WO2017103825A1 - Dérivés de quinolizinone utilisés comme inhibiteurs de pi3k - Google Patents

Dérivés de quinolizinone utilisés comme inhibiteurs de pi3k Download PDF

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WO2017103825A1
WO2017103825A1 PCT/IB2016/057635 IB2016057635W WO2017103825A1 WO 2017103825 A1 WO2017103825 A1 WO 2017103825A1 IB 2016057635 W IB2016057635 W IB 2016057635W WO 2017103825 A1 WO2017103825 A1 WO 2017103825A1
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amino
alkyl
compound
quinolizin
oxo
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PCT/IB2016/057635
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English (en)
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Manojkumar Ramprasad SHUKLA
Nirmal Kumar JANA
Sachin Jaysing Mahangare
Prashant Popatrao VIDHATE
Dipak Raychand LAGAD
Anand Jagannath TARAGE
Sanjeev Anant Kulkarni
Venkata P. Palle
Rajender Kumar Kamboj
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Lupin Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring 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
    • 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

Definitions

  • the present invention relates to quinolizinone derivatives, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, combinations with suitable medicament, pharmaceutical compositions containing them, methods of making of quinolizinone derivatives, and their use as PI3K inhibitor.
  • Oncogenic cellular transformation and cancer is associated with enhanced PI3K signalling as a result of mutational activation and overexpression of class I PI3K and genetic or epigenetic inactivation of PTEN (Ali et al. , J. Natl Cancer Inst 1991 , 1922-1932; Cantley et al. , Science 2002, 296, 1655-1657; Campbell et al , Cancer Res. 2004, 64, 7678-7681 ; Cully et al, Nat. Rev. Cancer 2006, 6, 184-192; Vogt et al. , Trends Biochem. Set 2007, 32, 342- 349) .
  • Phosphatidylinositol 3-kinases a family of lipid enzymes catalyzes the phosphorylation of the 3-OH of the inositol ring. It has a central role in regulating a wide range of cellular processes including metabolism, survival, motility, differentiation and cell activation (Vanhaesebroeck et al, Annu. Rev. Biochem. 2001 , 70, 535). Its estimated that PI3K signalling pathway has 50-100 downstream effectors in every eukaryotic cell. These lipid enzymes are classified into 3 major classes, I, II & III, based on their structure and in vitro substrate specificity (Wymann M.
  • PI3K kinases include four isoforms: PI3K ⁇ , ⁇ , ⁇ and ⁇ . Both PI3K a and PI3K ⁇ are known to be expressed ubiquitously, while PI3K ⁇ and PI3K ⁇ are restricted mainly to hematopoietic cells (Vanhaesebroeck et al , Proc. Natl Acad. Set USA 1997, 94, 4330-4335). The catalytic subunit of the pi 10a, ⁇ ⁇ and pi 10 ⁇ isoforms is constitutively bound to a p85 regulatory subunit.
  • PI3K pathway is not only via RTKs, but also by RAS and GPCR (Irene Brana and Lillian L Siu. , BMC Medicine 2012, 10, 161).
  • RAS protein is by direct interaction with pi 10a, ⁇ ⁇ , and ⁇ ⁇ subunits, while GPCRs can interact with ⁇ ⁇ and ⁇ ⁇ ⁇ subunits (Vanhaesebroeck et al. , Nat. Rev. Mol. Cell Biol. 2010, 1 1, 329-341).
  • the mode of regulation by upstream signalling also differs among the four PI3K isoforms.
  • the ⁇ isoform is linked to G protein-coupled receptors, whereas the PI3K a and PI3K ⁇ isoforms are activated by signals from receptor tyrosine kinases.
  • the PI3K ⁇ isoform can accept input from both receptor tyrosine kinases and from G protein-coupled receptors (Kang et al, Proc. Natl. Acad. Sci. USA 2006, 103, 1289-94).
  • PI3K activity is functionally antagonized by phosphatase and tensin homolog (PTEN) , a tumor suppressor gene that encodes a lipid phosphatase that removes the phosphate from the 3-OH position of 3-phosphoinositides, reducing the cellular pool of PI(3,4,5)P3 by converting it back to PI(4,5)P2 (Liu et al. , Nat. Rev. Drug Discov. 2009, 8, 627-44). Loss of PTEN expression has been shown to activate the PI3K/Akt/mTOR pathway and also correlates with poor prognosis and thereby reduced survival in human cancer (LoPiccolo et al , Drug Resist. Updat. 2008, 11 , 32-50).
  • PTEN tensin homolog
  • PIK3CA mutations are reported in several cancer types, including glioblastoma multiforme, breast cancer, endometrial cancer, colorectal cancer and hepatocellular carcinoma. PIK3CA mutations are oncogenic per se promoting tumor formation in several preclinical models without other molecular aberrations (Ikenoue et al , Cancer Res. 2005, 65, 4562-4567; Isakoff et al , Cancer Res. 2005, 65, 10992- 1 1000; Zhao et al , Proc. Natl. Acad. Set USA 2005, 102, 18443- 18448). PI3Ka is the most frequently found mutated isoform in human cancers.
  • exon 9 in the helical domain of pi 10a are common in colorectal cancer
  • exon 20 in the kinase domain of pi 10a are common in uterine, breast cancer and ovarian cancers (Janku et al, PLOS One 201 1 , 7, 6).
  • the non-alpha isoforms of class I PI3K have no cancer-specific mutations, but their differential expression has been observed in several cancers. Reported data also suggests involvement of non-alpha isoforms of class I PI3K in solid tumors.
  • Recent studies show that certain PTEN- deficient human cancer cell lines are sensitive to inactivation of pi 10 ⁇ rather than pi 10a (Wee et al. , Proc. Natl Acad. Set USA 2008, 105, 13057-62; Torbett et al , Biochem. J. 2008, 415, 97-1 10). In vivo studies however suggest that pi 10 ⁇ isoform-specific targeting may be cytotoxic to B cells with minimal toxicity to other hematopoietic cell types.
  • ⁇ ⁇ is specifically overexpressed in human pancreatic intraepithelial neoplasia and ductal carcinoma, which correlates with increased levels of PIP3 and phosphorylated Akt (Edling et al., Clin. Cancer Res. 2010, 16, 4928-4937; El Haibi et al, Mol. Cancer 2010, 9, 85). Increased expression of pi 10 ⁇ is also seen in chronic myeloid leukemia (Hickey and Cotter. , J. Biol. Chem. 2006, 281, 2441-50; Knobbe et al. , Neuropatnol. Appl. Neurobiol. 2005, 31 , 486-90).
  • class I PI3Ks are involved in survival mechanism and progression of many cancer types and therefore is one among the most sought after targets in cancer therapeutics. So, targeting PI3K itself or downstream effectors of PI3K is an approach that has the potential to be of huge therapeutic benefit.
  • the present invention provides a compound of formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its combination with suitable medicament, its pharmaceutical composition and its use as PI3K inhibitor
  • R 1 is selected from substituted- or unsubstituted- heteroaryl, -0-R la and -NH- R la ; wherein each R la independently is substituted- or unsubstituted- heteroaryl;
  • R 3 is selected from hydrogen, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstituted- cycloalkenyl;
  • R 4 is independently selected at each occurrence from halogen, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or unsubstituted-heterocycle, substituted- or unsubstituted- carbocycle, and -OR 6 ;
  • R 6 is substituted- or unsubstituted- alkyl
  • R 7 and R 8 are each independently selected from hydrogen and substituted- or unsubstituted- alkyl
  • n is an integer selected from 0 to 2;
  • n is an integer selected from 1 , 2, 3, and 4;
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I) and a pharmaceutically acceptable carrier.
  • the invention provides a method of treating or preventing a disorder responsive to the inhibition of PI3K activity in a mammal suffering therefrom, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) .
  • the present invention provides a compound of formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its combination with suitable medicament, its pharmaceutical composition and its use as PI3K inhibitor
  • R 1 is selected from substituted- or unsubstituted- heteroaryl, -0-R l and -NH- R la ; wherein each R la independently is substituted- or unsubstituted- heteroaryl;
  • R 3 is selected from hydrogen, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstituted- cycloalkenyl;
  • R 4 is independently selected at each occurrence from halogen, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or unsubstituted- heterocycle, substituted- or unsubstituted- carbocycle, and -OR 6 ;
  • R 6 is substituted- or unsubstituted- alkyl
  • R 7 and R 8 are each independently selected from hydrogen and substituted- or unsubstituted- alkyl
  • n is an integer selected from 0 to 2;
  • n is an integer selected from 1 , 2, 3, and 4;
  • each R 9 independently is selected from the group consisting of alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
  • each R 9b independently is selected from the group consisting of hydrogen, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
  • R 9c is selected from the group consisting of alkyl, hydroxylalkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl.
  • R 1 is -NH-R la ; wherein R la is substituted- or unsubstituted- heteroaryl.
  • R 1 is -NH-R la ; wherein R la is selected from
  • R A is selected from hydrogen and amino; and R B is selected from hydrogen and alkyl.
  • R 2 is substituted- or unsubstituted- alkyl.
  • R 2 is methyl
  • R 3 is selected from hydrogen, substituted- or unsubstituted- alkyl, and substituted- or unsubstituted- aryl.
  • R 3 is selected from hydrogen, methyl, and phenyl optionally substituted by halogen.
  • R 4 is halogen
  • R 4 is fluorine
  • n is an integer selected from 0 and 1.
  • the present invention provides a compound of the general formula (la), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt,
  • R 1A is -NH-R la ; wherein R la is substituted- or unsubstituted- heteroaryl;
  • R ⁇ is substituted- or unsubstituted- alkyl
  • R 3A is selected from hydrogen, substituted- or unsubstituted- alkyl, and substituted- or unsubstituted- aryl;
  • n is an integer selected from 0 and 1 ;
  • each R 9 independently is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
  • each R 9a independently is selected from the group consisting of alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl; and each R 9b independently is selected from the group consisting of hydrogen, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl.
  • the present invention provides a compound of the general formula (lb), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt,
  • R 1B is -NH-R la wherein R la is substituted- or unsubstituted- heteroaryl; R 2B is substituted- or unsubstituted- alkyl;
  • R 3B is substituted- or unsubstituted- aryl
  • R 4B is halogen
  • R 5B is substituted- or unsubstituted- aryl
  • n is an integer selected from 0 and 1 ;
  • each R 9 independently is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl; each R 9a independently is selected from the group consisting of alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl; and
  • each R 9b independently is selected from the group consisting of hydrogen, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl.
  • R 1A and R 1B is -NH-R la ; wherein R la is selected from
  • alkyl' means a straight chain or branched hydrocarbon containing from 1 to 20 carbon atoms.
  • the alkyl chain may contain 1 to 10 carbon atoms. More preferably alkyl chain may contain up to 6 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.
  • alkenyl' means an alkyl group containing at least one double bond.
  • perhaloalkyl' means an alkyl group as defined hereinabove wherein all the hydrogen atoms of the said alkyl group are substituted with halogen.
  • the perhaloalkyl group is exemplified by trifiuoromethyl, pentafiuoroethyl, and the like.
  • 'amino' means -NH 2 .
  • 'cycloalkyl' as used herein, means a monocyclic, bicyclic, or tricyclic non-aromatic ring system containing from 3 to 14 carbon atoms, preferably monocyclic cycloalkyl ring containing 3 to 6 carbon atoms.
  • monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl cycloheptyl, and cyclooctyl.
  • Bicyclic ring systems include monocyclic ring system fused across a bond with another cyclic system which may be an alicyclic ring or an aromatic ring.
  • Bicyclic rings also include spirocyclic systems wherein the second ring gets annulated on a single carbon atom.
  • Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge.
  • Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3. 1. l]heptane,bicyclo[2.2. l]heptane,bicyclo[2.2.2]octane,bicyclo[3.2.2]no nane,bicyclo[3.3. l]nonane, and bicyclo[4.2.
  • Tricyclic ring systems are the systems wherein the bicyclic systems as described above are further annulated with third ring, which may be an alicyclic ring or aromatic ring. Tricyclic ring systems are also exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3. 1.0 3 7 ]nonane, and tricyclo[3.3. 1.1 3 7 ]decane (adamantane).
  • 'cycloalkenyl' means a cycloalkyl group containing at least one double bond.
  • 'carbocycle' means a cyclic system made up of carbon atoms, which includes cycloalkyl, cycloalkenyl and aryl.
  • 'aryl' refers to a monovalent monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system.
  • aryl groups include phenyl, naphthyl, anthracenyl, fiuorenyl, indenyl, azulenyl, and the like.
  • Aryl group also include partially saturated bicyclic and tricyclic aromatic hydrocarbons, e.g., tetrahydro-naphthalene.
  • heteroaryT refers to a 5- 14 membered monocyclic, bicyclic, or tricyclic ring system having 1-4 ring heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon (with appropriate hydrogen atoms unless otherwise indicated), wherein at least one ring in the ring system is aromatic.
  • Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1 , 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent.
  • heteroaryl groups include, but not limited to, pyridyl, 1-oxo- pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, benzoxazolyl, benzofuranyl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl,
  • 'heterocycle' or 'heterocyclic' or 'heterocyclyl' means a 'cycloalkyl' group wherein one or more of the carbon atoms replaced by heteroatom selected from N, S and O.
  • the heterocycle may be connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocycle.
  • monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1 ,3-dioxanyl, 1 ,3-dioxolanyl, 1 ,3-dithiolanyl, 1 ,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothi
  • bicyclic heterocycle include, but are not limited to, 1 ,2,3,4-tetrahydroisoquinolin-2-yl, 1 ,2,3,4-tetrahydroquinolin- 1-yl, 1 ,3- benzodioxolyl, 1 ,3-benzodithiolyl, 2,3-dihydro- 1,4-benzodioxinyl, 2,3-dihydro- 1- benzofuranyl, 2,3-dihydro- l-benzothienyl, 2,3-dihydro- lH-indolyl, and 1 ,2,3,4- tetrahydroquinolinyl.
  • heterocycle also includes bridged and spiro heterocyclic systems such as azabicyclo[3.2. l]octane, azabicyclo[3.3. l]nonane, 8-oxa-3-azabicyclo[3.2. l]octan-3-yl, 3-oxa-8-azabicyclo[3.2. l]octan-8-yl, 6-oxa- 3-azabicyclo[3.1. l]heptan-3-yl,8-azabicyclo[3.2. l]octan-8-yl,3- azabicyclo[3.2. l]octan-3-yl, 3-azabicyclo[3.
  • oxo attached to carbon forms a carbonyl
  • oxo substituted on cyclohexane forms a cyclohexanone, and the like.
  • 'annulated' means the ring system under consideration is either annulated with another ring at a carbon atom of the cyclic system or across a bond of the cyclic system as in the case of fused or spiro ring systems.
  • bridged' means the ring system under consideration contain an alkylene bridge having 1 to 4 methylene units joining two non-adjacent ring atoms.
  • a range of the number of atoms in a structure is indicated (e.g. , a Ci to C20 alkyl, C2 to C20 alkenyl etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used.
  • a range of 1-6 carbon atoms e.g., Ci to Ce
  • 2-6 carbon atoms e.g., C2 to Ce
  • 3-6 carbon atoms e.g., C3 to Ce
  • alkyl, alkenyl, etc. referenced herein encompasses and specifically describes 1 , 2, 3, 4, 5, and/ or 6 carbon atoms, as appropriate, as well as any sub-range thereof (e.g. , 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms as appropriate).
  • the invention provides a compound, its stereoisomers, racemates, and pharmaceutically acceptable salt thereof as described hereinabove wherein the compound of general formula (I) is selected from: (S)-4-amino-6-((l-(7-fluoro- l-(4-fluorophenyl)-4-oxo-3-phenyl-4H- quinolizin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (Compound 1);
  • the pyridine carboxyldehyde compound of formula (ii) undergoes Wittig reaction with phosphate compound of formula (iii) to give compound of formula (iv) which undergoes cyclization with suitable reagent such as p-TSA, PPA to give quinolizin-4-one compound of formula (vi).
  • suitable reagent such as p-TSA, PPA to give quinolizin-4-one compound of formula (vi).
  • the compound of formula (iv) may also undergo hydrolysis with basic condition such as NaOH, KOH etc. to give compound of formula (v) .
  • Cyclization of compound of formula (v) with EDC.HCl/HOBt/NEt 3 or HATU/DIPEA gives the compound of formula (vi).
  • Bromination of compound of formula (vi) with NBS gives compound of formula (vii) which undergoes Suzuki coupling with boronic acid compound of formula
  • the compounds of formula (I) wherein R 5 is halogen (CI or F) are prepared same as compound of formula (xv) from compound of formula (xiv) with NCS or n-fiuorobenzene sulfonimide.
  • the compound of formula (xv) undergoes Suzuki coupling with boronic acid (xvi) to give compound of formula (I).
  • compound of formula (xii) undergoes Boc protection and bromination with NBS to give the compound of formula (xvii).
  • the compound of formula (xvii) undergoes Suzuki coupling with boronic acid (xvi) and which further undergoes Boc deprotection to form intermediate of formula (xviii) which couples with the compound of formula (xiii) to give compound of formula (I) .
  • the compound of formula (vi) was treated with ethylene glycol and BF3.Et 2 0 to form the cyclic acetal compound of formula (xix) which is brominated with NBS to form bromo intermediate compound of formula (xx).
  • the compound of formula (xx) undergoes Suzuki coupling with methylboronic acid to form compound (xxi) which undergoes deprotection with HC1 (hydrochloric acid) to form compound (xxii).
  • the compound of formula (xxii) reacts with (S)-sulfinamide to form imine (xxiii) which undergoes reductive animation with NaBH 4 followed by crystallization to give chiral compound (xxiv).
  • the compound of formula (xxiv) undergoes hydrolysis with hydrochloric acid to give compound of formula (xxv) .
  • the compound of formula (xxv) couples with R la -Cl (xiii) to form compound of formula (xxvi) which undergoes bromination with NBS to form compound of formula (xxvii) .
  • Suzuki coupling of compound (xxvii) with R 5 -B(OH) 2 (xvi) gives compound of formula (I), wherein R 3 is alkyl.
  • the compounds of formula (I), wherein R 1 is -NH-R la , R 3 is hydrogen, R 2 , R 4 and R 5 are as defined herein above, are prepared by the following procedure depicted in Scheme - 3.
  • the intermediates and the compounds of the present invention can be obtained in a pure form in any manner known per se, for example, by distilling off the solvent in vacuum and/or re-crystallizing the residue obtained from a suitable solvent, such as pentane, diethyl ether, isopropyl ether, chloroform, dichlorome thane, ethyl acetate, acetone or their combinations or subjecting it to one of the purification methods, such as column chromatography (e.g. flash chromatography) on a suitable support material such as alumina or silica gel using an eluent such as dichloromethane, ethyl acetate, hexane, methanol, acetone and their combinations.
  • a suitable solvent such as pentane, diethyl ether, isopropyl ether, chloroform, dichlorome thane, ethyl acetate, acetone or their combinations
  • the purification methods such as column chromatography (e
  • work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate, filtration and evaporation of the solvent.
  • Purification includes purification by silica gel chromatographic techniques, generally using a mobile phase with suitable polarity.
  • Salts of compound of formula (I) can be obtained by dissolving the compound in a suitable solvent, for example in a chlorinated hydrocarbon, such as methyl chloride or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol, which was then treated with the desired acid or base as described in Berge S.M. et al., "Pharmaceutical Salts, a review article in Journal of Pharmaceutical sciences volume 66, page 1- 19 (1977)" and in “Handbook of Pharmaceutical Salts - Properties, Selection, and Use," by P. H. Einrich Stahland Camille G.wermuth, Wiley- VCH (2002).
  • a suitable solvent for example in a chlorinated hydrocarbon, such as methyl chloride or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol
  • the salt can be of an alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g. , calcium), or ammonium.
  • alkali metal e.g., sodium or potassium
  • alkaline earth metal e.g. , calcium
  • ammonium e.g., sodium or potassium
  • the compounds of the invention or a composition thereof can potentially be administered as a pharmaceutically acceptable acid-addition, base neutralized or addition salt, formed by reaction with inorganic acids, such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base, such as sodium hydroxide, potassium hydroxide.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, mal
  • the conversion to a salt is accomplished by treatment of the base compound with at least a stoichiometric amount of an appropriate acid.
  • the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol, methanol, and the like, and the acid is added in a similar solvent.
  • the mixture is maintained at a suitable temperature (e.g., between 0 °C and 50 °C).
  • the resulting salt precipitates spontaneously or can be brought out of solution with a less polar solvent.
  • stereoisomers of the compounds of formula (I) of the present invention may be prepared by stereospecific syntheses or resolution of racemic compound using an optically active amine, acid or complex forming agent, and separating the diastereomeric salt/complex by fractional crystallization or by column chromatography.
  • the compounds of formula (I) of the present invention can exist in tautomeric forms, such as keto-enol tautomers. Such tautomeric forms are contemplated as an aspect of the present invention and such tautomers may be in equilibrium or predominant in one of the forms.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising compounds of the general formula (I) as defined above, its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.
  • the present invention further provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, its tautomeric forms, its stereoisomers, and its pharmaceutically acceptable salts in combination with the usual pharmaceutically acceptable carriers, diluents, excipients, and the like.
  • the pharmaceutically acceptable carrier or excipient is preferably one that is chemically inert to the compound of the invention and one that has no detrimental side effects or toxicity under the conditions of use.
  • Such pharmaceutically acceptable carriers or excipients include saline (e.g. , 0.9% saline), Cremophor EL ® (which is a derivative of castor oil and ethylene oxide available from Sigma Chemical Co., St.
  • a preferred pharmaceutical carrier is polyethylene glycol, such as PEG 400, and particularly a composition comprising 40% PEG 400 and 60% water or saline. The choice of carrier will be determined in part by the particular compound chosen, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention.
  • compositions for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, intrathecal, intraperitoneal, rectal, and vaginal administration are merely exemplary and are in no way limiting.
  • compositions for parenteral administration that comprise a solution of the compound of the invention dissolved or suspended in an acceptable carrier suitable for parenteral administration, including aqueous and non-aqueous, isotonic sterile injection solutions.
  • compositions include solutions containing anti- oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol (for example in topical applications), or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, dimethylsulf oxide, glycerol ketals, such as 2,2-dimethyl- l ,3-dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose
  • Oils useful in parenteral formulations include petroleum, animal, vegetable, and synthetic oils. Specific examples of oils useful in such formulations include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral oil. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl- -aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
  • the parenteral formulations typically will contain from about 0.5% or less to about 25% or more by weight of a compound of the invention in solution. Preservatives and buffers can be used. In order to minimize or eliminate irritation at the site of injection, such compositions can contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • HLB hydrophile-lipophile balance
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.
  • Topical formulations including those that are useful for transdermal drug release, are well known to those of skill in the art and are suitable in the context of the present invention for application to skin.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of a compound of the invention dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a pre-determined amount of the compound of the invention, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations can include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients.
  • Lozenge forms can comprise the compound ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising a compound of the invention in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the compound of the invention, such excipients as are known in the art.
  • a compound of the present invention, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation.
  • a compound or epimer of the invention is preferably supplied in finely divided form along with a surfactant and propellant.
  • Typical percentages of the compounds of the invention can be about 0.01% to about 20% by weight, preferably about 1% to about 10% by weight.
  • the surfactant must, of course, be nontoxic, and preferably soluble in the propellant.
  • Representative of such surfactants are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride.
  • Mixed esters, such as mixed or natural glycerides can be employed.
  • the surfactant can constitute from about 0.
  • compositions 1% to about 20% by weight of the composition, preferably from about 0.25% to about 5%.
  • the balance of the composition is ordinarily propellant.
  • a carrier can also be included as desired, e.g. , lecithin, for intranasal delivery.
  • aerosol formulations can be placed into acceptable pressurized propellants, such as dichlorodifiuoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer. Such spray formulations can be used to spray mucosa.
  • the compounds of the invention can be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases.
  • bases such as emulsifying bases or water-soluble bases.
  • Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the compound ingredient, such carriers as are known in the art to be appropriate.
  • the concentration of the compound in the pharmaceutical formulations can vary, e.g., from less than about 1% to about 10%, to as much as about 20% to about 50% or more by weight, and can be selected primarily by fluid volumes, and viscosities, in accordance with the particular mode of administration selected.
  • a typical pharmaceutical composition for intravenous infusion could be made up to contain 250 ml of sterile Ringer's solution, and 100 mg of at least one compound of the invention.
  • Actual methods for preparing parenterally administrable compounds of the invention will be known or apparent to those skilled in the art and are described in more detail in, for example, Remington's Pharmaceutical Science (17 th ed., Mack Publishing Company, Easton, PA, 1985).
  • the compound of the invention can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes.
  • Liposomes can serve to target a compound of the invention to a particular tissue, such as lymphoid tissue or cancerous hepatic cells. Liposomes can also be used to increase the half-life of a compound of the invention. Many methods are available for preparing liposomes, as described in, for example, Szoka et al., Ann. Rev. Biophys. Bioeng., 9, 467 (1980) and U.S. Patents 4,235,871, 4,501 ,728, 4,837,028, and 5,019,369.
  • the compounds of the invention can be administered in a dose sufficient to treat the disease, condition or disorder.
  • doses are known in the art (see, for example, the Physicians' Desk Reference (2004)).
  • the compounds can be administered using techniques such as those described in, for example, Wasserman et al. , Cancer, 36, pp. 1258- 1268 (1975) and Physicians' Desk Reference, 58th ed., Thomson PDR (2004).
  • Suitable doses and dosage regimens can be determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound of the present invention. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the present method can involve the administration of about 0. 1 to about 50 mg of at least one compound of the invention per kg body weight of the individual. For a 70 kg patient, dosages of from about 10 g to about 200 mg of the compound of the invention would be more commonly used, depending on a patient's physiological response.
  • the dose of the pharmaceutically active agent(s) described herein for methods of treating or preventing a disease or condition as described above can be about 0.001 to about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg, 0.002 mg, 0.005 mg, 0.010 mg, 0.015 mg, 0.020 mg, 0.025 mg, 0.050 mg, 0.075 mg, 0.1 mg, 0. 15 mg, 0.2 mg, 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg/kg body weight per day.
  • the dose of the pharmaceutically active agent(s) described herein for the described methods can be about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 0.020 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 750 mg, or 1000 mg/kg body weight per day.
  • Another aspect of the present invention is provision of a method of treatment or prevention of a disorder responsive to the inhibition of PI3K activity in a mammal suffering therefrom, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I), (la), or (lb).
  • Another aspect of the present invention is provision of a method of treating or preventing a disorder responsive to the inhibition of PI3K activity in a mammal suffering therefrom, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I), (la), or (lb), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt.
  • PI3K inhibitors reported herein can be used for the treatment of diseases and/or disorders that include but are not limited to cancer, inflammatory disorders or auto-immune disorders. PI3K inhibitors mentioned herein can be used as single agents and/or in combination with other chemotherapeutic agents.
  • Cancers that can be treated and/or prevented with PI3K inhibitors include but are not, limited to acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS-related (e.g. Lymphoma and Kaposi's Sarcoma) or viral-induced cancer.
  • AIDS-related e.g. Lymphoma and Kaposi's Sarcoma
  • said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g. , psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
  • a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g. , psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
  • the disclosure provides to a method of treating a hyperproliferative disorder in a subject that comprises administering to said subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable form (e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives) thereof, or pharmaceutical compositions as provided herein.
  • a pharmaceutically acceptable form e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives
  • said method relates to the treatment of cancer such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS- related (e.g., Lymphoma and Kaposi's Sarcoma) or viral-induced cancer.
  • cancer such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian, prostate
  • said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e. g. , benign prostatic hypertrophy (BPH)).
  • a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e. g. , benign prostatic hypertrophy (BPH)).
  • Patients that can be treated with compounds, or a pharmaceutically acceptable form (e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives) thereof, or pharmaceutical compositions as provided herein, according to the methods as provided herein include, for example, but not limited to, patients that have been diagnosed as having psoriasis; restenosis; atherosclerosis; BPH; breast cancer such as a ductal carcinoma in duct tissue in a mammary gland, medullary carcinomas, colloid carcinomas, tubular carcinomas, and inflammatory breast cancer; ovarian cancer, including epithelial ovarian tumors such as adenocarcinoma in the ovary and an adenocarcinoma that has migrated from the ovary into the abdominal cavity; uterine cancer; cervical cancer such as adenocarcinoma in the cervix epithelial including squamous cell carcinoma and adenocarcinomas; prostate
  • blastic plasmacytoid dendritic cell neoplasm acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and myelodysplasia syndrome (MDS); bone cancer; lung cancer such as non-small cell lung cancer (NSCLC), which is divided into squamous cell carcinomas, adenocarcinomas, and large cell undifferentiated carcinomas, and small cell lung cancer; skin cancer such as basal cell carcinoma, melanoma, squamous cell carcinoma and actinic keratosis, which is a skin condition that sometimes develops into squamous cell carcinoma; eye retinoblastoma; cutaneous or intraocular (eye) melanoma; primary liver cancer (cancer that begins in the liver); kidney cancer; thyroid cancer such as papillary, follicular, medullary and ana
  • central nervous system cancers such as primary brain tumor, which includes gliomas (astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme), Oligodendroglioma, Ependymoma, Meningioma, Lymphoma, Schwannoma, and Medulloblastoma; peripheral nervous system (PNS) cancers such as acoustic neuromas and malignant peripheral nerve sheath tumor (MPNST) including neurofibromas and schwanno
  • Exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, haemolytic autoimmune anaemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gout flare, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter's arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus,
  • gastrointestinal disorder e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis) and inflammatory
  • the inflammatory disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis and prostatistis.
  • the inflammatory condition is an acute inflammatory condition (e.g. , for example, inflammation resulting from infection).
  • the inflammatory condition is a chronic inflammatory condition (e.g., conditions resulting from asthma, arthritis and inflammatory bowel disease).
  • the compounds can also be useful in treating inflammation associated with trauma and non-inflammatory myalgia.
  • Immune disorders include, but are not limited to, arthritis(including rheumatoid arthritis, spondyloarthopathies, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amylosis, acute painful shoulder, psoriatic, and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), enuresis, eosinophilic disease, gastrointestinal disorder (e.g., selected from peptic ulcers,
  • relapsing polychondritis e.g., atrophic polychondritis and systemic polychondromalacia
  • a gastroprokinetic agent e.g., ileus, postoperative ileus and ileus during sepsis; gastroesophageal reflux disease (GORD, or its synonym GERD
  • GORD gastroesophageal reflux disease
  • GERD gastroesophageal reflux disease
  • GERD eosinophilic esophagitis
  • gastroparesis such as diabetic gastroparesis
  • food intolerances and food allergies and other functional bowel disorders such as nonulcerative dyspepsia (NUD) and non-cardiac chest pain (NCCP, including costochondritis)
  • a method of treating inflammatory or autoimmune diseases comprising administering to a subject (e.g., a mammal) a therapeutically effective amount of a compound, or a pharmaceutically acceptable form (e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives) thereof, or pharmaceutical compositions as provided herein.
  • a subject e.g., a mammal
  • a pharmaceutically acceptable form e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives
  • Further aspect of the present invention is provision of a compound formula (I), (la), or (lb), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt, for use in treating or preventing a disorder responsive to the inhibition of ⁇ 3 ⁇ and PI3K5 activity in a mammal suffering therefrom, wherein said disorder is cancer, inflammatory disorders or autoimmune disorders.
  • Yet another aspect of the present invention is provision of a compound formula (I), (la), or (lb), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt, for use in treating or preventing a disorder responsive to the inhibition of PI3K5 activity in a mammal suffering therefrom.
  • Further aspect of the present invention is provision of a compound formula (I), (la), or (lb), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt, for use in treating or preventing a disorder responsive to the inhibition of PI3K5 activity in a mammal suffering therefrom, wherein said disorder is cancer, inflammatory disorders or auto-immune disorders.
  • treat do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect.
  • the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal.
  • a disorder, including symptoms or conditions thereof may be reduced by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%.
  • the treatment, prevention, amelioration, or inhibition provided by the inventive method can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer.
  • treatment,” “prevention,” “amelioration,” or “inhibition” can encompass delaying the onset of the disorder, or a symptom or condition thereof.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and! or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • an appropriate "effective" amount in any individual case is determined using techniques, such as a dose escalation study.
  • the term subject includes an "animal" which in turn includes a mammal such as, without limitation, the order Rodentia, such as mice, and the order Lagomorpha, such as rabbits.
  • the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs) .
  • the mammals are from the order Artiodactyla, including Bovines (cows) and Swine (pigs) or of the order Perssodactyla, including Equines (horses).
  • the mammals are of the order Primates, Ceboids, or Simoids (monkeys) or of the order Anthropoids (humans and apes).
  • the mammal is human.
  • the term "patient” encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non- mammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • Another aspect of the present invention is a pharmaceutical composition of compound of formula (I), (la), or (lb) in combination with at least one other known anticancer agent, or a pharmaceutically acceptable salt of said agent.
  • Step-2 Preparation of 3-((5-fiuoropyridin-2-yl)methylene)-4-oxopentanoic acid
  • Step-5 Preparation of 2-Acetyl-7-fiuoro-3- henyl-4H-quinolizin-4-one
  • Step-6 Preparation of (S)-N-(l-(7-fiuoro-4-oxo-3-phenyl-4H-quinolizin-2- yl) ethylidene) - 2-methylpropane- 2- sulfanamide
  • the combined organic layer was filtered through Celite bed and the bed was washed with DCM, the combined filtrate was then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product.
  • the crude product was purified by flash column chromatography which yielded N-( l-(7-fiuoro-4-oxo-3-phenyl-4H-quinolizin-2-yl)ethylidene)-2-methylpropane- 2-sulfinamide (66 g, 62.7% yield) , m/z 385.
  • Step-7 Preparation of (S)-N-((S)- l-(7-fiuoro-4-oxo-3-phenyl-4H-quinolizin-2- yl)ethyl)-2-methylpropane-2-sulfinamide
  • reaction mixture was quenched with ammonium chloride solution and extracted with ethyl acetate (3 X 500 mL), the combined organic layer was washed with saturated brine solution ( 1 X 500 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain (S)-N- l-(7-fiuoro-4-oxo-3- phenyl-4H- quinolizin- 2-yl) ethyl) - 2-methylpropane-2- sulfanamide .
  • Step-8 Preparation of (S)-2-( l-Aminoethyl)-7-fiuoro-3-phenyl-4H-quinolizin one
  • Step-9 Preparation of (S)-tert-butyl (l-(7-fiuoro-4-oxo-3-phenyl-4H-quinolizin- 2-yl) ethyl) carbamate
  • Step- 10 Preparation of (S)-tert-butyl (l-(l-bromo-7-fiuoro-4-oxo-3-phenyl-4H- quinolizin- 2-yl) ethyl) carbamate
  • Step- 1 1 Preparation of (S)-tert-butyl (l-(7-fiuoro- l-(4-fiuorophenyl)-4-oxo-3- phenyl-4H- quinolizin- 2-yl) ethyl) carbamate
  • Step- 12 Preparation of (S)-2-(l-aminoethyl)-7-fiuoro- l-(4-fiuorophenyl)-3- phenyl-4H-quinolizin-4-one
  • Step- 1 Preparation of 2-acetyl-7-fiuoro-3-iodo-4H-quinolizin-4-one
  • Step-2 Preparation of (S)-N-(l-(7-fiuoro-3-iodo-4-oxo-4H-quinolizin-2- yl) ethylidene) - 2-methylpropane- 2- sulfanamide
  • Step-3 Preparation of (S)-N-(l-(l-bromo-7-fiuoro-3-iodo-4-oxo-4H-quinolizin-2- yl) ethylidene) - 2-methylpropane- 2- sulfanamide
  • Step-4 Preparation of (S)-N-(l-(l-bromo-7-fiuoro-4-oxo-4H-quinolizin-2- yfjethyl) -2-methylpropane-2-sulfinamide
  • Step-5 Preparation of 2-(l-aminoethyl)- l-bromo-7-fiuoro-4H-quinolizin-4-one
  • Step-6 Preparation of tert-butyl (l-(l-bromo-7-fluoro-4-oxo-4H-quinolizin-2- yl) ethyl) carbamate
  • Step-7 Preparation of tert-butyl (l-(7-fiuoro-4-oxo- l-phenyl-4H-quinolizin- yl) ethyl) carbamate
  • Step-8 Preparation of 2-(l-aminoethyl)-7-fluoro- l-phenyl-4H-quinolizin-4-one
  • This solid product was purified through flash chromatography using 45% ethyl acetate-hexane as an eluent to give pure product.
  • This pure solid was dissolved in DCM (25 mL) and added hexane (25 mL) under sonication, a solid product precipitated out, filtered and dried under high vacuum to obtain pure product.
  • Step- 1 Preparation of (S)-4-amino-6-((l-(7-fiuoro-4-oxo-3-phenyl-4H-quinolizin- 2-yl)ethyl)amino)-pyrimidine-5-carbonitrile
  • Step-2 Preparation of (S)-4-amino-6-((l-( l-bromo-7-fiuoro-4-oxo-3-phenyl-4H- quinolizin- 2-yl) ethyl) amino) pyrimidine- 5- carbonitrile
  • Step-3 Preparation of (S)-4-amino-6-((l-(7-fiuoro- l-(4-fiuorophenyl)-4-oxo-3- phenyl-4H-quinolizin-2-yl)eth l)amino)pyrimidine-5-carbonitrile
  • reaction vial was purged with nitrogen, the cap was tightened carefully and was exposed to microwave heating for 1 h.
  • the reaction mixture was cooled to room temperature and the mixture was extracted with ethyl acetate (3 X 20 mL), washed with water and brine, dried over potassium carbonate, and the solvent was removed under reduced pressure to give crude product.
  • the crude product was purified on CombiFlash ® and preparative HPLC to give a pure intermediate. This intermediate (170 mg, 0.399 mmol) was refluxed in HCl (3987 ul, 3.99 mmol) for 1 h.
  • Step- 1 Preparation of 7-fiuoro-2-(2-methyl- l ,3-dioxolan-2-yl)-4H-quinolizin-4- one
  • Step-2 Preparation of 3-bromo-7-fiuoro-2-(2-methyl- l,3-dioxolan-2-yl)-4H- quinolizin-4-one
  • Step-3 Preparation of 7-fiuoro-3-methyl-2-(2-methyl- l ,3-dioxolan-2-yl)-4H- quinolizin-4-one
  • Step-5 Preparation of (S)-N-(l-(7-fiuoro-3-methyl-4-oxo-4H-quinolizin-2- yl) ethylidene) - 2-methylpropane- 2- sulfanamide
  • Step-6 Preparation of (S)-N-((S)- l-(7-fiuoro-3-methyl-4-oxo-4H-quinolizin-2- yl)ethyl)-2-methylpropane-2-sulfinamide
  • Step-7 Preparation of (S)-2-(l-aminoethyl)-7-fiuoro-3-methyl-4H-quinolizin-4- one
  • Step-8 Preparation of (S)-4-amino-6-((l-(7-fiuoro-3-methyl-4-oxo-4H-quinolizin- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile
  • Step-9 Preparation of (S)-4-amino-6-((l-(l-bromo-7-fiuoro-3-methyl-4-oxo-4H- quinolizin- 2-yl) ethyl) amino) pyrimidine- 5- carbonitrile
  • Step- 10 Preparation of (S)-4-amino-6-((l-(7-fiuoro- l-(4-fiuorophenyl)-3-methyl- 4- OXO-4H- quinolizin- 2-yl) ethyl) amino) pyrimidine- 5- carbonitrile
  • the racemic product was purified through chiral HPLC to give two fractions.
  • the first-eluting enantiomer on CHIRALPAK ® IA column is 43a (RT-4.03) and the second-eluting enantiomer on CHIRALPAK ® IA column is 43b (RT-5.93).
  • MDA-MB- 453 cell line harboring PI3Ka activating mutation and 786-0 cells having constitutive expression of ⁇ 3 ⁇ were used for analyzing the inhibition of PI3Ka and ⁇ 3 ⁇ respectively.
  • Cells were seeded in 96-well clear bottom plate at a density of 40000 cells/ well and incubated overnight at 37 °C and 5% C0 2 . Cells were then supplemented with complete medium and were treated with compounds for 1 h at 37 °C and 5% CO 2 .
  • RLU of control cells - RLU of lysis buffer blank ⁇ 3 ⁇ inhibition IC 50 of the compounds of invention is provided in Table 1 below: Compounds with IC50 between 50 nM and 500 nM are grouped under group A, and compounds with IC50 between 501 nM and 5000 nM are grouped under group B.
  • the IC 50 value against ⁇ 3 ⁇ of the Compounds 1, 14 and 37 in the present invention is between 75 nM and 3000 nM.
  • Raw 264.7 cells were maintained in DMEM (Sigma) supplemented with
  • fetal bovine serum heat inactivated
  • FBS fetal bovine serum
  • streptomycin 100 U penicillin/mL
  • streptomycin 100 g/mL
  • Cells were harvested by detachment with trypsin-EDTA, centrifuged and resuspended in complete medium.
  • Cells were seeded at a density of 40000 cells/well in complete medium (100 L/well) into 96-well clear bottom plates and incubated for 1 day at 37 °C, 5% CO2. Next day, the medium was removed by gentle aspiration and replaced with 100 ⁇ ih medium without serum and incubated for 1 h at 37 °C, 5% CO2.
  • the IC50 value against ⁇ 3 ⁇ of the Compounds 1, 14 and 37 in the present invention is between 90 nM and 2000 nM.
  • Raji cells were maintained in RPMI- 1640 (Sigma) supplemented with 10% fetal bovine serum (heat inactivated) (FBS, Sigma), 100 U penicillin/ mL, and 100 g/mL streptomycin and incubated at 37 °C and 5% CO 2 . Cells were centrifuged and resuspended in a complete medium. The required numbers of cells were transferred to a tissue culture flask containing medium without serum for 1 h at 37 °C, 5% CO 2 .
  • FBS fetal bovine serum
  • HBSS Hank's Balanced Salt Solution
  • AlphaScreen® SureFire® Cell-based Assay (Perkin-Elmer, Waltham, MA, USA) was performed to measure phosphorylation of AKT, in the cells according to the manufacturer's instructions. The luminescence was measured using an alpha technology- compatible plate reader BMG Labtech, Germany) at 520-620 nm. Percentage inhibition was calculated according to formula:
  • PI3K8 inhibition IC50 of the compounds of invention is provided in Table 2 below: Compounds with IC 50 between 1 nM and 100 nM are grouped under group A, and compounds with IC 50 between 101 nM and 500 nM are grouped under group B. Table 2:

Abstract

L'invention concerne des composés de formule (I), leurs formes tautomères, leurs stéréoisomères et leurs sels pharmaceutiquement acceptables, dans laquelle R1 - R5 et n sont tels que définis dans la description, des compositions pharmaceutiques comprenant un composé, un tautomère, un stéréoisomère, ou un sel de celui-ci, et des procédés de traitement ou de prévention de maladies ou de troubles, par exemple, le cancer, qui sont sensibles au traitement ou à la prévention par l'inhibition de l'enzyme PI3K d'un sujet.
PCT/IB2016/057635 2015-12-18 2016-12-15 Dérivés de quinolizinone utilisés comme inhibiteurs de pi3k WO2017103825A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10751339B2 (en) 2018-01-20 2020-08-25 Sunshine Lake Pharma Co., Ltd. Substituted aminopyrimidine compounds and methods of use

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
US5019369A (en) 1984-10-22 1991-05-28 Vestar, Inc. Method of targeting tumors in humans
WO2001081346A2 (fr) 2000-04-25 2001-11-01 Icos Corporation Inhibiteurs de la phosphatidyl-inositol 3-kinase delta humaine
WO2010151735A2 (fr) 2009-06-25 2010-12-29 Amgen Inc. Composés hétérocycliques et leurs utilisations
WO2011008487A1 (fr) 2009-06-29 2011-01-20 Incyte Corporation Pyrimidinones comme inhibiteurs de pi3k
WO2013012915A1 (fr) 2011-07-19 2013-01-24 Infinity Pharmaceuticals Inc. Composés hétérocycliques et leurs utilisations
WO2013032591A1 (fr) 2011-08-29 2013-03-07 Infinity Pharmaceuticals Inc. Composés hétérocycliques et leurs utilisations
WO2016001855A1 (fr) 2014-07-04 2016-01-07 Lupin Limited Dérivés de quinolizinone utilisés comme inhibiteurs de pi3k
WO2016066142A1 (fr) 2014-11-01 2016-05-06 Shanghai Fochon Pharmaceutical Co., Ltd. Inhibiteurs de certaines protéines kinases

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
US5019369A (en) 1984-10-22 1991-05-28 Vestar, Inc. Method of targeting tumors in humans
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
WO2001081346A2 (fr) 2000-04-25 2001-11-01 Icos Corporation Inhibiteurs de la phosphatidyl-inositol 3-kinase delta humaine
WO2010151735A2 (fr) 2009-06-25 2010-12-29 Amgen Inc. Composés hétérocycliques et leurs utilisations
WO2011008487A1 (fr) 2009-06-29 2011-01-20 Incyte Corporation Pyrimidinones comme inhibiteurs de pi3k
WO2013012915A1 (fr) 2011-07-19 2013-01-24 Infinity Pharmaceuticals Inc. Composés hétérocycliques et leurs utilisations
WO2013032591A1 (fr) 2011-08-29 2013-03-07 Infinity Pharmaceuticals Inc. Composés hétérocycliques et leurs utilisations
WO2016001855A1 (fr) 2014-07-04 2016-01-07 Lupin Limited Dérivés de quinolizinone utilisés comme inhibiteurs de pi3k
WO2016066142A1 (fr) 2014-11-01 2016-05-06 Shanghai Fochon Pharmaceutical Co., Ltd. Inhibiteurs de certaines protéines kinases

Non-Patent Citations (40)

* Cited by examiner, † Cited by third party
Title
"ASHP Handbook on Injectable Drugs", 1986, TOISSEL, pages: 622 - 630
"Pharmaceutics and Pharmacy Practice", 1982, J.B. LIPPINCOTT COMPANY, pages: 238 - 250
"Physicians' Desk Reference", 2004
"Physicians' Desk Reference", 2004, THOMSON PDR
"Remington's Pharmaceutical Science", 1985, MACK PUBLISHING COMPANY
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING COMPANY, pages: 1445
ALI ET AL., J. NATL. CANCER INST., 1991, pages 1922 - 1932
BERGE S.M ET AL.: "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19
CAMPBELL ET AL., CANCER RES., vol. 64, 2004, pages 7678 - 7681
CANTLEY ET AL., SCIENCE, vol. 296, 2002, pages 1655 - 1657
CANTRELL ET AL., J. CELL. SET, vol. 114, 2001, pages 1439 - 45
CULLY ET AL., NAT. REV. CANCER, vol. 6, 2006, pages 184 - 192
EDLING ET AL., CLIN. CANCER RES., vol. 16, 2010, pages 4928 - 4937
EL HAIBI ET AL., MOL. CANCER, vol. 9, 2010, pages 85
HICKEY; COTTER., J. BIOL. CHEM., vol. 281, 2006, pages 2441 - 50
IKENOUE ET AL., CANCER RES., vol. 65, 2005, pages 4562 - 4567
IRENE BRANA; LILLIAN L SIU., BMC MEDICINE, vol. 10, 2012, pages 161
ISAKOFF ET AL., CANCER RES., vol. 65, 2005, pages 10992 - 11000
JANKU ET AL., PLOS ONE, vol. 7, 2011, pages 6
JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 2 - 19
JU HE ET AL., J. LIPID RES., vol. 48, 2008, pages 1807 - 1815
KANG ET AL., PROC. NATL. ACAD. SCI. USA, vol. 103, 2006, pages 1289 - 94
KNOBBE ET AL., NEUROPATHOL. APPL. NEUROBIOL., vol. 31, 2005, pages 486 - 90
LIU ET AL., NAT. REV. DRUG DISCOV, vol. 8, 2009, pages 627 - 44
LOPICCOLO ET AL., DRUG RESIST. UPDAT., vol. 11, 2008, pages 32 - 50
P. H. EINRICH STAHLAND CAMILLE G.WERMUTH: "Handbook of Pharmaceutical Salts - Properties, Selection, and Use", 2002, WILEY- VCH
SAMUELS ET AL., SCIENCE, vol. 304, 2004, pages 554
SUJOBERT ET AL., BLOOD, vol. 106, 2005, pages 1063 - 6
SZOKA ET AL., ANN. REV. BIOPHYS. BIOENG., vol. 9, 1980, pages 467
TORBETT ET AL., BIOCHEM. J., vol. 415, 2008, pages 97 - 110
VANHAESEBROECK ET AL., ANNU. REV. BIOCHEM., vol. 70, 2001, pages 535
VANHAESEBROECK ET AL., NAT. REV. MOL. CELL BIOL, vol. 11, 2010, pages 329 - 341
VANHAESEBROECK ET AL., NAT. REV. MOL. CELL. BIOL., vol. 11, 2010, pages 329 - 41
VANHAESEBROECK ET AL., PROC. NATL. ACAD. SET USA, vol. 94, 1997, pages 4330 - 4335
VOGT ET AL., TRENDS BIOCHEM. SCL, vol. 32, 2007, pages 342 - 349
WASSERMAN ET AL., CANCER, vol. 36, 1975, pages 1258 - 1268
WEE ET AL., PROC. NATL. ACAD. SET USA, vol. 105, 2008, pages 13057 - 62
WYMANN M.; PIROLA L., BIOCHIM. BIOPHYS. ACTA, vol. 1436, 1998, pages 127
ZHAO ET AL., ONCOGENE, vol. 27, 2008, pages 5486 - 5496
ZHAO ET AL., PROC. NATL. ACAD. SET USA, vol. 102, 2005, pages 18443 - 18448

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* Cited by examiner, † Cited by third party
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US10751339B2 (en) 2018-01-20 2020-08-25 Sunshine Lake Pharma Co., Ltd. Substituted aminopyrimidine compounds and methods of use

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