WO2016202800A1 - Dérivés de pyrrolotriazinone en tant qu'inhibiteurs de pi3k - Google Patents

Dérivés de pyrrolotriazinone en tant qu'inhibiteurs de pi3k Download PDF

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WO2016202800A1
WO2016202800A1 PCT/EP2016/063635 EP2016063635W WO2016202800A1 WO 2016202800 A1 WO2016202800 A1 WO 2016202800A1 EP 2016063635 W EP2016063635 W EP 2016063635W WO 2016202800 A1 WO2016202800 A1 WO 2016202800A1
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methyl
group
pyrrolo
mmol
ethyl
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Joan Taltavull Moll
Marta Mir Cepeda
Maria Pilar Forns Berenguel
Montserrat Erra Sola
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Almirall SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to novel compounds having PI3K activity.
  • This invention also relates to pharmaceutical compositions containing them, processes for their preparation and their use in the treatment of several disorders.
  • Phosphoinositide 3-Kinases are among the enzymes involved in early signalling events to a plethora of different types of stimuli.
  • PI3Ks phosphorylate the 3-hydroxyl group of the inositol ring of phosphatidylinositol
  • Ptdlns Ptdlns-4-phosphate
  • Ptdlns4P Ptdlns-4-phosphate
  • Ptdlns-4,5-bisphosphate Ptdlns(4,5)P2
  • the resulting 3-phosphoinositides mediate correct localization and subsequent activation of a number of downstream effector proteins that bind to the lipids via specific lipid binding sequences such as the pleckstrin homology (PH) domain
  • PI3K class I The PI3K family is divided into 3 different classes (PI3K class I, class II, and class III), depending on substrate preference and structural features.
  • the best characterized is the PI3K class I with the preferential substrate Ptdlns- (4,5)P2. It englobes 4 different isoforms which originally were further subdivided into class IA (p1 10a, p1 10b, p1 10d), binding to a p85 type of regulatory subunit, and class IB (p1 10g) which is regulated by p101 and p87 subunits.
  • p1 10a PI3Ka or PI3Ka
  • p1 10b PI3Kb or ⁇ 3 ⁇
  • p1 10g PI3Kg or ⁇ 3 ⁇
  • p1 10d PI3Kd or PI3K5
  • PI3Kd and PI3Kg are involved in activation of immune cells by a large variety of different stimuli.
  • Pharmacological inhibition or genetic deficiency in active p1 10d has been shown to inhibit T cell proliferation and cytokine production in response to different stimuli such as anti-CD3, anti-CD3/CD28, superantigen or antigen in vitro (Ji H, Blood 2007; Okkenhaug K, Science 2002; Garcon F, 2009; Soond DR, Blood 2010; Herman SEM, Blood June 3, 2010; William O, Chemistry & Biology 17, 2010) and to suppress concanavalin A and anti-CD3 induced cytokine production as well as antigen- dependent tissue retention in vivo (Soond DR, Blood 2010; Jarmin SJ, JCI 2008).
  • B cell function is critically dependent on functional PI3Kd activity as demonstrated by suppressed B cell proliferation and cytokine release in vitro in response to anti-lgM (Bilancio A, Blood 107, 2006), toll like receptor agonists such as LPS and oligodeoxynucleotides (Dil N, Mol Immunol 46, 2009) or impaired ability to stimulate antigen-specific T cells (Al-Alwan M, JI 2007) in the absence of functional p1 10d or pharmacological inhibition.
  • PI3Kg deficient mice display partially suppressed antibody production upon immunization (Garcon F, 2009; Durand CA, JI
  • mast cell degranulation was reduced in cells from mice with inactivated PI3Kd or by pharmacological inhibition of PI3Kd (AN K, Nature 431 :1007-101 1 , 2004; AN K, Journal of Immunology 180:2538-2544, 2008) and basophil activation via the FcE receptor is suppressed by pharmacological inhibition of PI3Kd (Lannutti BJ, Blood Oct.
  • PI3Kd inhibition inhibits migration of mouse neutrophils to fMLP in an under-agarose migration assay by inhibiting cell polarization and directional movement (Sadhu C, JI 170, 2003) and mouse PI3Kd deficient or inhibitor treated neutrophils show slightly (25%) reduced in vitro chemotaxis to LTB4, whereas in vivo accumulation in the lung in response to LPS was reduced by more than 80%, indicating an important role of PI3Kd in endothelial cells for mediating PMN
  • TNF induced neutrophil infiltration to an air pouch in mice and elastase release is partially inhibited by a PI3Kd selective inhibitor (Sadhu C, Biochem Biophys Res Comm 308, 2003).
  • PI3Kd selective inhibitor Sadhu C, Biochem Biophys Res Comm 308, 2003.
  • TNF mediated priming of oxidative burst by human neutrophils depends on PI3Kd activity (Condliffe AM, Blood 106, 2005).
  • PI3Kg seems to affect primarily chemotaxis of different immune cells induced by various mediators and chemokines (Martin AL, Jl 180, 2008; Thomas MS, J Leukoc Biol 84, 2008; Jarmin SJ, JCI 2008; Matthew T, Immunology 126, 2008), as well as degranulation and oxidative burst of innate immuce cells induced by GPCR mediated stimuli such as fMLP, IL-8 or C5a (Condliffe AM, Blood 106, 2005; Yum HK, Jl 167, 2001 ; Pinho V, Jl 179, 2007
  • PI3Kd inhibition Puri KD, Blood 2004;103:3448
  • inflammation in response to LPS or tobacco smoke exposure is suppressed by a dual PI3Kd/g inhibitor
  • PI3Kd seems to be involved in the reduction of responsiveness to corticosteroid treatment associated with oxidative stress and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • PI3Kd selective inhibitor To Y, AJRCCM 182:897- 904, 2010.
  • in vitro induction of corticosteroid resistance by oxidative stress is prevented by PI3Kd inhibition (To Y, AJRCCM 2010).
  • lung macrophages display increased expression of PI3Kd and phosphorylation of its downstream effector Akt and non-selective PI3K or PI3Kd- selective inhibition restored the impaired inhibitory efficacy of dexamethasone in PBMC from COPD patients (To Y, AJRCCM 182:897-904, 2010; Marwick JA, JACI 125:1 146-53, 2010).
  • PI3Kd inhibition was effective in a model of contact hypersensitivity (Soond DR, Blood Jan 2010).
  • Soond DR Blood Jan 2010
  • PI3Kd inhibition was effective in a model of contact hypersensitivity (Soond DR, Blood Jan 2010).
  • PI3Kd deficiency or pharmacological inhibition of PI3Kd attenuated T cell activation and function and reduced T cell numbers in the CNS suggesting a therapeutic benefit of PI3Kd inhibitor in multiple sclerosis and other Th17-mediated autoimmune diseases (Haylock-Jacobs S, J. Autoimmun 2010).
  • genetic deficiency or pharmacological inhibition of PI3Kd diminished joint erosion in a mouse model of inflammatory arthritis (Randis TM, Eur J Immunol 38, 2008).
  • PI3Kd overexpression seems to contribute to excessive vascular contraction and PI3Kd inhibition normalized vascular contractive responses in a mouse model of type I diabetes, suggesting a therapeutic potential of PI3Kd blockade to treat vascular dysfunction in diabetic patients (Pinho JF, Br. J. Pharmacol 161 , 2010).
  • pharmacolocical inactivation of PI3Kd or dual PI3Kd/g dual inhibition is effective in the treatment of cancers including but not restricted to leukemias, such as chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukaemia, non-hodgkins lymphoma, B-cell lymphoma, acute myeloid leukaemia, myelo-dysplastic syndrome or myelo-proliferative diseases.
  • leukemias such as chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukaemia, non-hodgkins lymphoma, B-cell lymphoma, acute myeloid leukaemia, myelo-dysplastic syndrome or myelo-proliferative diseases.
  • the selective PI3Kd inhibitor CAL-101 demonstrated anti-proliferative properties on different tumor cells in vitro and efficacy in cancer patients with a dysregulated PI3Kd activity, such as chronic lymphocytic leukemia (Hermann SE, Blood 1 16:2078-88, 2010; Lannutti BJ, Blood Oct. 2010).
  • a dysregulated PI3Kd activity such as chronic lymphocytic leukemia (Hermann SE, Blood 1 16:2078-88, 2010; Lannutti BJ, Blood Oct. 2010).
  • novel pyrrolotriazinone derivatives for use in the treatment of conditions in which targeting of the PI3K pathway or inhibition of PI3 Kinases can be therapeutically useful.
  • n represents an integer selected from 1 or 2;
  • X and Y each independently represent a nitrogen atom or CR3 group
  • Ri and R2 each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group
  • R3 represents a hydrogen atom, a halogen atom, a hydroxyl, a linear or branched C1-C4 alkyl group, a C1-C4 alkoxy group or a C1-C4 haloalkyl group;
  • Z represents a -CH((CH2)o-i-NR a R b )- group, a -NH- group or a -N(Ci-C3 alkyl)- group;
  • R a and R b each independently represent a hydrogen atom or a linear or branched C1-C4 alkyl group; or R a and R b together with the nitrogen atom to which they are attached form a monocyclic 3- to 7-membered heterocyclyl group optionally containing at least one further heteroatom selected from O, S and N.
  • the invention further provides synthetic processes and intermediates described herein, which are useful for preparing said compounds.
  • the invention is also directed to a compound of the invention as described herein for use in the treatment of the human or animal body by therapy.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compounds of the invention and a pharmaceutically-acceptable diluent or carrier.
  • the invention is also directed to the compounds of the invention as described herein, for use in the treatment of a pathological condition or disease susceptible to
  • Phosphoinositide 3-Kinases in particular wherein the pathological condition or disease is selected from 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; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid artritis (RA), multiple sclerosis (MS), amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis,
  • RA rheumatoid artritis
  • MS multiple sclerosis
  • amyotrophic lateral sclerosis Crohn's disease
  • ulcerative colitis systemic lupus
  • autoimmune hemolytic anemia type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis, sarcoidosis, atopic dermatitis, allergic rhinitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and actinic keratosis (AK).
  • COPD chronic obstructive pulmonary disease
  • COPD cystic fibrosis
  • CF cystic fibrosis
  • sarcoidosis atopic dermatitis
  • allergic rhinitis contact dermatitis
  • the pathological condition or disease is selected from asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the invention is also directed to use of the compounds 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 Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is as defined above.
  • PI3Ks Phosphoinositide 3-Kinases
  • the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is as defined above.
  • PI3Ks Phosphoinositide 3-Kinases
  • the invention also provides a combination product comprising (i) the compounds of the invention as described herein; and (ii) one or more additional active substances which are known to be useful in the treatment of respiratory diseases; allergic diseases;
  • inflammatory or autoimmune-mediated 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; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid artritis (RA), multiple sclerosis (MS), amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis,
  • RA rheumatoid artritis
  • MS multiple sclerosis
  • amyotrophic lateral sclerosis Crohn's disease
  • ulcerative colitis systemic lupus erythematosis
  • autoimmune hemolytic anemia type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis, sarcoidosis, atopic dermatitis, allergic rhinitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and actinic keratosis (AK).
  • COPD chronic obstructive pulmonary disease
  • COPD cystic fibrosis
  • CF cystic fibrosis
  • sarcoidosis atopic dermatitis
  • allergic rhinitis contact dermatitis
  • C1-C4 alkyl embraces linear or branched radicals having 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms. Examples include methyl, ethyl, n- propyl, i-propyl, n-butyl, sec-butyl or t-butyl radicals.
  • C1-C4 haloalkyl group is an alkyl group, for example a C1-C4 or C1-C2 alkyl group, which is bonded to one or more, preferably 1 , 2 or 3 halogen atoms.
  • said haloakyl group is chosen from -CCI3, -CHF2 and -CF3.
  • C1-C4 alkoxy (or alkyloxy) embraces linear or branched oxy- containing radicals each having alkyl portions of 1 to 4 carbon atoms.
  • 3- to 7-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C3-C7 carbocyclic ring system, preferably C5-C6 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 3- to 7-membered heterocyclyl radicals include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl or thiomorpholinyl.
  • substituents may be the same or different.
  • atoms, radicals, moieties, chains and cycles present in the general structures of the invention are "optionally substituted".
  • substituents 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.
  • substituents When two or more substituents are present, each substituent may be the same or different. The substituents are typically themselves unsubstituted.
  • halogen atom embraces chlorine, fluorine, bromine and iodine atoms.
  • a halogen atom is typically a fluorine, chlorine or bromine atom, most preferably chlorine or fluorine.
  • halo when used as a prefix has the same meaning.
  • any reference to a compound of formula (I) throughout the present specification includes a reference to any isomer, polymorph, pharmaceutically acceptable salt, N-oxide, isotope, solvate or prodrug of such compound of formula (I).
  • Compounds containing one or more chiral centre may be used in enantiomerically or diastereoisomerically pure form, in the form of racemic mixtures and in the form of mixtures enriched in one or more stereoisomer.
  • the compounds of Formula (I) as described and claimed encompass the racemic forms of the compounds as well as the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures.
  • enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine.
  • the resulting diastereoisomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
  • Stereoisomer conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. "Stereochemistry of Organic Compounds" by Ernest L. Eliel (Wiley, New York, 1994).
  • Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers.
  • Oki (Oki, M; Topics in Stereochemistry 1983, 1 ) defined atropisomers as conformers that interconvert with a half-life of more than 1000 seconds at a given temperature.
  • the scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual atropisomers (an atropisomer "substantially free" of its corresponding enantiomer) and stereoisomer-enriched mixtures, i.e. mixtures of atropisomers. Separation of atropisomers is possibly by chiral resolution methods such as selective crystallization.
  • Atroposelective synthesis may be carried out by use of chiral auxiliaries like a Corey-Bakshi-Shibata (CBS) catalyst (asymmetric catalyst derived from proline) in the total synthesis of knipholone or by approaches based on thermodynamic equilibration when an isomerization reaction favors one atropisomer over the other.
  • CBS Corey-Bakshi-Shibata
  • the compounds of Formula (I) may exhibit the phenomena of tautomerism and structural isomerism.
  • Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the compounds of Formula
  • the compounds of formula (I) may exist in different physical forms, i.e. amorphous and crystalline forms.
  • the compounds of the invention may have the ability to crystallize in more than one form, a characteristic which is known as polymorphism.
  • Polymorphs can be distinguished by various physical properties well known in the art such as X-ray diffraction pattern, melting point or solubility. All physical forms of the compounds of formula (I), including all polymorphic forms (“polymorphs”) or amorphous forms thereof, are included within the scope of the invention.
  • Pharmaceutically acceptable salts are included within the scope of the invention.
  • 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 salt embraces salts with a pharmaceutically acceptable acid or base.
  • 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.
  • Salts derived from fumaric, hydrobromic, hydrochloric, acetic, sulfuric, methanesulfonic, xinafoic, and tartaric acids are particularly preferred.
  • Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts.
  • 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
  • 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, methanesulphonate and p-toluenesulphonate.
  • X- is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X- is chloride, bromide, trifluoroacetate or methanesulphonate. N-oxides
  • an N-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.
  • the invention also includes isotopically-labeled derivatives of the compounds 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 2H and 3H, carbon, such as 1 1 C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 1231 and 1251, nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P, and sulfur, such as 35S.
  • Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, 3H, and carbon-14, 14C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, 2H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes, such as 1 1 C, 18F, 150 and 13N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled derivatives of the compounds 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-labeled reagent in place of the non-labeled reagent otherwise employed.
  • Preferred isotopically-labeled derivatives 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 2H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • 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. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate.
  • 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.
  • Prodrugs of the compounds described herein are also within the scope of the invention.
  • certain derivatives of the compounds 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).
  • PI3Kd inhibitor generally refers to a compound that inhibits the activity of the PI3Kd isoform more effectively than other isoforms of the PI3K family.
  • PI3Kd/g inhibitor generally refers to a compound that inhibits the activity of both the PI3Kd isoform and the PI3Kg isoform more effectively than other isoforms of the PI3K family.
  • the relative efficacies of compounds as inhibitors of an enzyme activity can be established by determining the concentrations at which each compound inhibits the activity to a predefined extent and then comparing the results.
  • the preferred determination is the concentration that inhibits 50% of the activity in a biochemical assay, i.e., the 50% inhibitory concentration or "IC50.”
  • IC50 determinations can be accomplished using conventional techniques known in the art. In general, an IC50 can be determined by measuring the activity of a given enzyme in the presence of a range of concentrations of the inhibitor under study. The experimentally obtained values of enzyme activity then are plotted against the inhibitor concentrations used. The concentration of the inhibitor that shows 50% enzyme activity (as compared to the activity in the absence of any inhibitor) is taken as the IC50 value.
  • a PI3Kd inhibitor alternatively can be understood to refer to a compound that exhibits a 50% inhibitory concentration (IC50) with respect to PI3Kd that is at least of less than about 100 ⁇ , preferably of less than about 50 ⁇ , more preferably of less than about 20 ⁇ , even more preferably of less than about 10 ⁇ PI3K HTRF assay (as described in Gray et al. Anal Biochem, 2003; 313: 234-45).
  • IC50 inhibitory concentration
  • n 1
  • Ri and R2 represent a hydrogen atom.
  • X represents a CR 3 group and Y represents a nitrogen atom.
  • R 3 represents a hydrogen atom.
  • Z represents a -CH((CH2)o-iNR a R b )- group.
  • R a and R b each independently represent a hydrogen atom or a methyl group.
  • n 1 ;
  • Ri and R2 represent a hydrogen atom
  • X represents a CH group and Y represents a nitrogen atom
  • Z represents a -CH((CH 2 )o-iNR a R b )- group
  • R a and R b each independently represent a hydrogen atom or a methyl group.
  • n 1 or 2;
  • Ri and f3 ⁇ 4 represent a hydrogen atom or a methyl group;
  • R3 represents a hydrogen atom, a methoxy group, a methyl group, a -CF3 group, a fluorine atom or a hydroxyl group
  • R a and R b each independently represent a hydrogen atom or a methyl group; or R a and R b together with the nitrogen atom to which they are attached form a pyrrolidinyl group.
  • Particular individual compounds of the invention include:
  • therapeutically effective amount refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
  • treatment refers to the treatment of a disease or medical condition in a human patient which includes:
  • 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 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 G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • compounds of general Formula (I) may be prepared by the synthetic route illustrated in Scheme 1 , from compounds of general Formula (II) where Zi represents an halogen by treatment with compounds of Formula (III) where Z2 represents a boronic acid or ester using standard Suzuki coupling conditions.
  • compounds of Formula (I) can be obtained from compounds of general Formula (II) where Zi represents a boronic acid or ester by treatment with compounds of Formula (III) where Z2 represents an halogen using also standard Suzuki coupling conditions.
  • boronic acids or esters can be prepared from the corresponding halogenated derivatives by treatment with standard reagents well known for those skilled in the art, such as 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane or bis(pinacolato)diboron in the presence of a palladium catalyst such as bis(diphenylphosphino)ferrocene-palladium (ll)dichloromethane complex, an appropriate base such as potassium carbonate and in a suitable solvent such as dioxane at a temperature ranging from 60°C to 120°C.
  • a palladium catalyst such as bis(diphenylphosphino)ferrocene-palladium (ll)dichloromethane complex
  • an appropriate base such as potassium carbonate
  • a suitable solvent such as dioxane at a temperature ranging from 60°C to 120°C.
  • compounds of general Formula (III) can be prepared by reductive amination from compounds of general Formula (IV) where Z3 is a carboxaldehyde and the corresponding amines of general Formula (V) as is shown in Scheme 2, with the presence of a reducing agent such as sodium triacetoxyborohydride and in a solvent such as dichloroethane or methanol.
  • compounds of general Formula (III) can be prepared by nucleophilic substitution from compounds of general Formula (IV) where Z3 is a methylene group attached to a leaving group by treatment with the corresponding amine of general Formula (V) with or without the presence of a base and in a solvent such as ethanol or methanol.
  • compounds of general Formula (I) may be prepared by the synthetic route illustrated in Scheme 3, from compounds of general Formula (VI) by treatment with compounds of general Formula (V) using the same general methods as described for compounds of Formula (III).
  • compounds of general Formula (VI) may be prepared by standard Suzuki conditions well known for those skilled in the art, from an halogenated derivative of general Formula (II) and a boronic acid or ester of general Formula (IV) or the other way around.
  • Concentration or evaporation refers to evaporation under vacuum using a Buchi rotatory evaporator.
  • Reaction products were purified, when necessary, in a Biotage SP1 ® automated purification system. Purifications in normal phase were made in the solvent system as indicated. Purifications in reverse phase were made using a Cie column and two different methods depending on the compound. Method A consist of a gradient of water-acetonitrile/MeOH (1 : 1 ) (0.1 % v/v ammonium formate both phases) from 0% to 100% acetonitrile/MeOH (1 : 1 ) in 40 column volumes. Method B consist of a gradient of water-acetonitrile (0.1 % v/v formic acid both phases) from 0% to 100% acetonitrile in 40 column volumes. The appropriate fractions were collected and the solvents evaporated under reduced pressure and/or lyophilized.
  • Preparative HPLC-MS were performed on a Waters instrument equipped with a 2767 injector/collector, a 2525 binary gradient pump, a 2996 PDA detector, a 515 pump as a make-up pump and a ZQ4000 Mass spectrometer detector or on a Agilent 1200 Series coupled to an Agilent 6120 Mass spectrometer detector. Both systems were equipped with a Symmetry Prep Cie (19 x 300 mm, 7 ⁇ ) column or a XBridge Prep Cie (19 x 100 mm, 5 ⁇ ) column.
  • the mobile phase was formic acid (0.4 mL), ammonia (0.1 mL), methanol (500 mL) and acetonitrile (500 mL) (B) and formic acid (0.5 mL), ammonia (0.125 mL) and water (1000 mL) (A), the specific gradients used are specified in each particular case.
  • the flow rate was 20 mL/min.
  • the mobile phase was formic acid (0.4 mL), ammonia (0.1 mL), methanol (500 mL) and acetonitrile (500 mL) (B) and formic acid (0.5 mL), ammonia (0.125 mL) and water (1000 mL) (A) and a gradient between 0 to 95% of B was used.
  • UPLC ACQUITY UPLC BEH C-18 (2.1 x50mm, 1 .7 [im) 1 H Nuclear Magnetic Resonance Spectra were recorded on a Varian Mercury plus operating at a frequency of 400 MHz for the 1 H spectra. Samples were dissolved in the specified deuterated solvent. Tetramethylsilane was used as reference.
  • Ethyl 5-bromo-2-(trifluoromethyl)nicotinate 250 mg, 0.88 mmol was dissolved in 3 mL tetrahydrofuran.
  • Lithium aluminium hydride powder 95% 88 mg, 2.32 mmol was added portionwise and the mixture was stirred at 0°C for 1 h.
  • Water (0.2 mL), sodium hydroxide (2N, 0.2 mL) and brine (0.5 mL) were added and the mixture was stirred at room temperature for 1 h more.
  • the crude was filtered through a pad of Celite ® and then purified by SP1 ® Purification System (hexane-ether) to obtain 94 mg (44% yield) of desired compound.
  • PREPARATION 21 1 -(1 -((4-Bromopyridin-2-yl)methyl)piperidin-4-yl)-A/,A/-dimethylmethanamine
  • reaction mixture was filtered through a pad of Celite ® and poured into water and ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1 ® Purification System (dichloromethane- dichloromethane/methanol/NhUOH) to give 77 mg (63% yield) of the title compound as a white solid.
  • reaction mixture was filtered through a pad of Celite ® and washed with water and brine.
  • organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to give 1 10 mg (99% yield) of the title compound as an orange oil that was used in the next step without further purification.
  • reaction mixture was filtered through a pad of Celite ® and re-dissolved with ethyl acetate.
  • the organic was washed with a saturated solution of sodium carbonate, dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain a dark oil.
  • the residue was purified by SP1 ® Purification System (dichloromethane-dichloromethane/methanol) to give 166 mg (62% yield) of the title compound as a brown oil.
  • phenylpyrrolo[2,1-/][1 ,2,4]triazin-4(3/-/)-one 34 mg, 0.045 mmol
  • trifluoroacetic acid 0.6 mL
  • ammonia 7N in methanol, 2 mL
  • the crude was extracted with ethyl acetate and washed with water.
  • the organic layer was washed with aqueous carbonate solution and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 25 mg (92% yield) of the pure desired compound.
  • phenylpyrrolo[2,1-/][1 ,2,4]triazin-4(3/-/)-one (70 mg, 0.093 mmol) was treated with trifluoroacetic acid (0.6 mL) and ammonia (7N in methanol, 1.2 mL) according to the method described in Example 1.
  • the crude was basified with sodium hydroxide and extracted twice with dichloromethane. The organics were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to give 40 mg (70% yield) of title compound as a brown oil.
  • phenylpyrrolo[2,1-/][1 ,2,4]triazin-4(3/-/)-one (60 mg, 0.08 mmol) was treated with trifluoroacetic acid (2 mL) and ammonia (7N in methanol, 1 1 mL) according to the method described in Example 1 .
  • the solvent was concentrated and purified by reverse phase using SP1 ® Purification System to give 40 mg (80% yield) od the title compound as a white solid.
  • phenylpyrrolo[2,1-/][1 ,2,4]triazin-4(3/-/)-one (500 mg, 0.14 mmol) was treated with trifluoroacetic acid (2 ml.) and ammonia (7N in methanol, 2 mL) according to the method described in Example 1.
  • the solvent was concentrated under reduced pressure and purified by reverse phase using preparative HPLC-MS purification system to obtain 10 mg (13% yield) of the title compound as a white solid.
  • PI3Ka PI3Ka
  • PI3Kb PI3K5
  • PI3Kg PI3Kg
  • PI-3 Kinase HTRF kit (ref. #33-037) and the different PI3K recombinant isoforms (ref. #14-602, ref. #14-603, ref .#14-604, ref .#15-558 for Alpha, Beta, Delta and Gamma respectively) were purchased at Millipore (expressed in insect cells). ATP was purchased at Sigma Aldrich (ref. #A7699).
  • Reaction time and enzyme concentration in the assay will depend of each batch.
  • the compounds of formula (I) are potent inhibitors of Phosphoinositide 3-kinase delta (PI3kd).
  • Preferred compounds of the invention possess an IC50 value for the inhibition of PI3Kd (determined as defined above) of less than 10 nM.
  • the invention is also directed to a compound of the invention as described herein for use in the treatment of the human or animal body by therapy.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • pyrrolotriazinone derivatives defined herein may also be combined with other active compounds in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of PI3Ks.
  • the combinations of the invention can optionally comprise one or more additional active substances which are known to be useful in the treatment of respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection;
  • the combinations of the invention can optionally comprise one or more additional active substances which are known to be useful in the treatment of neoplastic diseases (e.g. leukemia, lymphomas, solid tumors); transplant rejection, bone marrow transplant applications (e.g., graft- versus-host disease); autoimmune diseases (e.g.
  • rheumatoid arthritis multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus
  • erythematosus, dermatomyositis and blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa); respiratory inflammation diseases (e.g. asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis); skin inflammatory diseases (e.g., atopic dermatitis, contact dermatitis, eczema or psoriasis); premalignant and malignant skin conditions (e.g.
  • BCC basal cell carcinoma
  • SCC squamous cell carcinoma
  • AK actinic keratosis
  • neurological disorders and pain such as pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain
  • the combinations of the invention can optionally comprise one or more additional active substances which are known to be useful in the treatment of neoplastic diseases leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatiti
  • the combinations of the invention can optionally comprise one or more additional active substances which are known to be useful in the treatment of neoplastic diseases leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, type I diabetes, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and actinic keratosis
  • the combinations of the invention comprise (i) a compound of the invention as defined above; and (ii) another compound selected from the group consisting of an Adenoside A2A agonist, an agent for treating cardiovascular disorders, an agent for treating diabetes, and an agent for treating liver disease, an anti-allergic agent, an anticholinergic agent, an anti-inflammatory agent, an anti-infective agent, a p2-adrenergic agonist, a Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitor, a chemotherapeutic agent, a corticosteroid, an ⁇ / ⁇ (IkB kinase beta or IKK2) inhibitor, an immunosuppressant, a Janus kinase (JAK) inhibitor, a topically acting p38 Mitogen-Activated Protein Kinase (p38 MAPK) inhibitor, a
  • PDE Phosphosdiesterase
  • Spleen tyrosine kinase (Syk) inhibitor for simultaneous, separate or sequential use in the treatment of the human or animal body.
  • the combinations of the invention can optionally comprise one or more additional active substances selected from
  • Dyhydrofolate reductase inhibitors such as Methotrexate or CH- 1504;
  • DHODH Dihydroorotate dehydrogenase
  • Immunomodulators such as Glatiramer acetate (Copaxone),
  • Inhibitors of DNA synthesis and repair such as Mitoxantrone or Cladribine;
  • Immunosuppressants such as Imuran (azathioprine) or Purinethol (6-mercaptopurine or 6-MP);
  • Anti-alpha 4 integrin antibodies such as Natalizumab (Tysabri) ;
  • Alpha 4 integrin antagonists such as R-1295 , TBC-4746, CDP-323, ELND-002, Firategrast or TMC-2003;
  • Corticoids and glucocorticoids such as prednisone or
  • methylprednisolone fluticasone, mometasone, budesonide, ciclesonide or beta-metasone;
  • Fumaric acid esters such as BG-12
  • TNF-alpha Tumor necrosis factor-alpha Antagonists such as Ethanercept
  • Anti-CD20 (lymphocyte protein) monoclonal antibodies such as Rituximab, Ocrelizumab Ofatumumab or TRU-015;
  • Anti-CD52 lymphocyte protein monoclonal antibodies such as alemtuzumab
  • Anti-CD25 (lymphocyte protein) such as daclizumab
  • Anti-CD88 (lymphocyte protein), such as eculizumab or
  • IL-6R Anti-lnterleukin 6 Receptor
  • IL-12R Anti-lnterleukin 12 Receptor
  • IL- 23R Interleukin 23 Receptor
  • Inosine-monophosphate dehydrogenase (IMPDH) inhibitors such as mycophenolate mophetyl, ribavirin, mizoribine or mycophenolic acid;
  • Cannabinoid receptor agonists such as Sativex
  • Chemokine CCR1 antagonists such as MLN-3897 or PS-031291 ;
  • Chemokine CCR2 antagonists such as INCB-8696;
  • Necrosis factor-kappaB NF-kappaB or NFKB
  • Activation Inhibitors such as Sulfasalazine, Iguratimod or MLN-0415;
  • Adenosine A 2A agonists such as ATL-313, ATL-146e, CGS-21680,
  • S1 P Sphingosine-1 (S1 P) phosphate receptor agonists
  • S1 P Sphingosine-1 (S1 P) liase inhibitors such as LX2931 ;
  • Spleen tyrosine kinase (Syk) inhibitors such as R-1 12;
  • PKC Protein Kinase Inhibitors
  • Beta adrenergic agonists such as formoterol, indacaterol or
  • MABA molecules with dual activity: beta-adrenergic agonists and muscarinic receptor antagonists
  • Histamine 1 (H1 ) receptor antagonists such as azelastine or
  • CysLT Cysteinyl leukotriene
  • Mast cell stabilizers such as nedocromil or chromoglycate
  • FLAP 5-lipoxygenase-activating protein
  • 5-lipoxygenase (5-LO) inhibitors such as WY-50295T;
  • Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitors such as OC-459, AZD-1981 , ACT-129968, QAV-680; II) Vitamin D derivatives like calcipotriol (Daivonex) ;
  • Anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs) or selective cyclooxygenase-2 (COX-2) inhibitors such as aceclofenac, diclofenac, ibuprofen, naproxen, apricoxib, celecoxib, cimicoxib, deracoxib, etoricoxib, lumiracoxib, parecoxib sodium, rofecoxib, selenocoxib-1 or valdecoxib;
  • NSAIDs non-steroidal anti-inflammatory drugs
  • COX-2 selective cyclooxygenase-2
  • PDE Phosphosdiesterase
  • ss Xanthine derivatives, such as theophylline or theobromine
  • tt p38 Mitogen-Activated Protein Kinase (p38 MAPK) Inhibitors such as ARRY-797;
  • inhibitor such as ARRY-142886 or ARRY-438162
  • JK Janus kinase inhibitors
  • tofacitinib previously known as tasocitinib or CP-690,550
  • INCB-18424 from Incyte
  • Interferons comprising Interferon beta 1 a such as Avonex from
  • Interferon alpha such as Sumiferon MP
  • EGFR Epidermal Growth Factor Receptor
  • Antineoplastic agents such as Docetaxel, Estramustine, Anthracyc lines, (doxorubicin (Adriamycin), epirubicin (Ellence), and liposomal doxorubicin (Doxil)), Taxanes (docetaxel (Taxotere), paclitaxel (Taxol), and protein-bound paclitaxel (Abraxane)), Cyclophosphamide (Cytoxan), Capecitabine (Xeloda), 5 fluorouracil (5 FU), Gemcitabine (Gemzar) or Vinorelbine (Navelbine).
  • Antineoplastic agents such as Docetaxel, Estramustine, Anthracyc lines, (doxorubicin (Adriamycin), epirubicin (Ellence), and liposomal doxorubicin (Doxil)), Taxanes (docetaxel (Taxotere), paclitaxel (
  • the compounds of formula (I) and the combinations of the invention may be used in the treatment of 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 such as polycythemia vera, essential thrombocythemia or mielofibrosis); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors, wherein the use of a PI3K inhibitor is expected to have a beneficial effect, for example leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus ery
  • the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and actinic keratosis.
  • the active compounds in the combination product may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.
  • all active agents would be administered at the same time, or very close in time.
  • one or two actives could be administered in the morning and the other (s) later in the day.
  • one or two actives could be administered twice daily and the other (s) once daily, either at the same time as one of the twice-a-day dosing occurred, or separately.
  • at least two, and more preferably all, of the actives would be administered together at the same time.
  • at least two, and more preferably all actives would be administered as an admixture.
  • the invention also encompasses the use of a combination of the compounds of the invention together with one or more other therapeutic agents for the manufacture of a formulation or medicament for treating the above mentioned diseases.
  • the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is selected from respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection;
  • PI3Ks Phosphoinositide 3-Kinases
  • MPDs myeloproliferative disorders
  • mielofibrosis cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psorias
  • the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and actinic keratosis.
  • the active compounds in the combinations of the invention may be administered by any suitable route, depending on the nature of the disorder to be treated, e.g. orally (as syrups, tablets, capsules, lozenges, controlled-release preparations, fast-dissolving preparations, etc); topically (as creams, ointments, lotions, nasal sprays or aerosols, etc); by injection (subcutaneous, intradermic, intramuscular, intravenous, etc.) or by inhalation (as a dry powder, a solution, a dispersion, etc).
  • the active compounds in the combination i.e. the pyrrolotnazinone derivatives of the invention, and the other optional active compounds may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.
  • One execution of the present invention consists of a kit of parts comprising a pyrrolotnazinone derivative of the invention together with instructions for simultaneous, concurrent, separate or sequential use in combination with another active compound useful in the treatment of respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders;
  • cardiovascular diseases cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo- dysplastic syndrome; myeloproliferative disorders (MPDs such as polycythemia vera, essential thrombocythemia or mielofibrosis); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, asthma
  • the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and actinic keratosis.
  • Another execution of the present invention consists of a package comprising a pyrrolotnazinone derivative of the invention and another active compound useful in the treatment of 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 such as polycythemia vera, essential thrombocythemia or mielofibrosis); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis
  • the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and actinic keratosis.
  • compositions according to the present invention comprise the compounds of the invention in association with a pharmaceutically acceptable diluent or carrier.
  • the term pharmaceutical composition refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts, or N-oxides, or isotopically-labeled derivative thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • a physiologically/pharmaceutically acceptable diluent or carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • the invention further provides pharmaceutical compositions comprising the compounds of the invention in association with a pharmaceutically acceptable diluent or carrier together with one or more other therapeutic agents for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of
  • Phosphoinositide 3-Kinases such as the ones previously described.
  • the invention is also directed to pharmaceutical compositions of the invention for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is selected from respiratory diseases; allergic diseases;
  • PI3Ks Phosphoinositide 3-Kinases
  • inflammatory or autoimmune-mediated 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 such as polycythemia vera, essential thrombocythemia or mielofibrosis); cancer and
  • hematologic malignancies leukemia, lymphomas and solid tumors; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus
  • erythematosus dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and actinic keratosis.
  • pemphigus vulgaris bullous pemphigoid and epidermolysis bullosa
  • asthma chronic obstructive pulmonary disease
  • cystic fibrosis cystic fibrosis
  • idiopathic pulmonary fibrosis sarcoidosis
  • allergic rhinitis atopic dermatitis
  • contact dermatitis contact dermatitis
  • the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and actinic keratosis.
  • the invention also encompasses the use of a pharmaceutical composition of the invention for the manufacture of a medicament for treating these diseases.
  • the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Phosphoinositide 3-Kinases (PI3Ks), in particular wherein the pathological condition or disease is selected from respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated diseases; function disorders and neurological disorders; cardiovascular diseases; viral infection;
  • PI3Ks Phosphoinositide 3-Kinases
  • MPDs myeloproliferative disorders
  • mielofibrosis cancer and hematologic malignancies, leukemia, lymphomas and solid tumors; more in particular wherein the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psorias
  • compositions which comprise, as an active ingredient, at least a compound of formula (I) or a pharmaceutically acceptable salt, or N-oxide, or isotopically-labeled derivative thereof in association with a pharmaceutically acceptable excipient such as a carrier or diluent.
  • the active ingredient may comprise 0.001 % to 99% by weight, preferably 0.01 % to 90% by weight, of the composition depending upon the nature of the formulation and whether further dilution is to be made prior to application.
  • the compositions are made up in a form suitable for oral, inhalation, topical, nasal, rectal, percutaneous or injectable administration.
  • compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001 .
  • the pharmaceutically acceptable excipients which are admixed with the active compound or salts of such compound, to form the compositions of this invention are well-known per se and the actual excipients used depend inter alia on the intended method of administering the compositions. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • the compounds of the invention may be administered orally (peroral administration; per os (latin)). Oral administration involve swallowing, so that the compound is absorbed from the gut and delivered to the liver via the portal circulation (hepatic first pass metabolism) and finally enters the gastrointestinal (Gl) tract.
  • oral administration involve swallowing, so that the compound is absorbed from the gut and delivered to the liver via the portal circulation (hepatic first pass metabolism) and finally enters the gastrointestinal (Gl) tract.
  • compositions for oral administration may take the form of tablets, retard tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder inhalation, or liquid preparations, such as mixtures, solutions, elixirs, syrups or suspensions, all containing the compound of the invention; such preparations may be made by methods well-known in the art.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • the compounds of the invention can also be administered via the oral mucosal.
  • delivery of drugs is classified into three categories: (a) sublingual delivery, which is systemic delivery of drugs through the mucosal membranes lining the floor of the mouth, (b) buccal delivery, which is drug
  • the compounds of the invention can also be administered by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using
  • the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.
  • Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator.
  • Formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier substance) such as lactose or starch. Use of lactose is preferred.
  • a suitable powder base carrier substance
  • lactose or starch.
  • Each capsule or cartridge may generally contain between 0.001 -50 mg, more preferably 0.01-5 mg of active ingredient or the equivalent amount of a
  • the active ingredient (s) may be presented without excipients.
  • Packaging of the formulation may be suitable for unit dose or multi-dose delivery.
  • the formulation can be pre-metered or metered in use. Dry powder inhalers are thus classified into three groups: (a) single dose, (b) multiple unit dose and (c) multi dose devices.
  • inhalers of the first type single doses have been weighed by the manufacturer into small containers, which are mostly hard gelatine capsules.
  • a capsule has to be taken from a separate box or container and inserted into a receptacle area of the inhaler.
  • the capsule has to be opened or perforated with pins or cutting blades in order to allow part of the inspiratory air stream to pass through the capsule for powder entrainment or to discharge the powder from the capsule through these perforations by means of centrifugal force during inhalation.
  • the emptied capsule has to be removed from the inhaler again.
  • disassembling of the inhaler is necessary for inserting and removing the capsule, which is an operation that can be difficult and burdensome for some patients.
  • Some capsule inhalers have a magazine from which individual capsules can be transferred to a receiving chamber, in which perforation and emptying takes place, as described in WO 92/03175.
  • Other capsule inhalers have revolving magazines with capsule chambers that can be brought in line with the air conduit for dose discharge (e. g. WO91/02558 and GB 2242134). They comprise the type of multiple unit dose inhalers together with blister inhalers, which have a limited number of unit doses in supply on a disk or on a strip. Blister inhalers provide better moisture protection of the medicament than capsule inhalers. Access to the powder is obtained by perforating the cover as well as the blister foil, or by peeling off the cover foil.
  • Multi-dose inhalers do not contain pre-measured quantities of the powder formulation. They consist of a relatively large container and a dose measuring principle that has to be operated by the patient. The container bears multiple doses that are isolated individually from the bulk of powder by volumetric displacement.
  • compositions of the invention can be administered in aerosols which operate via propellant gases or by means of so-called atomisers, via which solutions of pharmacologically-active substances can be sprayed under high pressure so that a mist of inhalable particles results.
  • atomisers such as the Respimat® which is described, for example, in PCT Patent Applications Nos. W0 91/14468 and WO 97/12687, reference here is being made to the contents thereof.
  • Spray compositions for topical delivery to the lung by inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant.
  • Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the active ingredient (s) and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e. g.
  • dichlorodifluoromethane trichlorofluoromethane, dichlorotetra-fluoroethane, especially 1 ,1 , 1 , 2-tetrafluoroethane, 1 ,1 , 1 ,2, 3,3, 3- heptafluoro-n-propane or a mixture thereof.
  • Carbon dioxide or other suitable gas may also be used as propellant.
  • the aerosol composition may be excipient free or may optionally contain additional formulation excipients well known in the art such as surfactants (eg oleic acid or lecithin) and cosolvens (eg ethanol).
  • additional formulation excipients well known in the art such as surfactants (eg oleic acid or lecithin) and cosolvens (eg ethanol).
  • Pressurised formulations will generally be retained in a canister (eg an aluminium canister) closed with a valve (eg a metering valve) and fitted into an actuator provided with a mouthpiece.
  • Medicaments for administration by inhalation desirably have a controlled particle size.
  • the optimum particle size for inhalation into the bronchial system is usually 1 -10 ⁇ , preferably 2-5 ⁇ . Particles having a size above 20 ⁇ are generally too large when inhaled to reach the small airways.
  • the particles of the active ingredient as produced may be size reduced by conventional means eg by micronisation.
  • the desired fraction may be separated out by air classification or sieving.
  • the particles will be crystalline.
  • the particles should be large while in the inhaler, but small when discharged into the respiratory tract.
  • an excipient such as lactose or glucose is generally employed.
  • the particle size of the excipient will usually be much greater than the inhaled medicament within the present invention.
  • lactose it will typically be present as milled lactose, preferably crystalline alpha lactose monohydrate.
  • compositions for nasal mucosa administration are typically applied by a metering, atomizing spray pump and are in the form of a solution or suspension in an inert vehicle such as water optionally in combination with conventional excipients such as buffers, anti-microbials, tonicity modifying agents and viscosity modifying agents.
  • inert vehicle such as water
  • excipients such as buffers, anti-microbials, tonicity modifying agents and viscosity modifying agents.
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal,
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions.
  • Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
  • Other means of topical administration include delivery by electroporation, iontophoresis,
  • Compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. viii) Ocular Administration
  • Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH- adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable ⁇ e.g. absorbable gel sponges, collagen) and nonbiodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example,
  • hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. ix) Other Technologies
  • Compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • the amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is typically in the range of 0.01-3000 mg, more preferably 0.5-1000 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof per day. Daily dosage may be administered in one or more treatments, preferably from 1 to 4 treatments, per day.
  • the pharmaceutical compositions of the invention are made up in a form suitable inhaled or topical administration, being particularly preferred the inhaled administration.
  • compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
  • each active which is required to achieve a therapeutic effect will, of course, vary with the particular active, the route of administration, the subject under treatment, and the particular disorder or disease being treated.
  • Citric acid 0,5 g

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Abstract

L'invention concerne de nouveaux dérivés de pyrrolotriazinone ayant la structure chimique de formule (I) ; ainsi qu'un procédé pour leur préparation, des compositions pharmaceutiques les comprenant et leur utilisation en thérapie en tant qu'inhibiteurs de phosphoïnositides 3-kinases (PI3K).
PCT/EP2016/063635 2015-06-16 2016-06-14 Dérivés de pyrrolotriazinone en tant qu'inhibiteurs de pi3k Ceased WO2016202800A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112028892A (zh) * 2020-07-29 2020-12-04 天津全和诚科技有限责任公司 4-氨基-吡咯并三嗪衍生物在制备抗肺纤维化制剂中的应用
CN114560876A (zh) * 2021-01-26 2022-05-31 浙江永太科技股份有限公司 一种瑞德西韦有关物质及其制备方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112028892A (zh) * 2020-07-29 2020-12-04 天津全和诚科技有限责任公司 4-氨基-吡咯并三嗪衍生物在制备抗肺纤维化制剂中的应用
CN114560876A (zh) * 2021-01-26 2022-05-31 浙江永太科技股份有限公司 一种瑞德西韦有关物质及其制备方法

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