation Definition
TEA Triethyl amine
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TLC Thin-layer chromatography
Tr Trityl
TrCl Triphenylmethyl chloride
Ts Tosyl
TsCl 4-Toluenesulfonyl chloride
UPLC Ultra-performance liquid chromatography
The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration only and not limiting the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims. Where reactions are described as having been carried out in a similar manner to earlier, more completely described reactions, the general reaction conditions used were essentially the same. Work up conditions used were of the types standard in the art, but may have been adapted from one reaction to another. In the procedures that follow, reference to the product of a Description or Example by number is typically provided. This is provided merely for assistance to the skilled chemist to identify the starting material used. The starting material may not necessarily have been prepared from the batch referred to.
A compound of the invention as well as intermediate of the invention can be produced according to the following procedures. SYNTHETIC PREPARATION OF THE COMPOUND OF THE INVENTION
Synthesis of intermediates
Scheme 1A
Figure imgf000083_0001
(IVc) (llle)
Scheme 1C
Method B1
/ v Method A1 / ( (HM2, ccaattaallyysstt)) /
R— Hal + Cbz-lsT ^— BPin »- Cbz— IsT — R *■ HlsT — R
(Me) (lllf) (IVb)
Scheme ID
Figure imgf000083_0002
(llf) (lllg) (IVd) Method Al: General procedure for the preparation of piperidine Intermediates of formula (Ilia) or (Illf) by Suzuki coupling
The reaction is typically performed by combining an appropriate aryl or heteroaryl halide of formula R^-Hal (1 equiv.) and N-Boc-l,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester of formula (Ila) or N-Cbz-l,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester of formula (He) (1-1.2 equiv.) in the presence of a palladium catalyst (0.05-0.2 equiv.), such as Pd(PPh3)4, Pd(dppf)Cl2 xCH2Cl2 or any other suitable catalyst, and a base (1-5 equiv.), such as sodium carbonate or potassium carbonate, in a suitable solvent or a mixture of solvents (typically, a mixture of dioxane and water) under inert atmosphere. The resulting mixture is stirred at the temperature of typically 120 °C for 2-18 h by using conventional heating or for 15-40 min at 120 °C by using microwave irradiation. The expected Intermediate of formula (Ilia) or (Illf) may be isolated and, if desired, further purified by methods known to one skilled in the art. Example Al.l
Illustrative synthesis of Methyl 3-(l-terf-butoxycarbonyl-3,6-dihydro-2H-pyridin-4- yl)-l-(p-tolylsulfonyl)pyrrolo[2,3-Z>]pyridine-5-carboxylate
Figure imgf000084_0001
To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine- 1-carboxylate (298.3 mg, 1.2 equiv.), methyl 3-bromo-l-(p- tolylsulfonyl)pyrrolo[2,3-£]pyridine-5-carboxylate (329.0 mg, 1 equiv. 0.804 mmol), and potassium carbonate (111.1 mg, 1 equiv.) in degassed dioxane/water 2: 1 (10.0 mL), Pd(PPh3)4 (92.9 mg, 0.1 equiv.) was added and the solution was further degassed by bubbling argon for 5 minutes. Microwave flask was sealed and heated at 120 °C in a sand bath for two hours. The solution was cooled to RT, transferred to a separately funnel containing distilled water, and extracted with EtOAc (3 x 100 mL). Combined organic extracts were dried over Na2S04, filtered, and the solvent was removed in vacuo to yield the crude product, which was purified by flash chromatography on silica gel (eluting with a cyclohexane/EtOAc gradient, 0-25 % of EtOAc) to afford the expected product (322.4 mg). LCMS: MW (calc'd): 511.6; MS (ES+, m/z): 512.2 [M+H]+.
Example A1.2
Illustrative synthesis of terf-Butyl 4-furo [3,2-6] pyridin-3-yl-3,6-dihydro-2H- pyridine- 1-carboxylate
Figure imgf000085_0001
A mixture of tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-l-carboxylate (371 mg, 1 equiv.), 3-bromofuro[3,2-£]pyridine (238 mg, 1 equiv.) and tetrakis(triphenylphosphine)palladium(0) (277 mg, 0.2 equiv.) was dissolved in a mixture of 1,4-dioxane (12 mL) and a 2 M aq. solution of sodium carbonate (1.8 mL, 3 equiv.), and the solution was purged with argon for 5 min. The resulting mixture was sealed in a microwave vial and heated under microwave irradiation for 30 min at 120 °C. The reaction mixture was poured into water and extracted with EtOAc (2χ). Combined organic extracts were washed with water and brine, dried, and the solvent was removed in vacuo. The obtained crude product was purified by flash chromatography on silica gel (eluting with a cyclohexane/EtOAc gradient, 0-30 % of EtOAc) to afford the expected product (270 mg). LCMS: MW (calc'd): 300.4; MS (ES+, m/z): 301.5 [M+H]+; 245.5 [M- tBu+H]+; 201.5 [M-Boc+H]+.
Method A2: General procedure for the preparation of piperidine Intermediates of formulae (Ilia), (IIIc) and (Hid) by condensation
The reaction is typically performed by adding an appropriate heteroaryl of formula R^-H (1-1.2 equiv.) and KOH or KOtBu (3-4 equiv.) to a solution of an appropriate Boc-4- piperidone derivative of formula (lib) or (lid) (1 equiv.) in ethanol or methanol. The resulting mixture is heated at room temperature to reflux for 4-24 h. The expected Intermediate of formulae (Ilia), (IIIc) and (Hid) may be isolated and, if desired, further purified by methods known to one skilled in the art. Example A2.1
Illustrative synthesis of terf-Butyl 2-methyl-4-(lH-pyrrolo [2,3-6] pyridin-3-yl)-3,6- dihydro-2H-pyridine-l-carboxylate and terf-Butyl 6-methyl-4-(lH-pyrrolo[2,3- Z>]pyridin-3-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (two regioisomers)
Figure imgf000086_0001
To a solution of tert-butyl 2-methyl-4-oxo-piperidine-l-carboxylate (500 mg, 1 equiv.) in MeOH (5.0 mL), lH-pyrrolo[2,3-6]pyridine (332 mg, 1.2 equiv.) and KOH (394 mg, 3 equiv.) were added, and the resulting mixture was stirred under reflux for 9 h and at RT for 18 h. The reaction was quenched by an addition of a saturated aq. solution of ammonium chloride (25 mL) and the mixture was extracted twice with ethyl acetate. Combined organic extracts were washed with brine, dried over Na2SC>4, filtered, and the solvent was removed in vacuo to afford the expected product as a mixture of two regioisomers (730 mg), which was used without further purification in the next reaction step. LCMS: MW (calc'd): 313.4; MS (ES+, m/z): 314.3 [M+H]+.
Method A3: General procedure for the preparation of piperidine Intermediate of formula (Ilia) by Suzuki coupling
The reaction is performed by combining an appropriate arylboronic acid of formula R1- B(OH)2 (1.2 equiv.) and l-(tert-butoxycarbonyl)-l,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate of formula (lie) (1 equiv.) in the presence of a palladium catalyst (0.01 equiv.), such as Pd-PEPPSI-IPr, and a base (1.3 equiv.), such as potassium tert-butoxide in a suitable solvent (such as z'PrOH) under inert atmosphere. The resulting mixture is stirred at RT for 18-48 h. The expected Intermediate of the formula (Ilia) may be isolated and, if desired, further purified by methods known to one skilled in the art. Example A3.1
Illustrative synthesis of terf-Butyl 4-(2,4-dimethylphenyl)-3,6-dihydro-2H-pyridine-l- carboxylate
Figure imgf000087_0001
A 10-mL flask was charged with potassium tert-butoxide (219 mg, 1.3 equiv.) and PEPPSI-IPr catalyst (10 mg, 0.01 equiv.). The flask was sealed and content was purged with argon. Then, degassed isopropanol (5 mL) was added, and the content was stirred at room temperature for 10 min. (2,4-Dimethylphenyl)boronic acid (216.3 mg, 1.2 equiv.) was added as a solid, followed by tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro- 2H-pyridine-l-carboxylate (500 mg, 1 equiv.). The reaction mixture was stirred at RT for 48 h, and then diluted with EtOAc. The mixture was transferred to a separatory funnel containing distilled water and extracted with EtOAc (2x200 mL). The combined organic extracts were dried over anhydrous Na2S04, filtered, and the solvent was removed in vacuo. The obtained crude product was purified by flash chromatography on silica gel (eluting with a cyclohexane/EtOAc gradient, 0-5 % of EtOAc) to afford the expected product (250 mg). LCMS: MW (calc'd): 287.4; MS (ES+, m/z): 232.2 [M-tBu+H]+.
Method Bl: General procedure for the preparation of piperidine Intermediates of formula (Illb), (Hie) or (IVb) by hydrogenation/hydrogenolysis
Typically, to a MeOH or EtOH solution of an appropriate intermediate of formulae (Ilia), (IIIc), (Hid) or (Illf), where the double bond functionality is present, catalyst (10 wt% Pd/C or Pt02) is added, and the resulting mixture is hydrogenated at atmospheric pressure (balloon filled with hydrogen) or in Parr apparatus at 2-5 bar for 1-48 h. The expected Intermediate of formulae (Illb), (Hie) or (IVb) may be isolated and, if desired, further purified by methods known to one skilled in the art. Example Bl.l
Illustrative synthesis of terf-Butyl 4-furo[3,2-Z>]pyridin-3-ylpiperidine-l-carboxylate
Figure imgf000088_0001
To a solution of tert-butyl 4-furo[3,2-^]pyridin-3-yl-3,6-dihydro-2H-pyridine-l- carboxylate (270 mg, 1 equiv.) in MeOH (15 mL), 10 wt% Pd/C (96 mg, 0.1 equiv.) was added. The resulting mixture was stirred under H2 at atmospheric pressure (balloon filled with hydrogen) at RT for 5 h. The mixture was filtered through a pad of Celite, the pad was washed with MeOH, and the filtrate was concentrated in vacuo to afford the expected product (245 mg), which was used in the next reaction step without further purification. LCMS: MW (calc'd): 302.4; MS (ES+, m/z): 303.5 [M+H]+.
Method B2: General procedure for the preparation of piperidine Intermediates of formula (IHb) or (Hie) by transfer hydrogenation with ammonium formate
The reaction is typically performed by adding ammonium formate (1-10 equiv.) and 10 wt% Pd/C (0.08-0.5 equiv.) to a solution of an appropriate Intermediate of formulae (Ilia) or (IIIc) and (Hid) (1 equiv.) in EtOH, MeOH, or any other suitable solvent. The resulting mixture is heated typically at 50-90°C for 30 min to 30 h to afford the expected Intermediate of formula (Illb) or (Hie), which may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example B2.1
Illustrative synthesis of terf-Butyl 2-methyl-4-(lH-pyrrolo [2,3-6] pyridin-3- yl)piperidine-l-carboxylate
Figure imgf000088_0002
To a solution of two regioisomers, tert-butyl 2-methyl-4-(lH-pyrrolo[2,3-£]pyridin-3-yl)- 3,6-dihydro-2H-pyridine-l-carboxylate and tert-butyl 6-methyl-4-(lH-pyrrolo[2,3- £]pyridin-3-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (730 mg, 1 equiv.) in EtOH (15 mL), ammonium formate (734 mg, 5 equiv.) and 10 wt% Pd/C (195 mg) were added. The mixture was sealed in a reaction tube and stirred at 90 °C for 90 min. The mixture was then filtered over a pad of Celite, the pad was washed thoroughly with MeOH, and the filtrate was evaporated to dryness to afford the expected product (780 mg), which was used in the next step without further purification. LCMS: MW (calc'd): 315.4; MS (ES+, m/z): 316.3 [M+H]+.
Method R: General procedure for the preparation of piperazine Intermediate of formula (Illg) by Buchwald-Hartwig reaction
The reaction is typically performed under argon atmosphere by adding a 1.3 M THF solution of LiHMDS (2.5 equiv.) to a mixture of an appropriate heteroaryl halide of formula R^-Hal (1 equiv.), 1-Boc-piperazine of formula (Ilf) (1.2-1.3 equiv.), RuPhos (0.02-0.05 equiv.) and Ruphos pre-catalyst, MTBE adduct (0.02-0.05 equiv.) in THF. The resulting mixture is purged with argon for 5 min, and then sealed in a vial and heated for 3 h at 70-75 °C. The expected Intermediate of formula (Illg) may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example R.1
Illustrative synthesis of terf-Butyl 4-(lH-pyrrolo[2,3-Z>]pyridin-3-yl)piperazine-l- carboxylate
Figure imgf000089_0001
To a mixture of tert-butyl piperazine- 1-carboxylate (224 mg, 1.2 equiv.), 3-bromo-lH- pyrrolo[2,3-£]pyridine (197 mg, 1 equiv.), RuPhos (9.3 mg, 0.02 equiv.) and Ruphos Pd Gl, MTBE adduct (16.3 mg, 0.02 equiv.) in THF (2 mL), under argon atmosphere, a 1.3 M THF solution of LiHMDS (1.92 mL, 2.5 equiv.) was added. The resulting mixture was purged with argon for 5 min, and was then sealed in a vial and heated at 70 °C for 3 h. The reaction mixture was cooled to RT, quenched by an addition of 1 M HC1 (1.5 mL), diluted with EtOAc and poured into a sat. solution of sodium bicarbonate. After extracting with 3 portions of EtO Ac, combined organic extracts were dried, and the solvent was removed in vacuo. The obtained residue was purified by flash chromatography on silica gel (eluting with a cyclohexane/EtOAc gradient, 0-100 % of EtO Ac) to afford the expected product (165 mg). LCMS: MW (calc'd): 302.4; MS (ES+, m/z): 303.2 [M+H]+.
Method C: General procedure for the preparation of piperidine Intermediates of formula (IVa), (IVb) or (IVc) and piperazine Intermediate of formula (IVd) by N-Boc deprotection
Typically, to a solution of a Boc-protected amine compound of formula (Ilia), (Illb), (Hie) or (Illg) in a suitable solvent or a mixture of solvents (typically, DCM), TFA (2-150 equiv.) is added, and the reaction mixture is stirred at room temperature for 1 to 24 h to give the corresponding free amine. The expected Intermediate of formula (Iva), (IVb) or (IVc) may be isolated and, if desired further purified by methods known to one skilled in the art.
Alternatively, to a solution of a Boc-protected amine compound of formula (Ilia), (Illb), (Hie) or (Illg) in a suitable solvent (typically DCM), 4.0 M solution of HC1 in dioxane (20-200 equiv.) is added and the reaction mixture is stirred at RT for 1 to 24 hours to give the corresponding amine hydrochloride salt, which is isolated typically by solvent removal and, if desired, may be further purified by methods known to one skilled in the art.
Example C.l
Illustrative synthesis of 3-(4-Piperidyl)furo [3,2-6] pyridine
Figure imgf000090_0001
To a solution of tert-butyl 4-furo[3,2-£]pyridin-3-ylpiperidine-l-carboxylate, (657 mg, 1 equiv.) in DCM (7 mL), TFA (3.3 mL, 20 equiv.) was added. The resulting mixture was stirred at RT for 2 h. The reaction mixture was evaporated to dryness. The crude product was applied to a SCX column and eluted with MeOH, followed by 7 M ammonia in MeOH. Ammonia/MeOH fractions were combined and evaporated in vacuo to afford the expected product (451 mg), which was used in the next step without further purification. LCMS: MW (calc'd): 202.2; MS (ES+, /// r): 203.5 [M+H]+.
Example C.2
Illustrative synthesis of 3-Piperazin-l-yl-lH-pyrrolo[2,3-Z>]pyridine
Figure imgf000091_0001
To a solution of tert-butyl 4-(lH-pyrrolo[2,3-£]pyridin-3-yl)piperazine-l-carboxylate (160 mg, 1 equiv.) in DCM (4 mL), TFA (608 μΐ^, 15 equiv.) was added. The resulting mixture was stirred at RT for 4 h. The reaction mixture was applied to SCX column and eluted with MeOH. Compound was desorbed by elution with 2 M ammonia in MeOH. Ammonia/MeOH fraction was evaporated in vacuo to afford the expected product (105 mg). LCMS: MW (calc'd): 202.3; MS (ES+, m/z): 203.1 [M+H]+.
Example C.3
Illustrative synthesis of Methyl 3-(4-piperidyl)-l-(p-tolylsulfonyl)pyrrolo[2,3- Z>]pyridine-5-carboxylate hydrochloride salt
Figure imgf000091_0002
To a solution of methyl 3-(l-tert-butoxycarbonyl-4-piperidyl)-l-(p- tolylsulfonyl)pyrrolo[2,3-£]pyridine-5-carboxylate (54 mg, 1 equiv.) in DCM (4 mL), 4.0 M solution of HCI in dioxane (2 mL) was added and the solution was stirred at RT for 30 min. The solvent was removed in vacuo to afford the expected product (47 mg), which was used in the next reaction step without release of the base. LCMS: MW (calc'd): 413.5; MS (ES+, m/z): 414.2 [M+H]+. General Synthetic Methods for Preparation of the Compounds of Invention
Method D: Sulfonamidation reaction
Figure imgf000092_0001
(IVa-d)
Typically, to a solution of an appropriate Intermediate of formula (IVa-d) (1 equiv.) in THF, DMF (or any other suitable solvent), TEA, D/'PEA or other suitable base (2-10 equiv.) and a corresponding arylsulfonyl chloride (0.9-5 equiv.) are added. The reaction mixture is stirred at room temperature for 15 min to 24 h. The expected sulfonamide product may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example D.l
Illustrative synthesis of 3-[l-(4-ieri-Butylphenyl)sulfonyl-4-piperidyl]-5-fluoro-lH- pyrrolo [2,3-6] pyridine {Compound 34)
Figure imgf000092_0002
To a solution of 5-fluoro-3-(4-piperidyl)-lH-pyrrolo[2,3-£]pyridine (21.8 mg, 1 equiv.) in DMF (1 mL) was added TEA (64 μΙ_, 4.5 equiv.), followed by solid 4-tert- butylbenzenesulfonyl chloride (20.9 mg, 0.9 equiv.), and the reaction mixture was stirred at 25 °C for 18 h. Water (50 pL) was added, and the reaction mixture was purified by preparative HPLC-MS to yield the expected product (13.3 mg). LCMS: MW (calc'd): 415.5; MS (ES+, m/z): 416.1 [M+H]+. Example D.2
Illustrative synthesis of l-(4-tert-Butylphenyl)sulfonyl-4-(2,4- dimethylphenyl)piperazine {Compound 58)
Figure imgf000093_0001
To a solution of l-(2,4-dimethylphenyl)piperazine (50
Figure imgf000093_0002
1 equiv.) in THF (2.0 mL) was added TEA (185 μΐ., 5 equiv.), followed by solid 4-tert-butylbenzenesulfonyl chloride (123.3 mg, 2 equiv.), and the reaction mixture was stirred at RT for two hours. The reaction mixture was purified by preparative TLC eluting with 25% EtOAc/heptane to yield the expected product (101.1 mg). LCMS: MW (calc'd): 386.5; MS (ES+, mlz): 387.2 [M+H]+.
Example D.3
Illustrative synthesis of 3-[l-(l-Benzylpyrazol-4-yl)sulfonyl-4-piperidyl]-lH- pyrrolo [2,3-6] pyridine (Compound 115)
Figure imgf000093_0003
To a stirred solution of 3-(4-piperidyl)-lH-pyrrolo[2,3-£]pyridine (30 mg, 1 equiv.) and TEA (84 μΐ., 4 equiv.) in dry THF (1.5 mL) was added l-benzylpyrazole-4-sulfonyl chloride (42 mg, 1.1 equiv.) and the resulting mixture was stirred at RT for 2 h. The reaction was quenched with water and extracted with EtOAc (3 χ). Combined organic extracts were dried and the solvent was removed in vacuo. The obtained residue was purified by preparative HPLC-MS to afford the expected product (40 mg). LCMS: MW (calc'd): 421.2; MS (ES+, m/z): 422.6 [M+H]+.
Method E: General procedure for NTs- rotection
Figure imgf000094_0001
The reaction is typically performed by adding KOtBu (1 equiv.) to a solution of an appropriate Mi-functionality-containing heteroaryl, for example to a heteroaryl halide intermediate of formula R^Hal (1 equiv.), in THF, followed by an addition of TsCl (1- 1.5 equiv.) and the resulting mixture is stirred at RT for 1-5 h. 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.
Example E.l
Illustrative synthesis of Methyl 3-bromo-l-(p-tolylsulfonyl)pyrrolo[2,3-Z>]pyridine-5- carboxylate
Figure imgf000094_0002
To a suspension of methyl 3-bromo-lH-pyrrolo[2,3-£]pyridine-5-carboxylate (350 mg, 1 equiv.) in dry THF (15 mL) was added KOtBu (153.7 mg, 1 equiv.) and the mixture was stirred at 0 °C. Tosyl chloride (261.5 mg, 1 equiv.) was added, and the reaction mixture was stirred at 25 °C for one hour. The reaction mixture was transferred to a separatory funnel containing distilled water and extracted with EtOAc (3 x80 mL). Combined organic extracts were dried over Na2S04, filtered, and the solvent was removed in vacuo. Crude product was purified by recrystallization from DCM to yield the expected product (329 mg). LCMS: MW (calc'd): 409.3; MS (ES+ m/z): 409.0, 411.0 [M+H]+.
Method F: NTs-Deprotection
Figure imgf000095_0001
Typically, to a solution of an appropriate NTs-protected intermediate or final compound where nitrogen atom is Ts protected, in a suitable solvent or a mixture of solvents (typically, in a THF/MeOH mixture), caesium carbonate (1-12 equiv.) is added and the reaction mixture is stirred at room temperature to 55 °C for 1-24 h. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example F.l
Illustrative synthesis of 3-[l-(lH-Pyrazol-4-ylsulfonyl)-4-piperidyl]-lH-pyrrolo[2,3- c] pyridine
Figure imgf000095_0002
To a solution of l-(p-tolylsulfonyl)-3-[l-(lH-pyrazol-4-ylsulfonyl)-4- piperidyl]pyrrolo[2,3-c]pyridine (48.6 mg, 1 equiv.) in a THF/MeOH 2: 1 solvent mixture (1.2 mL), caesium carbonate (97.7 mg, 3 equiv.) was added and the resulting mixture was stirred at 50 °C for 3 h. The reaction mixture was evaporated and the obtained residue was purified by preparative HPLC-MS to afford the expected product (6.6 mg). LCMS: MW (calc'd): 331.4; MS (ES+, mlz): 332.1 [M+H]+.
Example F.2
Illustrative synthesis of Methyl 3-[l-(4-ieri-butylphenyl)sulfonyl-4-piperidyl]-lH- pyrrolo [2,3-6] pyridine-5-carboxylate (Compound 66 )
Figure imgf000096_0001
To a solution of methyl 3-[l-(4-tert-butylphenyl)sulfonyl-4-piperidyl]-l-(p- tolylsulfonyl)pyrrolo[2,3-£]pyridine-5-carboxylate (29 mg, 1 equiv.) in THF/MeOH 2: 1 (1 mL) was added caesium carbonate (46.5 mg, 3 equiv.) and the reaction mixture was stirred at 25 °C. After one hour, the reaction was stopped and was purified by preparative HPLC- MS to yield the expected product (8.6 mg). LCMS: MW (calc'd): 455.6; MS (ES+, m/z): 456.1 [M+H]+.
Method G: Azaindole N-allylation
Figure imgf000096_0002
Typically, to a solution of an azaindole derivative (1 equiv.) in DMF (or any other suitable solvent), NaH, 60 % dispersion in mineral oil (2 equiv.) is added. The resulting mixture is stirred for 30 min, and then the corresponding allyl halide (1.3 equiv.) is added. The reaction mixture is stirred at RT for 30 min to 24 h. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example G.l
Illustrative synthesis of N-[4-[[4-(l-Allylpyrrolo[2,3-Z>]pyridin-3-yl)-l- piperidyl] sulfonyl] phen l] acetamide
Figure imgf000097_0001
To a solution of N-[4-[[4-(lH-pyrrolo[2,3-*]pyridin-3-yl)-l- piperidyl]sulfonyl]phenyl] acetamide (120 mg, 1 equiv.) in dry DMF (2 mL) was added NaH, 60% dispersion in mineral oil (24 mg, 2 equiv.), and the resulting mixture was stirred at RT for 30 min. Allyl bromide (33.7 μΐ., 1.3 equiv.) was added, and the stirring was continued at RT for 2 h. The reaction mixture was quenched by an addition of water (10 mL), and the mixture was extracted with EtOAc (3 x50 mL). Combined organic extracts were dried over Na2S04, filtered, and the solvent was removed in vacuo to yield the crude product. The crude product was purified by preparative HPLC-MS to yield the expected product (30 mg). LCMS: MW (calc'd): 438.5; MS (ES+, m/z): 439.7 [M+H]+.
Method HI: Amide cou ling with HATU, HBTU or TBTU
Figure imgf000097_0002
Typically, to a solution of an appropriate carboxylic acid (1.1 equiv.) in a suitable solvent (such as DMF), D/'PEA (3-5 equiv.) and a coupling reagent, such as HATU, HBTU, or TBTU (1-2.5 equiv.) are added, and the reaction mixture is stirred at RT for 10 min to 30 min. An appropriate amine compound (1 equiv.) is added and the reaction mixture is stirred at RT for 30 min to 18 h. The expected amide product may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example Hl.l
Illustrative synthesis of N-ieri-Butyl-4-methoxy-5-[[4-(lH-pyrrolo[2,3-6]pyridin-3-yl)- l-piperidyl]sulfonyl]thiophene-3-carboxamide (Compound 15 )
Figure imgf000098_0001
To a solution of 4-methoxy-5-[[4-(lH-pyrrolo[2,3-£]pyridin-3-yl)-l- piperidyl]sulfonyl]thiophene-3-carboxylic acid (40 mg, 1 equiv.) in DMF (2 mL) was added D/'PEA (50 μΐ^, 3 equiv.), and the solution was stirred at RT for 30 min. Then HBTU was added (72 mg, 2 equiv.), followed by an addition of tert-butylamine (12 μΐ^, 1.2 equiv.). The reaction mixture was stirred at RT for one hour, and then diluted with EtOAc and washed with distilled water (3 x 10 mL) and with brine (10 mL). Organic extracts were dried over Na2S04, filtered, and the solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel (eluting with 9% MeOH/DCM) to afford the expected product (39 mg). LCMS: MW (calc'd): 476.6; MS (ES+, m/z): Ml .1 [M+H]+.
Method H2: Amide synthesis with acid chloride
Figure imgf000098_0002
Typically, to a solution of an amine (1.0 equiv.) in dry THF is added a base such as TEA (3 equiv.), followed by acid chloride (0.91 equiv.). The reaction mixture is stirred at 25 °C for 30 min. The expected amide product can be isolated and, if desired, further purified by methods familiar to one skilled in the art. Example H2.1
Illustrative synthesis of l-[3-[l-(4-ieri-Butylphenyl)sulfonyl-4-piperidyl]-6,8-dihydro- 5H-imidazo[l,2- ]pyrazin-7-yl]ethanone (Compound 45 )
Figure imgf000099_0001
To a solution of 3-[l-(4-tert-butylphenyl)sulfonyl-4-piperidyl]-5, 6,7,8- tetrahydroimidazo[l,2-a]pyrazine (23 mg, 1 equiv.) in dry THF (3 mL) was added TEA (24 μΐ., 3 equiv.) followed by AcCl (3.7 μΐ., 0.91 equiv.). The reaction mixture was stirred at 25 °C for 18 h. The solvent was removed in vacuo and the remaining solid was purified by preparative HPLC-MS to yield the expected product (6 mg). LCMS: MW (calc'd): 444.6; MS (ES+, m/z): 445.2 [M+H]+.
Method H3. Primary amide formation
Figure imgf000099_0002
A mixture of a carboxylic acid (1 equiv.), HOBt (2 equiv.), EDC'HCl (2 equiv.), and H4CI (2 equiv.) is dissolved in DMF. D/'PEA (4 equiv.) is added and the reaction mixture is stirred at RT under Ar for 3 h. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art. Example H3.1
Illustrative synthesis of 2-[4-[l-(4-tert-Butylphenyl)sulfonyl-4- piperidyl]phenoxy]acetamide (Compound 44 )
Figure imgf000100_0001
A mixture of 2-[4-[l-(4-tert-butylphenyl)sulfonyl-4-piperidyl]phenoxy]acetic acid (39 mg, 1 equiv.), HOBt (24.5 mg, 2 equiv.), EDC HCl (35 mg, 2 equiv.), and H4C1 (10 mg, 2 equiv.) was dissolved in DMF (500 L). D/'PEA (63 μΐ., 4 equiv.) was added and the reaction mixture was stirred under Ar at RT for 3 h. The solvent was removed in vacuo and the residue was partitioned betweed water and EtOAc. The aqueous phase was extracted with EtOAc. Combined organic extracts were washed with 1 M HCl and with brine, were dried over Na2S04, and the solvent was removed in vacuo to yield the crude product. The crude product was purified by column chromatography and by precipitation from EtOAc to yield the expected product (6.3 mg). LCMS: MW (calc'd): 430.6; MS (ES+, m/z): 431.2 [M+H]+.
Method H4: Amidation of unreactive anilines
Figure imgf000100_0002
Typically, to a solution of an appropriate carboxylic acid (5 equiv.) in a suitable solvent (such as DCM, DMF, or a mixture thereof) is added oxalyl chloride (8 equiv.) dropwise. The reaction mixture is stirred at RT for 1.5 h, and is then diluted with toluene and concentrated in vacuo. The resulting oil is taken up in THF and is added to a mixture of an appropriate aniline (1.0 equiv.) and NaH (2.1 equiv.) in THF at 0 °C. The reaction mixture is stirred at 0 °C for 45 min and at RT for 18 h. The expected amide product may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example H4.1
Illustrative synthesis of N-[4-[[4-(l-Allylpyrrolo[2,3-Z>]pyridin-3-yl)-l- piperid ljsulfonyl] phenyl] -3,5-dimethyl-isoxazole-4-carboxamide (Compound 7 )
Figure imgf000101_0001
To a solution of 3,5-dimethylisoxazole-4-carboxylic acid (178 mg, 5 equiv.) in dry DCM (3 mL) was added dry DMF (100 μΐ.), and then oxalyl chloride (176 μΐ., 8 equiv.) dropwise. The reaction mixture was stirred at RT for 1.5 h, and then diluted with toluene, and the solvent was removed in vacuo. In a separate flask, 4-[[4-(l-allylpyrrolo[2,3- £]pyridin-3-yl)-l-piperidyl]sulfonyl]aniline (100 mg, 1 equiv.) was taken up in dry THF (2 mL), the solution was cooled to 0 °C, and treated with NaH (21 mg, 2.1 equiv.). The reaction mixture was stirred at RT for 20 min, cooled to 0 °C and treated with a THF solution of the above prepared acid chloride (2 mL). The resulting mixture was stirred at 0 °C for 45 min, and at RT for 18 h. The reaction mixture was quenched by an addition of water and extracted with EtOAc. Combined organic extracts were dried over Na2S04, filtered, and the solvent was removed in vacuo to yield the crude product. The crude product was purified by preparative HPLC-MS to yield the expected product (17 mg). LCMS: MW (calc'd): 519.6; MS (ES+, /// r): 520.7 [M+H]+. Method H5: Azaindole N-amidation with TBTU
Figure imgf000102_0001
Typically, to a solution of a carboxylic acid derivative (2.5 equiv.) in dry DMF is added D/'PEA (7 equiv.) followed by TBTU (3 equiv.), and the mixture is stirred at RT for one hour. Azaindole derivative (1 equiv.) is added and the reaction mixture is stirred at RT for 30 min and at 100 °C for 2 h. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art. Example H5.1
Illustrative synthesis of [3-[l-(4-Aminophenyl)sulfonyl-4-piperidyl]pyrrolo[2,3- Z>]pyridin-l-yl]-(3,5-dimethylisoxazol-4-yl)methanone (Compound 14 )
Figure imgf000102_0002
To a solution of 3,5-dimethylisoxazole-4-carboxylic acid (58 mg, 2.5 equiv.) in DMF (3 mL) was added D/PEA (202 uL, 7 equiv.), followed by TBTU (160 mg, 3 equiv.). The reaction mixture was stirred at RT for one hour, and then 4-[[4-(lH-pyrrolo[2,3-£]pyridin- 3-yl)-l-piperidyl]sulfonyl]aniline (59 mg, 1 equiv.) was added. The reaction mixture was stirred at RT for 30 min, and at 100 °C for 2 h. The reaction mixture was cooled to RT, and the solvent was removed in vacuo. The residue was partitioned betweed EtOAc and water, organic phase was washed with brine, dried over Na2S04, filtered, and the solvent was removed in vacuo to yield the crude product. The crude product was purified by column chromatography, followed by preparative HPLC-MS to yield the expected product (11.5 mg). LCMS: MW (calc'd): 479.5; MS (ES+, m/z): 480.7 [M+H]+.
Method I: Ester hydroly
Figure imgf000103_0001
Suspension of an ester in a mixture of an aqueous solution of NaOH (1 M - 2 M) and MeOH or EtOH is stirred at 60-100 °C for 1-3 h. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example LI
Illustrative synthesis of 4-[[4-(lH-Pyrrolo[2,3-Z>]pyridin-3-yl)-l- piperidyljsulfonyl] benzoic acid
Figure imgf000103_0002
A suspension of ethyl 4-[[4-(lH-pyrrolo[2,3-^]pyridin-3-yl)-l-piperidyl]sulfonyl]benzoate (220 mg, 1 equiv.) in a mixture of 1 M NaOH (7 mL) and EtOH (7 mL) was heated with stirring at 60 °C for one hour, during which time the suspension completely dissolved. The reaction mixture was cooled to RT, and the solvent was partially removed in vacuo to yield an aqueous suspension, which was acidified to pH 1 by an addition of 2 M HCl. The precipitate was filtered off and dried to yield the expected product (190 mg). LCMS: MW (calc'd): 385.4; MS (ES+, m/z): 386.5 [M+H]+. Method J: NTr-protection
Figure imgf000104_0001
The reaction is typically performed by adding TEA (1 equiv.) to a mixture of an appropriate pyrazole compound (1 equiv.) in dry DMF at 0 °C, followed by TrCl (0.99 equiv.) and the resulting mixture is stirred at RT for 24 h. The expected Tr-protected product may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example J.l
Illustrative synthesis of 4-Iodo-l-trityl-pyrazole
Figure imgf000104_0002
4-Iodopyrazole (2.5 g, 1 equiv.) was dissolved in dry DMF (20 mL), and TEA (1.8 mL, 1 equiv.) was added at 0 °C. Then, trityl chloride (3.56 g, 0.99 equiv.) was added, and the reaction mixture was stirred at 0 °C to RT overnight. The mixture was then poured into ice water (250 mL) and was filtered. The obtained solid was washed with water (150 mL), and was then triturated with toluene (20 mL) and dried under vacuum to afford the expected product (3.48 g), which was used in the next reaction step without further purification.
Method K: Cop er-catalysed cou ling of thiobenzoic acid and heteroaryl iodides
Figure imgf000104_0003
The reaction is typically performed by adding Cul (0.1 equiv.) to the mixture of an appropriate heteroaryl iodide (1 equiv.), thiobenzoic acid (1.2 equiv.), 1, 10-phenantroline (0.2 equiv.), and a base, such as DIPEA (2 equiv.) in degassed toluene, and the resulting mixture is stirred under argon atmosphere at reflux for 16-24 h. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art. Example K.1
Illustrative synthesis of S-(l-Tritylpyrazol-4-yl) benzenecarbothioate
Figure imgf000105_0001
To a solution of 4-iodo-l-trityl-pyrazole (3.48 g, 1 equiv.), thiobenzoic acid (1.12 mL, 1.2 equiv.), 1, 10-phenantroline (0.22 mL, 0.2 equiv.) and D/PEA (2.78 mL, 2 equiv.) in toluene (16 mL) was added Cul (0.15 g, 0.1 equiv.). The resulting mixture was degassed and then stirred under argon at reflux temperature for 16 h. The reaction mixture was filtered through a pad of Celite, and the pad was washed with toluene. The solvent was removed under vacuum, and the crude product was purified by flash chromatography on silica gel (eluting with a cyclohexane/EtOAc gradient, 0-10 % of EtOAc) to afford the expected product (3.88 g).
Method L: Synthesis of sulfonyl chlorides from heteroaryl thiobenzoates
Figure imgf000105_0002
The reaction is typically performed by adding TCCA (1.2 equiv.) to the suspension of BnMesNCl (3.4 equiv.) in acetonitrile, and the resulting solution is added dropwise to a solution of an appropriate heteroaryl thiobenzoate in acetonitrile at 0 °C, followed by an addition of a base, such as Na2C03 (1 equiv.), and the resulting mixture is stirred at RT for 1 h. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art. Example L.l
Illustrative synthesis of l-Tritylpyrazole-4-sulfonyl chloride
Figure imgf000106_0001
To a stirred suspension of BnMesNCl (1.4 g, 3.4 equiv.) in acetonitrile (15 mL) was added TCCA (0.63 g, 1.2 equiv.) and the mixture was stirred for 30 minutes. The obtained clear yellow solution was added dropwise to a stirred solution of ^-(l-tritylpyrazoM-yl) benzenecarbothioate (1.0 g, 1 equiv.) in acetonitrile (15 mL) over 5 minutes at 0 °C. To this mixture was added a 1 M Na2C03 (2.24 mL, 1 equiv.) and the reaction was allowed to proceed at this temperature for one hour. The reaction mixture was poured into a saturated aq. solution of Na2C03 (60 mL) and extracted with EtOAc (2x50 mL). Combined organic extracts were washed with brine (60 mL), dried over Na2S04, filtered, and the solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel (eluting with a cyclohexane/EtOAc gradient, 0-10 % of EtOAc) to afford the expected product (385 mg).
Method M: NTr deprotection
Figure imgf000106_0002
Typically, to a solution of an appropriate NTr-protected pyrazole compound, in a suitable solvent or mixture of solvents (typically in DCM), TFA (2-20 equiv.) is added and the reaction mixture is stirred at room temperature for 1 to 48 h. The expected product may be isolated and, if desired further purified by methods known to one skilled in the art. Example M.l
Illustrative synthesis of l-(p-Tolylsulfonyl)-3-[l-(lH-pyrazol-4-ylsulfonyl)-4- piperidyl] py rrolo [2,3-c] pyridine
Figure imgf000107_0001
To a solution of l-(p-tolylsulfonyl)-3-[l-(l-tritylpyrazol-4-yl)sulfonyl-4- piperidyl]pyrrolo[2,3-c]pyridine, (353.6 mg, 1 equiv.) in DCM (3 mL), TFA (375 μΐ., 10 equiv.) was added. The resulting mixture was stirred at RT overnight, and then additional amount of TFA (375 μΐ., 10 equiv.) was added. The reaction mixture was left to stir at RT overnight. The reaction mixture was loaded onto a SCX column and eluted with MeOH followed by 2 M ammonia in MeOH. Ammonia/MeOH fraction was evaporated in vacuo to afford the expected product (230.7 mg), which was used in the next step without further purification. LCMS: MW (calc'd): 485.5; MS (ES+, m/z): 486.0 [M+H]+.
Method N: Acetamide cleava e
Figure imgf000107_0002
Typically, a solution of an acetamide derivative (1 equiv.) in a mixture of ethanol and 20% aqueous NaOH was heated at 100 °C with stirring for 1-6 h. The expected hydrolysis product may be isolated and, if desired, further purified by methods known to one skilled in the art. Example N.l
Illustrative synthesis of 4-[[4-(l-Allylpyrrolo[2,3-Z>]pyridin-3-yl)-l- piperidyljsulfonyl] aniline Compound 1 )
Figure imgf000108_0001
A solution of N-[4-[[4-(l-allylpyrrolo[2,3-6]pyridin-3-yl)-l- piperidyl]sulfonyl]phenyl]acetamide (380 mg, 1 equiv.) in a mixture of 20% aqueous NaOH (5 mL) and ethanol (5 mL) was heated with stirring at 100 °C for one hour. The solvent was partially removed in vacuo and the resulting aqueous suspension was extracted with EtOAc (3 x30 mL). Combined organic extracts were dried over Na2S04, filtered, and the solvent was removed in vacuo to yield the crude product. The crude product was purified by sonication with methanol and subsequently by preparative HPLC-MS to yield the expected product (17.5 mg). LCMS: MW (calc'd): 396.5; MS (ES+, m/z): 397.7 [M+H]+. Method P: Phenol 0-alkylation
Figure imgf000108_0002
Typically, to a solution of a phenol derivative (1 equiv.) in dry acetone or DMF is added K2CO3 or CS2CO3 (2.3-3.6 equiv.) followed by an alkyl halide derivative (1-10 equiv.). The resulting mixture is stirred at RT to reflux for 20 min to 48 h. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art. synthesis of terf-Butyl 4-[4-(cyanomethoxy)phenyl]piperidine
Figure imgf000109_0001
To a solution of tert-butyl 4-(4-hydroxyphenyl)piperidine-l-carboxylate (150 mg, 1 equiv.) in dry acetone (1.5 mL) was added K2CO3 (170 mg, 2.3 equiv.), followed by bromoacetonitrile (60 μΐ., 1.6 equiv.). The resulting miture was stirred under reflux for 2 min, and at RT for 20 min. The reaction mixture was then stirred at 40 °C for 40 min. The reaction mixture was cooled to RT and filtered. The precipitate was washed thoroughly with acetone. Combined filtrates were evaporated in vacuo and the remaining crude product was purified by column chromatography to yield the expected product (124 mg).
Method S: Phenol demethylation
Figure imgf000109_0002
A solution of a phenol methyl ether (1 equiv.) in DCM at 0 °C is treated with 1 M solution of BBr3 in DCM (7 equiv.). The resulting mixture is allowed to reach RT and is stirred at RT for 2 h. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art. Example S.l
Illustrative synthesis of 4- [l-(4-terf-Butylphenyl)sulfonyl-4-piperidyl] phenol (Compound 51 )
Figure imgf000110_0001
A solution of l-(4-tert-butylphenyl)sulfonyl-4-(4-methoxyphenyl)piperidine (15 mg, 1 equiv.) in dry DCM (1 mL) at 0 °C was treated with 1 M solution of BBr3 in DCM (271 μί, 7 equiv.), and the resulting mixture was allowed to reach RT, and was stirred at RT for 2 h. The reaction mixture was poured into water, and the product was extracted with DCM. Combined organic extracts were washed with brine, dried over Na2S04, filtered, and the solvent was removed in vacuo to yield the expected product (15 mg). LCMS: MW (calc'd): 373.5; MS (ES+, m/z): 374.2 [M+H]+.
Method T: Azaindole N-Boc protection
Figure imgf000110_0002
Suspension of an azaindole compound (1 equiv.) and DMAP (0.5 equiv.) in dry DCM is treated with di-tert-butyl dicarbonate (1.1 equiv.) and the resulting mixture is stirred at RT for 90 min. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art. Example T.l
Illustrative synthesis of terf-Butyl 3-[l-(4-ethoxycarbonylphenyl)sulfonyl-4- piperidyl] py rrolo [2,3-6] ridine- 1-carboxylate
Figure imgf000111_0001
A suspension of ethyl 4-[[4-(lH-pyrrolo[2,3-^]pyridin-3-yl)-l-piperidyl]sulfonyl]benzoate (90 mg, 1 equiv.) and DMAP (13 mg, 0.5 equiv.) in dry DCM (10 mL) was treated with di- tert-butyl dicarbonate (52 mg, 1.1 equiv.) and the resulting mixture was stirred at RT for 90 min. The reaction was quenched by an addition of a sat. NaHC03 solution and the stirring was continued at RT for 10 min. Layers were separated, the organic layer was dried over Na2S04, and the the solvent was removed in vacuo. The obtained crude product was purified by flash chromatography on silica gel (eluting with 9% MeOH/DCM) to yield the expected product (107 mg). LCMS: MW (calc'd): 513.6; MS (ES+, mlz): 514.8 [M+H]+.
Method O: General rocedure for N-Boc deprotection
Figure imgf000111_0002
Typically, to a solution of a Boc-protected amine compound in a suitable solvent or a mixture of solvents (typically, DCM), TFA (2-150 equiv.) is added, and the reaction mixture is stirred at room temperature for 1 to 24 h to give the corresponding free amine. The expected product may be isolated and, if desired further purified by methods known to one skilled in the art.
Alternatively, to a solution of a Boc-protected amine compound in a suitable solvent (typically DCM), 4.0 M solution of HC1 in dioxane (20-200 equiv.) is added and the reaction mixture is stirred at RT for 1 to 24 hours to give the corresponding amine hydrochloride salt, which is isolated typically by solvent removal and, if desired, may be further purified by methods known to one skilled in the art. Example O.l
Illustrative synthesis of 3-[l-(4-terf-Butylphenyl)sulfonyl-4-piperidyl]-5,6,7,8- tetrahydroimidazo [1 ,2- ] razine )
Figure imgf000112_0001
To a solution of tert-butyl 3-[l-(4-tert-butylphenyl)sulfonyl-4-piperidyl]-6,8-dihydro-5H- imidazo[l,2-a]pyrazine-7-carboxylate (45 mg, 1 equiv.) in DCM (4 mL) was added 4.0 M solution of HCl in dioxane (2 mL, 89 equiv.) and the solution was stirred for four hours. The solvent was removed in vacuo to yield the crude product, which was taken up in MeOH and was passed over a SPE column (HC03) eluting with MeOH. The solvent was removed in vacuo to yield the expected product (23 mg). LCMS: MW (calc'd): 402.5; MS (ES+, m/z): 403.2 [M+H]+.
Example 0.2
Illustrative synthesis of l-(4-terf-But lphenyl)sulfonylpiperidin-4-amine
Figure imgf000112_0002
To a solution of tert-butyl N-[l-(4-tert-butylphenyl)sulfonyl-4-piperidyl]carbamate (830.1 mg, 1 equiv.) in dry DCM (3 mL) was added TFA (3 mL). The reaction mixture was stirred at RT for 1 hour. The reaction mixture was loaded onto a SCX column and eluted with MeOH. Compound was desorbed by elution with 1.4 M ammonia in MeOH. Ammonia/MeOH fraction was evaporated in vacuo to give the expected product (651.3 mg). LCMS: MW (calc'd): 296.4; MS (ES+, m/z): 297.5 [M+H]+.
Method Q: Nitrile reduction to amine
Figure imgf000113_0001
To a suspension of a nitrile compound (1 equiv.) in dry THF under Ar is added borane- dimethyl sulfide complex (4-10 equiv.), and the resulting mixture is stirred under reflux for one hour and at RT for 18 h. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example Q.l
Illustrative synthesis of 2-[4-[l-(4-terf-Butylphenyl)sulfonyl-4- piperidyl]phenoxy]ethanamine (Compound 41 )
Figure imgf000113_0002
To a suspension of 2-[4-[l-(4-tert-butylphenyl)sulfonyl-4-piperidyl]phenoxy]acetonitrile (165 mg, 1 equiv.) in dry THF (2 mL) under Ar was added borane-dimethyl sulfide complex (800 μΐ^, 4 equiv.), and the resulting mixture was stirred under reflux for one hour and at RT for 18 h. The reaction was quenched by a slow addition of water (5 mL). The solvent was partially removed in vacuo and the resulting aqueous suspension was extracted with DCM. Combined organic extracts were dried over Na2SC"4, filtered, and the solvent was removed in vacuo to yield the crude product (164 mg). The crude product was purified by preparative HPLC-MS to yield the expected product (14 mg). LCMS: MW (calc'd): 416.6; MS (ES+, m/z): All .3 [M+H]+.
Method U: Grignard addition to esters
Figure imgf000114_0001
Suspension of an ester compound (1 equiv.) in dry THF under Ar at -15 °C is treated with a 3 M solution of MeMgBr in Et20 (3-10 equiv.). The resulting mixture is stirred at -15 °C to RT for 30 min to 72 h under Ar. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example Ul.l
Illustrative synthesis of 2-[4-[[4-(lH-Pyrrolo[2,3-Z>]pyridin-3-yl)-l- piperidyljsulfonyl] phenyl propan-2-ol (Compound 4)
Figure imgf000114_0002
A suspension of tert-butyl 3-[l-(4-ethoxycarbonylphenyl)sulfonyl-4-piperidyl]pyrrolo[2,3- £]pyridine-l-carboxylate (103 mg, 1 equiv.) in dry THF (10 mL) at -15 °C under Ar was treated with a 3 M solution of MeMgBr in Et20 (195 μΐ., 3 equiv.). The resulting mixture was stirred at -15 °C for 30 min and at RT for 48 h. The reaction mixture was cooled to -15 °C and additional MeMgBr was added (100 μΐ., 1.5 equiv.). The resulting mixture was stirred at RT for 5 h. Additional MeMgBr was added (200 μΐ., 3 equiv.), and the resulting mixture was stirred at RT for 30 min. The reaction was quenched by an addition of a sat. aq. H4CI solution. Layers were separated, and the aqueous layer was extracted with EtOAc. Combined organic extracts were dried over Na2S04, filtered, and the solvent was removed in vacuo to yield the crude product (77 mg). The crude product was purified by preparative HPLC-MS to yield the expected product (26 mg). LCMS: MW (calc'd): 399.5; MS (ES+, mlz): 400.7 [M+H]+.
Method V: Reduction of esters
Figure imgf000115_0001
To a suspension of LiAlH4 (11.5 equiv.) in dry THF at 0 °C is added an ester derivative (1 equiv.), and the reaction mixture is stirred at 0 °C for one hour. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example V.l
Illustrative synthesis of [l-[4-[[4-(lH-Pyrrolo[2,3-Z>]pyridin-3-yl)-l- piperidyljsulfonyl] phenyl] cyclopropyl] methanol (Compound 5 )
Figure imgf000115_0002
To a suspension of LiAlH4 (50 mg, 11.5 equiv.) in dry THF (10 mL) at 0 °C was added methyl 1 - [4- [ [4-( lH-pyrrolo [2,3 -6]pyridin-3 -yl)- 1 - piperidyl]sulfonyl]phenyl]cyclopropanecarboxylate (50 mg, 1 equiv.), and the resulting reaction mixture was stirred at 0 °C for one hour. The reaction was quenched by a dropwise addition of a 5% aq. NaOH solution (2 mL) with vigorous stirring for 5 min. The resulting mixture was filtered over Celite, and the filtrate was evaporated in vacuo. Viscous residue was resuspended in Et20 (4 mL), whereupon the product formed a white precipitate which was filtered off, resuspended in MeOH (1 mL), and filtered off to yield the expected product (25 mg). LCMS: MW (calc'd): 411.5; MS (ES+ mlz): 412.7 [M+H]+.
Method W: SNAr
Alk Al k
/ /
H et— X + H N H et— N
\ \
Alk Al k
To the suspension of a heteroaryl halide (1 equiv.) in dry THF is added a base (such as TEA, 4 equiv.), followed by a primary or secondary amine (13 equiv.), and the resulting reaction mixture is heated at 100 °C in MW for 20 min to 2 h. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example W.l
Illustrative synthesis of N /V-Dimethyl-5-[[4-(lH-pyrrolo[2,3-6]pyridin-3-yl)-l- piperidyl]sulfonyl]pyridin-2-amine Compound 2 )
Figure imgf000116_0001
To a suspension of 3-[l-[(6-chloro-3-pyridyl)sulfonyl]-4-piperidyl]-lH-pyrrolo[2,3- £]pyridine (35 mg, 1 equiv.) in dry THF (2 mL) was added TEA (52 μΐ., 4 equiv.), followed by a 2 M solution of dimethylamine in THF (140 μΐ., 3 equiv.), and the resulting reaction mixture was heated in a MW reactor at 100 °C for 15 min. The reaction mixture was cooled to RT, and additional dimethylamine was added (230 μΐ., 5 equiv.), and the reaction mixture was heated at 100 °C for 20 min. The reaction mixture was cooled to RT, and additional dimethylamine was added (230 μΐ., 5 equiv.), and the reaction mixture was heated at 100 °C for 40 min. The reaction mixture was partitioned betweed water (5 mL) and EtOAc (15 mL), and the aqueous layer was reextracted with EtOAc. Combined organic extracts were dried over Na2S04, filtered, and the solvent was removed in vacuo to yield the crude product. The crude product was suspended in Et20/MeOH 15: 1 (3.2 mL), and the precipitate was filtered off to afford the expected product (19 mg). LCMS: MW (calc'd): 385.5; MS (ES+, m/z): 386.7 [M+H]+.
Method X: Reductive amination
Figure imgf000117_0001
To a solution of a primary amine (1 equiv.) in a suitable solvent (such as dry 1,2-DCE or dry MeOH) is added an aldehyde (1-1.2 equiv.), and the resulting reaction mixture is stirred at RT for 1-24 h. Reducing agent, such as NaBLL. or NaBH(OAc)3 (1.6-3 equiv.), is added, and the reaction mixture is stirred at RT for 10 min to 24 h. The expected product may be isolated and, if desired, further purified by methods known to one skilled in the art.
Example X.l
Illustrative synthesis of terf-Butyl 4-[(4-pyridylamino)methyl]piperidine-l- carboxylate
Figure imgf000117_0002
To a solution of 4-aminopyridine (200 mg, 1 equiv.) in dry 1,2-DCE (10 mL), tert-butyl 4- formylpiperidine-1 -carboxylate (650 μΐ., 1.2 equiv.) was added, and the reaction mixture was stirred at RT for one hour. NaBH(OAc)3 (1.36 g, 3 equiv.) was added, and the reaction mixture was stirred at RT for 18 h. The reaction mixture was partitioned between EtOAc (20 mL) and sat. aq. NaHC03 (15 mL), and the organic phase was washed with sat. aq. NaHC03 (2x 15 mL) and with brine (15 mL). The organic phase was dried over Na2S04, filtered, and the solvent was removed in vacuo to afford the expected product (378.8 mg), which was used in the next reaction step without purification. LCMS: MW (calc'd): 291.4; MS (ES+, m/z): 292.6 [M+H]+. Example X.2
Illustrative synthesis of l-(4-ieri-Butylphenyl)sulfonyl-N-(4-pyridylmethyl)piperidin- 4-amine {Compound 82)
Figure imgf000118_0001
To a solution of l-(4-tert-butylphenyl)sulfonylpiperidin-4-amine (150 mg, 1 equiv.) in dry MeOH (4 mL), pyridine-4-carbaldehyde (47.7 μΐ., 1 equiv) was added. The reaction mixture was stirred at RT for 24 h. NaB¾ (30.6 mg, 1.6 equiv.) was added portionwise, and the reaction mixture was stirred at RT for 10 min. Water (20 mL) was added, and the mixture was extracted with DCM (3 x20 mL). Combined organic extracts were dried over Na2S04, filtered, and the solvent was removed in vacuo to yield the expected product (184.8 mg). LCMS: MW (calc'd): 387.5; MS (ES+, m/z): 388.8 [M+H]+.
Method Y: N-alk lation of pyrazole sulfonamides
Figure imgf000118_0002
Typically, to a solution of an appropriate pyrazole sulfonamide compound (1 equiv.) in a suitable solvent or mixture of solvents (typically DMF), base (1-5 equiv.), such as potassium carbonate, D/'PEA or TEA, and alkyl halide (1-5 equiv.) are added. The resulting mixture is stirred at RT to 140 °C for 2-48 h by using conventional heating or for 30 min to 4 h at 100-150 °C by using microwave irradiation. The expected amine product may be isolated and, if desired, further purified by methods known to one skilled in the art. Example Y.l
Illustrative synthesis of 3-[l-[l-(2,2-Dimethylpropyl)pyrazol-4-yl]sulfonyl-4- piperidyl]-lH-pyrrolo[2,3-Z>] ridine (Compound 108)
Figure imgf000119_0001
To a solution of 3-[l-(lH-pyrazol-4-ylsulfonyl)-4-piperidyl]-lH-pyrrolo[2,3-^]pyridine (33.1 mg, 1 equiv.) in dry DMF (1 mL), K2C03 (20.7 mg, 1.5 equiv.) and l-bromo-2,2- dimethylpropane (18.9 \L, 1.5 equiv.) were added. The reaction mixture was left to stir at room temperature overnight. Next morning, the reaction was not complete. The reaction mixture was heated under microwave irradiation for 4 hours at 100 °C. Sample was filtrated and purified by preparative HPLC-MS to afford the expected product (5.7 mg). LCMS: MW (calc'd): 401.5; MS (ES+, /// r): 402.8 [M+H]+.
Method Z: S nthesis of urea compounds on pyrazole sulfonamides using triphosgene
Figure imgf000119_0002
The reaction is typically performed by adding an appropriate amine (1-8 equiv.) and base (2-10 equiv.) (such as TEA or D/'PEA) to a solution of triphosgene (0.3-1.5 equiv.) in a suitable solvent, such as THF, at 0 °C to room temperature. The resulting mixture is stirred for 20 min to 24 h at 0 °C to room temperature, and then mixed with a THF solution (or suspension) of an appropriate pyrazole sulfonamide compound (0.5-1 equiv.) to which, if required, additional amount of base, such as TEA or D/'PEA may be added. The reaction mixture is stirred at room temperature for 1-24 h. The expected urea product may be isolated and, if desired, further purified by methods known to one skilled in the art. Example Z.l
Illustrative synthesis of N-terf-Butyl-N-methyl-3-[l-(lH-pyrazol-4-ylsulfonyl)-4- piperidyl]pyrrolo[2,3-Z>]pyridine-l-carboxamide (Compound 118) and N-ieri-Butyl-3- [l-[l-[teri-butyl(methyl)carbamoyl]pyrazol-4-yl]sulfonyl-4-piperidyl]-N-methyl- pyrrolo[2,3-Z>]pyridine-l-carboxamide (Compound 112)
Figure imgf000120_0001
Triphosgene (21.9 mg, 0.74 equiv.) was dissolved in dry THF (1 mL). Then, a solution of N-tert-butylmethylamine (57.7 μΐ., 4 equiv.) and TEA (40 μΐ^, 3 equiv.) in dry THF (0.5 mL) was added dropwise. The resulting slurry was stirred at RT for 90 minutes, and then it was added to a suspension of 3-[l-(lH-pyrazol-4-ylsulfonyl)-4-piperidyl]-lH-pyrrolo[2,3- £]pyridine (33.1 mg, 1 equiv.) and TEA (30 μΐ., 3 equiv.) in dry THF (1 mL), and the mixture was stirred at RT overnight. The reaction was not complete. Triphosgene (21.9 mg, 0.74 equiv.) was dissolved in dry THF (1 mL). Then, a solution of N-tert- butylmethylamine (57.7 μΕ, 4 equiv.) and TEA (40 μΕ, 3 equiv.) in dry THF (0.5 mL) was added dropwise. The resulting slurry was stirred at RT overnight. Next morning, N-tert- butylmethylamine solution was added to the reaction mixture and the mixture was stirred overnight. The reaction mixture was diluted with DCM, and washed with water and brine. The organic layer was dried over phase separator filter tube and concentrated under reduced pressure. The obtained residue was purified by preparative HPLC-MS. The expected product was not obtained. Two by-products were isolated. Compound 118 (7.3 mg). LCMS: MW (calc'd): 444.5; MS (ES+, m/z): 445.9 [M+H]+. Compound 112 (12.6 mg). LCMS: MW (calc'd): 557.7; MS (ES+, m/z): 559.0 [M+H]+. Table with Representative Compounds of Formula (I):
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Cpd MS ( /:.. δ NMR Data Starting Sequence of Chemical
# ES+) Int/Cpd# Methods Name
Hz, IH), 2.39 (t,J=1 1.60 Hz, 2H), morpholin-4-
2.01 (d, J=1 1.90 Hz, 2H), 1.65-1.79 ylmethanone
(m, 2H) ppm.
14 IH NMR (500 MHz, DMSO-d6) δ:
8.23 (dd, J=1.37, 4.73 Hz, IH), 8.12 [3-[l-(4- (dd, J=1.53, 7.93 Hz, IH), 7.73 (s, aminophenyl)
IH), 7.40 (d, J=8.85 Hz, 2H), 7.28 Method D using 4- ulfonylpiperi
3-(4- (dd, J=4.73, 7.78 Hz, IH), 6.68 (d, acetamidob enzene n-4- piperidyl)- J=8.54 Hz, 2H), 6.08 (s, 2H), 3.68 (d, sulfonyl chloride, yl]pyrrolo[2,3
480.7 1H- J=1 1.60 Hz, 2H), 2.80 (t, J=12.05 Hz, N, 0 using 3,5- b]pyridin-l- pyrrolo[2,3- IH), 2.29-2.38 (m, 2H), 2.27 (s, 3H), dimethylisoxazol- yl]-(3,5- b]pyridine
2.10 (s, 3H), 2.02 (d, J=1 1.90 Hz, 4-carboxylic acid dimethyl-1,2- 2H), 1.66-1.77 (m, 2H) ppm. oxazol-4- yl)methanone
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Cpd MS ( /:.. δ NMR Data Starting Sequence of Chemical
# ES+) Int/Cpd# Methods Name
23 IH NMR (600 MHz, DMSO-d6) δ:
1 1.33 (br. s., IH), 8.59 (d, J=7.70 Hz,
IH), 8.14 (dd, J=1.56, 4.68 Hz, IH),
8.08-8.10 (m, 2H), 7.85-7.88 (m,
2H), 7.83 (dd, J=1.28, 7.89 Hz, IH),
7.20 (d, J=2.20 Hz, IH), 6.95 (dd,
J=4.77, 7.89 Hz, IH), 3.98-4.07 (m, N-(oxan-4-yl)
Method D using
IH), 3.88 (td, J=1.97, 10.00 Hz, 2H), 3-(4- 4-[4-(lH- ethyl 4- 3.77 (d, J=1 1.92 Hz, 2H), 3.39 (dt, piperidyl)- pyrrolo[2,3- chloro sulfony lb enz
469.6 J=2.02, 1 1.74 Hz, 2H), 2.70-2.78 (m, 1H- b]pyridin-3- oate, I, J using
IH), 2.38-2.45 (m, 2H), 1.97 (d, pyrrolo[2,3- yl)piperidin-l tetrahydropyran-4- J=1 1.00 Hz, 2H), 1.77 (dd, J=2.20, b]pyridine yl]sulfonylbe amine
12.47 Hz, 2H), 1.68 (dq, J=3.58, zamide 12.56 Hz, 2H), 1.54-1.63 (m, 2H)
ppm.
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Cpd MS (/>// , δ NMR Data Starting Sequence of Chemical
# ES+) Int/Cpd# Methods Name
8.44 Hz, IH), 7.24 (d, J=2.38 Hz, pyrrolo[2,3- IH), 7.01 (dd, J=4.77, 7.89 Hz, IH), b]pyridine 4.56 (s, 2H), 3.67 (d, J=12.10 Hz,
2H), 3.00 (dt, J=2.20, 12.29 Hz, 2H),
2.92 (tt, J=3.62, 11.88 Hz, IH), 2.02
(d, J=10.64 Hz, 2H), 1.65 (dq,
J=3.94, 12.44 Hz, 2H) ppm.
IH NMR (500 MHz, DMSO-d6) δ:
V/ 8.18 (d, J=2.75 Hz, IH), 7.63-7.73
(m, 4H), 7.30 (dd, J=3.05, 8.54 Hz,
IH), 7.16 (d, J=8.54 Hz, IH), 3.78 2-[l-(4-tert- (s, 3H), 3.74 (d, J= 11.60 Hz, 2H), 5-methoxy- Method D using 4- butylphenyl)s 2.57-2.67 (m, IH), 2.25-2.40 (m, 2-(4- tert- Ifonylpiperidi
39 389.2
2H), 1.87 (d, J=10.99 Hz, 2H), 1.69 piperidyl)- butylbenzenesulfo -4-yl]-5- (dq, J=3.97, 12.41 Hz, 2H), 1.32 (s, pyridine nyl chloride methoxypyrid 9H) ppm. ne
Cpd MS ( /:.. δ NMR Data Starting Sequence of Chemical
# ES+) Int/Cpd# Methods Name
40 IH NMR (400 MHz, CDC13) δ: 7.67
Method Al using 4-(3- - 7.62 (m, 2H), 7.52 - 7.48 (m, 2H),
K2C03, B l using benzylimidaz 7.40 (d, J = 1.0 Hz, IH), 7.32 - 7.26
l-benzyl-5- Pd/C, C using HC1 -4-yl)-l-(4- (m, 3H), 6.93 (dd, J = 7.6, 2.0 Hz,
438.19 bromo- in dioxane, D tert- 2H), 6.82 (s, IH), 5.01 (s, 2H), 3.78
imidazole using 4-tert- butylphenyl)s (d, J = 12.0 Hz, 2H), 2.28 (td, J =
butylbenzenesulfo lfonylpiperidi 1 1.5, 4.2 Hz, 3H), 1.76 - 1.64 (m,
nyl chloride e
4H), 1.33 (s, 9H) ppm.
IH NMR (500 MHz, DMSO-d6) δ:
7.64-7.73 (m, 4H), 7.09 (d, J=8.54
Hz, 2H), 6.85 (d, J=8.54 Hz, 2H), tert-butyl 4-
//\\ Method P using 2-[4-[l-(4-ter
3.99 (t, J=5.49 Hz, 2H), 3.76 (d, (4- bromoacetonitrile, butylphenyl)s J=1 1.90 Hz, 2H), 3.02 (t, J=5.34 Hz, hydroxyphe
C using TFA, D lfonylpiperidi
41 417.3 2H), 2.37-2.46 (m, IH), 2.26-2.35 nyl)- using 4-tert- -4- (m, 2H), 1.75 (d, J=12.21 Hz, 2H), piperidine- butylbenzenesulfo yl]phenoxy]et 1.59 (dq, J=3.51, 12.46 Hz, 2H), 1- nyl chloride, Q anamine 1.33 (s, 9H) ppm. carboxylate
Cpd MS (/>// , δ NMR Data Starting Sequence of Chemical
# ES+) Int/Cpd# Methods Name
42 IH NMR (500 MHz, DMSO-d6) δ:
7.97 (d, J=2.44 Hz, IH), 7.65-7.72 2-methoxy- 5-[l-(4-tert-
(m, 4H), 7.54 (dd, J=2.44, 8.54 Hz, 5-(4- Method D using 4- butylphenyl)s
'V/ IH), 6.72 (d, J=8.54 Hz, IH), 3.79 piperidyl)- tert- lfonylpiperidi
389.2
(s, 3H), 3.73-3.78 (m, 2H), 2.43-2.47 pyridine butylbenzenesulfo -4-yl]-2-
(m, IH), 2.24-2.34 (m, 2H), 1.77 (d, dihydrochlo nyl chloride methoxypyrid
J=10.99 Hz, 2H), 1.59-1.70 (m, 2H), ride ne
1.33 (s, 9H) ppm.
43 IH NMR (500 MHz, DMSO-d6) δ:
7.65-7.73 (m, 4H), 7.17 (d, J=8.54
Hz, 2H), 6.96 (d, J=8.85 Hz, 2H), tert-butyl 4-
Method P using 2-[4-[l-(4-ter 5.11 (s, 2H), 3.76 (d, J=11.60 Hz, (4- bromoacetonitrile, butylphenyl)s 2H), 2.42-2.48 (m, IH), 2.25-2.35 hydroxyphe
W/ C using TFA, D lfonylpiperidi
413.2 (m, 2H), 1.77 (d, J=11.29 Hz, 2H), nyl)- using 4-tert- -4- 1.62 (dq, J=3.97, 12.51 Hz, 2H), 1.33 piperidine- butylbenzenesulfo yl]phenoxy]a (s, 9H) ppm. 1- nyl chloride tonitrile carboxylate
Figure imgf000147_0001
Figure imgf000148_0001
Cpd MS ( /:., δ NMR Data Starting Sequence of Chemical
# ES+) Int/Cpd# Methods Name
(m, 2H), 1.97 (d, J=10.97 Hz, 2H),
1.54-1.77 (m, 2H) ppm.
IH NMR (600 MHz, DMSO-d6) δ: 3-[4-(4-tert-
Method R, C using
1 1.09 (d, J=1.83 Hz, IH), 8.14 (dd, 3-bromo- butylphenyl)s
TFA, D using 4- J=1.56, 4.68 Hz, IH), 7.89 (dd, 1H- lfonylpiperazi
48 399.16 tert- J=1.10, 7.89 Hz, IH), 7.68-7.73 (m, pyrrolo[2,3- -l-yl]-lH- butylbenzenesulfo
4H), 6.91-6.95 (m, 2H), 3.00-3.09 b]pyridine pyrrolo[2,3- nyl chloride
(m, 8H), 1.32 (s, 9H) ppm. b]pyridine
49 IH NMR (500 MHz, DMSO-d6) δ:
12.97 (br. s., IH), 7.62-7.75 (m, 4H),
tert-butyl 4- 7.07 (d, J=8.54 Hz, 2H), 6.79 (d, P using ethyl 2-[4-[l-(4-ter
(4- J=8.85 Hz, 2H), 4.60 (s, 2H), 3.76 bromoacetate, C butylphenyl)s hydroxyphe
(d, J=1 1.60 Hz, 2H), 2.39-2.47 (m, using TFA, D lfonylpiperidi
432.2 nyl)- IH), 2.27-2.35 (m, 2H), 1.76 (d, using 4-tert- -4- piperidine- J=10.99 Hz, 2H), 1.59 (dq, J=3.81, butylbenzenesulfo yl]phenoxy]a
1- 12.56 Hz, 2H), 1.33 (s, 9H) ppm. nyl chloride, I tic acid
carboxylate
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Cpd MS (/>// , δ NMR Data Starting Sequence of Chemical
# ES+) Int/Cpd# Methods Name
56 IH NMR (600 MHz, DMSO-d6): δ:
8.16 (dd, J=1.28, 4.95 Hz, IH), 7.65- Method R, C using 3-[4-(4-tert-
3- 7.70 (m, 4H), 7.58 (d, J=8.07 Hz, TFA, D using 4- butylphenyl)s bromofuro[
400.14 IH), 6.91 (dd, J=4.95, 8.07 Hz, IH), tert- lfonylpiperazi
3,2- 5.76 (d, J=0.73 Hz, IH), 3.44-3.48 butylbenzenesulfo -l-yl]furo[3,2 b]pyridine
(m, 4H), 3.01-3.05 (m, 4H), 1.29 (s, nyl chloride b]pyridine 9H) ppm.
IH NMR (300 MHz, CDC13) δ: 8.90
(s, IH), 8.14-8.11 (m, IH), 7.58 (dd,
J=8.6, 1.8 Hz, IH), 7.49 (dt, J=8.6,
0.8 Hz, IH), 7.38-7.34 (m, IH), Method Al using 5-[4-(3- 7.33-7.30 (m, IH), 6.73-6.71 (m, Na2C03, Bl using methylimidaz
5-bromo-l- IH), 6.70-6.66 (m, IH), 3.90 (d, Pd/C, C using HCl 1-4-
57 345.09 methyl- J=l 1.8 Hz, 2H), 3.47 (s, 3H), 2.45- in dioxane, D yl)piperidin-l imidazole
2.29 (m, 3H), 1.91 (d, J=12.6 Hz, using lH-indole-5- yl]sulfonyl-
Figure imgf000153_0001
2H), 1.78 (td, J=12.7, 12.3, 3.9 Hz, sulfonyl chloride lH-indole
2H) ppm.
Figure imgf000154_0001
Cpd MS ( /:.. δ NMR Data Starting Sequence of Chemical
# ES+) Int/Cpd# Methods Name
IH NMR (600 MHz, DMSO-d6) δ:
1 1.01 (br. s., IH), 8.23 (dd, J=1.47,
E, Al using 3-[l-(4-tert- 4.59 Hz, IH), 7.65-7.71 (m, 5H),
3-bromo- Na2C03, B2, C butylphenyl)s 7.34 (d, J=2.38 Hz, IH), 7.03 (dd,
1H- using TFA, D lfonylpiperidi
60 398.2 J=4.58, 8.07 Hz, IH), 3.73 (d,
pyrrolo[3,2- using 4-tert- -4-yl]-lH- J=1 1.74 Hz, 2H), 2.84 (tt, J=3.60,
b]pyridine butylbenzenesulfo pyrrolo[3,2- 1 1.81 Hz, IH), 2.35-2.42 (m, 2H),
nyl chloride, F b]pyridine 2.04-2.10 (m, 2H), 1.81 (dq, J=4.03,
Figure imgf000155_0001
12.47 Hz, 2H), 1.32 (s, 9H) ppm.
IH NMR (500 MHz, DMSO-d6): δ:
1 1.93 (s, IH), 8.50 (s, IH), 8.44 (s, 3-[l-(4-tert-
IH), 7.67-7.74 (m, 4H), 7.45 (s, IH), A2 using KOH, B l butylphenyl)s
3.75 (d, J= 1 1.60 Hz, 2H), 2.82-2.91 using Pd/C, C lfonylpiperidi
(trifluorom
(m, IH), 2.36 (t, J=1 1.14 Hz, 2H), using TFA, D -4-yl]-5-
61 466 ethyl)- 1H- 2.01 (d, J=1 1.90 Hz, 2H), 1.68 (dq, using 4-tert- (trifluorometh pyrrolo[2,3- J=3.66, 12.41 Hz, 2H), 1.34 (s, 9H) butylbenzenesulfo 1)-1H- b]pyridine
ppm. nyl chloride pyrrolo[2,3- b]pyridine
Cpd MS (/>// , δ NMR Data Starting Sequence of Chemical
# ES+) Int/Cpd# Methods Name
62
Al using K2C03,
1H NMR (500 MHz, CDC13) δ: l-(4-tert- Bl using Pd/C, C
><o¾a , 7.74-7.70 (m, 2H), 7.57-7.53 (m, 5-bromo- butylphenyl)s using HC1 in
2H), 6.61 (s, 1H), 3.92-3.84 (m, 2H), 1,2- lfonyl-4-(2,3-
376.18 dioxane, D using
3.38 (s, 3H), 2.49-2.35 (m, 3H), 2.33 dimethyl- dimethylimid
4-tert- (s, 3H), 1.98-1.89 (m, 2H), 1.82- imidazole zol-4- butylbenzenesulfo
1.72 (m, 2H), 1.36 (s, 9H) ppm. yl)piperidine nyl chloride
Al using K2C03,
Bl using Pd/C, C
using HC1 in
3-[l-(4-tert-
3- dioxane, D using
butylphenyl)s bromoimid 4-tert- lfonylpiperidi
63 399.13 azo[l,2- butylbenzenesulfo
-4- a]pyrimidin nyl chloride
yl]imidazo[l, e
a]pyrimidine
Cpd MS (/>// , δ NMR Data Starting Sequence of Chemical
# ES+) Int/Cpd# Methods Name
IH NMR (300 MHz, DMS0-d6) δ:
3-[l-(4-tert- 9.04 (d, J=1.39 Hz, IH), 8.58 (dd,
Al using Na2C03, butylphenyl)s J=1.48, 4.79 Hz, IH), 7.89 (d, J=4.88 3- C using TFA, D lfonyl-3,6- Hz, IH), 7.75-7.81 (m, 3H), 7.59- bromoimid
64 397.17 using 4-tert- dihydro-2H- 7.66 (m, 2H), 6.17-6.22 (m, IH), azo[l,2- butylbenzenesulfo pyridin-4- 3.78-3.85 (m, 2H), 3.30-3.36 (m, a]pyrazine
nyl chloride yl]imidazo[l, 2H), 2.51-2.60 (m, 2H), 1.23 (s, 9H)
a]pyrazine ppm.
IH NMR (400 MHz, DMS0-d6) δ:
11.16 (s, IH), 7.89 (d, J=2.69 Hz,
IH), 7.66-7.72 (m, 4H), 7.52 (d, Method E, Al 3-[l-(4-tert-
J=2.69 Hz, IH), 7.15 (d, J=2.57 Hz, 3-bromo-5- using Na2C03, Bl butylphenyl)s
IH), 3.76 (s, 3H), 3.70-3.78 (m, 2H), methoxy- using Pd/C, C lfonylpiperidi
65 428 2.67-2.77 (m, IH), 2.29-2.40 (m, 1H- using TFA, D -4-yl]-5-
2H), 1.99 (d, J=11.25 Hz, 2H), 1.58- pyrrolo[2,3- using 4-tert- methoxy-lH- λ 1.71 (m, 2H), 1.32 (s, 9H) ppm. b]pyridine butylbenzenesulfo pyrrolo[2,3- nyl chloride, F b]pyridine
Cpd MS ( /:.. δ NMR Data Starting Sequence of Chemical
# ES+) Int/Cpd# Methods Name
IH NMR (500 MHz, CDC13) δ: 9.53 Method E, Al methyl 3-[l-(
(s, IH), 8.99 (d, J=1.9 Hz, IH), 8.53 methyl 3- using K2C03, B l tert-
(d, J=1.9 Hz, IH), 7.76-7.72 (m, 2H), bromo-lH- using Pd/C, C butylphenyl)s
7.61-7.56 (m, 2H), 7.15-7.13 (m, pyrrolo[2,3- using HC1 in lfonylpiperidi
66 456.1
IH), 4.00-3.93 (m, 5H), 2.79 (tt, b]pyridine- dioxane, D using -4-yl]-lH-
J=12.2, 3.6 Hz, IH), 2.46 (td, J=12.0, 5- 4-tert- pyrrolo[2,3-
0 2.5 Hz, 2H), 2.14-2.06 (m, 2H), carboxylate butylbenzenesulfo b]pyridine-5-
1.96-1.85 (m, 2H), 1.39 (s, 9H) ppm. nyl chloride, F carboxylate
IH NMR (500 MHz, DMSO-d6) δ:
8.41 (d, J=6.71 Hz, IH), 7.68-7.74
(m, 4H), 7.52 (d, J=9.16 Hz, IH),
Method Al using 3-[l-(4-tert- 7.36 (s, IH), 7.15-7.20 (m, IH), 6.82-
3- Na2C03, B2, C butylphenyl)s 6.87 (m, IH), 3.73-3.80 (m, 2H),
bromoimid using TFA, D lfonylpiperidi
67 398.17 2.97-3.06 (m, IH), 2.39-2.46 (m,
azo[l,2- using 4-tert- -4- 2H), 2.06 (d, J=1 1.60 Hz, 2H), 1.62- a] pyridine butylbenzenesulfo yl]imidazo[l, 1.73 (m, 2H), 1.34 (s, 9H) ppm.
nyl chloride a] pyridine o
Figure imgf000159_0001
Cpd MS ( /:., δ NMR Data Starting Sequence of Chemical
# ES+) Int/Cpd# Methods Name
IH NMR (500 MHz, CDC13) δ : 8.50
(dd, J=4.7, 1.1 Hz, IH), 7.72 (d, Method Al using
J=8.5 Hz, 3H), 7.54-7.60 (m, 3H), K2C03, B l using 3-[l-(4-tert-
3- 7.21 (dd, J=8.2, 4.9 Hz, IH), 3.93 (d, Pd/C, C using HC1 butylphenyl)s bromofuro[
70 399.2 J=l 1.6 Hz, 2H), 2.89 (tt, J=l 1.9, 3.3 in dioxane, D lfonylpiperidi
3,2- Hz, IH), 2.48 (td, J=12.0, 2.3 Hz, using 4-tert- -4-yl]furo[3,2 b]pyridine
2H), 2.25 (d, J=12.2 Hz, 2H), 1.87 butylbenzenesulfo b]pyridine (qd, J=12.6, 4.0 Hz, 2H), 1.38 (s, 9H) nyl chloride
ppm.
IH NMR (300 MHz, CDC13) δ: 9.09
(d, J=1.2 Hz, IH), 8.62 (d, J=5.2 Hz,
IH), 7.66-7.73 (m, 2H), 7.49-7.57
4-[l-(4-tert- (m, 2H), 7.1 1 (dd, J=5.3, 1.1 Hz, IH), Method D using 4-
4-(4- butylphenyl)s 3.93 (d, J=1 1.8 Hz, 2H), 2.59 (tt, tert-
71 360.69 piperidyl)p lfonylpiperidi
J=1 1.8, 4.1 Hz, IH), 2.42 (td, J=1 1.8, butylbenzenesulfo
yrimidine -4- 3.0 Hz, 2H), 1.79-2.04 (m, 4H), 1.34 nyl chloride
yl]pyrimidine (s, 9H) ppm.
Cpd MS (/>// , δ NMR Data Starting Sequence of Chemical
# ES+) Int/Cpd# Methods Name
IH NMR (400 MHz, CDC13) δ: 7.99 1- (4- l-[l-(4-tert-
V/" (br. s., IH), 7.73 (d, J=7.7 Hz, IH), piperidyl)- butylphenyl)s 7.69 (d, J=8.6 Hz, 2H), 7.56 (d, J=8.7 3H- Method D using 4- lfonylpiperidi Hz, 2H), 7.28 (br. s., IH), 4.33-4.45 imidazo[4,5 tert-
72 415.71 -4-yl]-3H- (m, IH), 4.01 (d, J=11.9 Hz, 2H), -b]pyridin- butylbenzenesulfo
imidazo[4,5- 2.43-2.54 (m, 2H), 2.37 (dd, J=12.6, 2- one nyl chloride
b]pyridin-2- 8.7 Hz, 2H), 1.93 (d, J=10.5 Hz, 2H), bishydrochl
one
1.35 (s, 9H) ppm. oride
IH NMR (300 MHz, DMS0-d6) δ:
10.78 (br. s., IH), 7.65-7.74 (m, 4H),
7.47 (d, J=8.0 Hz, IH), 7.30 (d, J=8.0
V Hz, IH), 7.05 (d, J=2.3 Hz, IH), 3-[l-(4-tert-
Method D using 4- 6.98-7.05 (m, IH), 6.86-6.94 (m, 3-(4- butylphenyl)s tert-
73 397.74 IH), 3.75 (d, J=l 1.7 Hz, 2H), 2.68- piperidyl)- lfonylpiperidi butylbenzenesulfo
2.82 (m, IH), 2.35-2.46 (m, 2H), lH-indole -4-yl]-lH- nyl chloride
1.93-2.05 (m, 2H), 1.66 (qd, J=12.5, indole 3.7 Hz, 2H), 1.33 (s, 9H) ppm.
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Cpd MS ( /:., δ NMR Data Starting Sequence of Chemical
# ES+) Int/Cpd# Methods Name
1.88 (m, 4H), 1.34 (s, 9H) ppm.
IH NMR (400 MHz, CDC13) δ: 8.02
(br. s., IH), 7.93 (d, J=1.74 Hz, IH),
2-[4-(2,4- 7.49 (dd, J=1.76, 8.40 Hz, IH), 7.34 Method A3, B l
dimethylphen (dd, J=0.46, 8.52 Hz, IH), 7.03 (d, using Pd/C, C
(2,4- l)piperidin-l- J=7.88 Hz, IH), 6.95-6.99 (m, IH), using TFA, D
dimethylph yl]sulfonyl-
86 437.23 6.91 (br. s., IH), 3.95 (d, J=1 1.64 Hz, using 5,6,7,8,9, 10- enyl)boroni 5,6,7,8,9, 10- 2H), 2.80-2.89 (m, 4H), 2.44-2.54 hexahydrocyclohe
c acid hexahydrocyc (m, IH), 2.29 (td, J=3.17, 1 1.49 Hz, pta[b]indole-2- ohepta[b]indo 2H), 2.24 (s, 3H), 2.15 (s, 3H), 1.86- sulfonyl chloride
e
1.94 (m, 2H), 1.71-1.84 (m, 8H)
ppm.
87 IH NMR (400 MHz, CDC13) δ: 8.59
2-chloro-3- r (d, J=2.4 Hz, IH), 8.51 (d, J=6.0 Hz,
Method D using 6- methyl-5-(4- 2H), 7.89 (d, J=1.6 Hz, IH), 7.06 (d, 4-(4- chloro-5-methyl- pyridin-4-
352.7 J=6.0 Hz, 2H), 4.00-3.90 (m, 2H), piperidyl)p
pyridine-3- ylpiperidin-1- 2.50-2.38 (m, 6H), 1.98-1.78 (m, 4H) yridine
sulfonyl chloride yl)sulfonylpy ppm.
dine
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Cpd MS ( /:., δ NMR Data Starting Sequence of Chemical
# ES+) Int/Cpd# Methods Name
IH), 1.84 (dd, J=12.7, 2.0 Hz, 2H),
1.61-1.73 (m, 2H) ppm.
IH NMR (300 MHz, CDC13) δ: 8.52 4-[l-(5- (d, J=4.9 Hz, 2H), 7.33 (d, J=3.8 Hz, chlorothiophe
4-(4- Method D using 5- IH), 7.08 (d, J=6.1 Hz, 2H), 6.98 (d, -2-
101 343.5 piperidyl)p chlorothiophene-2- J=4.0 Hz, IH), 3.82-4.00 (m, 2H), yl)sulfonylpip yridine sulfonyl chloride
2.45-2.57 (m, 3H), 1.90-2.01 (m, ridin-4- 2H), 1.72-1.92 (m, 2H) ppm. yl]pyridine
IH NMR (300 MHz, CDC13) δ: 8.52
(d, J=6.1 Hz, 2H), 7.32 (s, IH), 6.99- 7.12 (m, 2H), 3.81-4.00 (m, 2H), 4-[l-(4,5- 2.48-2.61 (m, 3H), 1.93-2.02 (m, dichlorothiop
Method D using
2H), 1.75-1.93 (m, 2H) ppm. 4-(4- en-2- 4,5-
102 377.6 piperidyl)p yl)sulfonylpip dichlorothiophene- yridine ridin-4- 2-sulfonyl chloride
yl]pyridine
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Cpd MS ( /:., δ NMR Data Starting Sequence of Chemical
# ES+) Int/Cpd# Methods Name
Hz, 2H), 1.63-1.81 (m, 2H) ppm.
126 360.7 IH NMR (300 MHz, DMSO-d6) δ: 3-(4- General method D 3-[l-[(3,5- 13.06 (br.s., IH), 1 1.34 (s, IH), 8.15 piperidyl)- using 3,5- dimethyl-lH- (dd, J=1.3, 7.98 Hz, IH), 7.93 (dd, 1H- dimethyl-lH- pyrazol-4- J=1.14, 8.05 Hz, IH), 7.21 (d, J=2.41 pyrrolo[2,3- pyrazole-4- yl)sulfonyl]-4 Hz, IH), 6.94-7.02 (m, IH), 3.65 (d, b]pyridine sulfonyl chloride. piperidyl]-lH 12.9 Hz, 2H), 2.71-2.82 (m, IH), pyrrolo[2,3- 2.33 (s, 6H), 2.01 (d, J=12.9 Hz, 2H), b]pyridine 1.59-1.76 (m, 2H) ppm.
127 347.7 IH NMR (300 MHz, DMSO-d6) δ: 3-(4- General method D
1 1.36 (br. s., IH), 9.66 (s, IH), 8.16 piperidyl)- using 3- 3-methyl-4- (dd, J=1.39, 4.70 Hz, IH), 7.94 (d, 1H- methylisoxazole-4- [[4-(lH- J=6.79 Hz, IH), 7.24 (d, J=2.44 Hz, pyrrolo[2,3- sulfonyl chloride. pyrrolo[2,3- IH), 7.00 (dd, J=4.70, 7.84 Hz, IH), b]pyridine b]pyridin-3- 3.73 (d, J= 1 1.84 Hz, 2H), 2.76-3.02 yl)-l- (m, IH), 2.58-2.74 (m, 2H), 2.41 (s, piperidyl]sulf 3H), 2.05 (d, J=1 1.15 Hz, 2H), 1.62- nyljisoxazole 1.81 (m, 2H) ppm.
Figure imgf000187_0001
BIOLOGICAL ASSAYS
The potential for a compound of formula (I) obtained by the process of the present invention to act as a Hh modulator may be demonstrated in vitro.
Example 1
In vitro screening protocol (C3H assay)
Differentiation of C3H10T1/2 cells by mouse Sonic Hedgehog ligand (mSHH) - Measurement of Alkaline Phosphatase.
The procedure is based upon that described in Schaefer GI et al (J Am Chem Soc. 2013; 135(26):9675-80). In response to activation of the Hedgehog pathway with one of the PTCH1 ligands, e.g. mSHH, mouse C3H10T1/2 embryonic sarcoma cells differentiate and start to express alkaline phosphatase. Inhibitors of the pathway block differentiation and alkaline phosphatase expression.
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.
All media is removed and cell viability is determined by incubating the cells for 1 hour at 37°C in the presence of Promega Cell Titer-Blue® reagent and measuring the fluorescence at 560Εχ/590ΕΜ·
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 ½-2 hours at room temperature and substrate conversion is determined by detecting fluorescence at
Figure imgf000188_0001
IC50 ranges for compounds of the invention are presented in Table 2, whereby the IC50 ranges are as follows:
Figure imgf000189_0001
B: IC50 = 500-1000 nM
C: IC50 = 1000-5000 nM
D: ICso > 5000 nM
For reference both Sonidegib and Vismodegib were also run in the C3H assay, whereby the mean IC50 values were 1 InM and 6.3nM, respectively.
Table 2
Figure imgf000189_0002
Figure imgf000189_0003
Figure imgf000189_0004
ic50 ic50 ic50
Cpd# Cpd# Cpd#
Ranges Ranges Ranges
73 B 92 D 111 C
74 C 93 C 112 B
75 D 94 D 113 A
76 C 95 C 114 C
77 B 96 D 115 A
78 C 97 C 116 B
79 D 98 C 117 C
80 D 99 C 118 C
81 C 100 C 119 C
82 D 101 D 120 C
83 A 102 D 121 C
84 A 103 D 122 C
85 D 104 A 123 C
86 A 105 B 124 D
87 D 106 A 125 D
88 C 107 A 126 D
89 C 108 A 127 D
90 C 109 A 128 D
91 D 110 C 129 D
Example 2
Loss of potency in C3H10T1/2 cell differentiation assay associated with presence of SMO L416F mutation.
Table 3 below details the number of fold reduction in potency of a range of compounds of the invention when applied to the SMO L416F mutant cell line compared to the wild type. SMO mutation has been described in the literature (Pricl, Sabrina, et al.) as a key mutation causative of vismodegib resistance in the clinic by interfering with drug binding. As can observed from the data in Table 3, the loss of potency observed for compounds of the invention is less than that of vismodegib, which is considered to reflect the potential for overcoming resistance associated with vismodegib.
Table 3
Figure imgf000191_0001
Example 3
Differential potencies between SMO binding affinity and C3H10T1/2 cell differentiation
Standard Protocol for Smoothened (SMO) binding fluorescence polarisation assay.
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% γ-globulin, 0.01% pluronic acid pH7.4, plus protease Inhibitor cocktail). 8.5μ1 of the membrane suspension is added to each well of a black, low 5 volume 384 well mi crotitre 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%. 6.5μ1 of a 6.9nM BODIPY-cyclopamine solution is added to each of the wells (final assay concentration 3nM).
The plate is sealed and stored in the dark at room temperature for 24 hours prior to measurement of the fluorescence polarisation signal on a Perkin Elmer Envision multi-label reader.
15
Table 4 below 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 0 are considered to be reflective of alternate actions outside of direct SMO inhibition.
Table 4
Figure imgf000192_0001
Figure imgf000192_0002
7 >9.2 84 6.91 >\4 85 >5.67 >10 86 >1814 >2.1 97 >105 >28 98 >236 >3.2 99 >9. \7 >4.0 104 >2203 >33 106 >1004 >31 107 >286 >28 108 >682 >70 109 >736 >25 111 >2.80 >2.0 113 >9.52 >\2 114 >5.73 >18 115 >354 >9.3 116 >187 >5.2 117 9.18 >3.0 119 5.99 >27
1 3.2
Example 4
In vivo protocol:
Evaluation of the pharmacodynamic (PD) effect of compounds of Formula I and Sonidegib on a subcutaneous Calu-6 xenograft model.
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.
• Calu-6 tumour cells to be implanted into the flank of Balb/c mice and
treatment commenced once tumours reach a mean volume of ~300-400mm3
• The animals to be dosed for 4 days and terminated at 4 hours after the final dose Tumour samples to be collected and Glil expression levels to be measured as a readout of Hedgehog pathway activity
0547P.WO.Spec References:
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Claims

1. A compound of Formula (I) :
Figure imgf000200_0001
in which:
X is R3 or CR3R4;
R1 is hydrogen or together R1 and R4 represent a bond;
R2 is selected from: a fused 9-10 membered bicyclic heteroaryl, a 5-6 membered heteroaryl, a 6-10 membered aryl and a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl; each of which is optionally substituted by one or more groups independently selected from - R5R6, halogen, N02, phenyl, CN, -Ci_ 6alkyl-0-Ci-6alkyl, Ci-6alkyl, haloCi-6alkyl, -OCi-6alkyl, -Ci-6alkyl-OH, -Ci_ 6alkylC(=0)Ci-6alkyl, Ci-6alkylC(=0)OR7, -C(=0)OCi-6alkyl,
Figure imgf000200_0002
-
Figure imgf000200_0003
-C(=0)het1 (wherein het1 is a 5-6- membered unsaturated heterocyclyl), - HC(=0)het2 (wherein het2 is a 5-6-membered heteroaryl which is optionally substituted by one or more Ci-6alkyl), -C(=0) Hhet2;
R3 is selected from: a fused 9-10 membered bicyclic heteroaryl, a 5-6 membered heteroaryl, a 6-10 membered aryl, a fused 8-10 membered partially unsaturated bicyclic heterocyclyl and - H(CH2)mhet3 (wherein het3 is a 5-6-membered heteroaryl); each of which is optionally substituted by one or more groups independently selected from: halogen, OH, H2, Ci-6alkyl, -OCi-6alkyl, haloCi-6alkyl, C2-6alkenyl, -C(=0)OCi-6alkyl, -OCi-6alkyl( R8R9), -OCi-6alkyl(C=0)amino, -OCi. ealkylnitrile, -OCi-6alkyl(COOH), -C(=O) R10Ru, -C(=0)het4, (wherein het4 is a 5-6- membered heteroaryl which is optionally substituted by Ci-6alkyl) and Ci-6alkyl- phenyl (wherein phenyl is optionally substituted by Ci-4alkyl);
R4 is hydrogen or together R4 and R1 represent a bond;
R5, R6, R7, R8, R9, R10 and R11, which may be the same or different, are each hydrogen or Ci-6alkyl; and
m and n, which may be the same or different, are each 0 or 1 ; or a pharmaceutically acceptable salt or a solvate thereof;
provided that the compound of formula I is not 4-[l-(4-tert-butylphenyl) sulfonylpiperidin-4-yl]pyridine; and is not 2-[4-(2,4-dimethylphenyl)piperazin-l-yl] sulfonyl-5 , 6, 7, 8,9, 10-hexahydrocyclohepta[b] indole.
2. The compound according to claim 1, wherein
X is R3 or CR3R4;
R2 is selected from:
(i) a fused 9-10 membered bicyclic heteroaryl optionally substituted by one or more groups independently selected from -Ci-6alkyl-0-Ci-6alkyl, -C(=0)NHC1- ealkyl;
(ii) 5-6 membered heteroaryl optionally substituted by one or more groups independently selected from - R5R6, halogen, N02, Ci-6alkyl, haloCi-6alkyl, -OCi. ealkyl, -Ci-6alkyl-OH, -Ci-6alkyl C(=0)Ci-6alkyl, -C(=0)OCi-6alkyl, phenyl, -
Figure imgf000201_0001
(wherein het1 is a 5-6-membered unsaturated heterocyclyl);
(iii) 6-10 membered aryl optionally substituted by one or more groups independently selected from halogen, H2, CN, N02, Ci-6alkyl, haloCi-6alkyl, Ci_ 6alkyl-OH, Ci-6alkylC(=0)OR7,
Figure imgf000201_0002
(wherein het2 is a 5-6-membered heteroaryl which is optionally substituted by one or more Ci-6alkyl), -C(=0) Hhet2, -C(=0)het1;
(iv) a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl optionally substituted by one or more groups;
R3 is selected from:
(i) a fused 9-10 membered bicyclic heteroaryl optionally substituted by one or more groups independently selected from halogen, Ci-6alkyl, C2-6alkenyl, haloCi-6alkyl, -OCi-6alkyl, -C(=0)OCi-6alkyl, -C(=O) R10Ru, -C(=0)het4, (het4 is a 5-6-membered heteroaryl which is optionally substituted by Ci-6alkyl);
(ii) 5-6 membered heteroaryl optionally substituted by one or more groups independently selected from Ci-6alkyl, -OCi-6alkyl, Ci-6alkyl-phenyl (wherein phenyl is optionally substituted by Ci-4alkyl);
(iii) 6-10 membered aryl optionally substituted by one or more groups independently selected from halogen, -OCi-6alkyl( R8R9), -OCi-6alkyl(C=0)amino, - OCi-6alkylnitrile, -OCi-6alkyl(COOH), OH, Ci-6alkyl, -OCi-6alkyl, haloCi-6alkyl, H2;
(iv) a fused 8-10 membered partially unsaturated bicyclic heterocyclyl optionally substituted by one or more groups -C(=0)OCi-6alkyl; and
(v) - H(CH2)mhet3 (wherein het3 is a 5-6-membered heteroaryl);
R1, R4, R5, R6, R7, R8, R9, R10, R11, m and n are each as herein defined;
or a pharmaceutically acceptable salt or a solvate thereof;
provided that the compound of formula I is not 4-[l-(4-tert-butylphenyl) sulfonylpiperidin-4-yl]pyridine; and is not 2-[4-(2,4-dimethylphenyl)piperazin-l-yl] sulfonyl-5 , 6, 7, 8,9, 10-hexahydrocyclohepta[b] indole.
3. The compound according to any one of the preceding claims, wherein X is R3.
4. The compound according to any one of claims 1 or 2, wherein X is CR3R4.
5. The compound according to any one of the preceding claims, wherein when R2 is a fused 9-10 membered bicyclic heteroaryl a preferred bicyclic heteroaryl is selected from the grou :
Figure imgf000202_0001
each of which is optionally substituted as herein defined.
6. The compound according to any one of claims 1 to 4, wherein when R2 is a 5- 6 membered heteroaryl a preferred heteroaryl is selected from the group:
Figure imgf000203_0001
Figure imgf000203_0002
Figure imgf000203_0003
each of which is optionally substituted as herein defined.
7. The compound according to any one of claims 1 to 4, wherein when R2 is a 6- 10 membered aryl a preferred aryl is:
Figure imgf000203_0004
which is optionally substituted as herein defined.
8. The compound according to any one of claims 1 to 4, wherein when R2 is a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl a preferred bicyclic or tricyclic heterocyclyl is:
Figure imgf000203_0005
which is optionally substituted as herein defined.
9. The compound according to any one of the preceding claims, wherein when R3 is a fused 9-10 membered bicyclic heteroaryl, a preferred bicyclic heteroaryl is selected from the group:
Figure imgf000204_0001
each of which is optionally substituted as herein defined.
10. The compound according to any one of claims 1 to 8, wherein when R3 6 membered heteroaryl, a preferred heteroaryl is selected from the group:
Figure imgf000205_0001
Figure imgf000205_0002
each of which is optionally substituted as herein defined.
11. The compound according to any one of claims 1 to 8, wherein when R3 is a fused 8-10 membered partially unsaturated bicyclic heterocyclyl a preferred partially unsaturated bicyclic heterocyclyl is selected from the group:
Figure imgf000205_0003
each of which is optionally substituted as herein defined.
12. The compound according to any one of claims 1 to 8, wherein when R is a 6- 10 membered aryl, a preferred is selected from the group:
Figure imgf000205_0004
each of which is optionally substituted as herein defined.
13. The compound according to any one of the preceding claims, wherein
14. The compound according to any one of claims 1 to 12, wherein n is 1.
15. The compound according to any one of the preceding claims, wherein the compound is selected from the group consisting of:
4- [4-( 1 -prop-2-enylpyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylaniline; [ 1 ] N,N-dimethyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyridin-2- amine; [2]
3 - [ 1 -(4-cyclopropylphenyl)sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -bjpyridine; [3 ] 2-[4-[4-(lH-pyrrolo[2,3-b]pyridin-3-yl)piperidin-l-yl]sulfonylphenyl]propan-2-ol; [4] [ 1 - [4-[4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 - yl] sulfonylphenyl] cyclopropyl] methanol; [5 ]
methyl 1 - [4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylphenyl] cyclopropane- 1-carboxylate; [6]
3 , 5 -dimethyl-N- [4- [4-( 1 -prop-2-enylpyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 - yl]sulfonyl phenyl]- l,2-oxazole-4-carboxamide; [7]
N- [4-methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl- 1 , 3 -thiazol-
2- yl] acetamide; [8]
morpholin-4-yl- [5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylfuran-2- yl] methanone; [9]
N-tert-butyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylfuran-2- carboxamide; [10]
5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl-N- [rac-(2R)- 1 -hydroxy-
3- methylbutan-2-yl]furan-2-carboxamide; [11]
[4-methoxy-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylthiophen-3 - yl]-morpholin-4-ylmethanone; [12]
[ 1 -methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyrrol-2-yl] - morpholin-4-ylmethanone; [13]
[3 - [ 1 -(4-aminophenyl)sulfonylpiperidin-4-yl]pyrrolo [2,3 -b]pyridin- 1 -yl] -(3 , 5 - dimethyl- 1 ,2-oxazol-4-yl)methanone; [ 14]
N-tert-butyl-4-methoxy-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl thiophene-3-carboxamide; [15] 4-methoxy-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl-N- [rac-(2R)- 1 -hydroxy-3 -methylbutan-2-yl]thiophene-3 -carboxamide; [16]
N-tert-butyl- 1 -methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 - yl] sulfonylpyrrole-2-carboxamide; [ 17]
4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl-N- [rac- 1 -hydroxy-3 - methylbutan-2-yl]benzamide; [18]
morpholin-4-yl- [4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylphenyl] methanone; [19]
N-propan-2-yl-4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 - yl]sulfonylbenzamide; [20]
[cis-2, 6-dimethylmorpholin-4-yl] - [4- [4-( 1 H-pyrrolo [2, 3 -b]pyridin-3 -yl)piperidin- 1 - yl] sulfonylphenyl]methanone; [21]
N-(3 , 5 -dimethyl- 1 ,2-oxazol-4-yl)-4- [4-( 1 H-pyrrolo [2, 3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylbenzamide; [22]
N-(oxan-4-yl)-4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylbenzamide;
[23]
3 - [ 1 -(3 , 5 -dimethylphenyl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine; [24] 3-[l-(6-nitropyridin-3-yl)sulfonylpiperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine; [25] ethyl 3 -methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl- 1 H- pyrazole-4-carboxylate; [26]
3 - [ 1 - [[4-(trifluoromethyl)phenyl] methylsulfonyl]piperidin-4-yl] - 1 H-pyrrolo [2,3- b]pyridine; [27]
3-(l-benzylsulfonylpiperidin-4-yl)-lH-pyrrolo[2,3-b]pyridine; [28]
3 - [ 1 -(6-chloropyridin-3 -yl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine; [29]
3 - [ 1 -(2-nitrophenyl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine; [30] methyl 2-methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylfuran-3 - carboxylate; [31]
ethyl 5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylfuran-3 -carboxylate;
[32]
3 - [ 1 - [3 , 5 -bis(trifluoromethyl)phenyl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3- b]pyridine; [33]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -5 -fluoro- 1 H-pyrrolo [2,3 -b]pyridine;
[34]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]thieno[2,3-b]pyridine; [35] 3 - [ [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylmethyl]benzonitrile; [36] 3-[rac-(2S)-l-(4-tert-butylphenyl)sulfonyl-2-methyl-4-piperidyl]-lH-pyrrolo[2,3- b]pyridine; [37]
3- [l-[(2,4-dichlorophenyl)methylsulfonyl]piperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine;
[38]
2-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-5-methoxypyridine; [39]
4- (3-benzylimidazol-4-yl)-l-(4-tert-butylphenyl)sulfonylpiperidine; [40]
2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] ethanamine; [41 ]
5- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-2-methoxypyridine; [42]
2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] acetonitrile; [43 ]
2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] acetamide; [44]
1 - [3 - [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] -6, 8-dihydro-5H-imidazo [1,2- a]pyrazin-7-yl]ethanone; [45]
3 - [4-(4-tert-butylphenyl)sulfonylpiperazin- 1 -yl]- 1 ,2-benzothiazole; [46]
3-[l-(lH-benzimidazol-5-ylsulfonyl)piperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine; [47]
3- [4-(4-tert-butylphenyl)sulfonylpiperazin-l-yl]-lH-pyrrolo[2,3-b]pyridine; [48] 2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] acetic acid; [49]
2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] -N,N- dimethylethanamine; [50]
4- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]phenol; [51]
2- [4-(lH-pyrrolo[2,3-b]pyridin-3-yl)piperidin-l-yl]sulfonyl-5,6,7,8,9, 10- hexahydrocyclohepta[b]indole; [52]
3- [l-(lH-indol-5-ylsulfonyl)piperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine; [53] tert-butyl 3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-6,8-dihydro-5H- imidazo[l,2-a]pyrazine-7-carboxylate; [54]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -6, 7-dihydro-5H-pyrrolo [1,2- a] imidazole; [55]
3-[4-(4-tert-butylphenyl)sulfonylpiperazin-l-yl]furo[3,2-b]pyridine; [56]
5 - [4-(3 -methylimidazol-4-yl)piperidin- 1 -yl] sulfonyl- 1 H-indole; [57]
l-(4-tert-butylphenyl)sulfonyl-4-(2,4-dimethylphenyl)piperazine; [58]
5 - [4-(4-methoxyphenyl)piperidin- 1 -yl] sulfonyl- 1 H-indole; [59]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-lH-pyrrolo[3,2-b]pyridine; [60]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -5 -(trifluoromethyl)- 1 H-pyrrolo [2,3- b] pyridine; [61] l-(4-tert-butylphenyl)sulfonyl-4-(2,3-dimethylimidazol-4-yl)piperidine; [62]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]imidazo[l,2-a]pyrimidine; [63] 3 - [ 1 -(4-tert-butylphenyl)sulfonyl-3 , 6-dihydro-2H-pyridin-4-yl] imidazo [1,2- a] pyrazine; [64]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -5 -methoxy- 1 H-pyrrolo [2,3- b] pyridine; [65]
methyl 3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine-5 - carboxylate; [66]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]imidazo[l,2-a]pyridine; [67]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -5 , 6, 7, 8-tetrahydroimidazo [1,2- a]pyridine; [68]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]thieno[3,2-b]pyridine; [69]
3- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]furo[3,2-b]pyridine; [70]
4- [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl]pyrimidine ; [71 ]
1 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -3 H-imidazo [4, 5 -b]pyridin-2-one;
[72]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] - 1 H-indole ; [73 ]
l-(4-tert-butylphenyl)sulfonyl-4-(4-methyl-l,2,4-triazol-3-yl)piperidine; [74]
3- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine; [75]
4- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]aniline; [76]
1- (4-tert-butylphenyl)sulfonyl-4-(3-methylimidazol-4-yl)piperidine; [77]
5- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-l,3-oxazole; [78]
2- (4-pyridin-4-ylpiperazin- 1 -yl) sulfonyl-5 , 6, 7, 8, 9, 10-hexahydrocyclohepta[b] indole;
[79]
1 -(4-tert-butylphenyl)sulfonyl-4-pyridin-4-ylpiperazine; [80]
N-[[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]methyl]pyridin-4-amine; [81]
1- (4-tert-butylphenyl)sulfonyl-N-(pyridin-4-ylmethyl)piperidin-4-amine; [82] 4-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]quinolone; [83]
2- (4-pyridin-4-ylpiperidin-l-yl)sulfonyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole;
[84]
4-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-3-methylpyridine; [85]
2- [4-(2,4-dimethylphenyl)piperidin- 1 -yl] sulfonyl-5 , 6, 7, 8, 9, 10- hexahydrocyclohepta[b]indole; [86]
2-chloro-3-methyl-5-(4-pyridin-4-ylpiperidin-l-yl)sulfonylpyridine; [87] 4-[l-(4-bromophenyl)sulfonylpiperidin-4-yl]pyridine; [88]
4-[l-[(2,4-dichlorophenyl)methylsulfonyl]piperidin-4-yl]pyridine; [89]
4-[l-(4-chloro-2,5-dimethylphenyl)sulfonylpiperidin-4-yl]pyridine; [90]
4-[ 1 -(2,5-dichlorothiophen-3-yl)sulfonylpiperidin-4-yl]pyridine; [91 ]
3- [(4-pyridin-4-ylpiperidin-l-yl)sulfonylmethyl]benzonitrile; [92]
4- [l-[3,5-bis(trifluoromethyl)phenyl]sulfonylpiperidin-4-yl]pyridine; [93] methyl 2-methyl-5-(4-pyridin-4-ylpiperidin-l-yl)sulfonylfuran-3-carboxylate; [94] 4-[l-[4-(trifluoromethyl)phenyl]sulfonylpiperidin-4-yl]pyridine; [95]
4- [ 1 -(3 , 5 -dimethylphenyl) sulfonylpiperidin-4-yl]pyridine; [96]
l-(4-tert-butylphenyl)sulfonyl-4-[4-(trifluoromethyl)phenyl]piperidine; [97]
1 -(4-tert-butylphenyl)sulfonyl-4-naphthalen- 1 -ylpiperidine; [98]
l-(4-tert-butylphenyl)sulfonyl-4-(4-methoxyphenyl)piperidine; [99]
4-[l-[[4-(trifluoromethyl)phenyl]methylsulfonyl]piperidin-4-yl]pyridine; [100]
4-[ 1 -(5-chlorothiophen-2-yl)sulfonylpiperidin-4-yl]pyridine; [101]
4-[ 1 -(4,5-dichlorothiophen-2-yl)sulfonylpiperidin-4-yl]pyridine; [ 102]
4-[ 1 -(2,4-dichlorophenyl)sulfonylpiperidin-4-yl]pyridine; [103]
1 -(4-tert-butylphenyl)sulfonyl-4-(2,4-dimethylphenyl)piperidine; [ 104]
2,4-diphenyl-5-(4-pyridin-4-ylpiperidin- 1 -yl)sulfonyl- 1 ,3 -thiazole; [105]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3- b] pyridine; [108]
3 - [ 1 - [ 1 -(3 , 3 , 3 -trifluoro-2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H- pyrrolo[2,3-b]pyridine; [109]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3- c] pyridine; [110]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] -6-methyl- 1 H- pyrrolo[2,3-b]pyridine; [111]
N-tert-butyl-3 - [ 1 - [ 1 - [tert-butyl(methyl)carbamoyl] pyrazol-4-yl] sulfonylpiperidin-4- yl]-N-methylpyrrolo[2,3-b]pyridine-l-carboxamide; [112]
3 - [ 1 - [ 1 -(2-methoxy-2-methylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H- pyrrolo[2,3-b]pyridine; [113]
3 - [ 1 - [ 1 -(2-methoxy-2-methylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H- pyrrolo[3,2-b]pyridine; [114]
3 - [ 1 -( 1 -benzylpyrazol-4-yl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine; [115] 3 - [ 1 - [ 1 - [ [ 1 -(trifluoromethyl)cyclopropyl] methyl]pyrazol-4-yl] sulfonylpiperidin-4-yl] - lH-pyrrolo[2,3-b]pyridine; [116]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [3 ,2- b]pyridine; [117]
N-tert-butyl-N-methyl-3-[l-(lH-pyrazol-4-ylsulfonyl)piperidin-4-yl]pyrrolo[2,3- b]pyridine- 1 -carboxamide; [118]
3- [l-[l-(2,2-dimethylpropyl)pyrazol-4-yl]sulfonylpiperidin-4-yl]furo[3,2-b]pyridine;
[119]
2- methyl- 1 - [4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyrazol- 1 - yl]propan-2-ol; [120]
4- [ 1 -[ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl]pyridine; [121] l-[4-(4-furo[3,2-b]pyridin-3-ylpiperidin-l-yl)sulfonylpyrazol-l-yl]-3,3- dimethylbutan-2-one; [122]
rac-(2R)- 1 -[4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyrazol- 1 - yl]propan-2-ol; [123]
5 - methyl-4- [ [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)- 1 -piperidyl] sulfonyl] isoxazole; [ 124]
3 - [ 1 -( 1 -methylpyrazol-4-yl)sulfonyl-4-piperidyl] - 1 H-pyrrolo [2,3 -b]pyridine; [125] 3 - [ 1 - [(3 , 5-dimethyl- 1 H-pyrazol-4-yl) sulfonyl] -4-piperidyl] - 1 H-pyrrolo [2,3- b]pyridine; [126]
3 -methyl-4- [ [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)- 1 -piperidyl] sulfonyl] isoxazole; [127]
6- methyl-3 - [ 1 -( 1 -methylpyrazol-4-yl)sulfonyl-4-piperidyl] - 1 H-pyrrolo [2,3- b]pyridine; [128] and
3 - [ 1 -( 1 H-imidazol-2-ylsulfonyl)-4-piperidyl] -6-methyl- 1 H-pyrrolo [2,3 -b]pyridine;
[129]
or a pharmaceutically acceptable salt or a solvate thereof.
16. A compound of Formula (I):
Figure imgf000211_0001
or a pharmaceutically acceptable salt, or a solvate, or a solvate of the salt thereof, for use as a medicament, wherein:
X is R3 or CR3R4;
R1 is hydrogen or together R1 and R4 represent a bond;
R2 is selected from: a fused 9-10 membered bicyclic heteroaryl, a 5-6 membered heteroaryl, a 6-10 membered aryl and a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl; each of which is optionally substituted by one or more groups independently selected from - R5R6, halogen, N02, phenyl, CN, -Ci_ 6alkyl-0-Ci-6alkyl, Ci-6alkyl, haloCi-6alkyl, -OCi-6alkyl, -Ci-6alkyl-OH, -Ci_ 6alkylC(=0)Ci-6alkyl, Ci-6alkylC(=0)OR7, -C(=0)OCi-6alkyl,
Figure imgf000212_0001
-
Figure imgf000212_0002
-C(=0)het1 (wherein het1 is a 5-6- membered unsaturated heterocyclyl), - HC(=0)het2 (wherein het2 is a 5-6-membered heteroaryl which is optionally substituted by one or more Ci-6alkyl), -C(=0) Hhet2;
R3 is selected from: a fused 9-10 membered bicyclic heteroaryl, a 5-6 membered heteroaryl, a 6-10 membered aryl, a fused 8-10 membered partially unsaturated bicyclic heterocyclyl and - H(CH2)mhet3 (wherein het3 is a 5-6-membered heteroaryl); each of which is optionally substituted by one or more groups independently selected from: halogen, OH, H2, Ci-6alkyl, -OCi-6alkyl, haloCi-6alkyl, C2-6alkenyl, -C(=0)OCi-6alkyl, -OCi-6alkyl( R8R9), -OCi-6alkyl(C=0)amino, -OCi. ealkylnitrile, -OCi-6alkyl(COOH), -C(=O) R10Ru, -C(=0)het4, (wherein het4 is a 5-6- membered heteroaryl which is optionally substituted by Ci-6alkyl) and Ci-6alkyl- phenyl (wherein phenyl is optionally substituted by Ci-4alkyl);
R4 is hydrogen or together R4 and R1 represent a bond;
R5, R6, R7, R8, R9, R10 and R11, which may be the same or different, are each hydrogen or Ci-6alkyl; and
m and n, which may be the same or different, are each 0 or 1 ;
or a pharmaceutically acceptable salt or a solvate thereof.
17. The compound according to claim 17, wherein
X is NR3 or CR3R4;
R2 is selected from:
(i) a fused 9-10 membered bicyclic heteroaryl optionally substituted by one or more groups independently selected from -Ci-6alkyl-0-Ci-6alkyl,
ealkyl; (ii) 5-6 membered heteroaryl optionally substituted by one or more groups independently selected from - R5R6, halogen, N02, Ci-6alkyl, haloCi-6alkyl, -OCi. ealkyl, -Ci-6alkyl-OH, -Ci-6alkyl C(=0)Ci-6alkyl, -C(=0)OCi-6alkyl, phenyl, -
Figure imgf000213_0001
(wherein het1 is a 5-6-membered unsaturated heterocyclyl);
(iii) 6-10 membered aryl optionally substituted by one or more groups independently selected from halogen, H2, CN, N02, Ci-6alkyl, haloCi-6alkyl, Ci_ 6alkyl-OH, Ci-6alkylC(=0)OR7,
Figure imgf000213_0002
(wherein het2 is a 5-6-membered heteroaryl which is optionally substituted by one or more Ci-6alkyl), -C(=0) Hhet2, -C(=0)het1;
(iv) a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl optionally substituted by one or more groups;
R3 is selected from:
(i) a fused 9-10 membered bicyclic heteroaryl optionally substituted by one or more groups independently selected from halogen, Ci-6alkyl, C2-6alkenyl, haloCi-6alkyl, -OCi-6alkyl, -C(=0)OCi-6alkyl, -C(=O) R10Ru, -C(=0)het4, (het4 is a 5-6-membered heteroaryl which is optionally substituted by Ci-6alkyl);
(ii) 5-6 membered heteroaryl optionally substituted by one or more groups independently selected from Ci-6alkyl, -OCi-6alkyl, Ci-6alkyl-phenyl (wherein phenyl is optionally substituted by Ci-4alkyl);
(iii) 6-10 membered aryl optionally substituted by one or more groups independently selected from halogen, -OCi-6alkyl( R8R9), -OCi-6alkyl(C=0)amino, - OCi-6alkylnitrile, -OCi-6alkyl(COOH), OH, Ci-6alkyl, -OCi-6alkyl, haloCi-6alkyl, H2;
(iv) a fused 8-10 membered partially unsaturated bicyclic heterocyclyl optionally substituted by one or more groups -C(=0)OCi-6alkyl; and
(v) - H(CH2)mhet3 (wherein het3 is a 5-6-membered heteroaryl);
R1, R4, R5, R6, R7, R8, R9, R10, R11, m and n are each defined in claim 16.
18. The compound according to any one of the claims 16 or 17, wherein the compound is selected from the group consisting of:
4- [4-( 1 -prop-2-enylpyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylaniline; [ 1 ] N,N-dimethyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyridin-2- amine; [2] 3 - [ 1 -(4-cyclopropylphenyl)sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine; [3 ] 2-[4-[4-(lH-pyrrolo[2,3-b]pyridin-3-yl)piperidin-l-yl]sulfonylphenyl]propan-2-ol; [4] [ 1 - [4-[4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 - yl] sulfonylphenyl] cyclopropyl] methanol; [5 ]
methyl 1 - [4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylphenyl] cyclopropane- 1-carboxylate; [6]
3 , 5 -dimethyl-N- [4- [4-( 1 -prop-2-enylpyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 - yl]sulfonyl phenyl]- l,2-oxazole-4-carboxamide; [7]
N- [4-methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl- 1 , 3 -thiazol-
2- yl] acetamide; [8]
morpholin-4-yl- [5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylfuran-2- yl] methanone; [9]
N-tert-butyl- 5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylfuran-2- carboxamide; [10]
5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl-N- [rac-(2R)- 1 -hydroxy-
3- methylbutan-2-yl]furan-2-carboxamide; [11]
[4-methoxy-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylthiophen-3 - yl]-morpholin-4-ylmethanone; [12]
[ 1 -methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyrrol-2-yl] - morpholin-4-ylmethanone; [13]
[3 - [ 1 -(4-aminophenyl)sulfonylpiperidin-4-yl]pyrrolo [2,3 -b]pyridin- 1 -yl] -(3 , 5 - dimethyl- 1 ,2-oxazol-4-yl)methanone; [ 14]
N-tert-butyl-4-methoxy-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl thiophene-3-carboxamide; [15]
4- methoxy-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl-N- [rac-(2R)- 1 -hydroxy-3 -methylbutan-2-yl]thiophene-3 -carboxamide; [16]
N-tert-butyl- 1 -methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 - yl] sulfonylpyrrole-2-carboxamide; [ 17]
4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl-N- [rac- 1 -hydroxy-3 - methylbutan-2-yl]benzamide; [18]
morpholin-4-yl- [4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylphenyl] methanone;
[19]
N-propan-2-yl-4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 - yl]sulfonylbenzamide;
[20] [cis-2, 6-dimethylmorpholin-4-yl] - [4- [4-( 1 H-pyrrolo [2, 3 -b]pyridin-3 -yl)piperidin- 1 - yl] sulfonylphenyljmethanone;
[21]
N-(3 , 5 -dimethyl- 1 ,2-oxazol-4-yl)-4- [4-( 1 H-pyrrolo [2, 3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylbenzamide;
[22]
N-(oxan-4-yl)-4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylbenzamide;
[23]
3 - [ 1 -(3 , 5 -dimethylphenyl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine;
[24] 3-[l-(6-nitropyridin-3-yl)sulfonylpiperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine;
[25] ethyl 3 -methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonyl- 1 H- pyrazole-4-carboxylate;
[26]
3 - [ 1 - [[4-(trifluoromethyl)phenyl] methylsulfonyl]piperidin-4-yl] - 1 H-pyrrolo [2,3- b]pyridine;
[27]
3-(l-benzylsulfonylpiperidin-4-yl)-lH-pyrrolo[2,3-b]pyridine;
[28]
3 - [ 1 -(6-chloropyridin-3 -yl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine;
[29]
3 - [ 1 -(2-nitrophenyl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine;
[30] methyl 2-methyl-5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylfuran-3 - carboxylate;
[31]
ethyl 5 - [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylfuran-3 -carboxylate;
[32]
3 - [ 1 - [3 , 5 -bis(trifluoromethyl)phenyl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3- b]pyridine;
[33]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -5 -fluoro- 1 H-pyrrolo [2,3 -b]pyridine;
[34]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]thieno[2,3-b]pyridine;
[35]
3 - [ [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylmethyl]benzonitrile;
[36]
3-[rac-(2S)-l-(4-tert-butylphenyl)sulfonyl-2-methyl-4-piperidyl]-lH-pyrrolo[2,3- b]pyridine;
[37]
3- [l-[(2,4-dichlorophenyl)methylsulfonyl]piperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine;
[38]
2-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-5-methoxypyridine;
[39]
4- (3-benzylimidazol-4-yl)-l-(4-tert-butylphenyl)sulfonylpiperidine;
[40]
2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] ethanamine;
[41 ]
5- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-2-methoxypyridine;
[42]
2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] acetonitrile;
[43 ] 2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] acetamide;
[44]
1 - [3 - [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] -6, 8-dihydro-5H-imidazo [1,2- a]pyrazin-7-yl]ethanone;
[45]
3 - [4-(4-tert-butylphenyl)sulfonylpiperazin- 1 -yl]- 1 ,2-benzothiazole;
[46]
3-[l-(lH-benzimidazol-5-ylsulfonyl)piperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine;
[47]
3- [4-(4-tert-butylphenyl)sulfonylpiperazin-l-yl]-lH-pyrrolo[2,3-b]pyridine;
[48] 2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] acetic acid;
[49]
2- [4- [ 1 -(4-tert-butylphenyl) sulfonylpiperidin-4-yl] phenoxy] -N,N- dimethylethanamine;
[50]
4- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]phenol;
[51]
2- [4-(lH-pyrrolo[2,3-b]pyridin-3-yl)piperidin-l-yl]sulfonyl-5,6,7,8,9, 10- hexahydrocyclohepta[b]indole;
[52]
3- [l-(lH-indol-5-ylsulfonyl)piperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine;
[53] tert-butyl 3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-6,8-dihydro-5H- imidazo[l,2-a]pyrazine-7-carboxylate;
[54]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -6, 7-dihydro-5H-pyrrolo [1,2- a] imidazole;
[55]
3-[4-(4-tert-butylphenyl)sulfonylpiperazin-l-yl]furo[3,2-b]pyridine;
[56]
5 - [4-(3 -methylimidazol-4-yl)piperidin- 1 -yl] sulfonyl- 1 H-indole;
[57]
l-(4-tert-butylphenyl)sulfonyl-4-(2,4-dimethylphenyl)piperazine;
[58]
5 - [4-(4-methoxyphenyl)piperidin- 1 -yl] sulfonyl- 1 H-indole;
[59]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-lH-pyrrolo[3,2-b]pyridine;
[60]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -5 -(trifluoromethyl)- 1 H-pyrrolo [2,3- b] pyridine;
[61]
l-(4-tert-butylphenyl)sulfonyl-4-(2,3-dimethylimidazol-4-yl)piperidine;
[62]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]imidazo[l,2-a]pyrimidine;
[63] 3 - [ 1 -(4-tert-butylphenyl)sulfonyl-3 , 6-dihydro-2H-pyridin-4-yl] imidazo [1,2- a] pyrazine;
[64]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -5 -methoxy- 1 H-pyrrolo [2,3- b] pyridine;
[65]
methyl 3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine-5 - carboxylate;
[66]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]imidazo[l,2-a]pyridine;
[67] 3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -5 , 6, 7, 8-tetrahydroimidazo [1,2- a]pyridine;
[68]
3-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]thieno[3,2-b]pyridine;
[69]
3- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]furo[3,2-b]pyridine;
[70]
4- [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl]pyrimidine ;
[71 ]
1 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] -3 H-imidazo [4, 5 -b]pyridin-2-one;
[72]
3 - [ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl] - 1 H-indole ;
[73 ]
l-(4-tert-butylphenyl)sulfonyl-4-(4-methyl-l,2,4-triazol-3-yl)piperidine;
[74]
3- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-lH-pyrrolo[2,3-b]pyridine;
[75]
4- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]aniline;
[76]
1- (4-tert-butylphenyl)sulfonyl-4-(3-methylimidazol-4-yl)piperidine;
[77]
5- [l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-l,3-oxazole;
[78]
2- (4-pyridin-4-ylpiperazin- 1 -yl) sulfonyl-5 , 6, 7, 8, 9, 10-hexahydrocyclohepta[b] indole;
[79]
1 -(4-tert-butylphenyl)sulfonyl-4-pyridin-4-ylpiperazine;
[80]
N-[[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]methyl]pyridin-4-amine;
[81]
1- (4-tert-butylphenyl)sulfonyl-N-(pyridin-4-ylmethyl)piperidin-4-amine;
[82] 4-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]quinolone;
[83]
2- (4-pyridin-4-ylpiperidin-l-yl)sulfonyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole;
[84]
4-[l-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-3-methylpyridine;
[85]
2- [4-(2,4-dimethylphenyl)piperidin- 1 -yl] sulfonyl-5 , 6, 7, 8, 9, 10- hexahydrocyclohepta[b]indole;
[86]
2- chloro-3-methyl-5-(4-pyridin-4-ylpiperidin-l-yl)sulfonylpyridine;
[87]
4-[l-(4-bromophenyl)sulfonylpiperidin-4-yl]pyridine;
[88]
4-[l-[(2,4-dichlorophenyl)methylsulfonyl]piperidin-4-yl]pyridine;
[89]
4-[l-(4-chloro-2,5-dimethylphenyl)sulfonylpiperidin-4-yl]pyridine;
[90]
4-[ 1 -(2,5-dichlorothiophen-3-yl)sulfonylpiperidin-4-yl]pyridine;
[91 ]
3- [(4-pyridin-4-ylpiperidin-l-yl)sulfonylmethyl]benzonitrile;
[92]
4- [l-[3,5-bis(trifluoromethyl)phenyl]sulfonylpiperidin-4-yl]pyridine;
[93] methyl 2-methyl-5-(4-pyridin-4-ylpiperidin-l-yl)sulfonylfuran-3-carboxylate;
[94] 4-[l-[4-(trifluoromethyl)phenyl]sulfonylpiperidin-4-yl]pyridine;
[95]
4- [ 1 -(3 , 5 -dimethylphenyl) sulfonylpiperidin-4-yl]pyridine;
[96] l-(4-tert-butylphenyl)sulfonyl-4-[4-(trifluoromethyl)phenyl]piperidine;
[97]
1 -(4-tert-butylphenyl)sulfonyl-4-naphthalen- 1 -ylpiperidine;
[98]
1- (4-tert-butylphenyl)sulfonyl-4-(4-methoxyphenyl)piperidine;
[99]
4-[l-[[4-(trifluoromethyl)phenyl]methylsulfonyl]piperidin-4-yl]pyridine;
[100] 4-[ 1 -(5-chlorothiophen-2-yl)sulfonylpiperidin-4-yl]pyridine;
[101]
4-[ 1 -(4,5-dichlorothiophen-2-yl)sulfonylpiperidin-4-yl]pyridine;
[ 102]
4-[ 1 -(2,4-dichlorophenyl)sulfonylpiperidin-4-yl]pyridine;
[103]
1 -(4-tert-butylphenyl)sulfonyl-4-(2,4-dimethylphenyl)piperidine;
[ 104]
2,4-diphenyl-5-(4-pyridin-4-ylpiperidin- 1 -yl)sulfonyl- 1 ,3 -thiazole;
[105]
4-[ 1 -(4-tert-butylphenyl)sulfonylpiperidin-4-yl]pyridine;
[ 106]
2- [4-(2,4-dimethylphenyl)piperazin- 1 -yl] sulfonyl- 5 , 6, 7, 8, 9, 10- hexahydrocyclohepta[b]indole;
[ 107]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3- b] pyridine;
[108]
3 - [ 1 - [ 1 -(3 , 3 , 3 -trifluoro-2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H- pyrrolo[2,3-b]pyridine;
[109]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3- c] pyridine;
[110]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] -6-methyl- 1 H- pyrrolo[2,3-b]pyridine;
[111]
N-tert-butyl-3 - [ 1 - [ 1 - [tert-butyl(methyl)carbamoyl] pyrazol-4-yl] sulfonylpiperidin-4- yl]-N-methylpyrrolo[2,3-b]pyridine-l-carboxamide;
[112]
3 - [ 1 - [ 1 -(2-methoxy-2-methylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H- pyrrolo[2,3-b]pyridine;
[113]
3 - [ 1 - [ 1 -(2-methoxy-2-methylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H- pyrrolo[3,2-b]pyridine;
[114]
3 - [ 1 -( 1 -benzylpyrazol-4-yl) sulfonylpiperidin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridine;
[115]
3 - [ 1 - [ 1 - [ [ 1 -(trifluoromethyl)cyclopropyl] methyl]pyrazol-4-yl] sulfonylpiperidin-4-yl] - lH-pyrrolo[2,3-b]pyridine;
[116]
3 - [ 1 - [ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl] - 1 H-pyrrolo [3 ,2- b]pyridine;
[117]
N-tert-butyl-N-methyl-3-[l-(lH-pyrazol-4-ylsulfonyl)piperidin-4-yl]pyrrolo[2,3- b]pyridine- 1 -carboxamide;
[118] 3-[l-[l-(2,2-dimethylpropyl)pyrazol-4-yl]sulfonylpiperidin-4-yl]furo[3,2-b]pyridine;
[119]
2- methyl- 1 - [4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyrazol- 1 - yl]propan-2-ol;
[120]
4-[ 1 -[ 1 -(2,2-dimethylpropyl)pyrazol-4-yl] sulfonylpiperidin-4-yl]pyridine;
[121] l-[4-(4-furo[3,2-b]pyridin-3-ylpiperidin-l-yl)sulfonylpyrazol-l-yl]-3,3- dimethylbutan-2-one;
[122]
rac-(2R)- 1 -[4- [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)piperidin- 1 -yl] sulfonylpyrazol- 1 - yl]propan-2-ol;
[123]
5 -methyl-4- [ [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)- 1 -piperidyl] sulfonyl] isoxazole;
[ 124]
3 - [ 1 -( 1 -methylpyrazol-4-yl)sulfonyl-4-piperidyl] - 1 H-pyrrolo [2,3 -b]pyridine;
[125] 3 - [ 1 - [(3 , 5-dimethyl- 1 H-pyrazol-4-yl) sulfonyl] -4-piperidyl] - 1 H-pyrrolo [2,3- b]pyridine;
[126]
3 -methyl-4- [ [4-( 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)- 1 -piperidyl] sulfonyl] isoxazole;
[127] 6-methyl-3 - [ 1 -( 1 -methylpyrazol-4-yl)sulfonyl-4-piperidyl] - 1 H-pyrrolo [2,3- b]pyridine;
[128] and
3 - [ 1 -( 1 H-imidazol-2-ylsulfonyl)-4-piperidyl] -6-methyl- 1 H-pyrrolo [2,3 -b]pyridine;
[129]
or a pharmaceutically acceptable salt or a solvate thereof.
19. The compound according to any one of claims 16 to 18, wherein the compound is for use as a medicament, for the treatment of a disease or condition associated with the abnormal activation or malfunction of the Hedgehog (Hh) signalling pathway.
20. The compound according to claim 19, wherein the disease or condition associated with the abnormal activation or malfunction of the Hh signalling pathwayi s one or more of cancer, fibrosis and chronic graft-versus-host disease (cGVHD). 21. The compound according to claim 20, wherein the disease is cancer.
22. The compound according to claim 20, wherein the disease is fibrosis.
23. The compound according to claim 22, wherein the fibrosis is pulmonary fibrosis.
24. The compound according to claim 20, wherein the disease is chronic graft- versus-host disease (cGVHD).
25. A compound according to any one of claims 1 to 24, in combination with a second therapeutically active ingredient. 26. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 15; and a pharmaceutically acceptable carrier.
27. The pharmaceutical composition according to claim 26, wherein the compound is for use as a medicament, for the treatment of a disease or condition associated with the abnormal activation or malfunction of the Hh signalling pathway.
28. The pharmaceutical composition according to claim 27, wherein 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).
29. The pharmaceutical composition according to claim 28, wherein the disease is cancer.
30. The pharmaceutical composition according to claim 28, wherein the disease is fibrosis.
31. The pharmaceutical composition according to claim 30, wherein the fibrosis is pulmonary fibrosis.
32. The pharmaceutical composition according to claim 28, wherein the disease is chronic graft-versus-host disease (cGVHD).
33. A pharmaceutical composition according to claim 26 comprising a further therapeutic agent.
34. The pharmaceutical composition according to claim 33, wherein the further therapeutic agent is an agent for prophylaxis and/or treatment of diseases and/or conditions associated with the abnormal activation and/or malfunction of Hh signalling pathway.
35. 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:
Figure imgf000221_0001
in which:
X is R3 or CR3R4;
R1 is hydrogen or together R1 and R4 represent a bond;
R2 is selected from: a fused 9-10 membered bicyclic heteroaryl, a 5-6 membered heteroaryl, a 6-10 membered aryl and a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl; each of which is optionally substituted by one or more groups independently selected from - R5R6, halogen, N02, phenyl, CN, -Ci_ 6alkyl-0-Ci-6alkyl, Ci-6alkyl, haloCi-6alkyl, -OCi-6alkyl, -Ci-6alkyl-OH, -Ci_ 6alkylC(=0)Ci-6alkyl, Ci-6alkylC(=0)OR7, -C(=0)OCi-6alkyl,
Figure imgf000221_0002
-
Figure imgf000221_0003
-C(=0)het1 (wherein het1 is a 5-6- membered unsaturated heterocyclyl), - HC(=0)het2 (wherein het2 is a 5-6-membered heteroaryl which is optionally substituted by one or more Ci-6alkyl), -C(=0) Hhet2;
R3 is selected from: a fused 9-10 membered bicyclic heteroaryl, a 5-6 membered heteroaryl, a 6-10 membered aryl, a fused 8-10 membered partially unsaturated bicyclic heterocyclyl and - H(CH2)mhet3 (wherein het3 is a 5-6-membered heteroaryl); each of which is optionally substituted by one or more groups independently selected from: halogen, OH, H2, Ci-6alkyl, -OCi-6alkyl, haloCi-6alkyl, C2-6alkenyl, -C(=0)OCi-6alkyl, -OCi-6alkyl( R8R9), -OCi-6alkyl(C=0)amino, -OCi. ealkylnitrile, -OCi-6alkyl(COOH), -C(=O) R10Ru, -C(=0)het4, (wherein het4 is a 5-6- membered heteroaryl which is optionally substituted by Ci-6alkyl) and Ci-6alkyl- phenyl (wherein phenyl is optionally substituted by Ci-4alkyl);
R4 is hydrogen or together R4 and R1 represent a bond;
R5, R6, R7, R8, R9, R10 and R11, which may be the same or different, are each hydrogen or Ci-6alkyl; and
m and n, which may be the same or different, are each 0 or 1 ;
or a pharmaceutically acceptable salt or a solvate thereof.
36. The method according to claim 35, wherein
X is R3 or CR3R4;
R2 is selected from:
(i) a fused 9-10 membered bicyclic heteroaryl optionally substituted by one or more groups independently selected from -Ci-6alkyl-0-Ci-6alkyl,
Figure imgf000222_0001
ealkyl;
(ii) 5-6 membered heteroaryl optionally substituted by one or more groups independently selected from - R5R6, halogen, N02, Ci-6alkyl, haloCi-6alkyl, -OCi. 6alkyl, -Ci-6alkyl-OH, -Ci-6alkyl C(=0)Ci-6alkyl, -C(=0)OCi-6alkyl, phenyl, -
Figure imgf000222_0002
(wherein het1 is a 5-6-membered unsaturated heterocyclyl);
(iii) 6-10 membered aryl optionally substituted by one or more groups independently selected from halogen, H2, CN, N02, Ci-6alkyl, haloCi-6alkyl, Ci_ 6alkyl-OH, Ci-6alkylC(=0)OR7,
Figure imgf000222_0003
(wherein het2 is a 5-6-membered heteroaryl which is optionally substituted by one or more Ci-6alkyl), -C(=0) Hhet2, -C(=0)het1;
(iv) a fused 8-14 membered partially unsaturated bicyclic or tricyclic heterocyclyl optionally substituted by one or more groups;
R3 is selected from:
(i) a fused 9-10 membered bicyclic heteroaryl optionally substituted by one or more groups independently selected from halogen, Ci-6alkyl, C2-6alkenyl, haloCi-6alkyl, -OCi-6alkyl, -C(=0)OCi-6alkyl, -C(=O) R10Ru, -C(=0)het4, (het4 is a 5-6-membered heteroaryl which is optionally substituted by Ci-6alkyl); (ii) 5-6 membered heteroaryl optionally substituted by one or more groups independently selected from Ci-6alkyl, -OCi-6alkyl, Ci-6alkyl-phenyl (wherein phenyl is optionally substituted by Ci-4alkyl);
(iii) 6-10 membered aryl optionally substituted by one or more groups independently selected from halogen, -OCi-6alkyl( R8R9), -OCi-6alkyl(C=0)amino, -
OCi-6alkylnitrile, -OCi-6alkyl(COOH), OH, Ci-6alkyl, -OCi-6alkyl, haloCi-6alkyl, H2;
(iv) a fused 8-10 membered partially unsaturated bicyclic heterocyclyl optionally substituted by one or more groups -C(=0)OCi-6alkyl; and
(v) - H(CH2)mhet3 (wherein het3 is a 5-6-membered heteroaryl);
R1, R4, R5, R6, R7, R8, R9, R10, R11, m and n are each as herein defined;
or a pharmaceutically acceptable salt or a solvate thereof.
37. The method according to claims 35 or 36, wherein the compound is selected from the group consisting of compounds [1] to [129].
or a pharmaceutically acceptable salt or a solvate thereof.
38. The method according to any one of claims 35 to 37, wherein the disease or condition associated with the abnormal activation or malfunction of the Hh signalling pathwayis one or more of cancer, fibrosis and chronic graft-versus-host disease (cGVHD).
39. The method according to claim 38, wherein the disease is cancer. 40. The method according to claim 38, wherein the disease is fibrosis.
41. The method according to claim 40, wherein the fibrosis is pulmonary fibrosis.
42 The method according to claim 38, wherein the disease is chronic graft- versus-host disease (cGVHD).
43. The compound, composition or method as herein described with reference to the accompanying description.
0547P.WO.Spec
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