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WO2017220431A1 - Dérivés de pyrazole condensés utilisés en tant qu'inhibiteurs de jak - Google Patents

Dérivés de pyrazole condensés utilisés en tant qu'inhibiteurs de jak Download PDF

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WO2017220431A1
WO2017220431A1 PCT/EP2017/064708 EP2017064708W WO2017220431A1 WO 2017220431 A1 WO2017220431 A1 WO 2017220431A1 EP 2017064708 W EP2017064708 W EP 2017064708W WO 2017220431 A1 WO2017220431 A1 WO 2017220431A1
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pyridin
pyrazolo
methyl
ethyl
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Laura Vidal Gispert
Oriol Llera Soldevila
Elena Gomez Castillo
Juan Antonio Alonso Diez
Bernat Vidal Juan
Jacob Gonzalez Rodriguez
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Almirall SA
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Almirall SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • JAK-deficient cell lines and mice have validated the essential role of each JAK protein in receptor signalling: JAK1 in class II cytokine receptors (IFN and IL- 10 family), those sharing the gp130 chain (IL-6 family) and the common gamma chain (IL-2, IL- 4, IL-7, IL-9, IL- 15 and IL-21 ) (Rodig et al. (1998). Disruption of the JAK1 gene demonstrates obligatory and nonredundant roles of the JAKs in cytokine-induced biological response. Cell, 93:373; Guschin et al. (1995).
  • JAK1 protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6.
  • Kinase-negative mutants of JAK1 can sustain intereferon-gamma-inducible gene expression but not an antiviral state.
  • JAK2 is essential for signalling through a variety of cytokine receptors.
  • JAK3 in receptors sharing the common gamma chain (IL-2 family)
  • IL-2 family common gamma chain
  • Park et al. (1995). Developmental defects of lymphoid cells in JAK3 kinase-deficient mice. Immunity, 3:771 ; Thomis et al., (1995). Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking JAK3. Science, 270:794; Russell et al., (1995). Mutation of JAK3 in a partient with SCID: Essential role of JAK3 in lymphoid development.
  • Receptor stimulation leads sequentially to JAK activation by phosphorylation, receptor phosphorylation, STAT protein recruitment and STAT activation and dimerization.
  • the STAT dimer then functions as a transcription factor, translocating to the nucleus and activating the transcription of multiple response genes.
  • STAT1 STAT2
  • STAT3, STAT4 STAT5a
  • STAT5b STAT6
  • Each particular cytokine receptor associates preferentially with a particular STAT protein.
  • Some associations are independent of cell type (ex: IFNg- STAT1 ) while others may be cell type dependent (Murray PJ, (2007).
  • the JAK-STAT signaling pathway input and output integration. J Immunol, 178: 2623).
  • JAK3-deficient mice are viable but display abnormal lymphopoiesis which leads to a reduced thymus size (10- 100 fold smaller than wild type). JAK3-deficient peripheral T cells are unresponsive and have an activated/memory cell phenotype (Baird et al., (1998). T cell development and activation in JAK3-deficient mice. J. Leuk. Biol.
  • mice like SCID humans, have no NK cells, probably due to the absence of IL-15 signaling, a survival factor for these cells.
  • JAK3 knockout mice unlike SCID patients, show deficient B cell lymphopoiesis while in human patients, B cells are present in circulation but are not responsive leading to hypoglobulinemia (O'Shea et al., (2004). JAK3 and the pathogenesis of severe combined immunodeficiency. Mol Immunol, 41 : 727). This is explained by species-specific differences in IL-7 function in B and T cell development in mice and humans. On the other hand, Grossman et al. (1999. Dysregulated myelopoiesis in mice lacking JAK3. Blood, 94:932:939) have shown that the loss of JAK3 in the T-cell compartment drives the expansion of the myeloid lineages leading to dysregulated myelopoiesis.
  • JAK2-deficient mice are embrionically lethal, due to the absence of definitive erythropoiesis.
  • Myeloid progenitors fail to respond to Epo, Tpo, IL-3 or GM-CSF, while G-CSF and IL-6 signaling are not affected.
  • JAK2 is not required for the generation, amplification or functional differentiation of lymphoid progenitors (Parganas et al., (1998). JAK2 is essential for signaling through a variety of cytokine receptors. Cell, 93:385).
  • Tyk2-deficient mice show an impaired response to IL-12 and IL-23 and only partially impaired to IFN-alpha (Karaghiosoff et al., (2000). Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity, 13:549; Shimoda et al., (2000). Tyk2 plays a restricted role in IFNg signaling, although it is required for IL-12-mediated T cell function. Immunity, 13:561 ). However, human Tyk2 deficiency demonstrates that Tyk2 is involved in the signaling from IFN- a, IL-6, IL-10, IL-12 and IL-23 (Minegishi et al., (2006). Human Tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity, 25:745).
  • JAK kinases in transducing the signal from a myriad of cytokines makes them potential targets for the treatment of diseases in which cytokines have a pathogenic role, such as dermatological diseases; respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors.
  • diseases in which cytokines have a pathogenic role such as dermatological diseases; respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymph
  • the compounds described in the present invention are simultaneously potent JAK1 , JAK2 and JAK3 inhibitors, i.e. pan-JAK inhibitors.
  • R 2 is selected from the group consisting of a hydrogen atom, a halogen atom and a linear or branched C1-4 alkyl group;
  • X is selected from the group consisting of -O- and a -NR 8 - group
  • R', R", R m , R IV , R v , R VI and R VM each independently represent a hydrogen atom, a linear or branched C 1 -3 alkyl group, a monocyclic C3-7 cycloalkyl group, a benzyl group, a linear or branched C 1 -3 hydroxyalkyl group, a linear or branched C 1 -3 alkoxy group or a linear or branched C1-3 alkoxy-Ci-3 alkyl group; and • n, p, and q each independently have a value from 0 to 3.
  • the invention further provides synthetic processes and intermediates described herein, which are useful for preparing said fused pyrazole derivatives.
  • the invention is also directed to use of the fused pyrazole derivatives of the invention as described herein, in the manufacture of a medicament for treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from a dermatological disease, a respiratory disease, an allergic disease, an inflammatory or autoimmune-mediated disease, a function disorder, a neurological disorder, a cardiovascular disease, a viral infection, a metabolism/endocrine function disorder, a neurological disorder, pain, bone marrow and organ transplant rejection, myelo-dysplastic syndrome, a myeloproliferative disorder (MPDs), cancer, an hematologic malignancy, leukemia, lymphoma and solid tumor.
  • JAK Janus Kinases
  • the pathological condition or disease is selected from atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitits, dermatomyositis, cutaneous T-cell lymphoma, Sezary syndrome, pyoderma gangrenosum, lichen planus, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes,
  • C1-C6 hydroxyalkyl embraces linear or branched alkyl radicals having 1 to 6 carbon atoms, any one of which may be substituted with one or more hydroxyl radicals.
  • examples of such radicals include hydroxym ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl and hydroxyhexyl.
  • C1-C3 hydroxyalkyl embraces linear or branched alkyl radicals having 1 to 3 carbon atoms, any one of which may be substituted with one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl or hydroxypropyl.
  • C1-C2 hydroxyalkyl embraces linear or branched alkyl radicals having 1 to 2 carbon atoms, any one of which may be substituted with one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl or hydroxyethyl.
  • C1-C4 alkoxy (or alkyloxy) embraces linear or branched oxy-containing radicals each having alkyl portions of 1 to 4 carbon atoms.
  • Examples of C1-C4 alkoxy radicals include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy or t-butoxy.
  • C1-C3 alkoxy (or alkyloxy) embraces linear or branched oxy-containing radicals each having alkyl portions of 1 to 3 carbon atoms.
  • Examples of C1-C3 alkoxy radicals include methoxy, ethoxy, n-propoxy and i-propoxy.
  • (C1-6 alkoxy)-(Ci-6 alkyl) embraces linear or branched radicals having 1 to 6 carbon atoms substituted with a C1-5 alkoxy group.
  • Examples of (C1-6 alkoxy)-(Ci-6 alkyl) include methoxy-methyl, ethoxy-methyl, methoxy-ethyl, ethoxy-ethyl, methoxy-propyl, propoxy- methyl, ethoxy-propyl, propoxy-ethyl, propoxy-propyl, methoxy-butyl, ethoxy-butyl, methoxy- pentyl, ethoxy-pentyl and methoxy-hexyl.
  • (C1-3 alkoxy)-(Ci-3 alkyl) embraces linear or branched radicals having 1 to 3 carbon atoms substituted with a C1-3 alkoxy group.
  • Examples of (C1-3 alkoxy)-(Ci-3 alkyl) include methoxy-methyl, ethoxy-methyl, methoxy-ethyl, ethoxy-ethyl, methoxy-propyl, propoxy- methyl, ethoxy-propyl, propoxy-ethyl and propoxy-propyl.
  • 5- to 6-membered heteroaryl radical embraces typically a 5- to 6- membered ring system comprising at least one heteroaromatic ring and containing from 1 to 4, preferably from 1 to 2, heteroatoms selected from O, S and N.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, oxadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, triazolyl, 1 ,2,4-oxadiazolyl, or 1 ,2,3,4-oxatriazolyl.
  • 4- to 6-membered heterocyclyl radical embraces typically a non- aromatic, saturated or unsaturated C4-6 carbocyclic ring system in which one or more, for example 1 , 2, 3 or 4 of the carbon atoms, preferably 1 or 2 of the carbon atoms, are replaced by a heteroatom selected from N, O and S.
  • Examples of 5- to 6-membered heterocyclyl radicals include piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl, triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl, 4,5-dihydro-oxazolyl, 1 ,3- dioxol-2-one, tetrahydrofuranyl, 3-aza-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl or 1 ,4-azathianyl.
  • C1-C2 monoalkylamino is represented by the formula -NH(Ci-C2 alkyl) wherein the term C 1 -C 2 alkyl is a described above.
  • Representative examples include methylamino group or ethylamino group.
  • these atoms, radicals, moieties, chains and cycles can be either unsubstituted or substituted in any position by one or more, for example 1 , 2, 3 or 4, substituents, whereby the hydrogen atoms bound to the unsubstituted atoms, radicals, moieties, chains and cycles are replaced by chemically acceptable atoms, radicals, moieties, chains and cycles.
  • the term pharmaceutically acceptable salt refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal.
  • Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.
  • Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid; and organic acids, for example citric, fumaric, gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic, p-toluenesulphonic acid, xinafoic (1-hydroxy-2-naphthoic acid), napadisilic (1 ,5-naphthalenedisulfonic acid) and the like.
  • organic acids for example citric, fumaric, gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic
  • Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including alkyl amines, arylalkyl amines, heterocyclyl amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • salts according to the invention are quaternary ammonium compounds wherein an equivalent of an anion (X " ) is associated with the positive charge of the N atom.
  • X " may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate
  • organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphon
  • an N-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.
  • solvate is used herein to describe a molecular complex comprising a compound of the invention and an amount of one or more pharmaceutically acceptable solvent molecules.
  • hydrate is employed when said solvent is water.
  • solvate forms include, but are not limited to, compounds of the invention in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof.
  • one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate. Furthermore, it is specifically contemplated that in the present invention, more than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a dihydrate. Additionally, it is specifically contemplated that in the present invention less than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a hemihydrate. Furthermore, solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non-solvate form of the compounds.
  • the invention also includes isotopically-labelled fused pyrazole derivatives of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as C, 3 C and 4 C, chlorine, such as 36 CI, fluorine, such as 8 F, iodine, such as 23 l and 25 l, nitrogen, such as 3 N and 5 N, oxygen, such as 5 0, 7 0 and 8 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • Preferred isotopically-labelled compounds include deuterated derivatives of the compounds of the invention.
  • deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium.
  • Deuterium (D or 2 H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.
  • Isotopically-labelled fused pyrazole derivatives of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labelled reagent in place of the non-labelled reagent otherwise employed.
  • tautomer means two or more forms or isomers of an organic compound that readily could be interconverted into each other via a common chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond.
  • tautomerism The concept of tautomerizations is called tautomerism. Because of the rapid interconversion, tautomers are generally considered to be the same chemical compound. In solutions in which tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH.
  • fused pyrazole derivatives of the present invention include all the possible tautomeric forms.
  • Examples of tautomeric forms included in the present invention are disclosed in Formula (I)*, formula (i)* or formula (ii)*
  • Prodrugs of the fused pyrazole derivatives described herein are also within the scope of the invention.
  • certain derivatives of the fused pyrazole derivatives of the present invention which derivatives may have little or no pharmacological activity themselves, when administered into or onto the body may be converted into compounds of the present invention having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of the present invention with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
  • G represents a CR 4 group and G 2 represents a CR 7 group.
  • R represents a group of formula (i) wherein R 2 represents a hydrogen atom, a chlorine atom or a fluorine atom; preferably R 2 represents a hydrogen atom .
  • X represents a -NR 8 - group, preferably a -NH- group. Alternativately, X may represent -0-.
  • R 4 represents a hydrogen atom, a -O-R 5 group, a -NHR 5 group, a monocyclic 5- to 6-membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a monocyclic 5- to 6- membered saturated or unsaturated heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched Ci-6 alkyl group, a linear or branched Ci-6-hydroxyalkyl group and a -(CH 2 )(o- 2 )NR l R M group; preferably R 4 represents a hydrogen atom or a -O-R 5 group.
  • R 7 represents a hydrogen atom, a fluorine atom, or a methyl group; preferably R 7 represents a hydrogen atom.
  • R VI and R v each independently represent a hydrogen atom, a linear or branched C1-3 alkyl group, a linear or branched C 1 -3 hydroxyalkyl group, or a linear or branched
  • pyridinyl groups are unsubstituted or substituted by one or more halogen atoms
  • R 4 represents a hydrogen atom, a -0-R 5 group, a -NHR 5 group, a monocyclic 5- to 6- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a monocyclic 5- to 6-membered saturated or unsaturated heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched C 1 -5 alkyl group, a linear or branched
  • R' and R" each independently represent a hydrogen atom or a linear or branched
  • a -CO(CH 2 )-OH group a -CO(CH 2 )-CN group and a pyrazinyl group, wherein the pyrazinyl group is substituted by a -CN group
  • Q is a group of formula Qb wherein R 0 is selected from the group consisting of a methyl group, a hydroxyl group and a -CH2-CN group
  • Q is a group of formula Qc wherein R VI is selected from the group consisting of a -CH 3 group, a -CH 2 OH group and a -CH 2 -OCH3 group, R VI 1 is a hydrogen atom and R is selected from the group consisting of a phenyl group, a pyrimidinyl group and a pyridinyl group, wherein the pyrimidinyl and pyridinyl groups are substituted by a fluorine atom;
  • the compounds of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It will be appreciated that wherein 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 G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • amino-protecting group refers to a protecting group suitable for preventing undesired reactions at amino nitrogen.
  • Representative amino-protecting groups include but are not limited to formyl group; tetrahydropyranyl (THP) group; acyl groups, for example alkanoyl groups such as acetyl; alkoxycarbonyl groups such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenyloxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr) and 1 ,1-di-(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), trimethylsiloxyethoxymethyl (SEM) and the like. Processes for preparing compounds of the invention are provided as
  • compounds of general Formula (I) may be prepared following the synthetic route illustrated in Scheme 1 :
  • G is a CR 4 group (R 4 is as defined in the claims) and G 2 is a CR 7 group, wherein R 7 is a hydrogen atom
  • compounds of formula (2a) may be prepared following the synthetic routes depicted in Scheme 2.
  • Compounds of formula (2a) may be obtained from triflate derivatives of formula (7) by reaction with compounds of formula (8), wherein Y is a boronic acid or a boronate ester, under Suzuki- Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457).
  • Such reactions may be catalysed by a suitable palladium catalyst such as [1 ,1 - bis(diphenylphosphino)ferrocene]palladium(ll) dichloride or tetrakis(triphenylphosphine) palladium(O), in a solvent such as 1 ,4-dioxane or 1 ,2-dimethoxyethane, in the presence of a base such as cesium carbonate or sodium carbonate, at temperatures ranging from 80 °C to 1 10 °C, with or without the use of microwave irradiation.
  • a suitable palladium catalyst such as [1 ,1 - bis(diphenylphosphino)ferrocene]palladium(ll) dichloride or tetrakis(triphenylphosphine) palladium(O)
  • a solvent such as 1 ,4-dioxane or 1 ,2-dimethoxyethane
  • a base such as ces
  • compounds of formula (2a) may be obtained from triflate derivatives of formula (7) by reaction with compounds of formula (8), wherein Y is a stannane and R 4 is a -CN group, in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), in a solvent such as 1 ,4-dioxane at a temperature ranging from 100°C to 180°C.
  • a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0)
  • Triflate derivatives of formula (7) may be obtained from alcohol derivatives of formula (6) by reaction with suitable reagents such as /V-phenyl-bis(trifluoroethansulfonimide) in the presence of a base such as triethylamine, in a solvent such as dimethylformamide.
  • suitable reagents such as /V-phenyl-bis(trifluoroethansulfonimide) in the presence of a base such as triethylamine, in a solvent such as dimethylformamide.
  • Alcohol derivatives of formula (6) may be obtained from compounds of formula (5) by deprotection of the -OBn group, using hydrogen gas at atmospheric pressure and a suitable catalyst such as palladium on carbon in a solvent such as methanol at room temperature.
  • Compounds of formula (5) may be prepared by reaction of chloropyrazolopyridine derivatives of formula (3) with compounds of formula (4), wherein X is a -NH- group , and Q is as defined in the claims , using a suitable catalyst such as tris(dibencylidenoacetone)dipalladium(0), in the presence of a ligand such as ( ⁇ )-2,2'-bis(diphenylphosphino)-1 , 1 '-binaphthalene and a base, for example potassium fert-butoxide, in a solvent such as toluene at a temperature ranging from 80°C to reflux.
  • compounds of formula (2a) may be prepared by reaction of compounds of formula (9) with compounds of formula (4), wherein X is a -NH- group using a suitable catalyst such as tris(dibencylidenoacetone)dipalladium(0), in the presence of a ligand such as ( ⁇ )-2,2'-bis(diphenylphosphino)-1 , 1 '-binaphthalene, and a base, for example potassium fert-butoxide, in a solvent such as toluene at a temperature ranging from 80°C to reflux.
  • a suitable catalyst such as tris(dibencylidenoacetone)dipalladium(0)
  • a ligand such as ( ⁇ )-2,2'-bis(diphenylphosphino)-1 , 1 '-binaphthalene
  • a base for example potassium fert-butoxide
  • the compound of formula (10) is prepared according to standard literature methods as described in the experimental section.
  • the reaction of the dihalogenated pyrazolopyridine (10) with halogenating reagent such as A/-iodosuccinimide, in a solvent such as dimethylformamide, at a temperature from 0 °C to the boiling point of the solvent yields the compound of formula (11 ).
  • Protection of trihalogenated pyrazolopyridine (1 1 ) with a suitable protecting group such as SEM, in a solvent such as dimethylformamide, in the presence of a base such as cesium carbonate at room temperature gives rise to compounds of formula (12).
  • Such reactions may be catalysed by a suitable palladium catalyst such as [1 , 1 - bis(diphenylphosphino)ferrocene]palladium(ll) dichloride or tetrakis(triphenylphosphine) palladium(O), in a solvent such as 1 ,4-dioxane or 1 ,2-dimethoxyethane, in the presence of a base such as cesium carbonate or sodium carbonate at temperatures ranging from 80 °C to 1 10 °C, with or without the use of microwave irradiation to furnish compounds of formula (3).
  • a suitable palladium catalyst such as [1 , 1 - bis(diphenylphosphino)ferrocene]palladium(ll) dichloride or tetrakis(triphenylphosphine) palladium(O)
  • a solvent such as 1 ,4-dioxane or 1 ,2-dimethoxyethane
  • compounds of formula (16) may be obtained from compounds of formula (15) by reaction with compounds of formula (8), wherein Y is a boronic acid or a boronate ester, under Suzuki- Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457).
  • Such reactions may be catalysed by a suitable palladium catalyst such as [1 , 1 - bis(diphenylphosphino)ferrocene]palladium(ll) dichloride or tetrakis(triphenylphosphine) palladium(O), in a solvent such as 1 ,4-dioxane or 1 ,2-dimethoxyethane, in the presence of a base such as cesium carbonate or sodium carbonate at temperatures ranging from 80 °C to 1 10 °C with or without the use of microwave irradiation.
  • a suitable palladium catalyst such as [1 , 1 - bis(diphenylphosphino)ferrocene]palladium(ll) dichloride or tetrakis(triphenylphosphine) palladium(O)
  • a solvent such as 1 ,4-dioxane or 1 ,2-dimethoxyethane
  • a base such as cesium carbon
  • Such reactions may be catalysed by a suitable palladium catalyst such as [1 , 1'-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride or tetrakis(triphenylphosphine)palladium(0), in a solvent such as 1 ,4-dioxane or 1 ,2- dimethoxyethane, in the presence of a base such as cesium carbonate or sodium carbonate at temperatures ranging from 80 °C to 1 10 °C, with or without the use of microwave irradiation to furnish compounds of formula (9).
  • a suitable palladium catalyst such as [1 , 1'-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride or tetrakis(triphenylphosphine)palladium(0)
  • a solvent such as 1 ,4-dioxane or 1 ,2- dimethoxyethane
  • a base such
  • compounds of formula (19) may also be prepared by reaction of trihalogenated pyrazolopyridines of formula (12) with the corresponding heterocyclic or linear amines or alcohol derivatives of formula (8), wherein Y is a hydrogen atom or a metal atom, in the presence of a base such as sodium hydrogencarbonate or A/-ethyl-A/-isopropylpropan-2-amine, without the use of a solvent or in a solvent such as ⁇ , ⁇ '-dimethylacetamide or 1-methylpyrrolidin-2-one at temperatures ranging from 80°C to 130 °C, with or without the use of microwave irradiation.
  • a base such as sodium hydrogencarbonate or A/-ethyl-A/-isopropylpropan-2-amine
  • Such reactions may be catalysed by a suitable palladium catalyst such as [1 , 1'-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride or tetrakis(triphenylphosphine)palladium(0), in a solvent such as 1 ,4-dioxane or 1 ,2- dimethoxyethane, in the presence of a base such as cesium carbonate or sodium carbonate at temperatures ranging from 80 °C to 1 10 °C, with or without the use of microwave irradiation to furnish compounds of formula (21 ).
  • a suitable palladium catalyst such as [1 , 1'-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride or tetrakis(triphenylphosphine)palladium(0)
  • a solvent such as 1 ,4-dioxane or 1 ,2- dimethoxyethane
  • Such reactions may be catalysed by a suitable palladium catalyst such as [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride or tetrakis(triphenylphosphine) palladium(O), in a solvent such as 1 ,4-dioxane or 1 ,2- dimethoxyethane, in the presence of a base such as cesium carbonate or potassium carbonate at temperatures ranging from 80 °C to 1 10 °C, with or without the use of microwave irradiation to furnish compounds of formula (27).
  • a suitable palladium catalyst such as [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride or tetrakis(triphenylphosphine) palladium(O)
  • a solvent such as 1 ,4-dioxane or 1 ,2- dimethoxyethane
  • Reaction of pyridines of formula (27) with halogenating reagent such as A/-bromosuccinimide, in a solvent such as dimethylformamide at a temperature ranging from 0 °C to room temperature yields the compounds of formula (28).
  • Reaction of the aminopyridines of formula (28) with a suitable reagent such as as acetic anhydride, potassium acetate and isoamylnitrite in the presence of 1 ,4,7,10, 13,16-hexaoxacyclooctadecane and in a solvent such as chloroform at 65 °C furnishes pyrazolopyridines of formula (29).
  • Such reactions may be catalysed by a suitable palladium catalyst such as [1 ,1'- bis(diphenylphosphino)ferrocene]palladium(ll) dichloride or tetrakis(triphenylphosphine) palladium(O), in a solvent such as 1 ,4-dioxane or 1 ,2-dimethoxyethane in the presence of a base such as cesium carbonate or sodium carbonate at temperatures ranging from 80 °C to 1 10 °C, with or without the use of microwave irradiation to furnish compounds of formula (32).
  • a suitable palladium catalyst such as [1 ,1'- bis(diphenylphosphino)ferrocene]palladium(ll) dichloride or tetrakis(triphenylphosphine) palladium(O)
  • a solvent such as 1 ,4-dioxane or 1 ,2-dimethoxyethane
  • Compounds of formula (34) may be treated with compounds of formula (14) wherein Z is a boronic acid or a boronate ester, under Suzuki-Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457).
  • Such reactions may be catalysed by a suitable palladium catalyst such as [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride or tetrakis(triphenylphosphine)palladium(0), in a solvent such as 1 ,4-dioxane or 1 ,2- dimethoxyethane, in the presence of a base such as cesium carbonate or sodium carbonate, at temperatures ranging from 80 °C to 1 10 °C, with or without the use of microwave irradiation to furnish compounds of formula (2d).
  • a suitable palladium catalyst such as [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride or tetrakis(triphenylphosphine)palladium(0)
  • a solvent such as 1 ,4-dioxane or 1 ,2- dimethoxyethane
  • compounds of formula (2e), wherein G is a nitrogen atom group and G 2 is a CR 7 group, wherein R 7 is a hydrogen atom may be prepared following the synthetic route illustrated in Scheme 9.
  • Compound of formula (36) may be reacted with a halogenating reagent such as N- iodosuccinimide, in a solvent such as dimethylformamide, at a temperature from 0 °C to the boiling point of the solvent, to yield the compounds of formula (37).
  • a halogenating reagent such as N- iodosuccinimide
  • a suitable protecting group such as SEM
  • a base such as cesium carbonate at room temperature
  • Compounds of formula (38) may be reacted with amines of formula (4), wherein X is a -NH- group, using a suitable catalyst such as tris(dibencylidenoacetone)dipalladium(0), in the presence of a ligand such as ( ⁇ )-2,2'- bis(diphenylphosphino)-1 , 1 '-binaphthalene and a base, for example potassium fert-butoxide, in a solvent such as toluene at a temperature ranging from 80°C to reflux to give rise to compounds of formula (39).
  • a suitable catalyst such as tris(dibencylidenoacetone)dipalladium(0)
  • a ligand such as ( ⁇ )-2,2'- bis(diphenylphosphino)-1 , 1 '-binaphthalene
  • a base for example potassium fert-butoxide
  • Compounds of formula (39) may be treated with compounds of formula (14), wherein Z is a boronic acid or a boronate ester, under Suzuki-Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457).
  • Such reactions may be catalysed by a suitable palladium catalyst such as [1 , 1 - bis(diphenylphosphino)ferrocene]palladium(ll) dichloride or tetrakis(triphenylphosphine) palladium(O), in a solvent such as 1 ,4-dioxane or 1 ,2-dimethoxyethane, in the presence of a base such as cesium carbonate or sodium carbonate, at temperatures ranging from 80 °C to 1 10 °C, with or without the use of microwave irradiation to furnish compounds of formula (2e).
  • a suitable palladium catalyst such as [1 , 1 - bis(diphenylphosphino)ferrocene]palladium(ll) dichloride or tetrakis(triphenylphosphine) palladium(O)
  • a solvent such as 1 ,4-dioxane or 1 ,2-dimethoxyethane
  • compounds of Formula (I), in which the residue at G , G 2 , or Q contains an alcohol, phenol or carboxylic acid moiety functionalized with an appropriate protecting group such as benzyl (Bn) or methoxy (OMe), may be deprotected at the alcohol, phenol or carboxylic acid moiety under standard conditions (Greene's Protective Groups in Organic Synthesis, ISBN: 0471697540).
  • an appropriate protecting group such as benzyl (Bn) or methoxy (OMe
  • the free alcohol moiety may then be oxidized under standard conditions to give the corresponding aldehyde.
  • compounds of Formula (I), in which the residue at G , G 2 , or Q contains an amine moiety functionalized with an appropriate protecting group such as tert- butoxycarbonyl (BOC) or benzyloxycarbonyl (CBZ), may be deprotected at the amine moiety under standard conditions (Greene's Protective Groups in Organic Synthesis, ISBN: 0471697540).
  • BOC tert- butoxycarbonyl
  • CBZ benzyloxycarbonyl
  • 6-Chloro-2-methylpyridin-3-amine (25 g, 0.18 mol) was dissolved in methanol (650 ml.) and cooled to 0°C. Glacial acetic acid (20 ml_, 0.31 mol) was added and, after that, bromine (16 ml_, 0.31 mol) was added dropwise and the reaction was stirred at 0°C for 30 minutes. A solution of sodium bisulfite was added and the organic solvents were removed under reduced pressure. The resulting aqueous phase was extracted with ethyl acetate (x3). The combined organics were washed with a saturated solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The resulting oil was treated with isopropilic ether, filtered and dried in the vacuum oven to yield the title compound (28.7 g, 74%) as a yellow solid.
  • the crude was purified by flash chromatography (hexanes to diethyl ether/ethanol (95:5) both eluents with 0.1 % of diethylamine) to yield the title compound (150 mg, 52%) as a white solid which was a mixture of regioisomers (5: 1 ).
  • reaction mixture was filtered through Celite®, eluted with ethyl acetate and the filtrate was concentrated under reduced pressure.
  • the resulting crude was purified by flash chromatography (hexanes to diethyl ether) to yield the title compound (150 mg, 54%) as a yellow solid.
  • A/-Bromosuccinimide (1.58 g, 8.85 mmol) was added portionwise to a solution of 2,5- dimethylpyridin-3-amine (Preparation 30a, 1.08 g, 8.85 mmol) in A/,A/-dimethylformamide (80 ml.) at 0°C.
  • the reaction mixture was allowed to stir at 0°C for 1 hour before adding water (300 ml.) and solid sodium bicarbonate until the pH of the mixture was slightly basic.
  • the resulting mixture was allowed to reach room temperature and extracted with ethyl acetate (x3).
  • 6-Bromo-2,5-dimethylpyridin-3-amine (Preparation 30b, 149 mg, 0.74 mmol) was dissolved in chloroform (5 mL). Potassium acetate (87 mg, 0.89 mmol) and acetic anhydride (0.28 mL, 2.96 mmol) were added and the reaction was stirred at 55°C for 2 hours. Then the reaction mixture was cooled to 0°C. 1 ,4,7,10,13, 16-Hexaoxacyclooctadecane (20 mg, 0.07 mmol) and isoamylnitrite (0.22 mL, 1.63 mmol) were added and the resulting mixture was stirred at 70°C overnight.
  • reaction mixture was partitioned between ethyl acetate and water, the organics were washed with brine, dried with a Phase Separator® and concentrated to dryness.
  • the resulting crude was purified by flash chromatography (hexanes to diethyl ether) to yield the title compound (180 mg, 58%) as a white solid.
  • the reaction mixture was partitioned between ethyl acetate and water, the organics were washed with brine, dried with a Phase Separator® and concentrated to dryness.
  • the resulting crude was purified by flash chromatography (hexanes to diethyl ether) to yield the title compound (373 mg, 60%) as a colourless oil.
  • the reaction mixture was partitioned between ethyl acetate and water, the organics were washed with brine, dried with a Phase Separator® and concentrated to dryness.
  • the resulting crude was purified by flash chromatography (hexanes to diethyl ether) to yield the title compound (2.62 g, 81 %) as a white oil.
  • a microwave reactor was charged with 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 - - pyrazole (0.50 g, 2.58 mmol), 2,2-dimethyloxirane (0.57 ml_, 6.44 mmol), cesium carbonate (1.25 g, 3.84 mmol) and acetonitrile (5 ml_).
  • the reaction mixture was subjected to microwave irradiation for 1 hour at 130 °C.
  • the solid was filtered, washed with dichloromethane and the filtrate was concentrated in vacuo to yield the title compound (0.28 g, 42%) as an oil.
  • Tris(dibenzylideneacetone)dipalladium(0) (1 19 mg, 0.13 mmol) and ( ⁇ )-2,2'- bis(diphenylphosphino)-1 ,1 '-binaphthalene (162 mg, 0.26 mmol) were added, the reaction vessel was sealed and the mixture was stirred at 100°C for 1.5 hours.
  • the crude was filtered through Celite ® and eluted with dichloromethane. The filtrate was concentrated under reduced pressure and the crude was purified by flash chromatography (hexanes to diethyl ether) to yield the title compound (400 mg, 66%) as a colourless oil.
  • Example 1 a 208 mg, 0.39 mmol
  • trifluoroacetic acid 1.5 ml_
  • the mixture was stirred at room temperature for 1 hour.
  • the crude was evaporated under reduced pressure, re-dissolved in ammonia solution 7 N in methanol (6 ml.) and stirred at room temperature for 4 hours.
  • the resulting mixture was concentrated under reduced pressure and partitioned between water and ethyl acetate.
  • the organic layer was washed twice with brine, dried and concentrated.
  • the crude was purified by flash chromatography (hexanes to diethyl ether) to yield the title compound (109 mg, 77%) as a colourless oil.
  • the crude was concentrated and treated with chlorotrimethylsilane (73 pL, 5.56 mmol) and sodium iodide (87 mg, 5.56 mmol) in acetonitrile (3 mL) according to the method described in Example 1 c.
  • the crude was purified by reverse phase chromatography (C-18 silica from Waters ® , water to methanol) to yield the title compound (22 mg, 22%) as a yellow solid.
  • Example 4a 1 H-pyrazolo[4,3-/ ]pyridin-5-amine (Example 4a, 153 mg, 0.33 mmol) was treated with trifluoroacetic acid (1.3 mL, 17.00 mmol) and ammonia solution 7 N in methanol (4.7 mL, 33.00 mmol) according to the method described in Example 1 b.
  • the crude was purified by flash chromatography (hexanes to diethyl ether) to yield the title compound (105 mg, 90%) as a solid.
  • Example 5a (/?)-2-Hydroxy-1-(3-((3-(2-methoxypyridin-3-yl)-2H-pyrazolo[4,3-5]pyridin-5-yl)amino)piperidin-1- yl)ethanone (Example 5a, 15 mg, 0.03 mmol) was treated with chlorotrimethylsilane (14 ⁇ _, 0.1 1 mmol) and sodium iodide (17 mg, 0.1 1 mmol) in acetonitrile (0.5 ml.) according to the method described in Example 1 c. The crude was purified by reverse phase chromatography (C-18 silica from Waters ® , water to methanol) to yield the title compound (63 mg, 62%) as a yellow solid.
  • Example 8b 130 mg, 0.23 mmol was treated with trifluoroacetic acid (0.9 mL, 12.00 mmol) and ammonia 7 N in methanol (3.3 mL, 23.00 mmol) following the procedure described in Example 1 b to yield the title compound (79 mg, 84%) as a yellow solid.
  • Example 8c (S)-3-(5-Chloro-2-methoxypyridin-3-yl)-A/-(1-(5-fluoropyridin-2-yl)ethyl)-2 - -pyrazolo[4,3- / ]pyridin-5-amine ( Example 8c, 79 mg, 0.20 mmol) was treated with chlorotrimethylsilane (63 pL, 0.50 mmol) and sodium iodide (74 mg, 0.49 mmol) according to the method described in Example 1 c. The crude was purified by reverse phase chromatography (C-18 silica from Waters ® , water to methanol) to yield the title compound (37 mg, 49%) as a yellow solid.
  • Example 10c 35 mg, 0.08 mmol was treated with chlorotrimethylsilane (30 ⁇ _, 0.24 mmol) and sodium iodide (35 mg, 0.23 mmol) in acetonitrile (1 mL) according to the method described in Example 1 c.
  • the crude was purified by reverse phase chromatography (C-
  • the crude was purified by flash chromatography (hexanes to diethyl ether/ethanol (98:2) both eluents with 0.1 % of diethylamine) to yield the title compound (70 mg, 50%) as a yellow oil.
  • Example 1 1a (trimethylsilyl)ethoxy)methyl)-1 H-pyrazolo[4,3-b]pyridine-5,7-diamine
  • Example 1 1a 70 mg, 0.12 mmol
  • trifluoroacetic acid 500 ⁇ _, 6.50 mmol
  • ammonia solution 7 N in methanol (2 mL) according to the method described in Example 1 b.
  • the crude was purified by reverse phase chromatography (C-18 silica from Waters ® , water to methanol) to yield the title compound (34 mg, 44%) as a yellow solid.
  • Example 13a 1-((2-(trimethylsilyl)ethoxy)methyl)-1 - -pyrazolo[4,3-5]pyridin-5-amine (Example 13a, 50 mg, 0.09 mmol) was treated with hydrochloric acid (4 M in dioxane, 3 mL, 20.00 mmol) at 50°C for 4 hours according to the method described in Example 7b to yield the title compound (23 mg, 61 %) as a yellow solid.
  • Example 14a 160 mg, 0.15 mmol was treated with trifluoroacetic acid (592 ⁇ _, 7.70 mmol) and ammonia (7 N in methanol, 2.2 mL, 15.00 mmol) according to the method described in Example 1 b to yield the title compound (36 mg, 97%) as a white solid.
  • pyrazolo[4,3-/ ]pyridine (Example 21 b, 47 mg, 0.08 mmol) was treated with hydrochloric acid (4 M in dioxane, 500 ⁇ _, 2.00 mmol) at 50°C for 3 hours in dioxane (2 mL) and then ammonia (7 N in methanol, 2 mL) according to the method described in Example 7b.
  • the crude was purified by reverse phase chromatography (C-18 silica from Waters ® , water to methanol) to yield the title compound (35 mg, 99%) as a yellow solid.
  • Example 23d 35 mg, 0.07 mmol was treated with chlorotrimethylsilane (29 ⁇ _, 0.23 mmol) and sodium iodide (34 mg, 0.23 mmol) in acetonitrile (1 ml.) at 70°C for 1 hour according to the method described in Example 1 c.
  • the crude was purified by reverse phase chromatography (C-18 silica from Waters ® , water to methanol) to yield the title compound (24 mg, 69%) as a yellow solid.
  • Example 25a 150 mg, 0.31 mmol was treated with 2-((1 r,4r)-4-aminocyclohexyl)acetonitrile (51 mg, 0.37 mmol), 2'-(dicyclohexylphosphino)-A/,A/-dimethylbiphenyl-2-amine (38 mg, 0.06 mmol), potassium fert-butoxide (69 mg, 0.61 mmol) and tris(dibenzylideneacetone) dipalladium(O) (28 mg, 0.03 mmol) in toluene (4 mL) at 100°C for 1 hour according to the method described in Example 1 a.
  • Example 25c yl)amino)cyclohexyl)acetonitrile
  • Example 25c 170 mg, 0.26 mmol
  • chlorotrimethylsilane 98 ⁇ _, 0.78 mmol
  • sodium iodide 1 16 mg, 0.78 mmol
  • acetonitrile 4 ml.
  • the crude was purified by reverse phase chromatography (C-18 silica from Waters ® , water to methanol) to yield the title compound (41 mg, 36%) as a yellow solid.
  • Example 26c 74 mg, 0.20 mmol was dissolved in A/,A/-dimethylformamide (1.5 mL).
  • 2- Hydroxyacetic acid (19 mg, 0.25 mmol) 1-[bis(dimethylamino)methylene]-1 - -1 ,2,3-triazolo[4,5- / ]pyridinium 3-oxid hexafluorophosphate (93 mg, 0.24 mmol) and triethylamine (57 ⁇ _, 0.41 mmol) were added and the reaction mixture was stirred at room temperature overnight.
  • the crude was partitioned between ethyl acetate and water.
  • the crude was purified by flash chromatography (hexanes to diethyl ether/ethanol (95:5) both eluents with 0.1 % of diethylamine) to yield the title compound (105 mg, 85%) as a beige solid which was a mixture of regioisomers (5:1 ).
  • pyrazolo[4,3-/ ]pyridin-5-amine (Example 32, 97 mg, 0.24 mmol) was dissolved in dichloromethane (2 ml_). The mixture was cooled to 0°C and boron tribromide (1 M in dicloromethane, 500 ⁇ _, 0.50 mmol) was added and the reaction was stirred for 1 hour. More boron tribromide (1 M in dicloromethane, 1 18 ⁇ _, 0.12 mmol) was added and the reaction was stirred at room temperature overnight. The mixture was evaporated under reduced pressure and redissolved in methanol. Ammonia (7 N in methanol, 2 ml.) was added and evaporated again. The residue was purified by reverse phase chromatography (C-18 silica from Waters ® , water to methanol) to yield the title compound (65 mg, 70%) as a white solid.
  • Example 34c 1 16 mg, 0.14 mmol
  • (S)-1-(5-fluoropyridin-2- yl)ethanamine 28 mg, 0.20 mmol
  • potassium fert-butoxide 38 mg, 0.34 mmol
  • tris(dibenzylideneacetone)dipalladium(0) 15 mg, 0.02 mmol
  • ( ⁇ )-2,2'- bis(diphenylphosphino)-1 ,1 '-binaphthalene 21 mg, 0.03 mmol) in toluene (2 ml.) at 100°C for 1 hour according to the method described in Example 1 a.
  • the crude was purified by flash chromatography (hexanes to diethyl ether) to yield the title compound (96 mg, 80%) as a yellow oil.
  • Example 36a 1 10 mg, 0.20 mmol was treated with hydrochloric acid (4 M in dioxane, 4.8 ml_, 19.50 mmol) and two drops of methanol at room temperature overnight and then ammonia (7 N in methanol, 8 ml.) according to the method descried in Example 30b.
  • the crude was purified by reverse phase chromatography (C-18 silica from Waters ® , water to methanol) to yield the title compound (29 mg, 44%) as a white solid.

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Abstract

L'invention concerne de nouveaux dérivés de pyrazole condensés ; ainsi qu'un procédé pour leur préparation, des compositions pharmaceutiques les comprenant et leur utilisation en thérapie comme inhibiteurs des Janus kinases (JAK).
PCT/EP2017/064708 2016-06-20 2017-06-15 Dérivés de pyrazole condensés utilisés en tant qu'inhibiteurs de jak Ceased WO2017220431A1 (fr)

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RU2805061C2 (ru) * 2018-03-08 2023-10-11 Виктория Линк Лтд Лечение демиелинизирующих заболеваний
WO2023204754A1 (fr) * 2022-04-21 2023-10-26 Aslan Pharmaceuticals Pte Ltd Traitement d'une maladie auto-immune de la peau
US12084453B2 (en) 2021-12-10 2024-09-10 Incyte Corporation Bicyclic amines as CDK12 inhibitors
WO2024240231A1 (fr) * 2023-05-24 2024-11-28 长春金赛药业有限责任公司 Inhibiteur sélectif de fgfr2/3, composition pharmaceutique et utilisation de celui-ci
US12318380B2 (en) 2018-03-08 2025-06-03 Victoria Link Ltd. Treatment of demyelinating diseases
CN120441547A (zh) * 2025-05-06 2025-08-08 大连医科大学附属第二医院 一种新型的脂肪酸酰胺水解酶（faah）抑制剂及其在疾病治疗中的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014172513A2 (fr) * 2013-04-18 2014-10-23 Arrien Pharmaceuticals Llc Inhibiteurs d'itk et de jak3 3,5-(non)substitué-1h-pyrrolo[2,3-b]pyridine, 1h-pyrazolo[3,4-b]pyridine et 5h-pyrrolo[2-,3-b]pyrazine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014172513A2 (fr) * 2013-04-18 2014-10-23 Arrien Pharmaceuticals Llc Inhibiteurs d'itk et de jak3 3,5-(non)substitué-1h-pyrrolo[2,3-b]pyridine, 1h-pyrazolo[3,4-b]pyridine et 5h-pyrrolo[2-,3-b]pyrazine

Non-Patent Citations (31)

* Cited by examiner, † Cited by third party
Title
"Bioreversible Carriers in Drug Design, Pergamon Press", 1987, AMERICAN PHARMACEUTICAL ASSOCIATION
"Design of Prodrugs", 1985, ELSEVIER
"Greene's Protective Groups in Organic Synthesis", ISBN
"Pro-drugs as Novel Delivery Systems", vol. 14, ACS SYMPOSIUM SERIES
"Remington: The Science and Practice of Pharmacy", 2001, LIPPINCOTT WILLIAMS & WILKINS
"Stereochemistry of Organic Compounds", 1994, WILEY
BAIRD ET AL.: "T cell development and activation in JAK3-deficient mice", J. LEUK. BIOL, vol. 63, 1998, pages 669
BRISCOE ET AL.: "Kinase-negative mutants of JAK1 can sustain intereferon-gamma-inducible gene expression but not an antiviral state", EMBO J., vol. 15, 1996, pages 799
DISANTO ET AL.: "Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain", PNAS, vol. 92, 1995, pages 377
GROSSMAN ET AL.: "Dysregulated myelopoiesis in mice lacking JAK3", BLOOD, vol. 94, no. 932, 1999, pages 939
GUSCHIN ET AL.: "A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6", EMBO J., vol. 14, 1995, pages 1421
KARAGHIOSOFF ET AL.: "Partial impairment of cytokine responses in Tyk2-deficient mice", IMMUNITY, vol. 13, 2000, pages 549
MINEGISHI ET AL.: "Human Tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity", IMMUNITY, vol. 25, 2006, pages 745
MIYAURA, N.; SUZUKI, A, CHEM. REV, vol. 1995, no. 95, pages 2457
MIYAURA, N.; SUZUKI, A, CHEM. REV, vol. 95, 1995, pages 2457
MIYAURA, N.; SUZUKI, A, CHEM. REV., vol. 95, 1995, pages 2457
MIYAURA, N.; SUZUKI, A. CHEM. REV, vol. 95, 1995, pages 2457
MURRAY PJ: "The JAK-STAT signaling pathway: input and output integration", J IMMUNOL, vol. 178, 2007, pages 2623
MURRAY PJ: "The JAK-STAT signalling pathway: input and output integration", J IMMUNOL, vol. 178, 2007, pages 2623
O'SHEA ET AL.: "JAK3 and the pathogenesis of severe combined immunodeficiency", MOL IMMUNOL, vol. 41, 2004, pages 727, XP002348159
PARGANAS ET AL.: "JAK2 is essential for signaling through a variety of cytokine receptors", CELL, vol. 93, 1998, pages 385
PARGANAS ET AL.: "JAK2 is essential for signalling through a variety of cytokine receptors", CELL, vol. 93, 1998, pages 385
PARK ET AL.: "Developmental defects of lymphoid cells in JAK3 kinase-deficient mice", IMMUNITY, vol. 3, 1995, pages 771
PESCHON ET AL.: "Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice", J EXP MED, vol. 180, 1994, pages 1955
RODIG ET AL.: "Disruption of the JAK1 gene demonstrates obligatory and non-redundant roles of the JAKs in cytokine-induced biological response", CELL, vol. 93, 1998, pages 373
RODIG ET AL.: "Disruption of the JAK1 gene demonstrates obligatory and nonredundant roles of the JAKs in cytokine-induced biological response.", CELL, vol. 93, 1998, pages 373
RUSSELL ET AL.: "Mutation of JAK3 in a partient with SCID: Essential role of JAK3 in lymphoid development", SCIENCE, vol. 270, 1995, pages 797
SHIMODA ET AL.: "Tyk2 plays a restricted role in IFNg signaling, although it is required for IL-12-mediated T cell function", IMMUNITY, vol. 13, 2000, pages 561
T. W. GREENE; G. M. WUTS: "Protecting Groups in Organic Synthesis", 1999, WILEY
THOMIS ET AL.: "Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking JAK3", SCIENCE, vol. 270, 1995, pages 794
VON FREEDEN-JEFFRY ET AL.: "Lymphopenia in Interleukin (IL)-7 Gene-deleted Mice Identifies IL-7 as a non-redundant Cytokine", J EXP MED, vol. 181, 1995, pages 1519

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