WO2016087488A1 - Régime d'administration de dérivés de 2,3-dihydroimidazo[1,2-c]quinazoline substitués par un amino-alcool - Google Patents

Régime d'administration de dérivés de 2,3-dihydroimidazo[1,2-c]quinazoline substitués par un amino-alcool Download PDF

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WO2016087488A1
WO2016087488A1 PCT/EP2015/078292 EP2015078292W WO2016087488A1 WO 2016087488 A1 WO2016087488 A1 WO 2016087488A1 EP 2015078292 W EP2015078292 W EP 2015078292W WO 2016087488 A1 WO2016087488 A1 WO 2016087488A1
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compound
formula
administered
alkyl
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Ningshu Liu
Franziska SIEGEL
Robert Fricke
Olaf DOEHR
Ray VALENCIA
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Bayer Pharma Aktiengesellschaft
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to the use of PI3K inhibitor of formula (I) in the treatment of hyper-proliferative disorders and diseases associated with angiogenesis according to an intermittent administration (dosing) regimen (regime).
  • PI3K inhibitors The rationale for the use of PI3K inhibitors is based on the role(s) of PI3K kinases in key signaling pathways in cancer cells.
  • the PI3K family of lipid kinases generates 3'-phosphoinositides that bind to and activate a variety of cellular targets, initiating a wide range of signal transduction cascades (Vanhaesebroeck et al. , 2001 ; Toker, 2002; Pendaries ef al. , 2003; Downes et al. , 2005). These cascades ultimately induce changes in multiple cellular processes, including cell proliferation, cell survival, differentiation, vesicle trafficking, migration, and chemotaxis.
  • PI3Ks can be divided into three distinct classes based upon differences in both structure, and substrate preference. While members of the Class II family of PI3Ks have been implicated in the regulation of tumor growth (Brown & Shepherd, 2001 ; Traer et al. , 2006), the bulk of research has focused on the Class I enzymes and their role in cancer (Stauffer ef al. , 2005; Stephens et al. , 2005; Vivanco & Sawyers, 2002; Workman, 2004; Chen et al. , 2005; Hennessy et al. , 2005; Cully et al. , 2006).
  • Class I PI3Ks have traditionally been divided into two distinct sub-classes based upon differences in protein subunit composition.
  • the Class PI3Ks are comprised of a catalytic p1 10 catalytic subunit (pi 10a, ⁇ or ⁇ ) heterodimerized with a member of the p85 regulatory subunit family.
  • the Class IB PI3K catalytic subunit (pl lOy) heterodimerizes with a distinct p101 regulatory subunit (reviewed by Vanhaesebroeck & Waterfield, 1999; Funaki et al. , 2000; Katso et al. , 2001 ).
  • the C-terminal region of these proteins contains a catalytic domain that possesses distant homology to protein kinases.
  • the ⁇ 3 ⁇ structure is similar to Class p1 10s, but lacks the N-terminal p85 binding site (Domin & Waterfield, 1997). Though similar in overall structure, the homology between catalytic p1 10 subunits is low to moderate. The highest homology between the PI3K isoforms is in the kinase pocket of the kinase domain.
  • the Class PI3K isoforms associate with activated receptor tyrosine kinases (RTKs) (including PDGFR, EGFR, VEGFR. IGF1 -R, c-KIT, CSF-R and Met), or with tyrosine phosphorylated adapter proteins (such as Grb2, Cbl, IRS-1 or Gab1 ), via their p85 regulatory subunits resulting in stimulation of the lipid kinase activity.
  • RTKs receptor tyrosine kinases
  • tyrosine phosphorylated adapter proteins such as Grb2, Cbl, IRS-1 or Gab1
  • the oncogenic activity of these isoforms may require binding to ras (Kang et al., 2006).
  • the p1 10a and ⁇ ⁇ isoforms exhibit oncogenic activity independent of ras binding, through constitutive activation of Akt.
  • PIP3 Class I PI3Ks catalyze the conversion of PI(4,5)P 2 [PIP 2 ] to PI(3.4.5)P 3 [PIP 3 ].
  • the production of PIP3 by PI3K affects multiple signaling processes that regulate and coordinate the biological end points of cell proliferation, cell survival, differentiation and cell migration.
  • PIP3 is bound by Pleckstrin-Homology (PH) domain-containing proteins, including the phosphoinositide-dependent kinase, PDK1 and the Akt proto- oncogene product, localizing these proteins in regions of active signal transduction and also contributing directly to their activation (Klippel et al. , 1997; Fleming et al.
  • Akt phosphorylates and regulates multiple regulatory kinases of pathways that directly influence cell cycle progression and cell survival.
  • Akt Akt promotes tumor cell survival by regulating components of the apoptotic and cell cycle machinery.
  • Akt is one of several kinases that phosphorylate and inactivate pro- apoptotic BAD proteins (del Peso et al. , 1997; Pastorino et al. , 1999).
  • Akt may also promote cell survival through blocking cytochrome C-dependent caspase activation by phosphorylating Caspase 9 on Ser 196 (Cardone ef al. , 1998).
  • Akt impacts gene transcription on several levels.
  • the Akt-mediated phosphorylation of the MDM2 E3 ubiquitin ligase on Ser 166 and Ser 186 facilitates the nuclear import of MDM2 and the formation and activation of the ubiquitin ligase complex.
  • Nuclear MDM2 targets the p53 tumor suppressor for degradation, a process that can be blocked by LY294002 (Yap et al. , 2000; Ogawara et al. , 2002). Downregulation of p53 by MDM2 negatively impacts the transcription of p53-regulated pro-apoptotic genes (e.g.
  • Forkhead activity also impacts pro-apoptotic and pro-angiogenic gene transcription including the transcription of Fas ligand (Ciechomska et al. , 2003) Bim, a pro-apoptotic Bcl-2 family member (Dijkers et al. , 2000), and the Angiopoietin-1 (Ang-1 ) antagonist, Ang-2 (Daly et al. , 2004).
  • Fas ligand Ciechomska et al. , 2003
  • Bim a pro-apoptotic Bcl-2 family member
  • Ang-1 Angiopoietin-1
  • Ang-2 Ang-2
  • Forkhead transcription factors regulate the expression of the cyclin-dependent kinase (Cdk) inhibitor p27 Kip1 .
  • PI3K inhibitors have been demonstrated to induce p27 Kip1 expression resulting in Cdk1 inhibition, cell cycle arrest and apoptosis (Dijkers et al., 2000).
  • Akt is also reported to phosphorylate p21 Cip1 on Thr 45 and p27 Kip on Thr 157 facilitating their association with 14-3-3 proteins, resulting in nuclear export and cytoplasmic retention, preventing their inhibition of nuclear Cdks (Zhou ef al. , 2001 ; Motti et al. , 2004; Sekimoto et al. , 2004).
  • Akt phosphorylates IKK (Romashkova & Makarov, 1999), leading to the phosphorylation and degradation of ⁇ ⁇ and subsequent nuclear translocation of NFKB, resulting in the expression of survival genes such as IAP and Bcl-Xi .
  • Akt The PI3K Akt pathway is also linked to the suppression of apoptosis through the JNK and p38 MAPK MAP Kinases that are associated with the induction of apoptosis.
  • Akt is postulated to suppress JNK and p38 MAPK signaling through the phosphorylation and inhibition of two JNK p38 regulatory kinases, Apoptosis Signal-regulating Kinase 1 (ASK1 ) (Kim et al. , 2001 ; Liao & Hung, 2003; Yuan et al. , 2003), and Mixed Lineage Kinase 3 (MLK3) (Lopez-llasaca ef al. , 1997; Barthwal ef al.
  • ASK1 Apoptosis Signal-regulating Kinase 1
  • MLK3 Mixed Lineage Kinase 3
  • inhibitors of the PI3K pathway may promote the activities of co-administered cytotoxic drugs.
  • GSK3 activity is elevated in quiescent cells, where it phosphorylates cyclin Di on Ser 286 , targeting the protein for ubiquitination and degradation (Diehl ef al. , 1998) and blocking entry into S-phase.
  • Akt inhibits GSK3 activity through phosphorylation on Ser 9 (Cross et al. , 1995). This results in the elevation of Cyclin Di levels which promotes cell cycle progression.
  • Inhibition of GSK3 activity also impacts cell proliferation through activation of the wnt/beta-catenin signaling pathway (Abbosh & Nephew, 2005; Naito et a/. , 2005; Wilker et a/. , 2005; Segrelles et a/. , 2006).
  • Akt mediated phosphorylation of GSK3 results in stabilization and nuclear localization of the beta-catenin protein, which in turn leads to increased expression of c-myc and cyclin D1 , targets of the beta-catenin/Tcf pathway.
  • PI3K signaling is utilized by many of the signal transduction networks associated with both oncogenes and tumor suppressors, PI3K and its activity have been linked directly to cancer.
  • Overexpression of both the p1 10a and p1 10 ⁇ isoforms has been observed in bladder and colon tumors and cell lines, and overexpression generally correlates with increased PI3K activity (Benistant et a/. , 2000).
  • Overexpression of p1 10a has also been reported in ovarian and cervical tumors and tumor cell lines, as well as in squamous cell lung carcinomas. The overexpression of p1 10a in cervical and ovarian tumor lines is associated with increased PI3K activity (Shayesteh et a/.
  • PIK3CA somatic mutations in the gene encoding p1 10a
  • the data collected to date suggests that PIK3CA is mutated in approximately 32% of colorectal cancers (Samuels ef a/., 2004; Ikenoue ef a/. , 2005), 18-40% of breast cancers (Bachman ef a/. , 2004; Campbell ef a/. , 2004; Levine ef a/. , 2005; Saal ef a/. , 2005; Wu ef al., 2005), 27% of glioblastomas (Samuels et al., 2004; Hartmann ef a/.
  • PIK3CA mutations have been reported in oligodendroma, astrocytoma, medulloblastoma, and thyroid tumors as well (Broderick ef al. , 2004; Garcia-Rostan ef al., 2005). Based upon the observed high frequency of mutation, PIK3CA is one of the two most frequently mutated genes associated with cancer, the other being K-ras. More than 80% of the PIK3CA mutations cluster within two regions of the protein, the helical (E545K) and catalytic (H1047R) domains.
  • siRNA-mediated downregulation of ⁇ ⁇ inhibits both Akt phosphorylation and HeLa cell tumor growth in nude mice (Czauderna et a/. , 2003).
  • siRNA-mediated downregulation of p l S () ⁇ was also shown to inhibit the growth of malignant glioma cells in vitro and in vivo (Pu et a/. , 2006).
  • Inhibition of PI3K function by dominant-negative p85 regulatory subunits can block mitogenesis and cell transformation (Huang et ai, 1996; Rahimi et at. , 1996).
  • Activation of PI3K has also been shown to lead to expression of multidrug resistant protein-1 (MRP-1 ) in prostate cancer cells and the subsequent induction of resistance to chemotherapy (Lee ef al. , 2004).
  • MRP-1 multidrug resistant protein-1
  • PI3K signaling in tumorigenesis is further underscored by the findings that the PTEN tumor suppressor, a PI(3)P phosphatase, is among the most commonly inactivated genes in human cancers (Li ef al. , 1997; Steck ef al., 1997; Ali ef al. , 1999; Ishii ef al. , 1999). PTEN dephosphorylates PI(3.4,5)P 3 to PI(4,5)P 2 thereby antagonizing PI3K-dependent signaling. Cells containing functionally inactive PTEN have elevated levels of PIP3, high levels of activity of PI3K signaling (Haas-Kogan et al. , 1998; Myers et al.
  • the signaling inputs to Class I PI3Ks are diverse and can be deduced through genetic analyses.
  • activation of AKT was impaired in p1 10odeficient murine embryonic fibroblasts (MEFs) upon stimulation by classical Receptor Tyrosine Kinase (RTK) ligands (e.g. , EGF, insulin, IGF-1 , and PDGF) (Zhao et al. , 2006).
  • RTK Receptor Tyrosine Kinase
  • MEFs in which ⁇ 1 10 ⁇ is ablated or replaced by a kinase-dead allele of ⁇ 1 10 ⁇ respond normally to growth factor stimulation via RTKs (Jia ef al. , 2008).
  • ⁇ 1 10 ⁇ catalytic activity is required for AKT activation in response to GPCR ligands (such as LPA).
  • GPCR ligands such as LPA
  • p1 10a appears to carry the majority of the PI3K signal in classic RTK signaling and is responsible for tumor cell growth, proliferation, survival, angiogenesis and metabolism, whereas ⁇ 1 10 ⁇ mediates GPCR signaling from mitogens and chemokines and therefore may regulate tumor cell proliferation, metabolism, inflammation and invasion (Vogt ef al. , 2009; Jia ef al. , 2009).
  • the mutation of the gene encoding p1 10 ⁇ is rare in tumors, but amplification of ⁇ 3 ⁇ has been found in many tumors (Benistant et al. , 2000; Brugge ef al. , 2007). Importantly, in a mouse prostate tumor model driven by PTEN deficiency, ablation of p1 10a was shown to have no effect on tumorigenesis (Jia et al. , 2008).
  • PTEN-deficient human cancer cell lines e.g., PC-3, U87MG, and BT549
  • p1 10 ⁇ inhibits downstream activation of AKT, cell transformation, and the growth of PTEN-deficient cells and tumor xenografts
  • Genetic studies have suggested that the kinase activity of p1 10 ⁇ is essential in cellular transformation caused by PTEN loss. For example, adding back a kinase-dead p1 10 ⁇ , but not its wild-type counterpart, impaired focus formation in PTEN-deficient PC3 cells depleted for endogenous p1 10 ⁇ (Wee et al., 2008).
  • PIK3CA and loss-of-function of PTEN were found in 30-50% and 35-60% of gastric cancer patients, respectively, although PIK3CA and PTEN mutation rate was reported to be less than 7% of each (Byun et al., 2003; Oki et al. , 2006; Li et al., 2005; Sanger Database).
  • tumor types While a subset of tumor types are solely dependent on PI3Ka signaling, other tumors are dependent on ⁇ 3 ⁇ signaling or on a combination of both PI3Ka and ⁇ 3 ⁇ signaling.
  • PI3K inhibitors exhibiting balanced inhibition of both PI3K and ⁇ 3 ⁇ isoforms.
  • PI3K inhibitors displaying equipotent (i.e. balanced) inhibitory activity against both PI3Ka and ⁇ 3 ⁇ to obtain the desired therapeutic effect and which simultaneously present no or reduced adverse events/effects to the patient.
  • potent suppression of PI3K pathway in tumors by the PI3K inhibitor may be necessary and/or advantageous to achieve suitable or improved therapeutic efficacy (e.g. for increased tumor killing efficacy and/or for a better disease control).
  • PI3K inhibitors for the treatment of cancer faces the challenge of generating sufficient therapeutic window (via sufficient inhibition of tumour cell proliferation and survival), whilst maintaining an acceptable toxicological profile (by allowing normal cells and organs to function to a sufficient extent).
  • PI3K inhibitors currently being developed in clinic showed significant side effects and severe adverse events, such as hyperglycaemia.
  • Gl toxicity, liver toxicity, pneumonitis, Pneumocystis pneumonia (PCP), etc. before demonstrating substantial anti-tumor efficacy.
  • Some toxicities are mode of action related. Therefore, there is an urgent clinical need to provide new therapeutic options which:
  • PI3K inhibitors for the treatment of hyper-proliferative disorders and/or diseases associated with angiogenesis.
  • the Applicant has found a surprisingly advantageous dosing regimen for the administration of PI3K inhibitors, particularly for the administration of PI3K inhibitors of formula (I) as described herein, which:
  • the present invention relates to a compound of formula (I)
  • R 1 represents -(CH 2 )n-(CHR 4 )-(CH 2 ) m -N(R 5 )(R 5' ) ;
  • R 2 represents a heteroaryl of structure :
  • X represents N or C-R 6 .
  • X' represents O, S, NH, N-R 6 , N or C-R 6 ,
  • R 4 is hydroxy
  • R 5 and R 6 are the same or different and are, independently of each other, a hydrogen atom, or a Ci-Ce-alkyl, Cs-Ce-cycloalkyl-Ci-Ce-alkyl, or C -Ce-alkoxy-Ci-Ce- alkyl,
  • R 5 and R 5 taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R 6' groups ; each occurrence of R 6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci-Ce-alkyl, C2-Ce-alkenyl, C ⁇ -Ce-alkynyl, Cs-Ce-cycloalkyl, Cs- Ce-cycloalkyl-Ci-Ce-alkyl, aryl, aryl-d-Ce-alkyl, heteroaryl, heteroaryl-Ci-Ce-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-Ce-alkyl, -Ci-Ce- alkyl-OR 7 , -C
  • the compound of formula (I) for use in the prophylaxis or treatment of a hyper-proliferative and/or angiogenesis disorder, wherein in each administration cycle the compound of formula (I) is administered for a period of one to five days, followed by a period of three to six days in which the compound of formula (I) is not administered or placebo is administered.
  • a second aspect of the present invention relates to the use of a compound of formula (I) as defined herein, for the manufacture of a medicament for the prophylaxis or treatment of a hyper-proliferative and/or angiogenesis disorder, wherein in each administration cycle the compound of formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same is administered for a period of one to five days, followed by a period of three to six days in which the compound of formula (I) is not administered or placebo is administered.
  • a third aspect of the present invention relates to a method of prophylaxis or treatment of a hyper-proliferative and/or angiogenesis disorder, comprising administering to a patient suffering from said disorder, in each administration cycle, a compound of formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same as defined herein for a period of one to five days, followed by a period of three to six days in which the compound of formula (I) is not administered or placebo is administered.
  • a method of treating at least one pathological state in a patient in need thereof comprising administering to a patient (in each administration cycle) a pharmacologically effective dose of a compound of formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same as defined herein for a period of one to five days, followed by a period of three to six days in which the compound of formula (I) is not administered or placebo is administered.
  • a method for inhibiting PI3K in a subject comprising administering (in each administration cycle) an effective dose of a compound of general formula (I), a compound of formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same as defined herein for a period of one to five days, followed by a period of three to six days in which the compound of formula (I) is not administered or placebo is administered, to the subject.
  • the present invention also relates to a package comprising a pharmaceutical composition of a compound of the general formula (I) in combination with instructions to administer said composition (in each administration cycle) for a period of one to five days, followed by a period of three to six days in which the compound of formula (I) is not administered or placebo is administered.
  • halogen atom or halo is to be understood as meaning a fluorine, chlorine, bromine or iodine atom.
  • Ci-Ce-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 . 2. 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1 ,2-dimethylpropyl, neo-pentyl, 1 , 1 -dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 - methylpentyl, 2-ethylbutyl, 1 -ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1 , 1 , 1
  • Ci-Ce-alkoxy is to be understood as preferably meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl, in which the term “alkyi” is defined supra, e.g. a methoxy, ethoxy, n-propoxy, i so- pro poxy, n- butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomer thereof.
  • Ci-Ce-alkoxy-Ci-Ce-alkyr is to be understood as preferably meaning a linear or branched, saturated, monovalent alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a Ci-Ce- alkoxy group, as defined supra, e.g.
  • C2-C6-alkenyl is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms ("Ci-Cs-alkenyl”), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other.
  • Said alkenyl group is, for example, a vinyl, allyl, (E)-2- methylvinyl, (Z)-2-methylvinyl.
  • Ca-Ce-alkynyl is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-alkynyl").
  • Said C2-Ce-alkynyl group is, for example, ethynyl, prop-1 -ynyl, prop- 2-ynyl, but-1 -ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4- ynyl, hex-1 -ynyl, hex-2-inyl, hex-3-inyl, hex-4-ynyl, hex-5-ynyl, 1 -methylprop-2-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1 -methylbut-2-ynyl, 3-methylbut-1 -ynyl, 1 - ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1 -methylp
  • Cs-Ce-cycloalkyl is to be understood as preferably meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5, or 6 carbon atoms.
  • Said Cs-Ce-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, or a bicyclic hydrocarbon ring, e.g. a perhydropentalenylene or decalin ring.
  • Said cycloalkyl ring can optionally contain one or more double bonds e.g.
  • cycloalkenyl such as a cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group, wherein the bond between said ring with the rest of the molecule may be to any carbon atom of said ring, be it saturated or unsaturated.
  • alkylene is understood as preferably meaning an optionally substituted hydrocarbon chain (or “tether”) having 1 , 2, 3, 4, 5, or 6 carbon atoms, i.e. an optionally substituted -CH2- ("methylene” or “single membered tether” or, for example -C(Me)2-), -CH2-CH2- ("ethylene”, “dimethylene”, or “two-mem bered tether"), -CH2-CH2-CH2- ("propylene”, “trimethylene”, or “three-membered tether"), -CH2-CH2- CH2-CH2- ("butylene”, “tetramethylene”, or “four-membered tether"), -CH2-CH2-CH2- CH2-CH2- ("pentylene " , "pentamethylene” or "five-mem bered ether”), or -CH2-CH2- CH2-CH2-CH2- ("hexylene ' , "hexamethylene " , or six-membered tether)
  • said 3- to 8-membered heterocycloalkyl can contain 2, 3, 4, 5, 6 or 7 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "3- to 8-membered heterocycloalkyl"), more particularly said heterocycloalkyl can contain 4 or 5 carbon atoms, and one or more of the above- mentioned heteroatom-containing groups (a "5- to 7-membered heterocycloalkyl").
  • said heterocycloalkyl can be a 4- membered ring, such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or a 7-membered ring, such as a diazepanyl ring, for example.
  • said heterocycloalkyl can be benzo fused.
  • Said heterocyclyl can be bicyclic, such as, without being limited thereto, a 5,5- membered ring, e.g. a hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl) ring, or a 5,6- membered bicyclic ring, e.g. a hexahydropyrrolo[1 ,2-a]pyrazin-2( 1 H)-yl ring, or 8-oxa- 3-azabicyclo[3.2.1 ]oct-3-yl ring, for example.
  • a 5,5- membered ring e.g. a hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl) ring
  • a 5,6- membered bicyclic ring e.g. a hexahydropyrrolo[1 ,2-a]pyrazin-2( 1 H)-yl ring
  • said nitrogen atom-containing ring can be partially unsaturated, i.e. it can contain one or more double bonds, such as, without being limited thereto, a 2,5-dihydro-1 H-pyrrolyl, 4H-[1 ,3,4]thiadiazinyl, 4.5-dihydrooxazolyl, or 4H- [1 ,4]thiazinyl ring, for example, or, it may be benzo-fused, such as, without being limited thereto, a dihydroisoquinolinyl ring, for example.
  • aryl is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, mono-, or bi- or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 1 1 , 12. 13 or 14 carbon atoms (a "Ce-Ci4-aryl” group), particularly a ring having 6 carbon atoms (a "Ce-aryl” group), e.g. a phenyl group; or a biphenyl group, or a ring having 9 carbon atoms (a "Cg-aryl” group), e.g. an indanyl or indenyl group, or a ring having 10 carbon atoms (a "Cio-aryl” group), e.g.
  • a articular example of an aryl group is one of the following possible structures : in which z represents O, S, NH or N(Ci-Ce-alkyl), and * indicates the point of attachment of said aryl group with the rest of the molecule.
  • heteroaryl is understood as preferably meaning a monovalent, monocyclic- , bicyclic- or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl” group), particularly 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur, and in addition in each case can be benzocondensed.
  • said heteroaryl is of structure
  • X represents N or C-R 6 .
  • X' represents O, S, NH, N-R 6 , N or C-R 6 ,
  • R 7 and R 7' may be the same or different and is independently a hydrogen atom, or a d-Ce-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Cs-Ce-cycloalkyl, Cs- Ce-cycloalkyl-C -Ce-alklyl, Cs-Ce-cycloalkenyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-Ce-alkyl, or heteroaryl-Ci-Ce-alkyl ;
  • R 8 is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci-Ce-alkyl, Ci-Ce-alkoxy, C2-Ce-alkenyl, C2-Ce-alkynyl, Cs-Ce- cycloalkyl, Cs-Ce-cycloalkyl-Ci-Ce-alkyl, Ci-Ce-cycloalkenyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-Ci-Ce-alkyl, or heteroaryl-Ci-Ce-alkyl.
  • said heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl efc, and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, efc, and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl,
  • the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof.
  • the term pyridinyl or pyridinylene includes pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene.
  • Ci-Ce as used throughout this text, e.g. in the context of the definition of "Ci-Ce-alkyl” or “Ci-Ce-alkoxy” is to be understood as meaning an alkyi group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “Ci-Ce” is to be interpreted as any sub-range comprised therein, e.g.
  • C2-C6 as used throughout this text, e.g. in the context of the definitions of "C2-Ce-alkenyl” and “C2-Ce-alkynyl”, is to be understood as meaning an alkenyl group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C2-C6” is to be interpreted as any sub-range comprised therein, e.g. C- -Ce . C3-C5. C3-C4 , C2-C3. C2-C4 , C2-C5 ; particularly C2-C3.
  • Cs-Ce as used throughout this text, e.g. in the context of the definition of "Cs-Ce-cycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C3-C6” is to be interpreted as any sub-range comprised therein, e.g. Cs-Ce , C4-C5 , C3-C5 , C3-C4 , C4-C6, C 5 -Ce ; particularly Cs-Ce.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • the term "one or more times”, e.g. in the definition of the substituents of the compounds of the present invention (e.g. component A, B or C), is understood as meaning “one, two, three, four or five times, particularly one, two, three or four times, more particularly one, two or three times, even more particularly one or two times " .
  • the plural form of the word components, compounds, salts, polymorphs, hydrates, solvates and the like is used herein, this is taken to mean also a single component, compound, salt, polymorph, isomer, hydrate, solvate or the like.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • carbonyl refers to an oxygen atom bound to a carbon atom of the molecule by a double bond.
  • the compounds of this invention may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms may be present in the (R)- and/or (Sj-configuration, resulting in racemic mixtures in the case of a single asymmetric center, and diastereomeric mixtures in the case of multiple asymmetric centers.
  • asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention.
  • Preferred compounds are those, which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racem ic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • Tautomers are two or more compounds that are related by the migration of a hydrogen atom accompanied by the switch of one or more single bonds and one or more adjacent double bonds.
  • the compounds of this invention may exist in one or more tautomeric forms.
  • a compound of Formula I may exist in tautomeric form la, tautomeric form lb, or tautomeric form lc, or may exist as a mixture of any of these forms. It is intended that all such tautomeric forms are included within the scope of the present invention.
  • the present invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts, co-precipitates, metabolites, hydrates, solvates and prodrugs of all the compounds of examples.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1 -19.
  • Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid.
  • Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and chorine salts.
  • acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
  • Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art.
  • acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-na
  • Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, or butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyi sulfate, or diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, or butyl chlorides,
  • a solvate for the purpose of this invention is a complex of a solvent and a compound of the invention in the solid state.
  • Exemplary solvates would include, but are not limited to, complexes of a compound of the invention with ethanol or methanol. Hydrates are a specific form of solvate wherein the solvent is water.
  • Constituents which are optionally substituted as stated herein may be substi-tuted, unless otherwise noted, one or more times, independently from one another at any possible position. When any variable occurs more than one time in any constituent, each definition is independent.
  • heteroarylic, or heterocyclic groups mentioned herein can be substituted by their given substituents or parent molecular groups, unless otherwise noted, at any possible position, such as e.g. at any substitutable ring carbon or ring nitrogen atom. Analogously it is being understood that it is possible for any heteroaryl or heterocyclyi group to be attached to the rest of the molecule via any suitable atom if chemically suitable. Unless otherwise noted, any heteroatom of a heteroarylic ring with unsatisfied valences mentioned herein is assumed to have the hydrogen atom(s) to satisfy the valences.
  • rings containing quaternizable amino- or imino-type ring nitrogen atoms may be preferably not quaternized on these amino- or imino-type ring nitrogen atoms by the mentioned substituents or parent molecular groups.
  • Preferred compounds are those which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques already known in the art.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g. , chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable chiral HPLC columns are manufactured by Diacel, e.g. , Chiracel OD and Chiracel OJ among many others, all routinely selectable.
  • Enzymatic separations, with or without derivatisation are also useful.
  • the optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature.
  • isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium ), 1 C, 13 C, 4 C, 15 N, 7 0, 8 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 8 F, 36 CI, 62 Br, 3 l , 1 l , 29 l and 3 1 1 , respectively.
  • isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium ), 1 C, 13 C, 4 C, 15 N, 7 0, 8 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 8 F, 36 CI, 62 Br, 3 l , 1 l , 29 l
  • isotopic variations of a compound of the invention are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14. i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo ha If- life or reduced dosage requirements and hence may be preferred in some circumstances.
  • isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorphs, or as a mixture of more than one polymorphs, in any ratio.
  • continuous dosing is to be understood as a dosing regime in which the administration of a dose of PI3K inhibitor occurs every day (i.e. without days in which a PI3K inhibitor is not administered) or no more than one day mediates the administration of two consecutive doses of a PI3K inhibitor, from the day treatment with a PI3K inhibitor starts until the day treatment with a PI3K inhibitor is completed and/or discontinued.
  • One day is to be understood as a period of 24 hours.
  • Administration of a dose may occur at any period (e.g. morning, afternoon, night, etc) or at any time of the day.
  • administration of a dose of the PI3K inhibitor may occur at the same time or period of the day on each day. During treatment with a PI3K inhibitor, administration may occur at different periods or times of the day, for each day. Daily dosing of a PI3K inhibitor may occur in one single dose of a PI3K inhibitor in each day (i.e. once-daily) or in two or more doses of a PI3K inhibitor (twice-daily, thrice daily, etc).
  • days in which a PI3K inhibitor is administered during an administration cycle may also be called “days on”.
  • days in which the PI3K is not administered or placebo is administered during an administration cycle may also be called “days off. Accordingly, the intermittent dosing of the present invention can be described as:
  • any subcombinations of days on and days off according to the invention may be represented in the same manner (e.g. two days on followed by 5 days off).
  • the intermittent dosing of the present invention can also be described as:
  • the intermittent dosing of the present invention can also be described as:
  • any subcombinations of the consecutive days of administration of the PI3K inhibitor (days ON) and of days in which the PI3K is not administered (days OFF) according to the invention may be represented in the same manner (e.g. PI3K inhibitor is administered for two consecutive days, followed by a period of five days in which a PI3K inhibitor is not administered).
  • Administration of a dose containing a PI3K inhibitor may occur in any period (e.g. morning, afternoon, night, etc) or at any time of the day.
  • administration of a dose of the PI3K inhibitor may occur at the same time or period of the day, in each day the PI3K is administered.
  • administration may occur at different periods or times of the day, for each day in which a PI3K inhibitor is administered, in which case the time elapsed between the administrations of the PI3K inhibitor in two consecutive days may be smaller or larger than 24 hours.
  • Daily dosing of a PI3K inhibitor may occur in one single dose of a PI3K inhibitor in each day it is administered (i.e. once-daily) or in two or more doses of a PI3K inhibitor in each day it is administered (twice-daily, thrice daily, etc).
  • administration cycle is to be understood as the total number of days comprising:
  • said administration cycle takes a total of four (i.e. one day on followed by three days off) to eleven days (i.e. five days on followed by six days off) to be completed, depending on the number of days on and days off.
  • one or more administration cycles according to the invention may be necessary to be performed for a suitable or improved therapeutic effect to be achieved (in which case it can also be described as "the treatment is repeated for X administration cycles " , X being any number between 1 and 4 (i.e. 2 to 5 administration cycles in total), according to the present invention, or it may also be described - when the administration cycle consists of 7 days - as "the treatment is repeated (weekly) for X weeks", X being any number between 1 and 4, according to the present invention).
  • break " or "break period" is to be understood as one or more days (typically four to eight days) in which the compound of formula (I) is not administered or in which placebo is administered, following or preceding an administration cycle. For example, after an administration cycle is completed (i.e. after three to six days off) additional four to eight days may be necessary for the function of PI3K kinase in normal cells to be restored before a new administration cycle begins.
  • the PI3K inhibitor e.g. Compound A1
  • the PI3K inhibitor used in the treatment of a cancer is administered according to a 20N/50FF intermittent schedule in which the administration cycle is repeated three times followed by a break period of seven days, it may (also) be described as follows:
  • a PI3K in the treatment of cancer is administered for two consecutive days, followed by a period of five days in which PI3K inhibitor is not administered, the treatment is repeated weekly for 3 weeks followed by one week without administration of PI3K inhibitor.
  • one to five days is to be understood as meaning one, two, three, four or five consecutive days. It is to be understood further that said term “one to five days " is to be interpreted as any sub-range comprised therein, e.g. one to four days, one to three days, one to two days, two to five days, two to four days, two to three days, three to five days, three to four days, four to five days, etc. The invention relates to all such sub-ranges.
  • the term "three to six days”, as used throughout this text, e.g. in the context of the definition of number of days (in each administration cycle) in which the compound of formula (I) is not administered (to the patient) or placebo is administered, i.e. days off, is to be understood as meaning three, four, five or six consecutive days. It is to be understood further that said term “three to six days” is to be interpreted as any sub-range comprised therein, e.g. three to six days, three to five days, three to four days, four to six days, four to five days, five to six days, etc. The invention relates to all such sub-ranges.
  • the PI3K inhibitor is a compound of formula (I) supra, wherein
  • R represents -(CH 2 )n-(CHR 4 )-(CH 2 ) m -N(R 5 )(R 5' ) ;
  • R 2 represents a heteroaryl of structure :
  • R 3 is methyl
  • R 4 is hydroxy
  • R 5 and R 5' are the same or different and are, independently of each other, a hydrogen atom, or a d-Ce-alkyl, Cs-Ce-cycloalkyl-Ci-Ce-alkyl, or Ci-Ce-alkoxy-Ci-Ce- alkyl,
  • R 5 and R 5' taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R 6' groups ; each occurrence of R 6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci-Ce-alkyl, C 2 -Ce-alkenyl, C 2 -Ce-alkynyl, C:,-Ce-cycloalkyl, C- - Ce-cycloalkyl-C -Ce-alkyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, heteroaryl-Ci-Ce-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-Ce-alkyl, -Ci-Ce- alkyl-
  • each occurrence of R 6' may be the same or different and is independently Ci-Ce-alkyl, Cs-Ce-cycloalkyl-Ci-Ce-alkyl, or Ci-Ce-alkyl-OR 7 ; each occurrence of R 7 and R 7' may be the same or different and is independently a hydrogen atom, or a Ci-Ce-alkyl, C2-C
  • * represents the point of attachment with the rest of the structure of general formula (I), or a stereoisomer, a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
  • the compound of formula (I) supra is selected from the group consisting of :
  • the compound of formula (I) supra is selected from the group consisting of :
  • the PI3K inhibitor is a compound of formula (I) supra, wherein :
  • R 1 represents -(CH 2 )n-(CHR 4 )-(CH 2 ) m -N(R 5 )(R 5' ) ;
  • R 2 represents a heteroaryi of structure :
  • X represents N or C-R 6 ;
  • R 3 is methyl ;
  • R 4 is hydroxy
  • R 5 and R 5' are the same or different and are, independently of each other, a hydrogen atom, or a Ci-Ce-alkyI, Cs-Ce-cycloalkyl-Ci-Ce-alkyl, or Ci-Ce-alkoxy-C -Ce- alkyl,
  • R 5 and R 5 taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R 6' groups ; each occurrence of R 6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci-Ce-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, CrrCe-cycloalkyl, C: 3 - Ce-cycloalkyl-Ci-Ce-alkyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, heteroaryl-Ci-Ce-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-Ce-alkyl, -C -Ce- alkyl-OR 7 , -
  • the compound of formula (I) is selected from the group consisting of :
  • the compound of formula (I) supra is N-(8- ⁇ [(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy ⁇ -7-methoxy-2,3-dihydroimidazo[1 ,2- c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the compound of formula (I) supra is ⁇ /-(8- ⁇ [(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy ⁇ -7-methoxy-2.3-dihydroimidazo[1 ,2- c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide or a physiologically acceptable salt thereof, or a mixture of same.
  • the compound of formula (I) supra is N-(8- ⁇ [(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy ⁇ -7-methoxy-2,3-dihydroimidazo[1 ,2- c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide.
  • each administration cycle the compound of formula (I) is administered for a period of one, two, three, four or five days, followed by a period of three, four, five or six days in which the compound of formula (I) is not administered or placebo is administered.
  • Said administration cycle takes a total of four (i.e. one day on followed by three days off) to eleven days (i.e. five days on followed by six days off) to be completed, depending on the number of days on and days off.
  • each administration cycle the compound of formula (I) is administered for a period of one, two, three, four or five days, followed by a period of four, five or six days in which the compound of formula (I) is not administered or placebo is administered.
  • Said administration cycle takes a total of five (i.e. one day on followed by four days off) to eleven days (i.e. five days on followed by six days off) to be completed, depending on the number of days on and days off.
  • each administration cycle the compound of formula (I) is administered for a period of two, three or four days, followed by a period of four, five or six days in which the compound of formula (I) is not administered or placebo is administered.
  • Said administration cycle takes a total of six (i.e. two days on followed by four days off) to ten days (i.e. four days on followed by six days off) to be completed, depending on the number of days on and days off.
  • each administration cycle the compound of formula (I) is administered for a period of one, two or three days, followed by a period of four, five or six days in which the compound of formula (I) is not administered or placebo is administered.
  • Said administration cycle takes a total of five (i.e. one day on followed by four days off) to nine days (i.e. three days on followed by six days off) to be completed, depending on the number of days on and days off.
  • each administration cycle the compound of formula (I) is administered for a period of one to four days, followed by a period of three to six days in which the compound of formula (I) is not administered or placebo is administered.
  • Said administration cycle takes a total of four (i.e. one day on followed by three days off) to ten days (i.e. four days on followed by six days off) to be completed, depending on the number of days on and days off.
  • each administration cycle the compound of formula (I) is administered for a period of one to four days, followed by a period of four to six days in which the compound of formula (I) is not administered or placebo is administered.
  • Said administration cycle takes a total of five (i.e. one day on followed by four days off) to ten days (i.e. four days on followed by six days off) to be completed, depending on the number of days on and days off.
  • each administration cycle the compound of formula (I) is administered for a period of one to three days, followed by a period of four to six days in which the compound of formula (I) is not administered or placebo is administered.
  • Said administration cycle takes a total of four (i.e. one day on followed by three days off) to ten days (i.e. four days on followed by six days off) to be completed, depending on the number of days on and days off.
  • each administration cycle the compound of formula (I) is administered for a period of one to two days, followed by a period of five to six days in which the compound of formula (I) is not administered or placebo is administered.
  • Said administration cycle takes a total of six (i.e. one day on followed by five days off) to eight days (i.e. two days on followed by six days off) to be completed, depending on the number of days on and days off.
  • each administration cycle the compound of formula (I) is administered for a period of one day (i.e. one day on), followed by a period of three to six days in which the compound of formula (I) is not administered or placebo is administered (i.e. three to six days off).
  • Said administration cycle takes a total of four (i.e. one day on followed by three days off) to seven days (i.e. one day on followed by six days off) to be completed, depending on the number of days on and days off.
  • each administration cycle the compound of formula (I) is administered for a period of two days (i.e. two days on), followed by a period of three to six days in which the compound of formula (I) is not administered or placebo is administered (i.e. three to six days off).
  • Said administration cycle takes a total of five (i.e. two days on followed by three days off) to eight days (i.e. two days on followed by six days off) to be completed, depending on the number of days on and days off.
  • each administration cycle the compound of formula (I) is administered for a period of three days (i.e. three days on), followed by a period of three to six days in which the compound of formula (I) is not administered or placebo is administered (i.e. three to six days off).
  • Said administration cycle takes a total of six (i.e. three days on followed by three days off) to nine days (i.e. three days on followed by six days off) to be completed, depending on the number of days on and days off.
  • each administration cycle the compound of formula (I) is administered for a period of four days, followed by a period of three to six days in which the compound of formula (I) is not administered or placebo is administered.
  • Said administration cycle takes a total of seven (i.e. four days on followed by three days off) to ten days (i.e. four days on followed by six days off) to be completed, depending on the number of days on and days off.
  • each administration cycle the compound of formula (I) is administered for a period of five days, followed by a period of three to six days in which the compound of formula (I) is not administered or placebo is administered.
  • Said administration cycle takes a total of eight (i.e. five days on followed by three days off) to eleven days (i.e. five days on followed by six days off) to be completed, depending on the number of days on and days off.
  • each administration cycle the compound of formula (I) is administered for a period of one day (i.e. one day on), followed by a period of four to six days in which the compound of formula (I) is not administered or placebo is administered (i.e. four to six days off).
  • Said administration cycle takes a total of five (i.e. one day on followed by four days off) to seven days (i.e. one day on followed by six days off) to be completed, depending on the number of days on and days off.
  • each administration cycle the compound of formula (I) is administered for a period of two days (i.e. two days on), followed by a period of four to six days in which the compound of formula (I) is not administered or placebo is administered (i.e. four to six days off).
  • Said administration cycle takes a total of six (i.e. two days on followed by four days off) to eight days (i.e. two days on followed by six days off) to be completed, depending on the number of days on and days off.
  • each administration cycle the compound of formula (I) is administered for a period of three days (i.e. three days on), followed by a period of four to six days in which the compound of formula (I) is not administered or placebo is administered (i.e. four to six days off).
  • Said administration cycle takes a total of seven (i.e. three days on followed by four days off) to nine days (i.e. three days on followed by six days off) to be completed, depending on the number of days on and days off.
  • each administration cycle the compound of formula (I) is administered for a period of four days, followed by a period of four to six days in which the compound of formula (I) is not administered or placebo is administered.
  • Said administration cycle takes a total of eight (i.e. four days on followed by four days off) to ten days (i.e. four days on followed by six days off) to be completed, depending on the number of days on and days off.
  • each administration cycle the compound of formula (I) is administered for a period of five days, followed by a period of four to six days in which the compound of formula (I) is not administered or placebo is administered.
  • Said administration cycle takes a total of nine (i.e. five days on followed by four days off) to eleven days (i.e. five days on followed by six days off) to be completed, depending on the number of days on and days off.
  • Table A Embodiments according to the aspects of the invention. Each row represents a specific embodiment of the invention.
  • the administration cycle may be performed one or more times, for example the administration cycle may be performed one, two, three, four or five times, followed by an optional break period of four to eight days (for example four, five, six, seven or eight days) in which the compound of formula (I) is not administered.
  • the compound of formula (I) is administered once-daily in the days on.
  • the compound of formula (I) is administered once-daily according to a 1 day on followed by 6 days off dosing schedule for 21 days followed by 4 to 8 days (break period) without treatment with a PI3K inhibitor.
  • the compound of formula (I) is administered once-daily according to a 2 days on followed by 5 days off dosing schedule for 21 days followed by 4 to 8 days (break period) without treatment with a PI3K inhibitor.
  • the compound of formula (I) is administered once-daily according to a 2 days on followed by 5 days off dosing schedule for 21 days followed by 7 days (break period) without treatment with a PI3K inhibitor.
  • the compound of formula (I) is administered once-daily according to a 3 days on followed by 4 days off dosing schedule for 21 days followed by 4 to 8 days (break period) without treatment with a PI3K inhibitor.
  • the compound of formula (I) is administered once-daily according to a 4 days on followed by 3 days off dosing schedule for 21 days followed by 4 to 8 days (break period) without treatment with a PI3K inhibitor.
  • the administration cycle is performed one or more times, for example one, two, three, four or five times.
  • the administration cycle is performed one, two, three or four times followed by a break period of four to eight days (for example four, five, six, seven or eight days) in which the compound of formula (I) is not administered.
  • the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the specific initial and maintenance dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • the compound of formula (I) is administered orally.
  • the compound of formula (I) is administered orally.
  • the term 'effective daily dose' is the effective daily amount of compound administered in the days it is administered according to the dosing regimen.
  • effective daily doses of compounds of general formula (I) are in the range of about 50 to about 400 mg/day, preferably about 100 to about 300 mg/day, more preferably about 150 to about 250 mg/day, for example specific daily doses of 50 mg, 100 mg, 150mg, 200 mg, 250mg, 300mg or 400 mg (all per day).
  • dose unit refers to the amount of compound administered in each dosing periodicity.
  • individual dosage units of compounds of general formula (I) are in the range of about 50 to about 400 mg, more preferably about 100 to about 300 mg, even more preferably about 150 to about 250 mg, for example 50 mg, 100 mg, 150mg, 200 mg, 250mg, 300mg or 400 mg.
  • the patient may take one dosage unit containing the total amount of the compound of general formula (I) or two or more dosage units which add up to the desired effective daily dose.
  • total amount in each administration cycle refers to the cumulative amount of compound administered in the days it is administered in the each administration cycle (i.e. total cumulative amount in days on).
  • the compound of formula (I) is administered in a total amount of about 200 mg to about 1000 mg in each administration cycle.
  • the compound of formula (I) is administered in a total amount of about 300 mg to about 900 mg in each administration cycle.
  • the compound of formula (I) is administered in a total amount of about 400 mg to about 800 mg in each administration cycle.
  • the compound of formula (I) is administered in an amount of about 50 mg to about 400 mg per day, in the days it is administered.
  • the compound of formula (I) is administered in an amount of about 100 mg to about 400 mg per day, in the days it is administered.
  • the compound of formula (I) is administered in an amount of about 100 mg to about 300 mg per day, in the days it is administered. According to an embodiment, the compound of formula (I) is administered in an amount of about 150 mg to about 250 mg per day, in the days it is administered.
  • the compounds of this invention can be administered as the sole pharmaceutical agent according to the dosing regimen of the present invention or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the present invention relates also to such combinations.
  • the compounds of this invention can be combined with known anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof.
  • Other indication agents include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, antimetabolites, DNA-intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, toposisomerase inhibitors, biological response modifiers, or anti-hormones.
  • the additional pharmaceutical agent can be aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, azathioprine, BCG or tice BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine , bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine, cladribine, clodronic acid
  • UFT uridine, valrubicin. vesnarinone. vinblastine, vincristine, vindesine, vinorelbine, virulizin, zinecard, zinostatin stimalamer, zofran, ABI-007, acolbifene, actimmune, affinitak, aminopterin, arzoxifene, asoprisnil, atamestane, atrasentan, sorafenib, avastin, CCI-779, CDC-501 , Celebrex, cetuximab, crisnatol, cyproterone acetate, decitabine, DN-101 , doxorubicin- TC, dSLIM, dutasteride, edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-
  • a compound of general formula (I) as defined herein can optionally be administered in combination with one or more of the following: 131 l-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate.amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, benda
  • cinacalcet cisplatin, cladribine, clodronic acid, clofarabine, crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin
  • epirubicin epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, gosereli
  • Optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 1 1 th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5- fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednis
  • anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et a/. , publ.
  • anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifen and topotecan.
  • the compounds of the invention may also be administered in combination with protein therapeutics.
  • Such protein therapeutics suitable for the treatment of cancer or other angiogenic disorders and for use with the compositions of the invention include, but are not limited to, an interferon (e.g., interferon .alpha., .beta., or .gamma.) supraagonistic monoclonal antibodies, Tuebingen, TRP-1 protein vaccine, Colostrinin, anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab, trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1 , bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab, rhMBL, MFE-CP1 + ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35, MT-103, rinfabate, AS- 1402,
  • Monoclonal antibodies useful as the protein therapeutic include, but are not limited to, muromonab-CD3, abciximab, edrecolomab, daclizumab, gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab, efalizumab, adalimumab, omalizumab, muromomab-CD3, rituximab, daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.
  • a compound of general formula (I) as defined herein can optionally be administered in combination with one or more of the following: ARRY-162, ARRY-300, ARRY-704, AS-703026, AZD-5363, AZD-8055, BEZ-235, BGT-226, BKM-120, BYL-719, CAL- 101 , CC-223, CH-5132799, deforolimus, E-6201 , enzastaurin , GDC-0032, GDC- 0068, GDC-0623, GDC-0941 , GDC-0973, GDC-0980, GSK-21 10183, GSK-2126458, GSK-2141795, MK-2206, novolimus, OSI-027, perifosine, PF-04691502, PF- 05212384, PX-866, rapamycin, RG-7167, RO-4987655, RO-5126766, selumetinib, TAK-733, trametini
  • cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will serve to: (1 ) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone,
  • the compound of formula (I) is used or administered in combination with one or more additional active ingredients selected from : a taxane, such as Docetaxel, Paclitaxel, or Taxol; an epothilone, such as Ixabepilone, Patupilone, or Sagopilone; Mitoxantrone; Predinisolone; Dexamethasone; Estramustin; Vinblastin; Vincristin; Doxorubicin; Adriamycin; Idarubicin; Daunorubicin; Bleomycin; Etoposide; Cyclophosphamide; Ifosf amide; Procarbazine; Melphalan; 5- Fluorouracil; Capecitabine; Fludarabine; Cytarabine; Ara-C; 2-Chloro-2 ' - deoxyadenosine; Thioguanine; an anti-androgen, such as Flutamide, Cyproterone acetate, or Bicalutamide; Bortez
  • the compound of formula (I) is used or administered according to the dosing regimen of the present invention in combination with an anti- hyperproliferative, cytotoxic and/or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
  • an anti- hyperproliferative, cytotoxic and/or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin
  • the compound of formula (I) is used or administered according to the dosing regimen of the present invention in combination with an anti- hyperproliferative, cytotoxic and/or cytostatic agent selected from 5-FU, capecitabine, oxaliplatin and paclitaxel, or combinations thereof.
  • an anti- hyperproliferative, cytotoxic and/or cytostatic agent selected from 5-FU, capecitabine, oxaliplatin and paclitaxel, or combinations thereof.
  • the compound of formula (I) is used or administered in combination with a pharmaceutically acceptable salt of the alkaline-earth radionuclide radium-223, such as radium-223 dichloride.
  • the combination comprising compound of formula (I) and a pharmaceutically acceptable salt of the alkaline-earth radionuclide radium-223, such as radium-223 dichloride is used or administered in combination with an anti-androgen therapy, such as, an androgen biosynthesis inhibitor, such as, ketoconazole and abiraterone, and/or an androgen receptor blocker, such as, bicalutamide, nilutamide, flutamide or enzalutamide.
  • said anti-androgen is selected from bicalutamide, enzalutamide and abiraterone.
  • the dosing regimen of the compound of formula (I) and the other active ingredients may be the same or different: each may be administered at the same time or at different times; the compounds of the combination may be administered on the same day or in different days. It will therefore be appreciated that the compounds of the combination may be administered sequentially (e.g. before or after) or concomitantly, either in the same pharmaceutical formulation (i.e. together), or in different pharmaceutical formulations (i.e. separately). Simultaneously in the same formulation is as a unitary formulation whereas simultaneously in different pharmaceutical formulations is non-unitary.
  • the administration regime of each of the two or more compounds in a combination therapy may also differ with respect to the route of administration.
  • the compound of formula (I) is administered simultaneously, concomitantly, separately or sequentially with the additional one or more additional active ingredients.
  • the compound of formula (I) is compound A1 (Cpd A1 ) or W-(8- ⁇ [(2 )-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy ⁇ -7-methoxy-2,3- dihydroimidazo[1 : 2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide.
  • a compound of the present invention may be used according to the dosing regimen of the present invention to sensitize a cell to radiation. That is, treatment of a cell with a compound of the present invention according to the dosing regimen of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA damage and cell death than the cell would be in the absence of any treatment with a compound of the invention.
  • the cell is treated with at least one compound of the invention.
  • the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the invention according to the dosing regimen of the present invention in combination with conventional radiation therapy.
  • the present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated one or more compounds of the invention according to the dosing regimen of the present invention prior to the treatment of the cell to cause or induce cell death.
  • the cell is treated with at least one compound according to the dosing regimen of the present invention, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.
  • a cell is killed by treating the cell with at least one DNA damaging agent. That is, after treating a cell with one or more compounds of the invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell.
  • DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g. , cisplatinum), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents.
  • a cell is killed by treating the cell with at least one method to cause or induce DNA damage.
  • Such methods include, but are not limited to, activation of a cell signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage.
  • a DNA repair pathway in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an abnormal accumulation of DNA damage in a cell.
  • a compound of the invention is administered to a cell according to the dosing regimen of the present invention prior to the radiation or orther induction of DNA damage in the cell.
  • a compound of the invention is administered to a cell concomitantly with the radiation or orther induction of DNA damage in the cell.
  • a compound of the invention is administered to a cell immediately after radiation or orther induction of DNA damage in the cell has begun.
  • the cell is in vitro. In another embodiment, the cell is in vivo.
  • the compounds of the present invention have surprisingly been found to effectively inhibit PI3K and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by PI3K, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g.
  • leukaemias and myelodysplastic syndrome including leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
  • the present invention covers a compound of general formula (I), or a stereoisomer, a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described and defined herein, for use in the treatment or prophylaxis of a disease according to the dosing regimen of the present invention, as mentioned supra.
  • Another particular aspect of the present invention is therefore the use of a compound of general formula (I) described supra for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease according to the dosing regimen of the present invention, as mentioned supra.
  • the diseases referred to in the two preceding paragraphs are diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by PI3K, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g.
  • leukaemias and myelodysplastic syndrome including leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
  • inappropriate within the context of the present invention, in particular in the context of "inappropriate cellular immune responses, or inappropriate cellular inflammatory responses", as used herein, is to be understood as preferably meaning a response which is less than, or greater than normal, and which is associated with, responsible for, or results in, the pathology of said diseases.
  • the use is in the treatment or prophylaxis of diseases according to the dosing regimen of the present invention, wherein the diseases are haemotological tumours, solid tumours and/or metastases thereof.
  • the present invention relates to a method for using the compounds according to the dosing regimen of the present invention and compositions thereof, to treat mammalian hyper-proliferative disorders.
  • Compounds can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof ; etc. which is effective to treat the disorder.
  • Hyper-proliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
  • BPH benign prostate hyperplasia
  • solid tumors such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
  • Those disorders also include lymphomas, sarcomas, and leukemias.
  • breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
  • Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
  • Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
  • Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.
  • Lymphomas include, but are not limited to AIDS-related lymphoma, non- Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • treating or “treatment” as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma.
  • the pathological states treated by the compounds are hyper-proliferative and/or angiogenesis disorder of humans which benefit from administration of a PI3K inhibitor.
  • the hyper-proliferative and/or angiogenesis disorder is a disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response, more particularly a disorder mediated by the phosphotidylinositol-3-kinase (PI3K) pathway, even more particularly is a haemotological tumour, a solid tumour and/or metastases thereof, e.g.
  • PI3K phosphotidylinositol-3-kinase
  • leukaemias and myelodysplastic syndrome including leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
  • the hyper-proliferative and/or angiogenesis disorder is gastric cancer.
  • Suitable methods and uses of the compound of formula (I) for the treatment of breast cancer, prostate cancer, multiple myeloma, hepatocyte carcinoma, lung cancer, in particular non-small cell lung carcinoma, colorectal cancer, melanoma, pancreatic cancer and/or metastases thereof are described in PCT/EP2014/076051 (WO2015082378) and in priority applications EP14163752.0 and EP13195567.6 which are all three incorporated by reference herein in their entirety.
  • the hyper-proliferative and/or angiogenesis disorder is breast cancer, prostate cancer, multiple myeloma, hepatocyte carcinoma, lung cancer, in particular non-small cell lung carcinoma, colorectal cancer, melanoma, pancreatic cancer and/or metastases thereof.
  • Suitable methods and uses of the compound of formula (I) for the treatment of breast cancer, prostate cancer, multiple myeloma, hepatocyte carcinoma, lung cancer, in particular non-small cell lung carcinoma, colorectal cancer, melanoma, pancreatic cancer with bone metastases are described in PCT/EP2014/076051 (WO2015082378) and in priority applications EP14163752.0 and EP13195567.6 which are all three incorporated by reference herein in their entirety.
  • the hyper-proliferative and/or angiogenesis disorder is breast cancer, prostate cancer, multiple myeloma, hepatocyte carcinoma, lung cancer, in particular non-small cell lung carcinoma, colorectal cancer, melanoma, pancreatic cancer with bone metastases.
  • the hyper-proliferative and/or angiogenesis disorder is cancer with PTEN loss or PIK3CA mutation and KRAS wild type.
  • the hyper-proliferative and/or angiogenesis disorder is locally advanced or metastatic endometrial or breast cancer with PTEN loss or PIK3CA mutation and KRAS wild type, or indolent non-Hodgkin's lymphoma (iNHL).
  • the PI3K inhibitor is selected from the group of PI3K inhibitors consisting of buparlisib, idelalisib, BYL-719, dactolisib, PF-05212384, pictilisib, ZSTK-474, GSK-2636771 , duvelisib, GS-9820, PF-04691502, SAR-245408, SAR- 245409, sonolisib, Archexin, GDC-0032, GDC-0980, apitolisib, pilaralisib, DLBS 1425, PX-866, voxtalisib, AZD-8186, BGT-226, DS-7423, GDC-0084, GSK-2126458, INK-1 1 17, SAR-260301 , SF-1 126, AMG-319, BAY-1082439, CH-5132799, GSK- 2269557, P-7170, PWT-33597,
  • the present invention also provides methods for the treatment of disorders associated with aberrant mitogen extracellular kinase activity, including, but not limited to stroke, heart failure, hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, cystic fibrosis, symptoms of xenograft rejections, septic shock or asthma.
  • Effective amounts of compounds of the present invention can be used to treat such disorders, including those diseases (e.g., cancer) mentioned in the Background section above. Nonetheless, such cancers and other diseases can be treated with compounds of the present invention, regardless of the mechanism of action and/or the relationship between the kinase and the disorder.
  • aberrant kinase activity or "aberrant tyrosine kinase activity,” includes any abnormal expression or activity of the gene encoding the kinase or of the polypeptide it encodes. Examples of such aberrant activity, include, but are not limited to, over-expression of the gene or polypeptide ; gene amplification ; mutations which produce constitutively-active or hyperactive kinase activity ; gene mutations, deletions, substitutions, additions, etc.
  • the present invention also provides for methods of inhibiting a kinase activity, especially of mitogen extracellular kinase, comprising administering an effective amount of a compound of the present invention, including salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g.: esters) thereof, and diastereoisomeric forms thereof.
  • Kinase activity can be inhibited in cells (e.g.. in vitro), or in the cells of a mammalian subject, especially a human patient in need of treatment.
  • the present invention also provides methods of treating disorders and diseases associated with excessive and/or abnormal angiogenesis.
  • Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism.
  • a number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal- vein occlusion, and retinopathy of prematurity [Aiello et al. New Engl. J. Med. 1994, 331 , 1480 ; Peer et al. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD ; see, Lopez et al. Invest. Opththalmol. Vis. Sci.
  • neovascular glaucoma neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc.
  • RA rheumatoid arthritis
  • restenosis in-stent restenosis
  • vascular graft restenosis etc.
  • the increased blood supply associated with cancerous and neoplastic tissue encourages growth, leading to rapid tumor enlargement and metastasis.
  • the growth of new blood and lymph vessels in a tumor provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer.
  • compounds of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, e.g., by inhibiting and/or reducing blood vessel formation ; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.
  • PI3K-inhibitors mentioned in the prior art as well as in the lists above have been disclosed for the treatment or prophylaxis of different diseases, especially cancer.
  • FIG. 1 PI3K pathway inhibition in GXA3027 patient derived gastric tumor models treated with different dosing schedules of Compound A1.
  • Patient derived GXA 3027 gastric cancer cells were implanted subcutaneously (s.c.) onto NMRI nude mice. When tumors had reached a size of approximately 700 mm 3 , compound A1 was dosed at 75 mg/kg, QD (once daily, A and D), or 450 mg/kg, QW (once weekly, B and E), or 200 mg/kg 20n/50ff (C and F). Compound A1 was administered orally with indicated doses and dosing schedules. Levels of p-AKT (A, B, and C) and p-RAS40 (D, E, and F) in tumors were assessed.
  • Figure 2 Relationship of PI3K inhibitor Compound A1 exposure in plasma and p-PRAS40 in tumors in GXA3027 tumor bearing mice treated with different dosing schedules of Compound A1.
  • the exposure of Compound A1 (A) and inhibition of p-PRAS40 (B) were measured at the indicated time post 1 st administration.
  • Patient derived GXA 3027 gastric cancer cells were implanted subcutaneously (s.c.) onto NMRI nude mice.
  • compound A1 was dosed at 75 mg/kg, QD (once daily continuously, A and D), or 450 mg/kg, QW (once weekly, B and E), or 200 mg/kg 20n/50ff (C and F).
  • Compound A1 was administered orally once daily at the indicated doses and dosing schedules.
  • Levels of activated caspase 3 (A, B, and C), cleaved PARP (D, E, and F) in tumors and tumor growth inhibition as well as response rate (G) were assessed.
  • KPL4 cells were implanted subcutaneously (s.c.) onto nude rats. When tumors had reached a size of approximately 30 mm 2 , animals were randomized and compound A1 was dosed at 15 mg/kg, QD continuously, or 105 mg/kg, QW (once weekly), or 55 mg/kg 20n/50ff.
  • treatment and variations such as 'treat' or 'treating' refer to any regime that can benefit a human or non-human animal.
  • compounds of formula (I) can be used for prophylaxis (preventative treatment).
  • Treatment may include curative, alleviation or reducing effects, such effects relating to one or more of the symptoms associated with the hyper-proliferative and/or angiogenesis disorders.
  • One particular embodiment of the invention that can be mentioned is a compound of formula (I), particularly /V-(8- ⁇ [(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy ⁇ -7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide (compound A1 : ex.
  • One particular embodiment of the invention that can be mentioned is a compound of formula (I), particularly N-(8- ⁇ [(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy ⁇ -7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide (compound A1 : ex.
  • the compounds of general formula (I) may also be present in the form of stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
  • Suitable physiologically acceptable counter ions are known to the art.
  • prodrugs of compounds of the general formula (I) in order to alter the therapeutic profile of the active compound.
  • the compound of formula (I) is administered as a pharmaceutical composition.
  • inert pharmaceutically acceptable carriers are admixed with the active compounds.
  • the pharmaceutically acceptable carriers may be solid or liquid. Solid form preparations include powders, tablets, dispersible granules and capsules.
  • a solid carrier can be one or more substances which may also act as diluent, flavouring agent, solubiliser, lubricant, suspending agent, binder, glidant, or disintegrant; it may also be an encapsulating material.
  • the pharmaceutical composition is in unit dosage form, e.g. a packaged preparation, the package containing discrete quantities of the preparation, for example packaged tablets, capsules and powders in vials or ampoules.
  • the pharmaceutical composition is a tablet.
  • the compound of formula (I) is administered orally, preferably as an oral tablet or capsule, more preferably as an oral tablet.
  • Example 1 Immediate release tablet manufactured via fluid bed granulation containing the compound of general formula (I) and optionally subsequent film- coating
  • the weights and dimensions may vary by about ⁇ 10%.
  • Wet granulation process The fluidized bed granuiator was charged with presieved Compound (A1 ) micronized, mannitol and microcrystalline cellulose. A wet granulation process was performed by adding the granulation liquid containing hypromellose 5cP and sodium laurilsulfate in purified water in bulk. The granules were dried and sieved.
  • Compound (A1 ) micronized, mannitol and microcrystalline cellulose.
  • a wet granulation process was performed by adding the granulation liquid containing hypromellose 5cP and sodium laurilsulfate in purified water in bulk. The granules were dried and sieved.
  • Tabletting The final blend was compressed into tablets. The uncoated tablets were tested regarding uniformity of mass, thickness, resistance to crushing of tablets, friability and disintegration.
  • a batch of tablet cores may be divided in several sub-batches for optional coating. Lacquer yellow was suspended in purified water in bulk to result in a homogeneous coating suspension which was sprayed on the tablets. The coated tablets were tested regarding uniformity of mass, thickness and disintegration. Optionally, tablets with coating defects may be selected out.
  • the amount of active ingredient may be reduced or increased by adjusting the amounts of the excipients, as can readily be determined by those skilled in the art.
  • the batch size for manufacturing of tablets may be scaled-up or scaled-down using equivalent equipment and processing, i.e. same operating principle, as can readily be determined by those skilled in the art.
  • Example 2 An in vivo PK/PD experiments with NMRI nu/nu mice bearing tumor xenograft. As tumor model the Asian gastric tumor model GXA 3027 was chosen.
  • Tumor fragments were obtained from xenografts in serial passage in nude mice. After removal from donor mice, tumors were cut into fragments (4-5 mm diameter) and placed in PBS until subcutaneous implantation. Mice under isoflurane anaesthesia received unilateral, subcutaneous tumor implants in the flank. Animals and tumor implants were monitored daily until the maximum number of implants showed clear signs of beginning solid tumor growth. At randomization, the volume of growing tumors was initially determined. Animals bearing at least one tumor of a volume of 300 - 600 mm 3 , were distributed in experimental groups according to the study protocol. The day of randomization is designated as day 0 of an experiment. Compound A1 was assessed at three different dosing schedules. A control group was included. Blood, tumor and tissue samples were collected at selected time points after application of Compound A1. At each time point, three mice per treatment group were sacrificed.
  • Compound A1 showed dose proportional increase in the plasma of animals in the groups of 450 mg/kg, QW (once weekly) and 200 mg/kg, 20n/50ff.
  • the elimination of Compound A1 appeared at 96h in both 450 mg/kg, QW group and 200 mg/kg, 20n/50ff group.
  • the Cm ax also showed dose linearity between 75-450 mg/kg.
  • Example 3 In vivo mechanism of action and pathway inhibition profile.
  • Pathway activation measured by the levels of p-AKT(S473) and downstream signalling molecule p-PRAS40 in extracts from tumor tissue were analysed with an ELISA-based assay.
  • the assays are based on the MULTI-SPOT® Assay System (Fa. Meso Scale Discovery, Cat# N41 100B-1 for p-AKT and K150JZD-1 for p-PRAS40) and were conducted following manufactures instructions.
  • the duration of potent inhibition of p-AKT was much longer > 24 h compared to 2 h observed in the low dose 75mg/kg, QD group.
  • the overall profile of p-PRAS40 inhibition by Compound A1 with different dosing regimen is very similar to the p-AKT inhibition profile.
  • treatment of PI3K inhibitor Compound A1 at 75 mg/kg, QD schedule led to a transient potent inhibition of p-PRAS40 at 2 h (80.6%), reduced inhibition at 8 h (58.9%) and at 24 h the p-PRAS40 recovered to the levels of vehicle control.
  • high dose 450 mg/kg intermittent QW dosing generated an initial prolonged (>24 h vs 2 h) and more potent maximum inhibition (92.4% vs 80.6%) of p- PRAS40 and released the cells from pathway inhibition from 96 till 168 h (3 days).
  • concentrations of Compound A1 dosed at 450 mg/kg reached 9179 pg/L at 2 h (correlated with greater than 92% p-PRAS40 inhibition), which was not achievable for 75 mg/kg dosing group.
  • a concentration of 1907 pg/L at 24 h correlated with approx. 80% p-PRAS40 inhibition was comparable to the exposure and maximum inhibition at 2 h observed in 75 mg/kg dosing group.
  • plasma concentration of Compound A1 at 48 h correlated with approx. 60% p-PRAS40 inhibition was comparable to the exposure and p-PRAS40 inhibition at 8 h observed in 75 mg/kg dosing group.
  • administration of Compound A1 with different dosing regimens showed a clear PK PD relationship.
  • pathway inhibition 50-80% inhibition of p-PRAS40
  • an approx. 16 h recovery period ⁇ 50% pathway inhibition
  • Example 5A In vivo efficacy of Compound A1 dosed continuously or intermittently in GXA3027 patient derived gastric tumor model in mice as a single agent and in combination with cisplatin and capecitabine.
  • Compound A1 was administered p.o. once daily at 60 mg/kg, 20n/50ff at 210 mg/kg, or once weekly at 420 mg/kg with the same weekly cumulative dose of 420 mg/kg in GXA3027 patient derived gastric tumor model in N RI nu/nu mice.
  • Anti-tumor activity was determined as tumor growth inhibition relative to the vehicle control group and starting tumor volumes and is expressed as the ratio of group median relative tumor volumes (Vtreat m ent-Vinitiai)/(Vcontroi- Vinitiai)%; T/C [%]).
  • the animal body weight was monitored as a measure for treatment-related toxicity. Measurements of tumor size and body weight were performed 2-3 times weekly.
  • Statistical analysis was assessed using SigmaStat software. A one-way analysis of variance was performed and differences to the control are compared by a pair-wise comparison procedure (Dunn's method). Relative T/C ratios were calculated with final tumor areas at study end, if not mentioned otherwise.
  • Paclitaxel in combination with weekly COMPOUND A1 (500/400 mg/kg) was highly active with an optimal T/C value of 9.1 % and an overall tumor stasis with 3/8 partial tumor remissions.
  • the combination effect of paclitaxel plus intermittent weekly COMPOUND A1 therefore has to be assessed by tumor growth delay.
  • Vehicle b 0.9% saiine, vehicle x: 0.1 N HCI ph 4.0
  • Example 6 In vivo efficacy of Compound A1 dosed continuously or intermittently in KPL4 breast tumor model in rats.
  • All Compound A1 treatment group demonstrated potent anti-tumor efficacy in KPL-4 breast cancer xenografts on nude rats.
  • the T/C assessed by both final tumor area and tumor weight indicated that the best anti-tumor efficacy was achieved with QW at 105 mg/kg dosing regimen (T/Carea/weight 0.15/0.1 1 , Table 10 and Figure 4).
  • the two intermittent dosing groups demonstrated much better disease control rate (80% and 50% for QW and 20n/50ff groups, respectively), while the continuous QD group reached only 10% disease control rate assessed according to the clinically used RECIST criteria.
  • Table 10 Summary of efficacy assessment of Compound A1 with different dosing regimens in KPL4 breast cancer cell line in nude rats.
  • Example 8 Clinical trial in patients with cancer: dosage regimen 2 days on / 5 days off
  • Compound A1 is administered on Day1 , Day2, Day8, Day9, Day15, and Day16 of each 28-day cycle (Table 1 1 ) to define the safety profile, PK, and biomarker and tumor response profile in subjects with locally advanced or metastatic endometrial cancer or breast cancer [with PTEN (loss) or PIK3CA mut and KRAS wt tumors (determined at pre-screening using circulating tumor DNA)] and subjects with indolent non-Hodgkin's lymphoma (iNHL).
  • a cycle for this study is defined as a period of 28 days (which includes three administration cycles plus seven days break period). Daily dosage may be adjusted (reduced or increased) according to patient's clinical response and/or occurrence of adverse events.
  • Table 11 Administration of Compound A1 once daily in 28-day cycles
  • Compound A1 was tested in a 4-week, repeat-dose toxicity study in Wistar rats with once daily oral doses of 0. 5.0, 10.0 and 15.0 mg/kg.
  • One additional high dose group receiving a cumulative dose of 105 mg/kg (15.0 mg/kg/day x 7 days) was included with an intermittent treatment schedule (once weekly, a total of 3 administrations).
  • Main group animals were sacrificed at the end of the respective treatment periods. Satellite animals were used for toxicokinetic evaluation and to assess the reversibility of potential compound-related effects in a 4-week recovery period.
  • Lymph nodes showed minimal to moderate atrophy and minimal to slight lymphoid depletion at the low daily dose and higher.
  • the weekly high dose showed a similar extend as the daily low dose.
  • three male animals showed minimal lymphoid hyperplasia in the mesenteric lymph node.
  • lymphoid depletion and atrophy had disappeared.
  • An increased hematopoiesis in the spleen was observed in several animals in all dose groups including controls at the end of the recovery period. No difference was seen any more in comparison to the weekly high dose group.
  • Compound related histological findings in lymphatic organs after the end of treatment and at the end of a 4-week recovery period are given below.
  • Table 13 Compound related histological findings in lymphatic organs in animals at termination of the 4 week recovery period.
  • PI3K inhibitors currently in clinical development are mainly being dosed orally and continuously. With only a few PI3K inhibitors demonstrating clinical activity, the majority of the PI3K inhibitors showed side effects before reaching substantial anti-tumor efficacy. Surprisingly we have found that intermittent treatment according to the dosage regimen described herein led to a better anti-tumor efficacy compared to continuous treatment. Based on the anticipated mode-of-action, for an effective inhibition of tumor growth and survival a potent suppression of PI3K pathway in tumor tissue by the PI3K inhibitor may be advantageous. The same may apply to other PI3K mediated disorders.

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Abstract

La présente invention concerne un composé de formule (I), tel que défini dans la description, destiné à être utilisé dans la prophylaxie ou le traitement d'un trouble hyperprolifératif et/ou de l'angiogenèse. Au cours de chaque cycle d'administration, le composé de formule (I) est administré pendant une période allant d'un à cinq jours, suivie par une période de trois à six jours durant laquelle le composé de formule (I) n'est pas administré ou un placebo est administré.
PCT/EP2015/078292 2014-12-03 2015-12-02 Régime d'administration de dérivés de 2,3-dihydroimidazo[1,2-c]quinazoline substitués par un amino-alcool WO2016087488A1 (fr)

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US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
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US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
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WO2021260443A1 (fr) * 2020-06-24 2021-12-30 Bayer Aktiengesellschaft Associations de 2,3-dihydroimidazo[1,2-c]quinazolines

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