HK1194995B

HK1194995B - Use of substituted 2,3-dihydroimidazo[1,2-c]quinazolines

Info

Publication number: HK1194995B
Application number: HK14108442.1A
Authority: HK
Inventors: 刘宁姝; C‧施奈德
Original assignee: Bayer Intellectual Property Gmbh
Priority date: 2011-04-05
Filing date: 2012-03-29
Publication date: 2018-06-15

Description

use of substituted 2, 3-dihydroimidazo [1,2-C ] quinazolines

The present invention relates to:

-use of a 2, 3-dihydroimidazo [1,2-c ] quinazoline compound or a pharmaceutical composition comprising the same as the only active agent or a) a combination of said compound or a pharmaceutical composition comprising said compound and b) one or more other active agents in the manufacture of a medicament for the treatment or prevention of cancer, such as breast cancer, which is clinically divided into several subtypes, such as hormone receptor positive breast cancer, Her2 receptor positive breast cancer, triple negative breast cancer (triple negative breast cancer) and inflammatory breast cancer;

-a combination of a) said compound and b) one or more other active agents;

-a pharmaceutical composition for the treatment of cancer comprising said compound as the only active agent;

-a pharmaceutical composition comprising a combination of a) said compound and b) one or more other active agents;

-use of biomarkers involved in modification of Bcl expression, HER family expression and/or activation, PIK3CA signalling (signaling) and/or PTEN loss for predicting sensitivity and/or tolerance of a cancer patient to said compound and providing a theory-based (ratinoale-based) synergistic combination as defined herein to increase sensitivity and/or overcome tolerance; and

-a method of determining the levels of components of one or more of Bcl expression, HER family expression and/or activation, PIK3CA signaling, and/or PTEN loss.

Background

The concept of developing anti-cancer drugs targeting aberrantly active protein kinases has met with much success over the last decade. In addition to the role of protein kinases, lipid kinases also play an important role in generating the second messengers of critical regulation. The PI3K family of lipid kinases produces 3' -phosphoinositides that bind to and activate a variety of cellular targets, initiating a broad signal transduction cascade (Vanhaaesebroeck et al, 2001; Toker,2002; Pendaries et al, 2003; Downes et al, 2005). These cascades ultimately induce changes in a variety of cellular processes including cell proliferation, cell survival, differentiation, vesicle trafficking (vesicle trafficking), migration, and chemotaxis.

PI3K can be classified into three different categories based on differences in structure and substrate preference. Although members of the class II family of PI3K have been implicated in the regulation of tumor growth (Brown & Shepherd,2001; Trater et al, 2006), most studies have focused on class I enzymes and their role in cancer (Vivanco & Sawyers,2002; Workman,2004; Chen et al, 2005; Hennessy et al, 2005; Cully et al, 2006).

Class I PI3K is generally divided into two distinct subclasses based on differences in protein subunit composition. I th_API 3K-like class consists of catalytic p110 catalytic subunits (p110 α, p110 β or p 110. gamma.) heterodimerizing with members of the p85 regulatory subunit family_BPI 3-like 3K catalytic subunit (p 110. gamma.) heterodimerization with a different p101 regulatory subunit (Vanhaaesebroeck)&Waterfield,1999; Funaki et al, 2000; Katso et al, 2001). The C-terminal region of these proteins contains a catalytic domain with a homology to the protein kinase. PI3K gamma structure and I_AClass p110 is similarBut lacks the N-terminal p85 binding site (Domin)&Waterfield, 1997). Although similar in overall structure, homology between catalytic p110 subunits is low to moderate. The highest homology between PI3K subtypes is in the kinase pocket (kinase pocket) of the kinase domain.

Class I PI3K subtypes are associated with activated Receptor Tyrosine Kinases (RTKs) (including PDGFR, EGFR, VEGFR, IGF1-R, c-KIT, CSF-R, and Met), cytokine receptors, GPCRs, integrins, or with tyrosine phosphorylation adaptor proteins (e.g., Grb2, Cbl, IRS-1, or Gab1) through their p85 regulatory subunits that produce stimulation of lipid kinase activity. Activation of lipid kinase activity of the p110 β and p110 γ subtypes has been demonstrated to occur in response to binding of activated forms of the ras oncogene (Kodaki et al, 1994). Indeed, the oncogenic activity of these subtypes may require binding to ras (Kang et al, 2006). In contrast, p110 α and p110 subtypes exhibit oncogenic activity through constitutive activation of Akt, independent of ras binding.

Class I PI3K catalyzing PI (4,5) P₂[PIP₂]To PI (3,4,5) P₃[PIP₃]The transformation of (3). PIP produced by PI3K₃Affecting a number of signal transduction processes that regulate and coordinate the biological endpoints of cell proliferation, cell survival, differentiation, and cell migration. PIP3 is bound via Pleckstrin-homology (PH) domain-containing proteins, including phosphoinositide-dependent kinase, PDK1 and Akt proto-oncogene products, that localize these proteins in the active signaling region and also directly facilitate their activation (Klippel et al, 1997; Fleming et al, 2000; Itoh;)&Takenawa,2002; Lemmon, 2003). Co-localization (co-localization) of PDK1 with Akt promotes phosphorylation and activation of Akt. Akt at Ser⁴⁷³The carboxyl terminal phosphorylation of (A) promotes Thr³⁰⁸Phosphorylation in the Akt activation cycle (Chan)&Tsichlis,2001; Hodgkinson et al, 2002; Scheid et al, 2002; Hresko et al, 2003). Once activated, Akt phosphorylates and regulates a variety of regulatory kinases that directly influence pathways of cell cycle progression and cell survival.

Many of the effects of Akt activation are influenced by its paradoxDown-regulation of pathways that are responsive to cell survival and are often dysregulated in cancer. Akt promotes tumor cell survival by modulating the composition of apoptotic and cell cycle mechanisms. Akt is one of several kinases that phosphorylate and inactivate pro-apoptotic BAD proteins (del Peso et al, 1997; Pasorino et al, 1999). Akt can also be induced by placing caspase 9 at Ser¹⁹⁶Up-phosphorylation to block cytochrome C-dependent caspase activation, thereby promoting cell survival (Cardone et al, 1998).

Akt affects gene transcription at various levels. MDM2E3 ubiquitin ligase at Ser¹⁶⁶And Ser¹⁸⁶Akt-mediated phosphorylation on MDM2 promotes nuclear import and formation and activation of the ubiquitin ligase complex. Nuclear MDM2 targets p53 tumor inhibitors for degradation (a process that can be blocked by LY 294002) (Yap et al, 2000; Ogawara et al, 2002). Down-regulation of p53 by MDM2 negatively affects p 53-regulated pro-apoptotic genes (e.g., Bax, Fas, PUMA, and DR5), cell cycle inhibitors p21^Cip1And PTEN tumor suppressor transcription (Momand et al, 2000; Hupp et al, 2000; Mayo et al, 2002; Su et al, 2003). Similarly, Akt-mediated phosphorylation of the Forkhead transcription factors FKHR, FKHRL and AFX (Kops et al, 1999; Tang et al, 1999) promotes their binding to 14-3-3 proteins and export from the nucleus to the cytosol (Brunet et al, 1999). This functional inactivation of Forkhead activity also affects the transcription of pro-apoptotic and pro-angiogenic genes, including Fas ligand (cieshomska et al, 2003), Bim (pro-apoptotic Bcl-2 family members) (Dijkers et al, 2000), and angiopoietin-1 (Ang-1) antagonist Ang-2(Daly et al, 2004). Forkhead transcription factor regulating cyclin dependent kinase (Cdk) inhibitor p27^Kip1Expression of (2). Indeed, it has been demonstrated that PI3K inhibitors induce p27^Kip1Expression, leading to Cdk1 inhibition, cell cycle arrest and apoptosis (Dijkers et al, 2000). Akt also reported p21^Cip1Thr of (A) to¹⁴⁵And p27^Kip1Thr of (A) to¹⁵⁷Phosphorylation, facilitating their association with the 14-3-3 protein, leading to nuclear transport and cytoplasmic retention, preventing their inhibition of nuclear Cdks (Zhou et al, 2001; Motti et al, 2004; Sekimot et alo et al, 2004). In addition to these effects, Akt phosphorylates IKK (Romashkova)&Makarov,1999), leads to phosphorylation and degradation of I κ B and subsequent nuclear translocation of NF κ B, resulting in surviving genes such as IAP and Bcl-X_LExpression of (2).

The PI3K/Akt pathway also passes through JNK and p38 associated with apoptosis induction^MAPKMAP kinase is associated with apoptosis inhibition. Akt is hypothesized to regulate kinases (apoptosis signal regulating kinase 1(ASK1) by two JNK/p38 (Kim et al, 2001; Liao)&The phosphorylation and inhibition of Hung,2003; Yuan et al, 2003) and mixed lineage kinase (mixed linkage kinase)3(MLK3) (Lopez-Ilasaca et al, 1997; Barthwal et al, 2003; Figueroa et al, 2003)) inhibits JNK and p38MAPK signaling. P38 was observed in tumors treated with cytotoxic agents^MAPKInduction of Activity, and those that induce cell death are required (in Olson&Halahan, reviewed in 2004). Thus, inhibitors of the PI3K pathway may promote the activity of co-administered cytotoxic drugs.

Other roles of PI3K/Akt signaling involve the modulation of cell cycle progression through modulation of glycogen synthase kinase 3(GSK3) activity. GSK3 activity is elevated in quiescent cells where it renders cyclin D₁Ser on²⁸⁶Phosphorylate, target proteins for ubiquitination and degradation (Diehl et al, 1998) and block entry into the S-phase. Akt is mediated through Ser⁹Inhibits GSK3 activity (Cross et al, 1995). This results in cyclin D promoting cell cycle progression₁Inhibition of GSK3 activity also affects cell proliferation through activation of the wnt/β -catenin signaling pathway (Abbosh)&Akt-mediated phosphorylation of GSK3 leads to stabilization and nuclear localization of β -catenin, which in turn leads to increased expression of c-myc and cyclin D1 (a target of the β -catenin/Tcf pathway), Nephew,2005; Naito et al, 2005; Wilker et al, 2005; Segrelles et al, 2006).

Although PI3K signaling is utilized by many signaling networks associated with oncogenes and tumor suppressors, PI3K and its activity are directly associated with cancer. Overexpression of the p110 α and p110 β subtypes has been observed in bladder and colon tumors as well as cell lines, and is often associated with increased PI3K activity (bnistant et al, 2000). Overexpression of p110 α has been reported in ovarian and cervical tumors and tumor cell lines as well as in squamous cell lung cancer. Overexpression of p110 α in cervical and ovarian tumor cell lines has been associated with increased PI3K activity (Shayesteh et al, 1999; Ma et al, 2000). Increased PI3K activity has been observed in colorectal cancer (Phillips et al, 1998), and increased expression has been observed in breast cancer (Gershtein et al, 1999).

In recent years, somatic mutations in the gene encoding p110 α (PIK3CA) have been identified in a variety of cancers. The data collected to date indicate mutations in approximately 32% of colorectal cancers (Samuels et al, 2004; Ikenoue et al, 2005), 18-40% of breast cancers (Bachman et al, 2004; Campbell et al, 2004; Levine et al, 2005; Saal et al, 2005; Wu et al, 2005), 27% of glioblastomas (Samuels et al, 2004; Hartmann et al, 2005; Gallia et al, 2006), 25% of gastric cancers (Samuels et al, 2004; Byun et al, 2003; Li et al, 2005), 36% of hepatocellular carcinomas (Lee et al, 2005), 4-12% of ovarian cancers (Levine et al, 2005; Wang et al, 2006), 4% of lung cancers (Samuels et al, 2004; Whyte & Holbeck, 2005), and up to 40% of endometrial cancers (Oda et al, 3 CA). PIK3CA mutations have been reported in oligodendrogliomas (oligodendromas), astrocytomas, medulloblastomas, and thyroid tumors (Broderick et al, 2004; Garcia-Rostan et al, 2005). Based on the high frequency of mutations observed, PIK3CA is one of the two most frequently mutated genes associated with cancer, while the other is K-ras. More than 80% of the PIK3CA mutations cluster in two regions of the protein, the helical domain (E545K) and the catalytic domain (H1047R). Biochemical analysis and protein expression studies have demonstrated that both of these mutations result in increased constitutive p110 α catalytic activity and are carcinogenic in nature (Bader et al, 2006; Kang et al, 2005; Samuels & Ericson, 2006). PIK3CA knock-out mouse embryonic fibroblasts have recently been reported to be deficient in signal transduction downstream of various growth factor receptors (IGF-1, insulin, PDGF, EGF) and to be resistant to transformation by various oncogenic RTKs (IGFR, wild-type EGFR and EGFR, i.e., somatic mutation of Her 2/Neu) (Zhao et al, 2006).

Functional studies of PI3K in vivo have shown that siRNA-mediated down-regulation of p110 β inhibits both Akt phosphorylation and HeLa cell tumor growth in nude mice (Czauderna et al, 2003). In similar experiments, siRNA-mediated down-regulation of p110 β has also been shown to inhibit growth of malignant glioma cells in vitro and in vivo (Pu et al, 2006). Inhibition of PI3K function by a dominant negative p85 regulatory subunit blocks mitogenesis and cell transformation (Huang et al, 1996; Rahimi et al, 1996). A number of somatic mutations in the genes encoding the p85 α and p85 β regulatory subunits of PI3K, which lead to increased 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 block mitogenesis and can induce apoptosis in vitro (Roche et al, 1994; Roche et al, 1998; Benistant et al, 2000). In vivo proof of principle (proof-of-principle) studies using PI3K inhibitors LY294002 and wortmannin have shown that PI3K signaling slows tumor growth in vivo (Powis et al, 1994; Schultz et al, 1995; Semba et al, 2002; Ihle et al, 2004).

Overexpression of class I PI3K activity or stimulation of their lipid kinase activity has been associated with tolerance to targeted (e.g., imatinib and trastuzumab) and cytotoxic chemotherapy approaches as well as 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 demonstrated that activation of PI3K results in the expression of multiple drug resistance protein-1 (MRP-1) in prostate cancer cells and subsequent induction of resistance to chemotherapy (Lee et al, 2004).

The importance of PI3K signaling in tumorigenesis is further underscored by the following findings: the PTEN tumor inhibitor PI (3) P phosphatase belongs to the most frequently inactivated gene of human cancers (Li et al, 1997; Steck et al, 1997; Ali et al, 1999; Ishii et al, 1999). PTEN makes PI (3,4,5) P₃Dephosphorizing to PI (4),5)P₂Thereby antagonizing PI 3K-dependent signaling. Cells containing functionally inactivated PTEN with elevated PIP₃Horizontal, high levels of PI3K signaling activity (Haas-Kogan et al, 1998; Myers et al, 1998; Taylor et al, 2000), increased proliferative potential, and reduced sensitivity to pro-apoptotic stimuli (Stambolic et al, 1998). Reconstitution of functional PTEN inhibits PI3K signaling (Taylor et al, 2000), inhibits cell growth and re-sensitizes cells to pro-apoptotic stimuli (Myers et al, 1998; Zhao et al, 2004). Similarly, functional repair of PTEN in tumors lacking functional PTEN inhibits tumor growth in vivo (Stahl et al, 2003; Su et al, 2003; Tanaka)&Grossman,2003) and sensitising the cells to cytotoxic agents (Tanaka)&Grossman,2003)。

The class I PI3K family clearly plays an important role in the regulation of multiple signal transduction pathways that promote cell survival and cell proliferation, and activation of their lipid kinase activity contributes significantly to the development of human malignancies. In addition, inhibition of PI3K could potentially overcome cellular mechanisms that cause resistance to chemotherapeutic agents. Thus, potent inhibitors of class I PI3K activity in vivo have the potential to not only inhibit tumor growth but also sensitize tumor cells to pro-apoptotic stimuli.

In inflammatory diseases, signal transduction pathways originating at chemoattractant receptors are considered to be important targets for controlling leukocyte mobility. Leukocyte transfer is controlled by chemoattractant factors, which activate the heterotrimeric GPCR and thereby trigger a variety of downstream intracellular events. Cause free Ca²⁺Migration, cytoskeletal reorganization and directed movement signal transduction following one of these pathways relies on a second lipid-derived signal generated by PI3K activity (Wymann et al, 2000; Stein and Waterfield, 2000).

PI3K γ regulates cAMP baseline levels in cells and controls contractility. Recent studies have shown that changes in the baseline level of cAMP contribute to increased contractility in mutant mice. Thus, this study suggests that PI3K γ inhibitors could potentially treat congestive heart failure, ischemia, pulmonary hypertension, renal failure, cardiac hypertrophy, atherosclerosis, thromboembolism, and diabetes.

PI3K inhibitors are expected to block signal transduction from GPCRs and block activation of a variety of immune cells, leading to a broad anti-inflammatory spectrum with potential for the treatment of inflammatory and immunoregulatory diseases, including asthma, atopic dermatitis, rhinitis, allergic diseases, Chronic Obstructive Pulmonary Disease (COPD), septic shock, arthropathies, autoimmune disorders such as rheumatoid arthritis and graves' disease, diabetes, cancer, myocardial contractile disorders, thromboembolism and atherosclerosis.

Breast cancer is a worldwide health problem, and in american women, the disease is the second most common cause of cancer death. In the united states, approximately 1 out of every 8 women will have invasive breast cancer (invasive breast cancer) throughout their lifetime. In 2010, it was expected that 207,090 new cases of invasive breast cancer and 54,010 new cases of non-invasive breast cancer could be predicted to be diagnosed. In 2010, approximately 39,840 women were expected to die of breast cancer. Classification and treatment selection are generally based on receptor status. The three most important in the current classification are the Estrogen Receptor (ER), the Progesterone Receptor (PR) and HER 2/neu. Cells with or without these receptors are called ER positive (ER +), ER negative (ER-), PR positive (PR +), PR negative (PR-), HER2 positive (HER2+) and HER2 negative (HER 2-). Cells that do not carry these receptors at all are called basal-like (basal-like) or triple negative (triple negative). Recently DNA-based classification has also been used in the clinic. Such as specific DNA mutations or gene expression characteristics recognized in cancer cells, this classification can guide the selection of treatments (either by targeting these changes, or by predicting from the DNA characteristics which non-targeted therapy is most effective).

It has been found that in human breast cancer, the frequently activated and/or mutated PI3K/PTEN/AKT pathway contributes to the development and progression of breast cancer and drug resistance. Since genetic alterations in PIK3CA and PTEN and activation of the PI3K pathway are observed in almost all breast cancer subtypes (e.g., HER2 positive, hormone receptor positive, or triple negative breast cancer), it is important to clearly develop strategies for PI3K pathway inhibitors of breast cancer. Accordingly, the present invention identifies molecular markers that predict the sensitivity and/or resistance of cancer patients to PI3K inhibitors described herein. In addition, the present invention relates to the identification of drug resistance mechanisms, thereby providing a theory-based synergistic combination to overcome drug resistance.

To the best of the applicant's knowledge, there is no specific disclosure in the prior art of 2, 3-dihydroimidazo [1,2-c ] quinazoline compounds that are effective in the treatment or prevention of inflammatory, triple negative, Her2 receptor positive and hormone receptor positive breast cancers.

It has been found (and this is the basis of the present invention) that 2, 3-dihydroimidazo [1,2-c ] quinazoline compounds as described and defined herein exhibit a beneficial effect in the treatment or prevention of breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer and hormone receptor positive breast cancer.

Thus, according to a first aspect, the present invention relates to the use of a 2, 3-dihydroimidazo [1,2-c ] quinazoline compound, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, or a pharmaceutical composition comprising such a compound, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as the sole active agent in the manufacture of a medicament for the treatment or prevention of cancer (such as breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer and hormone receptor positive breast cancer).

According to a second aspect, the invention relates to a combination of:

a) a 2, 3-dihydroimidazo [1,2-c ] quinazoline compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; and

b) one or more further active agents, in particular active agents selected from the group consisting of antiangiogenic agents, anti-hyperproliferative agents, anti-inflammatory agents, analgesics, immunomodulatory agents, diuretic agents, antiarrhythmic agents, antihypercholesterolemic agents, antilipidemic agents, antidiabetic agents or antiviral agents, more in particular one or more further active agents selected from the group consisting of:

bcl inhibitors, such as ABT-737, ABT-263(Navitoclax), EM20-25, YC137, GX-015-070 (Obakura), titrocaricin A (Tetrocarin A), UCB-1350883, AT-101((-) -gossypol), SPC-2004 (Belannono), IG-105, WL-276, BI-97C1, I-VRL (Immunovivorebine), DATS (allicin), CNDO-103 (apogossypol), D-G-3139 (Gennases)), Evotec, PIB-1402, EU-517;

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides (antisense oligonucleotides), such as BclKlex; and

mTOR pathway inhibitors, such as rapamycin or rapamycin analogues, e.g. rapamycin (sirolimus), everolimus (RAD-001, Afinitor), azolosprolimus (ABT-578, Endeavor), Temisirolimus (Temisirolimus) (CCI-779, Torisel (torasel)), ridaforolimus (AP-23576, MK-8669), TAFA-93; or mTOR kinase inhibitors, such as WYE-132, OSI-027, INK-128, OSI-027, AZD-2014, AZD-8055, CC-223, ABI-009, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKI-402, SB-2015, WYE-354, KU-0063794, X-387, BEZ-235.

According to a third aspect, the present invention relates to a pharmaceutical composition comprising as sole active agent a 2, 3-dihydroimidazo [1,2-c ] quinazoline compound, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, for use in the treatment of cancer (such as breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer and hormone receptor positive breast cancer).

According to a fourth aspect, the present invention relates to a pharmaceutical composition comprising a combination of:

bcl inhibitors, such as ABT-737, ABT-263(Navitoclax), EM20-25, YC137, GX-015-070 (Obakura), titricin A, UCB-1350883, AT-101((-) -gossypol), SPC-2004 (Belanoxanol), IG-105, WL-276, BI-97C1, I-VRL (Immunovivorebine), DATS (allicin), DO-103 (apogossypol), D-G-3139 (Netsu), Emotec, PIB-1402, EU-517;

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

mTOR pathway inhibitors, such as rapamycin or rapamycin analogues, e.g. rapamycin (sirolimus), everolimus (RAD-001, Afinitor), oxazololimus (ABT-578, Endeavor), temsirolimus (CCI-779, temsirolimus), diphospholimus (AP-23576, MK-8669), TAFA-93; or mTOR kinase inhibitors, such as WYE-132, OSI-027, INK-128, OSI-027, AZD-2014, AZD-8055, CC-223, ABI-009, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKI-402, SB-2015, WYE-354, KU-0063794, X-387, BEZ-235.

According to a fifth aspect, the present invention relates to the use of a combination of:

a) a 2, 3-dihydroimidazo [1,2-c ] quinazoline compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;

or a pharmaceutical composition comprising such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;

and

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

According to a sixth aspect, the present invention relates to the use of biomarkers involved in the modification of Bcl expression, HER family expression and/or activation, PIK3CA signalling and/or PTEN deletion for predicting the sensitivity and/or tolerance of a cancer (such as breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, HER2 receptor positive breast cancer and hormone receptor positive breast cancer) patient to a 2, 3-dihydroimidazo [1,2-c ] quinazoline compound as defined herein, to provide a theory-based synergistic combination as defined herein to overcome tolerance (patient stratification).

According to a seventh aspect, the invention relates to a method of determining the levels of components of one or more of Bcl expression, HER family expression and/or activation, PIK3CA signaling, and/or PTEN deletion, wherein:

in the expression of Bcl, the component is for example Bcl,

-in said HER family expression and/or activation, PIK3CA signalling, said component is for example EGF-R, and

in the PTEN absence, the component is, for example, PTEN.

According to a particular embodiment of any of the above aspects of the invention, the breast cancer is inflammatory breast cancer.

According to a particular embodiment of any of the above aspects of the invention, the breast cancer is triple negative breast cancer.

According to a particular embodiment of any of the above aspects of the invention, the breast cancer is Her2 receptor positive breast cancer.

According to a particular embodiment of any of the above aspects of the invention, the breast cancer is hormone receptor positive breast cancer.

Detailed Description

The present invention relates in a first aspect to a compound of general formula (a) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as sole active agent:

wherein:

x represents CR⁵R⁶Or NH;

Y¹represents CR³Or N;

the chemical bond between represents a single bond or a double bond, with the proviso that whenWhen representing a double bond, Y²And Y³Independently represent CR⁴Or N, and whenWhen represents a single bond, Y²And Y³Independently represent CR³R⁴Or NR⁴；

Z¹、Z²、Z³And Z⁴Independently represent CH and CR²Or N;

R¹represents aryl, optionally having 1-3 substituents selected from R¹¹、C_3-8Cycloalkyl (optionally having 1-3 substituents selected from R)¹¹A substituent of (1); c_1-6Alkyl optionally substituted by aryl, heteroaryl, C_1-6Alkoxyaryl, aryloxy, heteroaryloxy or substituted with one or more halogens; c_1-6Alkoxy optionally substituted by carboxy, aryl, heteroaryl, C_1-6Alkoxyaryl, aryloxy, heteroaryloxy or substituted with one or more halogens; or a saturated or unsaturated 3-15 membered monocyclic or bicyclic heterocycle optionally having 1-3 substituents selected from R¹¹And contains 1 to 3 heteroatoms selected from N, O and S,

wherein

R¹¹Represents halogen, nitro, hydroxy, cyano, carboxyl, amino, N- (C)_1-6Alkyl) amino, N- (hydroxy C)_1-6Alkyl) amino, N-di (C)_1-6Alkyl) amino, N- (C)_1-6Acyl) amino, N- (formyl) -N- (C)_1-6Alkyl) amino, N- (C)_1-6Alkanesulfonyl) amino, N- (carboxy-C)_1-6Alkyl) -N- (C_1-6Alkyl) amino, N- (C)_1-6Alkoxycarbonyl) amino, N- [ N, N-di (C)_1-6Alkyl) aminomethylene]Amino, N- [ N, N-di (C)_1-6Alkyl) amino (C)_1-6Alkyl) methylene]Amino, N- [ N, N-di (C)_1-6Alkyl) amino C_2-6Alkenyl radical]Amino, aminocarbonyl, N- (C)_1-6Alkyl) aminocarbonyl, N-di (C)_1-6Alkyl) aminocarbonyl, C_3-8Cycloalkyl radical, C_1-6Alkylthio radical, C_1-6Alkanesulfonyl, sulfamoyl, C_1-6Alkoxycarbonyl, N-arylamino (wherein the aryl group optionally has 1-3 substituents selected from R)¹⁰¹N- (aryl C)_1-6Alkyl) amino (wherein said aryl group optionally has 1-3 substituents selected from R¹⁰¹Substituent(s) of aryl group C_1-6Alkoxycarbonyl (wherein said aryl optionally has 1-3 substituents selected from R¹⁰¹Substituent of (1)), C)_1-6Alkyl (which is optionally mono-halo, di-halo, tri-halo, amino, N- (C)_1-6Alkyl) amino or N, N-di (C)_1-6Alkyl) amino substitution), C_1-6Alkoxy (which is optionally mono-halo, di-halo, tri-halo, N- (C)_1-6Alkyl) sulfonamido or N- (aryl) sulfonamido), or a 5-7 membered saturated or unsaturated ring having 1-3 heteroatoms selected from O, S and N, and optionally having 1-3 heteroatoms selected from R¹⁰¹The substituent(s) of (a),

wherein

R¹⁰¹Represents halogen, carboxyl, amino, N- (C)_1-6Alkyl) amino, N-di (C)_1-6Alkyl) amino, aminocarbonyl, N- (C)_1-6Alkyl) aminocarbonyl, N-di (C)_1-6Alkyl) aminocarbonyl, pyridinyl, C_1-6Alkyl (optionally substituted with cyano or mono-, di-or trihalo), and C_1-6Alkoxy (optionally substituted by cyano, carboxy, amino, N- (C)_1-6Alkyl radical)Amino, N-di (C)_1-6Alkyl) amino, aminocarbonyl, N- (C)_1-6Alkyl) aminocarbonyl, N-di (C)_1-6Alkyl) aminocarbonyl or mono-, di-, or trihalo substitution);

R²represents hydroxy, halogen, nitro, cyano, amino, N- (C)_1-6Alkyl) amino, N-di (C)_1-6Alkyl) amino, N- (hydroxy C)_1-6Alkyl) amino, N- (hydroxy C)_1-6Alkyl) -N- (C_1-6Alkyl) amino, C_1-6Acyloxy, amino C_1-6Acyloxy, C_2-6Alkenyl, aryl, 5-7 membered saturated or unsaturated heterocyclic ring having 1-3 heteroatoms selected from O, S and N, and optionally substituted by hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy, oxo, amino C_1-6Alkyl, N- (C)_1-6Alkyl) amino, N-di (C)_1-6Alkyl) amino, N- (C)_1-6Acyl) amino, N- (C)_1-6Alkyl) carbonylamino, phenyl C_1-6Alkyl, carboxyl, C_1-6Alkoxycarbonyl, aminocarbonyl, N- (C)_1-6Alkyl) aminocarbonyl or N, N-di (C)_1-6Alkyl) amino, -C (O) -R²⁰)，

Wherein

R²⁰Is represented by C_1-6Alkyl radical, C_1-6Alkoxy, amino, N- (C)_1-6Alkyl) amino, N-di (C)_1-6Alkyl) amino, N- (C)_1-6Acyl) amino, or a 5-7 membered saturated or unsaturated heterocyclic ring having 1-3 heteroatoms selected from O, S and N, and optionally substituted with C_1-6Alkyl radical, C_1-6Alkoxy, oxo, amino, N- (C)_1-6Alkyl) amino, N-di (C)_1-6Alkyl) amino, N- (C)_1-6Acyl) amino, phenyl or benzyl substituted), C_1-6Alkyl (optionally substituted by R)²¹Substituted), or C_1-6Alkoxy (optionally substituted by R)²¹Substitution),

wherein

R²¹Represents cyano, monoHalogen, dihalogen or trihalogen, hydroxy, amino, N- (C)_1-6Alkyl) amino, N-di (C)_1-6Alkyl) amino, N- (hydroxy C)_1-6Alkyl) amino, N- (halophenyl C_1-6Alkyl) amino, amino C_2-6Alkylene, C_1-6Alkoxy, hydroxy C_1-6Alkoxy, -C (O) -R²⁰¹、-NHC(O)-R²⁰¹、C_3-8Cycloalkyl, isoindolinyl, phthalimidyl, 2-oxo-1, 3-oxazolidinyl, aryl or a 5-or 6-membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from O, S and N, and optionally substituted by hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxycarbonyl, hydroxy C_1-6Alkoxy, oxo, amino C_1-6Alkyl, N- (C)_1-6Alkyl) amino, N-di (C)_1-6Alkyl) amino, N- (C)_1-6Acyl) amino or benzyl substitution),

wherein

R²⁰¹Represents a hydroxyl group, an amino group, N- (C)_1-6Alkyl) amino, N-di (C)_1-6Alkyl) amino, N- (halophenyl C_1-6Alkyl) amino, C_1-6Alkyl, amino C_1-6Alkyl, amino C_2-6Alkylene radical, C_1-6Alkoxy, 5-or 6-membered saturated or unsaturated heterocycle (having 1-4 heteroatoms selected from O, S and N, and optionally substituted by hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxycarbonyl, hydroxy C_1-6Alkoxy, oxo, amino, N- (C)_1-6Alkyl) amino, N-di (C)_1-6Alkyl) amino, N- (C)_1-6Acyl) amino or benzyl substitution);

R³represents hydrogen, halogen, aminocarbonyl or C_1-6Alkyl (optionally substituted by aryl C)_1-6Alkoxy or mono-, di-, or trihalo substitution);

R⁴represents hydrogen or C_1-6An alkyl group;

R⁵represents hydrogen or C_1-6An alkyl group; and is

R⁶Represents halogen, hydrogen or C_1-6An alkyl group;

or a combination of:

a) such a 2, 3-dihydroimidazo [1,2-c ] quinazoline compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

mTOR pathway inhibitors, such as rapamycin or rapamycin analogues, e.g. rapamycin (sirolimus), everolimus (RAD-001, Afinitor), oxazololimus (ABT-578, Endeavor), temsirolimus (CCI-779, temsirolimus), diphospholimus (AP-23576, MK-8669), TAFA-93; or mTOR kinase inhibitors, such as WYE-132, OSI-027, INK-128, OSI-027, AZD-2014, AZD-8055, CC-223, ABI-009, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKI-402, SB-2015, WYE-354, KU-0063794, X-387, BEZ-235;

or a pharmaceutical composition comprising such a combination,

for the manufacture of a medicament for the treatment or prevention of cancer, such as breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer and hormone receptor positive breast cancer.

In a particular embodiment of the above first aspect, the present invention relates to as the only active agent a compound selected from the group consisting of:

n- (7, 8-dimethoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) nicotinamide;

2- (7, 8-dimethoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -1-pyridin-3-ylethenol;

n- (7, 8-dimethoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -1H-benzimidazole-5-carboxamide;

6- (acetylamino) -N- (7, 8-dimethoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) nicotinamide;

n- {5- [2- (7, 8-dimethoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -1-hydroxyethenyl ] pyridin-2-yl } acetamide;

2- ({5- [ 2-hydroxy-2-pyridin-3-ylvinyl ] -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-8-yl } oxy) -N, N-dimethylacetamide;

2- [ 7-methoxy-8- (tetrahydro-2H-pyran-2-ylmethoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -1-pyridin-3-ylethenol;

2- [8- (2-hydroxyethoxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -1-pyridin-3-ylethenol;

({5- [ 2-hydroxy-2-pyridin-3-ylvinyl ] -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-8-yl } oxy) acetic acid;

4- ({5- [ 2-hydroxy-2-pyridin-3-ylvinyl ] -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-8-yl } oxy) butyric acid;

({5- [ 2-hydroxy-2-pyridin-3-ylvinyl ] -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-8-yl } oxy) acetonitrile;

2- [ 7-methoxy-8- (2H-tetrazol-5-ylmethoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -1-pyridin-3-ylethenol;

2- [ 7-methoxy-8- (4-morpholin-4-yl-4-oxobutoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -1-pyridin-3-ylethenol;

5- [ 1-hydroxy-2- (8-morpholin-4-yl-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) ethenyl ] pyridin-3-ol;

n- (2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -5-hydroxynicotinamide;

6- (acetylamino) -N- (7, 9-dimethoxy-8-methyl-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) nicotinamide;

n- (8, 9-dimethoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -5-hydroxynicotinamide;

5-hydroxy-N- (7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) nicotinamide;

n- (7, 8-dimethoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -5- [ (4-methoxybenzyl) oxy ] nicotinamide;

n- (7, 8-dimethoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -5-hydroxynicotinamide;

5-hydroxy-N- [8- (trifluoromethyl) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

n- {8- [3- (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) propoxy ] -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } nicotinamide;

n- (7-bromo-8-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) nicotinamide;

6-amino-N- (8-methoxy-2, 3-dihydroimidazo 1,2-c ] quinazolin-5-yl) nicotinamide;

1- (1H-benzoimidazol-5-yl) -2- (8, 9-dimethoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) ethyl enol;

2- (8, 9-dimethoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -1- (2, 4-dimethyl-1, 3-thiazol-5-yl) ethyl enol;

n- (9-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -1H-benzimidazole-5-carboxamide;

n- (8-bromo-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) nicotinamide;

n- (8-bromo-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -1H-benzimidazole-5-carboxamide;

n- (8-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -1H-benzimidazole-5-carboxamide;

n- (8-methyl-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -1H-benzoimidazole-5-carboxamide;

n- [8- (trifluoromethyl) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -1H-benzimidazole-5-carboxamide;

n- (7-fluoro-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -1H-benzimidazole-5-carboxamide;

n- (7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) nicotinamide;

n- (8-chloro-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -1H-benzimidazole-5-carboxamide;

6- (acetylamino) -N- (8-morpholin-4-yl-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) nicotinamide;

1- (1H-benzoimidazol-5-yl) -2- (8-morpholin-4-yl-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) ethyl enol;

n- {5- [ 1-hydroxy-2- (8-morpholin-4-yl-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) vinyl ] pyridin-2-yl } acetamide;

6-methyl-N- (8-morpholin-4-yl-2, 3-dihydroimidazo 1,2-c ] quinazolin-5-yl) nicotinamide;

1- (1H-benzimidazol-5-yl) -2- [8- (4-methylpiperazin-1-yl) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] ethyl enol;

n- (2,3-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -3H-imidazo [4,5-b ] pyridine-6-carboxamide;

n- (7, 8-dimethoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -3H-imidazo [4,5-b ] pyridine-6-carboxamide;

1H-benzoimidazole-5-carboxamide, N- [7- (trifluoromethyl) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -amide;

n- (7, 9-dimethoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -1H-benzimidazole-5-carboxamide;

n- {5- [2- (7, 9-dimethoxy-8-methyl-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -1-hydroxyethenyl ] pyridin-2-yl } acetamide;

n- {5- [2- (7-bromo-9-methyl-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -1-hydroxyethenyl ] pyridin-2-yl } acetamide; and

2- (8, 9-dimethoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -1-pyridin-3-ylethenol;

or a combination of:

a) such a 2, 3-dihydroimidazo [1,2-c ] quinazoline compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; and

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

Another embodiment of the present invention comprises as the only active agent a compound of formula (I) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof:

wherein:

R¹is represented by- (CH)₂)_n-(CHR⁴)-(CH₂)_m-N(R⁵)(R^5’)；

R²Represents an optionally substituted by 1,2 or 3R⁶A group-substituted heteroaryl;

R³represents an alkyl or cycloalkyl group;

R⁴represents hydrogen, hydroxy or alkoxy; and is

R⁵And R^5’May be the same or different and independently represent hydrogen, alkyl, cycloalkylalkyl or alkoxyalkyl; or R⁵And R^5’May form, together with the nitrogen atom to which they are attached, a 3-7 membered nitrogen containing heterocyclic ring, said 3-7 membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur, and optionally substituted with one or more R^6’Substituted by groups; or R⁴And R⁵May form, together with the atoms to which they are attached, a 5-6 membered nitrogen containing heterocyclic ring, said 5-6 membered nitrogen containing heterocyclic ring optionally containing one or more nitrogen, oxygen or sulfur atoms and optionally substituted with one or more R^6’Substituted by groups;

each occurrence of R⁶May be the same OR different and are independently halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclylalkyl, alkyl-OR⁷alkyl-SR⁷alkyl-N (R)⁷)(R^7’) alkyl-COR⁷、-CN、-COOR⁷、-CON(R⁷)(R^7’)、-OR⁷、-SR⁷、-N(R⁷)(R^7’) or-NR⁷COR⁷Each of which may optionally be substituted by one or more R⁸Substituted by groups;

each occurrence of R^6’May be the same OR different and are independently alkyl, cycloalkylalkyl OR alkyl-OR⁷；

Each occurrence of R⁷And R^7’May be the same or different, and is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heterocycle, heterocyclylalkyl, or heteroarylalkyl;

each occurrence of R⁸Independently is nitro, hydroxy, cyano, formyl, acetyl, halogen, amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heterocycle, heterocyclylalkyl, or heteroarylalkyl;

n is an integer from 1 to 4, and m is an integer from 0 to 4, with the proviso that when R is⁴And R⁵When they form a 5-6 membered nitrogen containing ring together with the atoms to which they are attached, n + m is 4 or less;

or a combination of the following:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

In a preferred embodiment, the invention comprises as the only active agent a compound of formula (I) (wherein R is²Is optionally substituted by 1,2 or 3R⁶Group-substituted nitrogen-containing heteroaryl) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;

or a combination of the following:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

In another preferred embodiment, the invention comprises as the only active agent a compound of formula (I) (wherein R is⁵And R^5’Independently alkyl) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;

or a combination of the following:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

In a further preferred embodiment, the invention comprises as the only active agent a compound of formula (I) (wherein R is⁵And R^5’Together with the nitrogen atom to which they are attached form a 5-6 membered nitrogen containing heterocyclic ring, said 5-6 membered nitrogen containing heterocyclic ring containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur, and optionally substituted with one or more R^6’Substituted with groups) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;

or a combination of the following:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

In a further preferred embodiment, the present invention comprises as the only active agent a compound of formula (I) (wherein R is⁴Is hydroxy) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;

or a combination of the following:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

In another preferred embodimentIn one embodiment, the invention includes as the sole active agent a compound of formula (I) (wherein R is⁴And R⁵Together with the atoms to which they are attached form a 5-6 membered nitrogen containing heterocyclic ring, said 5-6 membered nitrogen containing heterocyclic ring optionally containing one or more nitrogen, oxygen or sulfur atoms and optionally substituted with one or more R⁶Substituted with groups) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;

or a combination of the following:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

In a further preferred embodiment, the present invention comprises as the only active agent a compound of formula (I) (wherein R is³Is methyl) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;

or a combination of the following:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

In a further preferred embodiment, the present invention comprises as the only active agent a compound of formula (I) (wherein R is²Is optionally substituted by 1,2 or 3R⁶Group-substituted pyridines, pyridazines, pyrimidines, pyrazines, pyrroles, oxazoles, thiazoles, furans or thiophenes; more preferably optionally substituted with 1,2 or 3R⁶Group-substituted pyridine, pyridazine, pyrimidine, pyrazine, pyrrole, oxazole or thiazole) or physiologically acceptable salts, solvates, hydrates or stereoisomers thereof;

or a combination of the following:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

In a particular embodiment, the invention comprises as the only active agent a compound of formula (Ia) (wherein R is²As defined above) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof:

or a combination of the following:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

In another particular embodiment, the invention comprises as the only active agent a compound of formula (Ib) (wherein R is²As defined above) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof:

or a combination of the following:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

In another particular embodiment, the invention comprises as the only active agent a compound of formula (Ic) (wherein R is²As defined above) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof:

or a combination of the following:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

In another particular embodiment, the invention includes as the only active agent a compound of formula (Id) (wherein R is²And R⁴As defined above) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof:

or a combination of the following:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

In another particular embodiment, the invention comprises as the only active agent a compound of formula (Ie) (wherein R is²And R⁴As defined above) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof:

or a combination of the following:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

In a preferred embodiment, the invention comprises as the only active agent a compound of formulae (I) - (V) (wherein R is²Is optionally substituted by 1,2 or 3R⁶Group-substituted pyridines, pyridazines, pyrimidines, pyrazines, pyrroles, oxazoles, thiazoles, furans or thiophenes; more preferably, wherein R²Is optionally substituted by 1,2 or 3R⁶Substituted by radicalsPyridine, pyridazine, pyrimidine, pyrazine, pyrrole, oxazole or thiazole) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;

or a combination of the following:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

In a further preferred embodiment, the present invention comprises as the only active agent the following compounds or their physiologically acceptable salts, solvates, hydrates or stereoisomers:

2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide, N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -5-carboxylic acid amide;

n- (8- {3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] propoxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) nicotinamide;

n- (8- {3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] propoxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -2, 4-dimethyl-1, 3-thiazole-5-carboxamide;

2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -1, 3-thiazole-5-carboxamide;

2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] isonicotinamide;

2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -4-methyl-1, 3-thiazole-5-carboxamide;

2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -4-propylpyrimidine-5-carboxamide;

n- {8- [2- (4-ethylmorpholin-2-yl) ethoxy ] -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } nicotinamide;

n- {8- [2- (dimethylamino) ethoxy ] -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } pyrimidine-5-carboxamide;

n- (8- {3- [2- (hydroxymethyl) morpholin-4-yl ] propoxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) nicotinamide;

n- {8- [3- (dimethylamino) propoxy ] -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } nicotinamide 1-oxide;

2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide;

2, 3-dihydroimidazo [1,2c ] quinazolin-5-yl ] -6- (2-pyrrolidin-1-ylethyl) nicotinamide, N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3;

6- (cyclopentylamino) -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

2- [8- (2-hydroxy-3-morpholin-4-ylpropoxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

n- { 7-methoxy-8- [3- (3-methylmorpholin-4-yl) propoxy ] -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } nicotinamide;

n- (8- {2- [4- (cyclobutylmethyl) morpholin-2-yl ] ethoxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) nicotinamide;

n- (7-methoxy-8- {2- [4- (2-methoxyethyl) morpholin-2-yl ] ethoxy } -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) nicotinamide;

n- {8- [ (4-ethylmorpholin-2-yl) methoxy ] -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } nicotinamide;

n- (7-methoxy-8- { [4- (2-methoxyethyl) morpholin-2-yl ] methoxy } -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) nicotinamide;

n- { 7-methoxy-8- [ (4-methylmorpholin-2-yl) methoxy ] -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } nicotinamide;

2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-4-carboxamide, N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3;

2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-4-carboxamide;

1-methyl-1H-imidazole-4-carboxamide, 2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2;

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

rel-N- (8- {3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] propoxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) -6-methylnicotinamide;

rel-6-acetylamino-N- (8- {3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] propoxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) nicotinamide;

1-methyl-1H-imidazole-5-carboxamide, N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -amide;

6-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -2-methylnicotinamide;

2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -4-methylpyrimidine-5-carboxamide;

6-amino-5-bromo-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -1, 3-oxazole-5-carboxamide;

2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide, 2, 3-dihydroimidazo [ 7-methoxy-8- (morpholin-2-ylmethoxy);

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

2-amino-N- {8- [3- (dimethylamino) propoxy ] -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } -1, 3-thiazole-5-carboxamide;

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

rel-6-amino-N- (8- {3- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] propoxy } -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl) nicotinamide;

2- [ (2-hydroxyethyl) amino ] -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide;

2- [ (3-methoxy-5-methyl-8-morpholin-3-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -pyrimidine-7-carboxamide;

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

2- [ (3-morpholin-4-ylpropyl) amino ] pyrimidine-5-carboxamide, 2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2;

2- [ (2-methoxyethyl) amino ] -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide;

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

6-amino-N- {8- [3- (dimethylamino) propoxy ] -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } nicotinamide;

2-pyrrolidin-1-ylpyrimidin-5-carboxamide, 2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2;

2- (4-methylpiperazin-1-yl) pyrimidine-5-carboxamide, 2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo;

2-morpholin-4-ylpyrimidin-5-carboxamide, 2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2;

2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -6-piperazin-1-ylnicotinamide hydrochloride;

6- [ (3S) -3-aminopyrrolidin-1-yl ] -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide hydrochloride hydrate;

6- [ (3R) -3-aminopyrrolidin-1-yl ] -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide hydrochloride;

6- [ (4-fluorobenzyl) amino ] -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

6- [ (2-furylmethyl) amino ] -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

6- [ (2-methoxyethyl) amino ] -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -6- (1H-pyrrol-1-yl) nicotinamide, N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2;

2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -6-morpholin-4-ylnicotinamide, N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2;

n- { 7-methoxy-8- [3- (methylamino) propoxy ] -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } nicotinamide;

6- [ (2, 2-dimethylpropionyl) amino ] -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

6- [ (cyclopropylcarbonyl) amino ] -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide

2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -6- (2,2, 2-trifluoroethoxy) nicotinamide, N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3;

2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -6- (trifluoromethyl) nicotinamide, N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2;

6- (isobutyrylamino) -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

n- { 7-methoxy-8- [3- (4-methylpiperazin-1-yl) propoxy ] -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } nicotinamide;

2- { [ (methylamino) carbonyl ] amino } -1, 3-thiazole-4-carboxylic acid methyl ester, {2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -2- { [ (methyl-amino) carbonyl ] amino } -7-methoxy-8- (3-morpholin-4-ylpropoxy) -amide;

n- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -6- { [ (methylamino) carbonyl ] amino } nicotinamide;

2- (methylamino) -1, 3-thiazole-4-carboxamide, N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -2;

2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide, 2, 3-dihydroimidazol-7-ylmethoxy-8- (2-morpholin-4-ylethoxy) -nicotinamide;

n- {8- [2- (dimethylamino) ethoxy ] -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } -2, 4-dimethyl-1, 3-thiazole-5-carboxamide;

n- {8- [2- (dimethylamino) ethoxy ] -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } -6-methylnicotinamide;

6- { [ (isopropylamino) carbonyl ] amino } -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -6-pyrrolidin-1-ylnicotinamide, N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2;

6- (dimethylamino) -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide, N- [ 7-methoxy-8- (3-piperidin-1-ylpropoxy) -2;

n- [ 7-methoxy-8- (2-pyrrolidin-1-ylethoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide, 2, 3-dihydroimidazol-7-yl-8- (2-piperidin-1-ylethoxy) -nicotinamide;

6- { [ (ethylamino) carbonyl ] amino } -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

6-fluoro-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -1, 3-oxazole-4-carboxamide;

2- (ethylamino) -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -1, 3-thiazole-4-carboxamide;

2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrazine-7-carboxamide;

n- [8- (2-aminoethoxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

6-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] isonicotinamide, N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2;

n- {8- [3- (diethylamino) propoxy ] -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } nicotinamide;

n- {8- [2- (diisopropylamino) ethoxy ] -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } nicotinamide;

n- {8- [2- (diethylamino) ethoxy ] -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } nicotinamide;

n- {8- [3- (dimethylamino) propoxy ] -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } nicotinamide;

n- {8- [2- (dimethylamino) ethoxy ] -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl } nicotinamide;

2- (methylamino) pyrimidine-5-carboxamide, N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -amide;

2- (methylthio) pyrimidine-5-carboxamide, N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -amide;

(iv) N- [8- (3-aminopropoxy) -7-methoxy-2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide trifluoroacetate;

2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] thiophene-2-carboxamide, N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2;

2, 4-dimethyl-1, 3-thiazole-5-carboxamide, 2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo;

2-methoxy-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide;

n- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -3-furoamide;

2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] thiophene-3-carboxamide, N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3;

2-methyl-1, 3-thiazole-4-carboxamide, 2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2;

6-methoxy-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

5-methoxy-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] -6-methylnicotinamide, N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2;

6- (acetylamino) -N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide;

2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] nicotinamide, N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3;

or a combination of the following:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

In a preferred embodiment, the present invention comprises as the only active agents the following compounds or their physiologically acceptable salts, solvates, hydrates or stereoisomers:

or a combination of the following:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

or a pharmaceutical composition comprising such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof,

In a preferred embodiment, the invention comprises a combination of:

a) 2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; and

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

In a preferred embodiment, the invention comprises a combination of:

b) one or more additional active agents selected from the group consisting of:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

or a pharmaceutical composition comprising such a combination,

In a preferred embodiment, the invention comprises a combination of:

b) one or more additional active agents selected from the group consisting of:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex;

or a pharmaceutical composition comprising such a combination,

In a preferred embodiment, the invention comprises a combination of:

b) one or more additional active agents which are ABT-737;

or a pharmaceutical composition comprising such a combination,

In a preferred embodiment, the invention comprises a combination of:

b) one or more additional active agents selected from the group consisting of:

or a pharmaceutical composition comprising such a combination,

In a preferred embodiment, the invention comprises a combination of:

b) one or more additional active agents which is rapamycin (sirolimus);

or a pharmaceutical composition comprising such a combination,

If there is a difference between a chemical name and a chemical structure shown in the figure, the chemical structure shown in the figure takes precedence over the chemical name given.

Without being bound by theory or mechanism, the present invention compares the compounds with those of the prior artThe compounds exhibit surprising inhibitory activity against phosphatidylinositol-3-kinase as well as chemical and structural stability. It is believed that this surprising activity is based on the structure of the compounds, particularly the basicity of these compounds due to R¹Is optionally substituted by R⁵And R^5’Substituted amino groups. In addition, R is appropriately selected³And R²The necessary activity is provided against the appropriate subtype to produce in vivo activity.

According to a particular embodiment of any of the above aspects or embodiments thereof of the invention, the breast cancer is inflammatory breast cancer.

According to a particular embodiment of any of the above aspects or embodiments thereof of the invention, the breast cancer is triple negative breast cancer.

According to a particular embodiment of any of the above aspects or embodiments thereof of the invention, said breast cancer is Her2 receptor positive breast cancer.

According to a particular embodiment of any of the above aspects or embodiments thereof of the invention, the breast cancer is hormone receptor positive breast cancer.

Definition of

The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing only carbon and hydrogen atoms, containing no unsaturation, from 1 to 8 carbon atoms, and attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1, 1-dimethylethyl (tert-butyl).

The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond, which may be straight or branched chain containing from about 2 to about 10 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-I-propenyl, 1-butenyl, and 2-butenyl.

The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing at least one carbon-carbon triple bond and containing from about 2 to 12 carbon atoms (presently preferred groups containing from about 2 to 10 carbon atoms), such as ethynyl.

The term "alkoxy" refers to an alkyl group, as defined herein, attached to the remainder of the molecule through an oxygen. Representative examples of alkoxy groups are methoxy and ethoxy.

The term "alkoxyalkyl" refers to an alkoxy group, as defined herein, appended to an alkyl group through an oxygen atom, which is further attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure for the remainder of the molecule. A representative example of such groups is-CH₂OCH₃、-CH₂OC₂H₅。

The term "cycloalkyl" refers to a non-aromatic mono-or polycyclic ring system containing about 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, examples of polycyclic cycloalkyl groups include perhydronaphthyl (perhydronapthyl), adamantyl and norbornyl bridged ring groups or spirobicyclic groups such as (4,4) non-2-yl.

The term "cycloalkylalkyl" refers to a cyclic group containing from 3 to 8 carbon atoms directly attached to the alkyl group which is then attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure such as cyclopropylmethyl, cyclobutylethyl, cyclopentylethyl.

The term "aryl" refers to an aromatic group containing 6 to 14 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl.

The term "arylalkyl" means an aryl group, as defined herein, appended directly to an alkyl group, as defined herein, and then attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure for the remainder of the molecule, e.g., -CH₂C₆H₅、-C₂H₅C₆H₅。

The term "heterocycle" refers to a stable 3-15 membered cyclic group consisting of carbon atoms and 1-5 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfurAnd (4) clustering. For the purposes of the present invention, the heterocyclic group may be a monocyclic, bicyclic, or tricyclic ring system, which may include fused, bridged, or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen, or sulfur atoms in the heterocyclic group may be optionally oxidized to various oxidation states. Additionally, the nitrogen atoms may optionally be quaternized; and the cyclic group may be partially or fully saturated (i.e., a heteroaryl or heteroaryl aromatic ring). Examples of such heterocyclic groups include, but are not limited to: azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepineA group selected from the group consisting of phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolyl, isoquinolyl, tetrazolyl, imidazolyl, tetrahydroisoquinolinyl (tetrahydroisoquinolinyl), piperidyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazaZ is aza radicalA phenyl group, a pyrrolyl group, a 4-piperidonyl group, a pyrrolidinyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an oxazolyl group, an oxazolinyl group, an oxazolidinyl group (oxacolidinyl group), a triazolyl group, an indanyl group, an isoxazolyl group, an isoxazolidinyl group (isooxacolidinyl group), a morpholinyl group, a thiazolyl group, a thiazolinyl group, a thiazolidinyl group, an isothiazolyl group, a quinuclidinyl group, an isothiazolidinyl group, an indolyl group, an isoindolyl group, an indolinyl group, an isoindolinyl group, an octahydroindolyl group, an octahydroisoindolyl group, a quinolyl group, an isoquinolyl group, a decahydroisoquinolyl group, a benzimidazolyl group, a thiadiazolyl group, a benzopyranyl group, a benzothiazolyl group, a furyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a thienyl group, a benzothienyl group, a thiomorpholinyl groupA morpholinyl sulfone (thiomorpholinyl sulfone), a dioxolanyl (dioxaphospholanyl), an oxadiazolyl, a chromanyl, or an isochroman group.

The term "heteroaryl" refers to a heterocyclic group as defined herein that is aromatic. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

The heterocyclic group may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

The term "heteroarylalkyl" refers to a heteroaryl ring group, as defined herein, directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom from the alkyl group that results in the creation of a stable structure.

The term "heterocyclyl" refers to heterocyclic groups as defined herein. The heterocyclic group may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

The term "heterocyclylalkyl" refers to a heterocyclic group as defined herein bonded directly to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom from the alkyl group that results in the creation of a stable structure.

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

The term "halogen" refers to the groups fluorine, chlorine, bromine and iodine.

When the plural form of the words compound, salt, polymorph, hydrate, solvate and the like are used herein, it is to be understood that reference to a compound, salt, polymorph, isomer, hydrate, solvate and the like in the singular is also intended.

The compounds of the present invention may contain one or more asymmetric centers, depending on the location and nature of the various substituents desired. Asymmetric carbon atoms may exist in either the (R) -or (S) -configuration, resulting in racemic mixtures with one asymmetric center and diastereomeric mixtures with multiple asymmetric centers. In some cases, asymmetry may also exist due to hindered rotation about a particular bond, for example, the central bond connects two substituted aromatic rings of a particular compound. The ring substituents may also be present in cis or trans form. All such configurations (including enantiomers and diastereomers) are contemplated to be within the scope of the present invention. Preferred compounds are those that produce a more desirable biological activity. Isolated, pure or partially purified isomers and stereoisomers, or racemic or diastereomeric mixtures of the compounds of the invention are included within the scope of the invention. Purification and isolation of such materials can be accomplished by standard techniques known in the art.

The invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts, co-precipitates, metabolites, hydrates, solvates and prodrugs of all the example compounds. The term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic or organic acid addition salts of the compounds of the present invention. See, for example, S.M.Berge et al, "pharmaceutical salts," J.pharm.Sci.1977,66, 1-19. Pharmaceutically acceptable salts include those obtained by reacting a main compound as a base with an inorganic acid or an organic acid to form a salt, such as salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, and citric acid. Pharmaceutically acceptable salts also include those salts formed from the principal compound as an acid and reacted with a suitable base, for example, sodium, potassium, calcium, magnesium, ammonium or chorine salts. Those skilled in the art will also recognize that acid addition salts of the claimed compounds can be prepared by reacting the compounds with the appropriate inorganic or organic acid by any of a variety of known methods. Alternatively, the alkali metal salts and alkaline earth metal salts of the acidic compounds of the present invention are prepared by reacting the compounds of the present invention with an appropriate base by various known methods.

Representative salts of the compounds of the present invention include conventional, non-toxic salts or quaternary ammonium salts formed, for example, from inorganic or organic acids or bases by methods well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate (camphorate), camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectate (pectinate), persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, sulfate, etc, Tartrate, thiocyanate, tosylate and undecanoate salts.

Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. In addition, basic nitrogen-containing groups may be quaternized with, for example, the following agents: lower alkyl halides such as methyl, ethyl, propyl or butyl chloride, bromide and iodide; dialkyl sulfates such as dimethyl, diethyl, dibutyl sulfate, or diamyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl bromide and phenethyl bromide and the like.

For the purposes of the present invention, solvates are solid complexes of a solvent and a compound of the invention. Exemplary solvates include, but are not limited to, complexes of the compounds of the present invention with ethanol or methanol. Hydrates are a particular form of solvate, wherein the solvent is water.

The synthesis of the above listed compounds is described in international patent application PCT/EP2003/010377 (published as WO2004/029055A 1) and international patent application PCT/US2007/024985 (published as WO 2008/070150), both of which are incorporated herein by reference.

According to another embodiment, the present invention relates to a 2, 3-dihydroimidazo [1,2-c ] quinazoline compound as defined herein (in particular 2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as sole active agent for use in the treatment of cancer (such as breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer and hormone receptor positive breast cancer).

Combination therapy

As mentioned above, the present invention relates to a combination of:

a) a 2, 3-dihydroimidazo [1,2-c ] quinazoline compound as defined above or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; or a pharmaceutical composition comprising such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;

and

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

In a preferred embodiment, the invention comprises a combination of:

a) 2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; or a pharmaceutical composition comprising such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;

and

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

In a preferred embodiment, the invention comprises a combination of:

and

b) one or more additional active agents selected from the group consisting of:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

In a preferred embodiment, the invention comprises a combination of:

and

b) one or more additional active agents selected from the group consisting of:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex.

In a preferred embodiment, the invention comprises a combination of:

and

b) one or more additional active agents which is ABT-737.

In a preferred embodiment, the invention comprises a combination of:

and

b) one or more additional active agents selected from the group consisting of:

In a preferred embodiment, the invention comprises a combination of:

and

b) one or more additional active agents which is rapamycin (sirolimus).

The compounds of the present invention may be administered as a single agent or in combination with one or more other agents (or "other active agents"), wherein the combination does not cause unacceptable adverse effects. For example, the compounds of the present invention may be combined with known anti-angiogenic, anti-hyperproliferative, anti-inflammatory, analgesic, immunomodulatory, diuretic, antiarrhythmic, antihypercholesterolemic, antilipidemic, antidiabetic or antiviral agents and the like, as well as mixtures and combinations thereof.

The additional agent or agents (or "other active agents") can be everolimus (afinitor), aldesleukin, alendronic acid, alpha-interferon (alfaferone), alitretinoin, allopurinol, sodium allopurinol for injection (alprim), palonosetron hydrochloride injection (aloxi), altretamine, aminoglutethimide, amifostine, amsacrine, anastrozole, dolasetron tablet (anzmet), alfa bepotastine injection (aranesp), arglabin, arsenic trioxide, exemestane tablet, 5-azacytidine, azathioprine, BCG or tide BCG, amastatin (bestatin), betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, uridine bromide, bortezomib, leucinolone, calcitonin, acanthin, acampath, capecitabine, interleukin, platinum, tacrolimus, leucomycin, or a combination thereof, Chlorambucil, cisplatin, cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin liposome (daunoxeme), dexamethasone sodium phosphate, estradiol valerate, dinierein 2(denileukin diftox), methylprednisolone, deslorelin, dexamethasone (dexomethasone), dexrazoxane, diethylstilbestrol, fluconazole, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, leuprorelin acetate (eligard), labyrin injection (elitek), epirubicin hydrochloride injection (ellence), aprepirubicin capsule (ement), epirubicin, alfa eptin alfa, alfa (epigen), etaplatin, levamisole, estradiol, estramustine, phosphoenolate, estramustine, phosphoenolate, etidronate, etidinamisole, Etoposide injection, etoposide, fadrozole, farston, filgrastim, finasteride, filgrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoromethyltestosterone, flutamide, formestane, fosetabine, fotemustine, fulvestrant, gamma-globulin (gammagard), gemcitabine, gemumab, imatinib mesylate (gleevec), carmustine wafer capsule (gliadel), goserelin, glasetron hydrochloride, herceptin, histrelin, topotecan (hydroxycamtin), hydrocortisone, erythroxylynoneadenine (eylindro-hydroxyonylidinenine), hydroxyurea, temozolomide, idarubicin, ifosfamide, alpha interferon, alpha 2 interferon, alpha-2A interferon, alpha-2B interferon, alpha-1, alpha-interferon, Alpha-n 3 interferon, interferon beta, gamma-1 a interferon, interleukin-2, interferon alpha (intron A), gefitinib tablet (iressa), irinotecan, granisetron, lapatinib, lentinan sulfate, letrozole, leucovorin, leuprorelin acetate, lenalidomide, levamisole, calcium levofolinate (levofolinic acid calceiumsalt), levothyroxine sodium (levothroid), levothyroxine sodium (levoxyl), lomustine, lonidamine, dronabinol, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrol tablet (menest), 6-mercaptopurine, mesna, methotrexate, metiveke, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, trite (myotretinose), platinum (Myocola), platinum (platinum), and so-L-2, Recombinant human interleukin 11 (neumegla), filgrastim (neupogen), nilutamide, tamoxifen, NSC-631570, OCT-43, octreotide, ondansetron hydrochloride, cefixime (orapred), oxaliplatin, paclitaxel, prednisone sodium phosphate (pidiaprefred), pemetrase, parroxin, pentostatin, streptolysin (pisibanil), pilocarpine hydrochloride, pirarubicin, plicamycin, porphycin, prednisolone, prednisone, equine estrogens, procarbazine, recombinant human erythropoietin alpha, rdaa 119, raltitrexed, recombinant human beta 1a injectate (rebif), rhenium-hydroxyethylphosphonate, rituximab, roscovitine (roferon-a), romotide, pilocarpine hydrochloride (sala), octreotide, sargentin, sibutramine, furatin, furazolidone, sibutramine, ambrosine, tretin, tretinomycin, prednisolone, prednisone, prednisolone-a, and others, Dry cell therapy, streptozocin, strontium chloride 89, sunitinib, levothyroxine sodium, tamoxifen, tamsulosin, tasonamine, testolactone, docetaxel injectable solution (taxotere), tesin interleukin, temozolomide, teniposide, testosterone propionate, methyltestosterone, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, troosulfan, tretinoin, methotrexate (trexal), trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, vilulizine, dexrazoxane, stastin (stastin slalomanid), ondansetron, ABI-007, aclobine, interferon gamma-1, zeaxanthin, amikavak, amitraz, Asoprisnil, astamestan, atrasentan, BAY43-9006 (sorafenib), bevacizumab (avastin), CCI-779, CDC-501, celecoxib, cetuximab, clinatol, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotarrin, efloronitine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implants, holmium-166 DOTMP, ibandronic acid, gamma interferon, PEGylated interferon alpha-2 b (intron-PEG), ixabepilone (ixabepilone), keyhole limpet hemocyanin (keye lipmomyceanin), L-651582, lanreotide, lasofoxifen, libra, farnesol protein transferase inhibitor (lonrnab), minoxidin (MTP-209), minoxidine liposome-6 MTP-MTP, MTP-209, milbexate-6, MTP-MTP, dox, and dox, Nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxel, disodium pamidronate, PN-401, QS-21, quazepam, R-1549, raloxifene, ranpirnase, 13-cis-retinoic acid, satraplatin, seocalcitol, T-138067, erlotinib hydrochloride tablets (tarceva), taxoprexin, thalidomide, alpha-1 thymosin, thiazoluralin, tipifarnib, tirapazamide, TLK-286, toremifene, TransMID-107R, valcephapatide, vapreotide, vatalanib (vatalanib), verteporfin, vinflunine, Z-100, zoledronic acid, or combinations thereof.

According to one embodiment, the additional agent or agents (or "other active agents") are selected from: 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinol, altretamine, aminoglutethimide, amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY80-6946, BAY1000394, BAY86-9766(RDEA119), belotecan (belotecan), bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, cabazitaxel (bazitaxel), calcium folinate, calcium levofolinate, capecitabine, carboplatin, carmofur, carmustine, rituximab (cisplatin), catapaucimaxob, celecoxib, western interleukin, bevacizumab, chlorambucil, chloracetic acid, loratadine, picloratadine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, dabecortine alpha, dasatinib (dasatinib), daunorubicin, decitabine, degarelix (degarelix), dinebin interleukin 2(denileukin diftox), deluzumab (denosumab), deslorelin, dibromospiro-ammonium chloride, docetaxel, deoxyfluorouracil, doxorubicin + estrone, eculizumab (ecumab), eculizumab, eletrinol, eletrinylammonium, itratepa (eltrombopag), endostatin, enocitabine, epirubicin, epitiazerol, epoetin alpha, epoetin beta, epta, eribulin (eribulin), erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fava, filgrastimethamine, fludarabine, flunomide, trospide, trospigotu, doxin, trospidrox, doxastin, doxin, doxastin, valtrexaprop-b, valtrexaprop-p, trospitrexaprop-b, trospile, trospitrexaprop-b, trospi, Gefitinib, gemcitabine, gemtuzumab, glutathione (glutoxim), goserelin, histamine dihydrochloride, histrelin, hydroxyurea, I-125 seeds, ibandronic acid, ibritumomab, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferon alpha, interferon beta, interferon gamma, ipimab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, legetin, lentinan, letrozole, leuprolide, levamisole, lisuride, lobaplatin, lomustine, lonidamine, maxolone, medroxyprogesterone, megestrol, melphalan, meindrostan, mercaptopurine, methotrexate, methoxsalen, methylketovalerate, methyltestosterone, mivampitide, miltefosine, miriplatin, miiplatin (miiplatin), dibromomannitol, mitoxantrone, mitomycin, gliptin, medroxyprin, mitomycin, imipramiperin, mibemectin, imipramiperin, and mitomycin, Mitotane, mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide, nimotuzumab, nimustine, nitrazine (nitracrine), ofatumumab, omeprazole, opper leukin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, pamidronic acid, panitumumab, pazopanib, pemetrexed, PEG-epothilones beta (methoxy PEG-epothilones beta), polyethylene glycol filgrastim (pegfilgrastim), polyethylene glycol interferon alpha-2 b, pemetrexed, pentazocine, pentostatin, pellomycin, phosphoramide, piscibacilide, pirarubicin, plerixafot, plicamycin, poliglusam, estradiol polyphosphate, polysaccharide-K, porphin sodium, larprimisum, prednimustine, procarbazine, quinacrine, raloxifene, raloxifenesin, triptoresinone, triptoresinolide, triptorellose, picamide, pemetrexendine, pem, Ramomustine, propyleneimine, regorafenib, risedronic acid, rituximab, romidepsin, rolimiprole, sargrastim, sipuleucel-T, cilazasugar, sobuzole, sodium glycin, sorafenib, streptozotocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tasonamine, tesil interleukin, tegafur + gimeracil + oteracil, temoporfil, temozolomide, temsirolimus, teniposide, testosterone, tetrodotril, thalidomide, thiotepa, thymalfasin, thioguanine, taslizumab, topotecan, toremifene, tositumomab, trastuzumab, osufovan, tretinoin, triptorelin, urotropine, urotropinirostrin, suramin, tretinoin, valvacizumab, vinpocetine, valdecoxib, valrubicin, tretazarin, tretinomycin, trovafloxacin, valdecoxib, tretinomycin, trovampil, tremulin, valdecoxib, valrubicin, tremulin, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, flurazole, yttrium-90 glass beads, cilastatin ester, zoledronic acid, and zorubicin.

The additional agent may also be: gemcitabine, paclitaxel, cisplatin, carboplatin, sodium butyrate, 5-FU, doxorubicin, tamoxifen, etoposide, trastuzumab, gefitinib, intron A, rapamycin, 17-AAG, U0126, insulin, an insulin derivative, a PPAR ligand, a sulfonylurea drug, an alpha-glucosidase inhibitor, biguanide, a PTP-1B inhibitor, a DPP-IV inhibitor, an 11-beta-HSD inhibitor, GLP-1, a GLP-1 derivative, GIP, a GIP derivative, PACAP, a PACAP derivative, a secretin or a secretin derivative.

Optional anti-hyperproliferative agents that may be added to the compositions include, but are not limited to, compounds listed in the cancer chemotherapeutic regimen of the Merck index 11 edition (1996) (incorporated by reference), such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, asparaginase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, and, Vincristine and vindesine.

Other anti-hyperproliferative agents suitable for use with The compositions of The present invention include, but are not limited to, those compounds recognized in Goodmann and Gilman's The pharmaceutical basic of Therapeutics (9 th edition), edited by Molinoff et al, McGraw-Hill, pages 1225-1287 (1996) (incorporated by reference) for use in The treatment of neoplastic disease, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2' -difluorodeoxycytidine, docetaxel, erythrononyladenine, ethisterone, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, Pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine.

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

In general, the use of cytotoxic and/or cytostatic agents in combination with a compound or composition of the invention will serve the following functions:

(1) produces better efficacy in reducing tumor growth or even eliminating tumors than either agent administered alone,

(2) allowing for the administration of smaller amounts of the administered chemotherapeutic agent,

(3) providing a chemotherapeutic treatment that is better tolerated by patients and has fewer harmful pharmacological complications than observed with single agent chemotherapy and certain other combination therapies,

(4) allowing the treatment of a wider range of different cancer types in mammals, particularly humans,

(5) providing a higher response rate in the treated patient,

(6) provides longer survival in the treated patient compared to standard chemotherapy treatment,

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

(8) Results in at least as good efficacy and tolerability as the single agents used alone, as compared to known cases where other cancer agents in combination produce an antagonistic effect.

According to one embodiment, the present invention relates to a combination wherein the 2, 3-dihydroimidazo [1,2-c ] quinazoline compound is 2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide.

According to one embodiment, the present invention relates to a combination wherein the further active agent is rapamycin or ABT-737.

According to one embodiment, the present invention relates to a combination wherein the 2, 3-dihydroimidazo [1,2-c ] quinazoline compound is 2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide and the further active agent is rapamycin or ABT-737.

Pharmaceutical compositions of the compounds of the invention

As mentioned above, the present invention relates to:

-a pharmaceutical composition comprising:

2, 3-dihydroimidazo [1,2-c ] quinazoline compounds or physiologically acceptable salts, solvates, hydrates or stereoisomers thereof as sole active agents for use in the treatment of cancer (such as breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer and hormone receptor positive breast cancer), and

-a pharmaceutical composition comprising a combination of:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

According to another embodiment, the present invention relates to a pharmaceutical composition comprising as sole active agent a 2, 3-dihydroimidazo [1,2-c ] quinazoline compound as defined herein, in particular a 2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, for use in the treatment of cancer (such as breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer and hormone receptor positive breast cancer).

The pharmaceutical composition comprises one or more compounds. These compositions can be utilized to achieve a desired pharmacological effect by administration to a patient in need thereof. For purposes of the present invention, a patient is a mammal, including a human, in need of treatment for a particular condition or disease. Accordingly, the present invention includes pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the present invention or a salt thereof. A pharmaceutically acceptable carrier is preferably one that is relatively non-toxic and non-injurious to a patient at concentrations consistent with effective activity of the active agent, such that any side effects caused by the carrier do not destroy the beneficial effects of the active agent. A pharmaceutically effective amount of a compound is preferably an amount that results in or affects the particular condition being treated. The compounds of the present invention may be administered together with a pharmaceutically acceptable carrier in any effective conventional dosage unit form including immediate release, sustained release and timed release formulations in the following manner: oral, parenteral, topical, nasal, ocular (ophthalmic), sublingual, rectal, vaginal administration and the like.

For oral administration, the compounds may be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges (lozenes), melt gels (melts), powders, solutions, suspensions or emulsions and may be prepared according to methods known in the art for the preparation of pharmaceutical compositions. The solid unit dosage form may be a capsule, which may be of the ordinary hard or soft capsule type, comprising, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of the present invention can be compressed into tablets with conventional tablet bases (e.g., lactose, sucrose, and corn starch) and in combination with: binders such as acacia, corn starch or gelatin, disintegrating agents such as potato starch, alginic acid, corn starch and guar gum, tragacanth, acacia for assisting the disintegration and dissolution of the tablets after administration, lubricants such as talc, stearic acid or magnesium stearate, calcium stearate or zinc stearate for improving the flowability of the tablet granulation and preventing adhesion of the tablet materials to the surfaces of the tablet dies and punches, dyes, colorants and flavouring agents such as peppermint, oil of wintergreen or cherry flavouring for improving the organoleptic properties of the tablets and making them more acceptable to the patient. Suitable excipients for oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols (e.g., ethanol, benzyl alcohol, and polyvinyl alcohol), with or without the addition of pharmaceutically acceptable surfactants, suspending agents, or emulsifying agents. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for use in the preparation of an aqueous suspension. They provide the active agent in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, such as those described above, may also be present.

The pharmaceutical composition of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, such as liquid paraffin, or a mixture of vegetable oils. Suitable emulsifying agents may be (1) natural gums, for example gum acacia and gum tragacanth, (2) natural phosphatides, for example soya bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, (4) condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active agent in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. The suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate; one or more colorants; one or more flavoring agents; and one or more sweetening agents, such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent and a preservative such as methyl and propyl parabens as well as flavoring and coloring agents.

The compounds of the invention may also be administered parenterally, i.e., subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly or intraperitoneally, in injectable doses of the compounds, preferably in a physiologically acceptable diluent with a pharmaceutical carrier, which may be a sterile liquid or a mixture of liquids, such as water, saline, aqueous dextrose and related sugar solutions, alcohols such as ethanol, isopropanol or cetyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2, 2-dimethyl-1, 1-dioxolane-4-methanol, ethers such as poly (ethylene glycol) 400, oils, fatty acids, fatty acid esters or glycerides or acetylated glycerides, with or without the addition of pharmaceutically acceptable surfactants such as soaps or detergents, suspending agents such as pectin, carbomer, methylcellulose, hypromellose or carboxymethylcellulose, or emulsifying agents and other pharmaceutically acceptable adjuvants.

Exemplary oils useful in the parenteral formulations of the invention are those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium and triethanolamine salts, and suitable detergents include cationic detergents such as dimethyl dialkyl ammonium halides, alkyl pyridinium halides and alkylamine acetates; anionic detergents such as alkyl sulfonates, aryl sulfonates and olefin sulfonates, alkyl sulfates and alkyl sulfosuccinates, olefin sulfates and olefin sulfosuccinates, ether sulfates and ether sulfosuccinates and monoglyceride sulfates and monoglycerides sulfosuccinates; nonionic detergents such as fatty amine oxides, fatty acid alkanolamides, and poly (oxyethylene-oxypropylene), ethylene oxide copolymers or propylene oxide copolymers; and amphoteric detergents such as alkyl-beta-aminopropionates and 2-alkylimidazoline quaternary ammonium salts, and mixtures thereof.

The parenteral compositions of the invention will typically comprise from about 0.5% to about 25% by weight of the active agent in solution. Preservatives and buffers may also be advantageously employed. To minimize or eliminate irritation at the injection site, such compositions may comprise a nonionic surfactant having a hydrophilic-lipophilic balance (HLB) of preferably from about 12 to about 17. The amount of surfactant in such formulations is preferably from about 5% to about 15% by weight. The surfactant may be a single component having the above HLB, or a mixture of two or more components having the desired HLB.

Exemplary surfactants for parenteral formulations are polyethylene sorbitan fatty acid esters such as sorbitan monooleate, and the high molecular weight adducts of ethylene oxide with a hydrophobic base formed by the condensation of propylene oxide and propylene glycol.

The pharmaceutical composition may be in the form of a sterile aqueous suspension for injection. Such suspensions may be formulated according to known methods using: suitable dispersing or wetting agents and suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally-occurring phosphatide, for example lecithin, condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile solution or suspension for injection in a non-toxic parenterally-acceptable diluent or solvent. Diluents and solvents which can be used are, for example, water, ringer's solution, isotonic sodium chloride solution and isotonic glucose solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. In this regard, any less irritating fixed oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compositions of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycols.

Another formulation used in the methods of the invention utilizes a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous delivery of a controlled amount of a compound of the present invention. The construction and use of transdermal patches for delivering agents is well known in the art (see, e.g., U.S. patent No.5,023,252 to 1991, published on 6/11, which is incorporated herein by reference). Such patches may be configured for continuous, pulsed, or on-demand delivery of the agent.

Controlled release formulations for parenteral administration include liposomal microspheres, polymeric microspheres, and polymeric gel formulations known in the art.

It may be desirable or necessary to deliver the pharmaceutical composition to a patient by a mechanical delivery device. The construction and use of mechanical delivery devices for delivering pharmaceutical agents is well known in the art. Direct techniques such as administering drugs directly to the brain typically involve placing a drug delivery catheter into the ventricular system of the patient to bypass the blood brain barrier. One such implantable delivery system for delivering agents to specific anatomical locations of the body is described in U.S. patent No.5,011,472 issued on 30/4 1991.

The compositions of the present invention may also contain, as necessary or desired, other conventional pharmaceutically acceptable formulation ingredients, which are commonly referred to as carriers or diluents. Conventional procedures for preparing such compositions into suitable dosage forms may be used. Such ingredients and procedures include those described in the following references, all of which are incorporated herein by reference: powell, M.F. et al, "compatibility of Excipients for particulate Formulations" PDA Journal of Pharmaceutical Science & Technology1998,52(5), 238-.

Common pharmaceutical ingredients that may be used to formulate the composition for the intended route of administration include:

acidulants (examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalizing agents (examples include, but are not limited to, ammonia, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine (triethanolamine), triethanolamine (trolamine));

adsorbents (examples include, but are not limited to, powdered cellulose and activated carbon);

aerosol propellants (examples include, but are not limited to, carbon dioxide, CCl₂F₂、F₂ClC-CClF₂And CClF₃)；

Air displacement agents (examples include, but are not limited to, nitrogen and argon);

antifungal preservatives (examples include, but are not limited to, benzoic acid, butyl paraben, ethyl paraben, methyl paraben, propyl paraben, sodium benzoate);

antibacterial preservatives (examples include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, and thimerosal);

antioxidants (examples include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, thioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite);

adhesive substances (examples include, but are not limited to, block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, polysiloxanes, and styrene-butadiene copolymers);

buffering agents (examples include, but are not limited to, potassium metaphosphate, dipotassium hydrogen phosphate, sodium acetate, anhydrous sodium citrate, and sodium citrate dihydrate);

a carrier (examples include, but are not limited to, acacia syrup, flavoring elixir, cherry syrup, cocoa syrup, orange syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection, and bacteriostatic water for injection);

chelating agents (examples include, but are not limited to, sodium edetate and edetic acid);

coloring agents (examples include, but are not limited to FD & C Red No.3, FD & C Red No.20, FD & C Yellow No.6, FD & C Blue No.2, D & C Green No.5, D & C Orange No.5, D & C Red No.8, caramel, and Red iron oxide);

clarifying agents (examples include, but are not limited to, bentonite);

emulsifying agents (examples include, but are not limited to, acacia, cetomacrogol, cetyl alcohol, glycerol monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include, but are not limited to, gelatin and cellulose acetate phthalate);

flavors (examples include, but are not limited to, anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil, and vanillin);

humectants (examples include, but are not limited to, glycerin, propylene glycol, and sorbitol);

abrasives (examples include, but are not limited to, mineral oil and glycerin);

oils (examples include, but are not limited to, peanut oil (arachis oil), mineral oil, olive oil, peanut oil (parautoil), sesame oil, and vegetable oils);

ointment bases (examples include, but are not limited to, lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment);

penetration enhancers (transdermal delivery) (examples include, but are not limited to, mono-or polyhydric alcohols, mono-or polyvalent alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalins, terpenes, amides, ethers, ketones, and ureas);

plasticizers (examples include, but are not limited to, diethyl phthalate and glycerol);

solvents (examples include, but are not limited to, ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection, and sterile water for rinsing);

hardening agents (examples include, but are not limited to, cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax, and yellow wax);

suppository bases (examples include, but are not limited to, cocoa butter and polyethylene glycol (mixtures));

surfactants (examples include, but are not limited to, benzalkonium chloride, nonoxynol 10, octoxynol 9, polysorbate 80, sodium lauryl sulfate, and sorbitan monopalmitate);

suspending agents (examples include, but are not limited to, agar, bentonite, carbomer, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, kaolin, methylcellulose, tragacanth and magnesium aluminum silicate);

sweetening agents (examples include, but are not limited to, aspartame, dextrose, glycerin, mannitol, propylene glycol, saccharin sodium, sorbitol, and sucrose);

tablet antiadherents (examples include, but are not limited to, magnesium stearate and talc);

tablet binders (examples include, but are not limited to, acacia, alginic acid, sodium carboxymethylcellulose, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);

tablet and capsule diluents (examples include, but are not limited to, dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium phosphate, sorbitol, and starch);

tablet coatings (examples include, but are not limited to, liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, methyl cellulose, ethyl cellulose, cellulose acetate phthalate, and shellac);

tablet direct compression excipients (examples include, but are not limited to, dibasic calcium phosphate);

tablet disintegrating agents (examples include, but are not limited to, alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, crospovidone, sodium alginate, sodium starch glycolate, and starch);

tablet glidants (examples include, but are not limited to, colloidal silicon dioxide, corn starch, and talc);

tablet lubricants (examples include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, and zinc stearate);

tablet/capsule opacifiers (examples include but are not limited to titanium dioxide);

tablet polishes (examples include, but are not limited to, carnauba wax and white wax);

thickening agents (examples include, but are not limited to, beeswax, cetyl alcohol, and paraffin wax);

tonicity agents (examples include, but are not limited to, glucose and sodium chloride);

viscosity increasing agents (examples include, but are not limited to, alginic acid, bentonite, carbomer, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium alginate, and gum tragacanth); and

wetting agents (examples include, but are not limited to, heptadecaethyleneoxycetanol (heptadecaethyleneoxycetanol), lecithin, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

The pharmaceutical composition of the present invention can be exemplified as follows:

sterile intravenous solution: sterile water for injection can be used to prepare a 5mg/mL solution of the desired compound of the invention, with the pH adjusted as necessary. The solution was diluted to 1-2mg/mL with sterile 5% glucose for administration and administered as an intravenous infusion over about 60 min.

Lyophilized powder for intravenous administration: sterile preparations can be prepared from (i)100-1000mg of the desired compound of the invention in the form of a lyophilized powder, (ii)32-327mg/mL sodium citrate, and (iii)300-3000mg dextran 40. The formulation is reconstituted to a concentration of 10-20mg/mL with sterile saline for injection or 5% glucose, then further diluted to 0.2-0.4mg/mL with saline or 5% glucose and administered as an intravenous bolus or intravenous infusion over 15-60 minutes.

Intramuscular injection suspension: the following solutions or suspensions can be prepared for intramuscular injection:

50mg/mL of the desired Water-insoluble Compound of the invention

5mg/mL sodium carboxymethylcellulose

4mg/mL TWEEN80

9mg/mL sodium chloride

9mg/mL benzyl alcohol

Hard capsule: a large number of unit capsules were prepared by filling standard two-piece hard capsules with 100mg of powdered active, 150mg of lactose, 50mg of cellulose and 6mg of magnesium stearate, respectively.

Soft capsule: a mixture of the active agent in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by a positive displacement pump into molten gelatin to form a soft capsule containing 100mg of the active agent. The capsules were washed and dried. The active agent can be dissolved in a mixture of polyethylene glycol, glycerol, and sorbitol to prepare a water-miscible drug mixture.

Tablet formulation: a number of tablets were prepared by conventional procedures such that the dosage unit contained 100mg of active agent, 0.2mg of colloidal silicon dioxide, 5mg of magnesium stearate, 275mg of microcrystalline cellulose, 11mg of starch and 98.8mg of lactose. Suitable aqueous and non-aqueous coatings may be employed to increase palatability, improve appearance and stability, or delay absorption.

Immediate release tablet/capsule: these are solid oral dosage forms prepared by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the drug. The active agent is mixed in a liquid containing ingredients such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze-drying and solid-state extraction techniques. The pharmaceutical compound can be tableted with a viscoelastic and thermoelastic sugar and a polymer or effervescent component to produce a porous matrix that is quick-releasing without the need for water.

Methods of treating cancer

The present invention also relates to a method of treating or preventing cancer, e.g. breast cancer, clinically classified into several subtypes, such as hormone receptor positive breast cancer, Her2 receptor positive breast cancer, triple negative breast cancer and inflammatory breast cancer, in a mammal, comprising administering a 2, 3-dihydroimidazo [1,2-c ] quinazoline compound, as defined herein, or a pharmaceutical composition comprising the same as the sole active agent, or administering a combination of: a) said compound or a pharmaceutical composition comprising said compound, and b) one or more further active agents as defined herein.

Embodiments of the above methods of treating or preventing cancer (e.g., breast cancer) are as described above with respect to the use of the compounds/combinations.

The present invention relates to methods of treating breast cancer in mammals using the compounds of the present invention and compositions thereof. In the treatment or prevention of breast cancer, the compounds may be used to inhibit, block, reduce the proliferation and/or cell division and/or the development of apoptosis in (etc.) cells. The method comprises administering to a mammal (including a human being) in need thereof an amount of a compound or combination of the invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, effective to treat or prevent breast cancer.

This condition has been well characterized in humans, but also exists with a similar etiology in other mammals, and they can be treated by administering the pharmaceutical compositions of the present invention.

Reference throughout this document to the use of the term "treating" or "treatment" is conventional, e.g., for the purpose of counteracting, alleviating, reducing, alleviating, ameliorating the condition of a disease or disorder, such as cancer, etc.

Dosage and administration

Effective dosages of the compounds of the invention for the treatment of the indicated conditions can be readily determined based on standard laboratory techniques known for evaluating compounds for the treatment or prevention of breast cancer, by standard toxicity tests and by standard pharmacological tests for determining the treatment of the conditions described hereinbefore in mammals, and by comparing these results with those of known drugs for the treatment of these conditions. The amount of active agent administered in the treatment of these conditions will vary widely depending upon such considerations as the particular compound and dosage unit used, the mode of administration, the course of treatment, the age and sex of the patient being treated and the nature and extent of the condition being treated.

The total amount of active agent to be administered is generally from about 0.001mg/kg to about 200mg/kg body weight/day, and preferably from about 0.01mg/kg to about 20mg/kg body weight/day. A clinically useful dosing regimen will be one to three times daily dosing to once every four weeks. In addition, a "drug withdrawal period" (where no drug is administered to the patient for a certain period of time) may be advantageous for the overall balance between pharmacological efficacy and tolerability. A unit dose may contain from about 0.5mg to about 1500mg of active agent and may be administered one or more times per day, or less than once per day. The average daily dose administered by injection, including intravenous, intramuscular, subcutaneous and parenteral injection, and using infusion techniques, may preferably be from 0.01 to 200mg/kg of total body weight. The average daily rectal dosage regimen is preferably from 0.01 to 200mg/kg of total body weight. The average daily vaginal dosage regimen is preferably 0.01-200mg/kg total body weight. The average daily topical dosage regimen is preferably 0.1-200mg administered one to four times daily. The transdermal concentration is preferably the concentration required to maintain a daily dose of 0.01-200 mg/kg. The average daily inhaled dose regimen is preferably from 0.01 to 100mg/kg of total body weight.

The specific starting and maintenance dosage regimen for each patient will, of course, vary depending upon the following factors: the nature and severity of the condition as determined by the clinician, the activity of the particular compound used, the age and general health of the patient, the time of administration, the route of administration, the rate of excretion of the drug, the drug combination, and the like. Thus, the desired therapeutic regimen and the amount of a compound of the invention, pharmaceutically acceptable salt, ester or composition thereof to be administered can be determined by one skilled in the art using routine therapeutic testing.

Biomarkers:

biomarkers for patient stratification are, for example, Bcl expression, HER family expression and/or activation, PIK3CA signaling, and/or PTEN loss for predicting sensitivity and/or tolerance of a cancer patient to the compound, thereby providing a theory-based synergistic combination as defined herein to overcome tolerance.

Examples

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention in any way:

example 1

According to the present invention, compounds are evaluated in a cell-based assay that measures the ability of a compound to inhibit tumor cell proliferation 72 hours after exposure of the tumor cells to a drug. Cell viability was examined by Invitrogen (Breast Oncopanel, Invitrogen, USA), or used as followsLuminescent CellViability Assay (Promega). Cells were plated at 300-5000 cells/well in 100. mu.L growth medium (96-well microplate) and 20. mu.L growth medium (384-well microplate) according to cell line or microplate (96-or 384-well). To pairFor each cell line assayed, cells were plated in separate plates to determine luminescence at the time points of t =0 hours and t =72 hours. The cells were then incubated overnight at 37 ℃ and the luminescence of the sample was measured at t = 0. Dose plates at the t =72 hour time point were treated with compounds diluted in growth medium. The cells were then cultured at 37 ℃ for 72 hours. The luminescence value of the sample was measured at t =72 hours. For data analysis, in brief, the value at t =0 was subtracted from the value determined at the t =72 hour time point for both the treated and untreated samples. The percent growth inhibition was determined using the percent difference in luminescence between the drug treated values and the control values.

Depending on the cell line, tumor cells were seeded at a concentration of 1000-. The cells were cultured overnight and then treated with compound (5 μ L). Caspase3/7 activity was then assayed at 24-48 h post-treatment using the Caspase-Glo3/7 detection kit (Promega Cat # G8212).

The combined effect of PI3K inhibitors and other drugs was evaluated using the combination index (combination index) isobologram analysis (isobologram analysis, Chou et al, Pharmacology Reviews 2006). The efficacy parameter (efficacy parameter) is the median effect (median effect) of the 72 hour cell proliferation assay and the 24 hour or 48 hour Caspase3/7 activity assay described above. Briefly, cells were plated with 25 μ l of medium in 384-well plates. After 24 hours, a continuous three-fold dilution was performed using 5 μ L of experimental medium containing a composition of drug 1(D1) or drug 2(D2) or D1 and D2 in different ratios (0.8xD1+0.2xD2,0.6xD1+0.4xD2,0.4xD1+0.6xD2,0.2xD1+0.8xD2,0.1xD1+0.9xD2) to generate 7 dose curves. Experiments were performed in triplicate. To determine EC₅₀And IC₅₀Linear regression analysis was used to determine the drug concentration that resulted in 50% inhibition or 50% efficacy. Calculation of E (I) C₅₀/E(I)C₉₀The component doses of D1 and D2 below were compared and used to plot isobolograms. The multiplex drug effect (multiple drug effect) was analyzed as described by Chou et al (pharmacogologyreviews 2006) and the combination index was calculated using the formula:

combination index = [ D1x ]/D1 '+ [ D2x ]/D2'

Wherein D1x and D2x are referred to in EC₅₀/IC₅₀Or EC₉₀/IC₉₀The concentrations of drug 1 and drug 2 in the combination; and D1 'and D2' refer to EC of D1 and D2, respectively, as single agents₅₀/IC₅₀Or EC₉₀/IC₉₀The value is obtained. In this assay, values less than 1.0 indicate synergistic interaction, values greater than 1.0 indicate antagonistic interaction, and values of approximately 1.0 indicate additive interaction.

Hereinafter, "compound of formula I" refers to 2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide of the following structural formula:

hereinafter, "compound a" refers to 2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide hydrochloride of the following structural formula or a solvate, hydrate, or tautomer thereof:

the synthesis of compound a is described in european patent application No. EP11161111.7, which is incorporated herein by reference in its entirety.

Synthesis of Compound A:

to a suspension of the compound of formula (I) (400g) in water (1.1L) was added 32% aqueous hydrochloric acid with stirring at room temperature until a pH of 3-4 was reached. An additional 90mL of water and 32% hydrochloric acid were added until a pH of 1.8-2.0 was reached. 160mL of ethanol was added to the mixture, followed by seeding. After stirring for 30 minutes, an additional 1740g of ethanol (2.2L) was added to the mixture over 5 hours, and the resulting mixture was stirred for 1 hour. The suspension is filtered and the residue is washed first with a mixture of 130g of water and 215g of ethanol, then with 80g of water and 255g of ethanol and then with 320g of pure ethanol. The filter cake was dried under vacuum at 40 ℃ to give 457g of product (99% of theory).

Characterization of compound a:

the chemical structure of compound a has been confirmed using the described methods of structural analysis.

IR and Raman spectroscopy

Apparatus and measurement conditions

Attribution of characteristic bands

Table (b): attributing characteristic active vibration into a spectrum, namely v ≡ stretching vibration; a.ident.bending vibration; out of the o.o.p.ident.plane.

V ≡ telescopic vibration; a.ident.bending vibration; out-of-plane o.o.p.ident.

The IR spectrum is given in fig. 7.

The raman spectrum is given in fig. 8.

Ultraviolet/visible spectrum

Apparatus and measurement conditions

The uv/vis spectrum is given in figure 9.

NMR spectrum

¹H-NMR spectrum

Instrumental and experimental parameters:

structural formula of NMR Signal assignment

Chemical shift, signal multiplicity, relative nuclear number:

a) reference numerals refer to structural formulae for attributing NMR-signals

b) S = singlet bS = broad singlet D = doublet

T = triplet M = multiplet

Of Compound A¹The H-NMR spectrum is shown in FIG. 10.

¹³C-NMR spectrum

Instrumental and experimental parameters:

chemical shift, signal multiplicity, relative nuclear number:

a) reference numerals refer to structural formulae for attributing NMR-signals

b) S = singlet (C) D = doublet (CH) T = triplet (CH)₂) Q = quartet (CH)₃)

Of Compound A¹³The C-NMR spectra are given in FIGS. 11 and 12.

Mass spectrometry

Parameters of the instrument

Mass spectrometer Waters ZQ

Ionization mode ESI (electrospray-ionization)

Solvent CH₃CN/H₂O

Spectrogram analysis


		481.2	46
354.1	5
		261.7	26
241.2	100

The mass spectrum of compound a is given in figure 13. Relative peak intensity reference spectrum

Elemental analysis

Elemental analysis was performed by Bayer Industry Services, Leverkusen, Germany.

Results

Elemental analysis was consistent with compound a containing 7% water.

Other methods for preparing Compound "A

To a suspension of 366g of the compound of formula (I) in 1015g of water, 183g of aqueous hydrochloric acid (32%) are added while maintaining the temperature at 20 ℃ (+ -2 ℃) until a pH =3-4 is reached. The resulting mixture was stirred at room temperature for more than 10 minutes. Filter and wash the filter cake with an additional 82g of water. The filtrate was adjusted to pH 1.8-2.0 using aqueous hydrochloric acid (32%). The mixture was stirred at room temperature for 10 minutes, 146g of ethanol (100%) was added, and stirring was continued for 10 minutes. 1g of seed crystals were added, followed by 1592g of ethanol over 5 hours. The resulting material was removed by filtration, washed with a water-ethanol mixture, and dried in vacuo to give 410g (97%) of compound a with a purity of >99% according to HPLC.

Molecular profiling analysis (molecular profiling) of compound A in 24 breast cancer cell lines shows that tumor cells with PIK3CA mutation and/or HER2 expression are extremely sensitive to compound A, and the average IC is₅₀Values were 17nM (n =7) and 19nM (n =8), respectively. In contrast, wild-type PIK3CA and HER2 negative breast cancer cells were relatively insensitive or tolerant to compound a, with average IC₅₀The value was 773nM (greater than about 40 fold). The anti-proliferative and apoptotic effects of compound a were studied using a panel of breast cancer cell lines representing differential receptor expression status and genetic alterations of PIK3CA and PTEN. For apoptosis induction, compound a showed strong activity in PIK3CA mutant and/or HER2 positive breast cancer cells (e.g. BT20, BT 474).

Then, the molecular characteristics responsible for the apoptosis induction sensitivity and/or tolerance modulated by compound a were identified. It was found that expression of Bcl-2, but not Mcl-1 or survival, determines sensitivity to apoptosis. Thus, tumor cells that lack Bcl-2 expression (such as KPL-4, BT-474, and BT-20) (even in the presence of high levels of EGFR and phospho-ERK in BT-20 cells) undergo apoptosis immediately upon exposure to Compound A. On the other hand, although Compound A had potent antiproliferative activity (single digit nMIC)₅₀) But expressing high levels of Bcl-2 (e.g., T47D (PIK3CA)^mut) Tolerance to apoptosis induced by compound a. The combination of compound a with ABT-737 (an inhibitor of Bcl-2, sensitizing T47D cells to apoptosis) further supports the hypothesis that simultaneous inhibition of PI3K and Bcl-2 in Bcl-2 positive breast cancer may synergistically enhance tumor killing.

On the other hand, PTEN^null、EGFR^highAnd Bcl-2 negative MDA-MB-468 tumor cells are not only insensitive to the inhibition of proliferation by Compound A, but are also resistant to the induction of apoptosis by Compound A. Inhibition of mTORC1 by rapamycin and/or mTORC2 by Rictor down-regulation (knockdown) sensitizes MDA-MB468 cells to the proliferation inhibition and induction of apoptosis by compound a.

In summary, compound a was compared to the absence of BclInduction of apoptosis in breast cancer cells expressing HER2 and/or PIK3CA mutations is extremely potent in the case of-2. The combination of compound A with an anti-Bcl drug or mTOR inhibitor may be in Bcl-2 positive tumors or EGFR expression/PTEN, respectively^nullA promising approach to achieve tumor response in breast tumors. These findings provide a theoretical basis for the development of personalized therapies for the treatment of breast cancer molecular subtypes.

FIG. 1 shows the IC of Compound A in the proliferation assay and genetic status of breast cancer cell lines₅₀The correlation of (a).

Figure 2 shows the cell growth inhibition kinetics of compound a. The xcelligene technology (Roche, germany) was used to monitor the effect on tumor cell growth after compound a treatment. The Cell Index (CI) (related to the number of cells stuck to the bottom of the plate) was measured every 15 minutes for a treatment period of 80 hours (Giorrano C, Masi A, Pizzini A, Sansone A, Consarlvi V, ChiaraluceR, Lucente G. Synthesis and activity of fibrosis peptide inhibited to the17-21beta-amyloid sequence Eur J Med chem.2009;44: 179-189). CI was normalized to the time point of treatment (CI =1 at 24 hours).

FIG. 3 shows Compound A-induced cleavage of PARP in BT-20, BT-474, ZR-75-1, T47D, and MDA-MB468 cells, studied by Western blot analysis using GAPDH as an internal protein control, at the indicated time points.

Fig. 4 shows the survival promoting molecules of the Bcl family studied in untreated cells (a). Cells were lysed and subjected to western blot analysis to detect Bcl-2, Mcl-1, and survivin (survivin). GAPDH was used as an internal protein control.

FIG. 5 shows a quantitative analysis of the combined effect of compound A and ABT-737 on Caspase3 and 7 induction in T47D cells (C). By passing3/7(Promega, USA) and was classified by the software Analyze5(Bayer health Care, Germany)Analysis of apoptosis induction by compound a and ABT-737 as single agents as well as in combination. The combined effect is described by an isobologram and a combination index based on the equation (Chou et al, 2006) described by Chou. Combination index<1. =1 and>1 indicate synergistic, additive and antagonistic effects, respectively.

FIG. 6 shows that MDA-MB-468 cells transfected with Lentivirus (Lentivirus) express shRNA against Rictor. The cells were evaluated by western blot analysis for expression of mTORC2 component rictor (a). PARP cleavage was induced by compound a treatment in combination with inhibition of mTORC1 or mTORC2 (B). shControl and shRictor MDA-MB468 cells were treated with indicated drugs for 48 hours and analyzed for lysis of PARP. GAPDH was used as an internal protein control.

Control substance

Rapamycin obtained from Sigma (St Louis, MO, USA) was used as reference inhibitor. ABT-737 was obtained from Selleck Chemicals (Houston, TX, USA).

In summary, compound a was extremely effective for inducing apoptosis in breast cancer cells expressing HER2 and/or PIK3CA mutations in the absence of Bcl-2. The combination of compound A and anti-Bcl drug or mTOR inhibitor should be in Bcl-2 positive tumor or EGFR expression/PTEN, respectively^nullAchieving tumor response in breast tumors provides a promising avenue. These findings provide a theoretical basis for the development of personalized therapies for the treatment of breast cancer molecular subtypes.

Thus, as mentioned above, the present invention relates to the use of biomarkers involved in the modification of Bcl expression, HER family expression and/or activation, PIK3CA signalling and/or PTEN deletion for predicting the sensitivity and/or tolerance of a cancer (such as breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, HER2 receptor positive breast cancer and hormone receptor positive breast cancer) patient to a 2, 3-dihydroimidazo [1,2-c ] quinazoline compound as defined herein to provide a theory-based synergistic combination as defined herein to overcome tolerance.

According to one embodiment, the present invention relates to the use of biomarkers involved in the modification of Bcl expression, HER family expression and/or activation, PIK3CA signalling and/or PTEN deletion for predicting the sensitivity and/or tolerance of a cancer (such as breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, HER2 receptor positive breast cancer and hormone receptor positive breast cancer) patient to a 2, 3-dihydroimidazo [1,2-c ] quinazoline compound as defined herein to provide a theory-based synergistic combination as defined herein to overcome tolerance (patient stratification).

According to one embodiment, the invention relates to a method of determining the levels of components of one or more of Bcl expression, HER family expression and/or activation, PIK3CA signaling, and/or PTEN deletion, wherein:

in said Bcl expression, said component is e.g. Bcl,

-in said HER family expression and/or activation, PIK3CA signaling, said component is for example EGF-R, and

-in the PTEN absence, the component is e.g. PTEN.

Furthermore, as mentioned above, the present invention relates to a combination of:

and

b) one or more further active agents as defined above, in particular an active agent selected from the group consisting of an anti-angiogenic agent, an anti-hyperproliferative agent, an anti-inflammatory agent, an analgesic, an immunomodulatory agent, a diuretic, an anti-arrhythmic agent, an anti-hypercholesterolemic agent, an anti-dyslipidemic agent, an anti-diabetic agent or an anti-viral agent, more in particular one or more further active agents selected from the group consisting of:

-a Bcl-binding peptide;

bcl siRNAs such as PNT-2258;

antisense oligonucleotides, such as BclKlex; and

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Claims

1. Use of 2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide, or a physiologically acceptable salt or stereoisomer thereof, or a pharmaceutical composition comprising such a compound, or a physiologically acceptable salt, or stereoisomer thereof, as the sole active agent in the manufacture of a medicament for the treatment or prevention of inflammatory, triple negative, Her2 receptor positive or hormone receptor positive breast cancer.

2. The following compositions:

a) 2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide or a physiologically acceptable salt or stereoisomer thereof; or a pharmaceutical composition comprising such a compound or a physiologically acceptable salt or stereoisomer thereof;

and

b) one or more additional active agents selected from the group consisting of:

-a Bc1 inhibitor selected from: ABT-737; and

-an mTOR pathway inhibitor selected from: rapamycin (sirolimus).

3. The composition of claim 2, wherein the additional active agent is rapamycin.

4. The composition of claim 2, wherein the additional active agent is ABT-737.

5. A pharmaceutical composition comprising a combination of:

a) 2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide or a physiologically acceptable salt or stereoisomer thereof; and

b) one or more additional active agents selected from the group consisting of:

-a Bc1 inhibitor selected from: ABT-737; and

-an mTOR pathway inhibitor selected from: rapamycin (sirolimus).

6. Use of a composition comprising or a pharmaceutical composition comprising such a combination for the manufacture of a medicament for the treatment or prevention of inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer:

a) 2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide or a physiologically acceptable salt or stereoisomer thereof;

or a pharmaceutical composition comprising said 2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide or a physiologically acceptable salt or stereoisomer thereof;

and

b) one or more additional active agents selected from the group consisting of:

-a Bc1 inhibitor selected from: ABT-737; and

-an mTOR pathway inhibitor selected from: rapamycin (sirolimus).