TW201625637A - Administration regime for aminoalcohol substituted 2,3-dihydroimidazo[1,2-C]quinazoline derivatives - Google Patents

Abstract

A compound of formula (I)as defined herein, 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.

Description

Dosing regimen of 2,3-dihydroimidazo[1,2-c]quinazoline derivatives substituted with amine alcohols

The present invention relates to the use of a PI3K inhibitor of formula (I) for the treatment of hyperproliferative disorders and diseases associated with angiogenesis according to a regimen of administration (regimen).

The use of PI3K inhibitors is based on the principle of the role of PI3K kinase in key signaling pathways in cancer cells.

The PI3K family of lipid kinases binds to and activates various cellular targets of 3'-phosphoinositol, thereby initiating a broad range of signal transduction cascades (Vanhaesebroeck et al, 2001; Toker, 2002; Pendaries et al, 2003; Downes et al. People, 2005). This grading ultimately induces changes in a variety of cellular processes, including cell proliferation, cell survival, differentiation, vesicle trafficking, migration, and chemotaxis.

PI3K can be divided into three different categories based on the difference between structure and substrate preference. Although members of the class II PI3K family are involved in the regulation of tumor growth (Brown and Shepherd, 2001; Traer et al., 2006), numerous studies have focused on class I enzymes and their role in cancer (Stauffer et al., 2005; Stephens et al, 2005; Vivanco and Sawyers, 2002; Workman, 2004; Chen et al, 2005; Hennessy et al, 2005; Cully et al, 2006).

Class I PI3K has traditionally been divided into two distinct subclasses based on differences in protein subunit composition. Class I _A PI3K includes a catalytic p110 catalytic subunit (p110α, β or δ) that is heterodimeric with a p85 regulatory subunit family member. In contrast, class I _B PI3K catalytic subunits (p110γ) differ from different p101 regulatory subunits for heterodimerization (reviewed by Vanhaesebroeck and Waterfield, 1999; Funaki et al., 2000; Katso et al., 2001). The C-terminal region of these proteins contains a catalytic domain with distant homology to protein kinases. The structure of PI3Kγ is similar to that of class I _A p110, but lacks the N-terminal p85 binding site (Domin and Waterfield, 1997). Although the overall structure is similar, the homology between the catalytic p110 subunits is low to moderate. The highest homology between the PI3K isoforms is in the kinase pocket of the kinase domain.

Class I _A PI3K isoforms via their p85 regulatory subunits with activated receptor tyrosine kinase (RTK) (including PDGFR, EGFR, VEGFR, IGF1-R, c-KIT, CSF-R and Met) or with tyramine Acid-phosphorylated adaptor proteins (eg, Grb2, Cbl, IRS-1 or Gabl) are associated, resulting in stimulation of lipid kinase activity. Activation of the phosphokinase activity of the p110β and p110γ isoforms has been shown to occur in conjunction with the activated form of the ras oncogene (Kodaki et al., 1994). In fact, the carcinogenic activity of this isoform may require binding to ras (Kang et al., 2006). In contrast, the p110α and p110δ isoforms exhibited carcinogenic activity independent of ras binding but by constitutive activation of Akt.

Class I PI3K catalyzes the conversion of PI(4,5)P ₂ [PIP ₂ ] to PI(3,4,5)P ₃ [PIP ₃ ]. The generation of PIP ₃ by PI3K affects a variety of signaling processes that regulate and regulate the biological endpoints of cell proliferation, cell survival, differentiation, and cell migration. PIP ₃ binds to a protein containing the Pleckstrin-Homology (PH) domain, including phosphoinositide-dependent kinase, PDK1 and Akt proto-oncogene products, localizing these proteins to activity It is also directly involved in the signal transduction region (Klippel et al., 1997; Fleming et al., 2000; Itoh and Takenawa, 2002; Lemmon, 2003). Localization of PDK1 and Akt facilitates phosphorylation and activation of Akt. Phosphorylation of the carboxy terminus of Akt on Ser ⁴⁷³ promotes phosphorylation of Thr ^{308 in} the Akt activation loop (Chan and Tsichlis, 2001; Hodgekinson et al, 2002; Scheid et al, 2002; Hresko et al, 2003). Once activated, Akt phosphorylates and regulates a variety of regulatory kinases that directly affect cell cycle progression and cell survival pathways.

Many of the effects of Akt activation are mediated through its negative regulation of the path that affects cell survival and is usually dysregulated in cancer. Akt promotes tumor cell survival by regulating components of apoptosis and cell cycle machinery. Akt is one of several kinases that phosphorylate and not activate the pro-apoptotic BAD protein (del Paso et al, 1997; Pastorino et al, 1999). Akt can also promote cell survival by blocking cytochrome C-dependent caspase activation by phosphorylating caspase 9 on Ser ¹⁹⁶ (Cardone et al., 1998).

Akt affects gene transcription at several levels. Phosphorylation of MDM2 E3 ubiquitin ligase on Akt-mediated Ser ¹⁶⁶ and Ser ¹⁸⁶ is beneficial to the nuclear import of MDM2 and the formation and activation of ubiquitin ligase complexes. Nuclear MDM2 targets p53 tumor suppressor to degrade it, which can be blocked by LY294002 (Yap et al., 2000; Ogawara et al., 2002). Down-regulation of p53 by MDM2 affects p53-regulated pro-apoptotic genes (eg, Bax, Fas, PUMA, and DR5), cell cycle inhibitors p21 ^Cip1, and PTEN tumor suppressor transcription (Momand et al., 2000; Hupp et al. Person, 2000; Mayo et al., 2002; Su et al., 2003). Similarly, Akt-mediated phosphorylation of the Forkhead transcription factor FKHR, FKHRL, and AFX (Kops et al., 1999; Tang et al., 1999) facilitates its binding to 14-3-3 protein and The nucleus is exported to the cytosol (Brunet et al., 1999). The inactivation of this forkhead function also affects apoptosis and pro-angiogenic gene transcription, including Fas ligand (Ciechomska et al., 2003), Bim (a pro-apoptotic Bcl-2 family member) (Dijkers et al. , 2000) and transcription of angiopoietin-1 (Ang-1) antagonist, Ang-2 (Daly et al., 2004). The forkhead transcription factor regulates the expression of the cell cycle regulatory protein-dependent kinase (Cdk) inhibitor p27 ^Kip1 . In fact, PI3K inhibitors have been shown to induce p27 ^Kip1 expression, leading to Cdk1 inhibition, cell cycle arrest and apoptosis (Dijkers et al., 2000). It has also been reported that Akt phosphorylates p27 ^Cip1 on Thr ¹⁴⁵ and p27 ^Kip1 on Thr ¹⁵⁷ , which facilitates its association with 14-3-3 protein, resulting in nuclear export and cytoplasmic retention, preventing its inhibition of nuclear Cdks (Zhou et al. People, 2001; Motti et al., 2004; Sekimoto et al., 2004). In addition to these effects, Akt phosphorylates IKK (Romashkova and Makarov, 1999), resulting in phosphorylation and degradation of IκB and subsequent nuclear translocation of NFκB, resulting in the expression of surviving genes such as IAP and Bcl-X _L.

The PI3K/Akt pathway is also associated with the inhibition of apoptosis by JNK and p38 ^MAPK MAP kinases involved in apoptosis induction. It is hypothesized that Akt via phosphorylation and inhibition of two JNK/p38 regulatory kinases, apoptosis signaling kinase 1 (ASK1) (Kim et al, 2001; Liao and Hung, 2003; Yuan et al, 2003) and mixed lineage kinase 3 ( MLK3) (Lopez-Ilasaca et al, 1997; Barthwal et al, 2003; Figueroa et al, 2003) suppresses JNK and p38 ^MAPK signaling. Induction of p38 ^MAPK activity was observed in cytotoxic agent treated tumors and was required for their agents to induce cell death (reviewed by Olson and Hallahan, 2004). Thus, inhibitors of the PI3K pathway promote the activity of co-administered cytotoxic drugs.

Another effect of PI3K/Akt signaling involves regulation of cell cycle progression via regulation of glycogen synthase kinase 3 (GSK3) activity. GSK3 activity in resting cells was increased in those cells in which cell cycle regulatory proteins on the Ser ²⁸⁶ phosphorylation of D _1, whereby the targeting of the protein so as ubiquitination and degradation (Diehl, et al., 1998) And block into the S phase. Akt inhibits GSK3 activity via phosphorylation on Ser ⁹ (Cross et al., 1995). This results cyclin D ₁ increased the content, thereby promoting cell cycle progression. Inhibition of GSK3 activity also affects cell proliferation via activation of the wnt/[beta]-catenin signaling pathway (Abbosh and Nephew, 2005; Naito et al, 2005; Wilker et al, 2005; Segreles et al, 2006). Akt-mediated GSK3 phosphorylation stabilizes β-catenin and localizes the nucleus, which in turn leads to increased expression of c-myc and cyclin D1, which are targets of the β-catenin/Tcf pathway.

Although PI3K signaling is utilized by many signal transduction networks involved in both oncogenes and tumor suppressor factors, PI3K and its activity have been directly linked to cancer. Overexpression of the p110α and p110β isoforms has been observed in bladder and colon tumors and cell lines, and overexpression is often associated with increased PI3K activity (Bénistant et al., 2000). It has also been reported that p110α is expressed in ovarian and cervical tumors and tumor cell lines as well as squamous cell lung cancer. Overexpression of p110α in cervical and ovarian tumor lines is associated with increased PI3K activity (Shayesteh et al., 1999; Ma et al., 2000). Elevated PI3K activity has been observed in colorectal cancer (Phillips et al, 1998) and increased performance has been observed in breast cancer (Gershtein et al, 1999).

In the past few years, somatic mutations in the gene encoding pi 10α (PIK3CA) have been identified in a variety of cancers. Data collected to date indicate that PIK3CA is in approximately 32% of colorectal cancer (Samuels et al, 2004; Ikenoue et al, 2005), 18% to 40% of breast cancer (Bachman et al, 2004; Campbell et al, 2004; Levine). Et al, 2005; Saal et al, 2005; Wu et al, 2005), 27% of gliomas (Samuels et al, 2004; Hartmann et al, 2005; Gallia et al, 2006), 25% of gastric cancer (Samuels et al, 2004; Byun et al, 2003; Li et al, 2005), 36% of hepatocellular carcinoma (Lee et al, 2005), 4% to 12% of ovarian cancer (Levine et al, 2005; Wang Et al., 2005), 4% of lung cancers (Samuels et al., 2004; Whyte and Holbeck, 2006) and up to 40% of endometrial cancers (Oda et al., 2005). PIK3CA mutations have also been reported in oligodendrogliomas, astrocytomas, medulloblastomas, and thyroid tumors (Broderick et al., 2004; Garcia-Rostan et al., 2005). Based on the observed high mutation frequency, 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 are clustered in two protein regions: the helix (E545K) and the catalytic (H1047R) domain. Biochemical analysis and protein expression studies have demonstrated that both mutations result in increased constitutive constitutive activity of pi 10a and are in fact carcinogenic (Bader et al, 2006; Kang et al, 2005; Samuels et al., 2005; Samuels and Ericson, 2006). Recently, it has been reported that embryonic fibroblasts of PIK3CA knockout mice have defects in signaling downstream of various growth factor receptors (IGF-1, insulin, PDGF, EGF), and have various transformations by various oncogenic RTKs. Resistance (IGFR, wild-type EGFR and somatic activation mutants of EGFR, Her2/Neu) (Zhao et al., 2006).

In vivo PI3K functional studies have demonstrated that siRNA-mediated down-regulation of p110β inhibits both Akt phosphorylation and HeLa cell tumor growth in nude mice (Czauderna et al., 2003). In a similar experiment, siRNA-mediated down-regulation of p110β was also shown to inhibit malignant glioma cell growth in vitro and in vivo (Pu et al., 2006). Mitosis and cell transformation can be blocked by a dominant negative p85 regulatory subunit that inhibits PI3K function (Huang et al, 1996; Rahimi et al, 1996). Several somatic mutations in the genes encoding the p85[alpha] and p85[beta] regulatory subunits of PI3K that result in elevated lipid kinase activity have also been identified in a variety of cancer cells (Janssen et al, 1998; Jimenez et al, 1998; Philp et al, 2001; Jucker et al., 2002; Shekar et al., 2005). Neutralizing PI3K antibodies also blocks mitogenesis and induces apoptosis in vitro (Roche et al, 1994; Roche et al, 1998; Bénistant et al, 2000). In vivo studies using PI3K inhibitors LY294002 and wortmannin confirmed that inhibition of PI3K signaling slows tumor growth in vivo (Powis et al., 1994; Shultz et al., 1995; Semba et al., 2002; Ihle). Et al., 2004).

Overexpression of class I PI3K activity or stimulation of its lipid kinase activity is associated with targeting (eg, imatinib and trastuzumab) and cytotoxic chemotherapeutic methods and resistance to radiation therapy ( West et al, 2002; Gupta et al, 2003; Osaki et al, 2004; Nagata et al, 2004; Gottschalk et al, 2005; Kim et al, 2005). It has also been shown that PI3K activation results in multidrug resistance protein-1 (MRP-1) being expressed in prostate cancer cells and subsequently induced resistance to chemotherapy (Lee et al., 2004).

The following findings further emphasize the importance of PI3K signaling in tumorigenesis: PTEN tumor suppressor PI (3) P phosphatase is particularly the most common inactivated gene in human cancer (Li et al, 1997; Steck et al, 1997; Ali et al., 1999; Ishii et al., 1999). PTEN so PI (3,4,5) P ₃ becomes dephosphorylated PI (4,5) P _2, thereby antagonizing PI3K-dependent signaling. Cells containing functionally inactive PTEN have elevated PIP ₃ levels and a high degree of PI3K signaling activity (Haas-Kogan et al, 1998; Myers et al, 1998; Taylor et al, 2000), increased proliferative potential and decreased Sensitivity to pro-apoptotic stimulation (Stambolic et al., 1998). Reconstruction of functional PTEN suppresses PI3K signaling (Taylor et al., 2000), inhibits cell growth, and re-sensitizes cells to pro-apoptotic stimulation (Myers et al, 1998; Zhao et al, 2004). Similarly, restoration of PTEN function in tumors lacking functional PTEN inhibits in vivo tumor growth (Stahl et al, 2003; Su et al, 2003; Tanaka and Grossman, 2003) and makes cells sensitive to cytotoxic agents (Tanaka and Grossman, 2003).

The signaling input to the class I PI3K is diverse and can be inferred by means of genetic analysis. Therefore, activation of AKT in p110α-deficient murine embryonic fibroblasts (MEF) after stimulation by classical receptor tyrosine kinase (RTK) ligands (eg, EGF, insulin, IGF-1, and PDGF) Damaged (Zhao et al., 2006). However, MEFs in which p110β is removed or replaced by a kinase-inactivated dual gene of p110β typically respond to growth factor stimulation via RTK (Jia et al., 2008). In contrast, p110β catalytic activity is required for AKT activation in response to GPCR ligands (eg, LPA). Thus, p110α appears to carry most of the PI3K signaling in classical RTK signaling and is responsible for tumor cell growth, proliferation, survival, angiogenesis and metabolism, while p110β mediates GPCR signaling from mitogens and chemokines and therefore Tumor cell proliferation, metabolism, inflammation and invasion can be modulated (Vogt et al, 2009; Jia et al, 2009).

Mutations in the gene encoding p110β are extremely rare in tumors, but amplification of PI3Kβ has been found in many tumors (Bénistant et al., 2000; Brugge et al., 2007). important In the mouse prostate tumor model driven by PTEN deficiency, it was shown that removal of p110α had no effect on tumor formation (Jia et al., 2008). In addition, in PTEN-deficient human cancer cell lines (eg, PC-3, U87MG, and BT549) of p110β but not p110α, inhibition of downstream activation of AKT, cell transformation, and growth of PTEN-deficient cells and tumor xenografts (Wee) Et al., 2008). Genetic studies have shown that the kinase activity of p110β is required for cell transformation caused by loss of PTEN. For example, the addition of kinase-inactivated p110β, rather than its wild-type counterpart, results in the formation of impaired lesions in endogenous p110β deficient PTEN-deficient PC3 cells (Wee et al., 2008). These studies demonstrate that PTEN-deficient tumor cells are dependent on p110β and its catalytic activity for signaling and growth.

Genetic alterations in the tumor suppressor gene PTEN are commonly 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, the coexisting genetic alterations of PIK3CA and PTEN were confirmed (Yuan and Cantley, 2008). In addition to mutations, amplification of PIK3CA and loss of PTEN function caused by various molecular mechanisms have been found. For example, amplification of PIK3CA and loss of function of PTEN were found in 30-50% and 35-60% of gastric cancer patients, respectively, but the mutation rate of PIK3CA and PTEN was reported to be less than 7% (Byun et al., 2003; Oki). Et al, 2006; Li et al., 2005; Sanger Database).

Although a subset of tumor types relies solely on PI3Kα signaling, other tumors rely on PI3Kβ signaling or on a combination of both PI3Kα and PI3Kβ signaling.

Therefore, there is still a need in the industry for PI3K inhibitors that exhibit balanced inhibition of both PI3K alpha and PI3K beta isoforms. In particular, there is a need in the art to demonstrate PI3K inhibitors that are resistant to the equivalent (ie, balanced) inhibitory activity of PI3K alpha and PI3K beta to achieve the desired therapeutic effect while exhibiting no adverse events/effects or adverse events/effects to the patient.

The Applicants have previously found compounds that exhibit balanced inhibition of both PI3K alpha and PI3K beta isoforms (see WO 2012/062748).

Based on the expected mode of action, PI3K inhibitors are effective against PI3K pathways in tumors Repression may be necessary and/or advantageous for achieving an appropriate or improved therapeutic effect (e.g., for increased tumor killing efficacy and/or for better disease control).

In addition, in addition to its important role in tumor formation, tumor growth, survival and metastasis, PI3K also regulates the development, metabolism and biological functions of many normal cells and organs. Therefore, PI3K inhibitors developed for the treatment of cancer face the generation of adequate therapeutic windows (through adequate inhibition of tumor cell proliferation and survival) while maintaining acceptable toxicological profiles (by allowing normal cells and organs to be sufficient) The extent to which it works) challenges. In fact, most of the PI3K inhibitors currently being clinically developed show significant side effects and serious adverse events (eg hyperglycemia, GI toxicity, hepatotoxicity, pneumonia, pneumocystic pneumonia) (Pneumocystis) before confirming substantial antitumor efficacy Pneumonia, PCP), etc.). Some toxicities are related to the mode of action. Therefore, there is an urgent need to provide the following novel treatment options: - effectively suppressing the PI3K pathway in tumor cells, thereby causing sufficient or improved therapeutic efficacy (eg, increased tumor killing efficacy and/or better disease control), and/or Maintaining or improving toxicological profiles in patients taking PI3K inhibitors to treat hyperproliferative disorders and/or diseases associated with angiogenesis (eg reducing the incidence and severity of certain side effects and/or certain adverse events) ).

The Applicant has surprisingly discovered a favorable dosing regimen for the administration of PI3K inhibitors, in particular for the administration of a PI3K inhibitor of formula (I) as set forth herein, which improves tumor tissue relative to continuous administration Repression of the PI3K pathway and/or improved therapeutic efficacy (eg, increased tumor killing efficacy and/or better disease control), and/or - administration of a compound of formula (I) to treat hyperproliferative disorders associated with angiogenesis To maintain or improve toxicological profiles in patients with and/or diseases (eg, by reducing the incidence and severity of certain side effects and/or certain adverse events observed under continuous administration).

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

Wherein: R ¹ represents -(CH ₂ ) _n -(CHR ⁴ )-(CH ₂ ) _m -N(R ⁵ )(R ^5' ); and R ² represents a heteroaryl group of the following structure:

It is optionally substituted with 1, 2 or 3 R ⁶ groups, wherein: * represents the attachment point of the heteroaryl group to the rest of the compound of formula (I), X represents N or CR ⁶ , X 'Represents O, S, NH, NR ⁶ , N or CR ⁶ , provided that when both X and X' are CR ⁶ , then one CR ⁶ is CH; R ³ is methyl; R ⁴ is hydroxyl; R ⁵ and R ^{5 'is the} same or different and independently of each other is a hydrogen atom or a C ₁ -C ₆ -alkyl group, a C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl group or a C ₁ -C ₆ -alkoxy group The base-C ₁ -C ₆ -alkyl group, or R ⁵ and R ^{5 '} together with the nitrogen atom to which they are bonded represent a 3 to 7 member nitrogen-containing heterocyclic ring, the heterocyclic ring optionally containing at least one selected from the group consisting of oxygen, nitrogen or sulfur. Other heteroatoms and which may optionally be substituted by one or more R ^{6 '} groups; each occurrence of R ⁶ may be the same or different and independently a hydrogen atom, a halogen atom, a C ₁ -C ₆ -alkyl group, C _2- C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl, aryl, aryl -C ₁ -C ₆ -alkyl, heteroaryl, heteroaryl-C ₁ -C ₆ -alkyl, 3 to 8 membered heterocyclic ring, 3 to 8 membered heterocyclyl-C ₁ -C ₆ -alkane , -C ₁ -C ₆ -alkyl-OR ⁷ , -C ₁ -C ₆ - Alkyl-SR ⁷ , -C ₁ -C ₆ -alkyl-N(R ⁷ )(R ^7' ), -C ₁ -C ₆ -alkyl-C(=O)R ⁷ , -CN, -C (=O)OR ⁷ , -C(=O)N(R ⁷ )(R ^7' ), -OR ⁷ , -SR ⁷ , -N(R ⁷ )(R ^7' ) or -NR ⁷ C(= O) 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 independently C ₁ -C ₆ -alkyl , C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkyl-OR ⁷ ; each occurrence of R ⁷ and R ^{7 '} may be the same or different and independently Hydrogen atom or C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyl- C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkenyl, aryl, aryl-C ₁ -C ₆ -alkyl, heteroaryl, 3 to 8 membered heterocyclic ring, 3 to 8 membered hetero Cyclo-C ₁ -C ₆ -alkyl or heteroaryl-C ₁ -C ₆ -alkyl; each occurrence of R ^{8 is} independently a halogen atom or a nitro group, a hydroxyl group, a cyano group, a methyl group, a Mercapto, amine, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ - ring alkyl, C ₃ -C ₆ - cycloalkyl, -C ₁ -C ₆ - alkyl, C ₁ -C ₆ - cycloalkenyl group, an aryl group, Group -C ₁ -C ₆ - alkyl, aryl, heteroaryl, 3-8 heterocyclyl, heterocyclyl -C ₁ -C ₆ - alkyl aryl or heteroaryl group -C ₁ -C ₆ - alkyl; n lines An integer of 1 and m is an integer of 1; the premise is when - R ⁵ and R ^5' together with the nitrogen atom to which they are bonded represent the following structure:

Wherein * represents an attachment point to the remainder of the structure of formula (I), then - the R ² heteroaryl of the structure:

Not for:

Wherein * represents an attachment point to the remainder of the structure of formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof; (I) a compound for use in preventing or treating a hyperproliferative and/or angiogenic disorder, wherein the compound of formula (I) is administered for a period of from 1 to 5 days in each administration cycle, followed by a period of from 3 to 6 days Compounds of formula (I) are not administered or placebo is administered.

A second aspect of the invention relates to the use of a compound of formula (I) as defined herein for the manufacture of a medicament for the prevention or treatment of hyperproliferative and/or angiogenic disorders, wherein in each administration cycle The compound of formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, is administered for a period of from 1 to 5 days, followed by 3 to 6 days. Compounds of formula (I) or placebo are not administered during the time period.

A third aspect of the invention relates to a method of preventing or treating a hyperproliferative and/or angiogenic disorder comprising administering to a patient suffering from the disorder a compound of formula (I) as defined herein in each administration cycle Or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof for a period of from 1 to 5 days, followed by a non-administration formula for a period of 3 to 6 days ( I) Compound or placebo.

According to another aspect of the invention, there is provided a method of treating at least one pathological condition in a patient in need thereof, comprising administering to the patient (in each administration cycle) a pharmacologically effective amount as defined herein a compound of formula (I) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof for a period of from 1 to 5 days, followed by a period of from 3 to 6 days Compounds of formula (I) are not administered or placebo is administered.

According to another aspect of the invention, there is provided a method of inhibiting PI3K in an individual comprising administering to the individual (in each administration cycle) an effective amount of a compound of formula (I), as defined herein, (I) a compound or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof for a period of from 1 to 5 days, followed by a period of from 3 to 6 days Administration of a compound of formula (I) or administration of a placebo.

The invention also relates to a package comprising a pharmaceutical composition of a compound of formula (I) and administering the composition (in each administration cycle) for a period of from 1 to 5 days, followed by 3 to 6 days Instructions for administering the compound of formula (I) or administering a placebo during the time period.

A. Definition

The term as referred to herein preferably has the following meaning: The term "halogen atom" or "halo group" is understood to mean a fluorine, chlorine, bromine or iodine atom.

The term "C ₁ -C ₆ -alkyl" is understood to preferably mean a straight or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. a group such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, t-butyl, t-butyl, isopentyl, 2-methylbutyl, 1 -methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 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 or an isomer thereof. Specifically, the group has 1, 2 or 3 carbon atoms ("C ₁ -C ₃ -alkyl"), methyl, ethyl, n-propyl or isopropyl.

The term "C ₁ -C ₆ -alkoxy" is understood to preferably mean a straight-chain or branched saturated monovalent hydrocarbon radical of the formula -O-alkyl, wherein the term "alkyl" is as defined above. , for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, second butoxy, pentyloxy, isopentyloxy Or n-hexyloxy or its isomers.

The term "C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl" is understood to preferably mean a straight-chain or branched saturated monovalent alkyl group as defined above, wherein in a hydrogen atom One or more of the same or different substitutions by a C ₁ -C ₆ -alkoxy group as defined above, for example methoxyalkyl, ethoxyalkyl, propyloxyalkyl, isopropoxy Alkyl, butoxyalkyl, isobutoxyalkyl, tert-butoxyalkyl, second butoxyalkyl, pentyloxyalkyl, isopentyloxyalkyl, hexyloxy Alkyl, wherein the term "C ₁ -C ₆ -alkyl" is as defined above, or an isomer thereof.

The term "C ₂ -C ₆ -alkenyl" is understood to preferably mean one or more double bonds and have 2, 3, 4, 5 or 6 carbon atoms, in particular 2 Or a straight or branched monovalent hydrocarbon group of 3 carbon atoms ("C ₂ -C ₃ -alkenyl"), it being understood that where the alkenyl group contains more than one double bond, the double bonds may Separated from each other or conjugated to each other. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2-ene , (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3- Alkenyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z) -pent-1-enyl, hex-5-alkenyl, (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-1-enyl, (Z)-hex-1- Alkenyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylpropane- 1-alkenyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3- Alkenyl, 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 - alkenyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, ( Z)-1-methylbut-1-enyl, 1,1-dimethylpropan-2- , 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-A Kepent-3-enyl, (Z)-1-methylpent-3-enyl, (E)-4-methylpent-2-enyl, (Z)-4-methylpent-2- Alkenyl, (E)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl, (E)-2-methylpent-2-enyl, (Z -2-methylpent-2-enyl, (E)-1-methylpent-2-enyl, (Z)-1-methylpent-2-enyl, (E)-4-A Pent-1-enyl, (Z)-4-methylpent-1-enyl, (E)-3-methylpent-1-enyl, (Z)-3-methylpent-1- Alkenyl, (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-ethyl -2-alkenyl, (E)-1-ethylbut-2-enyl, (Z)-1-ethyl -2-alkenyl, (E)-3-ethylbut-1-enyl, (Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E) 1-ethylbuten-1-enyl, (Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2 -isopropylpropan-2-enyl, 1-isopropylprop-2-enyl, (E)-2-propylprop-1-enyl, (Z)-2-propylprop-1- Alkenyl, (E)-1-propylprop-1-enyl, (Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl, ( Z)-2-isopropylpropan-1-enyl, (E)-1-isopropylpropan-1-enyl, (Z)-1-isopropylpropan-1-enyl, (E) -3,3-dimethylprop-1-enyl, (Z)-3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)vinyl, butyl - 1,3-dienyl, pentane-1,4-dienyl, hex-1,5-dienyl or methylhexadienyl. In particular, the group is a vinyl or allyl group.

The term "C ₂ -C ₆ -alkynyl" is understood to preferably mean one or more triple bonds and contain 2, 3, 4, 5 or 6 carbon atoms, in particular 2 Or a linear or branched monovalent hydrocarbon group of 3 carbon atoms ("C ₂ -C ₃ -alkynyl"). The C ₂ -C ₆ -alkynyl group (for example), ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-yne , pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl ,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- Alkynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methyl Kepent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-yne , 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-Dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. Specifically, the alkynyl group is an ethynyl group, a prop-1-ynyl group or a prop-2-ynyl group.

The term "C ₃ -C ₆ - cycloalkyl" is understood to mean preferably contains three saturated monovalent monocyclic 4, 5 or 6 carbon atoms of the bicyclic ring or a hydrocarbon ring. The C ₃ -C ₆ -cycloalkyl group is, for example, a monocyclic hydrocarbon ring such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group or a bicyclic hydrocarbon ring such as perhydropentarene (perhydropentalenylene). ) or decahydronaphthalene ring. The cycloalkyl ring may optionally contain one or more double bonds, such as a cycloalkenyl group, such as a cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group, wherein the ring is between the remainder of the molecule The bond can be bonded to any carbon atom of the ring, whether the ring is saturated or unsaturated.

The term "alkylene" is understood to preferably mean an optionally substituted hydrocarbon chain (or "tether" having one, two, three, four, five or six carbon atoms. ), that is, -CH ₂ - ("methylene" or "mono-chain" or such as -C(Me) ₂ -), -CH ₂ -CH ₂ - ("Extended Ethyl", "Dimethylene" or "binary tether"), -CH ₂ -CH ₂ -CH ₂ - ("extended propyl", "trimethylene" or "ternary tether"), -CH ₂ -CH ₂ -CH ₂ -CH ₂ - ("Strengthyl", "tetramethylene" or "quaternary tether"), -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ - ("",""pentamethylene" or "five-chain") or -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ - ("extension", "hexamethylene" or "Six dollar chain"). In particular, the alkylene chain has 1, 2, 3, 4 or 5 carbon atoms, more specifically 1 or 2 carbon atoms.

The term "3 to 8 membered heterocycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 2, 3, 4, 5, 6 or 7 carbon atoms and one or a plurality of hetero atom-containing groups selected from the group consisting of C(=O), O, S, S(=O), S(=O) ₂ , NRa, wherein R ^a represents a hydrogen atom or C ₁ -C ₆ - alkyl - group or halo -C ₁ -C ₆ - alkyl; the heterocyclic group may be attached to the remainder of the molecule via a (if present) to any carbon atom or a nitrogen atom of a person.

In particular, the 3 to 8 membered heterocycloalkyl group may contain 2, 3, 4, 5, 6 or 7 carbon atoms and one or more of the above-mentioned hetero atom-containing groups. ("3 to 8 membered heterocycloalkyl"), more specifically the heterocycloalkyl group may contain 4 or 5 carbon atoms and one or more of the above-mentioned hetero atom-containing groups ("5 Up to 7 members of heterocycloalkyl").

Specifically, but not limited to, the heterocycloalkyl group can be, for example, a 4-membered ring, such as azetidinyl, oxetanyl; or a 5-membered ring, such as tetrahydrofuranyl, dioxolane Dienyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl; or 6-membered ring, such as tetrahydropyranyl, hexahydropyridyl, morpholinyl, dithiaalkyl, thiomorpholinyl, hexahydro Pyrazinyl or trithiaalkyl; or a 7-membered ring, such as a diazepane ring. Optionally, the heterocycloalkyl group can be benzofused.

The heterocyclic group may be a bicyclic ring such as, but not limited to, a 5,5 membered ring, such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl) ring; or a 5,6 membered bicyclic ring, such as six Hydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring or, for example, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl ring.

As mentioned above, the ring containing a nitrogen atom may be a partially unsaturated ring, that is, it may contain one or more double bonds such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H. a [1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl ring; or it may be benzofused, such as (but not limited to) Dihydroisoquinolinyl ring.

The term "aryl" is understood to preferably mean an aromatic or partially aromatic monovalent having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms. Monocyclic or bicyclic or tricyclic hydrocarbon ring ("C ₆ -C ₁₄ -aryl"), specifically a ring having 6 carbon atoms ("C ₆ -aryl") (eg phenyl or biphenyl) a ring having 9 carbon atoms ("C ₉ -aryl") (eg, indanyl or fluorenyl) or a ring having 10 carbon atoms ("C ₁₀ -aryl") (eg, tetrahydrogenation) Naphthyl, dihydronaphthyl or naphthyl) or a ring having 13 carbon atoms ("C ₁₃ -aryl") (eg fluorenyl) or a ring having 14 carbon atoms ("C ₁₄ -aryl") (eg 蒽基). A specific example of an aryl group is one of the following possible structures:

Wherein z represents O, S, NH or N(C ₁ -C ₆ -alkyl), and * indicates the attachment point of the aryl group to the rest of the molecule.

The term "heteroaryl" is understood to preferably mean 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 Monovalent monocyclic, bicyclic or tricyclic aromatic ring systems ("5 to 14 membered heteroaryl") having 6 or 9 or 10 atoms and containing at least one hetero atom which may be the same or different, The atomic system is, for example, oxygen, nitrogen or sulfur, and additionally may be benzofused in each case.

Specifically, the heteroaryl group has the following structure:

It is optionally substituted by 1, 2 or 3 R ⁶ groups, wherein: * represents the attachment point of the heteroaryl group to the rest of the compound of formula (I) as defined above, X represents N Or CR ⁶ , X' represents O, S, NH, NR ⁶ , N or CR ⁶ , - each occurrence of R ⁶ may be the same or different and independently hydrogen atom, halogen atom, C ₁ -C ₆ -alkyl , C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl, aryl , aryl-C ₁ -C ₆ -alkyl, heteroaryl, heteroaryl-C ₁ -C ₆ -alkyl, 3 to 8 membered heterocyclic ring, 3 to 8 membered heterocyclic group -C ₁ -C ₆ -alkyl, -C ₁ -C ₆ -alkyl-OR ⁷ , -C ₁ -C ₆ -alkyl-SR ⁷ , -C ₁ -C ₆ -alkyl-N(R ⁷ )(R ^7' ) , -C ₁ -C ₆ -alkyl-C(=O)R ⁷ , -CN, -C(=O)OR ⁷ , -C(=O)N(R ⁷ )(R ^7' ), -OR ⁷ , -SR ⁷ , -N(R ⁷ )(R ^7' ) or -NR ⁷ C(=O)R ⁷ , each of which may be substituted by one or more R ⁸ groups as appropriate ;- Each occurrence of R ⁷ and R ^{7 '} may be the same or different and independently hydrogen atom or C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkenyl, aryl, aryl-C ₁ -C ₆ -alkyl, heteroaryl, 3 to 8 membered heterocyclic ring, 3 to 8 membered heterocyclic group -C ₁ -C ₆ -alkyl or heteroaryl-C ₁ -C ₆ -alkyl; - Each occurrence of R ^{8 is} independently a halogen atom or a nitro group, a hydroxyl group, a cyano group, a methyl group, an ethyl group Base, amine group, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkane , C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -cycloalkenyl, aryl, aryl-C ₁ -C ₆ -alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclic-C ₁ -C ₆ -alkyl or heteroaryl-C ₁ -C ₆ -alkyl.

More specifically, the heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, tri Azolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof (for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazole Or benzotriazolyl, oxazolyl, fluorenyl, isodecyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and benzo derivatives thereof (for example Quinoline, quinazolinyl, isoquinolinyl, etc.; or nitrogen a base, a pyridazinyl group, a fluorenyl group, etc., and a benzo derivative thereof; or Lolinyl, pyridazinyl, quinazolinyl, quinoxalinyl, naphthylpyridyl, acridinyl, oxazolyl, acridinyl, phenazinyl, phenothiazine, phenazinyl, Base or oxo group.

In general and unless otherwise mentioned, a heteroaryl or heteroaryl group includes all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative, non-limiting examples, the term pyridyl or extended pyridyl includes pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridine-4 - and pyridyl-4-yl; or the term thienyl or thienyl includes thiophene-2-yl, thiophen-2-yl, thiophen-3-yl and thiophen-3-yl.

The term "C ₁ -C ₆ " as used throughout this document is understood to mean having the meaning of, for example, "C ₁ -C ₆ -alkyl" or "C ₁ -C ₆ -alkoxy". 1 to 6 of a limited number of carbon atoms, that is, an alkyl group of 1, 2, 3, 4, 5 or 6 carbon atoms. It should be further understood that the term "C ₁ -C ₆ " should be interpreted as any subrange contained therein, such as C ₁ -C ₆ , C ₂ -C ₅ , C ₃ -C ₄ , C ₁ -C ₂ , C ₁ -C ₃ , C ₁ -C ₄ , C ₁ -C ₅ , C ₁ -C ₆ ; specifically C ₁ -C ₂ , C ₁ -C ₃ , C ₁ -C ₄ , C ₁ -C ₅ , C ₁ -C ₆ ; more specifically C ₁ -C ₄ ; in the case of "C ₁ -C ₆ -haloalkyl" or "C ₁ -C ₆ -haloalkoxy", even more specific For C ₁ -C ₂ .

Similarly, as used herein, the term "C ₂ -C ₆ " as used throughout the text is used in the context of, for example, the definitions of "C ₂ -C ₆ -alkenyl" and "C ₂ -C ₆ -alkynyl". It is understood to mean an alkenyl or alkynyl group having from 2 to 6 of a limited number of carbon atoms, ie 2, 3, 4, 5 or 6 carbon atoms. It should be further understood that the term "C ₂ -C ₆ " should be interpreted as any subrange contained therein, such as C ₂ -C ₆ , C ₃ -C ₅ , C ₃ -C ₄ , C ₂ -C ₃ , C ₂ - C ₄ , C ₂ - C ₅ ; specifically C ₂ - C ₃ .

Further, as used herein, the term "C ₃ -C ₆ " as used throughout the text is understood to mean having 3 to 6 in the context of the definition of "C ₃ -C ₆ -cycloalkyl", for example. a limited number of carbon atoms, i.e., a cycloalkyl group of 3, 4, 5 or 6 carbon atoms. It should be further understood that the term "C ₃ -C ₆ " should be interpreted as any subrange contained therein, such as C ₃ -C ₆ , C ₄ -C ₅ , C ₃ -C ₅ , C ₃ -C ₄ , C ₄ - C ₆ , C ₅ - C ₆ ; specifically C ₃ - C ₆ .

The term "substituted" means that one or more hydrogens on a given atom are replaced by a selection from the indicated group, provided that the normal valence of the specified atom is not exceeded and 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 the use of an optional substitution of a specified group (group or radical) or moiety.

Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system and, for example, replacing the available hydrogen on the ring system.

As used herein, the term "one or more" is understood to mean "1, 2, 3, in the definition of a substituent of, for example, a compound of the invention (eg, compound A, B or C). Next, 4 or 5 times, specifically 1 time, 2 times, 3 times or 4 times, more specifically 1 time, 2 times or 3 times, or even more specifically 1 time or 2 times.

If a plural component of a component, compound, salt, polymorph, hydrate, solvate or the like is used herein, it also means a single component, compound, salt, polymorph, isomer, hydrated , solvate or the like.

By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to withstand separation from the reaction mixture to a useful purity and formulated into an effective therapeutic.

The term "carbonyl" refers to an oxygen atom bonded to a carbon atom of a molecule by a double bond.

The compounds of the invention may contain one or more asymmetric centers depending on the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in ( R ) and/or ( S ) configurations to produce a racemic mixture in the case of a single asymmetric center and to produce a mixture of non-imagewise isomers in the case of multiple asymmetric centers . In some cases, the asymmetry may also be present due to limited rotation around a given bond, for example, the central bond of two substituted aromatic rings adjacent to a given compound. Substituents on the ring may also exist in cis or trans form. All such configurations, including image isomers and non-image isomers, are intended to be included within the scope of the invention. Preferred compounds are those which produce a more desirable biological activity. Individual, pure or partially purified isomers and stereoisomers or mixtures of racemic or non-imagewise isomers of the compounds of the invention are also included within the scope of the invention. Purification and separation of such materials can be accomplished by standard techniques known in the art.

Tautomers are sometimes referred to as proton-shifting tautomers, which are two or more compounds that are related to the transfer of a hydrogen atom by one or more single bonds and one or more adjacent double bonds. . The compounds of the invention may exist in one or more tautomeric forms. For example, a compound of formula I may exist in tautomeric form Ia , tautomeric form Ib or tautomeric form Ic or may be present as a mixture of any of these forms. All such tautomeric forms are intended to be included within the scope of the invention.

The invention also relates to useful forms of the compounds disclosed herein, such as pharmaceutically acceptable salts, coprecipitates, metabolites, hydrates, solvates, and prodrugs of all compounds of the various examples. The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the invention. See , for example, SM Berge et al., "Pharmaceutical Salts," J. Pharm . Sci. 1977, 66, 1-19. The pharmaceutically acceptable salts include those obtained by reacting a main compound which acts in a base form with an inorganic or organic acid to form a salt, for example, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, A salt of maleic acid, succinic acid and citric acid. Pharmaceutically acceptable salts also include those in which the main compound acts in acid form and reacts with a suitable base to form, for example, sodium, potassium, calcium, magnesium, ammonium and chloride salts. Those skilled in the art will further recognize that acid addition salts of the claimed compounds can be prepared by reacting the compound with a suitable inorganic or organic acid via any of a variety of conventional methods. Alternatively, the alkali metal and alkaline earth metal salts of the acidic compounds of the present invention can be prepared by subjecting the compounds of the present invention to a suitable base via various known methods.

Representative salts of the compounds of this invention include the conventional non-toxic salts and quaternary ammonium salts formed from, for example, inorganic or organic acids or bases by methods well known to those skilled in the art. For example, such acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, besylate, hydrogen sulfate, butyrate, citric acid Salt, camphorate, camphor sulfonate, cinnamate, cyclopentanoate, digluconate, lauryl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphoric acid Salt, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methane Acid salt, 2-naphthalenesulfonic acid Salt, nicotinic acid salt, nitrate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, Succinate, sulfonate, sulfate, tartrate, thiocyanate, tosylate and undecanoate.

The alkali salt includes alkali metal salts such as potassium salts and sodium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucosamine. Alternatively, the basic nitrogen-containing group can be subjected to quaternization with a reagent such as a lower alkyl halide such as methyl, ethyl, propyl or butyl chloride, bromide and iodide; a base such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate or diamyl sulfate; long chain halides such as sulfhydryl, lauryl, myristyl and stearyl chlorides, bromides and Iodide; aralkyl halides such as benzyl bromide and phenethyl bromide and others.

For the purposes of the present invention, a solvate is a complex of a solvent with a compound of the invention in solid form. Exemplary solvates can include, but are not limited to, complexes of the compounds of the invention with ethanol or methanol. The hydrated solvent is in the form of a specific solvate of water.

Unless otherwise stated, components substituted as described herein may be substituted one or more times independently of each other at any position. When any variable appears more than once in any component, each definition is independent.

Unless otherwise indicated, a heteroaryl or heterocyclyl as referred to herein may be substituted at any of its possible positions (eg, at any substitutable ring carbon or ring nitrogen atom) via its given substituent or parent molecular group. Similarly, it will be appreciated that any chemically suitable heteroaryl or heterocyclic group can be attached to the remainder of the molecule via any suitable atom. Unless otherwise stated, any heteroatom of a heteroaryl ring having an unsaturated valence as referred to herein is assumed to have a hydrogen atom to saturate the valences. Unless otherwise stated, a ring containing a quaternizable ammonium or imido ring nitrogen atom (-N=) is preferably not preferred on the amine or imido ring nitrogen atom. Reference is made to a quaternary ammonium group of a substituent or a parent molecular group.

Preferred compounds produce a more desirable biological activity. Single compound of the invention Individual, pure or partially purified isomers and stereoisomers or mixtures of racemic or non-image isomers are also included within the scope of the invention. Purification and isolation of such materials can be accomplished by standard techniques known to those skilled in the art.

Optical isomers can be obtained by resolution of the racemic mixture according to conventional methods, for example, by formation of a non-imagewise isomer salt using an optically active acid or base, or formation of a covalent non-image isomer. Examples of suitable acids are tartaric acid, diethyl tartaric acid, xylyl tartaric acid and camphorsulfonic acid. Mixtures of non-imageomers may be separated into their individual non-image isomers based on their physical and/or chemical differences by methods known in the art (e.g., by chromatography or fractional crystallization). The optically active base or acid is then released from the separated non-image isomer salt. Different processes for isolating optical isomers involve the use of a palm chromatography (eg, a palmitic HPLC column) with or without conventional derivatization, which is optimized to maximize separation of the mirror image isomers. . Suitable palm-shaped HPLC columns (especially Chirall OD and Chiracel OJ, for example) are manufactured by Diacel, all of which can be selected in a conventional manner. Separation of the enzyme with or without derivatization can also be used. The optically active compounds of the present invention can likewise be obtained by palm-forming synthesis using optically active starting materials.

If an "embodiment" is mentioned in the context of the present invention, it should be understood that it includes a plurality of possible combinations.

To limit the different types of isomers, refer to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

The invention also encompasses all suitable isotopic variations of the compounds of the invention. An isotopic variation of a compound of the invention is defined as an atomic substitution of at least one atom by atomic mass having the same atomic number but differing in atomic mass from that found generally or predominantly in nature. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example ² H(氘), ³ H(氚), ¹¹ C, respectively. , ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I. Certain isotopic variations of the compounds of the invention, such as those incorporating one or more radioisotopes (e.g., ³ H or ¹⁴ C), can be used in drug and/or matrix tissue distribution studies. Isotope containing bismuth and carbon-14 (i.e., ¹⁴ C) is preferred for its ease of preparation and detectability. In addition, substitution with isotopes such as hydrazine may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures known to those skilled in the art (e.g., by illustrative methods) or by the preparation of suitable isotopic variations using suitable reagents as set forth in the Examples below.

The invention includes all possible stereoisomers of the compounds of the invention, either as a single stereoisomer or in any ratio of any ratio of such stereoisomers. Isolation of a single stereoisomer of a compound of the invention (e.g., a single mirror image isomer or a single mirror image isomer) can be accomplished by any suitable novel method (e.g., chromatography, especially for palm chromatography).

The invention includes all possible tautomers of the compounds of the invention, either as a single tautomer or in any mixture in any ratio of such tautomers.

Furthermore, the invention includes all possible crystalline forms or polymorphs of the compounds of the invention in the form of a single polymorph or a mixture of more than one polymorph in any ratio.

The terms "continuous administration", "daily administration" or "continuous treatment" are to be understood as the following administration regimen: from the date of initiation of treatment with a PI3K inhibitor until the date of completion and/or cessation of treatment with a PI3K inhibitor, daily (ie, no date of administration of the PI3K inhibitor) dose of the PI3K inhibitor, or no more than one day between the administration of two consecutive doses of the PI3K inhibitor. One day should be understood as a 24-hour period. Dosing of the dose can be performed at any time (eg, morning, afternoon, evening, etc.) or at any time of the day. The administration of the dose of the PI3K inhibitor during the treatment with the PI3K inhibitor can be performed at the same time or time of day on each day. During treatment with a PI3K inhibitor, administration can be performed at different times or times on each day of the day. Daily administration of PI3K inhibitors Each day is performed in a single dose of PI3K inhibitor (i.e., once daily) or as two or more doses of PI3K inhibitor (twice per day, three times daily, etc.).

The terms "intermittent dosing (schedule)" and "intermittent dosing" should be understood to include the following dosing regimens/schedules: - a daily dose of a PI3K inhibitor for a period of 1 to 5 days, - not subsequently The total number of days between the two time periods together with the PI3K inhibitor or the placebo is 3 to 6 days, which constitutes a "dose cycle."

For the purposes of the present invention, the date of administration of the PI3K inhibitor during the administration cycle may also be referred to as the "dosing day." For the purposes of the present invention, the date of not administering PI3K or administering a placebo during the administration cycle may also be referred to as a "discontinuation day."

Thus, the intermittent administration of the present invention can be formulated as follows: - in the administration cycle, administration for 1 to 5 days (wherein the PI3K inhibitor is administered daily), - followed by withdrawal for 3 to 6 days (where PI3K is not administered) Inhibitor or placebo), any sub-combination of the dosing and withdrawal days according to the present invention may be expressed in the same manner (e.g., two dosing days followed by 5 dosing days).

The intermittent administration of the present invention can also be stated as follows: in the administration cycle, administration is carried out for 1 to 5 days / withdrawal for 3 to 6 days. Any sub-combination of the dosing day and the withdrawal date according to the present invention can be expressed in the same manner (e.g., 2 days of administration/5 days of withdrawal).

The intermittent administration of the present invention can also be stated as follows: - administration of a PI3K inhibitor for 1 to 5 consecutive days; - a period of 3 to 6 days after which no PI3K inhibitor is administered.

Any sub-combination of the date of administration of the PI3K inhibitor (dosing day) and the date of non-administration of PI3K (discontinuation day) according to the present invention may be expressed in the same manner (eg, administration of a PI3K inhibitor for two consecutive days) Then, no PI3K inhibitor was administered during the 5-day period).

The administration of the dose containing the PI3K inhibitor can be carried out at any time of the day (e.g., morning, afternoon, evening, etc.) or at any time. During treatment with PI3K inhibitors, The administration of the dose of the PI3K inhibitor can be carried out at the same time or time of day on the day of administration of PI3K. During treatment with a PI3K inhibitor, administration can occur at different times or times on the day of administration of PI3K, in which case the elapsed time between administration of the PI3K inhibitor over two consecutive days can be less than or More than 24 hours. The PI3K inhibitor can be administered daily at a single dose of the PI3K inhibitor (i.e., once daily) or two or more doses of the PI3K inhibitor per day (twice per day) , three times a day, etc.).

The term "administration cycle" is understood to include the total number of days: - the period of time during which the dose of PI3K inhibitor is administered for a period of 1 to 5 days - followed by the administration of a compound of formula (I) or administration of a placebo A period of 3 to 6 days, wherein the administration cycle takes a total of 4 days (ie, 3 dosing days after 1 dosing day) to 11 days (ie, 5 dosing days followed by 6 drug withdrawal days). This depends on the number of days of administration and the number of days of withdrawal.

One or more of the present administration cycles (ie, intermittent dosing) may be necessary to achieve a suitable or improved therapeutic effect from the date of treatment with the PI3K inhibitor until the date of completion and/or discontinuation of treatment with the PI3K inhibitor. (In this case, according to the invention, it may also be stated as "the treatment system repeats X administration cycles", and X is any value between 1 and 4 (ie a total of 2 to 5 administration cycles) Or, according to the present invention, when the administration cycle consists of 7 days, it can also be stated as "the treatment system repeats (weekly) X weeks", and X is any value between 1 and 4. For example, based on, for example, the non-limiting examples provided in this specification and/or based on the patient's response to treatment and/or suitable techniques/methods that are readily available, those skilled in the art are familiar with how to establish a dosing cycle and How to adjust the number of cycles that may be required if needed (eg during treatment).

The term "interruption" or "interruption period" is understood to mean not administering the compound of formula (I) or administering a placebo for one or more days (usually 4 to 8 days) after or prior to the administration cycle. For example, PI3K kinase in normal cells after completion of the administration cycle (ie after 3 to 6 drug withdrawal days) The recovery of the function may take an additional 4 to 8 days before starting a new cycle of investment. It can also be stated as, for example, "no dose of PI3K inhibitor for 4 to 8 days" or appropriate adjustment according to any interruption period of the present invention. When the interruption period consists of 7 days, it can also be stated as, for example, "do not administer a PI3K inhibitor for 1 week."

For example, in a specific embodiment of the present invention, administration is carried out for the treatment of cancer according to an intermittent schedule of 2 days of administration/discontinuation for 5 days, in which the administration cycle is repeated three times, followed by a 7-day interruption period. In the case of a PI3K inhibitor (eg Compound A1), it can also be stated as follows: - PI3K for the treatment of cancer is administered for two consecutive days, followed by no administration of the PI3K inhibitor over a period of 5 days, the treatment being repeated weekly Three weeks, followed by one week without PI3K inhibitor.

All of the specific embodiments of the present invention can be illustrated in accordance with the above examples, based on the respective number of dosing days, drug withdrawal days, last cycles of the administration cycle, and last additional dates of the interruption period as defined for the embodiments. Adjust appropriately.

As used throughout the text (eg, in the context of defining the number of days in which a compound of Formula (I) (to a patient) (ie, the date of administration) is administered (in the context of each administration cycle), the term "1 to 5 days" "It should be understood to mean 1, 2, 3, 4 or 5 consecutive days. It should be further understood that the term "1 to 5 days" should be interpreted as any subrange included therein, such as 1 to 4 days, 1 to 3 days, 1 to 2 days, 2 to 5 days, 2 to 4 days, 2 to 3 days, 3 to 5 days, 3 to 4 days, 4 to 5 days, and the like. The present invention is directed to all such sub-ranges.

Similarly, as described throughout the text (eg, in the context of defining the number of days in which a compound of formula (I) is administered (to a patient) or a placebo (ie, a day of withdrawal) (in the context of each administration cycle) As used, the term "3 to 6 days" is understood to mean 3, 4, 5 or 6 consecutive days. It should be further understood that the term "3 to 6 days" should be interpreted as any subrange included therein, such as 3 to 6 days, 3 to 5 days, 3 to 4 days, 4 to 6 days, 4 to 5 days, 5 to 6 days, etc. The present invention is directed to all such sub-ranges.

The invention will now be elucidated with reference to the drawings.

Figure 1. PI3K pathway inhibition in a GXA3027 patient-derived gastric tumor model treated with different dosing schedules for Compound A1.

Patient-derived GXA 3027 gastric cancer cells were implanted subcutaneously (sc) into NMRI nude mice. When the tumor reaches a size of about 700 mm ^{3 ,} it is administered at 75 mg/kg, QD (once a day, A and D) or 450 mg/kg, QW (weekly, B and E) or 200 mg/kg for 2 days / withdrawal. Compound A1 was administered for 5 days (C and F). Compound A1 was orally administered using the indicated dose and schedule of administration. The contents of p-AKT (A, B and C) and p-RAS40 (D, E and F) in the tumor were evaluated.

Figure 2. Relationship between PI3K inhibitor Compound A1 exposure in plasma and p-PRAS40 in tumors in mice bearing GXA3027 tumors treated with different drug administration schedules.

PK/PD relationship of continuous and intermittent treatment of Compound A1. Exposure of compound A1 (A) and inhibition of p-PRAS40 (B) were measured at the indicated time after the first administration.

Figure 3. In vivo inhibition of tumor survival by Compound A1 administered using different schedules.

Patient-derived GXA 3027 gastric cancer cells were implanted subcutaneously (sc) into NMRI nude mice. When the tumor reaches a size of about 700 mm ^{3 ,} it is administered at 75 mg/kg, QD (once a day, A and D) or 450 mg/kg, QW (weekly, B and E) or 200 mg/kg for 2 days/ Compound A1 was administered for 5 days (C and F). Compound A1 was orally administered once a day in the indicated dose and schedule. The levels of activated caspase 3 (A, B and C), cleavage of PARP (D, E and F) and tumor growth inhibition and response rate (G) were evaluated in tumors.

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

KPL4 cells were implanted subcutaneously (sc) into nude rats. When the tumor reached a size of about 30 mm ² , the animals were randomly assigned and administered with 15 mg/kg, QD continuously or 105 mg/kg, QW (weekly) or 55 mg/kg for 2 days/dose for 5 days. A1. A) tumor growth inhibition curve; B) body weight change during the treatment period; C) tumor weight at the end of treatment.

Figure 5. Efficacy of Compound A1 in a patient-derived GXA3027 gastric cancer xenograft model in nude mice.

Patient-derived GXA 3027 gastric cancer cells were implanted subcutaneously (sc) into NMRI nude mice. When the tumor reached a size of about 140 mm ³ , the animals were randomly assigned and Compound A1 was administered as a single agent or in combination with cisplatin and capecitabine using the dosing schedule and schedule as indicated in Table 7. The tumor weight of each individual animal at the end of treatment is presented. In addition, the relative tumor growth inhibition (TGI) was calculated using the equation [1-(T-T0/C-T0)] × 100, where T and C represent the average of tumors in the treatment group (T) and the control group (C), respectively. Size, and T0 refers to the size of the tumor when randomly assigned. In addition, the treatment response was assessed by means of clinically used RECIST criteria; the response rate (RR) was calculated as a percentage of animals with complete or partial responses.

According to an embodiment of the invention, the PI3K inhibitor is a compound of the above formula (I), wherein R ¹ represents -(CH ₂ ) _n -(CHR ⁴ )-(CH ₂ ) _m -N(R ⁵ )(R ^5' ) ; R ² represents a heteroaryl group of the following structure:

Wherein: * represents the attachment point of the heteroaryl group to the rest of the structure of formula (I); R ³ is a methyl group; R ⁴ is a hydroxyl group; R ⁵ and R ^{5 ' are the} same or different and independently hydrogen Atom or C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, or R ⁵ and R ^{5 '} together with the nitrogen atom to which they are bonded represent a 3 to 7 membered nitrogen-containing heterocyclic ring which optionally contains at least one other hetero atom selected from oxygen, nitrogen or sulfur and which may optionally be one or more Substituting R ^{6 '} groups; each occurrence of R ⁶ may be the same or different and independently hydrogen atom, halogen atom, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl, aryl, aryl-C ₁ -C ₆ -alkyl, hetero Aryl, heteroaryl-C ₁ -C ₆ -alkyl, 3 to 8 membered heterocyclic ring, 3 to 8 membered heterocyclic group -C ₁ -C ₆ -alkyl, -C ₁ -C ₆ -alkyl- OR ⁷ , -C ₁ -C ₆ -alkyl-SR ⁷ , -C ₁ -C ₆ -alkyl-N(R ⁷ )(R ^7' ), -C ₁ -C ₆ -alkyl-C(= O) R ⁷ , -CN, -C(=O)OR ⁷ , -C(=O)N(R ⁷ )(R ^7' ), -OR ⁷ , -SR ⁷ , -N(R ⁷ )(R ^7' ) or -NR ⁷ C (=O R ⁷ , each of which may be optionally substituted with one or more R ⁸ groups; each occurrence of R ^{6 '} may be the same or different and independently C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkyl-OR ⁷ ; each occurrence of R ⁷ and R ^{7 '} may be the same or different and independently hydrogen Atom or C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyl-C _1- C ₆ -alkyl, C ₃ -C ₆ -cycloalkenyl, aryl, aryl-C ₁ -C ₆ -alkyl, heteroaryl, 3 to 8 membered heterocyclic ring, 3 to 8 membered heterocyclic ring -C ₁ -C ₆ -alkyl or heteroaryl-C ₁ -C ₆ -alkyl; each occurrence of R ^{8 is} independently a halogen atom or a nitro group, a hydroxyl group, a cyano group, a decyl group, an ethyl group Base, amine group, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkane , C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -cycloalkenyl, aryl, aryl-C ₁ -C ₆ -alkyl, heteroaryl, a 3- to 8-membered heterocyclic ring, a heterocyclic group-C ₁ -C ₆ -alkyl or a heteroaryl-C ₁ -C ₆ -alkyl group; n is an integer of 1 and an integer of m is 1; R ⁵ and R ^5' together with the nitrogen atom to which it is combined represents the following structure:

Wherein * represents an attachment point to the remainder of the structure of formula (I), then - the R ² heteroaryl of the structure:

Not for:

Wherein * represents an attachment point to the remainder of the structure of formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, specifically physiology An acceptable salt or a mixture thereof.

According to an embodiment of the invention, the compound of formula (I) above is selected from the group consisting of: N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazole [1,2- c] quinazolin-5-yl)pyridine-3-carboxamide

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

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]pyridine-3-carboxamide

N-(8-{[(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)propyl]oxy}-7-A Oxy-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]quinazoline- 5-based}pyridine-3-carboxamide

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

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

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

N-{8-[3-(Dimethylamino)-2-hydroxypropoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazoline-5- Pyridyl-3-carboxamide

N-(8-{[(2R)-3-(dimethylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3-dihydroimidazole [1,2-c Quinazoline-5-yl)pyridine-3-carboxamide

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

N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazole [1,2- c] quinazolin-5-yl)-2-methylpyridine-3-carboxamide

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

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]-2-methylpyridine-3-carboxamide

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

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

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

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

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

N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazole [1,2- c]quinazolin-5-yl)-3H-imidazole[4,5-b]pyridine-6-carboxamide N-(8-{[(2R)-2-hydroxy-3-(morpholine-4) -yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1,3-thiazole-5-carboxamide

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]-1,3-thiazole-5-carboxamide

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

N-(8-{[(2R)-2-hydroxy-3-(hexahydropyridin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazole [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-dihydroimidazole [1,2- c] quinazolin-5-yl)-4-methyl-1,3-thiazole-5-carboxamide 2-amino-N-(8-{[(2R)-2-hydroxy-3-( Morpholin-4-yl)propyl]oxy}-7-methoxy-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-dihydroimidazole [1,2- c] quinazolin-5-yl)-1,3-oxazol-5-carboxamide

N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3-dihydroimidazole [1, 2-c]quinazolin-5-yl)-1,3-thiazol-5-carboxamide, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof Specifically, a physiologically acceptable salt or a mixture thereof.

According to an embodiment of the invention, the compound of formula (I) above is selected from the group consisting of: N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazole [1,2- c] quinazolin-5-yl)pyridine-3-carboxamide

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]pyridine-3-carboxamide

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

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

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

N-(8-{[(2R)-3-(dimethylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3-dihydroimidazole [1,2-c Quinazoline-5-yl)pyridine-3-carboxamide

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

N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazole [1,2- c] quinazolin-5-yl)-2-methylpyridine-3-carboxamide

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

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

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

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

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

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

N-(8-{[(2R)-2-hydroxy-3-(hexahydropyridin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazole [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-dihydroimidazole [1,2- c] quinazolin-5-yl)-1,3-oxazol-5-carboxamide, Or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, in particular a physiologically acceptable salt or a mixture thereof.

According to an embodiment of the invention, the PI3K inhibitor is a compound of the above formula (I), wherein: R ¹ represents -(CH ₂ ) _n -(CHR ⁴ )-(CH ₂ ) _m -N(R ⁵ )(R ^5' R ² represents a heteroaryl group of the following structure:

Wherein: * represents the attachment point of the heteroaryl group to the rest of the structure of formula (I), and X represents N or CR ⁶ ; R ³ is methyl; R ⁴ is hydroxy; R ⁵ and R ^{5 ' are the} same Or different and independently of each other, a hydrogen atom or a C ₁ -C ₆ -alkyl group, a C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl group or a C ₁ -C ₆ -alkoxy-C ₁ group -C ₆ -alkyl, or R ⁵ and R ^{5 '} together with the nitrogen atom to which they are bonded represent a 3 to 7 membered nitrogen-containing heterocyclic ring which optionally contains at least one other hetero atom selected from oxygen, nitrogen or sulfur and It may optionally be substituted by one or more R ^{6 '} groups; each occurrence of R ⁶ may be the same or different and independently hydrogen, halogen atom, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl, aryl, aryl-C ₁ -C ₆ -alkyl, heteroaryl, heteroaryl-C ₁ -C ₆ -alkyl, 3 to 8 membered heterocyclic ring, 3 to 8 membered heterocyclic group -C ₁ -C ₆ -alkyl, -C _1- C ₆ -alkyl-OR ⁷ , -C ₁ -C ₆ -alkyl-SR ⁷ , -C ₁ -C ₆ -alkyl-N(R ⁷ )(R ^7' ), -C ₁ -C ₆ -alkyl-C(=O)R ⁷ , -CN, -C(=O)OR ⁷ , -C(=O)N(R ⁷ )(R ^7' ), -OR ⁷ , -SR ⁷ , -N(R ⁷ (R ^{7 '} ) or - NR ⁷ C(=O)R ⁷ , each of which may be substituted with one or more R ⁸ groups as appropriate; each occurrence of R ^{6 '} may be the same or Different and independently C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkyl-OR ⁷ ; ⁷ and R ^{7 '} may be the same or different and independently hydrogen atom or C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ - ring Alkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkenyl, aryl, aryl-C ₁ -C ₆ -alkyl, heteroaryl a 3 to 8 membered heterocyclic ring, a 3 to 8 membered heterocyclyl-C ₁ -C ₆ -alkyl or heteroaryl-C ₁ -C ₆ -alkyl group; each occurrence of R ^{8 is} independently a halogen atom or Nitro, hydroxy, cyano, decyl, ethenyl, amine, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₂ -C ₆ -alkenyl, C ₂ - C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -cycloalkenyl, aryl, aryl -C ₁ -C ₆ -alkyl, heteroaryl, 3 to 8 membered heterocyclic ring, heterocyclic group -C ₁ -C ₆ -alkyl or heteroaryl-C ₁ -C ₆ -alkyl; n-line 1 An integer and m is an integer of 1; Their stereoisomers, tautomers, N- oxide, hydrate, solvate or salt thereof, particularly the physiologically acceptable salts thereof, or mixtures thereof concerned.

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-dihydroimidazole [1,2-c] Quinazoline-5-yl}pyridine-3-carboxamide

6-Amino-N-(8-{[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazole [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-dihydroimidazole [1,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide

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

2-Amino-N-{8-{[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazole [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-(8-{[(2R)-3-(dimethylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3-dihydroimidazole [1, 2-c]quinazolin-5-yl}pyrimidine-5-carboxamide, Or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, in particular a physiologically acceptable salt or a mixture thereof.

According to a preferred embodiment, the above compound of formula (I) 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 thereof, tautomer, N-oxidation a hydrate, a solvate or a salt or a mixture thereof.

According to a preferred embodiment, the above compound of formula (I) 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 physiologically acceptable salt thereof or a mixture thereof.

According to a preferred embodiment, the above compound of formula (I) 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, the compound of formula (I) is administered for one, two, three, four or five days in each administration cycle, followed by 3, 4, 5 or 6 days. Compounds of formula (I) or placebo are not administered during the time period. The administration cycle takes a total of 4 days (ie, 3 dosing days after 1 dosing day) to 11 days (ie, 5 dosing days followed by 6 drug withdrawal days), which is based on the dosing day and stop. The number of medicine days depends on the number of medicines.

According to an embodiment, the compound of formula (I) is administered for a period of 1 day, 2 days, 3 days, 4 days or 5 days in each administration cycle, followed by a period of 4 days, 5 days or 6 days. Cast (I) Compound or placebo. The administration cycle takes a total of 5 days (ie, 4 dosing days after 1 dosing day) to 11 days (ie, 5 dosing days followed by 6 drug withdrawal days), which is based on the dosing day and stop. The number of medicine days depends on the number of medicines.

According to an embodiment, the compound of formula (I) is administered for a period of 2 days, 3 days or 4 days in each administration cycle, followed by not administering formula (I) for a period of 4 days, 5 days or 6 days. Compound or placebo. The administration cycle takes a total of 6 days (ie, 2 dosing days followed by 4 drug withdrawal days) to 10 days (ie, 4 dosing days followed by 6 drug withdrawal days), which is based on the dosing day and stop The number of medicine days depends on the number of medicines.

According to an embodiment, the compound of formula (I) is administered for a period of 1 day, 2 days or 3 days in each administration cycle, followed by not administering formula (I) for a period of 4 days, 5 days or 6 days. Compound or placebo. The administration cycle takes a total of 5 days (ie, 4 dosing days after 1 dosing day) to 9 days (ie, 3 dosing days followed by 6 drug withdrawal days), which is based on the dosing day and stop The number of medicine days depends on the number of medicines.

According to an embodiment, the compound of formula (I) is administered for a period of from 1 to 4 days in each administration cycle, followed by administration of the compound of formula (I) or administration of a placebo over a period of 3 to 6 days. The administration cycle takes a total of 4 days (ie, 3 dosing days after 1 dosing day) to 10 days (ie, 4 dosing days followed by 6 drug withdrawal days), which is based on the dosing day and stop. The number of medicine days depends on the number of medicines.

According to an embodiment, the compound of formula (I) is administered for a period of from 1 to 4 days in each administration cycle, followed by administration of the compound of formula (I) or administration of a placebo over a period of 4 to 6 days. The administration cycle takes a total of 5 days (ie, 4 dosing days after 1 dosing day) to 10 days (ie, 4 dosing days followed by 6 drug withdrawal days), which is based on the dosing day and stop. The number of medicine days depends on the number of medicines.

According to an embodiment, the compound of formula (I) is administered for a period of from 1 to 4 days in each administration cycle, followed by administration of the compound of formula (I) or administration of a placebo over a period of 4 to 6 days. The administration cycle takes a total of 4 days (ie, 3 dosing days after 1 dosing day) to 10 days (ie, 4 dosing days followed by 6 drug withdrawal days), which is based on the dosing day and stop. The number of medicine days depends on the number of medicines.

According to an embodiment, the compound of formula (I) is administered for 1 to 2 days in each administration cycle The segment is then administered without the administration of a compound of formula (I) or a placebo over a period of 5 to 6 days. The administration cycle takes a total of 6 days (ie, 5 dosing days after 1 dosing day) to 8 days (ie, 2 dosing days followed by 6 drug withdrawal days), which is based on the dosing day and stop The number of medicine days depends on the number of medicines.

According to an embodiment, the compound of formula (I) is administered for a period of 1 day (i.e., 1 dosing day) in each administration cycle, followed by a period of 3 to 6 days (3 to 6 days off) Compounds of formula (I) are not administered or placebo is administered. The administration cycle takes a total of 4 days (ie, 3 dosing days after 1 dosing day) to 7 days (ie, 6 dosing days after 1 dosing day), which is based on the dosing day and stop. The number of medicine days depends on the number of medicines.

According to an embodiment, the compound of formula (I) is administered for a period of 2 days (i.e., 2 dosing days) in each administration cycle, followed by a period of 3 to 6 days (3 to 6 drug withdrawal days) Compounds of formula (I) are not administered or placebo is administered. The administration cycle takes a total of 5 days (ie, 2 dosing days followed by 3 drug withdrawal days) to 8 days (ie, 2 dosing days followed by 6 drug withdrawal days), which is based on the dosing day and stop The number of medicine days depends on the number of medicines.

According to an embodiment, the compound of formula (I) is administered for a period of 3 days (ie 3 dosing days) in each administration cycle, followed by a period of 3 to 6 days (3 to 6 days of withdrawal) Compounds of formula (I) are not administered or placebo is administered. The administration cycle takes a total of 6 days (ie, 3 dosing days followed by 3 drug withdrawal days) to 9 days (ie, 3 dosing days followed by 6 drug withdrawal days), which is based on the dosing day and stop The number of medicine days depends on the number of medicines.

According to an embodiment, the compound of formula (I) is administered for a period of 4 days in each administration cycle, followed by administration of the compound of formula (I) or administration of a placebo over a period of 3 to 6 days. The administration cycle takes a total of 7 days (ie, 4 dosing days followed by 3 drug withdrawal days) to 10 days (ie, 4 dosing days followed by 6 drug withdrawal days), which is based on the dosing day and stop The number of medicine days depends on the number of medicines.

According to an embodiment, the compound of formula (I) is administered for a period of 5 days in each administration cycle, followed by administration of the compound of formula (I) or administration of a placebo over a period of 3 to 6 days. The administration cycle takes a total of 8 days (ie, 5 dosing days followed by 3 drug withdrawal days) to 11 days (ie, 5 dosing days followed by 6 drug withdrawal days), which is based on the dosing day and stop The number of medicine days depends on the number of medicines.

According to an embodiment, the compound of formula (I) is administered for a period of 1 day (i.e., 1 dosing day) in each administration cycle, followed by a period of 4 to 6 days (4 to 6 drug withdrawal days) Compounds of formula (I) are not administered or placebo is administered. The administration cycle takes a total of 5 days (ie, 4 dosing days after 1 dosing day) to 7 days (ie, 6 dosing days after 1 dosing day), which is based on the dosing day and stop. The number of medicine days depends on the number of medicines.

According to an embodiment, the compound of formula (I) is administered for a period of 2 days (i.e., 2 dosing days) in each administration cycle, followed by a period of 4 to 6 days (4 to 6 drug withdrawal days) Compounds of formula (I) are not administered or placebo is administered. The administration cycle takes a total of 6 days (ie, 2 dosing days after 2 dosing days) to 8 days (ie, 2 dosing days followed by 6 drug withdrawal days), which is based on the dosing day and stop The number of medicine days depends on the number of medicines.

According to an embodiment, the compound of formula (I) is administered for a period of 3 days (ie 3 dosing days) in each administration cycle, followed by a period of 4 to 6 days (4 to 6 drug withdrawal days) Compounds of formula (I) are not administered or placebo is administered. The administration cycle takes a total of 7 days (ie, 3 dosing days followed by 4 drug withdrawal days) to 9 days (ie, 3 dosing days followed by 6 drug withdrawal days), which is based on the dosing day and stop The number of medicine days depends on the number of medicines.

According to an embodiment, the compound of formula (I) is administered for a period of 4 days in each administration cycle, followed by administration of the compound of formula (I) or administration of a placebo over a period of 4 to 6 days. The administration cycle takes a total of 8 days (ie, 4 dosing days followed by 4 drug withdrawal days) to 10 days (ie, 4 dosing days followed by 6 drug withdrawal days), which is based on the dosing day and stop The number of medicine days depends on the number of medicines.

According to an embodiment, the compound of formula (I) is administered for a period of 5 days in each administration cycle, followed by administration of the compound of formula (I) or administration of a placebo over a period of 4 to 6 days. The administration cycle takes a total of 9 days (ie, 5 dosing days followed by 4 drug withdrawal days) to 11 days (ie, 5 dosing days followed by 6 drug withdrawal days), which is based on the dosing day and stop The number of medicine days depends on the number of medicines.

Other embodiments of the invention are as set forth in Table A, wherein the compound of formula (I) is administered in each of the administration cycles for a period of "dosing" as defined in the first row, followed by a second Do not administer a compound of formula (I) or place a placebo during the period of the "drug withdrawal" date described in the line (for each example, the number of days spent completing the administration cycle is shown in the fourth row of Table A. ):

For the examples of Table A, the administration cycle can be carried out one or more times, for example, the administration cycle can be carried out once, twice, three times, four times or five times, followed by not administering the compound of formula (I) to An optional interruption period of 8 days (eg 4 days, 5 days, 6 days, 7 days or 8 days).

According to a preferred embodiment, the compound of formula (I) is administered once daily on the day of administration.

According to the embodiment, the compound of the formula (I) is administered once daily for 21 days according to the administration schedule of the next 6 days after the first administration day, and then 4 to 8 days without treatment with the PI3K inhibitor (interruption period) .

According to the embodiment, the compound of formula (I) is administered once daily for 21 days according to the administration schedule of the following 5 drug-discharging days, and then 4 to 8 days without treatment with PI3K inhibitor (interruption period) .

According to the examples, the compound of formula (I) was administered once daily for 21 days according to the dosing schedule for the next 5 dosing days on 2 dosing days, followed by 7 days without treatment with PI3K inhibitor (interruption period).

According to the examples, the compound of formula (I) was administered once daily for 21 days according to the dosing schedule of the subsequent 4 dosing days on the 3 dosing day, followed by 4 to 8 days of treatment without the PI3K inhibitor (interruption period).

According to the examples, the compound of formula (I) was administered once daily for 21 days according to the dosing schedule for the subsequent 3 dosing days on the 4 dosing day, followed by 4 to 8 days without treatment with the PI3K inhibitor (interrupted period).

According to an embodiment, the administration cycle is performed one or more times, for example, 1 time, 2 times, 3 times, 4 times or 5 times.

According to an embodiment, the administration cycle is performed once, twice, three times or four times, and then not in the interruption period of 4 to 8 days (for example, 4 days, 5 days, 6 days, 7 days or 8 days) And a compound of formula (I).

Dosage and administration

Based on standard laboratory techniques known for assessing compounds useful in the treatment of hyperproliferative disorders and angiogenic disorders, standard pharmacology by standard toxicity testing and by treatment for determining the conditions identified above in mammals Analysis and easy determination of the results by comparing the results with the results of using known agents for treating such conditions The compounds of the invention are useful for treating an effective dosage for each desired indication. The amount of active ingredient to be administered in the treatment of one of these conditions may vary widely depending on, for example, the particular compound and dosage unit employed, the mode of administration, the stage of treatment, the patient being treated Age and gender and the nature and severity of the condition being treated.

Of course, for each patient, the specific initial and sustained dosing regimen will vary with the nature and severity of the condition as determined by the attending diagnostician, the activity of the particular compound employed, the age and general condition of the patient, the time of administration, and the dosage. It varies with route, drug excretion rate, drug combination, and the like. The desired mode of treatment and the number of administrations of a compound of the invention, or a pharmaceutically acceptable salt or ester or composition thereof, can be determined by a person skilled in the art using a conventional therapeutic test.

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 the compound administered on the date the compound is administered according to the administration regimen.

In the present invention, the effective daily dose of the compound of the formula (I) is in the range of from about 50 mg/day to about 400 mg/day, preferably from about 100 mg/day to about 300 mg/day, more preferably about 150 mg/day. To a specific daily dose of about 250 mg/day, such as 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg or 400 mg (all daily).

As used herein, the term "dosage unit" refers to the amount of the compound administered during each administration cycle.

The individual dosage units of the compound of formula (I) are preferably in the range of from about 50 mg to about 400 mg, more preferably from about 100 mg to about 300 mg, even more preferably from about 150 mg to about 250 mg, such as 50 mg, 100 mg, 150 mg, 200 mg. , 250mg, 300mg or 400mg.

To achieve an effective daily dose, the patient may take one dosage unit containing the total amount of the compound of formula (I) or two or more dosage forms totaling the desired effective daily dose. yuan.

As used herein, the term "total amount" in each administration cycle refers to the cumulative amount of the compound administered on the day of administration of the compound in each administration cycle (ie, the total accumulation in the administration day). the amount).

According to an embodiment, the compound of formula (I) is administered in a total amount of from 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 from 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 from 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 from about 50 mg/day to about 400 mg/day on the date of administration.

According to an embodiment, the compound of formula (I) is administered in an amount from about 100 mg/day to about 400 mg/day on the date of administration.

According to an embodiment, the compound of formula (I) is administered in an amount from about 100 mg/day to about 300 mg/day on the date of administration.

According to an embodiment, the compound of formula (I) is administered in an amount from about 150 mg/day to about 250 mg/day on the date of administration.

Combination therapy

The compounds of the invention may be administered as a sole pharmaceutical agent or in combination with one or more other pharmaceutical agents in accordance with the administration regimen of the invention, wherein the combination does not cause unacceptable adverse effects. The invention is also related to such combinations. For example, the compounds of the invention can be combined with known anti-hyperproliferative or other indicators and the like, as well as mixtures and combinations thereof. Other indicators include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, antimetabolites, DNA-embedded antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerases Inhibitor, biological response modifier or anti-hormone Agent.

Other pharmaceutical agents may be aldesleukin, alendronic acid, alfofone, alitretinoin, allopurinol, aloprim. , aloxi, aldretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole (anastrozole), anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, Azathioprine, BCG or tice BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, sulphate Bleomycin sulfate, broxuridine, bortezomib, busulfan, calcitonin, acamtuzumab (campath), capecitabine (capecitabine) ), carboplatin, cassodex, cefesone, simmol (celmoleu) Kin), cerubidine, chlorambucil, cisplatin, cladribine, clodronic acid, cyclophosphamide, ar Cytarabine, dacarbazine, dactinomycin, daunorubicin liposome (DaunoXome), decadron, decatex phosphate, estradiol valerate (delestrogen), denileukin diftitox, depomedrol, deslorelin, dexrazoxane, diethylstilbestrol, diflucan, and more Docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, eligard, elitek, eure Ellence, emend, epirubicin, epoetin alfa, epogen, eptaplatin, ezetimisol (ergamisol), estradiol preparation (estrace), estradiol, estramustine phosphate sodium, ethinyl estradiol, ethymol (ethyol), hydroxyethyl phosphate (etidronic acid), etopophos, etoposide, fadrozole, farston, filgrastim, finasteride, non Gestretin, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU) , fluoxymesterone, flutamide, formestane, fosteabine, fotemustine, fulvestrant, gamma gamma Gammagard), gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron HCl, histamine Histrelin, hycamtin, hydrocortone, erythro-hydroxy adenine (erythro-h) Ydroxynonyladenine), hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferon alpha-2A, Interferon alpha-2B, interferon alpha-n1, interferon alpha-n3, interferon beta, interferon gamma-1a, interleukin-2, intron A, iressa, irinotecan (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, esterification Estrogen preparation (menest), 6-巯嘌呤, mesna sodium (Mesna), methotrexate, metvix, miltefosine, minocycline, mitomycin C, mitoxantrone Mitotane), mitoxantrone, Modrenal, Myocet, nedaplatin, neulasta, neumega, Newbernet (neupogen), nilutamide, nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCl, prednisone distillation tablets ( Orapred), oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin, Picibanil, pilocarpine HCl, pirarubicin, plicamycin, porfimer sodium, prenimustine ), prednisolone, prednisone, premarin, procarbazine, procrit, raltitrexed Raltitrexed), RDEA 119, 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 Tamsulosin), tasonermin, testolactone, taxotere, teceleukin, temozolomide, teniposide, propionate (testosterone) Propionate), testred, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, tortoise Remifenene, tositumomab, trastuzumab, Quo Shufan (treosulfan), tretinoin, trexall, trimethylmelamine, trimetrexate, triptorelin acetate, hydroxyp-hydroxynamate Ruilin, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine , virulizin, zinecard, zinostatin stimalamer, zofran, ABI-007, acolbifene, interferon gamma 1b (actimmune), affinitak, aminopterin, arzoxifene, asoprisnil, atamestane, atrasentan (atrasentan) ), sorafenib, avastin, CCI-779, CDC-501, celebrex, cetuximab, cristatol, acetonitrile Cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, etodoca Edeotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, histamine hydrogel implant, 鈥-166 DOTMP , ibandronic acid, interferon gamma, pegylated interferon (intron-PEG), ixabepilone, keyhole limpet hemocyanin, L-651582 , lanreotide, lasofoxifene, libra, lonafarnib, miproxifene, minodronate, MS-209 , liposomes MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, olimson (oblimersen) ), vincristine liposome preparation (onco-TCS), orsid (osidem), polyglutamic acid paclitaxel, pamidronate disodium, PN-401, QS-21, Quaxil (quazepam), R-1549, raloxifene, ranpirnase, 13-cis-retinoic acid, satraplatin, seocalcitol, T- 138067, tarceva, taxoprexin, thymosin alpha 1, tiazofurine, tipifarnib, tirapazamine, TLK-286, Torrimi Toremifene, trans MID-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z -100, zoledronic acid or a combination thereof.

In an embodiment of the invention, a compound of formula (I) as defined herein may optionally be administered in combination with one or more of the following: 131I-chTNT, abarelix, a Abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldileukin , alemtuzumab, alendronate, alibretin, hexamethylene melamine, amine phosphatine, amine glutamine, hexylamine hexylamine, amrubicin, ampicillin, ar Natrozol, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, acimozumab ( Arcitumomab), agrabin, arsenic trioxide, aspartate, axitinib, azacitidine, basiliximab, belototecan, benzene Bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide Biscentrene, bleomycin, bortezomib, buserelin, bosutinib, brutuximab vedotin, busulfan, kappa Cabazitaxel, cabozantinib, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carfezo Carfilzomib, carmofur, carmustine, catummaxomab, celecoxib, sir interleukin, ceritinib, west Tetuzumab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, chlorine Phosphonic acid, Clofarabine, cristantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dala Dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, dinisin 2, denosumab, depopopeptide Depreotide), deslorelin, dexrazoxane, dibrospidium chloride, di-dehydrated galactitol, diclofenac, docetaxel, dolasetron, deoxyfluoride Uridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, eltrombopam (eltrombopag), endostatin, enocitabine, enzalutamide, epirubicin, epititocolol, ebertin alfa (epoetin alfa) ), epoetin beta, epoetin, itraplatin, eribulin, erlotinib, esomeprazole, Glycol, estramustine, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, flumethontone, fluorouridine Glycosides, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fumustine, fulvestrant, gadobutrol, gent Gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib ), gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granule globular stimulating factor, histamine dihydrochloride , histamine, hydroxyurea, I-125 particles, lansoprazole, ibandronate, tiimumab, ibrutinib, idarubicin, ifosfamide , imatinib, imiquimod, improsulfan, indisetron, incadronic acid, giant Citrifolia alcohol methyl crotonate (ingenol mebutate), interference Au, interferon beta, interferon gamma, iobitidol, iobenguane (123I), iomeprol, ipilimumab, irinotecan, itricone Itraconazole, ixabepilone, lanreotide, lapatinib, issocholine, lenalidomide, lenograstim, lentinan, come Letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, Lonidadamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, guanidine, mesna, methadone ), methotrexate, methoxsalen, methyl ampicillin, methylprednisolone, methyl ketone, metirosine, mifamurtide, Mettifosin, miribatin, mitobronitol, mitoguazone, mitophorol Mitomycin, mitoxantrone, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, Nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, neda Platinum, narayabine, neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, ni Trotuzumab (nimotuzumab), nimustine, nitracrine, naluzumab, obbinutuzumab, octreotide, ofatumumab, high three tips Omecetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotin, orilotimod, oxaliplatin, hydroxy Oxycodone, oxymetholone, ozogamicine, p53 gene therapy, Taiping Purple Paclitaxel, palifermin, palladium-103 particles, palonosetron, pamidronic acid, panitumumab, pantoprazole, pazodazole Pazopanib, Pembellase, PEG-Epoetin beta (methoxy PEG-Epoetin beta), pembrolizumab, pegfilgrastim, polyethylene glycol interference Alpha-2b, pemetrexed, pentazocine, pentastatin, peplomycin, perflubutane, perfosfamide, patol Pertuzumab, Bisibani, Piluka, pirarubicin, pixantrone, plerixafor, pucamycin, pigolusam, Estradiol polyphosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porphyrin sodium, pralatrexate, Prednistatin, prednisone, procarbazine, procdazole, propranolol, quinagolide, rabeprazole, retortomo Monoclonal antibody (racotumomab), radium chloride-223, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, remus Ranimustine, rasburicase, razoxane, refamatetinib, regorafenib, risedronic acid, etidronate 186, rituximab, romidepsin, romiplostim, romopeptide, roniciclib, 153Sm (samarium (153Sm) lexidronam) , saxastatin, satumomab, secretin, sipuleucel-T, cilostazol, sobutrazol, sodium glycididazole, Sorafenib, stanozolol, streptozol, sunitinib, talaporfin, tamibarotene, tamoxifen, he sprayed him Tapentadol, tamoximin, ticlopin, m (99mTc) 巯 nomo monoclonal antibody (technetium (99mTc) nofetumomab merpentan), 99mTc-HYNIC-[Tyr3]- Octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide , fluorenone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alpha, thioguanine, tocilizumab, topotecan , toremifene, tosimozumab, trobectedin, tramadol, trastuzumab, trastuzumab, etoxin, troche, retinoic acid, Trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptamine Acid, ubenimex, valrubicin, vandetanib, vaprefen, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, Vinorelbine, vismodegib, vorinostat, vorozole, 钇-90 glass microspheres, net statin, net Giddings ester, zoledronic acid, zorubicin (zorubicin).

Optional anti-hyperproliferative agents that can be added to the composition include, but are not limited to, those listed in the Cancer Chemotherapy Drug Program in the 11th edition of the Merck Index (1996), which is incorporated herein by reference. Compounds such as aspartate proline, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, L-aspartate prolase, cyclophosphamide, cytarabine, Dacarbazine, dactinomycin, daunorubicin (danomycin), doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylene melamine, hydroxyl Urea, ifosfamide, irinotecan, formazan tetrahydrofolate, lomustine, nitrogen mustard, 6-oxime, mesna, methotrexate, mitomycin C, mitoxantrone醌, prednisolone, prednisone, procarbazine, raloxifene, streptozin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine and vindesine.

Other anti-hyperproliferative agents suitable for use in the compositions of the present invention include, but are not limited to, Goodman and Gilman, The Pharmacological Basis of Therapeutics (p. Version 9), edited by Molinoff et al., published by McGraw-Hill, pp. 1225-1287 (1996), which is incorporated herein by reference, which is incorporated herein by reference in its entirety, for the benefit of, for example, Aspartate glutaminase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel, erythrocyte Adenine adenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoromethyl ketone, flutamide, hydroxyprogesterone caproate, idarubicin , interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitoxantrone, paclitaxel, pentastatin, N-phosphonium decyl-L-aspartic acid (PALA) , pucamycin, semustine, teniposide, propionate propionate, thiotepa, trimethyl melamine, uridine and vinorelbine.

Other anti-hyperproliferative agents suitable for use in the compositions of the present invention include, but are not limited to, other anticancer agents such as epothilone and its derivatives, irinotecan, raloxifene and topotecan .

The compounds of the invention may also be administered in combination with a protein therapeutic. Such protein therapeutic agents suitable for treating cancer or other angiogenic disorders and suitable for use with the compositions of the invention include, but are not limited to, interferons (eg, interferon alpha, beta or gamma), super-exciting individuals Antibody, Tuebingen, TRP-1 protein vaccine, colostatin, anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab , trastuzumab, dinisin, rituximab, thymosin alpha 1, bevacizumab, mecasermin, mecasermin rinfabate, opp Rui interleukin, natalizumab, rhMBL, MFE-CP1+ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35, MT-103, Lin Feipei, AS-1402 , B43-Genistein, radioimmunotherapy agent based on L-19, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT-322, rhCC10, r(m)CRP, MORAb- 009, aviscurin, MDX-1307, Her-2 vaccine, APC-8024, NGR-hTNF, rhH1.3, IGN-311, endostatin, volociximab, PRO- 1762, come to Shalimumab (lex Atumumab), SGN- 40, Pertuzumab, EMD-273063, L19-IL-2 fusion protein, PRX-321, CNTO-328, MDX-214, tigapotide, CAT-3888, Rabezumab ( Labetuzumab), alpha-particle-emitting radioisotope-llinked lintuzumab, EM-1421, HyperAcute vaccine, tucotuzumab celmoleukin, galivizine Anti-galiximab, HPV-16-E7, Javelin-prostate cancer, Javelin-melanoma, NY-ESO-1 vaccine, EGF vaccine, CYT-004-MelQbG10, WT1 peptide, orgoviromab, Olfazumab, zalutumumab, cintredekin besudotox, WX-G250, Albuferon, aboxicept, denosumab, vaccine, CTP-37, Efungumab or 131I-chTNT-1/B. Monoclonal antibodies that can be used as protein therapeutics include, but are not limited to, morozumab-CD3 (muromonab-CD3), abciximab, edrezumab, daclizumab , gemtuzumab, alemtuzumab, temimumab, cetuximab, bevacizumab, efalizumab, adalimumab, omalim Anti- (omalizumab), morozumab-CD3 (muromomab-CD3), rituximab, daclizumab, trastuzumab, palivizumab, basiliximab and Infliximab.

A compound of formula (I) as defined herein may 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-2110183, GSK-2126458, GSK-2141795, MK-2206, Novolimus, OSI- 027, perifosine, PF-04691502, PF-05212384, PX-866, rapamycin, RG-7167, RO-4987655, RO-5126766, stermidine (selumetinib), TAK-733, trimetinib, triciribine, UCN-01, WX-554, XL-147, XL-765, zotarolimus, ZSTK-474.

In general, cytotoxic agents and/or cytostatic agents in combination with a compound or composition of the invention will be used to: (1) achieve better efficacy or even eliminate in reducing tumor growth compared to administration of only one agent alone. Tumors, (2) can be administered with smaller amounts of administered chemotherapeutic agents, (3) provide well tolerated and harmful pharmacological agents in patients compared to those observed with single agent chemotherapy and certain other combination therapies Chemotherapy with less complications, (4) providing a wide range of different cancer types for mammals, especially humans, (5) providing higher response rates in treated patients, (6) and standards Compared to chemotherapy treatment, providing longer survival time in the treated patient, (7) providing longer tumor progression time, and/or (8) compared to known cases in which other cancer agents produce an antagonistic effect, at least The use of these agents alone provides equally good efficacy and tolerability results.

According to an embodiment, the compound of formula (I) is used or administered in combination with one or more other active ingredients selected from the group consisting of taxanes such as docetaxel, paclitaxel or paclitaxel (Taxol); Ebo , for example, ixabepilone, Patugilone or Sagopilone; mitoxantrone; prednisolone; dexamethasone; estramustine; vinblastine; Vincristine; doxorubicin; doxorubicin; idarubicin; daunorubicin; bleomycin; etoposide; cyclophosphamide; ifosfamide; procarbazine; melphalan; 5-fluorouracil; capecitabine; fludarabine; arabinose Cytidine; Ara-C; 2-chloro-2'-deoxyadenosine; thioguanine; antiandrogen, such as flutamide, cyproterone acetate or bicalutamide; bortezomib; platinum derivative For example, cisplatin or carboplatin; chlorambucil; methotrexate; rituximab; and pharmaceutically acceptable salts of alkaline earth radioactive seed radium-223.

A suitable combination of a compound of formula (I) and a: 5-FU or 5-FU prodrug, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur , UFT or S-1; platinum-based antitumor agents, such as oxaliplatin, cisplatin or carboplatin; and taxanes, such as docetaxel or paclitaxel; or combinations thereof, as set forth in the priority application In EP 15159490.0, the case is hereby incorporated by reference in its entirety.

According to an embodiment, the compound of formula (I) is administered or administered in combination with an anti-hyperproliferative agent, a cytotoxic agent and a cytostatic agent selected from the group consisting of 5-FU or 5-FU before administration according to the present invention. For example, 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT or S-1; platinum-based antitumor agents such as oxaliplatin, cisplatin or card Platinum; and a taxane such as docetaxel or paclitaxel; or a combination thereof.

Suitable combinations of the compounds of the formula (I) with those selected from the group consisting of 5-FU, capecitabine, oxaliplatin and paclitaxel or combinations thereof are described in priority applications EP 15159490.0, EP 14196142.5 and EP 15164342.6 These cases are incorporated herein by reference in their entirety.

According to an embodiment, the compound of formula (I) is administered or administered in combination with an anti-hyperproliferation, cytotoxic agent and a cell growth inhibitor selected from the group consisting of 5-FU, capecitabine, oxaliplatin according to the present invention. Platinum and paclitaxel or a combination thereof.

Suitable combinations of the pharmaceutically acceptable salts of the compound of the formula (I) with the alkaline earth radioactive seed radium-223 are described in PCT/EP2014/076053 (WO2015/082378) and priority applications EP 14163751.2 and EP 13195566.8, all All three applications are incorporated herein by reference.

According to an embodiment, the compound of formula (I) is compatible with the alkaline earth radioactive seed radium-223. The accepted salt (for example, radium dichloride-223) is used in combination or administered. In an embodiment, a combination comprising a compound of formula (I) and a pharmaceutically acceptable salt of alkaline earth radioactive seed radium-223 (eg, radium dichloride-223) and anti-androgen therapy (eg, androgen biosynthesis inhibition) Agents, for example, ketoconazole and abiraterone and/or androgen receptor blockers (for example, bicalutamide, nilutamide, flutamide or enzalutamide) or Cast. Preferably, the antiandrogen is selected from the group consisting of bicalutamide, enzalutamide and abiraterone.

The administration regimen of the compound of formula (I) and 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 on different days. Thus, it will be appreciated that the combined compounds can be administered sequentially (e.g., before or after) or in the same pharmaceutical formulation (i.e., together) or in a different pharmaceutical formulation (i.e., separately). Simultaneously in the same formulation as a single formulation, while at the same time in a different pharmaceutical formulation is not a single. The route of administration of the two or more compounds in combination therapy may also vary.

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

In a preferred embodiment, the compound of formula (I) is compound A1 (Cpd A1) or 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.

Method of sensitizing cells to radiation

In various embodiments of the invention, the compounds of the invention may be used to sensitize cells to radiation in accordance with the dosage regimen of the invention. That is, treatment of cells with a compound of the present invention according to the administration scheme of the present invention prior to radiation treatment of cells renders the cells more susceptible to DNA damage and cell death than any treatment by which the cells are present without the use of the compounds of the present invention. In one aspect, the cells are treated with at least one compound of the invention.

Accordingly, the present invention also provides a method of killing cells, wherein a combination of one or more compounds of the present invention and conventional radiation therapy is administered to a cell according to the administration protocol of the present invention.

The invention also provides a method of making cells more susceptible to cell death, wherein the cells are treated with one or more compounds of the invention to cause or induce cell death in accordance with the dosage regimen of the invention prior to treating the cells. In one aspect, the cells are treated with at least one compound or at least one method or a combination thereof according to the administration scheme of the present invention after treating the cells with one or more compounds of the present invention for the purpose of inhibiting the function of normal cells or killing cells. To cause DNA damage.

In one embodiment, the cells are killed by treating the cells with at least one DNA damaging agent. That is, after treating the cells with one or more compounds of the invention to sensitize the cells to cell death, the cells are treated with at least one DNA damaging agent to kill the cells. DNA damaging agents for use in the present invention include, but are not limited to, chemotherapeutic agents (e.g., cisplatin), ionizing radiation (X-rays, ultraviolet radiation), carcinogens, and mutagens.

In another embodiment, the cells are killed by treating the cells with at least one method to cause or induce DNA damage. Such methods include, but are not limited to, activation of a cellular signaling pathway that results in DNA damage when the pathway is activated, inhibition of cellular signaling pathways that result in DNA damage when the pathway is inhibited, and induction of biochemical changes in the cell, Among them, changes lead to DNA damage. As a non-limiting example, the DNA repair pathway in a cell can be inhibited, thereby preventing repair of DNA damage and causing abnormal accumulation of DNA damage in the cell.

In one aspect of the invention, a compound of the invention is administered to a cell according to the dosage regimen of the invention prior to the induction of radiation or other DNA damage in the cell. In one aspect of the invention, a compound of the invention is administered to a cell while undergoing radiation or other DNA damage induction in the cell. In one aspect of the invention, the compounds of the invention are administered to cells immediately after initiation of radiation or other DNA damage induction in the cells.

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

As mentioned above, it has surprisingly been found that the compounds of the invention effectively inhibit PI3K and It can therefore be used to treat or prevent diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses or inappropriate cellular inflammatory responses or associated with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses or A disease in which an appropriate cellular inflammatory response, in particular, uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by PI3K, eg, a hematological tumor, a solid tumor, and/or Metastasis, such as leukemia and myelodysplastic syndromes, malignant lymphoma, head and neck tumors (including brain tumors and brain metastases), chest tumors (including non-small cell and small cell lung tumors), gastrointestinal tumors, endocrine tumors, breast and other Gynecological tumors, urinary system tumors (including kidney tumors, bladder tumors, and prostate tumors), skin tumors and sarcomas and/or their metastases.

Thus, according to another aspect, the invention encompasses a compound of formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, in particular, pharmaceutically The accepted salt or mixture thereof, as set forth and defined herein, is used in the treatment or prevention of a disease as mentioned above in accordance with the administration regimen of the present invention.

Accordingly, another embodiment of the invention is the use of a compound of formula (I) as set forth above for the manufacture of a pharmaceutical composition for treating or preventing a disease according to the administration regimen of the invention.

The diseases mentioned in the first two paragraphs are diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response or accompanying uncontrolled cell growth, proliferation and/or survival, inappropriate cells A disease in which an immune response or an inappropriate cell inflammatory response, in particular, uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cell inflammatory response is mediated by PI3K, for example, hematological tumor, solid tumor And/or its metastasis, such as leukemia and myelodysplastic syndrome, malignant lymphoma, head and neck tumors (including brain tumors and brain metastases), chest tumors (including non-small cell and small cell lung tumors), gastrointestinal tumors, endocrine tumors , breast and other gynecological tumors, urological tumors (including kidney tumors, bladder tumors and prostate tumors), skin tumors and sarcomas and / Or its transfer.

The term "inappropriate" as used herein, in the context of the present invention, particularly in the context of "inappropriate cellular immune response or inappropriate cellular inflammatory response", is understood to preferably mean less than or greater than normal and with such diseases. Pathologically related, causing or causing a response to the pathology.

Preferably, the use is for the treatment or prevention of a disease according to the administration regimen of the invention, wherein the diseases are hematological tumors, solid tumors and/or metastasis thereof.

Method for treating hyperproliferative disorders

The present invention relates to a method of treating a hyperproliferative disorder in a mammal using a compound according to the administration scheme of the present invention and a composition thereof. Compounds can be utilized to inhibit, block, reduce, reduce (etc.) cell proliferation and/or cell division and/or produce apoptosis. The method comprises administering to a mammal, including a human, in need thereof, an amount of a compound of the invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate thereof, effective to treat the condition, Solvate or ester. Hyperproliferative disorders include, but are not limited to, for example, psoriasis, keloids, and other hyperplasia of the skin, benign prostatic hyperplasia (BPH), solid tumors (eg, breast cancer, respiratory cancer, brain cancer, genital cancer, digestive tract cancer, Urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and its distant metastasis. These conditions also include lymphoma, sarcoma and leukemia.

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 respiratory cancer include, but are not limited to, small cell and non-small cell lung cancer as well as bronchial adenoma and pleural pulmonary blastoma.

Examples of brain cancer include, but are not limited to, brain stem and hypothalamic glioma, cerebellum and cerebral astrocytoma, medulloblastoma, ependymoma, and neuroectoderm and pineal tumor.

Tumors of the male genitalia include, but are not limited to, prostate cancer and testicular cancer. Tumors of the female genitalia include, but are not limited to, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, and Yin cancer and uterine sarcoma.

Tumors of the digestive tract include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer.

Tumors of the urinary tract include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvic cancer, ureteral cancer, urethral cancer, and human papillary renal cancer.

Eye cancer includes, but is not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variant), cholangiocarcinoma (hepatic duct cholangiocarcinoma), and mixed hepatocyte 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 cancer includes, but is not limited to, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip and oral cancer, and squamous cell carcinoma. Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease And central nervous system lymphoma.

Sarcomas include, but are not limited to, soft tissue sarcoma, 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.

Such conditions have been well characterized in humans and are also present in other mammals with similar causes and can be treated by administration of the pharmaceutical compositions of the invention.

The term "treating or treatment" as used throughout this document is used in a customary manner, for example, for the purpose of combating, alleviating, attenuating, alleviating, ameliorating the condition of a disease or condition (eg, cancer) or Care for the individual.

Preferably, the pathological condition treated by the compounds benefits from hyperproliferative and/or angiogenic disorders in a human administered a PI3K inhibitor.

According to an embodiment, the hyperproliferative and/or angiogenic disorder is a disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response, more specifically phospholipid inositol-3- A kinase (PI3K) pathway-mediated disorder, even more specifically a hematological tumor, a solid tumor, and/or its metastasis, such as leukemia and myelodysplastic syndromes, malignant lymphoma, head and neck tumors (including brain tumors and brain metastases) , chest tumors (including non-small cell and small cell lung tumors), gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors (including kidney tumors, bladder tumors and prostate tumors), skin tumors, and sarcomas and / Or its transfer.

Suitable methods and uses for the use of the compounds of the formula (I) for the treatment of gastric cancer are described in the priority applications EP 15159490.0, EP 14196142.5 and EP 15164342.6, each of which is incorporated herein by reference.

According to an embodiment, the hyperproliferative and/or angiogenic disorder is gastric cancer.

Suitable compounds for the treatment of breast cancer, prostate cancer, multiple myeloma, hepatocellular carcinoma, lung cancer (specifically non-small cell lung cancer), colorectal cancer, melanoma, pancreatic cancer and/or metastasis thereof The method and use are described in PCT/EP2014/076051 (WO2015082378) and priority application EP 14163752.0 and EP 13195567.6, all of which are incorporated herein by reference.

According to an embodiment, the hyperproliferative and/or angiogenic disorder is breast cancer, prostate cancer, multiple myeloma, hepatocellular carcinoma, lung cancer (specifically non-small cell lung cancer), colorectal cancer, melanoma, pancreatic cancer and/or Or its transfer.

A suitable method for treating breast cancer, prostate cancer, multiple myeloma, hepatocellular carcinoma, lung cancer (specifically, non-small cell lung cancer), colorectal cancer, melanoma, pancreatic cancer with bone metastasis, and the compound of formula (I) The use is described in PCT/EP2014/076051 (WO2015082378) and priority application EP 14163752.0 and EP 13195567.6, all of which are incorporated herein by reference.

According to an embodiment, the hyperproliferative and/or angiogenic disorder is breast cancer, prostate cancer, Multiple myeloma, hepatocellular carcinoma, lung cancer (specifically, non-small cell lung cancer), colorectal cancer, melanoma, pancreatic cancer are associated with bone metastasis.

According to an embodiment, the hyperproliferative and/or angiogenic disorder has a PTEN loss or a PIK3CA mutation and a KRAS wild type cancer.

According to an embodiment, the hyperproliferative and/or angiogenic disorder has a PTEN loss or PIK3CA mutation and a locally advanced or metastatic endometrial or breast cancer of the KRAS wild type or a slowly progressing non-Hodgkin's lymphoma (iNHL).

In other embodiments, the PI3K inhibitor is selected from the group consisting of a PI3K inhibitor consisting of: buparlisib, idelalisib, BYL-719, dactolisib, PF -05212384, pictilisib, ZSTK-474, GSK-2636771, duvelisib, GS-9820, PF-04691502, SAR-245408, SAR-245409, Sonolisib, Aco New (Archexin), GDC-0032, GDC-0980, apitolisib, pilaralisib, DLBS 1425, PX-866, voxtalisib, AZD-8186, BGT-226, DS -7423, GDC-0084, GSK-2126458, INK-1117, SAR-260301, SF-1126, 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-511, PQR-309, 17β-hydroxy wortmannin, 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-311, 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-1139, LY-294002, PF-04979064, PI-620, PKI-402, PWT-143, RP- 6530, 3-HOI-BA-01, AEZS-134, AS-041164, AS-252424, AS-605240, AS-605858, AS-606839, BCCA-621C, 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, HMPL-518, HS-104, HS-106, HS-116, HS-173, HS-196, IC-486068, INK-055, KAR 1141, 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, SHBM-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-111A, PI-708, PX-2000, WJD-008.

Method of treating a kinase disorder

The invention also provides methods of treating disorders associated with abnormal mitogen extracellular kinase activity, including but not limited to stroke, heart failure, hepatomegaly, cardiac enlargement, diabetes, Alzheimer's disease ( Alzheimer's disease), cystic fibrosis, symptoms of xenograft rejection, septic shock or asthma.

An effective amount of a compound of the invention can be used to treat such conditions, including those diseases (e.g., cancer) as mentioned in the Background section above. Moreover, the compounds of the invention can be used to treat such cancers and other diseases, regardless of the mechanism of action and/or the relationship between the kinase and the condition.

The phrase "abnormal kinase activity" or "abnormal tyrosine kinase activity" includes any abnormal expression or activity of a gene encoding a kinase or a polypeptide encoded thereby. Examples of such abnormal activities include, but are not limited to, overexpression of a gene or polypeptide; gene amplification; production of constitutive activity Or mutations in overactive kinase activity; gene mutations, deletions, substitutions, additions, and the like.

The invention also provides a method of inhibiting kinase activity, particularly mitogen extracellular kinase, comprising administering an effective amount of a compound of the invention, including salts, polymorphs, metabolites, hydrates, solvates, prodrugs thereof (eg, : ester) and its diastereomeric forms. Kinase activity can be inhibited in cells (e.g., in vitro) or in cells of a mammalian subject, particularly a human patient, in need of treatment.

Method of treating angiogenic disorders

The invention also provides methods of treating disorders and diseases associated with excessive and/or abnormal angiogenesis.

Inappropriate angiogenesis and ectopic performance may be harmful to organisms. A variety of pathological conditions are associated with neovascular growth. Such conditions include, for example, 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, posterior fibrous tissue hyperplasia, angiofibroma, inflammation, rheumatoid Arthritis (RA), restenosis, in-stent restenosis, restenosis after vascular grafting, etc. In addition, increased blood supply associated with cancerous and tumor tissue stimulates growth, leading to rapid tumor expansion and metastasis. In addition, the growth of new blood vessels and lymphatic vessels in tumors provides an escape pathway for renegade cells, thereby stimulating metastasis and leading to cancer spread. Thus, the compounds of the present invention can be used to treat and/or prevent any of the aforementioned angiogenic conditions, for example, by inhibiting and/or reducing angiogenesis; inhibiting, blocking, reducing, reducing, etc. endothelial cell proliferation. Or other types of cells involved in angiogenesis, as well as cell death or apoptosis that causes these cell types.

Compounds of formula (I) as set forth and defined herein can be prepared according to the methods of preparation contained in WO 2012/062748, which is incorporated herein by reference in its entirety.

The prior art and the PI3K-inhibitors mentioned in the above list have been disclosed for treatment Treat or prevent different diseases, especially cancer.

As used herein, the terms treatment and variations such as "treat or treating" refer to any regimen that can be beneficial to a human or non-human animal. In addition, prophylaxis (prophylactic treatment) can be carried out using a compound of formula (I). Treatment may include a healing effect, a palliative effect, or an attenuating effect, which effects are associated with one or more of the symptoms associated with hyperproliferative and/or angiogenic conditions.

A particular embodiment of the invention may be mentioned as a compound of formula (I), in particular 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: WO2013/062748 Example 14) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, in particular a physiologically acceptable salt or mixture, for use in preventing or treating excessive a proliferative and/or angiogenic disorder wherein the compound of formula (I) is administered for a period of from 1 to 5 days in each administration cycle, followed by administration of the compound of formula (I) or administration over a period of 3 to 6 days With placebo.

A particular embodiment of the invention may be mentioned as a compound of formula (I), in particular 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: WO2012/062748 Example 14) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, in particular a physiologically acceptable salt or mixture, for use in preventing or treating excessive A proliferative and/or angiogenic disorder wherein the compound of formula (I) is administered for a period of from 1 to 5 days, followed by administration of the compound of formula (I) or administration of a placebo over a period of 3 to 6 days.

Details of the preparation of the compounds of the general formula (I) can be found in WO 2012/062748 A1.

The compounds of the formula (I) may also be present in the form of their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, in particular physiologically acceptable salts or mixtures thereof. Suitable physiologically acceptable relative ions are known in the art.

Prodrugs of the compounds of formula (I) may also be employed in order to alter the therapeutic profile of the active compounds.

The compound of formula (I) is administered as a pharmaceutical composition. To prepare a pharmaceutical composition of a compound of formula I, a slowly progressing pharmaceutically acceptable carrier is mixed with the active compound. Pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, lozenges, dispersible granules and capsules. The solid carrier can be one or more substances which may also act as a diluent, flavor, solubilizer, lubricant, suspending agent, binder, slip aid or disintegrating agent; it may also be a packaging material.

Preferably, the pharmaceutical composition in unit dosage form is a packaged preparation, the package containing a discrete amount of preparation, such as a packaged lozenge, capsule and powder in a vial or ampule. Preferably, the pharmaceutical composition is a tablet.

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

Other aspects of the invention are as defined in the scope of the patent application.

Examples of experiments described herein were tested to illustrate the invention and the invention is not limited to the examples given.

Instance

Other abbreviations not specified herein have the meanings familiar to those skilled in the art.

The protocols and procedures described in the art as cited in the present application disclose the general synthetic routes and specific procedures within the experimental portion thereof to achieve the PI3K inhibitor compounds of the present invention. Compound A1 can be prepared according to Example 14 of WO 2012/062748, which is incorporated herein by reference in its entirety.

(N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazole [1,2 -c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide

Compound A1 (Cpd.A1)

Example 1: Instant release tablet containing a compound of formula (I) and optionally a film coating, as produced by fluidized bed granulation

1.1 Composition of a tablet containing the compound (A1)

^a weight and size can vary by about ± 10%.

^b yellow paint contains:

50.56% hypromellose

6.00% iron oxide yellow

10.12% polyethylene glycol 3350

10.12% talcum powder

23.20% titanium dioxide

1.2 Process 1.2.1 Lozenges 1-A to 1-E

Compound A1 coated lozenge

Wet granulation process: a fluidized bed granulator is charged with a pre-screened micronized compound (A1), mannitol and microcrystalline cellulose. The wet granulation process was carried out by adding a granulating liquid containing hypromellose 5cP and sodium lauryl sulfate to bulk purified water. The granules are dried and sieved.

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

Ingot: The final blend is compressed into a tablet. The mass uniformity, thickness, tablet crush resistance, brittleness and disintegration of the uncoated tablet were tested.

Coating: A batch of tablet cores can be divided into several sub-batch for optional coating. The yellow paint was suspended in bulk purified water to produce a homogeneous coated suspension which was sprayed onto the tablet. The mass uniformity, thickness and disintegration of the coated lozenge were tested. Lozenges with coating defects may be selected, as appropriate.

The amount of active ingredient can be reduced or increased by adjusting the amount of excipient, as can be readily determined by those skilled in the art.

The batch size of the lozenge can be scaled up or scaled down using equivalent equipment and processing (i.e., the same principles of operation) as readily determined by those skilled in the art.

Example 2: In vivo PK/PD experiments using NMRI nu/nu mice with tumor xenografts. The Asian gastric tumor model GXA 3027 was selected as a tumor model.

The study was performed using patient-derived tumor xenografts. Tumor fragments were obtained from serially passaged xenografts in nude mice. After removal from the donor mice, the tumors were cut into fragments (4-5 mm diameter) and placed in PBS until subcutaneous implantation. Mice under isoflurane anesthesia received a one-way subcutaneous tumor implant in the flank. Animals and tumor implants were monitored daily until the maximum number of implants showed clear signs of starting solid tumor growth. At random assignment, the volume of the growing tumor is initially determined. Animals having at least one tumor of 300 mm ³ to 600 mm ³ volume were distributed in the experimental group according to the research protocol. The date of random assignment is referred to as day 0 of the experiment. Compound A1 was evaluated under three different dosing schedules. The control group was included. Blood, tumor, and tissue samples were collected at selected time points after administration of Compound A1. At each time point, three mice/treatment groups were sacrificed.

A) Plasma drug exposure

To determine the exposure of Compound A1 in mice, blood was collected at 2 h, 8 h, 24 h, 48 h, 96 h, and 168 h after the first administration of Compound A1. The concentration of Compound A1 in plasma, tumor and tissue lysates was determined by HPLC tandem mass spectrometry after protein precipitation with acetonitrile. This analysis has a lower limit of quantitation (LLOQ) of 2 μg/L. The content of Compound A1 in the plasma of animals using the 75 mg/kg, QD (once per day) dosing schedule was higher at 2 h (mean 1363 μg/L), significantly lower at 8 h (mean 384 μg/L), and at 24 h Return to baseline (average 44 μg/L). Exposure to Compound A1 showed a proportional increase in the plasma dose of the animals in the group of 450 mg/kg, QW (once a week), and 200 mg/kg, 2 days of administration/5 days of withdrawal. In the group of 450 mg/kg, QW group and 200 mg/kg, 2 days of administration/5 days of withdrawal, the clearance of Compound A1 occurred at 96 h. Dose is also shown to be linear between Cmax and 75 mg/kg to 450 mg/kg.

Example 3 In vivo mechanism of action and path inhibition characteristics.

Path-based assays for the measurement of p-AKT (S473) and downstream signaling molecule p-PRAS40 in tumor tissue extracts were analyzed using ELISA-based assays. These analyses were performed based on the MULTI-SPOT® Assay System (Fa. Meso Scale Discovery, Cat. No. N41100B-1 (for p-AKT) and K150JZD-1 (for p-PRAS40)) and following the manufacturer's instructions.

Briefly, tumor samples of approximately 5 x 5 x 5 mm were dissolved in MSD lysis buffer on ice using Tissue Lyzer (Qiagen, Germany) in the presence of protease and phosphatase inhibitors. 20 μg of protein extract was used for each analysis. All measurements are performed in at least two copies. The content of p-AKT and p-PRAS40 in the tumor treated with Compound A1 was compared with that of the vehicle group.

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

- In tumors from the 450 mg/kg, QW cohort, the effective inhibition (>90%) of p-AKT lasted much longer than >2h observed in the low dose 75 mg/kg, QD cohort. 24h.

Compound A1 at -200 mg/kg for two consecutive days, observed at 2h and 8h >90% inhibition of p-AKT and >80% p-AKT inhibition was also observed at 48h. It should be noted that the p-AKT content was only about 30% of the control at 24 h after the first administration and before the second dose (compared to 75 mg/kg, 75% of the control in the QD cohort) . More than 50% p-AKT inhibition was maintained until 96 h.

- Therefore, continuous administration of Compound A1 has a short period of time effective to inhibit p-AKT (about 2 h), and weekly administration of the initial effective inhibition of p-AKT is prolonged (>24 h) and <50% Inhibition for up to 3 days (96-168h). Treatment of Compound A1 at 200 mg/kg for the first 2 days and administration of drug withdrawal day from day 3 to day 7 (ie, no administration of Compound A1) was obtained using 75 mg/kg, QD, and 450 mg/kg, QW. The suppression characteristics are displayed.

The overall properties of p-PRAS40 inhibition by Compound A1 using different administration protocols are very similar to the p-AKT inhibition properties. Therefore, treatment with the PI3K inhibitor Compound A1 at 75 mg/kg, QD schedule caused a transient effective inhibition of p-PRAS40 (80.6%) at 2 h, a decrease (58.9%) at 8 h, and at 24 h p - PRAS40 is restored to the level of the vehicle control. In contrast, intermittent QW administration with a high dose of 450 mg/kg produced an initial prolonged inhibition of p-PRAS40 (>24 h vs. 2 h) and a more effective maximal inhibition (92.4% vs. 80.6%) and from 96 h up to 168 h (3 days) The cells are released from the path inhibition. It should be noted that using a batch dosing schedule (QW at 450 mg/kg and 2 days of dosing/5 days at 200 mg/kg) only achieved >90% p-PRAS40 inhibition, but QD did not reach 75 mg/kg. .

The kinetics of p-PRAS40 inhibition was sufficiently correlated with the observed level of Compound A1 in serum (Figure 2). The concentration of Compound A1 administered at 75 mg/kg in serum reached about 1363 μg/L at 2 hours after administration (related to about 80% inhibition of p-PRAS40) and decreased to 383 μg/L at 5 hours (with about 60). % p-PRAS40 inhibition was associated) and was further reduced to a biologically unrelated concentration of 44 μg/L at 24 h (Table 2). Interestingly, the concentration of Compound A1 administered at 450 mg/kg reached 9179 μg/L at 2 h (associated with greater than 92% inhibition of p-PRAS40), which was not achievable for the 75 mg/kg administration group. In addition, a concentration of 1907 μg/L at 24 h (related to about 80% p-PRAS40 inhibition) was observed in the 75 mg/kg administration group. The exposure at 2 h was equivalent to the maximum inhibition. Finally, the concentration of Compound A1 in plasma (associated with approximately 60% p-PRAS40 inhibition) at 48 h was comparable to exposure and p-PRAS40 inhibition observed at 8 h in the 75 mg/kg administration group. Therefore, administration of Compound A1 using different administration protocols showed a clear PK/PD relationship.

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

The dosing regimen of continuous (QD) and intermittent (QW, 2 days of dosing / 5 days of dosing) produced a differential path inhibition pattern, as depicted in Table 3, Table 4 and Figure 1 of Example 3. therefore:

Administration of Compound A1 at 75 mg/kg (MTD) continuous QD caused about 8 h of pathway inhibition (50-80% inhibition of p-PRAS40) and a recovery period of about 16 h (<50% pathway inhibition) per day.

• The intermittent QW (450 mg/kg, under MTD) or 2 days of dosing / 5 days of discontinuation (200 mg/kg, at MTD) resulted in a stronger maximum path inhibition (>90%) at 2 h, And for the QW 450mg/kg regimen, the longer initial effective inhibition of p-PRAS40 (>80%) up to 24h and the administration of 2mg/dose for 5 days 200mg/kg Longer initial effective inhibition (>75%) of p-PRAS40 on day 1 and day 2 up to 8 h. On the other hand, the two administration regimens recovered from path inhibition from 96 h to 168 h (3 days/week).

We evaluated tumor survival inhibition by Compound A1 in a GXA3027 patient-derived gastric tumor model treated with the above-mentioned administration regimen. Induction of apoptosis protein (ie, activated caspase 3 and cleavage of PARP) in tumors was analyzed at 2h, 8h, 24h, 48h, 96h and 168h after the first administration of compound A1 (Table 5, Table) 6 and Figure 3). In the vehicle In the treated tumors, the levels of activated caspase 3 and lysed PARP were low and remained constant during the time course of the study and used as a baseline for comparison. Continuous daily treatment with 75 mg/kg of Compound A1 did not significantly induce tumor cell apoptosis during the treatment period (the caspase 3 content and the cleaved PARP content were only slightly increased (1.6-fold and 1.7-fold)). In contrast, caspase 3 (16.6-fold and 5.9-fold, respectively) and lysis were significantly induced at 200 mg/kg with weekly treatment at 450 mg/kg and administration for 2 days/dose for 5 days. PARP (6.6 times and 3.6 times, respectively). These results correlate with the observed serum exposure of Compound A1, >90% p-PRAS40 inhibition, indicating that induction of tumor cell death benefits from exposure of Compound A1 above a certain threshold and path inhibition (eg, p- PRAS40 inhibition), which can be achieved by intermittent administration of Compound A1.

Example 5A: In vivo efficacy of Compound A1 as a single agent and continuous or intermittent administration in combination with cisplatin and capecitabine in a GXA3027 patient-derived gastric tumor model in mice.

To compare the monotherapy and combination efficacy of Compound A1 using continuous and intermittent dosing regimens, once daily at 60 mg/kg, for 2 days/5 days for withdrawal at 210 mg/kg or once weekly at 420 mg/kg p.o. The same weekly cumulative dose of 420 mg/kg was found in Compound G1 in a GXA3027 patient-derived gastric tumor model in NMRI nu/nu mice. Antitumor activity was determined as tumor growth inhibition relative to the vehicle control group and onset of tumor volume and expressed as the ratio of median to tumor volume group (V _treatment - V _initial ) / (V _{control -} V _initial ) %; T/C [%]). Tumor response was assessed by measuring tumor size (tumor volume = (width) ² x length/2) using a double foot gauge. Animal weight was monitored as a measure of treatment-related toxicity. Tumor size and body weight were measured 2 to 3 times per week. Statistical analysis was evaluated using SigmaStat software. Single factor variance analysis was performed and the difference from the control was compared by a pairwise comparison program (Dunn's method). If not mentioned otherwise, the relative T/C ratio was calculated using the last tumor area at the end of the study. In addition, the treatment response is assessed by 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 the reaction rate was calculated accordingly (RR = number of animals with complete and partial response).

According to the results of the study of the mechanism of action from Examples 3 and 4, treatment with Compound A1 using QD, QW, or a 2-day/dose 5-day schedule was confirmed to have -2.2%, -13.8%, and -8.3%, respectively. The relative anti-tumor effect of T/C. Importantly, the highest activity of 78% RR (7/9 animals) was demonstrated by QW administration at 420 mg/kg/week, and the schedule of 2 days/dose for 5 days showed an RR of 56% (5/9 animals). And continuous QW administration produced 11% (1/9 animals) of RR (Figure 5). These data confirm the conclusion that the intermittent dosing schedule can cause comparable or even more potent anti-tumor activity of Compound A1, in particular higher RR, compared to the continuous QD dosing schedule. In combination with first-line chemotherapy for gastric cancer (eg, capecitabine and cisplatin), Compound A1 further enhances its anti-tumor activity in both T/C and RR using all three dosing schedules.

Example 5B: Antitumor activity of a combination of Compound A1 and paclitaxel

In vivo efficacy experiments evaluating the combined activity of paclitaxel and compound A1 in different administration schedules were performed in female nu/nu mice. The results of the experiments are summarized in Table 8.

Weekly paclitaxel (24 mg/kg/day) and 75 mg/kg/day po will be administered iv on day 0, day 7, day 14, and day 21 (on days 1 to 6, Continuous administration of 8 to 13 days, 15 to 20 days, 22 to 23 days) or with Compound A1 (on Day 1, Day 8, Day 15, and Day 22 (500/400 mg/kg/day)) Intermittent administration combination.

In the GXA 3023 tumor model, continuous administration of Compound A1 (75 mg/kg, QD) showed good anti-tumor activity with an optimal T/C value of 31.9%. Weekly administration of 500/400 mg/kg of Compound A1 showed extremely good efficacy with an optimal T/C value of 8.2% and overall tumor stagnation and 3/8 partial remission. Pacific paclitaxel monotherapy was moderately good with an optimal T/C value of 35.0%. Combination therapy with paclitaxel and continuous compound A1 (75/50 mg/kg) produced extremely good antitumor activity with an optimal T/C value of 15.6%. The combination of paclitaxel and weekly compound A1 (500/400 mg/kg) has high activity with an optimal T/C value of 9.1%, and overall tumor arrest and 3/8 partial tumor remission. Therefore, the combined effect of paclitaxel plus intermittent weekly compound A1 must be evaluated by tumor growth delay.

In the GXF 241 tumor model, continuous compound A1 administration showed good anti-tumor function The best T/C value was 17.9% and a partial remission was observed.

Intermittent administration of Compound A1 also produced better activity with an optimal T/C of 13.6 and partial tumor remission was observed in 4/8 mice. Pacific paclitaxel monotherapy has high activity with an optimal T/C value of 6.6%. Tumors of 7/8 animals entered partial remission. The combination of two paclitaxel/compound A1 treatments produced 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 the two combination therapy groups. A system demonstrating the extremely good anti-tumor activity of the two combination therapy groups is significant.

The combination treatment was more potent and beneficial in both cases than the concentration of the individual compound A1 given in the monotherapy.

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

In vivo efficacy studies were performed in nude rats using the KPL-4 breast cancer xenograft model, the study design is shown in Table 9.

All Compound A1 treatment groups demonstrated effective anti-tumor efficacy in KPL-4 breast cancer xenografts in nude rats. The best anti-tumor efficacy (T/C _area/weight = 0.15/0.11, Table 10 and Figure 4) was achieved using the TW of the final tumor area and tumor weight evaluation using the QW administration protocol at 105 mg/kg. Surprisingly, the group that was continuously administered at 75 mg/kg QD had a T/C _area/weight =0.29/0.32, which was better than once a week and better than the 2 days of dosing/dose for 5 days. Surprisingly, the two intermittent dosing groups confirmed far better disease control rates (80% and 50% for the QW cohort and the 2 day/dose 5 day group, respectively), while the continuous QD group only A 10% disease control rate is achieved, as assessed by the clinically used RECIST guidelines.

Importantly, a 20% disease control rate was also observed in animals in the vehicle control group. In general, a relatively high change in tumor size was observed between animals in a cohort. This was repeatedly observed when xenografted on nude rats using the KPL-4 tumor model.

The continuous treatment with Compound A1 was well tolerated and no significant body weight loss was observed (Fig. 4B, Table 10). When Compound A1 was administered intermittently, a brief weight loss was observed after administration of Compound A1, but the body weight returned to the level of the continuous QD group, followed by the next dose. One dose. This result clearly indicates that intermittent treatment of Compound A1 in the KPL4 model produces better anti-tumor efficacy and comparable tolerance compared to continuous once-a-day treatment.

Example 7: Clinical trial in patients with cancer: dose regimen, continuous administration

In an open-label, non-randomized phase I dose escalation study of oral Compound A1, the compound was administered once daily (QD) starting with 15 mg QD (ie, continuous administration). The cycle of this study was defined as the 21-day period.

Preliminary evaluation of safety data showed clinically relevant incidence of pneumonia and pneumocystic pneumonia (PcP) under MTD (200 mg). The effect of Compound A1 on PI3Kδ and its associated effect on B lymphocytes/changes in the immune system are hypothetical causes of pneumonia and PcP.

Example 8: Clinical Trial in Patients with Cancer: Dosage Schedule, 2 Dosing Days/5 Stop Day

In a non-randomized phase I study of open-labeling of oral Compound A1, the compound was administered at 200 mg QD for 21 days (ie 3 administration cycles) in a dosing schedule of 2 dosing days per 5 dosing days. Then, no treatment (ie, interruption period) was performed for 7 days, that is, compound A1 was administered on the first day, the second day, the eighth day, the ninth day, the 15th day, and the 16th day of each 28-day cycle (Table 11) individuals with slow-onset or metastatic endometrial cancer or breast cancer [with PTEN (loss) or PIK3CA mutations and KRAS wild-type tumors (using circulating tumor DNA assays at pre-screening)] Safety characteristics, PK and biomarker and tumor response characteristics are defined in individuals with advanced non-Hodgkin's lymphoma (iNHL). The cycle of this study was defined as a 28-day period (this included 3 cycles of administration plus 7 days of interruption). The daily dose can be adjusted (reduced or increased) depending on the patient's clinical response and/or the occurrence of adverse events.

It is expected that patients taking Compound A1 using the intermittent dosing schedule will use it relative to them. Continuous administration of Compound A1 showed a modified effect.

Example 9: Toxicity study using compound A1 for 4 weeks in rats

Compound A1 was tested in a 4-week repeated dose toxicity study in Wistar rats using a daily oral dose of 0 mg/kg, 5.0 mg/kg, 10.0 mg/kg, and 15.0 mg/kg. An additional high dose group receiving a cumulative dose of 105 mg/kg (15.0 mg/kg/day x 7 days) was included in the intermittent treatment schedule (once a week, for a total of 3 doses). The primary group of animals were sacrificed at the end of each treatment session. The toxicology assessment was performed using satellite animals and the reversibility of potential compound-related effects was evaluated during the 4-week recovery period.

The histological findings focused on the spleen and lymph nodes in the lymphoid organs are summarized as follows:

In the spleen, atrophy of the marginal zone and an increase in blood iron deposits were observed. The severity of atrophy in the marginal zone increased in a dose-dependent manner with increasing daily doses, with weekly high doses showing similar levels to daily low doses. An increase in the incidence and severity of hematite deposits was observed under daily administration and this was initiated in females at low doses. It is also present in male animals at high daily doses. An increase in extramedullary hematopoiesis was observed in the spleen under weekly compound administration.

At low daily doses and higher daily doses, lymph nodes showed minimal to moderate atrophy and minimal to mild lymphoid deficiency. High weekly doses show similar levels to daily low doses. In addition, three male animals showed minimal lymphoid hyperplasia in the mesenteric lymph nodes.

At the end of the recovery period, lymphoid deficiencies and atrophy disappear. Increased hematopoiesis in the spleen was observed in several animals in all dose groups (including controls) at the end of the recovery period. No differences were observed compared to the weekly high dose group.

Compound-related histological findings in lymphoid organs at the end of treatment and at the end of the 4-week recovery period are given below.

Table 12. Compound-related histological findings in lymphoid organs of animals at the end of the 4-week treatment period.

M = male, F = female

Number before/after the slash = animal killed by death or death and/or animal to be killed at the end of treatment

105mg/kg *=The compound is administered once a week for 3 weeks, and 10ml/kg is administered from the 2nd to the 7th day.

Rating:

1=very light, minimum 2 = light 3 = medium

4=significant 5=serious

M = male, F = female

Number before/after the slash = animal killed by death or death and/or animal to be killed at the end of treatment

105mg/kg *=The compound is administered once a week for 3 weeks, and 10ml/kg is administered from the 2nd to the 7th day.

Rating:

1=very light, minimum 2 = light 3 = medium

4=significant 5=serious

in conclusion:

Currently, PI3K inhibitors in clinical development are mainly administered orally and continuously. Since only a few PI3K inhibitors have demonstrated clinical activity, most PI3K inhibitors show side effects before achieving substantial anti-tumor efficacy. Surprisingly, we have found that intermittent treatment according to the dosage regimen described herein produces better anti-tumor efficacy than continuous treatment. Based on the expected mode of action, effective inhibition of tumor growth and survival may be beneficial by the effective suppression of the PI3K pathway in tumor tissue by PI3K inhibitors. This PI3K inhibitor can be applied to other PI3K mediated conditions. We have surprisingly found that initial high exposure to Compound A1 using intermittent administration results in stronger and longer path inhibition, as measured by p-AKT and p-PRAS40 versus continuous administration (under the corresponding MTD). Complete inhibition of p-PRAS40 (>90%) is associated with apoptosis induction in tumor cells (as assessed by cleavage of caspase 3 and PARP) and is based on intermittent administration rather than continuous administration at the corresponding MTD Give medicine to achieve. In addition, in vivo efficacy studies in the GXA 3027 gastric cancer model and the KPL4 breast tumor model demonstrated that intermittent therapy is surprisingly superior to continuous therapy. These pooled results clearly indicate that using the PI3K inhibitor to achieve better anti-tumor efficacy and/or maintaining or improving safety characteristics using the intermittent dosing schedule of the present invention, it is worthwhile to further use the inhibitor in a clinical setting.

Claims (69)

a compound of formula (I), Wherein: R ¹ represents -(CH ₂ ) _n -(CHR ⁴ )-(CH ₂ ) _m -N(R ⁵ )(R ^5' ); and R ² represents a heteroaryl group of the following structure: It is optionally substituted with 1, 2 or 3 R ⁶ groups, wherein: * represents the attachment point of the heteroaryl group to the rest of the compound of formula (I), X represents N or CR ⁶ , X 'Represents O, S, NH, NR ⁶ , N or CR ⁶ , provided that when both X and X' are CR ⁶ , then one CR ⁶ is CH; R ³ is methyl; R ⁴ is hydroxyl; R ⁵ and R ^{5 'is the} same or different and independently of each other is a hydrogen atom or a C ₁ -C ₆ -alkyl group, a C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl group or a C ₁ -C ₆ -alkoxy group The base-C ₁ -C ₆ -alkyl group, or R ⁵ and R ^{5 '} together with the nitrogen atom to which they are bonded represent a 3 to 7 member nitrogen-containing heterocyclic ring, the heterocyclic ring optionally containing at least one selected from the group consisting of oxygen, nitrogen or sulfur. Other heteroatoms and which may optionally be substituted by one or more R ^{6 '} groups; each occurrence of R ⁶ may be the same or different and independently hydrogen, halogen, C ₁ -C ₆ -alkyl, C _2- C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl, aryl, aryl -C ₁ -C ₆ -alkyl, heteroaryl, heteroaryl-C ₁ -C ₆ -alkyl, 3 to 8 membered heterocyclic ring, 3 to 8 membered heterocyclyl-C ₁ -C ₆ -alkane group, -C ₁ -C ₆ - alkyl -OR ^7, -C ₁ -C ₆ - Group -SR ^7, -C ₁ -C ₆ - alkyl ^{-N (R 7) (R 7} '), - C 1 -C 6 - alkyl ^{-C (= O) R 7,} -CN, -C ( =O)OR ⁷ , -C(=O)N(R ⁷ )(R ^7' ), -OR ⁷ , -SR ⁷ , -N(R ⁷ )(R ^7' ) or -NR ⁷ C(=O R ⁷ , each of which may be optionally substituted with one or more R ⁸ groups; each occurrence of R ^{6 '} may be the same or different and independently C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkyl-OR ⁷ ; each occurrence of R ⁷ and R ^{7 '} may be the same or different and independently hydrogen Atom or C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyl-C _1- C ₆ -alkyl, C ₃ -C ₆ -cycloalkenyl, aryl, aryl-C ₁ -C ₆ -alkyl, heteroaryl, 3 to 8 membered heterocyclic ring, 3 to 8 membered heterocyclic ring -C ₁ -C ₆ -alkyl or heteroaryl-C ₁ -C ₆ -alkyl; each occurrence of R ^{8 is} independently a halogen atom or a nitro group, a hydroxyl group, a cyano group, a decyl group, an ethyl group Base, amine group, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkane , C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -cycloalkenyl, aryl, aromatic -C ₁ -C ₆ -alkyl, heteroaryl, 3 to 8 membered heterocyclic ring, heterocyclyl-C ₁ -C ₆ -alkyl or heteroaryl-C ₁ -C ₆ -alkyl; An integer of 1 and m is an integer of 1; the premise is when the R ⁵ and R ^5' together with the nitrogen atom to which they are bonded represent the following structure: Where * represents an attachment point to the rest of the structure of formula (I), then the R ² heteroaryl of the following structure: Not for: Wherein * represents an attachment point to the remainder of the structure of formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof; A compound of formula (I) for use in preventing or treating a hyperproliferative and/or angiogenic disorder wherein the compound of formula (I) is administered for a period of from 1 to 5 days, followed by 3 to 6 days, in each administration cycle. The compound of formula (I) is administered or the placebo is administered during the time period. A compound as claimed in claim 1, wherein R ¹ represents -(CH ₂ ) _n -(CHR ⁴ )-(CH ₂ ) _m -N(R ⁵ )(R ^5' ); R ² represents a heteroaryl group of the following structure : Wherein: * represents the attachment point of the heteroaryl group to the rest of the structure of the formula (I); R ³ is a methyl group; R ⁴ is a hydroxyl group; and R ⁵ and R ^{5' are the} same or different and independently of each other a hydrogen atom or a C ₁ -C ₆ - alkyl, C ₃ - C ₆ - cycloalkyl, -C ₁ -C ₆ - alkyl or C ₁ -C ₆ - alkoxy, -C ₁ -C ₆ - alkyl, Or R ⁵ and R ^{5 '} together with the nitrogen atom to which they are bonded represent a 3 to 7 member nitrogen-containing heterocyclic ring which optionally contains at least one other hetero atom selected from oxygen, nitrogen or sulfur and which may optionally be 1 or Substituting a plurality of R ^{6 '} groups; each occurrence of R ⁶ may be the same or different and independently a hydrogen atom, a halogen atom, a C ₁ -C ₆ -alkyl group, a C ₂ -C ₆ -alkenyl group, a C ₂ - C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl, aryl, aryl-C ₁ -C ₆ -alkyl, Heteroaryl, heteroaryl-C ₁ -C ₆ -alkyl, 3 to 8 membered heterocyclic ring, 3 to 8 membered heterocyclic group -C ₁ -C ₆ -alkyl, -C ₁ -C ₆ -alkyl -OR ⁷ , -C ₁ -C ₆ -alkyl-SR ⁷ , -C ₁ -C ₆ -alkyl-N(R ⁷ )(R ^7' ), -C ₁ -C ₆ -alkyl-C( =O)R ⁷ , -CN, -C(=O)OR ⁷ , -C(=O)N(R ⁷ )(R ^7' ), -OR ⁷ , -SR ⁷ , -N(R ⁷ )( R ^7' ) or -NR ⁷ C (=O)R ⁷ , each of which may be substituted with one or more R ⁸ groups as appropriate; each occurrence of R ^{6 '} may be the same or different and independently C ₁ -C ₆ - Alkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkyl-OR ⁷ ; each occurrence of R ⁷ and R ^{7 '} may be the same or different and independent a hydrogen atom or a C ₁ -C ₆ -alkyl group, a C ₂ -C ₆ -alkenyl group, a C ₂ -C ₆ -alkynyl group, a C ₃ -C ₆ -cycloalkyl group, a C ₃ -C ₆ -cycloalkane -C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkenyl, aryl, aryl-C ₁ -C ₆ -alkyl, heteroaryl, 3 to 8 membered heterocyclic ring, 3 to 8 Heterocyclyl-C ₁ -C ₆ -alkyl or heteroaryl-C ₁ -C ₆ -alkyl; each occurrence of R ^{8 is} independently a halogen atom or a nitro group, a hydroxyl group, a cyano group, a decyl group , Ethyl, amino, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -cycloalkenyl, aryl, aryl-C ₁ -C ₆ -alkyl, hetero An aryl group, a 3 to 8 membered heterocyclic ring, a heterocyclic group -C ₁ -C ₆ -alkyl or a heteroaryl-C ₁ -C ₆ -alkyl group; n is an integer of 1 and an integer of m is 1; When the R ⁵ and When R ^{5 '} together with the nitrogen atom to which it is bonded represents the following structure: Where * represents the attachment point to the remainder of the structure of formula (I), then the R ² heteroaryl of the following structure: Not for: Wherein * represents an attachment point to the remainder of the structure of formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, specifically physiological A salt that is acceptable for learning or a mixture thereof. A compound as claimed in claim 1 or 2, wherein the compound of formula (I) is selected from the group consisting of N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)) Propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-3-carboxamide N-(8-{[( 2S)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazoline-5- Pyridyl-3-carboxamide 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]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-dihydroimidazole [ 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]quinazoline- 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-(pyrrolidine) -1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-3-carboxamide N-( 8-{[(2R)-2-hydroxy-3-(hexahydropyridin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazole [1,2-c] Quinazoline-5-yl)pyridine-3-carboxamide N-{8-[3-(dimethylamino)-2-hydroxypropoxy]-7-methoxy-2,3-di Hydrogen imidazo[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-methoxy-2,3-dihydroimidazo[1,2-c]quinazoline-5- Pyridyl-3-carboxamide 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)-3 -(azetidin-1-yl)-2-hydroxypropyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl) -2-methylpyridine-3-carboxamide N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxyl) 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-methoxy-2,3-dihydroimidazole [1,2-c] quin Oxazolin-5-yl)-2-methylpyridine-3-carboxamide N-(8-{[(2R)-2-hydroxy-3-(hexahydropyridin-1-yl)propyl]oxy }-7-Methoxy-2,3-dihydroimidazo[1,2-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-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]oxy}-7-methoxy-2,3-dihydroimidazole [ 1,2-c]quinazolin-5-yl)-2-methylpyridine-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 2-amino-N- {8-[2-Hydroxy-3-(morpholin-4-yl)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl Pyrimidine-5-carbamidamine 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]quinazoline-5- Pyrimidine-5-carbamide N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-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-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1, 3-thiazole-5-formamide 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]-1,3-thiazole-5-carboxamide N-(8-{ [(2R)-3-(azetidin-1-yl)-2-hydroxypropyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c] quinazole Porphyrin-5-yl)-1,3-thiazol-5-carboxamide N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazole [1,2- c] quinazolin-5-yl)-1,3-thiazole-5-carboxamide N-(8-{[(2R)-2-hydroxy-3-(hexahydropyridin-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]quinazoline -5-yl)-4-methyl-1,3-thiazol-5-carboxamide 2-amino-N-(8-{[(2R)-2-hydroxy-3-(morpholin-4- Propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-4-methyl-1,3-thiazole-5 -Procarbamide N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazole [ 1,2-c]quinazolin-5-yl)-1,3-oxazol-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-formamidine An amine, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, in particular a physiologically acceptable salt or a mixture thereof. The compound for use according to any one of claims 1 to 3, wherein the compound of the formula (I) is selected from the group consisting of N-(8-{[(2R)-2-hydroxy-3-(morpholine-) 4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-3-carboxamide 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]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- Propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-3-carboxamide N-(8-{[(2R)-2-hydroxy-3-(hexahydropyridin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazole [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-(dipropyl) -2-ylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-3- Formamide N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazole [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-carboxamide N -(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazole [1,2-c Uquinazoline-5-yl)-2-methylpyridine-3-carboxamide N-(8-{[(2R)-2-hydroxy-3-(hexahydropyridin-1-yl)propyl] Oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide N-(8-{ [(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3-dihydroimidazole [ 1,2-c]quinazolin-5-yl)-2-methylpyridine-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]quinazoline-5 -yl)-1,3-thiazole-5-formamide N-(8-{[(2R)-2-hydroxy-3-(hexahydropyridin-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)-1 , 3-oxazole-5-carboxamide, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, in particular a physiologically acceptable salt or mixture. A compound as claimed in claim 1, wherein R ¹ represents -(CH ₂ ) _n -(CHR ⁴ )-(CH ₂ ) _m -N(R ⁵ )(R ^5' ); R ² represents a heteroaryl group of the following structure : Wherein: * represents the attachment point of the heteroaryl group to the remainder of the structure of formula (I), and X represents N or CR ⁶ ; R ³ is methyl; R ⁴ is hydroxy; R ⁵ and R ^5' The same or different and independently of each other are a hydrogen atom or a C ₁ -C ₆ -alkyl group, a C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl group or a C ₁ -C ₆ -alkoxy-C group. ₁ -C ₆ -alkyl, or R ⁵ and R ^{5 '} together with the nitrogen atom to which they are bonded represent a 3 to 7 membered nitrogen-containing heterocyclic ring containing optionally at least one other hetero atom selected from oxygen, nitrogen or sulfur. And optionally substituted with 1 or more R ^{6 '} groups; each occurrence of R ⁶ may be the same or different and independently hydrogen atom, halogen atom, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl, aryl, aryl-C _1- C ₆ -alkyl, heteroaryl, heteroaryl-C ₁ -C ₆ -alkyl, 3 to 8 membered heterocyclic ring, 3 to 8 membered heterocyclic group -C ₁ -C ₆ -alkyl, - C ₁ -C ₆ -alkyl-OR ⁷ , -C ₁ -C ₆ -alkyl-SR ⁷ , -C ₁ -C ₆ -alkyl-N(R ⁷ )(R ^7' ), -C ₁ - C ₆ -alkyl-C(=O)R ⁷ , -CN, -C(=O)OR ⁷ , -C(=O)N(R ⁷ )(R ^7' ), -OR ⁷ , -SR ⁷ , -N(R ⁷ ) (R ^7' ) or -NR ⁷ C(=O)R ⁷ , each of which may be substituted by one or more R ⁸ groups as appropriate; R ^{6 '} may be the same for each occurrence Or different and independently C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkyl-OR ⁷ ; R ⁷ and R ^{7 '} may be the same or different and independently a hydrogen atom or a C ₁ -C ₆ -alkyl group, a C ₂ -C ₆ -alkenyl group, a C ₂ -C ₆ -alkynyl group, a C ₃ -C ₆ - Cycloalkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkenyl, aryl, aryl-C ₁ -C ₆ -alkyl, heteroaryl a 3 to 8 membered heterocyclic ring, a 3 to 8 membered heterocyclyl-C ₁ -C ₆ -alkyl or heteroaryl-C ₁ -C ₆ -alkyl group; each occurrence of R ^{8 is} independently a halogen atom Or nitro, hydroxy, cyano, decyl, ethenyl, amine, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -cycloalkenyl, aryl, aryl -C ₁ -C ₆ -alkyl, heteroaryl, 3 to 8 membered heterocyclic ring, heterocyclyl-C ₁ -C ₆ -alkyl or heteroaryl-C ₁ -C ₆ -alkyl; An integer of 1 and an integer of m Or stereoisomers thereof, tautomers, N- oxide, hydrate, solvate or salt thereof, particularly the physiologically acceptable terms or mixtures thereof. A compound as claimed in claim 1 or 5, wherein 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]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazoline -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 2-Amino-N-{8-[ 2-hydroxy-3-(morpholin-4-yl)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5 -carbamamine 2-amino-N-{8-{[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-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-dihydroimidazole [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 Stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, in particular physiologically acceptable salts or mixtures thereof. A compound of formula (I) as used in any one of claims 1 to 4, wherein the compound of formula (I) 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 Stereoisomers, tautomers, N-oxides, hydrates, solvates or salts or mixtures thereof. A compound of formula (I) as claimed in any one of claims 1 to 7, wherein the compound of formula (I) is administered for a period of one day in each administration cycle, followed by a period of from 3 to 6 days. The compound of formula (I) is administered or a placebo is administered. A compound of formula (I) as claimed in any one of claims 1 to 7, wherein the compound of formula (I) is administered for a period of 2 days in each administration cycle, followed by a period of 3 to 6 days. The compound of formula (I) is administered or a placebo is administered. A compound of formula (I) as claimed in any one of claims 1 to 7, wherein the compound of formula (I) is administered for a period of 3 days in each administration cycle, followed by a period of 3 to 6 days. The compound of formula (I) is administered or a placebo is administered. A compound of formula (I) as claimed in any one of claims 1 to 7, wherein the compound of formula (I) is administered for a period of 4 days in each administration cycle, followed by a period of 3 to 6 days. The compound of formula (I) is administered or a placebo is administered. A compound of formula (I) as claimed in any one of claims 1 to 7, wherein the compound of formula (I) is administered for a period of 5 days in each administration cycle, followed by a period of 3 to 6 days. The compound of formula (I) is administered or a placebo is administered. A compound of formula (I) as used in any one of claims 1 to 12, wherein the administration cycle is carried out once, twice, three times or four times. A compound of formula (I) as claimed in any one of claims 1 to 12, wherein the administration cycle is carried out once, twice, three times or four times, and then not administered during the interruption period of 4 to 8 days The compound of formula (I). The compound of formula (I) as used in any one of claims 1 to 14, wherein the compound of formula (I) is administered in a total amount of from about 200 mg to about 1000 mg in each administration cycle. The compound of formula (I) as used in any one of claims 1 to 15, wherein the compound of formula (I) is administered in a total amount of from about 400 mg to about 800 mg in each administration cycle. A compound of formula (I), as used in any one of claims 1 to 16, wherein the compound of formula (I) is administered in an amount of from about 50 mg/day to about 400 mg/day on the date of administration. A compound of formula (I) as used in any one of claims 1 to 17, wherein the compound of formula (I) is administered in an amount of from about 100 mg/day to about 400 mg/day on the date of administration. A compound of formula (I), as used in any one of claims 1 to 18, in combination with one or more other active ingredients selected from the group consisting of taxanes, such as docetaxel, paclitaxel (Paclitaxel) or paclitaxel (Taxol); epothilone, such as Ixabepilone, Patugpilone or Sagopilone; Mitoxantrone; Prednisolone; Dexamethasone; Estramustin; Vinblastin; Vincristin; Doxorubicin; Adriamycin ; Idarubicin; Daunorubicin; Bleomycin; Etoposide; Cyclophosphamide; Ifosfamide; Procarbazine; Melphalan; 5-fluorouracil; Capecitabine; Fludarabine; Cytarabine; Ara-C; 2-Chloro-2 '-Deoxyadenosine; Thioguanine; Antiandrogen, such as Flutamide, Cyproterone acetate or Bicalutamide; Bortezomib Platinum derivatives, such as Cisplatin or Carboplatin; Chlorambucil; Methotrexate; Rituximab; and alkaline earth radioactive radium 223 pharmaceutically acceptable salts. A compound of formula (I) for use in any one of claims 1 to 18 in combination with an anti-hyperproliferative agent, a cytotoxic agent and a cytostatic agent selected from the group consisting of 5-FU or 5-FU prodrugs, for example 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT or S-1; platinum-based antitumor agents, such as oxaliplatin, Cisplatin or carboplatin; and a taxane such as docetaxel or paclitaxel; or a combination thereof. A compound of formula (I) for use in any one of claims 1 to 18 in combination with a pharmaceutically acceptable salt of the alkaline earth radioactive seed radium-223, such as radium dichloride-223. A compound of formula (I) as used in any one of claims 1 to 21, wherein the compound of formula (I) is administered concomitantly, concomitantly, separately or sequentially with the other one or more other active ingredients. A compound of formula (I), as used in any one of claims 1 to 22, wherein the hyperproliferative and/or angiogenic disorder is uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammation Diseases of the reaction, more specifically those mediated by the phospholipid inositol-3-kinase (PI3K) pathway, and even more specifically hematological tumors, solid tumors and/or their metastases, such as leukemia and myelodysplastic syndromes , malignant lymphoma, head and neck tumors (including brain tumors and brain metastases), chest tumors (including non-small cells and small cell lung tumors), gastrointestinal tumors, endocrine tumors, milk House and other gynecological tumors, urological tumors (including kidney tumors, bladder tumors and prostate tumors), skin tumors and sarcomas and/or their metastases. A compound of formula (I), as used in any one of claims 1 to 22, wherein the hyperproliferative and/or angiogenic disorder is gastric cancer. A compound of the formula (I) for use according to any one of claims 1 to 22, wherein the hyperproliferative and/or angiogenic disorder is breast cancer, prostate cancer, multiple myeloma, hepatocellular carcinoma, lung cancer (specifically, non-small Cell lung cancer), colorectal cancer, melanoma, pancreatic cancer and/or its metastasis. A compound of the formula (I) for use according to any one of claims 1 to 22, wherein the hyperproliferative and/or angiogenic disorder is breast cancer, prostate cancer, multiple myeloma, hepatocellular carcinoma, lung cancer (specifically, non-small Cell lung cancer), colorectal cancer, melanoma, pancreatic cancer are associated with bone metastasis. A compound of formula (I), as used in any one of claims 1 to 22, wherein the hyperproliferative and/or angiogenic disorder has a PTEN loss or a PIK3CA mutation and a locally advanced or metastatic endometrial or breast cancer of the KRAS wild type Or indolent non-Hodgkin's lymphoma (iNHL). Use of a compound of formula (I) according to any one of claims 1 to 7 for the manufacture of a medicament for preventing or treating a hyperproliferative and/or angiogenic disorder, wherein in each administration cycle A compound of formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, is administered for a period of from 1 to 5 days, followed by a period of from 3 to 6 days. The compound of formula (I) is administered or a placebo is administered. The use of the compound of the formula (I) of claim 28, wherein the compound of the formula (I) is administered for a period of one day in each administration cycle, and then the formula is not administered for a period of from 3 to 6 days ( I) Compound or placebo. The use of a compound of formula (I) of claim 28, wherein in each of the administration cycles The compound of formula (I) is administered for a period of 2 days, followed by administration of the compound of formula (I) or administration of a placebo over a period of 3 to 6 days. The use of a compound of the formula (I) of claim 28, wherein the compound of the formula (I) is administered for a period of 3 days in each administration cycle, and then the formula is not administered for a period of 3 to 6 days ( I) Compound or placebo. The use of the compound of the formula (I) of claim 28, wherein the compound of the formula (I) is administered for a period of 4 days in each administration cycle, and then the formula is not administered for a period of 3 to 6 days ( I) Compound or placebo. The use of the compound of the formula (I) of claim 28, wherein the compound of the formula (I) is administered for a period of 5 days in each administration cycle, and then the formula is not administered for a period of 3 to 6 days ( I) Compound or placebo. The use of a compound of formula (I) according to any one of claims 28 to 33, wherein the administration cycle is carried out once, twice, three times or four times. The use of the compound of the formula (I) according to any one of claims 28 to 33, wherein the administration cycle is carried out once, twice, three times or four times, and then not in the interruption period of 4 to 8 days And the compound of formula (I). The use of a compound of formula (I) according to any one of claims 28 to 35, wherein the compound of formula (I) is administered in a total amount of from about 200 mg to about 1000 mg in each administration cycle. The use of a compound of formula (I) according to any one of claims 28 to 36, wherein the compound of formula (I) is administered in a total amount of from about 400 mg to about 800 mg in each administration cycle. The use of a compound of formula (I) according to any one of claims 28 to 37, wherein the compound of formula (I) is administered in an amount of from about 50 mg/day to about 400 mg/day on the date of administration. The use of a compound of formula (I) according to any one of claims 28 to 38, wherein the compound of formula (I) is administered in an amount of from about 100 mg/day to about 400 mg/day on the date of administration. The use of a compound of formula (I) according to any one of claims 28 to 39, in combination with one or more other active ingredients selected from the group consisting of taxanes such as docetaxel Race, paclitaxel or paclitaxel; epothilones, such as ixabepilone, paclipirone or sagopirone; mitoxantrone; prednisolone; dexamethasone; estramustine; vinblastine; Vincristine; doxorubicin; doxorubicin; idarubicin; daunorubicin; bleomycin; etoposide; cyclophosphamide; ifosfamide; procarbazine; melphalan; 5-fluorouracil; capecitabine; fludarabine; cytarabine; Ara-C; 2-chloro-2'-deoxyadenosine; thioguanine; antiandrogen, such as flutamide, acetate ring Progesterone or bicalutamide; bortezomib; platinum derivatives such as cisplatin or carboplatin; chlorambucil; methotrexate; rituximab; and alkaline earth radioactive radium-223 Acceptable salt. The use of a compound of formula (I) according to any one of claims 28 to 40, in combination with an anti-hyperproliferative, cytotoxic and cytostatic agent selected from the group consisting of 5-FU or 5-FU Drugs such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT or S-1; platinum-based antitumor agents such as oxaliplatin, cisplatin or Carboplatin; and a taxane such as docetaxel or paclitaxel; or a combination thereof. The use of a compound of formula (I) according to any one of claims 28 to 41, in combination with a pharmaceutically acceptable salt of the alkaline earth radioactive seed radium-223, such as radium dichloride-223. The use of a compound of formula (I) according to any one of claims 28 to 42, wherein the compound of formula (I) is administered simultaneously, concomitantly, separately or sequentially with the other one or more other active ingredients. The use of a compound of formula (I) according to any one of claims 28 to 42, wherein the hyperproliferative and/or angiogenic disorder is uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cells An inflammatory response, more specifically a condition mediated by the phospholipid inositol-3-kinase (PI3K) pathway, and even more specifically a hematological tumor, a solid tumor, and/or its metastasis, such as leukemia and myelodysplasia Syndrome, malignant lymphoma, head and neck tumors (including brain tumors and brain metastases), chest tumors (including non-small cell and small cell lung tumors), gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors (including Kidney tumors, bladder tumors and prostate tumors), skin tumors and sarcomas and/or their metastases. The use of a compound of formula (I) according to any one of claims 28 to 42, wherein the hyperproliferative and/or angiogenic disorder is gastric cancer. The use of a compound of formula (I) according to any one of claims 28 to 42, wherein the hyperproliferative and/or angiogenic disorder is breast cancer, prostate cancer, multiple myeloma, hepatocellular carcinoma, lung cancer (specifically Small cell lung cancer), colorectal cancer, melanoma, pancreatic cancer, and/or its metastasis. The use of a compound of formula (I) according to any one of claims 28 to 42, wherein the hyperproliferative and/or angiogenic disorder is breast cancer, prostate cancer, multiple myeloma, hepatocellular carcinoma, lung cancer (specifically Small cell lung cancer), colorectal cancer, melanoma, pancreatic cancer with bone metastasis. The use of a compound of formula (I) according to any one of claims 28 to 42, wherein the hyperproliferative and/or angiogenic disorder has a PTEN loss or a PIK3CA mutation and a locally advanced or metastatic endometrium of the KRAS wild type or Breast cancer or slow progression of non-Hodgkin's lymphoma (iNHL). A method of preventing or treating a hyperproliferative and/or angiogenic disorder comprising administering a compound of formula (I), or a stereoisomer thereof, according to claims 1 to 7 to a patient suffering from the disorder in each administration cycle a tautomer, an N-oxide, a hydrate, a solvate or a salt or a mixture thereof for a period of from 1 to 5 days, followed by not administering the compound of formula (I) or for a period of from 3 to 6 days With placebo. The method of claim 49, wherein the compound of formula (I) is administered for a period of one day in each administration cycle, and then the compound of formula (I) is not administered or administered over a period of from 3 to 6 days. Placebo. The method of claim 49, wherein the compound of formula (I) is administered for a period of 2 days in each administration cycle, followed by not administering the compound of formula (I) or administering for a period of 3 to 6 days. Placebo. The method of claim 49, wherein the compound of formula (I) is administered for a period of 3 days in each administration cycle, followed by not administering the compound of formula (I) or administering for a period of 3 to 6 days. Placebo. The method of claim 49, wherein the compound of formula (I) is administered for a period of 4 days in each administration cycle, followed by not administering the compound of formula (I) or administering for a period of 3 to 6 days. Placebo. The method of claim 49, wherein the compound of formula (I) is administered for a period of 5 days in each administration cycle, followed by not administering the compound of formula (I) or administering for a period of 3 to 6 days Placebo. The method of any one of claims 49 to 54, wherein the administration cycle is performed once, twice, three times or four times. The method of any one of claims 49 to 54, wherein the administration cycle is performed once, twice, three times or four times, and then the formula (I) is not administered during the interruption period of 4 to 8 days Compound. The method of any one of claims 49 to 56, wherein the compound of formula (I) is administered in a total amount of from about 200 mg to about 1000 mg in each administration cycle. The method of any one of claims 49 to 57, wherein the compound of formula (I) is administered in a total amount of from about 400 mg to about 800 mg in each administration cycle. The method of any one of claims 49 to 58, wherein the compound of formula (I) is administered in an amount of from about 50 mg to about 400 mg per day on the date of administration. The method of any one of claims 49 to 59, wherein the compound of formula (I) is administered in an amount of from about 100 mg to about 400 mg per day on the date of administration. The method of any one of claims 49 to 60, wherein the compound of formula (I) is associated with one or A combination of other active ingredients selected from the group consisting of taxanes such as docetaxel, paclitaxel or paclitaxel; epothilones such as ixabepilone, paclipirone or chagopiride;泼;prednisolone; dexamethasone; estramustine; vinblastine; vincristine; doxorubicin; doxorubicin; idarubicin; daunorubicin; bleomycin; etoposide Cyclophosphamide; ifosfamide; procarbazine; melphalan; 5-fluorouracil; capecitabine; fludarabine; cytarabine; Ara-C; 2-chloro-2'- Deoxyadenosine; thioguanine; antiandrogen, such as flutamide, cyproterone acetate or bicalutamide; bortezomib; platinum derivative, such as cisplatin or carboplatin; chlorambucil; Methotrexate; rituximab; and a pharmaceutically acceptable salt of an alkaline earth radioactive seed radium-223. The method of any one of claims 49 to 60, wherein the compound of formula (I) is administered in combination with an anti-hyperproliferative agent, a cytotoxic agent and a cytostatic agent selected from the group consisting of 5-FU or 5-FU Prodrugs such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT or S-1; platinum-based antitumor agents, such as oxaliplatin, cisplatin Or carboplatin; and a taxane such as docetaxel or paclitaxel; or a combination thereof. The method of any one of claims 49 to 60, wherein the compound of formula (I) is administered in combination with a pharmaceutically acceptable salt of the alkaline earth radioactive seed radium-223, such as radium dichloride-223. The method of any one of claims 49 to 63, wherein the compound of formula (I) is administered simultaneously, concomitantly, separately or sequentially with the other one or more other active ingredients. The method of any one of claims 49 to 64, wherein the hyperproliferative and/or angiogenic disorder is a disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response, Specifically, a condition mediated by the phospholipid inositol-3-kinase (PI3K) pathway, even more specifically a hematological tumor, a solid tumor, and/or a metastasis thereof, such as leukemia and myelodysplastic syndrome, malignant lymphoid Baroma, head and neck tumors (including brain tumors and brain metastases), chest tumors (including non-small cell and small cell lung tumors), gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors (including kidney tumors, Bladder tumors and prostate tumors, skin tumors and sarcomas and/or their metastases. The method of any one of claims 49 to 64, wherein the hyperproliferative and/or angiogenic disorder is gastric cancer. The method of any one of claims 49 to 64, wherein the hyperproliferative and/or angiogenic disorder is breast cancer, prostate cancer, multiple myeloma, hepatocellular carcinoma, lung cancer (specifically, non-small cell lung cancer), colon Rectal cancer, melanoma, pancreatic cancer and/or its metastasis. The method of any one of claims 49 to 64, wherein the hyperproliferative and/or angiogenic disorder is breast cancer, prostate cancer, multiple myeloma, hepatocellular carcinoma, lung cancer (specifically, non-small cell lung cancer), colon Rectal cancer, melanoma, and pancreatic cancer are associated with bone metastasis. The method of any one of claims 49 to 64, wherein the hyperproliferative and/or angiogenic disorder has a PTEN loss or a PIK3CA mutation and a locally advanced or metastatic endometrial or breast cancer of the KRAS wild type or a slow progression Jajin's lymphoma (iNHL).