NZ615502B2 - Use of substituted 2,3-dihydroimidazo[1,2-c]quinazolines - Google Patents

Abstract

The present invention relates to, use 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 of a pharmaceutical composition containing same, as a sole active agent, or of a combination of a) said compound or a pharmaceutical composition containing said compound and b) one or more further active agents, for the preparation of a medicament for the treatment or prophylaxis of cancer; - combinations of a) said compound and b) one or more further active agents; - a pharmaceutical composition comprising said compound as a sole active agent for the treatment of breast cancer; - a pharmaceutical composition comprising a combination of a) said compound and b) one or more further active agents; - use of biomarkers involved in the modification of Bel expression, HER family expression and/or activation, PIK3CA signaling and / or loss of PTEN for predicting the sensitivity and /or resistance of a cancer patient to said compound and providing a rationale-based synergistic combination as defined herein to increase sensitivity and/or to overcome resistance; and - a method of determining the level of a component of one or more of Bcl expression, HER family expression and/or activation, PIK3CA signaling and / or loss of PTEN. sition containing said compound and b) one or more further active agents, for the preparation of a medicament for the treatment or prophylaxis of cancer; - combinations of a) said compound and b) one or more further active agents; - a pharmaceutical composition comprising said compound as a sole active agent for the treatment of breast cancer; - a pharmaceutical composition comprising a combination of a) said compound and b) one or more further active agents; - use of biomarkers involved in the modification of Bel expression, HER family expression and/or activation, PIK3CA signaling and / or loss of PTEN for predicting the sensitivity and /or resistance of a cancer patient to said compound and providing a rationale-based synergistic combination as defined herein to increase sensitivity and/or to overcome resistance; and - a method of determining the level of a component of one or more of Bcl expression, HER family expression and/or activation, PIK3CA signaling and / or loss of PTEN.

Description

USE OF SUBSTITUTED 2,3-DIHYDROIMIDAZO[1,2-C]QU|NAZOL|NES The present invention relates to : - use of a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or of a pharmaceutical composition containing same, as a sole active agent, or of a combination of a) said compound or a pharmaceutical composition containing said compound and b) one or more further active agents, for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast cancer, which is classified into several subtypes in the clinic, such as hormone receptor positive breast cancer, Her2 receptor positive breast cancer, triple negative breast cancer and inflammatory breast cancer, as a single agent or in combination with one or more other active agents ; - ations of a) said compound and b) one or more r active agents ; - a pharmaceutical composition sing said compound as a sole active agent for the treatment of cancer ; - a pharmaceutical composition comprising a combination of a) said compound and b) one or more further active agents ; - use of biomarkers involved in the modification of Bcl expression, HER family expression and/or activation, P|K3CA signaling and / or loss of PTEN for predicting the ivity and/or resistance of a cancer patient to said compound and providing a ale-based synergistic combination as defined herein to increase sensitivity and/or to overcome resistance ; [Annotation] micheles None set by micheles ation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles ionNone set by micheles [Annotation] micheles Unmarked set by micheles - a method of determining the level of a component of one or more of Bcl expression, HER family expression and/or activation, P|K3CA signaling and / or loss of PTEN.

BACKGROUND OF THE ION In recent decades the concept of developing anti-cancer medications which target abnormally active protein kinases has led to a number of successes. In addition to the actions of protein kinases, lipid kinases also play an ant role in generating critical regulatory second messengers. The P|3K family of lipid kinases generates 3’- phosphoinositides that bind to and activate a y of cellular targets, initiating a wide range of signal transduction cascades (Vanhaesebroeck et al., 2001; Toker, 2002; Pendaries et al., 2003; Downes et al., 2005).

These cascades tely induce changes in multiple cellular processes, including cell proliferation, cell survival, differentiation, vesicle trafficking, migration, and chemotaxis.

P|3Ks can be divided into three distinct classes based upon differences in both structure, and substrate preference. While members of the Class II family of P|3Ks have been implicated in the regulation of tumor growth (Brown and Shepard, 2001; Traer et al., 2006), the bulk of research has d on the Class | enzymes and their role in cancer (Vivanco and Sawyers, 2002; Workman, 2004, Chen et al., 2005; Hennessey et al., 2005; er et al., 2005; Stephens et al., 2005; Cully et al., 2006).

Class | P|3Ks have traditionally been divided into two ct sub-classes based upon differences in protein subunit ition. The Class IA P|3Ks are comprised of a catalytic p110 catalytic t (p110c1, p11OB or p110y) heterodimerized with a member of the p85 regulatory subunit family. In contrast, the Class IB P|3K catalytic subunit ) heterodimerizes with a distinct p101 regulatory subunit (reviewed by [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by es [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles ionNone set by es [Annotation] micheles ed set by micheles Vanhaesebroeck and Waterfield, 1999; Funaki et al., 2000; Katso et al., 2001). The C-terminal region of these proteins contains a catalytic domain that possesses distant homology to protein kinases. The P|3Ky structure is similar to Class IA p1105, but lacks the N-terminal p85 binding site (Domin and Waterfield, 1997). Though similar in overall structure, the homology between catalytic p110 subunits is low to moderate. The highest homology between the P|3K isoforms is in the kinase pocket of the kinase .

The Class | P|3K isoforms associate with activated receptor tyrosine kinases (RTKs) (including PDGFR, EGFR, VEGFR, lGF1-R, c-KIT, CSF-R and Met), ne receptors, GPCRs, integrins, or with tyrosine phosphorylated adapter proteins (such as Grb2, Cbl, IRS-1 or Gab1), via their p85 regulatory subunits resulting in stimulation of the lipid kinase activity. Activation of the lipid kinase activity of the p11OB and p110y isoforms has been shown to occur in response to binding to activated forms of the ras Oncogene (Kodaki et al, 1994). In fact, the oncogenic activity of these ms may require binding to ras (Kang et al., 2006).

In contrast, the p110a and p1106 ms exhibit oncogenic ty independent of ras binding, through tutive activation of Akt.

Class | P|3Ks catalyze the conversion of PI(4,5)P2 [Ple] to PI(3,4,5)P3 [PIP3]. The production of P|P3 by P|3K affects multiple signaling processes that regulate and coordinate the biological end points of cell proliferation, cell survival, differentiation and cell migration. P|P3 is bound by Pleckstrin-Homology (PH) domain-containing proteins, including the phosphoinositide-dependent kinase, PDK1 and the Akt proto-oncogene product, localizing these proteins in s of active signal uction and also contributing directly to their activation (Klippel et al., 1997; Fleming et al., 2000; Itoh and Takenawa, 2002; Lemmon, 2003). This co-localization of PDK1 with Akt facilitates the phosphorylation and activation of Akt. Carboxy-terminal phosphorylation [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles ation] micheles Unmarked set by micheles of Akt on Ser473 es phosphorylation of Thr308 in the Akt activation loop (Chan and Tsichlis, 2001; Hodgekinson et al., 2002; Scheid et al., 2002; Hresko et al., 2003). Once active, Akt phosphorylates and regulates multiple regulatory kinases of pathways that directly nce cell cycle progression and cell survival.

Many of the effects of Akt activation are mediated via its negative regulation of pathways which impact cell survival and which are commonly dysregulated in . Akt promotes tumor cell survival by regulating components of the apoptotic and cell cycle machinery. Akt is one of several kinases that orylate and inactivate pro-apoptotic BAD proteins (del Paso et al., 1997; Pastorino et al., 1999). Akt may also promote cell survival through blocking cytochrome C-dependent caspase activation by phosphorylating Caspase 9 on Ser19" (Cardone et al., 1998).

Akt impacts gene transcription on several levels. The Akt-mediated phosphorylation of the MDM2 E3 ubiquitin ligase on Ser166 and Ser186 facilitates the nuclear import of MDM2 and the formation and activation of the ubiquitin ligase complex. Nuclear MDM2 targets the p53 tumor suppressor for degradation, a process that can be blocked by 02 (Yap et al., 2000; Ogarawa et al., 2002). Downregulation of p53 by MDM2 negatively s the transcription of p53-regulated pro-apoptotic genes (e.g. Bax, Fas, PUMA and DR5), the cell cycle inhibitor, p21C‘P1, and the PTEN tumor suppressor (Momand et al., 2000; Hupp et al., 2000; Mayo et al., 2002; Su et al., 2003). Similarly, the Akt-mediated phosphorylation of the Forkhead transcription factors FKHR, FKHRL and AFX (Kops et al., 1999; Tang et al., 1999), facilitates their binding to 14- 3-3 proteins and export from the cell nucleus to the cytosol t et al., 1999). This onal inactivation of Forkhead activity also impacts pro-apoptotic and pro-angiogenic gene transcription including the transcription of Fas ligand (Ciechomska et al., 2003) Bim, a pro- apoptotic Bcl-2 family member (Dijkers et al., 2000), and the [Annotation] micheles None set by micheles ation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] micheles ed set by micheles Angiopoietin-1 (Ang-1) antagonist, Ang-2 (Daly et al., 2004). ad transcription factors regulate the expression of the cyclin-dependent kinase (Cdk) inhibitor p27KiP1. , P|3K inhibitors have been demonstrated to induce p27Kip1 expression resulting in Cdk1 inhibition, cell cycle arrest and apoptosis (Dijkers et al., 2000). Akt is also reported to phosphorylate p21C‘P10n Thr145 and p27Kip1 on Thr157 facilitating their association with 143 proteins, resulting in r export and cytoplasmic retention, preventing their inhibition of nuclear Cdks (Zhou et al., 2001; Motti et al., 2004; Sekimoto et al., 2004). In addition to these effects, Akt phosphorylates IKK (Romashkova and Makarov, 1999), leading to the phosphorylation and degradation of IKB and subsequent nuclear translocation of NFKB, resulting in the expression of survival genes such as IAP and .

The PI3K/Akt pathway is also linked to the suppression of apoptosis through the JNK and p38MAPK MAP Kinases that are associated with the induction of apoptosis. Akt is postulated to suppress JNK and p38MAPK signaling through the phosphorylation and inhibition of two 8 regulatory kinases, Apoptosis Signal-regulating Kinase 1 (ASK1) (Kim et al., 2001: Liao and Hung, 2003; Yuan et al., 2003), and Mixed Lineage Kinase 3 (MLK3) -Ilasaca et al., 1997; al et al., 2003; Figueroa et al., 2003;). The induction of p38MAPK activity is observed in tumors treated with cytotoxic agents and is required for those agents to induce cell death (reviewed by Olson and Hallahan, 2004). Thus, inhibitors of the PI3K pathway may promote the activities of co- administered cytotoxic drugs.

An additional role for PI3K/Akt signaling involves the tion of cell cycle progression through modulation of Glycogen Synthase Kinase 3 3O (GSK3) activity. GSK3 activity is elevated in quiescent cells, where it phosphorylates cyclin D1 on Serzg", targeting the n for ubiquitination and ation (Diehl et al., 1998) and blocking entry [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles into e. Akt ts GSK3 activity through phosphorylation on Ser" (Cross et al., 1995). This results in the elevation of Cyclin D1 levels which promotes cell cycle progression. Inhibition of GSK3 activity also impacts cell proliferation through activation of the wnt/beta-catenin signaling pathway (Abbosh and Nephew, 2005; Naito et al., 2005; Wilker et al., 2005; Kim et al., 2006; les et al., 2006). Akt mediated phosphorylation of GSK3 results in stabilization and nuclear localization of the atenin protein, which in turn leads to increased expression of c-myc and cyclin D1, s of the beta-catenin/ch pathway.

Although P|3K signaling is utilized by many of the signal uction networks associated with both oncogenes and tumor suppressors, P|3K and its activity have been linked directly to cancer. Overexpression of both the p110a and p11OB isoforms has been observed in bladder and colon tumors and cell lines, and overexpression generally correlates with increased P|3K ty (Bénistant et al., 2000). Overexpression of p110a has also been reported in ovarian and cervical tumors and tumor cell lines, as well as in us cell lung carcinomas. The overexpression of p110c1 in cervical and ovarian tumor lines is associated with increased PI3K activity (Shayesteh et al., 1999; Ma et al., 2000). Elevated PI3K activity has been ed in colorectal carcinomas (Phillips et al., 1998) and increased expression has been observed in breast carcinomas tein et al., 1999).

Over the last few years, somatic ons in the gene encoding p110a (PIK3CA) have been identified in numerous cancers. The data collected to date suggests that P|K3CA is mutated in approximately 32% of colorectal s (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 (Byun et al., 2003; Samuels et al., 2004; Li et al., 2005), [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles 36% of hepatocellular carcinomas (Lee et al., 2005), 4-12% of n s (Levine et al., 2005; Wang et al., 2005), 4% of lung cancers (Samuels et al., 2004; Whyte and Holbeck, 2006), and up to 40% of endometrial s (Oda et al., 2005). P|K3CA mutations have been reported in oligodendroma, ytoma, medulloblastoma, and thyroid tumors as well (Broderick et al., 2004; Garcia-Rostan et al., 2005).

Based upon the observed high frequency of mutation, P|K3CA is one of the two most frequently mutated genes associated with cancer, the other being K-ras. More than 80% of the P|K3CA mutations cluster within two regions of the protein, the helical (E545K) and catalytic (H1047R) domains. Biochemical analysis and protein expression studies have demonstrated that both ons lead to increased constitutive p1100c catalytic ty and are in fact, oncogenic (Bader et al., 2006; Kang et al., 2005; Samuels et al., 2005; Samuels and Ericson, 2006). Recently, it has been reported that P|K3CA knockout mouse embryo fibroblasts are deficient in signaling downstream from various growth factor receptors (IGF-1, Insulin, PDGF, EGF), and are resistant to transformation by a variety of oncogenic RTKs (IGFR, wild-type EGFR and somatic activating mutants of EGFR, Her2/Neu)(Zhao et al., 2006).

Functional studies of P|3K in vivo have demonstrated that siRNA- mediated downregulation of p11OB inhibits both Akt phosphorylation and HeLa cell tumor growth in nude mice (Czauderna et al., 2003). In similar experiments, siRNA-mediated downregulation of p11OB was also shown to inhibit the growth of malignant glioma cells in vitro and in vivo (Pu et al., 2006). Inhibition of P|3K function by dominant-negative p85 regulatory subunits can block mitogenesis and cell transformation (Huang et al., 1996; Rahimi et al., 1996). Several somatic ons in the genes encoding the p85a and p858 regulatory ts of P|3K that 3O result in elevated lipid kinase activity have been identified in a number of cancer cells as well (Janssen et al., 1998; z et al., 1998; Philp et al., 2001; Jucker et al., 2002; Shekar et al., 2005). Neutralizing P|3K [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles ation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles ation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles antibodies also block mitogenesis and can induce apoptosis in vitro (Roche et al., 1994: Roche et al., 1998; ant et al., 2000). In vivo proof-of-principle studies using the P|3K inhibitors LY294002 and wortmannin, demonstrate that inhibition of PI3K signaling slows tumor growth in vivo (Powis et al., 1994; Shultz et al., 1995; Semba et al., 2002; Ihle et al., 2004).

Overexpression of Class | P|3K activity, or stimulation of their lipid kinase activities, is associated with resistance to both ed (such as imatinib and tratsuzumab) and cytotoxic chemotherapeutic ches, 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). Activation of PI3K has also been shown to lead to expression of multidrug resistant protein-1 (MRP-1) in prostate cancer cells and the subsequent induction of resistance to chemotherapy (Lee et al., 2004).

The importance of PI3K signaling in tumorigenesis is further underscored by the findings that the PTEN tumor suppressor, a Pl(3)P atase, is among the most commonly inactivated genes in human cancers (Li et al., 1997, Steck et al., 1997; Ali et al., 1999; lshii et al., 1999). PTEN dephosphorylates PI(3,4,5)P3 to Pl(4,5)P2 y antagonizing PI3K- dependent signaling. Cells containing functionally inactive PTEN have elevated levels of PIP3, high levels of activity of PI3K signaling (Haas- Kogan et al., 1998; Myers et al., 1998; Taylor et al., 2000), increased proliferative potential, and decreased sensitivity to pro-apoptotic stimuli olic et al., 1998). Reconstitution of a functional PTEN suppresses P|3K signaling (Taylor et al., 2000), inhibits cell growth and re-sensitizes cells to optotic i (Myers et al., 1998; Zhao et al., 2004).

Similarly, restoration of PTEN function in tumors lacking functional PTEN inhibits tumor growth in vivo (Stahl et al., 2003; Su et al., 2003; Tanaka and Grossman, 2003) and izes cells to cytotoxic agents (Tanaka and Grossman, 2003).

[Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] es None set by micheles [Annotation] micheles MigrationNone set by micheles ation] micheles Unmarked set by micheles The class | family of P|3Ks clearly plays an important role in the regulation of multiple signal transduction pathways that promote cell al and cell proliferation, and activation of their lipid kinase activity contributes significantly to the development of human malignancies. Furthermore, inhibition of PI3K may potentially circumvent the cellular mechanisms that underlie resistance to chemotherapeutic agents. A potent inhibitor of Class | P|3K activities would therefore have the potential not only to inhibit tumor growth but to also ize tumor cells to pro-apoptotic stimuli in vivo.

Signal transduction pathways originating from chemoattractant receptors are considered to be important targets in lling leukocyte motility in inflammatory diseases. Leukocyte trafficking is controlled by chemoattractant s that activate heterotrimeric GPCRs and thereby trigger a variety of downstream intracellular events. Signal transduction along one of these pathways that results in mobilization of free Ca2+, cytoskelatal reorganization, and directional movement depends on lipid- dervied second messengers producted by P|3K activity (Wymann et al., 2000; Stein and Waterfield, 2000).

P|3Ky modulates baseline cAMP levels and controls contractility in cells.

Recent research indicates that alterations in ne cAMP levels bute to the increased contractility in mutant mice. This research, therefore, shows that P|3Ky inhibitors afford potential treatments for tive heart failure, ia, pulmonary hypertension, renal failure, cardiac hypertrophy, sclerosis, oembolism, and diabetes.

P|3K inhibitors would be expected to block signal transduction from GPCRs and block the activation of various immune cells, g to a broad anti-inflammatory profile with potential for the treatment of [Annotation] micheles None set by es [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by es inflammatory and immunoregulatory diseases, including , atopic dermatitis, rhinitis, ic diseases, chronic obstructive pulmonary disease (COPD), septic shock, joint diseases, autoimmune pathologies such as rheumatoid arthritis and Graves’ disease, diabetes, cancer, myocardial contractility disorders, oembolism, and atherosclerosis.

Breast cancer is a world health problem, and in the United States this disease is the second most common cause of cancer death in women.

About 1 in 8 women in the United States (12%) will develop invasive breast cancer over the course of her lifetime. In 2010, an estimated 207,090 new cases of invasive breast cancer were expected to be diagnosed, along with 54,010 new cases of non-invasive breast .

About 39,840 women were expected to die in 2010 from breast cancer.

The classification and treatment options are usually based on the receptor status. The three most important in the present classification are estrogen receptor (ER), progesterone receptor (PR), and HER2/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 (HER2-). Cells with none of these receptors are called basal-like or triple negative. Recently, DNA-based classification is also used in the clinic. As ic DNA mutations or gene sion profiles are fied in the cancer cells, this classification may guide the selection of treatments, either by targeting these s, or by predicting from the DNA e which non-targeted therapies are most effective.

The Pl3K/PTEN/AKT pathway has been found to be frequently activated and/or mutated in human breast cancer, which contributes to the development and ssion of breast cancer, as well as drug resistance. As genetic alterations of PIK3CA and PTEN, as well as P|3K pathway activation are observed in almost all breast cancer subtypes, [Annotation] micheles None set by es [Annotation] micheles MigrationNone set by micheles [Annotation] es Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles such as HER2 positive, hormone receptor positive, or triple negative breast cancers, it is important to define the strategy for the pment of P|3K pathway inhibitors in breast cancer. The t ion is thus to identify molecular s predicting the sensitivity and/or resistance of the cancer patients toward the P|3K inhibitors described herein. Furthermore, the present invention also relates to the identification of resistance mechanisms and therefore provides a rationale-based synergistic combination to overcome the ance.

To the Applicant’s knowledge, no ic disclosure in the prior art is known that 2,3-dihydroimidazo[1,2-c]quinazoline compounds would be effective in the treatment or prophylaxis of inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

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, show a cial effect in the treatment or prophylaxis of breast cancer, in particular inflammatory breast , triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

Thus, in accordance with a first aspect, the present invention relates to the use of 2,3-dihydroimidazo[1,2-c]quinazoline compounds, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as a sole active agent, or of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, e, hydrate or stereoisomer f, for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast cancer, in particularinflammatory breast cancer, triple ve breast , Her2 receptor positive breast cancer, hormone receptor positive breast cancen [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles ionNone set by micheles [Annotation] micheles Unmarked set by micheles In accordance with a second aspect, the present invention s to combinations 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 an active agent selected from an anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents ed from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- ypol), SPC-2004 (Beclanorsen), lG-105, WL-276, Bl-97C1, I-VRL (lmmunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, FIB-1402, EU-517 ; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense y oligonucleotide, such as BclKlex ; and - an tor of the mTOR pathway, such as rapamycin or a rapamycin analogue, such as Rapamycin (Sirolimus), imus (RAD-001, Afinitor), limus (ABT-578, Endeavor), Temisirolimus (CCI-779, Torisel), Ridaforolimus 576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, such as WYE-132, OSl-027, INK-128, OSl-027, 14, AZD-8055, CC-223, ABI-009, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKl-402, SB-2015, WYE-354, KU-0063794, X-387, BEZ-235.

In accordance with a third aspect, the present invention relates to pharmaceuticalcompositions comprising a 2,3-dihydroimidazo[1,2- [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] micheles Unmarked set by es c]quinazoline compound, or a physiologically acceptable salt, solvate, hydrate or isomer thereof, as a sole active agent, for the treatment of cancer, e.g. breast cancer, in ular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

In ance with a fourth aspect, the present invention relates to pharmaceutical compositions comprising a combination of : a) a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a physiologically acceptable salt, solvate, e or stereoisomer thereof ; and b) one or more further active agents, in ular an active agent selected from an anti-angiogenesis, yper-proliferative, flammatory, sic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : - a Bcl inhibitor, such as ABT-737, 3 (Navitoclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), |G-105, WL-276, 1, |-VRL (Immunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, FIB-1402, EU-517 ; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKlex ; and - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, or), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, such as WYE-132, OSI-027, INK-128, OSI-027, AZD-2014, [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles ation] micheles MigrationNone set by micheles ation] micheles Unmarked set by micheles AZD-8055, CC-223, ABl-OO9, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKl-402, SB-2015, WYE-354, KU-0063794, X-387, BEZ-235.

In accordance with a fifth aspect, the present invention relates to the use of combinations of : a) a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a physiologically acceptable salt, e, hydrate or stereoisomer thereof ; or of a pharmaceutical ition containing such a compound or a physiologically acceptable salt, solvate, hydrate or isomer thereof, b) one or more further active agents, in particular an active agent selected from a n anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents ed from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), 5, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), |G-105, WL-276, BI-97C1, |-VRL (Immunovivorelbine), DATS ridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, FIB-1402, EU-517; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy ucleotide, such as BclKlex ; and - an inhibitor of the mTOR pathway, such as cin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, or), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, [Annotation] micheles None set by es [Annotation] micheles ionNone set by micheles ation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles Torisel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, such as WYE-132, OSI-027, INK-128, OSI-027, AZD-2014, AZD-8055, CC-223, ABI-009, EXEL-3885, EXEL-4451, , OXA-01, PKI-402, SB-2015, 4, 3794, X-387, BEZ-235 ; for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast cancer, in particular inflammatory beast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

In accordance with a sixth aspect, the present invention relates to use of biomarkers involved in the cation of Bcl expression, HER family expression and/or activation, PIK3CA signaling and / or loss of PTEN for predicting the sensitivity and/or resistance of a patient with cancer, e.g. breast , in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone or positive breast cancer, to a 2,3-dihydroimidazo[1,2-c]quinazoline compound as d herein, thus providing a rationale—based synergistic combination as defined herein to overcome the resistance nt stratification).

In accordance with a seventh aspect, the present invention relates to a method of determining the level of a component of one or more of Bcl expression, HER family expression and/or activation, PIK3CA signaling and / or loss of PTEN, wherein : - in said Bcl expression, said component is Bcl, for example, in said HER family expression and/or tion, PIK3CA signaling, said component is EGF-R, for example, and in said loss of PTEN, said component is PTEN, for example.

In accordance a particular embodiment of any of the above aspects of the present invention, said breast cancer is inflammatory breast cancer.

In ance a particular embodiment of any of the above aspects of the present ion, said breast cancer is triple negative breast In accordance a particular embodiment of any of the above aspects of the present invention, said breast cancer is Her2 receptor positive breast cancer.

In accordance a ular embodiment of any of the above aspects of the present invention, said breast cancer is hormone receptor positive breast cancer.

The present invention as claimed herein is described in the following items 1 to 7: 1. Use of 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomer as a sole active agent, or of a pharmaceutical composition containing such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, for the preparation of a medicament for the treatment or laxis of inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, or hormone receptor positive breast cancer. 2. A combination of : a) 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; 7443598_1 (GHMatters) P94796.NZ KIRSTENA or a pharmaceutical composition containing such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, and b) one or more further active agents selected from the group consisting of : - a Bcl inhibitor, selected from ABT-737, ABT-263 oclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), IG-105, , BI-97C1, DATS (Allitridin), 03 (Apogossypol), D-G-3139 (Genasense); - a Bcl binding peptide; - a Bcl siRNA, which is PNT-2258; - an antisense therapy oligonucleotide, which is BclKlex; and - an inhibitor of the mTOR pathway, selected from Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, Torisel), Ridaforolimus 576, MK-8669), 3, or an inhibitor of mTOR kinase, selected from WYE- 132, OSI-027, 8, 7, AZD-2014, AZD-8055, CC-223, ABI-009, NV-128, OXA-01, PKI-402, WYE-354, KU-0063794, X-387, BEZ-235. 3. The combination according to item 2, n said further active agent is rapamycin. 4. The combination according to item 2, wherein said further active agent is ABT-737.

. A pharmaceutical composition which comprises a combination of: a) 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- oimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a 7443598_1 (GHMatters) P94796.NZ KIRSTENA logically acceptable salt, solvate, hydrate or isomer thereof; and b) one or more further active agents selected from the group consisting - a Bcl inhibitor, selected fromABT-737, ABT-263 oclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), IG-105, , BI-97C1, DATS (Allitridin), CNDO-103 (Apogossypol), 39 ense); - a Bcl binding peptide; - a Bcl siRNA, which isPNT-2258; - an antisense therapy oligonucleotide, which isBclKlex; and - an inhibitor of the mTOR pathway, selected from Rapamycin (Sirolimus), Everolimus (RAD-001, or), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, selected from WYE- 132, OSI-027, INK-128, OSI-027, AZD-2014, AZD-8055, CC-223, ABI-009, NV-128, OXA-01, PKI-402, WYE-354, KU-0063794, X-387, BEZ-235. 6. Use of a combination of: a) 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a physiologically acceptable salt, solvate, e or stereoisomer thereof; or of a pharmaceutical composition containing said 2-amino-N-[7- methoxy(3-morpholinylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazolinyl]pyrimidinecarboxamide, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, b) one or more further active agents selected from the group consisting 7443598_1 (GHMatters) .NZ KIRSTENA - a Bcl inhibitor, selected from ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), IG-105, WL-276, BI-97C1, DATS (Allitridin), CNDO-103 (Apogossypol), D-G-3139 (Genasense); - a Bcl binding peptide; - a Bcl siRNA, which is PNT-2258; - an antisense therapy oligonucleotide, which is BclKlex; and - an inhibitor of the mTOR pathway, selected from Rapamycin imus), imus (RAD-001, Afinitor), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, 9), TAFA-93, or an inhibitor of mTOR kinase, such as WYE-132, OSI-027, INK-128, 7, AZD-2014, AZD-8055, CC-223, 9, NV- 128, OXA-01, PKI-402, WYE-354, KU-0063794, X-387, BEZ-235; or a pharmaceutical composition containing such a combination, for the preparation of a medicament for the treatment or prophylaxis of inflammatory breast cancer, triple negative breast , Her2 receptor ve breast cancer, hormone receptor positive breast cancer.

Detailed description of the ion A first aspect of the present invention relates to the use of a compound of general formula (A) : Y1 Y2 Z4 Y3 Z3 N Z1 N X O R1 7443598_1 (GHMatters) P94796.NZ KIRSTENA in which : X represents CR5R6 or NH; Y1 represents CR3 or N; the chemical bond between Y2------ Y3 ents a single bond or double bond, with the proviso that when theY2------ Y3 represents a double bond, Y2 and Y3 independently represent CR4 or N, and 7443598_1 (GHMatters) P94796.NZ KIRSTENA [Annotation] es None set by es ation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles ation] micheles Unmarked set by micheles when YzlY3 represents a single bond, Y2 and Y3 ndently represent CR3R4 or NR4; 21, 22, Z3 and Z4 independently represent CH or N; , CR2 R1 represents aryl optionally having 1 to 3 substituents selected from R", C3.g cycloalkyl optionally having 1 to 3 substituents selected from R", C14, alkyl optionally substituted by aryl, heteroaryl, CH, alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen, C14, alkoxy optionally substituted by carboxy, aryl, heteroaryl, C1-6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen, a 3 to 15 membered mono- or lic heterocyclic ring that is saturated or rated, optionally having 1 to 3 substituents selected from R", and contains 1 to 3 heteroatoms selected from the group consisting of N, O and wherein R11 represents halogen, nitro, hydroxy, cyano, carboxy, amino, N-(C1.6alkyl)amino, N-(hydroxyC1.6alkyl)amino, N,N- di(C1.6alkyl)amino, N-(C1—6acyl)amino, N-(formyl)-N- lkyl)amino, N-(C1.6alkanesulfonyl) amino, N-(carb- oxyC1—6alkyl)-N-(C1.6alkyl)amino, N-(C1. 6alkoxycabonyl)amino, N-[N,N-di(C1.6alkyl)amino meth- ylene]amino, N-[N,N-di(C1.6alkyl)amino (C1. 6alkyl)methylene]amino, N-[N,N-di(C1.6alkyl)amino C2. balkenyl]amino, aminocarbonyl, N-(C1.6alkyl)aminocarbonyl, N,N-di(C1.6alkyl)aminocarbonyl, C3.gcycloalkyl, CH, alkylthio, C1.6alkanesulfonyl, sulfamoyl, C1.6alkoxycarbonyl, [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] es Unmarked set by es [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles amino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R101, N-(aryl C1—6alkyl)amino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R101, aryl C1-6alkoxycarbonyl wherein said aryl moiety is optionally having 1 to 3 substituents selected from R101, C1.6alkyl ally substituted by mono-, di- or tri- halogen, amino, N-(C1.6alkyl)amino or N,N-di(C1. )amino, C1.6alkoxy optionally substituted by mono-, di- or tri- halogen, N-(C1.6alkyl)sulfonamide, or N-(aryl)sulfonamide, a 5 to 7 membered saturated or unsaturated ring having 1 to 3 heteroatoms selected from the group consisting of O, S and N, and optionally having 1 to 3 substituents selected from R101 wherein R101 represents halogen, carboxy, amino, N-(C1.6 alkyl)amino, N,N-di(C1.6alkyl)amino, aminocarbonyl, N-(C1.6alkyl)aminocarbonyl, N,N-di(C1. salkyl)aminocarbonyl, pyridyl, C1-6 alkyl optionally substituted by cyano or mono- di- or tri- n, C1.6alkoxy optionally substituted by cyano, carboxy, amino, N'(C1-6 alkyl)amino, (C1.6alkyl)amino, aminocarbonyl, N-(C1.6alkyl)aminocarbonyl, N,N- [Annotation] micheles None set by micheles [Annotation] micheles ionNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] es ionNone set by micheles [Annotation] micheles Unmarked set by micheles di(C1-6alkyl)aminocarbonyl or mono-, di- or tri- represents hydroxy, halogen, nitro, cyano, amino, N-(C1. 6alkyl)amino, N,N-di(C1.6alkyl)amino, N-(hydroxyC1. 6alkyl)amino, roxyC1.6alkyl)-N-(C1.6alkyl)amino, CH, acyloxy, aminoC1.6 acyloxy, C2.6alkenyl, aryl, a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by hydroxy, C14, alkyl, C14, alkoxy, oxo, amino, amino C1.6alkyl, N-(C1.6alkyl)amino, N,N-di(C1.6alkyl)amino, N-(CH, acyl)amino, N-(C1.6alkyl)carbonylamino, phenyl, phenyl C14, alkyl, carboxy, C1.6alkoxycarbonyl, aminocarbonyl, N-(C1. 6alkyl)aminocarbonyl, or N,N-di(C1.6alkyl)amino, -C(O)- R20 wherein R20 represents CH, alkyl, C14, alkoxy, amino, N-(C1. salkyl)amino, N,N-di(C1.6alkyl)amino, N-(C1-e acyl)amino, or a 5-7 membered saturated or unsaturated heterocyclic ring having 1 t o 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by C14> alkyl, C1-6 alkoxy, oxo, amino, N-(C1.6alkyl)amino, N,N-di(C1. )amino, N'(C1-6 acyl)amino, phenyl, or benzyl, C14, alkyl optionally substituted by R", C1-6 alkoxy optionally substituted by R21, wherein [Annotation] micheles None set by micheles [Annotation] es ionNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles represents cyano, mono-, di or tri- halogen, hydroxy, amino, N-(C1.6alkyl)amino, N,N-di(C1. 6alkyl)amino, N- (hydroxyCH, alkyl) amino, N- (halophenle1-6 alkyl) amino, amino C2-6 nyl, C14, alkoxy, hydroxyCH, alkoxy, C(O)- R201, -NHC(O)- R201, C3.gcycloalkyl, isoindolino, imidyl, 2-oxo-1,3- oxazolidinyl, aryl or a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms ed from the group consisting O, S and N and optionally substituted by hydroxy, C1-6 alkyl, C1-6 alkoxy, C14, alkoxycarbonyl, hydroxyC1.6 alkoxy, oxo, amino, aminoC1-6alkyl, N-(C1- 6alkyl)amino, N,N-di(C1.6alkyl)amino, N-(C1.6 acyl)amino, or benzyl, R201 represents hydroxy, amino, N-(C1. 6alkyl)amino, N,N-di(C1.6alkyl)amino, N- (halophenle1-e> alkyl) amino, C1-6alkyl, aminoCH> alkyl, aminoC2.e> alkylenyl, C1-6 alkoxy, a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N, and optionally substituted by y, C14, alkyl, C14, alkoxy, CH, alkoxycarbonyl, hydroxyC1—6 alkoxy, oxo, amino, N-(C1. 6alkyl)amino, (C1.6alkyl)amino, N- (C1-6 acyl)amino or benzyl; [Annotation] micheles None set by es ation] micheles ionNone set by micheles [Annotation] micheles Unmarked set by micheles ation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles R3 represents hydrogen, halogen, aminocarbonyl, or C14, alkyl optionally tuted by aryl C1-6 alkoxy or mono-, di- or tri- halogen; R4 represents hydrogen or C1-6 alkyl; R5 represents hydrogen or C1-6 alkyl; and R6 represents halogen, hydrogen or C14, alkyl, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as a sole active agent, or of combinations of : a) such 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 an active agent sel e c t e d f r o m a n anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or ral agent, more particularly one or more r active agents selected from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX07O (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), |G-105, , 1, |-VRL (Immunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, FIB-1402, EU-517 ; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKlex ; and [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles ation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), 3, or an inhibitor of mTOR kinase, such as WYE-132, OSl-027, INK-128, OSl-027, AZD-2014, AZD-8055, CC-223, ABI-009, EXEL-3885, EXEL-4451, NV-128, OXA-01, 2, SB-2015, WYE-354, 3794, X-387, BEZ-235 ; or of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, e, hydrate or isomer or of pharmaceutical compositions containing such combinations, for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor ve breast cancer, hormone or positive breast cancer.

In a particular embodiment of the above-mentioned first aspect, the present invention relates to the use of a compound selected from the following list, or a logically acceptable salt, solvate, hydrate or stereoisomer as a sole active agent, or of combinations of : a) such 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 an active agent selected from an anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, regulatory, ic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral [Annotation] micheles None set by micheles ation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles ionNone set by micheles [Annotation] micheles Unmarked set by micheles agent, more particularly one or more further active agents selected from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX070 clax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), lG-105, WL-276, Bl-97C1, |-VRL ovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, PlB-1402, EU-517 ; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKlex ; and - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, l), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, such as WYE-132, 7, INK-128, OSI-027, AZD-2014, AZD- 8055, CC-223, ABI-009, EXEL-3885, EXEL-4451, NV-128, , PKl-402, SB-2015, WYE-354, KU-0063794, X-387, BEZ-235 ; or of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, e, hydrate or stereoisomer thereof, or of ceutical compositions ning such ations for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast cancer, in particular inflammatory breast cancer, triple negative breast , Her2 receptor positive breast cancer, hormone receptor positive breast cancer : N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin yl)nicotinamide; [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] es Unmarked set by micheles [Annotation] es None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles 2-(7, 8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolinyl)—1-pyridin ylethylenol; N-(7, 8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolinyl)-1H- benzimidazolecarboxamide; 6-(acetamido)-N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin yl)nicotinamide; 2-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolinyl) hydroxyvinyl]pyridinyl}acetamide; 2-({5-[2-hydroxypyr1'd1'nylv1'nyl] methoxy-2,3-dihydroimidazo[1 ,2- c]quinazolinyl}oxy)-N,N-dimethylacetamide; 2-[7-methoxy(tetrahydro-ZH-pyranylmethoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrid1'nylethylenol; 2-[8-(2-hydroxyethoxy)methoxy-2,3-dihydroimidazo[1,2-c]quinazolin- 1-pyrid1'nylethylenol; ({5-[2-hydroxy-Z-pyn’dinylvinyl]methoxy-2,3-dihydroimidazo[1,2- c]quinazol1’nyl}oxy)acetic acid; 4-({5-[2-hydroxypyr1'dinylv1'nyl]methoxy-2,3-dihydroimidazo[1,2- c]quinazol1‘nyl}oxy)butanoic acid; ({5-[2-hydroxy-Z-pyridinylvinyl]methoxy-2,3-dihydroimidazo[1,2- c]quinazol1‘nyl}oxy)acetonitrile; 2-[7-methoxy(2H-tetrazolylmethoxy)-2,3-dihydroimidazo[1,2- c]quinazol1‘nyl]pyrid1'nylethylenol; 2-[7-methoxy(4-morpholinyloxobutoxy)-2,3-dihydroimidazo[1,2- c]quinazolinyl]pyrid1'nylethylenol; 5-[1-hydroxy(8-morpholinyl-2,3-dihydroimidazo[1,2-c]quinazolin yl)v1'nyl]pyridinol ; N-(2,3-dihydroimidazo[1,2-c]quinazolinyl)hydroxynicotinamide; 6-(acetamido)-N-(7,9-dimethoxymethyl-2,3-d1'hydro1'm1'dazo[1 ,2- c]quinazolinyl)nicotinamide; N-(8,9-d1'methoxy-2,3-dihydroimidazo[1,2-c]quinazolinyl) hydroxym'coti namide; [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] micheles Unmarked set by es [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles ed set by micheles -hydroxy-N-(7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin yl)nicotinamide; N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolinyl)[(4- methoxybenzyl)oxy]nicotinamide; N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolinyl) hydroxym'cotinamide; -hydroxy-N-[8-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolin yl]nicotinamide; N-{8-[3-(1 ,3-dioxo-1,3-dihydro-2H-iso1'ndolyl)propoxy]-2,3- dihydroimidazo[1,2-c]quinazolinyl}nicotinamide; N-(7-bromomethoxy-2,3-dihydroimidazo[1,2-c]quinazolin yl)nicotinamide; 6-amino-N-(8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin yl)nicotinamide; 1-(1H-benzimidazol-S-yl)(8,9-dimethoxy-2, 3-dihydroimidazo[1,2- c]quinazolinyl)ethylenol; 2-(8,9-dimethoxy-2,3-dihydro1'midazo[1,2-c]quinazolinyl)(2,4- dimethyl-1,3-thiazolyl)ethylenol; ethoxy-2,3-dihydroimidazo[1,2-c]quinazolinyl)-1H- idazolecarboxam1‘de; N-(8-bromo-2,3-dihydroimidazo[1,2-c]quinazolinyl)nicotinamide; N-(8-bromo-2,3-dihydroimidazo[1,2-c]quinazolinyl)-1H-benzimidazole- -carboxamide; N-(8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolinyl)-1H- benzimidazolecarboxamide; N-(8-methyl-2,3-dihydroimidazo[1,2-c]quinazolinyl)-1H- benzimidazolecarboxamide; N-[8-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolinyl]-1H- benzimidazolecarboxamide; N-(7-fluoro-2,3-dihydroimidazo[1,2-c]quinazolinyl)-1H-benzimidazole- -carboxamide; N-(7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolinyl)nicotinamide; [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by es [Annotation] micheles MigrationNone set by micheles ation] micheles Unmarked set by micheles N-(8-chloro-2,3-dihydroimidazo[1,2-c]quinazolinyl)—1H-benzimidazole- -carboxamide; tamido)-N-(8-morpholinyl-2,3-dihydroimidazo[1,2-c]quinazolin- -yl)nicotinamide; 1-(1H-benzimidazolyl)(8-morpholinyl-2,3-dihydroimidazo[1,2- azolinyl)ethylenol; N-{5- [1 -hydroxy(8-morpholinyl-2,3-dihydroimidazo[1 ,2- c]quinazolinyl)vinyl]pyridinyl}acetamide; 6-methyl-N-(8-morpholinyl-2, 3-dihydroimidazo[1,2-c]quinazolin yl)nicotinamide; 1-(1H-benzimidazol-S-yl)[8-(4-methylpiperazinyl)-2,3- dihydroimidazo[1,2-c]quinazolinyl]ethylenol; N-(2,3-dihydroimidazo[1,2-c]quinazolinyl)-3H-imidazo[4,5-b]pyridine- 6-carboxamide; N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolinyl)-3H- imidazo[4, 5-b] pyridinecarboxamide; N-[7-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolinyl]-1H- benzimidazolecarboxamide; N-(7,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolinyl)—1H- benzimidazolecarboxamide; N-{5-[2-(7,9-dimethoxymethyl-2,3-dihydroimidazo[1,2-c]quinazolin hydroxyvinyl]pyridin-Z-yl}acetamide; N-{5-[2-(7-bromomethyl-2,3-dihydroimidazo[1,2-c]quinazolinyl) hydroxyvinyl]pyridinyl}acetamide; and 2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolinyl)pyridin ylethylenol; Another embodiment of the present invention encompasses the use of a compound having the formula (I) : [Annotation] micheles None set by micheles ation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles or a physiologically able salt, solvate, hydrate or stereoisomer thereof, in which : R1 represents -(CHz)n-(CHR4)-(CH2)m-N(R5)(R5’) ; R2 represents a heteroaryl optionally substituted with 1, 2 or 3 R6 groups ; R3 represents alkyl or cycloalkyl ; R4 represents hydrogen, hydroxy or alkoxy ; and R5 and R5’ may be the same or different and ent independently, hydrogen, alkyl, cycloalkylalklyl, or alkoxyalkyl or R5 and R5’ may be taken together with the nitrogen atom to which they are bound to form a 3-7 membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from , nitrogen or sulfur and which may be optionally substituted with 1 or more R6’ , or R4 and R5 may be taken together with the atoms to which they are bound to form a 5-6 membered nitrogen ning heterocyclic ring optionally containing 1 or more nitrogen, oxygen or sulfur atoms and which may be optionally substituted with 1 or more R" groups ; [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles each occurrence of R6 may be the same or different and is independently n, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalklyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring, heterocyclylalkyl, alkyl-OR7, alkyl-SR7, N(R7)(R7’), alkyl-COR7,-CN, - COOR7, -CON(R7)(R7’), -OR7, -SR7, -N(R7)(R7’), or 7NR7COR7 each of which may be optionally substituted with 1 or more R8 groups ; each occurrence of R6’ may be the same or different and is independently alkyl, lkylalklyl, or alkyl-OR7; each occurrence of R7 and R7’ may be the same or different and is independently hydrogen, alkyl, alkenyl, l, cycloalkyl, cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl ; each occurrence of R8 is independently nitro, hydroxy, cyano, formyl, , halogen, amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl, aryl, heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl ; n is an integer from 1-4 and m is an integer from 0-4 with the proviso that when when R4 and R5 are taken together with the atoms to which they are bound to form a 5-6 membered nitrogen containing ring, n + m s 4 ; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as a sole active agent, or of ations of : a) such a hydroimidazo[1,2-c]quinazoline nd, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; and [Annotation] micheles None set by micheles ation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles b) one or more further active agents, in ular an active agent sel e c t e d f r o m a n anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, sic, regulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), |G-105, WL-276, BI-97C1, |-VRL (Immunovivorelbine), DATS ridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, FIB-1402, EU-517; - a Bcl binding e ; - a Bcl siRNA, such as PNT-2258 ; - an antisense y oligonucleotide, such as BclKlex ; and - an tor of the mTOR pathway, such as cin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, or), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, l), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, such as WYE-132, OSI-027, INK-128, OSI-027, AZD-2014, 55, 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 of pharmaceutical itions containing such compounds or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, or of pharmaceutical compositions ning such combinations, for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

[Annotation] micheles None set by es [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles ation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles In a preferred ment, the invention encompasses the use of a compound of Formula (I), wherein R2 is a nitrogen containing heteroaryl optionally substituted with 1, 2 or 3 R6 , or a physiologically acceptable salt, solvate, hydrate or isomer thereof, as a sole active agent, or of combinations of : a) such 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 , in particular an active agent selected from a n anti-angiogenesis, yper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), 5, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), |G-105, WL-276, BI-97C1, |-VRL (Immunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, FIB-1402, EU-517; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKleX ; and - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin analogue, such as Rapamycin imus), Everolimus (RAD-001, Afinitor), limus (ABT-578, Endeavor), rolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, such as WYE-132, 7, INK-128, 7, AZD-2014, AZD- 8055, CC-223, ABl-OO9, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKl-402, SB-2015, WYE-354, KU-0063794, X-387, BEZ-235 ;or of pharmaceutical [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles ionNone set by micheles [Annotation] micheles Unmarked set by micheles compositions containing such nds or a physiologically acceptable salt, solvate, hydrate or stereoisomer f, or of pharmaceutical compositions containing such combinations, for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast , in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

In another preferred embodiment, the invention encompasses the use of a compound of Formula (I), wherein R5 and R5’ are independently alkyl, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as a sole active agent, or of combinations of : a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a logically acceptable salt, solvate, hydrate or stereoisomer thereof ; and b) one or more further active agents, in particular an active agent sel e c t e d f r o m a n anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, ypercholsterolemia, anti-dyslipidemia, anti-diabetic or ral agent, more particularly one or more further active agents selected from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX07O (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), |G-105, WL-276, Bl-97C1, |-VRL ovivorelbine), DATS (Allitridin), 03 (Apogossypol), D-G- 3139 (Genasense), Evotec, FIB-1402, EU-517 ; - a Bcl binding peptide ; - a Bcl siRNA, such as 58 ; - an antisense therapy oligonucleotide, such as BclKlex ; and [Annotation] micheles None set by micheles ation] micheles MigrationNone set by micheles ation] micheles Unmarked set by micheles ation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles ation] micheles Unmarked set by micheles - an inhibitor of the mTOR pathway, such as rapamycin or a cin analogue, such as Rapamycin imus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, Torisel), rolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, such as WYE-132, OSl-027, INK-128, OSl-027, AZD-2014, AZD-8055, CC-223, ABI-009, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKl-402, 5, WYE-354, KU-0063794, X-387, BEZ-235 ; or of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, or of pharmaceutical compositions containing such combinations, for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

In still r preferred embodiment, the invention encompasses the use of a compound of Formula (I), wherein R5 and R5’ are taken together with the nitrogen atom to which they are bound to form a 5-6 membered nitrogen containing heterocyclic ring containing at least one additional heteroatom ed from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R" groups, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as a sole active agent, or of combinations of : a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a physiologically acceptable salt, e, hydrate or stereoisomer thereof ; and [Annotation] es None set by es [Annotation] micheles ionNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles b) one or more further active agents, in particular an active agent sel e c t e d f r o m a n anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, regulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, yslipidemia, anti-diabetic or antiviral agent, more ularly one or more further active agents ed from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 norsen), |G-105, WL-276, BI-97C1, |-VRL (Immunovivorelbine), DATS (Allitridin), 03 (Apogossypol), D-G- 3139 (Genasense), Evotec, FIB-1402, EU-517; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKlex ; and - an inhibitor of the mTOR pathway, such as cin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, 9), TAFA-93, or an inhibitor of mTOR kinase, such as WYE-132, OSI-027, INK-128, OSI-027, AZD-2014, AZD-8055, CC-223, ABI-OO9, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKI-402, SB-2015, WYE-354, 3794, X-387, BEZ-235 ; or of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, or of pharmaceutical compositions containing such combinations, for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast , hormone or positive breast cancer.

[Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles In yet another preferred embodiment, the invention encompasses the use of a compound of Formula (I), wherein R4 is hydroxyl, or a physiologically acceptable salt, solvate, e or stereoisomer thereof, as a sole active agent, or of combinations of : a) such a 2,3-dihydroimidazo[1,2-c]quinazoline nd, or a physiologically acceptable salt, solvate, hydrate or stereoisomer f ; and b) one or more further active agents, in particular an active agent selected from an anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, regulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents ed from the group consisting of : - a Bcl tor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), , WL-276, Bl-97C1, |-VRL (Immunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), , FIB-1402, EU-517; - a Bcl binding peptide ; - a Bcl siRNA, such as 58 ; - an antisense therapy oligonucleotide, such as x ; and - an inhibitor of the mTOR pathway, such as cin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus 78, Endeavor), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, such as WYE-132, OSI-027, INK-128, OSl-027, AZD-2014, AZD-8055, , ABI-009, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKI-402, SB-2015, WYE-354, KU-0063794, X-387, BEZ-235 ; [Annotation] micheles None set by micheles [Annotation] micheles ionNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles or of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, or of ceutical itions containing such combinations, for the ation of a medicament for the treatment or prophylaxis of cancer, e.g. breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor ve breast cancer.

In another preferred embodiment, the invention encompasses the use of a compound of Formula (I), wherein R4 and R5 are taken together with the atoms to which they are bound to form a 5-6 membered nitrogen containing heterocyclic ring ally ning 1 or more en, oxygen or sulfur atoms and which may be optionally substituted with 1 or more R6 groups, or a logically acceptable salt, solvate, hydrate or stereoisomer thereof, as a sole active agent, or of combinations of : a) such 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 , in particular an active agent selected from an anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, rhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GXO70 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- [Annotation] micheles None set by micheles [Annotation] es ionNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles ation] es Unmarked set by micheles )-Gossypol), SPC-2004 (Beclanorsen), lG-105, WL-276, BI-97C1, I-VRL (lmmunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, PIE-1402, EU-517 ; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKlex ; and - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, such as WYE-132, OSl-027, INK-128, OSl-027, AZD-2014, 55, CC-223, ABI-009, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKl-402, SB-2015, WYE-354, KU-0063794, X-387, BEZ-235 ; or of pharmaceutical compositions containing such nds or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, or of pharmaceutical itions containing such combinations, for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast cancer, in ular matory breast cancer, triple ve breast cancer, Her2 receptor positive breast cancer, hormone or positive breast cancer.

In yet another preferred ment, the invention encompasses the use of a compound of Formula (I), wherein R3 is methyl, or a physiologically acceptable salt, e, hydrate or stereoisomer thereof, as a sole active agent, or of combinations of : a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; and [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles ed set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by es b) one or more further active agents, in particular an active agent sel e c t e d f r o m a n anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : - a Bcl inhibitor, such as 7, ABT-263 (Navitoclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- ypol), 04 (Beclanorsen), |G-105, WL-276, BI-97C1, |-VRL (Immunovivorelbine), DATS (Allitridin), 03 (Apogossypol), D-G- 3139 (Genasense), Evotec, FIB-1402, EU-517; - a Bcl binding e ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKlex ; and - an tor of the mTOR pathway, such as rapamycin or a cin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, or), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, 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 of pharmaceutical itions ning such compounds or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, or of pharmaceutical compositions containing such combinations, for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast cancer, in particular matory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

[Annotation] es None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] es Unmarked set by micheles In still another preferred embodiment, the invention encompasses the use of a compound of Formula (I), wherein R2 is pyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole, le, furan or thiophene, optionally substituted with 1, 2 or 3 R6 groups; more preferably pyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole, optionally tuted with 1, 2 or 3 R6 groups, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as a sole active agent, or of combinations of : a) such 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 an active agent selected from an anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, yslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents ed from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), lG-105, WL-276, Bl-97C1, I-VRL (lmmunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 ense), Evotec, FIB-1402, EU-517 ; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKlex ; and - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin analogue, such as cin imus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, 9), TAFA-93, or an inhibitor of mTOR [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] es ed set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] es Unmarked set by es kinase, such as 2, OSl-027, INK-128, OSI-027, AZD-2014, AZD- 8055, CC-223, ABl-009, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKI-402, SB-2015, WYE-354, KU-0063794, X-387, BEZ-235 ;or of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, or of pharmaceutical compositions containing such combinations, for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast , in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor ve breast cancer.

In a distinct embodiment, the invention encompasses the use of a compound of a ()la Ow 2),; (la) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R2 is as defined above, or a physiologically able salt, solvate, hydrate or stereoisomer thereof, as a sole active agent, or of combinations of : a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; and [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by es [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles b) one or more further active , in particular an active agent sel e c t e d f r o m a n anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, regulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, yslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, -070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 norsen), |G-105, WL-276, BI-97C1, |-VRL (Immunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, PlB-1402, EU-517; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKlex ; and - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, Torisel), Ridaforolimus 576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, such as WYE-132, OSl-027, 8, OSI-027, AZD-2014, AZD- 8055, CC-223, ABI-009, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKl-402, SB-2015, WYE-354, KU-0063794, X-387, BEZ-235 ;or of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, or of pharmaceutical itions containing such combinations,for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast cancer, in particular matory breast cancer, triple negative breast cancer, Her2 receptor positive breast , hormone receptor positive breast cancer.

In another distinct embodiment, the invention encompasses the use of a compound of formula (lb) : [Annotation] es None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles 0 N/\/\o1:673MAW °\ Rz/Ko (lb) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R2 is as defined above, or a physiologically acceptable salt, e, hydrate or stereoisomer thereof, as a sole active agent, or of combinations of : a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a physiologically acceptable salt, solvate, e or stereoisomer thereof ; and b) one or more further active agents, in particular an active agent sel e c t e d f r o m a n anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), 5, YC137, GX070 clax), Tetrocarcin A, 50883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), lG-105, WL-276, Bl-97C1, |-VRL (Immunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, PlB-1402, EU-517 ; - a Bcl binding e ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKlex ; and [Annotation] micheles None set by micheles ation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin analogue, such as Rapamycin imus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, such as 2, OSl-027, 8, 7, AZD-2014, AZD-8055, CC-223, ABI-009, EXEL-3885, EXEL-4451, NV-128, , PKl-402, SB-2015, WYE-354, KU-0063794, X-387, BEZ-235 ; or of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, or of ceutical compositions containing such combinations, for the preparation of a medicament for the treatment or prophylaxis of , e.g. breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

In still another distinct ment, the invention encompasses the use of a nd of a (Ic) : 00ch73 Rz/KO (IC) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R2 is as defined above, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as a sole active agent, [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles ation] micheles None set by micheles [Annotation] micheles MigrationNone set by es [Annotation] micheles Unmarked set by micheles or of combinations of : a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a physiologically able salt, solvate, hydrate or stereoisomer thereof ; and b) one or more further active agents, in particular an active agent selected from a n anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : - a Bcl inhibitor, such as 7, ABT-263 (Navitoclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 norsen), lG-105, WL-276, BI-97C1, |-VRL (Immunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), , PlB-1402, EU-517; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy ucleotide, such as BclKlex ; and - an inhibitor of the mTOR pathway, such as cin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, or), Temisirolimus (CCI-779, Torisel), rolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, such as WYE-132, OSI-027, 8, 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 of pharmaceutical compositions containing such compounds or a physiologically able salt, solvate, hydrate or stereoisomer thereof, or of pharmaceutical itions containing such combinations, [Annotation] es None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles for the preparation of a medicament for the treatment or prophylaxis of , e.g. breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

In yet another ct embodiment, the invention encompasses the use of a compound of the formula (Id): oromw7 (Id) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R2 and R4 are as defined above, or a physiologically acceptable salt, solvate, hydrate or stereoisomer as a sole active agent, or of ations of : a) such a 2,3-dihydroimidazo[1,2-c]quinazoline nd, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; and b) one or more further active , in particular an active agent selected from a n anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, rhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : ation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] es Unmarked set by micheles - a Bcl inhibitor, such as ABT-737, ABT-263 oclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), lG-105, WL-276, BI-97C1, |-VRL (Immunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, PlB-1402, EU-517; - a Bcl g peptide ; - a Bcl siRNA, such as 58 ; - an nse therapy oligonucleotide, such as BclKlex ; and - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, Ton'sel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an tor of mTOR kinase, such as 2, OSI-027, INK-128, 7, AZD-2014, AZD-8055, CC-223, ABl-009, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKI-402, SB-2015, WYE-354, KU-0063794, X-387, BEZ-235 ; or of pharmaceutical itions containing such compounds or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, or of ceutical compositions containing such combinations, for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast cancer, in ular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

In yet another distinct embodiment, the invention encompasses the use of a compound of the formula (le) : [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles ed set by micheles ation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles ,_m, 77> ¥vo NAN, °\ Rz/KO ('6) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, n R2 and R4 are as defined above, or a physiologically acceptable salt, solvate, hydrate or isomer thereof, as a sole active agent, or of combinations of : a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a physiologically acceptable salt, solvate, e or stereoisomer thereof ; and b) one or more r active agents, in particular an active agent selected from an anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, rhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), |G-105, WL-276, Bl-97C1, |-VRL ovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, PIE-1402, EU-517 ; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles - an antisense therapy oligonucleotide, such as BclKlex ; and - an inhibitor of the mTOR y, such as rapamycin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, or), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, l), Ridaforolimus (AP-23576, MK-8669), 3, or an inhibitor of mTOR kinase, such as 2, OSl-027, 8, 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 of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, solvate, hydrate or isomer thereof, or of pharmaceutical compositions ning such combinations, for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast cancer, in ular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

In a red embodiment, the invention encompasses the use of a nd of formula (I) - (V), wherein R2 is pyridine, zine, pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene, optionally substituted with 1, 2 or 3 R6 groups; more preferrably wherein R2 is pyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole, optionally substituted with 1, 2 or 3 R6 groups, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as a sole active agent, or of combinations of : a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a physiologically able salt, solvate, hydrate or stereoisomer thereof ; and [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles b) one or more further active agents, in particular an active agent sel e c t e d f r o m a n anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, yslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), |G-105, WL-276, BI-97C1, |-VRL (Immunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 ense), Evotec, 02, ; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy ucleotide, such as BclKlex ; and - an tor of the mTOR pathway, such as rapamycin or a cin ue, such as Rapamycin (Sirolimus), Everolimus 01, Afinitor), limus (ABT-578, Endeavor), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, such as WYE-132, OSl-027, INK-128, OSI-027, AZD-2014, AZD- 8055, CC-223, ABI-009, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKl-402, SB-2015, WYE-354, KU-0063794, X-387, BEZ-235 ;or of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, or of pharmaceutical compositions containing such combinations,for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast cancer, in particular matory breast cancer, triple ve breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

In still r preferred embodiment, the invention encompasses the use of a compound having the formula : [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by es [Annotation] es Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] es Unmarked set by micheles N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2- c]quinazolinyl]pyrimidinecarboxamide; N-(8-{3-[(2R,6S)-2,6-dimethylmorpholinyl]propoxy}methoxy- 2,3-d1'hydroimidazo[1 ,2-c]quinazolinyl)nicotinamide ; N-(8-{3-[(ZR,6S)-2,6-dimethylmorpholinyl]propoxy}methoxy- 2,3-dihydroimidazo[1,2-c]quinazolinyl)-2,4-dimethyl-1,3- thiazolecarboxamide; 2-am1‘no-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]-1,3-thiazolecarboxamide; 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]isonicotinamide; 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1 ,2-c]qu1'nazolinyl]methyl-1 ,3-thiazole carboxamide; 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]propylpyrim1'dine—5- carboxamide; N-{8- [2-(4-ethylmorpholinyl)ethoxy]methoxy-2,3- dihydroimidazo[1,2-c]quinazolinyl}nicotinamide; N-{8- [2-(d1'methylamino)ethoxy] methoxy-2, 3- dihydroimidazo[1,2- c]quinazolinyl}pyri midinecarboxamide; N-(8-{3-[2-(hydroxymethyl)morpholinyl]propoxy}methoxy- 2,3-dihydroimidazo[1,2-c]quinazolinyl)nicotinamide; N-(8-{3-[2-(hydroxymethyl)morpholinyl]propoxy}methoxy- 2,3-dihydroimidazo[1,2-c]quinazolinyl)nicotinamide; N-{8- [3-(dimethylamino)propoxy] hoxy-2, 3- oimidazo[1,2- c]quinazolinyl}nicotinamide 1-oxide; o-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimid1'necarboxamide; [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles ed set by micheles N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2- c]quinazolinyl](2-pyrrol1'din-1 -ylethyl)nicotinamide; 6-(cyclopentylamino)-N-[7-methoxy(3-morpholinylpropoxy)- 2,3-d1'hydroimidazo[1 ,2-c]quinazolinyl]nicotinamide; N- [8- (2-hydroxymorpholinylpropoxy) methoxy-Z, 3- oimidazo[1,2-c]quinazolinyl]nicotinamide; N-{7-methoxy[3-(3-methylmorphol1’nyl)propoxy]-2,3- dihydroimidazo[1,2-c]quinazolinyl}nicotinamide; N-(8-{3-[2-(hydroxymethyl)morpholinyl]propoxy}methoxy- hydroimidazo[1,2-c]quinazolinyl)nicotinamide; N-(8-{2-[4-(cyclobutylmethyl)morpholinyl]ethoxy}methoxy- 2,3-dihydroimidazo[1,2-c]quinazolinyl)nicotinamide; N-(7-methoxy{2-[4-(2-methoxyethyl)morpholinyl]ethoxy}- 2,3-dihydroimidazo[1,2-c]quinazolinyl)nicotinamide; N-{8- [(4-ethylmorpholin-Z-yl)methoxy] methoxy-2,3- dihydroimidazo[1,2-c]quinazolinyl}nicotinamide; N-(7-methoxy{[4-(2-methoxyethyl)morpholinyl]methoxy}- hydroimidazo[1,2-c]quinazolinyl)nicotinamide; N-{7-methoxy[(4-methylmorphol1‘nyl)methoxy]-2, 3- dihydroimidazo[1,2-c]quinazolinyl}nicotinamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide; 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide; ethoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]methyl-1H-imidazole carboxamide; rel-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholinyl]propoxy} methoxy-Z,3-dihydroim1'dazo[1 ,2-c]qu1'nazolinyl)pyrimid1'ne carboxamide; [Annotation] micheles None set by es [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles ation] micheles Unmarked set by micheles rel-N-(8-{3-[(2R,6$)-2,6-dimethylmorpholinyl]propoxy} methoxy-Z,3-dihydroim1’dazo[1,2-c]quinazolinyl) methylm‘cotinamide; relacetam1’do-N-(8-{3-[(2R,6S)-2,6-dimethylmorphol1‘n yl]propoxy}methoxy-2,3-dihydroimidazo[1,2-c]quinazolin yl)nicotinam1'de; ethoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]methyl-1H-imidazole-S- carboxamide; 6-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]methylnicotinamide; 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]methylpyrimid1'ne carboxamide; 6-aminobromo-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]nicotinamide; 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- oimidazo[1,2-c]quinazolinyl]-1,3-oxazolecarboxamide; N-[7-methoxy(morpholinylmethoxy)—2,3-dihydroimidazo[1,2- c]quinazol1‘nyl]nicotinamide; 2-{[2-(dimethylamino)ethyl]amino}-N-{8-[3- (dimethylamino)propoxy]methoxy-2, 3-dihydroimidazo[1,2- azolinyl}pyri midinecarboxamide; 2-amino-N-{8- [3- (dimethylamino)propoxy]methoxy-2, 3- dihydroimidazo[1,2-c]quinazolinyl}-1,3-thiazolecarboxamide; relamino-N-(8-{3-[(ZR,65)-2,6-dimethylmorpholin yl]propoxy}methoxy-2,3-dihydroimidazo[1,2-c]quinazolin yl)pyrim1‘dinecarboxamide; relamino-N-(8-{3-[(ZR,6S)-2,6-dimethylmorpholin yl]propoxy}methoxy-2,3-dihydroimidazo[1,2-c]quinazolin yl)nicotinam1'de; [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] es Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles hydroxyethyl)amino] -N-[7-methoxy(3-morpholin ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolinyl]pyrimidine—5- carboxamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl][(3- methoxypropyl)amino]pyrimidine-S-carboxamide; 2-amino-N-{8- [3- (dimethylamino)propoxy]methoxy-2, 3- dihydroimidazo[1 ,2-c]qu1'nazolinyl}pyrimidinecarboxamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl][(3-morphol1‘n ylpropyl)amino]pyrimidine-S-carboxamide; 2-[(Z-methoxyethyl)amino]-N-[7-methoxy(3-morpholin ylpropoxy)-2,3-d1'hydroimidazo[1 ,2-C]quinazolinyl]pyn'midine-5— carboxamide; 2-{[2-(dimethylamino)ethyl]amino}-N-[7-methoxy(3-morphol1'n- 4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolinyl]pyrimidine- -carboxamide; 6-amino-N-{8- [3- (dimethylamino)propoxy]methoxy-2, 3- dihydroimidazo[1,2-c]quinazolinyl}nicotinamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrrolidinylpyrimid1'ne- -carboxamide; ethoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl](4-methylpiperazin yl)pyr1'midinecarboxamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- oimidazo[1,2-c]quinazolinyl]morpholinylpyrimidine- -carboxamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- oimidazo[1,2-c]quinazolinyl]piperazin ylnicotinamide hydrochloride; [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] es Unmarked set by micheles 6-[(3S)aminopyrrolidinyl]-N-[7-methoxy(3-morpholin ylpropoxy)-2,3-d1'hydroimidazo[1 ,2-c]quinazolinyl]nicotinamide hydrochloride hydrate; 6-[(3R)aminopyrrolidinyl]-N-[7-methoxy(3-morphol1'n oxy)-2,3-d1'hydroimidazo[1,2-c]quinazolinyl]nicotinamide hydrochloride; 6- [(4-fluorobenzyl)amino] - N - [7-methoxy(3-morpholin ylpropoxy)-2,3-d1'hydro1'midazo[1,2-c]quinazolinyl]nicotinamide; 6-[(2-furylmethyl)amino]-N- [7-methoxy(3-morpholin ylpropoxy)-2,3-d1‘hydro1‘midazo[1,2-c]quinazolinyl]nicotinamide; 6-[(2-methoxyethyl)amino]-N-[7-methoxy(3-morpholin ylpropoxy)-2,3-d1‘hydro1‘midazo[1,2-c]quinazolinyl]nicotinamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]qu1'nazolinyl](1H-pyrrol yl)nicotinamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- oimidazo[1,2-c]quinazolinyl]morpholin ylnicotinamide; ethoxy[3-(methylamino)propoxy] -2, 3- dihydroimidazo[1,2-c]quinazolinyl}nicotinamide; 6-[(2,2-dimethylpropanoyl)amino]-N-[7-methoxy(3-morpholin- 4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin yl]nicotinamide; 6-[(cyclopropylcarbonyl)amino]-N-[7-methoxy(3-morphol1'n ylpropoxy)-2,3-dihydroimidazo[1,2-C]quinazolinyl]nicotinamide N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl](2,2,2- trifluoroethoxy)n1'cotinamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl] (trifluoromethyl)nicotinamide; [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles ation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles ed set by micheles 6-(isobutyrylam1'no)-N-[7-methoxy(3-morpholinylpropoxy)- hydro1’midazo[1,2-c]quinazolinyl]nicotinamide; N-{7-methoxy[3-(4-methylpiperaz1'nyl)propoxy]-2,3- dihydroimidazo[1,2-c]quinazolinyl}nicotinamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl] hylamino)carbonyl]amino}1, 3-thiazolecarboxamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl] {[(methylamino)carbonyl]amino}m‘cotinamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl](methylamino)-1,3- lecarboxamide; N-[7-methoxy(2-morpholinylethoxy)-2,3-dihydroimidazo[1,2- c]quinazolinyl]nicotinamide; N-{8- [2-(dimethylamino)ethoxy] methoxy-2, 3- dihydroimidazo[1,2-c]quinazolinyl}-2,4-dimethyl-1,3-thiazole—5- amide; N-{8- [2-(dimethylamino)ethoxy] methoxy-2, 3- dihydroimidazo[1 ,2-c]quinazolinyl}methylm‘cot1‘namide; 6-{[(isopropylamino)carbonyl] amino} N- [7-methoxy(3- morpholinylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin yl]nicotinamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrrolidin ylnicotinamide; 6-(dimethylamino)—N- [7-methoxy(3-morpholinylpropoxy)—2,3- dihydroimidazo[1,2-c]quinazolinyl]nicotinamide; N-[7-methoxy(3-piper1'dinylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazol1‘nyl]nicotinamide; N-[7-methoxy(2-pyrrolid1’nylethoxy)-2,3-dihydroimidazo[1,2- c]quinazolinyl]nicotinamide; [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles N-[7-methoxy(2-piper1'din-1 -ylethoxy)-2,3-dihydroimidazo[1,2- azol1’nyl]nicotinam1'de; 6-{[(ethylamino)carbonyl]amino}-N- [7-methoxy (3 -morpholin ylpropoxy)-2,3-dihydro1’midazo[1,2-c]quinazolinyl]nicotinamide; 6-fluoro-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]nicotinamide; 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]-1,3-oxazolecarboxamide; 2-(ethylamino)-N-[7-methoxy(3—morphol1'nylpropoxy)—2,3- dihydroimidazo[1,2-c]quinazolinyl]-1,3-thiazolecarboxamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrazine-Z-carboxamide; N-[8-(2-am1'noethoxy)methoxy-2,3-dihydroimidazo[1 ,2- c]quinazolinyl]nicotinamide; 6-am1‘no-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]nicotinamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]isonicotinam1'de; N-{8- [3-(diethylamino)propoxy] methoxy-2, 3- dihydroimidazo[1,2-c]quinazolinyl}nicotinamide; N-{8- [2-(diisopropylamino)ethoxy] hoxy-2,3 - dihydroimidazo[1,2-c]quinazolinyl}nicotinamide; N-{8- [2-(diethylamino)ethoxy] methoxy-2, 3-dihydroimidazo[1,2- c]quinazol1‘nyl}nicotinam1‘de; N-{8- [3-(dimethylamino)propoxy] hoxy-2, 3- oimidazo[1,2-c]quinazolinyl}nicotinamide; N-{8- [2-(dimethylamino)ethoxy] methoxy-2, 3- dihydroimidazo[1,2-c]quinazolinyl}nicotinamide; ethoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl](methylamino)pyrimidine- -carboxamide; [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl](methylthio)pyrimidine carboxamide; N-[8-(3-aminopropoxy)methoxy-Z, droimidazo[1,2- c]quinazolinyl]nicotinamide trifluoroacetate; ethoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]thiophenecarboxamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- oimidazo[1,2-c]quinazolinyl]-2,4-dimethyl-1,3-thiazole—5- carboxamide; 2-methoxy-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]furamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]thiophenecarboxamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]methyl-1,3-thiazole carboxamide; 6-methoxy-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]nicotinamide; -methoxy-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]nicotinamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- oimidazo[1,2-c]quinazolinyl]methylnicotinamide; 6-(acetylamino)-N-[7-methoxy(3-morpholinylpropoxy)-2, 3- dihydroimidazo[1,2-c]quinazolinyl]nicotinamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]nicotinamide; or a physiologically acceptable salt, solvate, e or stereoisomer thereof, as a sole active agent, [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by es ation] micheles Unmarked set by micheles or of ations of : a) such a 2,3-dihydroimidazo[1,2-c]quinazoline nd, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; and b) one or more further active , in particular an active agent selected from a n anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, yslipidemia, iabetic or antiviral agent, more particularly one or more further active agents selected from the group ting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX070 clax), arcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), lG-105, WL-276, BI-97C1, |-VRL (Immunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, PlB-1402, EU-517; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKlex ; and - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an tor of mTOR kinase, such as WYE-132, OSI-027, INK-128, OSI-027, AZD-2014, AZD-8055, CC-223, ABI-009, EXEL-3885, EXEL-4451, NV-128, , PKI-402, SB-2015, WYE-354, KU-0063794, X-387, BEZ-235 ; or of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, solvate, e or stereoisomer thereof, or of pharmaceutical compositions containing such combinations, [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles ation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles for the preparation of a ment for the treatment or prophylaxis of cancer, e.g. breast cancer, in particular matory breast cancer, triple ve breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

In a preferred embodiment, the invention encompasses the use of a compound having the formula: ethoxy(3-morpholinylpropoxy)-2,3- oimidazo[1,2-c]quinazolinyl]nicotinamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]methylnicotinamide; -methoxy-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]nicotinamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]-2,4-dimethyl-1,3-thiazole—5- carboxamide; N-{8-[2-(dimethylamino)ethoxy]methoxy-2,3- dihydroimidazo[1,2-c]quinazolinyl}nicotinamide; N-{8-[3-(dimethylamino)propoxy]methoxy-2,3- dihydroimidazo[1,2-c]quinazolinyl}nicotinamide; 6-{[(isopropylamino)carbonyl]amino}-N-[7-methoxy(3- morpholinylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin yl]nicotinamide; N-{8-[2-(dimethylamino)ethoxy]methoxy-2,3- dihydroimidazo[1,2-c]quinazolinyl}-2,4-dimethyl-1,3-thiazole amide; N-[7-methoxy(2-morpholinylethoxy)-2,3-dihydroimidazo[1,2- c]quinazolinyl]nicotinamide; relamino-N-(8-{3-[(ZR,6S)-2,6-dimethylmorpholin yl]propoxy}methoxy-2,3-dihydroimidazo[1,2-c]quinazolin yl)nicotinamide; [Annotation] es None set by micheles [Annotation] micheles MigrationNone set by micheles ation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles relamino-N-(8-{3-[(2R,65)—2,6-dimethylmorpholin yl]propoxy}methoxy-2,3-dihydroimidazo[1,2-c]quinazolin yl)pyrimidinecarboxamide; 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide; N-{8-[2-(dimethylamino)ethoxy]methoxy-2,3- dihydroimidazo[1,2-c]quinazolinyl}pyrimidinecarboxamide; N-[7-methoxy(3-morpholinylpropoxy)-2,3- oimidazo[1,2- c]quinazolinyl]pyrimidinecarboxamide; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as a sole active agent, or of combinations of : a) such a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a physiologically able salt, solvate, hydrate or stereoisomer thereof ; and b) one or more r active agents, in particular an active agent selected from an anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, regulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX07O (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 norsen), |G-105, WL-276, Bl-97C1, |-VRL (Immunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), , FIB-1402, EU-517 ; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKlex ; and [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] es Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles - an inhibitor of the mTOR y, such as rapamycin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, such as WYE-132, OSl-027, INK-128, OSl-027, 14, AZD-8055, CC-223, ABI-009, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKl-402, SB-2015, 4, KU-0063794, X-387, BEZ-235 ; or of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, or of pharmaceutical itions containing such combinations, for the preparation of a ment for the treatment or laxis of cancer, e.g. breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

In a preferred embodiment, the invention encompasses the use of a nd having the formula : o-N-[7-methoxy(3-morpholinylpropoxy)—2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, o r a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; as a sole active agent, or of pharmaceutical compositions ning such a nd or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast cancer, in particular inflammatory breast cancer, [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles ation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

In a preferred embodiment, the invention asses the use of combinations of : a) 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; and b) one or more r active agents, in particular an active agent sel e c t e d f r o m a n anti-angiogenesis, anti-hyper-proliferative, flammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, iabetic or antiviral agent, more particularly one or more further active agents selected from the group ting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX07O (Obatoclax), arcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), |G-105, WL-276, Bl-97C1, |-VRL (Immunovivorelbine), DATS ridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, PIE-1402, EU-517 ; - a Bcl g peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKlex ; and - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin analogue, such as Rapamycin (Sirolimus), imus (RAD-001, Afinitor), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, such as WYE-132, OSI-027, 8, OSI-027, AZD-2014, [Annotation] es None set by es [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by es [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles AZD-8055, cc-223, ABI-OO9, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKI-402, 53-2015, va-354, KU-0063794, X-387, BEZ-235 ; or of pharmaceutical compositions containing such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, or of pharmaceutical compositions containing such combinations, for the preparation of a medicament for the treatment or laxis of cancer, e.g. breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

In a preferred embodiment, the invention encompasses the use of combinations of : a) 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a physiologically acceptable salt, solvate, e or stereoisomer thereof ; and b) one or more further active agents selected from the group consisting - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 norsen), |G-105, WL-276, BI-97C1, |-VRL (Immunovivorelbine), DATS ridin), 03 ssypol), D-G- 3139 (Genasense), Evotec, FIB-1402, EU-517 ; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKlex ; and ation] micheles None set by micheles [Annotation] micheles MigrationNone set by es [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, or), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), 3, or an inhibitor of mTOR kinase, such as WYE-132, OSl-027, INK-128, OSl-027, AZD-2014, AZD-8055, CC-223, ABI-009, EXEL-3885, EXEL-4451, , OXA-01, PKl-402, SB-2015, WYE-354, KU-0063794, X-387, BEZ-235 ; or of pharmaceutical itions containing such a compound or a logically acceptable salt, solvate, e or isomer or of pharmaceutical compositions containing such combinations, for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast , hormone receptor positive breast cancer.

In a preferred embodiment, the invention encompasses the use of combinations of : a) 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a physiologically acceptable salt, solvate, hydrate or isomer thereof ; and b) one or more further active agents selected from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), |G-105, WL-276, Bl-97C1, |-VRL [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles (lmmunovivorelbine), DATS ridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, PlB-1402, EU-517; - a Bcl binding e ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKlex ; or of pharmaceutical compositions containing such a nd or a physiologically acceptable salt, solvate, e or stereoisomer thereof, or of pharmaceutical itions ning such combinations, for the preparation of a medicament for the treatment or prophylaxis of cancer, e.g. breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast .

In a preferred embodiment, the invention encompasses the use of combinations of : a) 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- oimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; and b) one or more further active agents, which is ABT-737 ; or of pharmaceutical compositions containing such a compound or a physiologically able salt, solvate, hydrate or stereoisomer thereof, or of pharmaceutical compositions containing such combinations, for the preparation of a ment for the treatment or prophylaxis of cancer, e.g. breast cancer, in particular inflammatory breast cancer, [Annotation] es None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by es [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by es triple negative breast , Her2 or positive breast cancer, hormone or positive breast cancer.

In a preferred embodiment, the invention encompasses the use of combinations of : a) 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; and b) one or more further active agents selected from the group consisting of : - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, Endeavor), rolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, such as 2, OSl-027, INK-128, OSI-027, AZD-2014, AZD-8055, CC-223, ABI-009, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKl-402, SB-2015, WYE-354, KU-0063794, X-387, BEZ-235 ; or of pharmaceutical compositions containing such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, or of ceutical compositions containing such combinations, for the preparation of a ment for the treatment or prophylaxis of cancer, e.g. breast cancer, in particular inflammatory breast cancer, triple ve breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

[Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles In a preferred embodiment, the invention encompasses the use of combinations of : a) 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a physiologically able salt, solvate, hydrate or stereoisomer f ; and b) one or more further active agents, which is Rapamycin (Sirolimus) ; or of pharmaceutical compositions containing such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer or of pharmaceutical compositions containing such combinations, for the preparation of a medicament for the ent or laxis of cancer, e.g. breast cancer, in particular matory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast cancer.

Where there is a discrepancy n the chemical name and the chemical structure depicted, the chemical structure depicted takes precedence over the chemical name given.

Without being bound by theory or mechanism, the compounds of the present invention display surprising activity for the inhibition of phosphatidylinositolkinase and chemical and structural stability over those compounds of the prior art. It is believed that this sing activity is based on the chemical ure of the compounds, in ular the basicity of the compounds as a result of R1 being amino optionally substituted with R5 and R5’. Further, the appropriate choice ation] micheles None set by es [Annotation] micheles ionNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles ation] micheles Unmarked set by es of R3 and R2 provide the necessary ty against the appropriate isoforms to allow for activity in vivo.

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said breast cancer is inflammatory breast .

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said breast cancer is triple ve breast cancer.

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

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said breast cancer is hormone receptor positive breast cancer.

Definitions The term ‘alkyl‘ refers to a straight or branched arbon chain radical consisting solely of carbon and hydrogen atoms, containing solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, such as illustratively, methyl, ethyl, yl 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t- butyl).

The term "alkenyl " refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched or [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] es Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles branched chain having about 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l-propenyl, 1- butenyl, 2-and butenyl.

The term "alkynyl" refers to a straight or branched chain hydrocarbonyl radicals having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms (with radicals having in the range of about 2 up to 10 carbon atoms presently being preferred) e.g., ethynyl.

The term "alkoxy" denotes an alkyl group as d herein attached via oxygen linkage to the rest of the molecule. Representative examples of those groups are y and ethoxy.

The term "alkoxyakyl" denotes an alkoxy group as defined herein attached via oxygen linkage to an alkyl group which is then attached to the main structure at any carbon from alkyl group that results in the on of a stable structure the rest of the molecule. Representative es of those groups are eCHzoCHg, --CH20C2H5 .

The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of about 3 to 12 carbon atoms such as ropyl, cyclobutyl, cyclopentyl, cyclohexyl and examples of multicyclic cycloalkyl groups include perhydronapththyl, adamantyl and norbornyl groups bridged cyclic group or sprirobicyclic groups e.g sprio (4,4) nonyl.

The term alkylalkyl" refers to cyclic ring-containing radicals containing in the range of about about 3 up to 8 carbon atoms directly ed to alkyl group which is then also attached to the main structure at any carbon from the alkyl group that results in the on of a stable structure such as cyclopropylmethyl, cyclobuyylethyl, cyclopentylethyl.

[Annotation] micheles None set by es [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles The term "aryl" refers to aromatic radicals having in the range of 6 up to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, biphenyl .

The term "arylalkyl" refers to an aryl group as d herein ly bonded to an alkyl group as defined herein which is then attached to the main structure at any carbon from alkyl group that results in the creation of a stable structure the rest of the molecule. e.g., --CH2C6H5, C2H5C6H5 .

The term "heterocyclic ring" refers to a stable 3- to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. For es of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring s, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation . In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heteroaromatic or heteroaryl aromatic).

Examples of such cyclic ring radicals include, but are not d to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl inyl dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazil, pyridyl, pteridinyl, purinyl, olinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl pyridazinyl, oxazolyl oxazolinyl oxasolidinyl, triazolyl, indanyl, olyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, azolyl, lidinyl, isothiazolidinyl, indolyl, [Annotation] micheles None set by es [Annotation] micheles MigrationNone set by es [Annotation] micheles Unmarked set by es [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl quinolyl, nolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl ide thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, isochromanyl .

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

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

The term "heterocyclyl" refers to a cylic ring radical as defined herein. The heterocylyl 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 term "heterocyclylalkyl" refers to a heterocylic ring radical as defined herein directly bonded to alkyl group. The heterocyclylalkyl radical may be attached to the main ure at carbon atom in the alkyl group that results in the creation of a stable structure.

[Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] es Unmarked set by micheles The term "carbonyl" refers to an oxygen atom bound to a carbon atom of the molecule by a double bond.

The term "halogen" refers to radicals of fluorine, chlorine, bromine and iodine.

Where the plural form of the word compounds, salts, polymorphs, es, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.

The compounds of this invention may contain one or more asymmetric centers, ing upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration, ing in racemic mixtures in the case of a single asymmetric center, and diastereomeric mixtures in the case of multiple asymmetric centers. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the ied nds. Substituents on a ring may also be present in either cis or trans form. It is ed that all such configurations (including omers and diastereomers), are included within the scope of the present invention. Preferred compounds are those, which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric es of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.

The t invention also relates to useful forms of the compounds as disclosed herein, such as ceutically acceptable salts, co- precipitates, metabolites, es, solvates and prodrugs of all the [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles compounds of examples. The term "pharmaceutically acceptable salt" refers to a vely non-toxic, inorganic or organic acid addition salt of a compound of the t invention. For example, see S. M. Berge, et al. "Pharmaceutical " J. Pharm. Sci. 1977, 66, 1-19.

Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid. Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, ium, calcium, magnesium, ammonium, and chorine salts. Those skilled in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or c acid via any of a number of known s. Alternatively, alkali and ne earth metal salts of acidic compounds of the invention are prepared by reacting the nds of the ion with the appropriate base via a variety of known methods.

Representative salts of the compounds of this invention include the tional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include e, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, rsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, itaconate, lactate, e, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles ation] micheles Unmarked set by es [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles ed set by micheles picrate, pivalate, propionate, succinate, sulfonate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate.

Base salts include alkali metal salts such as ium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N- methyl-D-glucamine. Additionally, basic en containing groups may be quaternized with such agents as lower alkyl s such as methyl, ethyl, propyl, or butyl chlorides, es and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl sulfate, or diamyl es, long chain halides such as decyl, lauryl, myristyl and strearyl des, es and iodides, aralkyl halides like benzyl and phenethyl bromides and others.

A solvate for the purpose of this invention is a complex of a solvent and a compound of the invention in the solid state. Exemplary solvates would include, but are not limited to, complexes of a compound of the invention with ethanol or methanol. Hydrates are a ic form of solvate wherein the solvent is water.

The synthesis of the compounds listed above is described in International Patent Application No. , published as WO 2004/029055 A1, and in International Patent Application No.

PCT/USZOO7/024985, published as , both of which are hereby incorporated herein in their entirety by reference.

In accordance with another embodiment, the present invention relates to a 2,3-dihydroimidazo[1,2-c]quinazoline compound as defined , in particular 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as a sole agent, for the treatment of cancer, e.g. breast cancer, [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles ionNone set by micheles [Annotation] micheles Unmarked set by micheles in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone or ve breast cancen In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said breast cancer is inflammatory breast cancer.

In accordance a particular embodiment of any of the above aspects, or embodiments f, of the present invention, said breast cancer is triple ve breast cancer.

In accordance a particular embodiment of any of the above aspects, or embodiments f, of the present invention, said breast cancer is Her2 receptor positive breast cancer.

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said breast cancer is hormone receptor positive breast cancer.

Combination ies As mentioned supra, the present invention relates to combinations of : a) a 2,3-dihydroimidazo[1,2-c]quinazoline compound as defined supra, or a physiologically acceptable salt, solvate, hydrate or stereoisomer f ; or pharmaceutical compositions containing such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by es ation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by es [Annotation] micheles Unmarked set by micheles b) one or more further active agents, in particular an active agent sel e c t e d f r o m a n anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : - a Bcl inhibitor, such as ABT-737, 3 (Navitoclax), EM20-25, YC137, GX070 clax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), |G-105, WL-276, BI-97C1, |-VRL (Immunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, PlB-1402, EU-517; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense y oligonucleotide, such as BclKlex ; and - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin analogue, such as Rapamycin (Sirolimus), imus (RAD-001, Afinitor), Zotarolimus 78, Endeavor), Temisirolimus (CCI-779, Torisel), rolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, such as WYE-132, OSI-027, INK-128, OSI-027, AZD-2014, AZD-8055, CC-223, 9, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKI-402, SB-2015, WYE-354, KU-0063794, X-387, BEZ-235.

In a preferred embodiment, the invention encompasses combinations of: a) 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- oimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; or pharmaceutical compositions containing such a compound or a logically acceptable salt, solvate, hydrate or stereoisomer thereof ; [Annotation] micheles None set by micheles ation] es MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles ation] micheles Unmarked set by micheles b) one or more further active agents, in particular an active agent sel e c t e d f r o m a n anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, sic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 oclax), EM20-25, YC137, GXO70 (Obatoclax), Tetrocarcin A, 50883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), |G-105, WL-276, BI-97C1, |-VRL (Immunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, PlB-1402, EU-517 ; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKlex ; and - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, l), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, such as WYE-132, OSl-027, INK-128, OSI-027, AZD-2014, AZD- 8055, CC-223, 9, EXEL-3885, EXEL-4451, NV-128, OXA-01, PKl-402, SB-2015, 4, KU-0063794, X-387, BEZ-235.

In a preferred embodiment, the invention encompasses combinations of : a) 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a physiologically able salt, solvate, e or isomer thereof ; or pharmaceutical compositions containing such a compound or [Annotation] micheles None set by micheles [Annotation] micheles ionNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by es [Annotation] micheles Unmarked set by es a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; b) one or more further active agents selected from the group consisting - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), lG-105, WL-276, Bl-97C1, I-VRL (lmmunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, FIB-1402, EU-517 ; - a Bcl binding e ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as x ; and - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin ue, such as Rapamycin (Sirolimus), imus (RAD-001, or), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), 3, or an inhibitor of mTOR kinase, such as WYE-132, OSl-027, INK-128, OSl-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.

In a preferred embodiment, the ion encompasses combinations a) 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a physiologically acceptable salt, solvate, e or stereoisomer thereof ; or pharmaceutical compositions containing such a compound or [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles a physiologically acceptable salt, e, hydrate or stereoisomer thereof ; b) one or more r active agents selected from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, 50883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), lG-105, WL-276, Bl-97C1, I-VRL (lmmunovivorelbine), DATS (Allitridin), 03 ssypol), D-G- 3139 ense), Evotec, FIB-1402, EU-517 ; - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKlex.

In a preferred embodiment, the invention encompasses the use of combinations of : a) 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a physiologically acceptable salt, solvate, hydrate or isomer thereof ; or pharmaceutical compositions containing such a nd or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; b) one or more further active agents, which is ABT-737.

[Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] es None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles In a preferred embodiment, the invention asses combinations a) 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a logically acceptable salt, solvate, hydrate or stereoisomer thereof ; or pharmaceutical itions containing such a compound or a physiologically acceptable salt, solvate, hydrate or isomer thereof ; b) one or more further active agents selected from the group consisting - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, or), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR , 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.

In a preferred embodiment, the invention encompasses combinations of : a) 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a logically able salt, solvate, hydrate or stereoisomer f ; or pharmaceutical compositions containing such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; [Annotation] micheles None set by micheles [Annotation] micheles ionNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles ionNone set by micheles ation] micheles Unmarked set by micheles b) one or more further active agents, which is Rapamycin imus).

The compounds of this ion can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents (or "further active ") where the combination causes no unacceptable adverse effects. For example, the compounds of this invention can be combined with known anti- angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or ral agents, and the like, as well as with ures and combinations thereof.

The additional ceutical agent or agents (or "further active agent") can be, but are not limited to aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, azathioprine, ECG or tice BCG, bestatin, betamethasone acetate, thasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide, cytarabine, azine, dactinomycin, DaunoXome, decadron, on phosphate, delestrogen, denileukin diftitox, depo-medrol, deslorelin, dexomethasone, dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend, epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, estrace, estradiol, estramustine phosphate , ethinyl estradiol, ethyol, etidronic acid, etopophos, etoposide, fadrozole, [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles farston, filgrastim, finasteride, fligrastim, floxuridine, azole, abine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fosteabine, fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron HCl, herceptin, histrelin, hycamtin, hydrocortone, eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferon alfa-ZA, interferon alfa-ZB, interferon alfa-n1, eron 3, eron beta, interferon gamma-1a, interleukin-2, intron A, iressa, irinotecan, kytril, lapatinib, lentinan sulphate, letrozole, leucovorin, leuprolide, lide acetate, domide, levamisole, levofolinic acid calcium salt, levothroid, levoxyl, lomustine, lonidamine, marinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, menest, 6-mercaptopurine, Mesna, methotrexate, metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, al, Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide, ex, NSC-631570, OCT-43, octreotide, ondansetron HCl, orapred, oxaliplatin, axel, pediapred, pegaspargase, Pegasys, pentostatin, nil, pilocarpine HCl, pirarubicin, plicamycin, porfimer sodium, prednimustine, prednisolone, prednisone, premarin, procarbazine, procrit, RDEA 119, raltitrexed, rebif, rhenium-186 etidronate, rituximab, roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine, sizofiran, sobuzoxane, solu- medrol, sparfosic acid, stem-cell y, streptozocin, strontium-89 chloride, sunitinib, synthroid, tamoxifen, tamsulosin, tasonermin, tastolactone, taxotere, teceleukin, temozolomide, teniposide, testosterone nate, testred, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, tretinoin, trexall, trimethylmelamine, trimetrexate, triptorelin e, triptorelin pamoate, UFT, e, icin, vesnarinone, stine, vincristine, vindesine, lbine, virulizin, zinecard,zinostatin stimalamer, , ABI-007,acolbifene, [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by es [Annotation] es Unmarked set by micheles actimmune, affinitak, aminopterin, arzoxifene, asoprisnil, atamestane, atrasentan, BAY 43-9006 (sorafenib), avastin, CCI-779, CDC-501, ex, cetuximab, crisnatol, cyproterone acetate, bine, DN- 101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid, interferon gamma, -PEG, ixabepilone, keyhole limpet anin, L-651582, lanreotide, lasofoxifene, libra, lonafarnib, miproxifene, minodronate, MS-209, liposomal , MX-6, nafarelin, nemorubicin, neovastat, exed, oblimersen, CS, osidem, paclitaxel polyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, , raloxifene, ranpirnase, 13-cis -retinoic acid, satraplatin, seocalcitol, T-138067, a, taxoprexin, thalidomide, thymosin alpha 1, tiazofurine, tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acid or combinations thereof.

In accordance with an embodiment, the additional pharmaceutical agent or agents (or "further active agent") is selected from the group consisting of : 131l-chTNT, ix, erone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, amine, aminoglutethimide, amrubicin, amsacrine, anastrozole, arglabin, c trioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY 1000394, BAY 86-9766 (RDEA 119), belotecan, ustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, calcium linate, capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cetuximab, chlorambucil, chlormadinone, chlormethine, cisplatin, cladribine, clodronic acid, clofarabine, crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, omycin, darbepoetin alfa, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, deslorelin, dibrospidium [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] es ionNone set by es [Annotation] micheles Unmarked set by micheles chloride, docetaxel, doxifluridine, doxorubicin, doxorubicin + estrone, eculizumab, lomab, elliptinium acetate, eltrombopag, endostatin, abine, epirubicin, epitiostanol, epoetin alfa, epoetin beta, eptaplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, flutamide, formestane, fotemustine, fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glutoxim, goserelin, ine dihydrochloride, histrelin, hydroxycarbamide, |-125 seeds, ibandronic acid, ibritumomab tiuxetan, idarubicin, mide, imatinib, imiquimod, improsulfan, interferon alfa, interferon beta, interferon gamma, umab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, lenograstim, lentinan, ole, leuprorelin, levamisole, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, rol, melphalan, mepitiostane, mercaptopurine, methotrexate, methoxsalen, Methyl aminolevulinate, methyltestosterone, mifamurtide, miltefosine, miriplatin, mitobronitol, azone, mitolactol, mitomycin, mitotane, mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide, nimotuzumab, nimustine, nitracrine, umab, omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, pamidronic acid, panitumumab, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pegfilgrastim, peginterferon alfa-Zb, pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide, picibanil, pirarubicin, plerixafor, plicamycin, poliglusam, tradiol phosphate, polysaccharide-K, porfimer sodium, pralatrexate, prednimustine, procarbazine, quinagolide, raloxifene, raltitrexed, ranimustine, razoxane, regorafenib, risedronic acid, rituximab, romidepsin, romiplostim, mostim, sipuleucel-T, sizofiran, sobuzoxane, sodium idazole, sorafenib, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tasonermin, teceleukin, tegafur, tegafur + cil + il, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by es [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] es Unmarked set by micheles thymalfasin, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin, trilostane, triptorelin, trofosfamide, tryptophan, ex, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, stine, vindesine, vinflunine, vinorelbine, vorinostat, le, m-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

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

Optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to nds listed on the cancer chemotherapy drug regimens in the 11th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as ginase, bleomycin, carboplatin, carmustine, mbucil, cisplatin, colaspase, hosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, ecan, leucovorin, lomustine, mechlorethamine, 6- mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, solone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, anine, topotecan, vinblastine, vincristine, and vindesine.

[Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] es Unmarked set by micheles [Annotation] micheles None set by es [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles Other anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not d to those compounds acknowledged to be used in the treatment of neoplastic diseases in n and Gilman's The Pharmacological Basis of eutics (Ninth Edition), editor Molinoff et al., publ. by McGraw- Hill, pages 1225-1287, (1996), which is hereby incorporated by reference, such as aminoglutethimide, L-asparaginase, azathioprine, 5- azacytidine cladribine, an, diethylstilbestrol, 2',2'- difluorodeoxycytidine, docetaxel, erythrohydroxynonyl e, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, tatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine.

Other anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to other anti- cancer agents such as epothilone and its derivatives, irinotecan, raloxifen and topotecan.

Generally, the use of cytotoxic and/or cytostatic agents in combination with a nd or composition of the t invention will serve to: (1) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone, (2) provide for the stration of lesser amounts of the administered chemotherapeutic agents, [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles (3) provide for a chemotherapeutic treatment that is better tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, (4) provide for treating a broader spectrum of different cancer types in mammals, especially humans, (5) e for a higher response rate among treated patients, (6) provide for a longer survival time among treated patients compared to rd chemotherapy treatments, (7) provide a longer time for tumor progression, and/or (8) yield cy and bility results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.

In accordance with an embodiment, the invention s to combinations wherein said 2,3-dihydroimidazo[1,2-c]quinazoline compound is 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide.

In accordance with an embodiment, the invention relates to combinations n said further active agent is cin or 7.

In accordance with an embodiment, the invention relates to ations wherein said 2,3-dihydroimidazo[1,2-c]quinazoline compound is 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide and said further active agent is rapamycin or ABT-737.

[Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles ionNone set by micheles [Annotation] micheles Unmarked set by es ceutical itions of the compounds of the invention As mentioned supra, the present invention relates to pharmaceutical itions : comprising a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a physiologically acceptable salt, solvate, e or stereoisomer thereof, as a sole active agent, for the treatment of cancer, e.g. breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 or positive breast cancer, hormone receptor positive breast cancer, and comprising a pharmaceutical composition which comprises a combination of : a) a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a physiologically acceptable salt, solvate, hydrate or stereoisomer f ; and b) one or more further active , in particular an active agent selected from an anti-angiogenesis, anti-hyper- proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti- dyslipidemia, iabetic or antiviral agent, more particularly one or more further active agents ed from the group consisting of : - a Bcl inhibitor, such as ABT-737, ABT-263 (Navitoclax), EMZO- , YC137, GX070 (Obatoclax), Tetrocarcin A, UCB- 1350883, AT-101 ((-)-Gossypol), SPC-2004 (Beclanorsen), IG- 105, WL-276, BI-97C1, l-VRL (lmmunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G-3139 (Genasense), Evotec, PIB-1402, EU-517; - a Bcl binding peptide ; [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] es Unmarked set by micheles - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKlex ; and - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin ue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, Endeavor), Temisirolimus (CCl-779, Torisel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, 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, 2, SB-2015, 4, 3794, X-387, BEZ-235.

In accordance with another embodiment, the present invention relates to pharmaceutical compositions which se a 2,3- oimidazo[1,2-c]quinazoline compound as defined herein, in particular 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as a sole agent, for the treatment of cancer, e.g. breast , in particular inflammatory breast cancer, triple negative breast cancer, Her2 or positive breast cancer, hormone receptor ve breast cancen In accordance a particular embodiment of any of the above s, or embodiments f, of the present invention, said breast cancer is inflammatory breast cancer.

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said breast cancer is triple negative breast cancer.

[Annotation] es None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by es [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles ation] micheles Unmarked set by micheles In accordance a particular embodiment of any of the above aspects, or ments thereof, of the present invention, said breast cancer is Her2 receptor positive breast cancer.

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said breast cancer is hormone or positive breast cancer.

Said pharmaceutical compositions contain one or more compounds.

These compositions can be utilized to e the desired pharmacological effect by administration to a patient in need thereof. A t, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease.

Therefore, the present invention includes pharmaceutical compositions that are sed of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention. A pharmaceutically acceptable carrier is preferably a carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active agent so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active agent. A pharmaceutically effective amount of compound is preferably that amount which produces a result or exerts an influence on the particular condition being treated. The compounds of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, , erally, topically, y, ophthalmically, optically, sublingually, rectally, vaginally, and the like.

For oral stration, the nds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled n type ning, for example, tants, lubricants, and inert s such as lactose, sucrose, m ate, and corn starch.

In another embodiment, the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following stration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or ium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of Wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and ls, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be t as gs or to otherwise modify the physical form of the dosage unit. For ce tablets, pills or capsules may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They e the active agent in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already ned above. Additional [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles ation] es Unmarked set by micheles ation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles ents, for example those ning, flavoring and coloring agents described above, may also be t.

The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and l anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, yethylene sorbitan monooleate. The emulsions may also n sweetening and flavoring agents.

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

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

The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in preferably a physiologically acceptable diluent with a [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles ation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2- dimethyl-1,1-dioxolanemethanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid ide, or an acetylated fatty acid ide, with or t the addition of a ceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, ypropylmethylcellulose, or carboxymethylcellulose, or fying agent and other pharmaceutical adjuvants.

Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, 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. le soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine es; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta- aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as es.

The parenteral itions of this invention will typically contain from about 0.5% to about 25% by weight of the active agent in solution. ation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] es None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] es Unmarked set by micheles Preservatives and buffers may also be used ageously. In order to minimize or eliminate irritation at the site of injection, such compositions may n a nic surfactant having a hydrophile- lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about % to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.

Illustrative of surfactants used in parenteral ations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high lar weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.

The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl- cellulose, sodium te, polyvinylpyrrolidone, gum anth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a l ester derived from a fatty acid and a hexitol ide, for example polyoxyethylene sorbitan monooleate.

[Annotation] es None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] es Unmarked set by micheles The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally able diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer’s on, isotonic sodium chloride solutions and isotonic e solutions. In addition, sterile fixed oils are conventionally ed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of inj ectables.

A composition of the invention may also be administered in the form of suppositories for rectal stration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritation 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 glycol.

Another formulation ed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. ,023,252, issued June 11, 1991, incorporated herein by reference).

Such patches may be constructed for continuous, ile, or on demand delivery of pharmaceutical agents.

Controlled release formulations for parenteral stration include liposomal, polymeric phere and ric gel formulations that are known in the art.

[Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles ation] micheles Unmarked set by micheles [Annotation] es None set by micheles ation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a ical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for, for example, administering a drug ly to the brain usually involve placement of a drug delivery catheter into the t’s cular system to bypass the blood-brain r. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,011,472, issued April 30, 1991.

The itions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M. F. et al, "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1" PDA Journal of ceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. et a1, "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical e & Technology 1997, 51(4), 166-171. ly used pharmaceutical ingredients that can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents les include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); ation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles alkalinizing agents (examples include but are not limited to a solution, um carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered ose and activated charcoal); aerosol propellants (examples e but are not limited to carbon dioxide, CClez, F2ClC-CClF2 and 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, butylparaben, ethylparaben, methylparaben, propylparaben, sodium te); antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium de, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (examples include but are not d to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, ioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde ylate, sodium metabisulfite); binding materials (examples include but are not limited to block polymers, natural and tic , polyacrylates, polyurethanes, silicones, polysiloxanes and styrene-butadiene copolymers); [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles ation] es None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles buffering agents (examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium e, sodium citrate anhydrous and sodium citrate dihydrate) carrying agents (examples e but are not limited to acacia syrup, aromatic syrup, aromatic , cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, l oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection) chelating agents (examples include but are not limited to e disodium and edetic acid) colorants (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.

, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red); clarifying agents (examples include but are not limited to bentonite); emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl l, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate); encapsulating agents (examples include but are not limited to gelatin and cellulose e phthalate) flavorants (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 glycerol, propylene glycol and sorbitol); [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles levigating agents (examples include but are not limited to mineral oil and glycerin); oils (examples include but are not limited to s oil, mineral oil, olive oil, peanut oil, sesame oil and ble oil); ointment bases (examples include but are not limited to lanolin, hydrophilic nt, polyethylene glycol ointment, petrolatum, hydrophilic atum, white ointment, yellow ointment, and rose water ointment); penetration enhancers dermal ry) (examples e but are not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols, saturated or rated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, atidyl derivatives, cephalin, 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 irrigation); stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, in, stearyl alcohol, white wax and yellow wax); ation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by es [Annotation] micheles Unmarked set by micheles itory bases les include but are not limited to cocoa butter and polyethylene glycols (mixtures)); surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-palmitate); ding agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (examples e but are not limited to magnesium stearate and talc); tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and atinized starch); tablet and e diluents les e but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl ose, hydroxypropyl cellulose, hydroxypropyl [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles ation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles methylcellulose, methylcellulose, ellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate); tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch); tablet ts (examples include but are not limited to colloidal silica, corn starch and talc); tablet lubricants les include but are not limited to calcium stearate, magnesium stearate, l oil, stearic acid and zinc stea rate ); tablet/capsule nts (examples include but are not limited to titanium dioxide); tablet ing agents les include but are not limited to carnuba wax and white wax); thickening agents les include but are not limited to beeswax, cetyl alcohol and paraffin); ty agents (examples include but are not limited to dextrose and sodium chloride); viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles ation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth); g agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene te).

Pharmaceutical compositions according to the present invention can be rated as follows: Sterile IV on: A 5 mg/mL solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 — 2 mg/mL with sterile 5% dextrose and is administered as an IV infusion over about 60 minutes.

Lyophilized powder for IV administration: A e preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lypholized powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 — 3000 mg Dextran 40. The formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2 — 0.4 mg/mL, and is administered either IV bolus or by IV infusion over 15 - 60 minutes.

Intramuscular suspension: The following solution or suspension can be prepared, for intramuscular injection: 50 mg/mL of the desired, water-insoluble nd of this invention mg/mL sodium carboxymethylcellulose 4 mg/mL TWEEN 80 9 mg/mL sodium de 9 mg/mL benzyl alcohol ation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by es [Annotation] micheles Unmarked set by micheles Hard Shell Capsules: A large number of unit capsules are prepared by filling rd two-piece hard galantine capsules each with 100 mg of powdered active agent, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft Gelatin Capsules: A mixture of active agent in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active agent. The capsules are washed and dried. The active agent can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible ne mix.

Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active agent, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose.

Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and ity or delay tion. ate Release Tablets/Capsules: These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and ry of the medication.

The active agent is mixed in a liquid ning ingredient 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 drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.

[Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by es [Annotation] micheles ed set by micheles ?) Method of treating breast cancer The present invention also relates to a method of treating or prophylaxis of cancer, e.g. breast cancer, which is classified into several subtypes in the clinic, such as hormone receptor positive breast cancer, Her2 receptor positive breast cancer, triple negative breast cancer and inflammatory breast cancer, in a mammal, said method comprising administering a 2,3-dihydroimidazo[1,2-c]quinazoline nd as defined herein, or a pharmaceutical ition containing same, as a sole active agent, or stering a combination of a) said compound or a pharmaceutical composition containing said compound and b) one or more further active agents as defined herein.

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the t invention, said breast cancer is inflammatory breast cancer.

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said breast cancer is triple ve breast cancer.

In accordance a ular embodiment of any of the above s, or embodiments thereof, of the present invention, said breast cancer is Her2 or positive breast cancer.

In accordance a ular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said breast cancer is hormone receptor positive breast cancer.

The embodiments of the methods of treating or prophylaxis of cancer, e.g. breast cancer, as defined supra, are as described in the ation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by es [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by es [Annotation] micheles Unmarked set by micheles embodiments of the use of the nds/combinations, as described supra.

The present invention s to a method for using the nds of the present invention and compositions thereof, to treat mammalian breast cancer. Compounds can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis, in the treatment or prophylaxis of breast cancer. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound or combination of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc. which is effective for the treatment or prophylaxis of breast cancer.

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

The term "treating" or "treatment" as stated throughout this nt is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a e or disorder, such as a carcinoma.

Dose and administration Based upon standard laboratory techniques known to evaluate compounds useful for the treatment or prophylaxis of breast cancer, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by ison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for [Annotation] es None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] es Unmarked set by micheles [Annotation] micheles None set by micheles ation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles treatment of the indication. The amount of the active agent to be administered in the treatment of the condition can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.

The total amount of the active agent to be stered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be cial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1,500 mg of active agent, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage n will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The e daily tion dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.

Of course the specific initial and continuing dosage regimen for each t will vary according to the nature and severity of the condition as [Annotation] micheles None set by es [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles determined by the attending diagnostician, the activity of the ic compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present ion or a pharmaceutically able salt or ester or composition f can be ascertained by those skilled in the art using conventional treatment tests.

Biomarkers : Biomarkers used for patient stratification are e.g. Bcl expression, HER family expression and/or tion, P|K3CA signaling and / or loss of PTEN for predicting the sensitivity and/or resistance of a cancer patient to said nd, thus providing rationale-based synergistic combination as defined herein to overcome the resistance.

Examples: The invention is demonstrated in the following examples which are not meant to limit the invention in any way: Example 1 In accordance with the invention, the compound were assessed in a cell- based assay that measures the ty of the compounds to inhibit tumor cell proliferation following a 72-hour drug exposure. Cell viability was conducted by Invitrogen (breast Oncopanel, Invitrogen, USA), or was determined using CellTiter-Glo® Luminescent Cell Viability Assay [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] micheles ed set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by es [Annotation] micheles Unmarked set by micheles (Promega) as follows. Cells were plated at 300 — 5000 cells/well depending on the cell lines or microtiter plates (96- or 384-well) in 100 uL growth medium in 96-well and 20 uL growth medium in 384-well microtiterplate. For each cell line assayed, cells were plated onto a te plate for determination of luminescence at t = 0 hour and t = 72 hour time points. Following ght incubation at 37 0C, luminescence values for the t = 0 samples were determined. Dose plates for the t = 72 hour time points were treated with compounds diluted into growth medium. Cells were then incubated for 72 hours at 37 °C.

Luminescence values for the t = 72 hour samples were determined. For data analysis, briefly, t = 0 values were subtracted from those determined for the t = 72 hour time points, for both the treated and untreated samples. Percent differences in scence between drug- treated and control values were used to ine the percent inhibition of .

Tumor cells were seeded in 384-well plates at a concentration of 1000- 2500 cells/well/25 uL depending on cell lines. After overnight incubation, cells were treated with compounds (5 uL). Then, Caspase 3/7 activities were determined at 24 to 48 hours post-treatment using Caspase-Glo3/7 assay kits (Promega Cat # G8212).

The combination effects of PI3K inhibitors and other agent were evaluated using ation index isobologram analysis (Chou et al.

Pharmacology Reviews 2006). The cy parameters were the median effect in a 72-hour cell proliferation assay and the 24- or 48-hour Caspase 3/7 activity assay described above. Briefly, cells were plated in 384-well plate with 25 pl . After 24 hours, 5 uL of experimental media containing either drug 1 (D1), or drug 2 (D2), or the combination of D1 plus D2 at different ratios (0.8xD1+0.2xD2, 0.6xD1+0.4xD2, 0.4xD1+0.6xD2, 0.2xD1+0.8xD2, 0.1xD1+0.9xD2) were used to make serial three-fold dilutions to generate 7 dose curves. Experiments were [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles ted in triplicate. For determination of EC50$ and ICsos, a linear regression analysis are used to determine drug concentration which results in a 50% inhibition or efficacy. The corresponding component doses of D1 and D2 at the o/ E(I)C90 were calculated and used for ng isobolograms. The multiple drug effect was analyzed as described by Chou et al. (Pharmacology Reviews 2006) and the combination index was ated using the formula : Combination Index = [D1x]/ D1’ + [D2x]/ D2’ where D1x and D2x refer to the Drug 1 and Drug 2 concentration at EC50/IC5o or EC90/IC90, respectively, in combination; and D1’ and D2’ refer to the EC50/IC50 or EC90/IC90 values of D1 and D2, respectively, as single . In this analysis, values less than 1.0 indicate synergistic ctions, values greater than 1.0 indicate antagonistic interactions, and values around 1.0 indicate additive interactions.

In the following, "compound of a I" refers to 2-amino-N-[7- methoxy(3-morpholinylpropoxy)—2,3-dihydroimidazo[1,2- c]quinazolinyl]pyrimidinecarboxamide, of structure : p\/\N o N/\/\O/\%\NékNJKAN 0y I O\CH3 H LNVKNHZ or a solvate, hydrate or stereoisomer thereof.

[Annotation] es None set by micheles [Annotation] es MigrationNone set by micheles ation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by es [Annotation] micheles Unmarked set by micheles In the following, "compound A" refers to 2-amino-N-[7-methoxy(3- morpholinylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin yl]pyrimidine-S-carboxamide dihydrochloride, of structure : fix"To OMo/\/\N//\NH ‘/§N o 0. // CH3 N NHz . 2HCl, or a solvate, hydrate or stereoisomer thereof.

The synthesis of compound A is described in European patent application number EP 11 161 111.7, which is hereby incorporated herein in its entirety by reference.

Synthesis of compound A : To a suspension of the compound of formula I (400 g) in water (1,1 L) at room temperature was added a 32% aqueous 32% (aqueous) hydrochloric acid solution iswith stirring dosed at room temperature to a suspension of 400 g of the compound of formula (I) in 1.1 L water until a pH of 3-4 is was reached. Additional 90 mL water (90 mL) and 32% hydrochloric acid are were added until a pH of 1.8 to 2.0 is was attained. E160 mL l (160 mL) are dosed into was added to the mixture, followed by seed crystals. After ng for 30 minutes, 1740 gadditional l (2,2 L) are dosed within 5 hwas added into the mixture over 5 h, which isand the resulting mixture was subsequently stirred for 1 h. The suspension is filtered and the residue is washed first with a mixture of 130 g water and 215 g ethanol, secondly with a mixture of 80 g water and 255 g [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles l and then with 320 g pure ethanol, The filter cake is dried at 40 °C under vacuum to yield 457 g product (99% of theory).

Characterization of compound A: U: The chemical structure of compound A has been confirmed using the described methods of structural analysis.

IR and Raman oscopy Apparatus and measuring conditions Fr-IR / Fr-Raman-Spectrometer Bruker IFS 66v / Bruker RFS 100 Spectral resolution 2 cm‘1 / 2 cm'1 Number of interferograms 32 / 64 Wave number range 4000 — 500 cm'1 / 3500 — 100 cm'1 Laser power - / 350mW Sample preparation KBr pellet / solid in test tube Assignment of the characteristic bands Table: Assignment of the characteristic active vibrations to the spectrum with v a hing vibrations; 6 E bending ions; o.o.p. 2 out of plane.

Assigned Structure IR Band position [cm‘1] Raman Band on [cm'1] v N-H 3336 v =C-H 3176 3090 v C-H 2942 2990 - 2963 v NH+ 2687 - 2474 v Amide | 1669 1664 v C=C, v C=N, 6 N-H, Amide || 1618 — 1477 1619 - 1476 v C-O 1285 1291 6 =C-H o.o.p. 812 v a stretching vibrations; 5 a bending vibrations; o.o.p. 2 out of plane [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by es [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles The IR spectrum is given in Figure 7.

The Raman spectrum is given in Figure 8.

UVNIS spectroscopy tus and measuring conditions UV/VIS spectrometer Varian Cary 4 Cuvette Quartz, 1 cm Wave number range 200-800 nm Sample preparation 4.67 mg / 500 mL water Bands 309 nm The UV/vis spectrum is given in Figure 9.

NMR spectroscopy 1H-NMR-spectroscopv ent and experimental parameters: NMR spectrometer Bruker, model Avance Working frequency 500.13 MHZ Solvent Dimethylsulfoxide (DMSO'dé) Internal reference compound Tetramethylsilane (TMS) tration 3.08 mg/mL solution Diameter of sample tube 5 mm Temperature approx. 25°C Technique Fourier transform mode Spectral width 20.65ppm [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles ionNone set by micheles [Annotation] micheles ed set by micheles Digital resolution 0.079 HZ/Pt Pulse length 4.5 usec, 30° Pulse flip angle Acquisition time 6.34sec tion time 0.55ec No. of free induction decays 32 Structural Formula for the assignment of NMR s HCI HCI °1E>3010a 29 8 \ /\\E/\ K N/\V27 25 o 6aN11)l:\12015N 0y 33 7 13 |14\N17 /O H / 19 N NH2 32 23 Chemical shift, signal multiplicity, relative number of nuclei : H-atoms(a) Chemical shift Multiplicity and no. of nuclei (ppm) coupling constants H/molecule [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] micheles Unmarked set by es H-26 2.32 M 2 H-29; H-33 3.11; 3.48 M; M 2; 2 H-30; H-32 3.83; 3.98 M; M 2; 2 H-27 3.29 M 2 -OCH3 4.00 S 3 H-25 4.37 T 2 H-2; H-3 4.47; 4.19 T; T 2; 2 H-9 7.39 D 1 NHz 7.54 S 2 H-10 8.21 D 1 H-16; H-20 8.97 S 1; 1 HCl 11.1; 12.6 bS; bS 1; 1 H-12 13.4 b5 1 a) ing refers to the structural formula for the assignment of NMR-signals. b) S = Singlet bS = broad Singlet D = Doublet T = Triplet M = Multiplet The 1H-NMR Spectrum of compound A is given in Figure 10. 13C-NMR-spectroscopx Equipment and experimental parameters [Annotation] micheles None set by micheles ation] es MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by es NMR spectrometer Bruker, model Avance Working frequency 125.76 MHZ Solvent Dimethylsulfoxide-d6 (DMSO) Internal reference compound Tetramethylsilane (TMS) Concentration 37.2 mg/mL solution Diameter of sample tube 5 mm Temperature approx. 27°C Technique Fourier transform mode Spectral width 240.95 ppm Digital resolution 0.4624 Hz/ Pt Pulse length 11.0 usec, 90° Pulse flip angle ition time 1.08 sec Relaxation time 4 sec No. of free induction decays 256 [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by es [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles al shift, signal multiplicity, rel. no. of nuclei : C-atoms(a) Chemical shift Multiplicity and no. of nuclei 6 (ppm) ng constants (b) C/molecule C-26 22.73 C-2; C-3 44.96; 45.65 :"l _| C-29; C-33 50.84 C-27 53.01 OCH3 61.24 C-30; C-32 63.03 C-25 66.81 C-10a 100.79 C-9 112.17 C-15 118.16 C-10 123.86 C-6a 132.43 C-7 133.95 C-5 148.58 C-11 156.29 C-8 156.89 C-16; C-ZO 160.20 C-18 164.61 C=O 175.65 wmcmmmmmchm—l—{p—lq a) Numbering refers to the structural formula for the assignment of NMR- signals. b) s = Single (C) D = Doublet (CH)T = Triplet (CH2) Q = Quadruplet (CH3) [Annotation] micheles None set by es [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles ation] es None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles The 13C-NMR Spectra of compound A are given in Figures 11 and 12.

Mass Spectrometry Instrumental Parameters Mass spectrometer Waters ZQ Ionization mode ESI (Electrospray-Ionization) Solvent H20 Interpretation of the Spectrum Mass value gm/zi Rel. Intensity 1%! The Mass Spectrum of compound A is given in Figure 13. Refer to the spectrum for relative peak intensities. ation] es None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by es [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles tal Analysis Elemental analysis was conducted by Bayer Industry Services, usen, Germany.

Results Element Measured Calculated Calculated Difference [%] [%] including 7.0 % water C 47.5 49.9 46.4 1.1 H 5.7 5.5 5.9 0.2 N 19.1 20.3 18.8 0.3 O 18.1 11.6 17.0 1.1 Cl 11.9 12.8 11.9 0.0 Sum 102.3 100.1 100.0 - The elemental analysis is consistent with compound A with 7% water.

Further method of preparation of compound "A" To a suspension of 366 g of compound of formula (I) in 1015 g water, 183 g of an aqueous hydrochloric acid solution (32%) were added while maintaining the temperature at 20 °C (+-2°) until a pH of 3 to 4 was reached. The ing mixture was stirred at room temperature for more than 10 min. filtered and the filtercake washed with additional 82 g of water. The filtrate was adjusted to pH 1.8 to 2.0 using aqueous hydrochloric acid solution (32%). The mixture was stirred for 10 min. at room temperature, 146g of l (100%) were added and stirred for another 10 min.. 1 g of seed crystals were added, followed by 1592 g ethanol within 5 h. The resulting substance was removed by filtration, [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] es MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles washed with a water-ethanol mixture and dried in vacuo to give 410 g (97%) of compound A of a purity >99% according to HPLC.

Molecular profiling of Compound A in 24 breast tumor cell lines indicated that tumor cells with either PIK3CA mutation and/or HER2 expression were extremely sensitive to Compound A with an average |C50 value of 17 (n=7) and 19 nM (n=8), respectively. In contrast, wild type PIK3CA and HER2 negative breast cancer cells (n=12) were relatively insensitive or resistant to nd A with an average lC5o value of 773 nM (~40-fold higher). Using a set of breast cancer cell lines representing differential receptor expression status and c alterations of PIK3CA and PTEN, the anti-proliferative and apoptotic effects of Compound A were investigated. With regard to apoptosis induction, Compound A demonstrated strong activity in PIK3CA mutant and or HER2 positive breast tumor cells (such as BT20, BT474).

Next, the molecular features responsible for the sensitivity and/or resistance to Compound A mediated induction of sis were identified. It was found that the sion of Bcl-2, but not Mcl-1 nor surviving, determined sensitivity to apoptosis. Thus, tumor cells that lack Bcl-2 expression (such as KPL-4, BT-474, and BT—ZO), even in the ce of high levels of EGFR and phospho-ERK in BT-20 cells, immediately underwent apoptosis after exposure to Compound A. On the other hand, cells expressing high level of Bcl-2, such as T47D (PIK3CAmUt), were ant to apoptosis induced by Compound A, despite the potent anti-proliferative activity of Compound A (single-digit nM ICso). Combining Compound A with ABT-737, an tor of Bcl-2, sensitized T47D cells to apoptosis, further supporting the hypothesis that simultaneous inhibiting P|3K and Bcl-2 could istically enhance the tumor killing effect in Bcl-2 positive breast cancer.

[Annotation] micheles None set by es [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles ation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles On the other hand, PTENm‘", EGFRhigh and Bcl-2 negative MDA-MB-468 tumor cells, are not only insensitive to tion of proliferation, but also resistant to induction of sis by Compound A. Inhibition of mTORC1 by rapamycin and/or inhibition of mTORC2 by the knockdown of Rictor, sensitizes MDA-MB468 cells to Compound A with the respect to inhibition of proliferation and induction of apoptosis.

In conclusion, Compound A was extremely effective at inducing sis in breast cancer cells expressing HER2 and/or PIK3CA mutation in the absence of Bcl-2. Compound A in combination with anti-Bcl agents or mTOR inhibitors might be the promising approach to achieve tumor responses in Bcl-Z positive tumors or EGFR expressing/PTENnUll breast tumors, respectively. These findings provide a retionale for developing personalized therapies for the treatment of lar subtypes of breast cancen Figure 1 shows the correlation of ICsos of Compound A in proliferation assays and genetic status of breast cancer cell lines.

Figure 2 shows kinetics of cell growth tion by Compound A. The Xcelligenoe technique (Roche, Germany) was used to monitor effects on tumor cell growth after treatment by nd A. Cell index (Cl), which correlates with the number of cells attached to the bottom of the plate (Giordano C, Masi A, Pizzini A, Sansone A, Consalvi V, Chiaraluce R, e G. Synthesis and activity of fibrillogenesis e tors related to the 17-21 beta-amyloid sequence. Eur J Med Chem. 2009;44:179—189), was detected every 15 minutes for 80 hours treatment period. Cl was normalized to the time point of treatment (at 24h Cl =1).

Figure 3 shows induction of PARP ge by Compound A in BT-ZO, BT- 474, ZR1, T47D and MDA-MB468 cells investigated at the indicated [Annotation] micheles None set by es [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles int by western blot analysis using GAPDH as an internal protein control.

Figure 4 shows pro-survival molecules of the Bcl family investigated in untreated cells (A). Cells were lysed and western blot analysis was med to detect Bcl-Z, Mcl-1, and survivin. GAPDH was used as an internal protein l.

Figure 5 shows tative analysis of the combination effect of compound A and ABT-737 on Caspase 3 and 7 induction in T47D cells (C).

Apoptosis induction by compound A and ABT-737 as a single agent and in combination was igated by Caspase-Glo ® 3/7 (Promega, USA) and analyzed by software Analyze 5 (Bayer HealthCare, Germany). The combination effects are depicted by isobologram and combination index based on the a described by Chou (Chou et al., 2006).

Combination index < 1, =1, and > 1 indicate synergistic, additive, and antagonistic s, respectively.

Figure 6 shows MDA-MB-468 cells transfected with irus expressing shRNA against Rictor. The cellular expression of the mTORC2 component Rictor was ed by western blot analysis (A). Induction of PARP cleavage by compound A treatment in combination with tion of mTORC1 or mTORC2 (B). shControl and shRictor MDA-MB468 cells were treated with indicated agents for 48 hours, and cleavage of PARP was analyzed. GAPDH was used as an internal protein control.

CONTROL SUBSTANCES Rapamicin obtained from Sigma (St Louis, MO, USA) was used as a reference inhibitor. ABT-737 was obtained from Selleck Chemicals (Houston, TX, USA) ation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by es [Annotation] es Unmarked set by micheles In conclusion, Compound A was extremely ive at inducing apoptosis in breast cancer cells expressing HER2 and/or a PIK3CA mutation in the absence of Bcl-2. Compound A in combination with anti- Bcl agents or mTOR inhibitors should provide a promising approach to achieve tumor responses in Bcl-2 positive tumors or EGFR expressing/PTENnUll breast , respectively. These findings provide a retionale to develop alized therapies for the treatment of molecular subtypes of breast cancer.

Hence, as mentioned supra, the present invention relates to the use of biomarkers ed in the modification of Bcl expression, HER family expression and/or activation, PIK3CA signaling and / or loss of PTEN for predicting the sensitivity and/or resistance of a patient with cancer, e.g. breast , in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor ve breast cancer, to a 2,3-dihydroimidazo[1,2-c]quinazoline compound as defined herein, thus providing retionale-based istic combination as defined herein to overcome the resistance.

In accordance with an embodiment, the present invention relates to the use of biomarkers involved in the modification of Bcl expression, HER family expression and/or tion, P|K3CA signaling and / or loss of PTEN for predicting the sensitivity and/or resistance of a patient with cancer, e.g. breast cancer, in particular inflammatory breast cancer, triple negative breast cancer, Her2 receptor positive breast , hormone receptor positive breast cancer, to a 2,3-dihydroimidazo[1,2- c]quinazoline compound as defined herein, thus providing a retionale- based synergistic combination as defined herein to overcome the resistance (patient stratification).

[Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by es In accordance with an embodiment, the present invention relates to a method of determining the level of a component of one or more of Bcl expression, HER family expression and/or activation, P|K3CA signaling and / or loss of PTEN, wherein : - in said Bcl expression, said component is Bcl, for example, - in said HER family sion and/or tion, P|K3CA signaling, said component is EGF-R, for e, and - in said loss of PTEN, said component is PTEN, for example.

Further, as mentioned supra, the present invention thus relates to combinations of : a) a 2,3-dihydroimidazo[1,2-c]quinazoline nd as defined supra, or a physiologically able salt, e, e or stereoisomer thereof ; or pharmaceutical compositions containing such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer b) one or more further active agents, in particular an active agent selected from an anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, iabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : - a Bcl inhibitor, such as ABT-737, 3 (Navitoclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), |G-105, WL-276, BI-97C1, |-VRL (Immunovivorelbine), DATS (Allitridin), CNDO-103 (Apogossypol), D-G- 3139 (Genasense), Evotec, FIB-1402, EU-517; [Annotation] micheles None set by micheles ation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles - a Bcl binding peptide ; - a Bcl siRNA, such as PNT-2258 ; - an antisense therapy oligonucleotide, such as BclKlex ; and - an inhibitor of the mTOR pathway, such as rapamycin or a rapamycin analogue, such as Rapamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, or), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, 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, 2, SB-2015, WYE-354, 3794, X-387, BEZ-235, as defined supra.

In accordance a particular embodiment of any of the above aspects, or ments thereof, of the present invention, said breast cancer is inflammatory breast cancer.

In accordance a particular embodiment of any of the above aspects, or ments thereof, of the t ion, said breast cancer is triple negative breast cancer.

In accordance a ular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said breast cancer is Her2 receptor positive breast .

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said breast cancer is hormone receptor ve breast cancer.

[Annotation] micheles None set by micheles [Annotation] micheles MigrationNone set by micheles [Annotation] micheles Unmarked set by micheles [Annotation] micheles None set by micheles [Annotation] micheles ionNone set by micheles [Annotation] micheles Unmarked set by es References: 1. Abbosh, P. H.; Nephew, K. P. Multiple signaling pathways converge on b-catenin in thyroid cancer. Thyroid 2005, 15, 551 -561. 2. Ali, I. U.; Schriml, L. M.; Dean, M. Mutational spectra of PTEN /MMAC1 gene: a tumor suppressor with lipid atase activity.

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Claims (10)

1. Use of 7]2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- 5 oimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide,or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as a sole active agent, or of a pharmaceutical composition containing such a nd or a 10 physiologically acceptable salt, solvate, hydrate or stereoisomer for the preparation of a medicament for the treatment or prophylaxis of inflammatory breast cancer, triple negative breast , Her2 15 receptor positive breast cancer, or hormone receptor positive breast cancer.

2. A combination of : 20 a) 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a physiologically acceptable salt, e, hydrate or stereoisomer thereof ; or a pharmaceutical composit ion containing such a compound or a physiologically acceptable salt, 25 solvate, hydrate or stereoisomer thereof, b) one or more further active agents selected from the group consisting 30 of : 7443598_1 (GHMatters) P94796.NZ KIRSTENA - a Bcl inhibitor, selected from ABT-737, ABT-263 (Navitoclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), IG-105, WL-276, BI-97C1, DATS (Allitridin), CNDO-103 (Apogossypol), D-G-3139 (Genasense),; 5 - a Bcl binding peptide ; - a Bcl siRNA, which is PNT-2258 ; - an nse therapy oligonucleotide, which is BclKlex ; and - an inhibitor of the mTOR pathway, selected from R apamycin (Sirolimus), Everolimus (RAD-001, or), Zotarolimus (ABT-578, 10 or), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, selected from WYE- 132, OSI-027, INK-128, OSI-027, AZD-2014, AZD-8055, CC-223, ABI-009, NV-128, OXA-01, PKI-402, WYE-354, KU-0063794, X-387, 5. 15

3. The combination according to claim 2, wherein said further active agent is rapamycin.

4. The combination according to claim 2, wherein said further active agent is ABT-737.

5. A pharmaceutical ition which comprises a combination of : a) 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a 25 logically acceptable salt, solvate, e or stereoisomer thereof ; and b) one or more further active agents selected from the group ting of : 7443598_1 (GHMatters) P94796.NZ KIRSTENA - a Bcl inhibitor, selected from ABT-737, 3 (Navitoclax), EM20-25, YC137, GX070 clax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), IG-105, WL-276, BI-97C1, DATS ridin), CNDO-103 (Apogossypol), D-G-3139 (Genasense); 5 - a Bcl binding peptide ; - a Bcl siRNA, which is PNT-2258 ; - an antisense therapy oligonucleotide, which is BclKlex ; and - an inhibitor of the mTOR pathway, selected from R apamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus 78, 10 Endeavor), Temisirolimus (CCI-779, Torisel), rolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR kinase, ed from WYE- 132, OSI-027, INK-128, OSI-027, AZD-2014, AZD-8055, CC-223, ABI-009, NV-128, , PKI-402, WYE-354, KU-0063794, X-387, BEZ-235. 15

6. Use of a combination of : a) 2-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide, or a logically acceptable salt, solvate, hydrate or stereoisomer 20 thereof ; or of a pharmaceutical composition containing 2-amino-N-[7-methoxy pholinylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin yl]pyrimidinecarboxamideor a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, b) one or more further active agents selected from the group consisting of : 7443598_1 (GHMatters) P94796.NZ KIRSTENA - a Bcl inhibitor, selected from ABT-737, 3 (Navitoclax), EM20-25, YC137, GX070 (Obatoclax), Tetrocarcin A, UCB-1350883, AT-101 ((- )-Gossypol), SPC-2004 (Beclanorsen), , WL-276, BI-97C1, DATS (Allitridin), CNDO-103 (Apogossypol), D-G-3139 (Genasense); 5 - a Bcl g peptide ; - a Bcl siRNA, which is PNT-2258 ; - an antisense therapy oligonucleotide, which is BclKlex ; and - an inhibitor of the mTOR y, selected from R apamycin (Sirolimus), Everolimus (RAD-001, Afinitor), Zotarolimus (ABT-578, 10 Endeavor), Temisirolimus (CCI-779, Torisel), Ridaforolimus (AP-23576, MK-8669), TAFA-93, or an inhibitor of mTOR , such as WYE-132, OSI-027, INK-128, OSI-027, AZD-2014, AZD-8055, CC-223, ABI-009, NV- 128, OXA-01, PKI-402, WYE-354, KU-0063794, X-387, BEZ-235 ; 15 or a pharmaceutical composition containing such a ation, for the ation of a medicament for the ent or prophylaxis of inflammatory breast , triple negative breast cancer, Her2 receptor positive breast cancer, hormone receptor positive breast 20 cancer.

7. The use according to claim 1, substantially as hereinbefore described with reference to any one of the Examples. 25

8. The combination according to claim 2, substantially as hereinbefore described with reference to any one of the Examples.

9. The pharmaceutical composition ing to claim 5, substantially as hereinbefore described with reference to any one of the Examples. 7443598_1 (GHMatters) P94796.NZ KIRSTENA

10. The use according to claim 6, substantially as hereinbefore described with reference to any one of the Examples.