istration Regime For Aminoalcohol Substituted 2,3-dihydroimidazo| 1 ,2- c|quinazoiine Derivatives"

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).

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, β or δ) heterodimerized with a member of the p85 regulatory subunit family. In contrast, 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 ΡΙ3Κγ 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. Activation of the lipid kinase activity of the ρΙ ΙΟβ and p 1 10γ isoforms has been shown to occur in response to binding to activated forms of the ras Oncogene (Kodaki et al. , 1994). In fact, the oncogenic activity of these isoforms may require binding to ras (Kang et al., 2006). In contrast, the p1 10a and ρΐ ΐθδ isoforms exhibit oncogenic activity independent of ras binding, through constitutive activation of Akt.

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. , 2000; Itoh & Takenawa, 2002; Lemmon, 2003). This co-localization of PDK1 with Akt facilitates the phosphorylation and activation of Akt. Carboxy-terminal phosphorylation of Akt on Ser ⁴⁷³ promotes phosphorylation of Thr ³⁰⁸ in the Akt activation loop (Chan & Tsichlis, 2001 ; Hodgkinson et al. , 2002; Scheid et al. , 2002; Hresko et al. , 2003). Once active, Akt phosphorylates and regulates multiple regulatory kinases of pathways that directly influence cell cycle progression and cell survival.

Many of the effects of Akt activation are mediated via its negative regulation of pathways which impact cell survival and which are commonly dysregulated in cancer. 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. Bax, Fas, PUMA and DR5), the cell cycle inhibitor, p21 ^Cip1 , and the PTEN tumor suppressor (Momand et al. , 2000; Hupp et al. , 2000; Mayo et al. , 2002; Su et al. , 2003). Similarly, the Akt-mediated phosphorylation of the Forkhead transcription factors FKHR, FKHRL and AFX (Kops et al. , 1999; Tang ef al. , 1999), facilitates their binding to 14-3-3 proteins and export from the cell nucleus to the cytosol (Brunet et al. , 1999). This functional inactivation of 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). Forkhead transcription factors regulate the expression of the cyclin-dependent kinase (Cdk) inhibitor p27 ^Kip1 . Indeed, 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). In addition to these effects, Akt phosphorylates IKK (Romashkova & Makarov, 1999), leading to the phosphorylation and degradation of Ι κΒ and subsequent nuclear translocation of NFKB, resulting in the expression of survival genes such as IAP and Bcl-Xi .

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. , 2003; Figueroa ef al. , 2003). The induction of p38 ^MAPK activity is observed in tumors treated with cytotoxic agents and is required for those agents to induce cell death (reviewed in Olson & Hallahan, 2004). Thus, inhibitors of the PI3K pathway may promote the activities of co-administered cytotoxic drugs.

An additional role for PI3K/Akt signaling involves the regulation of cell cycle progression through modulation of Glycogen Synthase Kinase 3 (GSK3) activity. 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.

Although 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 10β 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/. , 1999; Ma et a/. , 2000). Elevated PI3K activity has been observed in colorectal carcinomas (Phillips et a/. , 1998) and increased expression has been observed in breast carcinomas (Gershtein ef a/. , 1999).

Over the last few years, somatic mutations in the gene encoding p1 10a (PIK3CA) have been identified in numerous cancers. 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/. , 2005; Gallia ef a/. , 2006), 25% of gastric cancers (Samuels et al., 2004; Byun ef al. , 2003; Li ef al. , 2005), 36% of hepatocellular carcinomas (Lee ef al. , 2005), 4-12% of ovarian cancers (Levine et al., 2005; Wang ef al. , 2005), 4% of lung cancers (Samuels et al., 2004; Whyte & Holbeck, 2006), and up to 40% of endometrial cancers (Oda ef al. , 2005). 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. Biochemical analysis and protein expression studies have demonstrated that both mutations lead to increased constitutive p1 10a catalytic activity and are in fact, oncogenic (Bader ef al. , 2006; Kang et al. , 2005; Samuels et a/. , 2005; Samuels & Ericson, 2006). Recently, it has been reported that PIK3CA knockout mouse embryo fibroblasts are deficient in signaling downstream from various growth factor receptors (IGF-1 , Insulin, PDGF, EGF), and are resistant to transformation by a variety of oncogenic RTKs (IGFR, wild-type EGFR and somatic activating mutants of EGFR, Her2/Neu) (Zhao ef a/. , 2006).

Functional studies of PI3K in vivo have demonstrated that siRNA-mediated downregulation of ρΙ ΙΟβ inhibits both Akt phosphorylation and HeLa cell tumor growth in nude mice (Czauderna et a/. , 2003). In similar experiments, siRNA- mediated downregulation of p l S ()β 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). Several somatic mutations in the genes encoding the p85a and ρ85β regulatory subunits of PI3K that result in elevated lipid kinase activity have been identified in a number of cancer cells as well (Janssen et a/. , 1998; Jimenez et a/. , 1998; Philp et a/. , 2001 ; Jucker et a/. , 2002; Shekar et a/., 2005). Neutralizing PI3K antibodies also block mitogenesis and can induce apoptosis in vitro (Roche et a/., 1994; Roche et a/. , 1998; Benistant et al., 2000). In vivo proof-of-principle studies using the PI3K inhibitors LY294002 and wortmannin, demonstrate that inhibition of PI3K signaling slows tumor growth in vivo (Powis et ai, 1994; Schultz ef al. , 1995; Semba ef al. , 2002; Ihle ef al. , 2004).

Overexpression of Class I PI3K activity, or stimulation of their lipid kinase activities, is associated with resistance to both targeted (such as imatinib and tratsuzumab) and cytotoxic chemotherapeutic approaches, as well as radiation therapy (West ef al. , 2002; Gupta ef al. , 2003; Osaki ef al. , 2004; Nagata ef al. , 2004; Gottschalk ef al. , 2005; Kim ef al. , 2005). 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).

The importance of 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. , 1998; Taylor et al. , 2000), increased proliferative potential, and decreased sensitivity to pro-apoptotic stimuli (Stambolic et al. , 1998). Reconstitution of a functional PTEN suppresses PI3K signaling (Taylor et al., 2000), inhibits cell growth and re-sensitizes cells to pro-apoptotic stimuli (Myers et al., 1998; Zhao ef al. , 2004). Similarly, restoration of PTEN function in tumors lacking functional PTEN inhibits tumor growth in vivo (Stahl et al. , 2003; Su et al., 2003; Tanaka & Grossman, 2003) and sensitizes cells to cytotoxic agents (Tanaka & Grossman, 2003).

The signaling inputs to Class I PI3Ks are diverse and can be deduced through genetic analyses. Thus, 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). However, MEFs in which ρ1 10β is ablated or replaced by a kinase-dead allele of ρ1 10β respond normally to growth factor stimulation via RTKs (Jia ef al. , 2008). In contrast, ρ1 10β catalytic activity is required for AKT activation in response to GPCR ligands (such as LPA). As such, 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 ρ1 10β 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 10β is rare in tumors, but amplification of ΡΙ3Κβ 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). Furthermore, in PTEN-deficient human cancer cell lines (e.g., PC-3, U87MG, and BT549) of p1 10β, but not p1 10a, inhibits downstream activation of AKT, cell transformation, and the growth of PTEN-deficient cells and tumor xenografts (Wee ef al., 2008). Genetic studies have suggested that the kinase activity of p1 10β is essential in cellular transformation caused by PTEN loss. For example, adding back a kinase-dead p1 10β, but not its wild-type counterpart, impaired focus formation in PTEN-deficient PC3 cells depleted for endogenous p1 10β (Wee et al., 2008). These studies demonstrate that PTEN-deficient tumor cells depend on ρ1 10β and its catalytic activity for signaling and growth. Genetic alteration of tumor suppressor gene PTEN is frequently found in many cancers (Liu et al.. 2009), such as endometrial cancer (43%), CRPC (35-79%), glioma (19%) and melanoma (18%). In the case of endometrial cancer, coexisting PIK3CA and PTEN genetic alteration was confirmed (Yuan & Cantley, 2008). In addition to mutation, amplification of PIK3CA and loss-of-function of PTEN by various molecular mechanisms have been discovered. For example, amplification of PIK3CA and loss-of-function of PTEN was 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).

While a subset of tumor types are solely dependent on PI3Ka signaling, other tumors are dependent on ΡΙ3Κβ signaling or on a combination of both PI3Ka and ΡΙ3Κβ signaling.

Accordingly, there is still a need for PI3K inhibitors exhibiting balanced inhibition of both PI3K and ΡΙ3Κβ isoforms. In particular, there is a need for PI3K inhibitors displaying equipotent (i.e. balanced) inhibitory activity against both PI3Ka and ΡΙ3Κβ to obtain the desired therapeutic effect and which simultaneously present no or reduced adverse events/effects to the patient.

The applicant has previously discovered compounds which show balanced inhibition of both PI3Ka and ΡΙ3Κβ isoforms (see WO2012/062748).

Based on the anticipated mode-of-action, 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).

Furthermore, in addition to PI3Ks' important role in tumorigenesis, tumor growth, survival and metastasis, it also regulates the development, metabolism and biological functions of many normal cells and organs. Therefore, development of 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). Indeed, the majority of 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:

- afford potent suppression of PI3K pathway in tumor cells which may lead to sufficient or improved therapeutic efficacy (e.g. increased tumor killing efficacy and/or better disease control), and/or

- maintain or improve the toxicological profile (e.g. reduced incidence and severity of certain side effects and/or certain adverse events), in patients taking PI3K inhibitors for the treatment of hyper-proliferative disorders and/or diseases associated with angiogenesis.

SUMMARY of the INVENTION

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:

- provide an improved suppression of PI3K pathway in tumor tissue and/or an improved therapeutic efficacy (e.g. increased tumor killing efficacy and/or a better disease control) over continuous dosing, and/or

- maintain or improve the toxicological profile (e.g. by reducing the incidence and severity of certain side effects and/or certain adverse events observed under continuous dosing), in patients taking the compounds of formula (I) for the treatment of hyper-proliferative disorders and/or diseases associated with angiogenesis.

Accordingly, in a first aspect the present invention relates to a compound of formula (I)

(I)

in which :

R ¹ represents -(CH ₂ )n-(CHR ⁴ )-(CH ₂ ) _m -N(R ⁵ )(R ^5' ) ;

R ² represents a heteroaryl of structure :

optionally substituted with 1 , 2 or 3 R ⁶ groups,

in which :

* represents the point of attachment of said heteroaryl with the rest of the compound of general formula (I),

X represents N or C-R ⁶ ,

X' represents O, S, NH, N-R ⁶ , N or C-R ⁶ ,

with the proviso that when X and X' are both C-R ⁶ , then one C-R ⁶ is C-H ; R ³ is methyl ;

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,

or

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 , -Ci-Ce-alkyl-SR ⁷ , -Ci-C ₆ -alkyl-N(R ⁷ )(R ^7' ), - C(=0)OR ⁷ , -C(=0)N(R ⁷ )(R ^r ), -OR ⁷ , -SR ⁷ , -N(R ⁷ )(R ⁷ ), or -NR ⁷ C(=0)R ⁷ each of which may be optionally substituted with 1 or more R ⁸ groups ; each occurrence of R ^6' may be the same or different and is independently Ci-Ce-alkyl, Cs-Ce-cycloalkyl-C-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-Ce-alkenyl, C2-Ce-alkynyl, Cs-Ce-cycloalkyl, C:,- 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-C-Ce-alkyl, or heteroaryl-C-Ce-alkyl ; each occurrence of 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, C:,-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 ; n is an integer of 1 and m is an integer of 1 with the proviso that when :

- said R ⁵ and R ^5' , taken together with the nitrogen atom to which they are bound, represent :

in which * represents the point of attachment with the rest of the structure of general formula (I),

then

- said R ² heteroaryl of structure :

is not

in which * 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, or a mixture of same;

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.

According to another aspect of the present invention there is provided 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.

According to another aspect of the invention there is provided 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.

A. Definitions

The terms as mentioned in the present text have preferably the following meanings :

The term "halogen atom" or "halo" is to be understood as meaning a fluorine, chlorine, bromine or iodine atom.

The term "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 - dimethylbutyl, 2,3-dimethylbutyl, 1 ,3-dimethylbutyl, or 1 ,2-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1 , 2 or 3 carbon atoms ("Ci-Cs-alkyl"), methyl, ethyl, n-propyl- or iso-propyl.

The term "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.

The term "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. methoxyalkyl, ethoxyalkyl, propyloxyalkyl, iso- propoxyalkyl, butoxyalkyl, iso-butoxyalkyl, tert-butoxyalkyl, sec-butoxyalkyl, pentyloxyalkyl, iso-pentyloxyalkyl, hexyloxyalkyl group, in which the term "Ci-Ce- alkyl" is defined supra, or an isomer thereof.

The term "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. homoallyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1 - enyl, (Z)-but-l -enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-l -enyl, (Z)-pent-l -enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex- 4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-l -enyl, (Z)-hex-l-enyl, isopropenyl, 2-methylprop-2-enyl, 1 -methylprop-2-enyl, 2-methylprop-

1- enyl, (E)-1 -methylprop-1 -enyl, (Z)-1-methylprop-1 -enyl, 3-methylbut-3-enyl, 2- methylbut-3-enyl. 1 -methylbut-3-enyl, 3-methylbut-2-enyl. (E)-2-methylbut-2-enyl, (Z)-

2- methylbut-2-enyl, (E)-1 -methylbut-2-enyl, (Z)-1 -methylbut-2-enyl, (E)-3-methylbut- 1-enyl, (Z)-3-methylbut-1 -enyl, (E)-2-methylbut-1 -enyl, (Z)-2-methylbut-1 -enyl, (E)-1 - methylbut-1 -enyl, (Z)-1-methylbut-1 -enyl, 1 , 1 -dimethylprop-2-enyl, 1 -ethylprop-1 - enyl, 1 -propylvinyl, 1 -isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2- methylpent-4-enyl, 1 -methylpent-4-enyl, 4-methylpent-3-enyl, (E)-3-methylpent-3- enyl, (Z)-3-methylpent-3-enyl, (E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl, (E)-

1- methylpent-3-enyl, (Z)-1 -methylpent-3-enyl, (E)-4-methylpent-2-enyl, (Z)-4- methylpent-2-enyl, (E)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl, (E)-2- methylpent-2-enyl, (Z)-2-methylpent-2-enyl, (E)-1 -meihylpent-2-enyl, (Z)-1 - methylpent-2-enyl, (E)-4-methylpent-1 -enyl, (Z)-4-methylpent-1 -enyl, (E)-3- methylpent-1 -enyl, (Z)-3-methylpent-1 -enyl, (E)-2-methylpent-1 -enyl, (Z)-2- methylpent-1 -enyl, (E)-1 -methylpent-1 -enyl, (Z)-1 -methylpent-1 -enyl, 3-ethylbut-3- enyl, 2-ethylbut-3-enyl, 1 -ethylbut-3-enyl, (E)-3-ethylbut-2-enyl, (Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl, (E)-1 -ethylbut-2-enyl, (Z)-1-ethylbut-2- enyl, (E)-3-ethylbut-1 -enyl, (Z)-3-ethylbut-1 -enyl, 2-ethylbut-1-enyl, (E)-1 -ethySbut-1 - enyl, (Z)-1 -ethylbut-1 -enyl, 2-propylprop-2-enyl, 1 -propylprop-2-enyl, 2-isopropylprop-

2- enyl, 1 -isopropylprop-2-enyl, (E)-2-propylprop-1 -enyl, (Z)-2-propylprop-1 -enyl, (E)- 1-propylprop-1 -enyl, (Z)-1 -propylprop-1 -enyl, (E)-2-isopropylprop-1 -enyl, (Z)-2- isopropylprop-1 -enyl, (E)-1 -isopropylprop-1 -enyl, (Z)-1-isopropylprop-1 -enyl, (E)-3.3- dimethylprop-1 -enyl, (Z)-3,3-dimethylprop-1 -enyl, 1 -(1 , 1 -dimeihylethyl)ethenyl, buta- 1 ,3-dienyl, penta-1 ,4-dienyl, hexa-1 .5-dienyl, or methylhexadienyl group. Particularly, said group is vinyl or allyl.

The term "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 -methylpent-4-ynyl, 2- methylpent-3-ynyl, 1 -methylpent-3-ynyl, 4-methylpent-2-ynyl, 1 -methylpent-2-ynyl, 4- methylpent-1 -ynyl, 3-methylpent-1 -ynyl, 2-ethylbut-3-ynyl, 1 -ethylbut-3-ynyl, 1 - ethylbut-2-ynyl, 1 -propylprop-2-ynyl, 1 -isopropylprop-2-ynyl, 2,2-dimethylbut-3-inyl, 1 , 1 -dimethylbut-3-ynyl, 1 .1 -dimethylbut-2-ynyl, or 3,3-dimethylbut-1-ynyl group. Particularly, said alkynyl group is ethynyl, prop-1 -ynyl, or prop-2-inyl.

The term "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.

The term "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-CH2- ("hexylene ^' , "hexamethylene ^" , or six-membered tether") group. Particularly, said alkylene tether has 1 , 2, 3. 4. or 5 carbon atoms, more particularly 1 or 2 carbon atoms.

The term "3- to 8-membered heterocycloalkyl ^" , is to be understood as meaning a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 2, 3, 4, 5, 6 or 7 carbon atoms, and one or more heteroatom-containing groups selected from C(=0), O, S, S(=0), S(=0) ₂ , NRa, in which R ^a represents a hydrogen atom, or a Ci- Ce-alkyl- or halo-Ci-Ce-alkyl- group ; it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, the nitrogen atom.

Particularly, 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").

Particularly, without being limited thereto, 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. Optionally, 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.

As mentioned supra, 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.

The term "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 tetralinyl, dihydronaphthyl, or naphthyl group, or a ring having 13 carbon atoms, (a "Cis-aryl" group), e.g. a fluorenyl group, or a ring having 14 carbon atoms, (a "Ci4-aryl" group), e.g. an anthranyl group. 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.

The term "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

optionally substituted with 1 , 2 or 3 ⁶ groups,

in which :

* represents the point of attachment of said heteroaryl with the rest of the compound of general formula (I) as defined supra,

X represents N or C-R ⁶ ,

X' represents O, S, NH, N-R ⁶ , N or C-R ⁶ ,

- 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, Cs-Ce- cycloalkyl, Cs-Ce-cycloalkyl-Ci-Ce-alkyl, aryl, aryl-Ci-Ce-alkyI, heteroaryl, heteroaryl- Ci-Ce-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci- Ce-alkyl, -Ci-Ce-alkyl-OR ⁷ , -Ci-Ce-alkyl-SR ⁷ , -Ci-C ₆ -alkyl-N(R ⁷ )(R ^7' ), -Ci-Ce-alkyl- C(=0)R ⁷ .-CN. -C(=0)OR ⁷ , -C(=0)N(R ⁷ )(R ^7' ), -OR ⁷ . -SR ⁷ . -N(R ⁷ )(R ^r ), or - NR ⁷ C(=0)R ⁷ each of which may be optionally substituted with 1 or more R ⁸ groups ;

- each occurrence of 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 ;

- each occurrence of 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.

More particularly, 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, efc; or azocinyl, indolizinyl, purinyl, efc, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl, efc.

In general, and unless otherwise mentioned, the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof. Thus, for some illustrative non-restricting example, 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.

The term "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. Ci-Ce , C2-C5 , C3-C4 , C1-C2 , C1-C3 , C1-C4 , C1-C5 , Ci-Ce _; particularly C1-C2 , C1-C3 , C1-C4 , C1-C5 , Ci-Ce _; more particularly C1-C4 ; in the case of "d-Ce-haloalkyl" or "Ci-Ce-haloalkoxy" even more particularly C1-C2.

Similarly, as used herein, the term "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.

Further, as used herein, the term "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.

The term "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.

The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

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.

As used herein, 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 ^" . Where 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.

By "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.

The term "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. In certain instances, 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, sometimes referred to as proton-shift 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. For example, 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. The term "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. Those skilled in the art will further recognize that 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. Alternatively, 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. For example, such 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-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate. pivalate. propionate, succinate, sulfonate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate.

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.

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.

The 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. Unless otherwise noted, rings containing quaternizable amino- or imino-type ring nitrogen atoms (-N=) 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. Examples of 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.

If in the context of the invention "embodiment" is mentioned it should be understood to include a plurality of possible combinations.

In order to limit different types of isomers from each other reference is made to lUPAC Rules Section E (Pure Appl Chem 45, 1 1 -30, 1976).

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. Examples of 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. Certain isotopic variations of a compound of the invention, for example, those in which one or more radioactive isotopes such as ³ H or ¹⁴ C are incorporated, 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.

Furthermore, 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.

The term "continuous dosing", "daily dosing" or "continuous treatment" 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. During treatment with a PI3K inhibitor, 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).

The term "intermittent dosing (schedule)", "intermittent administration" is to be understood as a dosing regimen/schedule which comprises:

- a period wherein the administration of a dose of PI3K inhibitor occurs every day for a period of one to five days,

- followed by a period of three to six days in which the PI3K inhibitor is not administered or placebo is administered,

The total number of days of these two periods together constituting an "administration cycle".

For the purpose of the present invention days in which a PI3K inhibitor is administered during an administration cycle may also be called "days on". For the purpose of the present invention 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:

- one to five days on (in which the PI3K inhibitor is administered every day),

- followed by three to six days off (in which the PI3K inhibitor is not administered or placebo is administered),

in an administration cycle. 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:

One to five on / three to six off, in an administration cycle. Any subcombinations of days on and days off according to the invention may be represented in the same manner (e.g. 2on/5off).

The intermittent dosing of the present invention can also be described as:

- PI3K inhibitor is administered for one to five consecutive days;

- followed by a period of three to six days in which the PI3K inhibitor is not administered.

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. During treatment with a PI3K inhibitor, 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. During treatment with a PI3K inhibitor, 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).

The term "administration cycle" is to be understood as the total number of days comprising:

- a period wherein the administration of a dose of PI3K inhibitor occurs every day 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,

wherein 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.

From the day treatment with a PI3K inhibitor starts until the day treatment with a PI3K inhibitor is completed and/or discontinued, one or more administration cycles according to the invention (i.e. intermittent dosing) 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). It is within the knowledge of the person skilled in the art how to establish and, if necessary (e.g. during treatment), how to adjust the number of administration cycles which may be needed, based, for example, on the non-limitative examples provided in the present specification and/or on the patients response to treatment and/or suitable techniques/methods readily available, for example. The term "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. It can also be described as, for example, "four to eight days without administration of PI3K inhibitor" or duly adapted according to any break period of the present invention. It can also be described as, for example, "one week without administration of PI3K inhibitor" when the break period consists of seven days.

As way of example, in a particular embodiment of the present invention when the PI3K inhibitor (e.g. Compound A1 ) 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.

All particular embodiments of the present invention may be described according to the above example, duly adapted to the respective number of days on, days off, eventual repetition of administration cycles and eventual additional days of break period as defined for the embodiment in question.

The term "one to five 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 administered (to the patient), i.e. days on, 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.

Similarly, 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.

DESCRIPTION OF THE INVENTION

According to an embodiment of the invention, 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 :

in which :

* represents the point of attachment of said heteroaryl with the rest of the structure of general formula (I) ;

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,

or

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-OR ⁷ . -Ci-C ₆ -alkyl-SR ⁷ , -Ci-C ₆ -alkyl-N(R ⁷ )(R ^7' ). -Ci-C ₆ -alkyl-C(=0)R ⁷ ,-CN, - C(=0)0R ⁷ , -C(=0)N(R ⁷ )(R ^7' ), -OR ⁷ , -SR ⁷ , -N(R ⁷ )(R ^7' ), or -NR ⁷ C(=0)R ⁷ each of which may be optionally substituted with 1 or more R ⁸ groups ; 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-Ce-alkenyl, C2-Ce-alkynyl, Cs-Ce-cycloalkyl, C3- Ce-cycloalkyl-C -Ce-alkyl, Cs-Ce-cycloalkenyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-C -Ce-alkyl, or heteroaryl-Ci-Ce-alkyl ; each occurrence of R ⁸ is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci-Ce-alkyl, Ci-Ce-alkoxy, C∑-Ce-alkenyl, C2-Ce-alkynyl, Cs-Ce- cycloalkyl, Cs-Ce-cycloalkyl-Ci-Ce-alkyl, d-Ce-cycloalkenyl, aryl, aryl-C -Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-Ci-Ce-alkyl, or heteroaryl-Ci-Ce-alkyl ; n is an integer of 1 and m is an integer of 1 ; with the proviso that when :

- said R ⁵ and R ⁵ , taken together with the nitrogen atom to which they are bound, re resent :

in which ^* represents the point of attachment with the rest of the structure of general formula (I),

then

- ² heteroaryl of structure :

is not :

in which * 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.

According to an embodiment of the invention, the compound of formula (I) supra is selected from the group consisting of :

N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methox y-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide

N-(8-{[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methox y-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide

N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxy propyl}oxy)-7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]pyridine-3-carboxamide

N-(8-{[(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)propyl]oxy}-7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide

N-{8-[2-hydroxy-3-(thiomorpholin-4-yl)propoxy]-7-methoxy- 2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl}pyridine-3-carboxamide

N-(8-{[(2R)-3-(azetidin-1 -yl)-2-hydroxypropyl]oxy}-7-methoxy-2 _! 3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide

N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide

N-(8-{[(2R)-2-hydroxy-3-(piperidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide

N-{8-[3-(dimethylamino)-2-hydroxypropoxy]-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl}pyridine-3-carboxamide

N-(8-{[(2R)-3-(dimethyiamino)-2-hydroxypropyl]oxy}-7-meihoxy -2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide

N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7-me thoxy-2,3- dihydroimidazo[1.2-c]quinazolin-5-yl)pyridine-3-carboxamide

N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methox y-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide N-(8-{[(2R)-3-(azeiidin-1-yl)-2-hydroxypropyl3oxy}-7-methoxy -2,3- di ydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxy propyl}oxy)-7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]-2-methylpyridine-3- carboxamide

N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1-yl)propyl]oxy}-7-metho xy-2,3- dihydroimidazo[1.2-c]quinazolin-5-yl)-2-methylpyridine-3-car boxamide

N-(8-{[(2R)-2-hydroxy-3-(piperidin-1-yl)propyl]oxy}-7-met hoxy-2.3- dihydroimidazo[ 2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide

N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7 -methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide

6-amino-N-{8-[2-hydroxy-3-(morpholin-4-yl)propoxy]-7-meth oxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl}pyridine-3-carboxamide

6-amino-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

N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1-yl)propyl]oxy}-7-me thoxy-2 _! 3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide

2-amino-N-{8-[2-hydroxy-3-(morpholin-4-yl)propoxy]-7-methoxy -2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide

2-amino-N-[8-({(2R)-3-[(2R,6S)-2.6-dimethylmorpholin-4-yl]-2 - hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5- yl] pyri m id i ne-5-carboxam ide

2-amino-N-(8-{[(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1]oc t-3- yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5- yl)pyrimidine-5-carboxamide dihydrochloride

2-amino-N-(8-{[(2R)-3-(dimeihylamino)-2-hydroxypropyl]oxy}-7 -methoxy- 2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methox y-2 _! 3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-3H-imidazo[4,5-b]pyridine-6- carboxamide

N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methox y-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide

N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpho!in-4-yl]-2-hydroxy propyl}oxy)-7- methoxy-2.3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]-1 ,3-thiazole-5- carboxamide

N-(8-{[(2R)-3-(azetidin-1-yl)-2-hydroxypropyl]oxy}-7-methoxy -2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-ihiazole-5-carboxamide

N-(8-{[(2 )-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2.3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide N-(8-{[(2R)-2-hydroxy-3-(piperidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide N-(8-{[(2R)-2-Hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-4-methyl-1 ,3-thiazole-5-carboxamide 2-amino-N-(8-{[(2R)-2-hydroxy-3-(morpho!in-4-yl)propyl]oxy}- 7-meihoxy- 2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)-4-methyl-1 ,3-thiazole-5- carboxamide

N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1.2-c]quinazolin-5-yl)-1 ,3-oxazole-5-carboxamide

N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7 -methoxy-2,3- dihydroimidazo[1.2-c]quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide. 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.

According to an embodiment of the invention, the compound of formula (I) supra is selected from the group consisting of :

N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-met hoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide

N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxy propyl}oxy)-7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]pyridine-3-carboxamide

N-(8-{[(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)propyl]oxy}-7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide

N-(8-{[(2R)-3-(azetidin-1 -yl)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1.2-c]quinazolin-5-yl)pyridine-3-carboxamide

N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide

N-(8-{[(2R)-2-hydroxy-3-(piperidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide

N-(8-{[(2R)-3-(dimethylamino)-2-hydroxypropyl]oxy}-7-methoxy -2,3- dihydroimidazo[1.2-c]quinazolin-5-yl)pyridine-3-carboxamide

N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7-me thoxy-2,3- dihydroimidazo[1.2-c]quinazolin-5-yl)pyridine-3-carboxamide

N-(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

N-(8-{[(2R)-3-(azetidin-1 -yl)-2-hydroxypropyl]oxy}-7-methoxy-2 _! 3- dihydroimidazo[1.2-c]quinazolin-5-yl)-2-methylpyridine-3-car boxamide

N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-meihy!pyridine-3-carboxamide

N-(8-{[(2R)-2-hydroxy-3-(piperidin-1 -yl)propyl]oxy}-7-methoxy-2 _! 3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-meihylpyridine-3-carboxamide

N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7 -methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-meihylpyridine-3-carboxamide

N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide

N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide

N-(8-{[(2R)-2-hydroxy-3-(piperidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-y!)-1 ,3-thiazole-5-carboxamide

N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2.3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-oxazole-5-carboxamide. 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.

According to an embodiment of the invention, 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 :

in which :

* represents the point of attachment of said heteroaryi with the rest of the structure of general formula (I), and

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,

or

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 , -d-Ce-alkyl-SR ⁷ , -Ci-C ₆ -alkyl-N(R ⁷ )(R ^7' ), - C(=0)OR ⁷ , -C(=0)N(R ⁷ )(R ⁷ ), -OR ⁷ , -SR ⁷ , -N(R ⁷ )(R ⁷ ), or -NR ⁷ C(=0)R ⁷ each of which may be optionally substituted with 1 or more R ⁸ groups ; each occurrence of R ^6' may be the same or different and is independently Ci-Ce-alkyl, CrrCe-cycloalkyl-Ci-Ce-alkyl, or Ci-Ce-alkyl-OR ⁷ ; each occurrence of R ⁷ and R ^" may be the same or different and is independently a hydrogen atom, or a Ci-Ce-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Cs-Ce-cycloalkyl, C3- Ce-cycloalkyl-Ci-Ce-alkyl, 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 ; each occurrence of R ⁸ is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci-Ce-alkyl, d-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 ; n is an integer of 1 and m is an integer of 1 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.

According to an embodiment, the compound of formula (I) is selected from the group consisting of :

6-amino-N-{8-[2-hydroxy-3-(morpholin-4-yl)propoxy]-7-methoxy -2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl}pyridine-3-carboxamide

6-Amino-N-(8-{[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]ox y}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide

6-Amino-N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]ox y}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide

2-Amino-N-{8-[2-hydroxy-3-(morpholin-4-yl)propoxy]-7-meth oxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide

2-Amino-N-(8-{[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]ox y}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide

2-amino-N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl ]-2-hydroxypropyl}oxy)-7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide

2-Amino-N-(8-{[(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)propyl]oxy}-7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide dihydrochloride

2-Amino-N-(8-{[(2R)-3-(dimethylamino)-2-hydroxypropyl]oxy}-7 -methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide,

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.

According to a preferred embodiment, 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.

According to a preferred embodiment, the compound of formula (I) supra, is Λ/-(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. According to a preferred embodiment, 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.

According to an embodiment, in 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.

According to an embodiment, in 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.

According to an embodiment, in 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.

According to an embodiment, in 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.

According to an embodiment, in 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.

According to an embodiment, in 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.

According to an embodiment, in 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.

According to an embodiment, in 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.

According to an embodiment, in 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.

According to an embodiment, in 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.

According to an embodiment, in 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.

According to an embodiment, in 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.

According to an embodiment, in 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.

According to an embodiment, in 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.

According to an embodiment, in 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.

According to an embodiment, in 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.

According to an embodiment, in 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.

According to an embodiment, in 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.

Additional embodiments of the invention are as described in table A, in which in each administration cycle the compound of formula (I) is administered for a period of "on" days as defined in the first column, followed by a period of "off days as described in the second column, in which the compound of formula (I) is not administered or placebo is administered (for each embodiment, the administration cycle taking the number of days indicated in the fourth column of Table A to be completed): Table A: Embodiments according to the aspects of the invention. Each row represents a specific embodiment of the invention.

For the embodiments of Table A. 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.

According to a preferred embodiment, the compound of formula (I) is administered once-daily in the days on. According to an embodiment, 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.

According to an embodiment, 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.

According to an embodiment, 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.

According to an embodiment, 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.

According to an embodiment, 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.

According to an embodiment, the administration cycle is performed one or more times, for example one, two, three, four or five times.

According to an embodiment, 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.

Dose and administration

Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative disorders and angiogenic disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, 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.

Of course 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.

In general, the compound of formula (I) is administered orally.

According to an embodiment, the compound of formula (I) is administered orally.

As used herein, the term 'effective daily dose' is the effective daily amount of compound administered in the days it is administered according to the dosing regimen.

In the present invention, 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).

As used herein, the term "dosage unit" refers to the amount of compound administered in each dosing periodicity.

It is preferred that 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.

In order to achieve a certain effective daily dose 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. As used herein, the term "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).

According to an embodiment, the compound of formula (I) is administered in a total amount of about 200 mg to about 1000 mg in each administration cycle.

According to an embodiment, the compound of formula (I) is administered in a total amount of about 300 mg to about 900 mg in each administration cycle.

According to an embodiment, the compound of formula (I) is administered in a total amount of about 400 mg to about 800 mg in each administration cycle.

According to an embodiment, 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.

According to an embodiment, 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.

According to an embodiment, 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.

Combination therapies

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. For example, 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, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadron phosphate, delestrogen, deniieukin diftitox, depo- medrol, deslorelin, dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend, epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, estrace, estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyol, etidronic acid, etopophos, etoposide, fadrozole, farston, filgrastim, finasteride, filgrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fosteabine, fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron HCI, histrelin, hycamtin, hydrocortone, eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferon alfa-2A, interferon alfa-2B, interferon alfa-n1 , interferon alfa-n3, interferon beta, interferon gamma-1 a, interleukin-2, intron A, iressa, irinotecan, kytril, lentinan sulfate, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, levofolinic acid calcium salt, levothroid, levoxyl, lomustine, lonidamine, marinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, menest, 6-mercaptopurine, Mesna, methotrexate, metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, Mod renal, Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide, nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCI, orapred, oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin, picibanil, pilocarpine HCI, pirarubicin, plicamycin, porfimer sodium, prednimustine, prednisolone, prednisone, premarin, procarbazine, procrit, raltitrexed, RDEA 1 19, rebif, rhenium-186 etidronate, rituximab, roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine, sizofiran, sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy, streptozocin, strontium- 89 chloride, synthroid, tamoxifen, tamsulosin, tasonermin, tastolactone, taxotere, teceleukin, temozolomide, teniposide, testosterone propionate, testred, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, tretinoin, trexail, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate. 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-166 DOTMP, ibandronic acid, interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafarnib, miproxifene, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, pamidronate disodium, PN-401 , QS-21 , quazepam, R- 1549, raloxifene, ranpirnase, 13-cis -retinoic acid, satraplatin, seocalcitol, T-138067, tarceva, taxoprexin, thymosin alpha 1 , tiazofurine, tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acid or combinations thereof.

In an embodiement of the present invention, 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, bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir. 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, enocitabine, enzalutamide. 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, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125 seeds, Iansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, lanreotide, lapatinib, lasocholine, lenalidomide, lenograstim, lentinan, letrozoie, leuprorelin, levamisoie, Ievonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, nedaplatin, nelarabine, neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, piicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, romidepsin, romiplostim, romurtide, roniciclib , samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, stanozolol, streptozocin, sunitinib. talaporfin. tamibarotene. tamoxifen, tapentadol. tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracii + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinoreibine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

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, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine.

Other 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. by McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by reference, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinoreibine.

Other 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, B43-genistein, L-19 based radioimmunotherapeutics, AC-9301 , NY-ESO-1 vaccine, I C-1 C1 1 , CT-322, rhCCI O, r(m)CRP, MORAb-009, aviscumine, MDX- 1307, Her-2 vaccine, APC-8024, NGR-hTNF, rhH1.3, IGN-31 1 , Endostatin, volociximab, PRO-1762, lexatumumab, SGN-40, pertuzumab, EMD-273063, L19-IL- 2 fusion protein, PRX-321 , CNTO-328, MDX-214, tigapotide, CAT-3888, labetuzumab, alpha-particle-emitting radioisotope-llinked lintuzumab, EM-1421 , HyperAcute vaccine, tucotuzumab celmoleukin, galiximab, HPV-16-E7, Javelin - prostate cancer, Javelin - melanoma, NY-ESO-1 vaccine, EGF vaccine, CYT-004- MelQbGI O, WT1 peptide, oregovomab, ofatumumab, zalutumumab, cintredekin besudotox, WX-G250, Albuferon, aflibercept, denosumab, vaccine, CTP-37, efungumab, or 131 l-chTNT-1/B. 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, trametinib, triciribine, UCN-01 , WX-554, XL-147, XL-765, zotarolimus, ZSTK-474

Generally, the use of 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,

(2) provide for the administration of lesser amounts of the administered chemo- therapeutic agents,

(3) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies,

(4) provide for treating a broader spectrum of different cancer types in mammals, especially humans,

(5) provide for a higher response rate among treated patients,

(6) provide for a longer survival time among treated patients compared to standard chemotherapy treatments,

(7) provide a longer time for tumor progression, and/or

(8) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.

According to an embodiment, 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; Bortezomib; a platinum derivative, such as Cisplatin, or Carboplatin; Chlorambucil; Methotrexate; ituximab; and a pharmaceutically acceptable salt of the alkaline-earth radionuclide radium-223.

Suitable combinations of the compound of formula (I) with an 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, are described in priority application EP15159490.0 which is incorporated by reference herein in its entirety. According to an embodiment, 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.

Suitable combinations of the compound of formula (I) with an agent selected from 5- FU, capecitabine, oxaliplatin and paclitaxel, or combinations thereof, are described in priority applications EP15159490.0.EP14196142.5 and EP15164342.6, which are incorporated by reference herein in their entirety.

According to an embodiment, 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.

Suitable combinations of the compound of formula (I) with a pharmaceutically acceptable salt of the alkaline-earth radionuclide radium-223 are described in PCT/EP2014/076053 (WO2015/082378) and in priority applications EP14163751.2 and EP13195566.8 which are all three incorporated by reference herein in their entirety.

According to an embodiment, 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. In an embodiment, 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. Preferably 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.

According to an embodiment, the compound of formula (I) is administered simultaneously, concomitantly, separately or sequentially with the additional one or more additional active ingredients.

In a preferred embodiment, 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.

Methods of Sensitizing Cells to Radiation

In a distinct embodiment of the present invention, 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. In one aspect, the cell is treated with at least one compound of the invention.

Thus, 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. In one aspect, after the cell is treated with one or more compounds of the invention, 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. In one embodiment, 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. In another embodiment, 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. By way of a non-limiting example, 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.

In one aspect of the invention, 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. In another aspect of the invention, a compound of the invention is administered to a cell concomitantly with the radiation or orther induction of DNA damage in the cell. In yet another aspect of the invention, a compound of the invention is administered to a cell immediately after radiation or orther induction of DNA damage in the cell has begun.

In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo.

As mentioned supra, 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, 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.

In accordance with another aspect therefore, 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, 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 term "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. Preferably, 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.

Method of treating hyper-proliferative disorders

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. Those disorders also include lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. Examples of 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.

Examples of 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. Examples of 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.

These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.

The term "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.

Preferably, the pathological states treated by the compounds are hyper-proliferative and/or angiogenesis disorder of humans which benefit from administration of a PI3K inhibitor.

According to an embodiment, 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. 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.

Suitable methods and uses of the compound of formula (I) for the treatment of gastric cancer, are described in priority applications EP15159490.0, EP14196142.5, and EP15164342.6, which are incorporated by reference herein in their entirety.

According to an embodiment, 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.

According to an embodiment, 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.

According to an embodiment, 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.

According to an embodiment, the hyper-proliferative and/or angiogenesis disorder is cancer with PTEN loss or PIK3CA mutation and KRAS wild type. According to an embodiment, 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).

In other embodiments, 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, CAL-263, RG-7603, LY-3023414, RP-5264, RV- 1729, taselisib, TGR-1202, GSK-418, INCB-040093, Panulisib, GSK-1059615, CNX- 1351 , AMG-51 1 , PQR-309, 17beta-Hydroxywortmannin, AEZS-129, AEZS-136, HM- 5016699, IPI-443, ONC-201 , PF-4989216, RP-6503, SF-2626, X-339, XL-499, PQR- 401 . AEZS-132, CZC-24832, KAR-4141 , PQR-31 1 , PQR-316, RP-5090, VS-5584, X- 480, AEZS-126, AS-604850, BAG-956, CAL-130, CZC-24758, ETP-46321 , ETP- 47187, GNE-317, GS-548202, HM-032, KAR-1 139, LY-294002, PF-04979064, Pl- 620, PKI-402, PWT-143, RP-6530,

3-HOI-BA-01 , AEZS-134, AS-041 164, AS-252424, AS-605240, AS-605858, AS- 606839, BCCA-621 C, CAY-10505, CH-5033855, CH-5108134, CUDC-908, CZC- 19945, D-106669, D-87503, DPT-NX7, ETP-46444, ETP-46992, GE-21 , GNE-123, GNE-151 , GNE-293, GNE-380, GNE-390, GNE-477, GNE-490, GNE-493, GNE-614, H PL-518, HS-104, HS-106, HS-1 16, HS-173, HS-196, IC-486068, INK-055, KAR 1 141 , KY- 12420, Wortmannin, Lin-05, NPT-520-34, PF-04691503, PF-06465603, PGNX-01 , PGNX-02, PI 620, PI-103, PI-509, PI-516, PI-540, PIK-75, PWT-458, RO- 2492, RP-5152, RP-5237, SB-2015, SB-2312, SB-2343, SHB -1009, SN 32976, SR-13179, SRX-2523, SRX-2558, SRX-2626, SRX-3636, SRX-5000, TGR-5237, TGX-221 , UCB-5857, WAY-266175, WAY-266176, EI-201 , AEZS-131 , AQX-MN100, KCC-TGX, OXY-1 1 1 A, PI-708, PX-2000, WJD-008.

Methods of treating kinase disorders

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.

The phrase "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.

Methods of treatjnfl^nfljo.qenic disorders

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. 1996, 37, 855], neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumor enlargement and metastasis. Moreover, 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. Thus, 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.

Compounds of formula (I) as described and defined herein can be prepared according to the preparation methods contained in WO2012/062748 which is incorporated herein by reference in its entirety.

The 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.

The present invention will now be described with reference to the accompanying drawings.

Figure 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.

PK/PD relationship of continuous and intermittent treatment 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.

Figure 3. In vivo inhibition of tumor survival by Compound A1 dosed with different schedules.

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 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.

Figure 4. Efficacy of Compound A1 in KPL4 breast tumor cell line xenograft model in nude rats.

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. A) Tumor growth inhibition curve; B) Body weight change during treatment period; C) Tumor weight at the end of treatment. .

Figure 5. Efficacy of Compound A1 in patient derived GXA 3027 gastric cancer xenograft model in nude mice.

Patient derived GXA 3027 gastric cancer cells were implanted subcutaneously (s.c.) onto NMRI nude mice. When tumors had reached a size of approximately 140 mm ³ , animals were randomized and compound A1 was dosed with dosing regimens and schedules as indicated in Table 7 as single agent or in combination with cisplatin and capecitabine. Tumor weights from each individual animal at the end of treatment were presented. In addition relative tumor growth inhibition (TGI) was calculated with the equation [1-(T-T0/C-T0)] x 100, where T and C represent the mean size of tumors in the treated (T) and control (C) groups, respectively, and TO refers to the tumor size at the randomization. Furthermore, treatment responses were evaluated by means of clinically used RECIST criteria; response rates (RR) were calculated as the percentage of animals with a complete or partial response.

As used herein, the term treatment and variations such as 'treat' or 'treating' refer to any regime that can benefit a human or non-human animal. In addition the 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. 14 of W 02013/062748) 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, for the prophylaxis or treatment of hyper-proliferative and/or angiogenesis disorders, 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.

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. 14 of WO2012/062748) 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, for the prophylaxis or treatment of hyper-proliferative and/or angiogenesis disorders, wherein 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.

Details of the preparation of compounds of general formula (I) can be found in WO2012 062748A1. 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.

It is also possible to use 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. For the preparation of pharmaceutical compositions of compounds of general formula I, 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.

Preferably 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. Preferably the pharmaceutical composition is a tablet.

In general, the compound of formula (I) is administered orally, preferably as an oral tablet or capsule, more preferably as an oral tablet.

Other aspects of the invention are as defined in the claims.

The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

Examples

Veh vehicle

Ave average

PI3Ki PI3K kinase inhibitor

Ctrl control

PR Partial Regression

SD Stable Disease

PD Progressive Disease

RTV Relative tumor volume

Cap. Capecitabine

Cisp. Cisplatin

Other abbreviations not specified herein have the meanings customary to the skilled person.

The schemes and procedures described in the art as cited in the present application disclose general synthetic routes and specific procedures within their experimental sections to arrive at the PI3K inhibitor compounds of the present invention. Compound A1 can be prepared as per example 14 of WO2012/062748, which is hereby incorporated in its entirety.

(N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-me thoxy-2 _! 3- hylpyridine-3-carboxamide)

Compound A1 (Cpd. A1 )

Example 1 : Immediate release tablet manufactured via fluid bed granulation containing the compound of general formula (I) and optionally subsequent film- coating

1.1 Composition of tablets containing compound (A1 )

Composition Tablet 1 -A Tablet 1 -B Tablet 1 -C Tablet 1 -D Tablet 1 -E m /tablet ^a 5 m 10 m 25 m 50 m 100 m

The weights and dimensions may vary by about ±10%.

b Lacquer yellow contains:

50.56 % Hypromellose

6.00 % Iron oxide yellow

10.12 % Macrogol 3350

10.12 % Talc

23.20 % Titanium dioxide 1.2 Process for manufacturing

1.2.1 Tablets 1-A to 1-E

Starting material Manufacturing step

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.

Final Blend: The granules were mixed with croscarmellose sodium and with sieved magnesium stearate in a blender.

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.

Coating: 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.

Table 1. Study Layout for Compound A1 :

The study was conducted using patient-derived tumor xenografts. 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.

A) Plasma drug exposure

To determine the exposure of Compound A1 in mice, blood was collected at 2h, 8h, 24h, 48h, 96h and 168h post 1 ^st administration of Compound A1. Concentrations of Compound A1 were determined in plasma, tumor and tissue lysates by HPLC- tandem mass spectrometry after protein precipitation with acetonitrile. The assay has a lower limit of quantitation (LLOQ) of 2 pg/L. The plasma levels of Compound A1 in the animals with 75 mg/kg, QD (once daily) dosing schedule was high at 2 h (average 1363 pg/L) significantly decreased at 8 h (average 384 pg/L) and come back to baseline at 24 h (average 44 pg/L). The exposure of 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.

Table 2. Plasma concentration of Compound A1 in animals treated with different dosing schedules

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.

Briefly tumor samples of approximately 5x5x5 mm were lysed on ice in MSD lysis buffer in the presence of protease and phosphatase inhibitors using Tissue Lyzer (Qiagen, Germany). Each assay used 20 pg of protein extract. All measurements where at least conducted in duplicate. Levels of p-AKT and p-PRAS40 in tumors treated with Compound A1 are compared to that in tumors from vehicle group. Table 3. p-AKT levels in tumors from mice treated with Compound A1 and vehicle

- Treatment of PI3K inhibitor Compound A1 at 75 mg/kg, QD schedule led to >90% and >80% inhibition of p-AKT at 2 and 8 hours post treatment, respectively. At 24 h, only about 25% inhibition of p-AKT was observed.

- In the tumors from 450 mg/kg, QW group, the duration of potent inhibition of p-AKT (>90%) was much longer > 24 h compared to 2 h observed in the low dose 75mg/kg, QD group.

-Treatment of Compound A1 at 200 mg/kg for continuous two days, >90% inhibition of p- AKT was observed at 2 and 8 h, and >80% p-AKT inhibition also observed at 48 h. Of note, at 24 h post 1 ^st administration and before the 2 ^nd dosage, the levels of p-AKT were only about 30% of control (compared to 75% of the control in the 75 mg/kg, QD group). Greater than 50% p-AKT inhibition was maintained until 96 h.

- Thus, continuous dosing of Compound A1 has a short time period to potently inhibit p- AKT (~2 h) on each day, while once weekly dosing has a prolonged initial potent inhibition of p-AKT (>24 h) and <50% inhibition for a continued 3 days (96-168h). Treatment of Compound A1 at 200 mg/kg for the first 2 days and giving drug holidays (i.e. not administering compound A1 ) from day 3 to day 7 showed an inhibition profile between the obtained with 75 mg/kg, QD and 450 mg/kg, QW.

Table 4. p-PRAS40 levels in tumors from mice treated with Compound A1 with different dosing schedules

The overall profile of p-PRAS40 inhibition by Compound A1 with different dosing regimen is very similar to the p-AKT inhibition profile. Thus, 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. In contrast, 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). Of note, > 90% p-PRAS40 inhibition was only reached with the intermittent dosing schedules (QW at 450 mg/kg and 20n/50ff at 200 mg/kg), but not QD at 75 mg/kg. The kinetics of p-PRAS40 inhibition correlated well with observed serum levels of Compound A1 (Figure 2). The concentration of Compound A1 dosed at 75 mg/kg in serum reached approximately 1363 pg/L (correlated with approx. 80% p-PRAS40 inhibition) at 2 hours and decreased to 383 pg/L (correlated with approx. 60% p-PRAS40 inhibition) at 5 hours and further reduced to a biological irrelevant concentration 44 pg/L at 24 h after dosing (Table 2). Interestingly, 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. Furthermore, 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. Finally, 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. Thus, administration of Compound A1 with different dosing regimens showed a clear PK PD relationship.

Example 4 Induction of tumor cell death in vivo by different dosing regimens

Table 5. Activation of caspase 3 in tumors from mice treated with Compound A1 at different dosin schedules

Continuous (QD) and intermittent (QW, 20n/50ff) dosing regimens result in differential patterns of pathway inhibition as depicted in Table 3, Table 4 and Figure 1 in example 3. Thus:

• Continuous QD administration of Compound A1 at 75 mg/kg (MTD) led to approx. 8h

pathway inhibition (50-80% inhibition of p-PRAS40) and an approx. 16 h recovery period (<50% pathway inhibition) on each day.

• Intermittent QW (450 mg/kg, at MTD) or 20n/50ff (200 mg/kg, at MTD) dosing regimens led to a stronger maximum pathway inhibition (>90%) at 2 h and much longer initial potent inhibition of p-PRAS40 (>80%) till 24 h for QW 450 mg/kg dosing regimen and (>75%) up to 8h on Dayl and Day2 for 20n/50ff, 200 mg/kg dosing group. On the other hand, both dosing regimen recovered from pathway inhibition from 96h-168h (3 days/week). We assessed tumor survival inhibition by Compound A1 in GXA3027 patient derived gastric tumor model treated with above mentioned dosing regimens. Induction of apoptotic proteins, namely activated caspase 3 and cleaved PARP in tumors was analysed at 2h, 8h, 24h, 48h, 96h and 168 h post 1 ^st administration of Compound A1 (Table 5, Table 6 and Figure 3). In vehicle treated tumors, levels of activated caspase 3 and cleaved PARP were low and remained constant over the time course of the study and were used as the base line for comparison. Continuous once daily treatment with 75 mg/kg of Compound A1 did not lead to significant induction of tumor cell apoptosis (both caspase 3 and cleaved PARP levels were only slightly increased (1.6 and 1.7-fold)) during the treatment period. In contrast, once weekly treatment with 450 mg/kg and 20n/50ff at 200 mg/kg led to a significant induction of both caspase 3 (16.6 fold and 5.9-fold, respectively) and cleaved PARP (6.6-fold and 3.6.fold, respectively). These results correlated with observed Compound A1 serum exposure, > 90% p-PRAS40 inhibition, suggesting that induction of tumor cell death benefits from Compound A1 exposure and pathway inhibition (e.g. p-PRAS40 inhibition) above a certain threshold, which could be achieved by intermittent administration of Compound A1.

Table 6. Induction of cleaved PARP in tumors from mice treated with Compound A1 at different dosing schedules

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.

In order to compare the monotherapy and combination efficacy of Compound A1 with continuous and intermittent dosing regimens, 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 [%]). Tumor response is assessed by determination of the tumor size (tumor volume = (width) ² x length/2) using a calliper. 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. Furthermore, treatment responses were evaluated by means of the clinically-used RECIST criteria (complete response, partial response, stable disease and progressive disease) (reference: Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1 ). EJC 15 2009;45:228-247) and response rates were calculated accordingly (RR = number of animals with complete and partial response).

In line with the results from the mechanism of action studies in example 3 and example 4, treatment of Compound A1 with QD, QW, or 20n/50ff schedule demonstrated strong antitumor efficacy with relative T/C of -2.2%, -13.8% and -8.3%, respectively. Importantly, QW dosing with 420 mg/kg/week displayed the strongest activity with 78% RR (7/9 animals), 20n/50ff schedule showed a RR of 56% (5/9 animals) and continuous QW dosing generated a RR of 1 1 % (1/9 animals) (Fig. 5). These data confirmed the conclusion that intermittent dosing schedule could lead to comparable or even more potent anti-tumor activity of compound A1 , particularly achieved higher RR compared to the continuous QD dosing schedule. Combination with 1 ^st line chemotherapy of gastric cancer (e.g. capecitabine and cisplatin), compoundAI could further enhance its anti-tumor activity with all three dosing schedules, with regard to both T/C and RR. Table 7. Study design for the efficacy assessment of Compound A1 with different dosing regimens in GXA3027 patient derived gastric tumor model in NMRI nu/nu mice

Example 5B: Anti-tumor Activity of COMPOUND A1 in Combination with Paciitaxel

The in vivo efficacy experiments assessing the combination activity of paciitaxel and COMPOUND A1 in different dosing schedule were performed in female nu/nu mice. The results of the experiments are summarized in Table 8.

Weekly paciitaxel (24 mg/kg/day) dosed i.v. on days 0, 7, 14, and 21 was combined with either continuous dosing of COMPOUND A1 at 75 mg/kg/day p.o. on days 1-6, 8-13, 15-20, 22- 23, or with intermittent dosing of COMPOUND A1 on days 1 , 8, 15, and 22 (500/400 mg/kg/day).

In GXA 3023 tumor model, continuous dosing of COMPOUND A1 (75 mg/kg, QD) displayed good anti-tumor activity with an optimal T/C value of 31.9%. Intermittent dosing 500/400 mg/kg, weekly of COMPOUND A1 showed very good efficacy with an optimal T/C value of 8.2% and overall tumor stasis and 3/8 partial remissions. Paciitaxel monotherapy was moderately good with an optimal T/C value of 35.0%. The combination therapy of paclitaxel with continuous COMPOUND A1 (75/50 mg/kg) resulted in very good anti-tumor activity with an optimal T/C value of 15.6%. 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.

In GXF 241 tumor model, continuous COMPOUND A1 dosing displayed good anti-tumor efficacy with an optimal T/C value of 17.9% with one partial remission observed.

Intermittent dosing of COMPOUND A1 also resulted in better activity with an optimal T/C of 13.6 and partial tumor remission observed in 4/8 mice. Paclitaxel monotherapy was highly active with an optimal T/C value of 6.6%. Tumors went into partial remission in 7/8 animals. The two paclitaxel/COMPOUND A1 combination therapies resulted in excellent and statistically significant anti-tumor efficacy with an optimal T/C value of 4.2% in both cases. Partial tumor remission was observed in 8/8 animals of both of the combination therapy groups. The very good anti-tumor activity of both combination therapy groups proved to be statistically significant.

The combination treatments were in both cases more active and beneficial than the respective COMPOUND A1 concentrations given in monotherapy.

Table 8 - Summary of Anti-tumor Efficacy of COMPOUND A1 given in Monotherapy and in Combination with Paclitaxel in Mice bearing the Gastric Cancers GXA 3023 and GXF 241

¹ Vehicle b: 0.9% saiine, vehicle x: 0.1 N HCI ph 4.0

² day 14 - last day in group 9 on which half of the animals were still alive and day 24 - last day of experiment n.r.: not reached

Example 6: In vivo efficacy of Compound A1 dosed continuously or intermittently in KPL4 breast tumor model in rats.

In vivo efficacy study was conducted using a KPL-4 breast cancer xenograft model in nude rats with the study design depicted in Table 9.

Table 9. Study design for the efficacy assessment of Compound A1 with different dosing regimens in KPL4 breast cancer ceil line in nude 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). Surprisingly, continuous dosing at 75 mg/kg QD group had T/C _ar ea/wei _g ht = 0.29/0.32, was inferior to the once weekly and to the 20n/50ff dosing group. Also surprisingly, 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.

Importantly, also 20% disease control rate was observed in the animal of the vehicle control group. In general, a relatively high variation in tumor size between animals of one group was observed. This has been repeatedly observed with the KPL-4 tumor model when xenog rafted on nude rats.

Continuous treatment with Compound A1 was well tolerated and no significant body weight loss was observed (Figure 4B. Table 10). When Compound A1 was dosed intermittently, a transient body weight loss was observed after Compound A1 was administered, but body weight was recovered to the levels of continuous QD group before giving the next dosage. This result clearly indicated that intermittent treatment of Compound A1 in KPL4 model produced better anti-tumor efficacy and comparable tolerability compared to the continuous once daily treatment.

Example 7: Clinical trial in patients with cancer: dosage regimen continuous dosing

In an open-label, non-randomized, Phase I dose-escalation study of oral Compound A1 was administered once daily (QD) continuously (i.e. continuous dosing) starting at 15 mg QD. A cycle for this study was defined as a period of 21 days.

The preliminary assessment of safety data showed that a clinically relevant incidence rate of pneumonitis and Pneumocystis pneumonia (PcP) occurred at MTD (200 mg). The Compound A1 activity on PI3K5 and related effects on B-lymphocytes / alteration of the immune system are assumed reasons for pneumonitis and PcP.

Example 8: Clinical trial in patients with cancer: dosage regimen 2 days on / 5 days off

In an open-label, non-randomized, Phase I study of oral Compound A1 given 200 mg QD in an intermittent 2 days on / 5 days off dosing schedule for 21 days (i.e. three administration cycles) followed by 7 days without treatment (i.e. break period), i.e. 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

Study drug Day(s)

1 2 3 - 7 8 9 10 - 14 15 16 17 - 28

Compound A1 X X None X X None X X None

Patients who take Compound A1 with the intermittent dosing schedule are expected to show improved effects relative to those taking the Compound A1 with continuous dosing.

Example 9 : Oral 4-Week Toxicity Study in Rats with Compound A1

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.

Histological findings in the lymphatic organs, focusing on the spleen and lymph nodes, are summarized below:

In the spleen, atrophy of the marginal zone and an increase in hemosiderin deposits were observed. The atrophy of the marginal zone increased dose dependently in severity with increase of daily doses, the weekly high dose showed a similar extent as the daily low dose. An increase in incidence and severity in hemosiderin deposits was seen with daily application and started at the low dose in female animals. It was also present in male animals at the high daily dose. With weekly compound application, an increase in extramedullary hematopoiesis was observed in spleen.

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. In addition, three male animals showed minimal lymphoid hyperplasia in the mesenteric lymph node.

At the end of the recovery period, 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 12. Compound related histological findings in lymphatic organs in animals at termination of the 4 week treatment period,

[number of animals affected (average severity grading, 1 - 5)]

control Compound A1 - treated animals

0 mg/kg 5 mg/kg 10 mg/kg 15 mg kg 105 mg kg ^*

Organ/Finding 10 M 10 F 10 M 9/1 F 10 M 10 F 10 M 10 F 10 M 10 F

Thymus

- Atrophy - - 1 21- 1 1 5 5 1 2

(2.0) (1.5/-) (2.0) (1.0) (1.2) (1 .6) (1.0) (1.5)

- Lymphoid Depletion - - 1 1/- 7 5 10 8 2 4

(1.0) (1.0/-) (1.7) (1.2) (1.3) (1 .6) (1.0) (1.0)

Spleen

- Marginal Zone Atrophy 1 2 10 8/1 10 10 10 10 8 4

(1 .0) (1.0) (1.9) (1.6/2.0) (3.3) (2.6) (3.5) (3.4) (1.9) (1.0)

- Hemosiderin Deposits - 3 - 7/1 - 6 9 9 - 3

(1.0) (1.4/2.0) (1.5) (1.6) (2.0) (1.0)

- Incr. Hemopoiesis 5 10 2 61- - 2 1 4 8 10

(1 .2) (1 -5) (1.0) (1.3/-) (1.0) (1.0) (1 .0) (1.6) (2.8)

Mandib. Lymph Nodes

- Atrophy - - 3 21- 4 3 6 4 3 4

(2.0) (1.5/-) (1.3) (1.3) (1.7) (1 .5) (1.0) (1.5)

Mesent. Lymph Node

- Atrophy - - 7 4/1 6 1 6 9 3 2

(1.1 ) (1.5/2.0) (1.2) (3.0) (1.3) (1.9) (1.0) (1.0)

- Lymphoid Depletion - - 1 1/- 1 1 1 3 - -

(1.0) (1.0/-) (1.0) (1.0) (2.0) (1.0)

- Lymphoid Hyperplasia - - - ./. - - - - 3 (10) -

Iliac Lymph Node

- Atrophy - 3 2 41- 6 6 7 9 - 1

(1.3) (1.0) (1.0/-) (1.7) (1.5) (2.0) (1 .8) (1.0)

- Lymphoid Depletion - - - ./. - - 1 (1.0) - - -

M = male, F = female

Numbers before / behind the slash = scheduled sacrificed animals at termination of treatment / dead and/or moribundly killed animal

105 mg/kg * = compound administration once a week for three weeks, days 2 to 7 administration of 10 ml/kg vehicle

Grading:

1 = very slight, minimal 2 = slight 3 =moderate

4 = marked 5 = massive

Table 13. Compound related histological findings in lymphatic organs in animals at termination of the 4 week recovery period.

[number of animals affected (average severity grading, 1 - 5)]

control Compound A1 - treated animals

0 mg/kg 5 mg/kg 10 mg/kg 15 mg/kg 105 mg/kg ^*

Organ/Finding 6 M 6 F 6 M 5/1 F 6 M 6 F 6 M 6 F 6 M 6 F

Thymus

- Apoptosis - - 1 (1.0) -1- - 1 (1.0) - - - -

Spleen

- Marginal Zone Atrophy 1 (1.0) - - -/- 1 (1.0) - - - - -

- Incr. Hemopoiesis 6 6 6 5/- 6 6 6 6 5 6

(1.5) (1.7) (2.3) (2.6/-) (1.8) (2.3) (1.7) (2.7) (1.2) (2.2)

- Hemosiderin Deposits - 1 1 3/1 - 3 - 3 - -

(1.0) (1.0) (1.0/1.0) (1.0) (1.0)

Mandib.Lymph Nodes

- Atrophy - - 3 (1.3) -/- - - 1 (1.0) - - 1 (1.0)

- Lymphoid Hyperplasia 3 1 - 1/1 3 2 - - 2 -

(1.7) (1.0) (1.0/1.0) (1.0) (1.0) (1.0)

Iliac Lymph Node

- Lymphoid Depletion 1 (1.0) - - ./. - - - - - -

M = male, F = female

Numbers before / behind the slash = scheduled sacrificed animals at termination of treatment / dead and/or moribundly killed animal

105 mg/kg * = compound administration once a week for three weeks, days 2 to 7 administration of 10 ml/kg vehicle

Grading:

1 = very slight, minimal 2 = slight 3 ^moderate

4 = marked 5 = massive

Conclusions:

The 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. We have surprisingly found that initial high exposure of Compound A1 with intermittent dosing led to stronger and more prolonged pathway inhibition measured by p-AKT and p-PRAS40 over continuous dosing (at the corresponding MTD). Complete inhibition of p-PRAS40 (>90%) correlated with the apoptosis induction (assessed by cleaved caspase 3 and PARP) in tumor cells and was achieved with intermittent but not with continuous dosing at the corresponding MTD. Furthermore, in vivo efficacy study in GXA 3027 gastric cancer model and KPL4 breast tumor model confirmed the surprising superiority of intermittent treatment vs continuous treatment. These collective results clearly show that the use of a PI3K inhibitor with the intermittent dosing schedule of the present invention, achieves a better anti-tumor efficacy and/or maintains or improves the safety profile, which merit its further use in clinical setting.