NZ712033B2 - Use of substituted 2,3-dihydroimidazo[1,2-c]quinazolines for treating lymphomas - Google Patents

Abstract

use of a 2,3-dihydroimidazo[l,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 fu rther active agents, for the preparation of a medicament for the treatment or prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL); - 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 non-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL); - 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 the expression of PI3K isoforms, BTK and IKK,, BCR activation, BCR downstream activation of NFKB pathway, c-Myc, EZH2, 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 the expression of PI3K isoforms, BTK and IKK„ BCR activation, BCR downstream activation of NFKB pathway, c-Myc, EZH2. edicament for the treatment or prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL); - 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 non-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL); - 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 the expression of PI3K isoforms, BTK and IKK,, BCR activation, BCR downstream activation of NFKB pathway, c-Myc, EZH2, 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 the expression of PI3K isoforms, BTK and IKK„ BCR activation, BCR downstream activation of NFKB pathway, c-Myc, EZH2.

Description

USE OF SUBSTITUTED 2,3-DIHYDROIMIDAZO[1,2-C]QU|NAZOL|NES FOR TREATING LYMPHOMAS 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 non-Hodgkin’s lymphoma (hereinafter abbreviated to ”NHL"), ularly lst line, 2nd line, relapsed, refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to ”FL”), chronic lymphocytic leukaemia (hereinafter abbreviated to ”CLL”), al zone lymphoma (hereinafter iated to "MZL"), e large B-cell lymphoma nafter abbreviated to ”DLBCL”), mantle cell ma (MCL), transformed lymphoma (hereinafter abbreviated to "TL”), or peripheral T-cell lymphoma (hereinafter abbreviated to ”PTCL”) ; as a single agent or in combination with one or more other active agents ; - 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 cancer; - a pharmaceutical composition comprising a combination of a) said compound and b) one or more further active agents; - use of biomarkers, such as the expression of P|3K isoforms, BTK, IKK, BCR tion, BCR downstream activation of NFKB pathway, c-Myc, EZH2, for predicting the sensitivity and/or resistance of a cancer patient to said nd and providing a rationale-based synergistic ation as defined herein to increase sensitivity and/or to overcome resistance ; W0 2014/166820 - a method of determining the level of a component of one or more of the expression of PI3K isoforms, BTK, IKK, BCR activation, BCR downstream activation of NFKB pathway, c- Myc, EZH2.

BACKGROUND OF THE INVENTION 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 important role in generating critical regulatory second messengers. The PI3K family of lipid kinases generates 3’- phosphoinositides that bind to and activate a variety of cellular targets, initiating a wide range of signal transduction cascades (Vanhaesebroeck et al., 2001; Toker, 2002; Pendaries et a/., 2003; Downes et al., 2005). These cascades ultimately induce changes in multiple ar ses, including cell proliferation, cell survival, differentiation, vesicle trafficking, migration, and chemotaxis.

PI3Ks can be divided into three distinct classes based upon differences in both structure, and substrate preference. While members of the Class II family of PI3Ks have been implicated in the tion of tumor growth (Brown and Shepard, 2001; Traer et 0]., 2006), the bulk of research has focused on the Class | enzymes and their role in cancer (Vivanco and Sawyers, 2002; Workman, 2004, Chen et al., 2005; Hennessey et a/., 2005; Stauffer et 0]., 2005; Stephens et a/., 2005; Cully et al., 2006).

Class | PI3Ks have ionally been divided into two distinct sub—classes based upon differences in n subunit composition. The Class IA PI3Ks are comprised of a tic p110 catalytic subunit L, p110I5 or p110y) heterodimerized with a member of the p85 regulatory subunit family. In contrast, the Class Ia PI3K catalytic subunit (p110y) heterodimerizes with a ct p101 regulatory subunit (reviewed by Vanhaesebroeck and Waterfield, 1999; Funaki et al., 2000; Katso et 0]., 2001). The C—terminal region of these proteins contains a catalytic domain that possesses distant homology to n kinases. The PI3Ky structure is similar to Class IA p1105, but lacks the inal p85 binding site (Domin and Waterfield, 1997). Though similar in overall structure, the homology between catalytic p110 subunits is low to moderate. The W0 2014/166820 highest homology between the P|3K isoforms is in the kinase pocket of the kinase domain.

The Class | P|3K isoforms associate with activated receptor ne kinases (RTKs) ding PDGFR, EGFR, VEGFR, , c-KIT, CSF-R and Met), cytokine receptors, GPCRs, integrins, or with tyrosine phosphorylated adapter proteins (such as Grb2, Cbl, IRS-1 or Gabl), via their p85 regulatory ts resulting in stimulation of the lipid kinase activity. Activation of the lipid kinase activity of the p110(3 and p110y isoforms has been shown to occur in se to binding to activated forms of the ras Oncogene (Kodaki et at, 1994). In fact, the oncogenic activity of these isoforms may require binding to ras (Kang et ai., 2006). In contrast, the p110<1 and p1106 isoforms t oncogenic ty independent of ras binding, through constitutive activation of Akt.

Class | P|3Ks catalyze the conversion of P|(4,5)P2 [Ple] to Pl(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 al, differentiation and cell migration. P|P3 is bound by Pleckstrin-Homology (PH) domain-containing proteins, including the phosphoinositide-dependent , PDK1 and the Akt proto—oncogene product, localizing these proteins in regions of active signal transduction and also contributing directly to their activation (Klippel et al., 1997; Fleming et a/., 2000; Itoh and wa, 2002; Lemmon, 2003). This co—localization of PDK1 with Akt facilitates the phosphorylation and activation of Akt. Carboxy-terminal phosphorylation of Akt on Ser473 promotes 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 tes multiple regulatory kinases of pathways that directly influence cell cycle progression and cell survival.

Many of the effects of Akt activation are mediated via its negative regulation of pathways which impact cell survival and which are commonly dysregulated in cancer.

Akt promotes tumor cell al by regulating components of the apoptotic and cell cycle ery. Akt is one of several kinases that phosphorylate and inactivate pro- apoptotic BAD proteins (del Paso et aL, 1997; Pastorino et a/., 1999). Akt may also W0 66820 promote cell survival through blocking rome ndent caspase activation by phosphorylating Caspase 9 on Ser196 (Cardone et 0]., 1998).

Akt impacts gene transcription on several levels. The Akt—mediated phosphorylation of the MDM2 E3 ubiquitin ligase on Ser166 and Ser186 facilitates the r import of MDMZ and the formation and activation of the ubiquitin ligase complex. Nuclear MDM2 targets the p53 tumor suppressor for degradation, a process that can be blocked by LY294002 (Yap et 0]., 2000; Ogarawa et al., 2002). Downregulation of p53 by MDMZ vely impacts the transcription of p53-regulated pro—apoptotic genes (e.g. Bax, Fas, PUMA and DRS), the cell cycle inhibitor, p210“, and the PTEN tumor suppressor (Momand et al., 2000; Hupp et al., 2000; Mayo et al., 2002; Su et a/., 2003). Similarly, the Akt-mediated phosphorylation of the Forkhead ription factors FKHR, FKHRL and AFX (Kops et a/., 1999; Tang et a/., 1999), facilitates their binding to 14—3—3 proteins and export from the cell nucleus to the cytosol (Brunet et a/., 1999). This functional inactivation of Forkhead activity also impacts pro-apoptotic and pro-angiogenic gene transcription including the transcription of Fas ligand omska et 01., 2003) Bim, a pro-apoptotic Bcl-2 family member (Dijkers et 0]., 2000), and the Angiopoietin-l (Ang—1) antagonist, Ang-Z (Daly et 0]., 2004). ad transcription factors regulate the expression of the cyclin-dependent kinase (Cdk) inhibitor p27Klp1. Indeed, PI3K inhibitors have been demonstrated to induce p27Kipl expression resulting in Cdkl inhibition, cell cycle arrest and apoptosis (Dijkers et 01]., 2000). Akt is also reported to phosphorylate lon Thr145 and p27Kipl on Thr157 facilitating their association with 14—3—3 proteins, resulting in nuclear export and asmic retention, preventing their inhibition of r Cdks (Zhou et al., 2001; Motti et al., 2004; to et al., 2004). In addition to these effects, Akt phosphorylates lKK (Romashkova and Makarov, 1999), leading to the phosphorylation and degradation of IIB and subsequent nuclear translocation of NFKB, resulting in the expression of survival genes such as IAP and BCl'XL.

The Pl3K/Akt pathway is also linked to the suppression of sis through the JNK and p38"""PK 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 JNK/p38 tory kinases, Apoptosis Signal—regulating Kinase 1 (ASKl) (Kim et a/., 2001: Liao and Hung, 2003; Yuan et 01., 2003), and Mixed Lineage W0 66820 Kinase 3 (MLK3) —llasaca et 0/1., 1997; Barthwal et 0/1., 2003; Figueroa et 0]., 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 an, 2004). Thus, inhibitors of the PI3K pathway may promote the activities of co- administered cytotoxic drugs.

An additional role for PI3K/Akt signaling involves the regulation of cell cycle progression through modulation of Glycogen Synthase Kinase 3 (GSK3) activity. GSK3 activity is elevated in quiescent cells, where it phosphorylates cyclin D1 on Ser286, targeting the protein for ubiquitination and degradation (Diehl et a/., 1998) and blocking entry into S- phase. Akt ts GSK3 activity through phosphorylation on Ser9 (Cross et a/., 1995).

This results in the ion of Cyclin D1 levels which promotes cell cycle progression.

Inhibition of GSK3 activity also impacts cell proliferation through activation of the wnt/beta—catenin ing pathway (Abbosh and Nephew, 2005; Naito et al., 2005; Wilker et 01., 2005; Kim et a/., 2006; Segrelles et a/., 2006). Akt mediated phosphorylation of GSK3 results in stabilization and r localization of the beta- n protein, which in turn leads to increased expression of c-myc and cyclin D1, targets of the beta-catenin/ch pathway.

Although PI3K signaling is utilized by many of the signal transduction ks associated with both oncogenes and tumor suppressors, PI3K and its activity have been linked directly to cancer. Overexpression of both the p110a and p110l3 isoforms has been observed in bladder and colon tumors and cell lines, and overexpression generally correlates with increased PI3K activity (Bénistant et al., 2000). Overexpression of p110a has also been reported in ovarian and cervical tumors and tumor cell lines, as well as in squamous cell lung omas. The overexpression of plloa in cervical and ovarian tumor lines is associated with increased PI3K activity (Shayesteh et a/., 1999; Ma et al., 2000). Elevated PI3K activity has been observed in colorectal carcinomas (Phillips et 01., 1998) and increased expression has been ed in breast carcinomas (Gershtein et a/., 1999).

Over the last few years, somatic mutations in the gene ng p110a (PIK3CA) have been identified in numerous cancers. The data collected to date suggests that P|K3CA is W0 2014/166820 2014/056768 mutated in approximately 32% of colorectal cancers (Samuels et al., 2004; Ikenoue et al., 2005), 18-40% of breast cancers (Bachman et al., 2004; Campbell et al., 2004; Levine et al., 2005; Saal et al., 2005; Wu et al., 2005), 27% of glioblastomas (Samuels et al., 2004; Hartmann et al., 2005, Gallia et al., 2006), 25% of gastric cancers (Byun et al., 2003; Samuels et al., 2004; Li et al., 2005), 36% of hepatocellular carcinomas (Lee et al., 2005), 4—12% of ovarian cancers (Levine et al., 2005; Wang et al., 2005), 4% of lung cancers (Samuels et al., 2004; Whyte and Holbeck, 2006), and up to 40% of endometrial cancers (Oda et al., 2005). P|K3CA mutations have been reported in oligodendroma, astrocytoma, 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 ntly mutated genes ated with cancer, the other being K-ras. More than 80% of the P|K3CA mutations cluster within two regions of the n, the helical (E545K) and catalytic (H1047R) domains. Biochemical analysis and protein expression studies have demonstrated that both mutations lead to increased constitutive p1100. catalytic activity 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 ut mouse embryo lasts are deficient in signaling downstream from various growth factor receptors (IGF—l, Insulin, PDGF, EGF), and are ant to transformation by a variety of oncogenic RTKs (IGFR, wild-type EGFR and somatic ting mutants of EGFR, Her2/Neu)(Zhao et al., 2006).

Functional studies of PI3K in vivo have demonstrated that siRNA-mediated downregulation of p110(5 ts both Akt phosphorylation and HeLa cell tumor growth in nude mice (Czauderna et al., 2003). In similar experiments, siRNA-mediated gulation of p110(5 was also shown to inhibit the growth of malignant glioma cells in vitro and in vivo (Pu et al., 2006). Inhibition of Pl3K function by dominant-negative p85 regulatory subunits can block mitogenesis and cell transformation (Huang et al., 1996; Rahimi et al., 1996). Several somatic mutations in the genes encoding the p85a and p856 regulatory subunits of Pl3K that result in elevated lipid kinase activity have been identified in a number of cancer cells as well (Janssen et al., 1998; Jimenez et al., 1998; Philp et al., 2001; Jucker et al., 2002; Shekar et al., 2005). Neutralizing Pl3K antibodies also block mitogenesis and can induce sis in vitro (Roche et al., 1994: Roche et al., 1998; Bénistant et al., 2000). In vivo proof-of-principle studies using the W0 2014/166820 P|3|< inhibitors LY294002 and wortmannin, trate that inhibition of PI3K signaling slows tumor growth in vivo (Powis et al., 1994; Shultz et 0]., 1995; Semba et al., 2002; lhle et 0/1., 2004).

Overexpression of Class | PI3K activity, or stimulation of their lipid kinase activities, is associated with resistance to both targeted (such as imatinib and tratsuzumab) and cytotoxic chemotherapeutic approaches, as well as radiation therapy (West et al., 2002; Gupta et 0]., 2003; Osaki et 0]., 2004; Nagata et 01., 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-l) in prostate cancer cells and the subsequent induction of resistance to chemotherapy (Lee et al., 2004).

The importance of PI3K signaling in genesis is further underscored by the findings that the PTEN tumor suppressor, a P|(3)P atase, is among the most commonly inactivated genes in human cancers (Li et a/., 1997, Steck et a/., 1997; Ali et a/., 1999; Ishii et a/., 1999). PTEN dephosphorylates PI(3,4,5)P3 to )P2 thereby antagonizing Pl3K-dependent signaling. Cells containing functionally inactive PTEN have elevated levels of Png, high levels of activity of P|3l< signaling (Haas-Kogan et 01., 1998; Myers et 01]., 1998; Taylor et al., 2000), increased proliferative potential, and decreased ivity to optotic stimuli (Stambolic et 0]., 1998). Reconstitution of a functional PTEN suppresses Pl3|< signaling r et a/., 2000), inhibits cell growth and re-sensitizes cells to pro-apoptotic stimuli (Myers et al., 1998; Zhao et a/., 2004). Similarly, restoration of PTEN function in tumors lacking functional PTEN inhibits tumor growth in vivo (Stahl et 01., 2003; Su et a/., 2003; Tanaka and Grossman, 2003) and izes cells to cytotoxic agents (Tanaka and Grossman, 2003).

The class I family of Pl3Ks clearly plays an important role in the regulation of multiple signal uction pathways that promote cell survival and cell proliferation, and tion of their lipid kinase activity contributes significantly to the development of human malignancies. Furthermore, inhibition of PI3K may potentially circumvent the cellular isms 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 sensitize tumor cells to pro-apoptotic stimuli in vivo.

W0 2014/166820 2014/056768 Signal transduction pathways originating from chemoattractant receptors are considered to be important targets in controlling leukocyte motility in inflammatory diseases. yte trafficking is controlled by chemoattractant factors that activate heterotrimeric GPCRs and y trigger a variety of downstream intracellular events.

Signal transduction along one of these pathways that results in mobilization of free Caz“, cytoskelatal reorganization, and directional movement depends on lipid-dervied second messengers producted by PI3K activity (Wymann et a/., 2000; Stein and ield, 2000).

P|3Ky modulates baseline cAMP levels and controls contractility in cells. Recent research indicates that alterations in baseline cAMP levels contribute to the sed contractility in mutant mice. This research, therefore, shows that P|3Ky inhibitors afford potential treatments for congestive heart failure, ischemia, pulmonary hypertension, renal failure, cardiac hypertrophy, atherosclerosis, thromboembolism, and diabetes.

P|3K inhibitors would be expected to block signal transduction from GPCRs and block the activation of various immune cells, leading to a broad anti-inflammatory profile with ial for the treatment of inflammatory and immunoregulatory diseases, including asthma, atopic dermatitis, rhinitis, allergic diseases, chronic obstructive pulmonary disease (COPD), septic shock, joint diseases, autoimmune pathologies such as rheumatoid arthritis and Graves’ e, diabetes, cancer, myocardial contractility disorders, thromboembolism, and atherosclerosis.

Activation of the Pl3K/AKT pathway by B-cell receptor signaling and its role in the pathogenesis of dgkin’s lymphoma (NHL) have been highlighted in a number of studies. However, the relative importance of phosphoinositide 3—kinase (PI3K) ms and other downstream s, e.g. Bruton’s tyrosine kinase (BTK) and IKB kinase (IKK), for eutic application in NHL has not been fully addressed. To answer this question, we 3O selected and characterized a panel of cell lines representing frequent ons CD79, MyD88, CARD11, Bch, c-Myc, or EZHZ in diffuse large B—cell lymphoma (DLBCL), a major type of aggressive NHL. Analyzing the expression of P|3K isoforms indicated that not only W0 2014/166820 P|3|<5, an isoform known to be enriched in lymphocytes, but also other 3 Pl3K isoforms are highly expressed. Sensitivity profiling of the pan-Pl3K inhibitor COMPOUND A (with potent ty against Pl3K(1[lC50 = 0.5 nM] and Pl3K5 [ICso = 0.7 nM]), the Pl3K5-selective inhibitor GS-1101, the irreversible BTK inhibitor ibrutinib (PG—32765), and the IKKB inhibitor BAY compound B revealed that the pan-Pl3K inhibitor COMPOUND A has a broader antitumor spectrum and is more effective than inhibition of PI3K6 or BTK only.

Further is of oncogenic signaling pathways discovered feedback activation of ERK by Pl3K6- or BTK-selective inhibition, and re-activation of IKK by IKKB tion. Combination of Pl3K inhibitor COMPOUND A with BTK or IKK inhibitors showed synergistic antitumor effects in a subset of tumor cell lines, indicating the heterogeneity of DLBCL and that a biomarker might be necessary for sfully developing COMPOUND A-based therapeutics in aggressive NHL. Taken er, these findings provide further insights into the mechanism of action of PI3K inhibitor COMPOUND A and t ongoing Phase II clinical studies in NHL patients Follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) are 2 of the most common non-Hodgkin’s lymphomas (NHLs) worldwide. There remains a high unmet medical need for effective eutics for tory and relapsed follicular lymphoma and DLBCL.

The al role of phosphoinositide 3—kinase (Pl3K)6 in regulating downstream events of the B-cell receptor (BCR) has been evident by the al benefit of 63-1101, a Pl3K6- selective inhibitor in follicular ma patients.

Several lines of evidence ted that a pan-Pl3K inhibitor may produce a better therapeutic benefit compared with Pl3K6-selective inhibition.

In PI3K6 ut mice, PI3KOL was shown to compensate tonic signaling, a characteristic of many B—cell malignancies (see reference 1A). 0 8% of DLBCL patients have a PIK3CA mutation and 37% have reduced PTEN expression or loss of function of PTEN. o In the clinic, -mediated constitutive Pl3K signaling appeared to limit the efficacy of p1105—selective inhibition in mantle cell lymphoma (see reference 2A).

W0 66820 0 Although the Pl3|<5~se|ective inhibitor GS—1101 demonstrated promising clinical response in indolent NHL, so far no efficacy has been shown in aggressive NHL, eg DLBCL. o COMPOUND A is a pan-PI3K inhibitor potently inhibiting PI3KOL and Pl3K6, with ICSO values of 0.5 and 0.7 nM, tively (see reference 3A). 0 In this study, we investigated the effects and the mechanism of action of inhibiting key molecular targets in NHL cells using the pan-PI3K inhibitor COMPOUND A, Pl3K6-selective inhibitor 65-1101, Bruton’s ne kinase (BTK) inhibitor ibrutinib (PG-32765), and an lKB kinase (IKK) inhibitor BAY compound B (see reference 4A) as single agents. 0 Based on the mechanism of action, the t patent application relates to and covers rational combination therapies for ive treatment of aggressive NHL.

The present invention is thus to fy lar s predicting the sensitivity and/or resistance of the cancer patients toward the P|3K inhibitors described herein.

Furthermore, the present ion also relates to the identification of resistance mechanisms and therefore provides a ale-based synergistic ation to overcome the resistance.

To the Applicant’s knowledge, no specific 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 non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T—cell lymphoma (PTCL).

It has been found, and this is the basis of the present invention, that 2,3- dihydroimidazo[1,2-c]quinazoline compounds, as bed and defined herein, show a beneficial effect in the treatment or prophylaxis of non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia W0 2014/166820 (CLL), marginal zone lymphoma (MZL), diffuse large B—cell ma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell ma (PTCL).

Thus, in accordance with a first aspect, the present invention s to the use of 2,3— dihydroimidazo[1,2—c)quinazoline compounds, or a logically acceptable salt, e, hydrate or isomer f, as a sole active agent, or of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, for the preparation of a medicament for the treatment or prophylaxis of dgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), c lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma ), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL).

In accordance with a second aspect, the present invention relates to combinations 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 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 ularly one or more further active agents selected from the group consisting of : Pl3K5—selective inhibitor 65-1101, BTK inhibitor ibrutinib, lKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766 (RDEA-119)).

In accordance with a third aspect, the present invention relates to pharmaceutical compositions comprising a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as a sole active agent, for the ent of non-Hodgkin’s lymphoma (NHL), ularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone W0 66820 lymphoma (MZL), diffuse large B—cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL).

In accordance 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, hydrate or stereoisomer thereof; and b) one or more further active agents, in particular an active agent selected from an anti- enesis, anti-hyper-proliferative, flammatory, 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 : PI3K6-selective inhibitor 65-1101, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766 (RDEA—119)).

In accordance with a fifth aspect, the present invention relates to the use of combinations of: a) a 2,3-dihydroimidazo[1,2-c]quinazo|ine compound, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; or of a ceutical ition containing such a 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, iabetic or antiviral agent, more ularly one or more r active agents selected from the group consisting of : Pl3K6—selective inhibitor 65-1101, BTK inhibitor ibrutinib, IKK tor BAY Compound B, and REFAMETINIB (BAY 86-9766 (RDEA-119)); W0 2014/166820 for the preparation of a medicament for the treatment or prophylaxis of non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular ular lymphoma (FL), chronic lymphocytic leukaemia (CLL), al zone lymphoma (MZL), diffuse large B—cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL).

In accordance with a sixth aspect, the present invention relates to use of biomarkers involved in the modification of target expression, BCR activation, BCR downstream activation of NFKB pathway, c-Myc, EZHZ, for predicting the sensitivity and/or ance of a patient with dgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, tory, indolent or agressive dgkin’s ma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell ma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL), to a 2,3-dihydroimidazoll,2- c]quinazoline compound as defined herein, thus providing a rationale-based istic combination as defined herein to overcome the resistance (patient 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 the expression of PI3K isoforms, BTK, IKK, BCR activation, BCR downstream activation of NFKB pathway, c-Myc, EZH2.

In accordance a particular ment of any of the above aspects of the present invention, said cancer is non-Hodgkin’s ma (NHL), ularly lst line, 2nd line, relapsed, refractory, nt or agressive non-Hodgkin’s lymphoma (NHL).

In accordance a particular embodiment of any of the above aspects of the present invention, said cancer is follicular lymphoma (FL).

In accordance a particular embodiment of any of the above aspects of the present invention, said cancer is chronic lymphocytic leukaemia (CLL).

W0 2014/166820 In ance a particular embodiment of any of the above aspects of the present invention, said cancer is marginal zone lymphoma (MZL).

In accordance a particular embodiment of any of the above aspects of the present invention, said cancer is diffuse large B—cell lymphoma (DLBCL).

In accordance a particular embodiment of any of the above s of the present invention, said cancer is mantle cell ma (MCL).

In accordance a particular embodiment of any of the above aspects of the present invention, said cancer is transformed lymphoma (TL).

In accordance a particular embodiment of any of the above aspects of the present invention, said cancer is peripheral T-cell lymphoma (PTCL).

Detailed description of the Invention A first aspect of the present invention relates to the use of a compound of general a (A) : YL’Y 24 / \E z’ \ / E2 ’ /A \z‘ N 2): o R1 in which : X represents CR5R6or NH; Y1 represents CR3 or N; the al bond between Y2:Y3 represents a single bond or double bond, W0 2014/166820 with the proviso that when theY2;Y3 ents a double bond, Y2 and Y3 independently represent CR4 or N, and when Y2'-'=Y3 represents a single bond, Y2 and Y3 independently represent CR3R4 or NR4; 21, 22, Z3 and 24 independently represent CH CR2 or N; 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, y, heteroaryloxy or one or more halogen, CM alkoxy optionally substituted by carboxy, aryl, heteroaryl, CM alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen, a 3 to 15 membered mono- or lic heterocyclic ring that is ted or unsaturated, optionally having 1 to 3 substituents ed from R“, and contains 1 to 3 heteroatoms selected from the group consisting of N, O and S, wherein R11 represents halogen, nitro, hydroxy, cyano, carboxy, amino, N— (C1_6alkyl)amino, roxyC1.6a|ky|)amino, N,N-di(C1_6a|kyl)amino, N- (C1.5acy|)amino, N-(formyl)-N—(C1.5alky|)amino, N—(C1.5a|kanesu|fonyi) amino, N-(carboxyC1.5a|ky|)-N-(C1.6a|ky|)amino, N-(Cl. salkoxycabonyllamino, N-[N,N-di(C1.5a|kyl)amino methylene]amino, N- [N,N-di(C1.5alkyI)amino (Cmalkyl)methylene]amino, N-[N,N-di(C1_ salkyl)amino C2.6alkeny|]amino, aminocarbonyi, N— (C1_6a|kyl)aminocarbonyl, (C1_5a|kyl)aminocarbonyl, C3.gcycloa|kyl, Cm alkylthio, C1.ea|kanesulfonyl, sulfamoyi, C1.ea|koxycarbonyl, N-arylamino wherein said aryl moiety is optionally having 1 to 3 sub- stituents selected from R101, N—(aryl C1.5alky|)amino wherein said aryl moiety is ally having 1 to 3 tuents selected from R101, aryl C1.ea|koxycarbonyl wherein said aryl moiety is optionally having 1 to 3 substituents selected from R101, W0 2014/166820 kyl optionally substituted by mono—, di- or tri— halogen, amino, N- (CJ—aalkyl)amino or N,N—di(C1.6a|ky|)amino, C1.5alkoxy optionally substituted by mono-, di— or tri- n, N— (C1.salkyl)su|fonamide, 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 ed from R101 wherein R101 represents halogen, carboxy, amino, N-(C1.6 alkyl)amino, N,N-di(C1_ ealkyl)amino, aminocarbonyl, N-(C1.5a|kyl)aminocarbonyl, N,N- di(C1.5alkyl)aminocarbonyi, pyridyl, CH alkyl optionally substituted by cyano or mono— di- or tri- halogen, Cmalkoxy optionally substituted by cyano, carboxy, amino, N— (CM alkyl)amino, N,N-di(C1.5a|kyl)amino, aminocarbonyl, N-(CJ. 5a|kyl)aminocarbonyl, N,N-di(C1.5a|kyl)aminocarbonyl or mono—, di- or tri- halogen; represents y, halogen, nitro, cyano, amino, N-(C1_6a|kyl)amino, N,N—di(C1.5alkyl)amino, N-(hydroxyC1.5a|ky|)amino, N-(hydroxyC1.5a|kyl)— N-(C1.6a|kyl)amino, CM acyloxy, 1.5acyloxy, Cztsalkenyl, 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 W0 2014/166820 hydroxy, C1.6 alkyl, C14; alkoxy, oxo, amino, amino Cyealkyl, N— (C1.5a|ky|)amino, N,N—di(C1.5alkyl)amino, N-(CH; acy|)amino, N- (C1.5alkyl)carbonylamino, phenyl, phenyl Clue alkyl, carboxy, C1.5a|koxycarbony|, aminocarbonyl, N-(C1.6a|kyl)aminocarbonyl, or N,N- di(C1_5aIkyl)amino, -C(O)- R20 wherein R20 represents Cm alkyl, C145 alkoxy, amino, N-(C1.5alky|)amino, N,N- 6alky|)amino, N-(CH acy|)amino, or a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 atoms selected from the group consisting O, S and N, and ally substituted by CH; alkyl, C“; alkoxy, oxo, amino, N-(C1_ 6alkyl)amino, N,N-di(C1.5alky|)amino, N-(C1.6 acyl)amino, phenyl, or , CH alkyl optionally tuted by R“, CH; alkoxy optionally substituted by R21, wherein R21 represents cyano, mono—, di or tri— halogen, hydroxy, amino, N-(C1.5a|kyl)amino, N,N-di(C1_5alkyl)amino, N- xyCm alkyl) amino, N- (halophenylcm alkyl) amino, amino Cm alkylenyl, C16 alkoxy, hydroxyC1.e alkoxy, -C(O)— R201, -NHC(O)- R201, C3.3cyc|oalkyl, isoindolino, phthalimidyl, 2-oxo-1,3-oxazo|idinyl, aryl or 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 ally substituted by hydroxy, (21.5 alkyl, CH alkoxy, C“; alkoxycarbonyl, hydroxyCH alkoxy, oxo, amino, aminoCl. 5a|ky|, N-(C1.5a|kyl)amino, N,N-di(C1.5alky|)amino, N-(C1.5 acyl)amino, or benzyl, W0 2014/166820 wherein R201 represents hydroxy, amino, N—(C1.6alky|)amino, N,N— di(C1.6alkyl)amino, N- (halophenylcm alkyl) amino, C1.6all<yl, aminoC1.e alkyl, 2~e alkylenyl, Cm 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 ally tuted by hydroxy, CH; alkyl, C145 alkoxy, CM alkoxycarbonyl, hydroxyCm alkoxy, oxo, amino, 5alkyl)amino, N,N-di(C1.5a|k- yl)amino, N-(CH acyllamino or benzyl; R3 represents hydrogen, halogen, aminocarbonyl, or CH; alkyl optionally substituted by aryl CH alkoxy or mono-, di- or tri- halogen; R4 represents hydrogen or CH alkyl; R5 ents hydrogen or CH alkyl; and R6 represents n, hydrogen or CH 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 , 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 selected from the group consisting of : selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766 (RDEA-119)); W0 2014/166820 or of pharmaceutical compositions containing such compounds or a logically 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 non-Hodgkin’s ma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), c lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell ma ), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL).

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 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, e, hydrate or stereoisomer thereof; and b) one or more further active agents, in particular an active agent selected from an anti- angiogenesis, yper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or ral agent, more particularly one or more further active agents selected from the group consisting of : Pl3K6—selective inhibitor GS-1101, BTK inhibitor ibrutinib, lKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766 (RDEA—119)); or of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, or of ceutical compositions ning such ations for the preparation of a medicament for the treatment or prophylaxis of non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic mia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell W0 2014/166820 lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma ( L), or peripheral T-cell lymphoma (PTCL) : N—(7,8-dimethoxy—2,3—dihyd roimidazo[l,2-c]qu inazolin-S—yl)n icotinamide; 2—(7, 8—dimethoxy—2,3-dihydroimidazo[1,2—c]quinazolin—S—yl)-1—pyridin-3—y|ethylenol; N-(7, 8-dimethoxy-2,3—dihydroimidazo[1,2-c]quinazolin-S-yl)—1H-benzimidazole—5— carboxamide; 6—(acetamido)-N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2—c]quinazolin-S-yl)nicotinamide; N-{5-[2-(7,8—dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-S-yl) hydroxyvinyl]pyridin-Z-y|}acetamide; 2-({5-[2-hydroxy—Z-pyridinylvinyl]—7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin yl}oxy)-N,N-dimethylacetamide; 2-[7-methoxy-8—(tetrahydro-ZH-pyran-Z-ylmethoxy)-2,3-dihydroimidazo[1,2- c]quinazolin-S-yl]—1—pyridin-3—ylethylenol; 2-[8-(2-hydroxyethoxy)methoxy-2,3-dihydroimidazo[1,2-c]quinazolinyl]—1-pyridin- hylenol; ({5-[2-hydroxy-2—pyridinylvinyl]methoxy—2,3-dihydroimidazo[l,2-c]quinazolin-B- yl}oxy)acetic acid; 4-({5-[2-hydroxy-Z—pyridinylvinyl]—7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin—8— lbutanoic acid; ({5-[2-hydroxypyridinylvinyl]-7—methoxy-2,3—dihydroimidazo[1,2-c]quinazolin—8— yl}oxy)acetonitri|e; 2-[7-methoxy—8-(2H—tetrazol-5—y|methoxy)-2,3-dihydroimidazo[1,2-c]quinazo|iny|] pyridinylethylenol; 2—[7-methoxy(4—morpholinyl-4—oxobutoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5— y|]pyridin-3—ylethylenol; ydroxy-Z-(8—morpholin-4—yl-2,3-dihydroimidazo[1,2-c]quinazolin-5— y|)vinyl]pyridino|; N—(2,3—dihydroimidazo[1,2-c]quinazolin-S-yl)-5—hydroxynicotinamide; 6-(acetamido)-N-(7,9—dimethoxy-S-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-S- yl)nicotinamide; -dimethoxy-2,3-dihyd roimidazo[1,2-c]quinazolinyl)—5-hyd roxyn icotinamide; W0 2014/166820 S—hyd roxy—N—(7—methoxy—2,3—dihyd roimidazo[1,2—c]quinazolin—S—yl )nicotinamide; N—(7,8—d imethoxy-2,3-dihyd roimidazo[1,2-c]quinazolin-S-yl)[(4— methoxybenzyl)oxy]nicotinamide; N—(7,8—dimethoxy-2,3-dihyd roimidazo[1,2—c]quinazolin—5—y|)—5—hyd roxyn icotinamide; -hyd roxy—N-[S-(trifluoromethyl)-2,3-dihyd azo[1,2—c]quinazolin-S-yl]nicotinamide; N—{8—[3—(1,3—dioxo— 1,3—d ihyd ro—ZH—isoindoI—Z—yl )propoxy]—2,3—d ihydroimidazo[1,2— c]quinazolin-S-y|}nicotinamide; N-(7—bromo-8—methoxy—Z,3-dihyd roimidazo[1,2-c]quinazolin-S-yl)nicotinamide; 6—amino-N—(8—methoxy-2,3-dihyd roimidazo[1,2-c]quinazoliny|)nicotinamide; 1-(1H-benzimidazoIyl )-2—(8,9-dimethoxy—2,3-dihyd roimidazo[1,2-c1quinazolin-S- yl)ethy|eno|; 2-(8,9—dimethoxy-2,3-dihyd roimidazo[1,2'c]quinazolin-S-yl )(2,4—dimethy|-1,3-thiazol- S-yl)ethy|eno|; ethoxy-2,3-dihyd roimidazo[1,2-c]quinazolin-S—yl )-1H-benzimidazoIe carboxamide; N-(8—bromo-2,3-dihydroimidazo[1,2-c]quinazo|inyl)nicotinamide; romo-2,3-dihydroimidazo[1,2-c]quinazo| in-S-yl enzimidazole carboxamide; N—(8—methoxy-2,3-dihyd roimidazo[1,2—c]quinazolin-S-yl )-1H-benzimidazole carboxamide; N-(8—methyI-2,3-dihydroimidazo[1,2-c]quinazolin-S-yl)-1H—benzimidazole carboxamide; N—[8—(trifl uoromethyI)-2,3-dihyd roimidazo[1,2-c]quinazolin-S-yl]-1H—benzimidazoIe carboxamide; N—(7-fluoro-2,3-dihyd roimidazo[1,2-c] quinazolin-S-yl enzimidazoIe-S-carboxamide; N-(7-methoxy-2,3-dihyd roimidazo[1,2-c]quinazolin-S-yl)nicotinamide; N-(8-chloro-2,3-dihydroimidazo[1,2-c]quinazolin-S-yl)-1H—benzimidazoIe-S-carboxamide; 6—(acetamido)-N—(8—morpho|in—4-yl—2,3-dihyd roimidazo[1,2-c1quinazolin-5— y|)nicotinamide; 1—(1H-benzimidazoIyl)(8—morpholiny|-2,3—dihydroimidazo[1,2-c]quinazolin-S— y|)ethy|eno|; N-{5-[1-hydroxy(8-morpholinyl-2,3-dihyd roimidazo[1,2-c]quinazolin-S- y|)viny|]pyridin-Z-yl}acetamide; W0 2014/166820 6—methyI—N—(8—morpholin-4—yl—2,3—dihydroimidazo[1,2—c]quinazolin—S—yl)nicotinamide; 1—(1H-benzimidazol—5-yl)[8—(4—methylpiperazin—l-yl)-2,3—dihyd roimidazo[1,2- c]quinazolin-S-yl]ethylenol; N—(2,3—dihydroimidazo[1,2-c]quinazolin—5-yl)—3H—imidazo[4,5-b]pyridine-G—carboxamide; N-(7,8—dimethoxy—2,3-dihyd roimidazo[1,2-c]quinazolin-5—yl)-3H-imidazo[4,5—b]pyridine— 6—carboxamide; N-[7-(trifl uoromethyl)—2,3-dihyd roimidazo[1,2-c]quinazolin-S-yl]—1H—benzimidazo|e carboxamide; -d imethoxy-2,3-dihyd roimidazo[1,2-c]qu inazolinyl)-1H-benzimidazole carboxamide; N—{5-[2-(7,9-dimethoxymethyl-2,3-dihyd roimidazo[1,2—c]qu inazolin-S-yl )-1— hyd roxyvinyl] pyridin-Z-y|}acetamide; N-{5-[2-(7—bromo-9—methy|-2,3-dihyd roimidazo[1,2-c]quinazolin-S-yl) yvinyl]pyridin-Z-yl}acetamide; and -dimeth oxy-2,3-dihyd roimidazo[1,2-c] quinazolinyl)pyridinylethylenol; Another embodiment of the present invention encompasses the use of a compound having the formula (I): O N NH or a physiologically able salt, solvate, hydrate or stereoisomer thereof, in which : Rl represents —(CH2)n-(CHR4)-(CH2)m-N(R5)(R5') ; W0 2014/166820 R2 represents a heteroaryl optionally substituted with 1, 2 or 3 R6 groups; R3 represents alkyl or cycloalkyl ; R4 represents en, hyd roxy or alkoxy; and RS and R5, may be the same or different and represent independently, en, alkyl, cycloalkylalklyl, or alkyl or R5 and RS' 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 oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more Re' , or R4 and RS may be taken together with the atoms to which they are bound to form a 5-6 membered nitrogen containing heterocyclic ring optionally containing 1 or more nitrogen, oxygen or sulfur atoms and which may be optionally substituted with 1 or more R61 groups ; each occurrence of R6 may be the same or different and is independently halogen, alkyl, l, alkynyl, cycloalkyl, cycloalkylalklyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring, heterocyclylalkyl, alkyl-OR7, alkyl-SR7, alkyl-N(R7)(R7'), alkyI—COR7,-CN, - COOR7, -CON(R7)(R7'), -OR7, —SR7, -N(R7)(R7'), or —NR7COR7 each of which may be optionally substituted with 1 or more R8 groups; each ence of R6' may be the same or different and is independently alkyl, lkylalklyl, or alkyl-OR7; each occurrence of R7 and RT may be the same or different and is ndently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl ; each occurrence of R8 is independently nitro, hydroxy, cyano, formyl, acetyl, halogen, amino, alkyl, alkoxy, l, alkynyl, lkyl, cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl ; W0 2014/166820 n is an integer from 1-4 and m is an integer from 0—4 with the o 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 combinations 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 agents, in particular an active agent selected from an anti- angiogenesis, anti-hyper—proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, ypercholsterolemia, anti—dyslipidemia, anti—diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : PI3K6—selective inhibitor 65-1101, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 6 (RDEA-119)); or of ceutical compositions containing such nds or a physiologically acceptable salt, solvate, hydrate or isomer thereof, or of pharmaceutical compositions containing such combinations, for the ation of a medicament for the ent or prophylaxis of non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL).

In a preferred embodiment, 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 groups, or a physiologically able 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 nd, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; and W0 2014/166820 2014/056768 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 selected from the group consisting of : — PI3K5-selective inhibitor GS—1101, BTK inhibitor ibrutinib, IKK inhibitor BAY nd B, and REFAMETINIB (BAY 86-9766 (RDEA—119)) ; 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 dgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell ma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T—cell lymphoma (PTCL).

In another preferred embodiment, the invention encompasses the use of a compound of a (I), wherein R5 and Rs’are independently alkyl, 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]quinazo|ine compound, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; and b) one or more further active agents, in ular an active agent ed 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 selected from the group consisting of: - Pl3K6-selective inhibitor GS-1101, BTK tor ibrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766 (RDEA-119)) ; W0 2014/166820 or of pharmaceutical compositions containing such compounds or a physiologically able salt, e, hydrate or stereoisomer thereof, or of pharmaceutical compositions containing such combinations, for the preparation of a medicament for the treatment or prophylaxis of non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell ma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL).

In still another preferred embodiment, the invention encompasses the use of a compound of a (I), wherein R5 and RS' 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 selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R3 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,Z-c]quinazoline compound, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; and b) one or more r active , in particular an active agent selected from an anti- angiogenesis, anti—hyper-proliferative, antiinflammatory, sic, immunoregulatory, ic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti—diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : - Pl3K6-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B, and REFAMETINlB (BAY 86-9766 (RDEA-119)); or of pharmaceutical compositions containing such compounds or a logically acceptable salt, solvate, hydrate or stereoisomer thereof, W0 2014/166820 or of pharmaceutical compositions containing such combinations, for the preparation of a medicament for the treatment or prophylaxis of non—Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or ive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B—cell lymphoma (DLBCL), mantle cell lymphoma (MCL), ormed ma (TL), or peripheral T—cell lymphoma (PTCL).

In yet another preferred embodiment, the ion encompasses the use of a nd of Formula (I), wherein R4 is hydroxyl, 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, flammatory, sic, immunoregulatory, diuretic, antiarrhytmic, anti—hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agent, more particularly one or more r active agents selected from the group consisting of: - Pl3K6-selective inhibitor 65-1101, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766 (RDEA-119)) ; or of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, e, hydrate or stereoisomer thereof, or of pharmaceutical compositions containing such combinations, for the preparation of a medicament for the treatment or prophylaxis of non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive dgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), c cytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell W0 2014/166820 lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma ( L), or peripheral T-cell lymphoma (PTCL).

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 optionally containing 1 or more nitrogen, oxygen or sulfur atoms and which may be ally substituted with 1 or more R6 groups, or a physiologically acceptable salt, solvate, e or isomer thereof, as a sole active agent, or of ations of: a) such a 2,3-dihydroimidazo[1,2-c]quinazo|ine 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, ic, antiarrhytmic, anti-hypercholsterolemia, yslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents selected from the group ting of: — Pl3K5-selective inhibitor l, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B, and REFAlVlETINlB (BAY 86—9766 (RDEA-119)) ; 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 ent or prophylaxis of non—Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T—cell lymphoma (PTCL).

W0 2014/166820 In yet another preferred embodiment, the ion encompasses the use of a compound of Formula (I), wherein R3 is , 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]quinazo|ine 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, ypercholsterolemia, anti-dyslipidemia, iabetic or ral agent, more particularly one or more further active agents selected from the group consisting of: - Pl3K5-selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 6 (RDEA-119)); 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 dgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s ma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T—cell lymphoma (PTCL).

In still r preferred embodiment, the invention encompasses the use of a compound of Formula (I), wherein R2 is pyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene, optionally tuted with 1, 2 or 3 R6 groups; more preferably pyridine, zine, 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, W0 2014/166820 or of combinations of: a) such a 2,3-dihydroimidazo[1,2-c]quinazo|ine compound, or a physiologically acceptable 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, immunoregulatory, diuretic, antiarrhytmic, anti—hypercholsterolemia, anti—dyslipidemia, anti-diabetic or antiviral agent, more ularly one or more further active agents selected from the group consisting of: - Pl3K5—selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B, and TINIB (BAY 86-9766 (RDEA-119)) ; or of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, solvate, hydrate or isomer thereof, or of pharmaceutical compositions containing such combinations, for the preparation of a medicament for the treatment or prophylaxis of non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive dgkin’s lymphoma (NHL), in ular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or eral T-cell lymphoma .

In a distinct embodiment, the invention encompasses the use of a compound of formula (Ia) Owomm7’> Rz/KO (la) W0 2014/166820 or a physiologically acceptable salt, e, hydrate or stereoisomer thereof, wherein R2 is as defined above, 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]quinazo|ine nd, 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, iabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of: - Pl3K5-selective inhibitor GS-llOl, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766 (RDEA-119)) ; or of pharmaceutical itions containing such nds 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 non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular ular lymphoma (FL), c lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL).

In r distinct embodiment, the invention encompasses the use of a compound of formula (lb): 0 N/\/\o$677)N/l\NH °\ Fag/KO W0 2014/166820 (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 hydroimidazo[1,2-c]quinazoline compound, or a physiologically acceptable salt, e, 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 ularly one or more further active agents selected from the group consisting of: - Pl3K5-selective inhibitor GS-llOl, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766 (RDEA-119)) ; or of pharmaceutical compositions containing such compounds or a physiologically able salt, solvate, hydrate or stereoisomer thereof, or of pharmaceutical compositions ning such combinations, for the preparation of a medicament for the treatment or laxis of non—Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, ed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or eral T-cell lymphoma (PTCL).

In still another distinct embodiment, the invention encompasses the use of a compound of formula (lc) : W0 2014/166820 comm,7') 0\ Rz/Ko (IC) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R2 is as defined above, or a physiologically able 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 compound, or a logically acceptable salt, solvate, hydrate or stereoisomer thereof; and b) one or more further active agents, in particular an active agent selected from an anti- enesis, 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: - Pl3K6—selective inhibitor GS-1101, BTK inhibitor ibrutinlb, IKK inhibitor BAY Compound B, and REFAIVIETINIB (BAY 86-9766 (RDEA-119)); or of pharmaceutical compositions ning such compounds or a physiologically acceptable salt, solvate, hydrate or isomer thereof, or of pharmaceutical compositions containing such combinations, for the preparation of a medicament for the treatment or laxis of dgkin’s lymphoma (NHL), particularly 1st line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in ular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T—cell lymphoma (PTCL).

W0 2014/166820 In yet another distinct embodiment, the invention encompasses the use of a compound of the formula (Id): O A j/\o N NH N O\ R2 0 (ldl or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R2 and R4 are 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, e, hydrate or stereoisomer thereof; and b) one or more further active agents, in particular an active agent selected from an anti- enesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, ic, antiarrhytmic, anti—hypercholsterolemia, anti-dyslipidemia, anti—diabetic or antiviral agent, more particularly one or more further active agents selected from the group ting of : — Pl3K5-selective inhibitor 1, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86—9766 (RDEA-119)); or of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, solvate, e or stereoisomer thereof, or of pharmaceutical compositions containing such combinations, W0 2014/166820 for the preparation of a medicament for the treatment or prophylaxis of non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, ed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), al zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or eral T—cell lymphoma (PTCL).

In yet another distinct embodiment, the invention encompasses the use of a compound of the formula (le): (Ie) or a physiologically acceptable salt, e, hydrate or stereoisomer thereof, n R2 and R4 are as d 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 b) one or more further active agents, in particular an active agent selected from an 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: - Pl3K6-selective inhibitor 1, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86—9766 (RDEA-119)) ; W0 2014/166820 or of ceutical compositions containing such compounds or a logically 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 non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, tory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone ma (MZL), diffuse large B—cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use of a compound of a (I) - (V), wherein R2 is pyridine, pyridazine, 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, ne, 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 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, yper-proliferative, antiinflammatory, sic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti—diabetic or ral agent, more ularly one or more further active agents selected from the group ting of: - Pl3K5—selective inhibitor GS—1101, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B, and TINIB (BAY 86—9766 (RDEA-119)) ; 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 non—Hodgkin’s lymphoma (NHL), W0 2014/166820 particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL).

In still another preferred embodiment, the ion encompasses the use of a compound having the formula: N-[7-methoxy(3-morpholin—4—ylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazolinyl]pyrimidinecarboxamide; N—(8—{3-[(2R,6S)-2,6—dimethylmorpholin—4-yl]propoxy}methoxy- hydroimidazo[1,2-c]quinazolin-S-yl)nicotinamide; N-(8—{3-[(2R,6$)-2,6-dimethylmorpholinyl]propoxy}methoxy- 2,3—dihydroimidazo[1,2-c]quinazolin-S-yl)—2,4-dimethyl-1,3—thiazo|e amide; Z-amino-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolinyl]-1,3-thiazo|e—5-carboxamide; Z—amino-N-[7—methoxy(3—morpho|in-4—ylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolin-S-yl]isonicotinamide; Z—amino—N-[7-methoxy(3—morpho|inylpropoxy)-2,3— dihydroimidazo[1,2-c]quinazolinyl]methyl—1,3—thiazole-S-carboxamide; 2—amino—N—[7-methoxy(3-morpho|in—4-ylpropoxy)-2,3—dihydroimidazo[1,2— c]quinazolinyl]—4-propylpyrimidinecarboxamide; N-{8—[2—(4—ethylmorpholinyl)ethoxy]—7-methoxy—2,3- roimidazo[1,2-c]quinazolinyl}nicotinamide; N—{8—[2-(dimethylamino)ethoxy]—7-methoxy-2,3-dihydroimidazo[1,2- c]quinazolin—5-yl}pyrimidinecarboxamide; N-(8—{3-[2-(hydroxymethyl)morpholin—4-yl]propoxy}methoxy- 2,3-dihydroimidazo[1,2-c]quinazolinyl)nicotinamide; N-(8—{3-[2-(hydroxymethyl)morpholin-4—yl]propoxy}—7-methoxy- 2,3-dihydroimidazo[1,2-c]quinazolinyl)nicotinamide; N-{8—[3-(dimethylamino)propoxy]methoxy-2,3—dihydroimidazo[1,2- c]quinazolinyl}nicotinamide 1-oxide; W0 2014/166820 2—amino-N—[7—methoxy—8—(3—morpholin—4—yl propoxy)—2,3—dihyd roimidazo[1,2— c] quinazolin—S-yl]pyrimidine-5—carboxamide; N—[7-methoxy(3-morpholin—4-yl propoxy)-2,3-dihyd roimidazo[1,2- c] quinazol in—5-yI]—6—(2—pyrro| idin-l—ylethy|)nicotinamide; 6-(cyclopentylamino)—N-[7-methoxy-8—(3-morpholinylpropoxy)- 2,3—dihydroimidazo[1,2-c]quinazo|in—5-yl]nicotinamide; N—[8—(2-hyd roxymorpholin-4—yl propoxy)methoxy-2,3-dihyd roimidazo[1,2— c]quinazolinyl]nicotinamide; ethoxy-8—[3-(3—methyl morpholin—4-yl)propoxy]—2,3-dihyd roimidazo[1,2— c]quinazolin—5-y|}nicotinamide; N-(8—{3-[2-(hyd roxymethyl)morph0|in-4—yl]propoxy}methoxy-2,3- dihyd roimidazo[1,2-c]quinazolin-S-yl)nicotinamide; N—(8-{2-[4-(cyclobutylmethyl)morphol i n—Z-yl] ethoxy}methoxy-2,3— dihyd roimidazo[1,2-c]quinazolin-S-yl)nicotinamide; N-(7-methoxy{2-[4—(2-methoxyethyl)morphol |]ethoxy}-2,3- clihydroimidazo[1,2-c]quinazo|iny|)nicotinamide; N—{8-[(4-ethylmorpholinyl)methoxy]methoxy-2,3-dihydroimidazo[1,2- c]quinazolin—5-y|}nicotinamide; ethoxy-8—{[4-(2-methoxyethyl)morpholin-2—yl]methoxy}-2,3- oimidazo[1,2-c]quinazo|in—5-yl)nicotinamide; N-{7-methoxy-S-[(4-methy|morpho|iny|)methoxy]-2,3-dihydroimidazo[1,2- c]quinazolin-S-yl}nicotinamide; N-[7-methoxy-8—(3-morpholin-4—yl propoxy)-2,3-dihyd roimidazo[1,2- c]quinazo|in—S-yl]pyrimidine-4—carboxamide; 2-amino-N-[7-methoxy—8-(3-morpholinyl propoxy)-2,3-dihyd roimidazo[1,2- c]quinazo|in-S-yl]pyrimidine-4—carboxamide; N-[7—methoxy-8—(3-morpholinyl propoxy)-2,3-dihyd roimidazo[1,2- c]quinazo|iny|]-1—methyl-1H-imidazoIe—4-carboxamide; rel—N-(8—{3-[(2R,6S)-2,6-dimethylmorpholin-4—yl]propoxy}methoxy—2,3- dihydroimidazo[1,2-c]quinazolin—S-yl)pyrimidine—5—carboxamide; (8—{3-[(2R,65)-2,6-dimethylmorpholin-4—yl]propoxy}methoxy—2,3- dihydroimidazo[1,2-c]quinazo|iny|)methylnicotinamide; W0 2014/166820 acetamido—N—(8—{3—[(2R,6$)—2,6—dimethylmorpholin-4—yl]propoxy} methoxy-2,3—dihyd roimidazo[1,2-c]quinazolin-S-yl)nicotinamide; N-[7-methoxy-8—(3-morpho|inyl propoxy)-2,3-dihyd roimidazo[1,2- c]quinazo|in—S-yl]—1—methyl—1H—imidazole—5—carboxamide; 6-amino-N-[7-methoxy—8—(3-morpholinyl propoxy)-2,3-dihyd roimidazo[1,2- azolin—S-yI]—2—methy|nicotinamide; 2—amino-N-[7-methoxy—8-(3-morpholin—4—yl propoxy)-2,3-d ihyd roimidazo[1,2- c]quinazolin-5~y|]-4—methyl pyrimid ine-S-carboxamide; 6—aminobromo-N—[7-methoxy-8—(3-morpho|in-4—ylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazo|inyl]nicotinamide; 2-amino-N-[7-methoxy—8-(3-morpho|in-4—yl propoxy)-2,3-d ihyd roimidazo[1,2- c]quinazolin-S-yl]-1,3-oxazolecarboxamide; N—[7-methoxy(morpholin—Z—ylmethoxy)—2,3-dihydroimidazo[1,2-c]quinazo|in- -yl]nicotinamide; 2-{[2-(dimethylamino)ethy|]amino}-N-{8—[3-(dimethylamino)propoxy] methoxy-2,3—dihyd roimidazo[1,2-c]quinazo|inyl}pyrimidine-S-carboxamide; 2-amino-N-{8—[3-(dimethylamino)propoxy]methoxy-2,3-dihyd roimidazo[1,2— c]quinazoliny|}-1,3—thiazoIe—S—carboxamide; rel-Z-amino-N-(S-{S-[(2R,6$)-2,6—dimethylmorpholinyl]propoxy}methoxy— 2,3-dihydroimidazo[1,2—c]quinazolin-S—yl)pyrimidine-S-carboxamide; relamino—N-(8—{3-[(2R,6S)—2,6-dimethylmorpholinyl]propoxy}methoxy— 2,3—dihydroimidazo[1,2-c]quinazolin—5—yl)nicotinamide; 2-[(2-hyd roxyethyl )amino]—N-[7-methoxy-8—(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolin-S-yl]pyrimidine—S-carboxamide; ethoxy-S-(3-morpho!in-4—yl propoxy)-2,3-dihyd roimidazo[1,2- c]quinazolin—S-yl]—2—[(3-methoxypropy|)amino]pyrimidine-S-carboxamide; 2-amino-N-{8-[3-(dimethylamino)propoxy]—7-methoxy-2,3-dihyd roimidazo[1,2— c]quinazo|in—S-yl}pyrimidine—5—carboxamide; N-[7—methoxy-8—(3-morpholin—4—yl propoxy)-2,3-dihyd azo[1,2- c] quinazoliny|][(3—morpho|inyl propyl )amino] pyrimidine-S—carboxamide; 2-[(2-methoxyethy| )amino]-N-[7-methoxy-8—(3—morpho|in-4—yl propoxy)—2,3- dihydroimidazo[1,2-c]quinazolin-S-yl]pyrimidine-S-carboxamide; W0 2014/166820 2—{[2—(dimethylamino)ethyl]amino}—N-[7—methoxy—8—(3—morpholin-4—ylpropoxy)- 2,3—dihydroimidazo[1,2-c]quinazolinyl]pyrimldine-S-carboxamide; 6—amlno-N—{8—[3-(dimethylamlno)propoxy]methoxy-2,3—dihydroimidazo[1,2— c]quinazolln-S-yl}nlcotinamide; N-[7-methoxy-8—(3-morpholin—4-ylpropoxy)—2,3-dlhydroimidazo[1,2- c]qulnazolinyl]-2—pyrrolidin-l-ylpyrimidine—S—carboxamide; N—[7-methoxy-8—(3-morpholin—4—ylpropoxy)-2,3-dihydroimidazo[1,2— c]quinazolinyl]—2-(4—methylpiperazin-l-yl)pyrimidine-S-carboxamide; N—[7-methoxy-8—(3-morpholin-4—ylpropoxy)-2,3-dihydroimldazo[1,2- c]quinazolin-S-yl]morpholinylpyrimidine-S-carboxamide; ethoxy-8—(3-morpholin-4—ylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazo|inyl]piperazln—1-y|nlcotlnamide hydrochloride; 6-[(3S)aminopyrrolidin-l-yl]—N-[7-methoxy-8—(3—morpholinylpropoxy)-2,3— dihydroimidazo[1,2-c]qulnazolin-S-yl]nicotinamide hydrochloride hydrate; 6-[(3R)aminopyrrolidiny|]—N-[7-methoxy-8—(3-morpholinylpropoxy)-2,3— dihydroimidazo[1,2-c]qulnazollnyl]nicotlnamide hydrochloride; 6-[(4—fluorobenzyl)amino]-N-[7—methoxy—8-(3-morpholin-4—ylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolln-5—yl]nicotinamide; 6-[(2-furylmethyl)amlno]—N-[7—methoxy(3-morphollnylpropoxy)—2,3- dihydroimidazo[1,2-c]quinazolinyl]nicotinamide; 6-[(2-methoxyethyl)amino]-N-[7-methoxy(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2—c]quinazolln—5-yl]nicotinamide; N-[7-methoxy—8—(3-morpholin-4—ylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazolin—5-y|]-6—(1H—pyrrol—1—y|)nicotinamide; N-[7-methoxy-8—(3-morpholin-4—ylpropoxy)-2,3-dihydrolmidazo[1,2- azoliny|]-6—morpholinylnicotinamide; N-{7-methoxy-8—[3—(methylamlno)propoxy]—2,3-dlhydroimidazo[1,2- c]quinazolin—5-y|}nicotinamlde; 6-[(2,2—dimethylpropanoyl)amino]-N-[7-methoxy(3-morpholinylpropoxy)— 2,3-dihydroimidazo[1,2-c]quinazo|in—S-yl]nicotinamide; 6-[(cyclopropylcarbonyl)amino]-N-[7-methoxy(3-morpholiny|propoxy)-2,3— clihydroimidazo[1,2-c]quinazoliny|]nicotinamide W0 2014/166820 N—[7—methoxy—8—(3—morpholin—4—yl propoxy)—2,3—dihyd roimidazo[1,2— c] quinazolin—S-yl]—6—(2,2,2-trifl uoroethoxy)nicotinamide; N—[7-methoxy-8—(3-morpholin—4-yl propoxy)-2,3-dihyd roimidazo[1,2— c]quinazolin—S-yl]—6—(trif|uoromethyl)nicotinamide; 6—(isobutyrylamino)-N-[7-methoxy-8—(3—morph0|in—4—ylpropoxy)-2,3- oimidazo[1,2—c]quinazo|in—5-yl]nicotinamide; N—{7-methoxy-8—[3-(4—methylpiperazin-l—yl)propoxy]—2,3-dihyd roimidazo[1,2— c]quinazolin-S-y|}nicotinamide; N-[7-methoxy-8—(3-morpholin—4—yl propoxy)-2,3-dihyd azo[1,2- c]quinazo|in-5'yl]{[(methylamino)carbonyl]amino}—1,3-thiazoIe—4- carboxamide; N—[7-methoxy'8-(3—morpho|in-4—yl propoxy)'2,3-dihyd roimidazo[1,2— c]quinazolin—S-yl]{[(methylamino)carbonyl]amino}nicotinamide; N—[7-methoxy-8—(3-morpho|in-4—yl propoxy)-2,3-dihyd azo[1,2- c] quinazolin—S-yl]—2-(methy|amino)-1,3-thiazole-4—carboxamide; N-[7-methoxy-8—(2-morpholinylethoxy)-2,3-dihyd roimidazo[1,2-c]quinazolin- -yl]nicotinamide; N—{8—[2-(dimethylamino)ethoxy]methoxy-2,3-dihydroimidazo[1,2— c]quinazolinyl}-2,4—dimethy|—1,3-thiazole-S-carboxamide; N-{8—[2-(dimethylamino)ethoxy]—7-methoxy-2,3—dihydroimidazo[1,2— c]quinazolinyl}-6—methyl n icotinamid e; 6-{[(isopropylamino)carbony|]amino}—N-[7—methoxy(3-morpho|in—4— ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo|inyl]nicotinamide; N-[7—methoxy—8—(3-morpholin-4—ylpropoxy)-2,3-dihydroimidazo[1,2— c]quinazolinyl]—6—pyrrolidin-1—ylnicotinamide; 6-(dimethylamino)—N-[7—methoxy(3—morpho|in-4—ylpropoxy)-2,3— dihydroimidazo[1,2-c]quinazolin-S-yl]nicotinamide; N-[7-methoxy(3-piperid in-l-ylpropoxy)-2,3—dihyd roimidazo[1,2-c]quinazo| in— -yl]nicotinamide; N—[7-methoxy(2-pyrrol -ylethoxy)—2,3-dihydroimidazo[1,2-c] quinazol in- -yl]nicotinamide; N-[7-methoxy(2-piperidin-l—ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-S- yl]nicotinamide; W0 2014/166820 6—{[(ethy|amino)carbonyl]amino}—N—[7-methoxy—8—(3—morpholin—4-ylpropoxy)— hydroimidazo[1,2-c]quinazolin-S-yl]nicotinamide; 6—fluoro-N-[7-methoxy-8—(3-morpho|in-4—yl y)-2,3-dihyd roimidazo[1,2- c]quinazo|inyl]nicotinamide; 2-amino-N-[7-methoxy—8—(3-morpholinyl propoxy)—2,3-dihyd roimidazo[1,2- c]quinazo|in-S-yl]—1,3—oxazole—4-carboxamide; 2—(ethylamino)-N—[7-methoxy—8—(3-morpholinylpropoxy)—2,3- dihydroimidazo[1,2-c]quinazolin-S—yl]-1,3—thiazo|ecarboxamide; N—[7-methoxy-8—(3-morpholinyl propoxy)-2,3-dihyd roimidazo[1,2- c]quinazo|in-S-yl]pyrazine-Z-carboxamide; N-[8-(2-aminoethoxy)—7-methoxy-2,3-dihyd roimidazo[1,2-c]quinazolin otinamide; 6-amino-N-[7—methoxy—8—(3-morpho|inyl propoxy)-2,3-d ihyd roimidazo[1,2- azolin-S-y|]nicotinamide; N—[7-methoxy(3-morpholin—4-yl propoxy)-2,3-dihyd azo[1,2- c]quinazolinyl]isonicotinamide; N-{8-[3-(diethylamino)propoxy]—7-methoxy-2,3-dihyd roimidazo[1,2- c]quinazolin-S-y|}nicotinamide; N-{8—[2-(diisopropylamino)ethoxy]—7-methoxy-2,3-dihyd roimidazo[1,2- c]quinazo|iny|}nicotinamide; N-{8—[2-(diethylamino)ethoxy]—7-methoxy—2,3-dihydroimidazo[1,2-c]quinazo|in- -yl}nicotinamide; N-{8-[3-(dimethylamino)pr0poxy]methoxy-2,3-dihyd roimidazo[1,2— c]quinazolinyl}nicotinamide; N-{8—[2-(dimethylamino)ethoxy]methoxy-2,3-dihydroimidazo[1,2- c]quinazolin-S-yl}nicotinamide; N-[7-methoxy-8—(3-morpholin-4—yl propoxy)-2,3-dihyd roimidazo[1,2- c]quinazo|iny|]—2—(methy|amino)pyrimidine-S-carboxamide; N-[7—methoxy-8—(3-morpholinyl propoxy)-2,3-dihyd roimidazo[1,2- c]quinazoliny|]—2-(methy|thio)pyrimidinecarboxamide; N-[8-(3-aminopropoxy)methoxy-2,3-dihyd roimidazo[1,2—c]quinazolin-S- yl]nicotinamide trifluoroacetate; W0 2014/166820 N—[7—methoxy—8—(3—morpholin—4—ylpropoxy)—2,3—dihydroimidazo[1,2— c]quinazolin—5-yl]thiophene-Z—carboxamide; N—[7-methoxy-8—(3-morpholin—4-ylpropoxy)-2,3-dihydroimidazo[1,2— c]quinazo|in—5-yl]—2,4—dimethyl—1,3—thiazoie—S—carboxamide; oxy—N-[7-methoxy—8—(3-morpholinylpropoxy)-2,3—dihydroimidazo[1,2- c]quinazo|in-5—yl]pyrimidine—S-carboxamide; N-[7-methoxy-8—(3-morpho|in—4—ylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazolin—S-yl]—3-furamide; ethoxy-8—(3-morpho|in—4—ylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazo|in-S-yl]thiophenecarboxamide; N-[7-methoxy-8—(3-morpholin—4—ylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazolinyl]—2-methy|—1,3-thiazole-4—carboxamide; 6-methoxy-N-[7—methoxy(3—morpho|inylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazolinyl]nicotinamide; 5-methoxy-N-[7-methoxy-8—(3—morpho|inylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazolin—S-y|]nicotinamide; N—[7-methoxy-8—(3-morpholinylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazo|in—5-y|]-6—methy|nicotinamide; 6-(acetylaminol-N-[7—methoxy-8—(3-morpholinylpropoxy)-2,3- dihydroimidazo[1,2-c]quinazolin—5-yl]nicotinamide; N-[7—methoxy-8—(3-morpho|in-4—ylpropoxy)-2,3-dihydroimidazo[1,2- azolin—5-yl]nicotinamide; 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, regulatory, diuretic, antiarrhytmic, anti—hypercholsterolemia, anti-dyslipidemia, anti—diabetic or antiviral agent, more ularly one or more further active agents selected from the group consisting of: W0 2014/166820 — P|3K5—selective inhibitor 1, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766 (RDEA-119)); or of pharmaceutical compositions containing such compounds or a physiologically acceptable salt, solvate, e or isomer f, or of pharmaceutical compositions containing such combinations, for the preparation of a medicament for the ent or prophylaxis of non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use of a compound having the formula: N-[7-methoxy(3-morpholinylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazolin—5-yl]nicotinamide; N-[7—methoxy(3-morpholinylpropoxy)-2,3-dihydroimidazo[1,2- azolinyl]methy|nicotinamide; 5-methoxy-N—[7-methoxy-8—(3-morpholiny|propoxy)—2,3—dihydroimidazo[1,2— c]quinazoliny|]nicotinamide; N-[7-methoxy-8—(3-morpholin—4—ylpropoxy)-2,3-dihydroimidazo[1,2— c]quinazolinyl]—2,4—dimethyl-1,3-thiazole-S-carboxamide; N—{8-[2-(dimethylamino)ethoxy]—7-methoxy-2,3-dihydroimidazo[1,2— clquinazolin—5-y|}nicotinamide; N-{8—[3—(dimethylamino)propoxy]methoxy-2,3—dihydroimidazo[1,2— azoliny|}nicotinamide; 6-{[(isopropylamino)carbony|]amino}—N-[7-methoxy—8—(3-morpholin-4— ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5—yl]nicotinamide; N-(8—[2-(dimethylamino)ethoxy]methoxy-2,3-dihydroimidazo[1,2— c]quinazolinyl}-2,4-dimethyl-1,3-thiazole-S-carboxamide; N-[7-methoxy(2-morpholin-4—ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin- -yl]nicotinamide; W0 2014/166820 2014/056768 rel—6—amino—N—(8—{3—[(2R,6S)—2,6—dimethylmorpholin-4—yl]propoxy}-7—methoxy— 2,3—dihydroimidazo[1,2-c]quinazolin-S-yl)nicotinamide; rel—2-amino—N-(S-{3-[(2R,6$)-2,6-dimethylmorpholinyl]propoxy}-7—methoxy— 2,3—dihydroimidazo[1,2-c]quinazo|inyl)pyrimidine-S-carboxamide; Z-amino-N-[7-methoxy—8—(3-morpholinylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazolin—S-yl]pyrimidine—5-carboxamide; 2-(dimethylamino)ethoxy]methoxy-2,3-dihydroimidazo[1,2— c]quinazolinyl}pyrimidine-S-carboxamide; N—[7-methoxy-8—(3-morpholin-4—ylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazolin—S-yl]pyrimidine-S-carboxamide; 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]quinazo|ine compound, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; and b) one or more further active agents, in ular an active agent selected from an anti- angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, regulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, iabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of: - Pi3K5—selective inhibitor GS—1101, BTK inhibitor ibrutinib, IKK inhibitor BAY nd B, and REFAMETINIB (BAY 86—9766 (RDEA-119)) ; 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 dgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular ma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell ma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T—cell lymphoma (PTCL).

W0 2014/166820 In a preferred embodiment, the invention encompasses the use of a compound having the formula : 2—amino-N-[7-methoxy-8—(3-morpholin—4—ylpropoxy)-2,3—dihydroimidazo[1,2— c]quinazolinyl]pyrimidine-S—carboxamide, or a physiologically acceptable salt, solvate, e or stereoisomer thereof; as a sole active agent, or of pharmaceutical compositions ning such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, for the ation of a medicament for the treatment or prophylaxis of non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-ceil lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T—cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use of a compound having the formula : Z-amino-N-[7-methoxy-8—(3-morpholin-4—ylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazo|in—5-yl]pyrimidine-S—carboxamide dihydrochloride; as a sole active agent, or of pharmaceutical compositions containing such a compound or a physiologically acceptable salt, solvate, hydrate or isomer thereof, for the ation of a medicament for the ent or prophylaxis of non—Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, nt or agressive non-Hodgkin’s ma (NHL), in particular follicular lymphoma (FL), chronic cytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-ceil W0 2014/166820 lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma ( L), or peripheral T-cell lymphoma (PTCL).

In a preferred embodiment, the ion encompasses the use of combinations of: a) 2-amino-N-[7-methoxy-8—(3—morpholinylpropoxy)-2,3—dihydroimidazo[1,2— c]quinazolin—5—yl]pyrimidine—S—carboxamide, 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, antiarrhytmic, anti-hypercholsterolemia, anti—dyslipidemia, anti—diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : - Pl3K5-selective tor GS—1101, BTK inhibitor ibrutinib, IKK inhibitor BAY nd B, and REFAMETINlB (BAY 6 (RDEA-119)); or of pharmaceutical compositions ning such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, or of pharmaceutical compositions containing such ations, for the preparation of a medicament for the treatment or prophylaxis of non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular ma (FL), c lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use of combinations of: W0 2014/166820 2014/056768 a) 2—amino—N—[7—methoxy—8—(3—morpholin-4—ylpropoxy)—2,3—dihydroimidazo[1,2- c]quinazolinyl]pyrimidine-S-carboxamide, or a physiologically acceptable salt, e, hydrate or stereoisomer thereof; and b) a further active agent which is Pl3K6—selective inhibitor 65-1101; 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 ent or prophylaxis of non-Hodgkin’s lymphoma (NHL), ularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), c lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL).

In a preferred embodiment, the invention encompasses the use of combinations of: a) 2-amino-N-[7-methoxy—8—(3-morpholin-4—ylpropoxy)-2,3—dihydroimidazo[1,2- c]quinazolinyl]pyrimidine—5-carboxamide, or a logically acceptable salt, solvate, hydrate or stereoisomer thereof; and b) a further active agent which is BTK inhibitor ibrutinib; 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 medicament for the ent or prophylaxis of non-Hodgkin’s lymphoma (NHL), particularly 1st line, 2nd line, relapsed, refractory, indolent or ive non-Hodgkin’s lymphoma (NHL), in ular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T—cell lymphoma (PTCL).

W0 2014/166820 2014/056768 In a preferred embodiment, the invention asses the use of combinations of: a) 2-amino—N-[7-methoxy—8—(3—morpholin-4—ylpropoxy)-2,3—dihydroimidazo[1,2- c]quinazolinyl]pyrimidinecarboxamide, or a physiologically acceptable salt, solvate, hydrate or stereolsomer thereof; and b) a further active agent which is lKK inhibitor BAY Compound B; or of pharmaceutical compositions containing such a compound or a physiologically acceptable salt, solvate, hydrate or stereolsomer thereof, or of pharmaceutical compositions ning such combinations, for the preparation of a medicament for the treatment or prophylaxis of non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), c lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), ormed lymphoma (TL), or peripheral T—cell lymphoma (PTCL).

In a red embodiment, the invention encompasses the use of combinations of : a) Z-amino-N-[7-methoxy(3—morpholin-4—ylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazolinyl]pyrimidine—5-carboxamide, or a physiologically acceptable salt, solvate, hydrate or stereolsomer thereof; and b) a further active agent which is REFAMETINIB (BAY 86-9766 (RDEA-119)) ; or of pharmaceutical compositions containing such a nd or a physiologically acceptable salt, solvate, e or stereolsomer thereof, or of pharmaceutical compositions containing such combinations, for the preparation of a medicament for the treatment or laxis of non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular ma (FL), chronic W0 2014/166820 lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B—cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T—cell lymphoma .

In a preferred embodiment, the invention encompasses the use of combinations of : a) o—N-[7-methoxy—8—(3—morphol in-4—ylpropoxy)-2,3-dihyd roimidazo[ 1,2- clquinazolin-S-yl]pyrimidine—S-carboxamide dihydrochloride; and b) a further active agent which is Pl3K6-selective inhibitor 65-1101; or of pharmaceutical compositions containing such a compound 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 non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B—cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T—cell lymphoma (PTCL).

In a red embodiment, the invention asses the use of combinations of: a) Z-amino-N-[7-methoxy-8—(3—morpholin—4—ylpropoxy)-2,3-dihydroimidazo[1,2— c]quinazolinyl]pyrimidine-S—carboxamide dihydrochloride ; and b) a further active agent which is BTK inhibitor ibrutinib; or of pharmaceutical compositions containing such a nd or a physiologically acceptable salt, e, e or stereoisomer thereof, or of pharmaceutical compositions containing such combinations, for the preparation of a medicament for the treatment or prophylaxis of dgkin’s lymphoma (NHL), ularly 1st line, 2nd line, relapsed, refractory, indolent or W0 2014/166820 ive non—Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL).

In a red embodiment, the invention encompasses the use of combinations of : a) 2-amlno—N-[7-methoxy—8—(3-morpholin-4—ylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazolin-S-yl]pyrimidine-S—carboxamide dihydrochloride ; and b) a further active agent which is IKK inhibitor BAY nd B; or of pharmaceutical compositions containing such a compound or a logically 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 non-Hodgkin’s lymphoma (NHL), ularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s ma (NHL), in particular follicular ma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T—cell ma (PTCL).

In a preferred embodiment, the invention encompasses the use of ations of: a) 2-amino-N-[7-methoxy—8—(3—morpholinylpropoxy)-2,3—dihydroimidazo[1,2- c]quinazolinyl]pyrimidine-S-carboxamide dihydrochloride; and b) a further active agent which is REFAMETINIB (BAY 86—9766 (RDEA—119)) ; 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, W0 2014/166820 for the preparation of a medicament for the treatment or prophylaxis of non-Hodgkin’s ma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T—cell lymphoma (PTCL).

Where there is a discrepancy between the chemical name and the al structure depicted, the chemical structure depicted takes ence over the chemical name given.

Without being bound by theory or ism, the nds 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 surprising activity is based on the chemical ure of the compounds, in particular the basicity of the compounds as a result of R1 being amino optionally substituted with R5 and RS'. Further, the riate choice of R3 and R2 e the necessary activity 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 cancer is non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, nt or agressive non-Hodgkin’s ma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), e large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL).

Definitions The term ‘alkyl‘ refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing solely of carbon and hydrogen atoms, ning no unsaturation, having from one to eight carbon atoms, and which is W0 2014/166820 attached to the rest of the molecule by a single bond, such as illustratively, methyl, ethyl, n—propyl 1—methylethyl opyl), 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 branched chain having about 2 to about 10 carbon atoms, e.g., ethenyl, 1—propenyl, enyl (allyl), iso-propenyl, 2- methyl-I-propenyl, 1—butenyl, 2-and butenyl.

The term ”alkynyl” refers to a straight or ed chain arbonyl 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" s an alkyl group as defined herein attached via oxygen linkage to the rest of the molecule. Representative examples of those groups are methoxy 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 creation of a stable structure the rest of the molecule. entative examples of those groups are —CHZOCH3, --CH20C2H5.

The term alkyl" denotes a non-aromatic mono or multicyclic ring system of about 3 to 12 carbon atoms such as cyclopropyl, 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) non-Z—yl.

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

W0 2014/166820 The term "aryl" refers to aromatic radicals having in the range of 6 up to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, biphenyi.

The term ”arylalky Ill refers to an aryl group as defined herein directly 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 le. e.g., --CH2C6H5, "CZHSCeHS - The term "heterocyclic ring” refers to a stable 3- to 15 ed 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 purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring , which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the cyclic 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 ic). Examples of such heterocyclic ring ls include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl inyl dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazil, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl tetrahydroisouinolyl, piperidinyl, piperazinyl, Z-oxopiperazinyl, 2—oxopiperidinyl, 2—oxopyrrolidinyl, zepinyl, yl, pyrrolyl, 4—piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl pyridazinyl, oxazolyl oxazolinyl oxasolidinyl, triazolyl, indanyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazoiyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl yl, isoquinolyl, droisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, hienyl, thiamorpholinyl, thiamorpholinyl sulfoxide thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, nyl, isochromanyl .

W0 2014/166820 2014/056768 The term "heteroaryi" refers to heterocyclic ring radical as defined herein which are aromatic. The heteroaryi 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 cyclic 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 heteroaryi ring radical as defined herein directly bonded to alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom from alkyl group that results in the creation of a stable stru ctu re .

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 ocyclylalkyl" refers to a heterocylic ring radical as defined herein directly bonded to alkyl group. The heterocyclylalkyl radical may be ed to the main structure at carbon atom in the alkyl group that results in the creation of a stable stru ctu re.

The term nyl" 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, hydrates, 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 n one or more asymmetric centers, depending upon the location and nature of the various substituents desired.

Asymmetric carbon atoms may be present in the (R) or (5) uration, resulting in W0 2014/166820 2014/056768 racemic es 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 ing two tuted ic rings of the specified compounds. Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention. Preferred compounds are those, which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.

The present 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 compounds of examples. The term “pharmaceutically acceptable salt” refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et of. aceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, ic 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 d with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and chorine salts.

Those skilled in the art will r recognize that acid on salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate nic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the nds of the invention with the appropriate base via a variety of known methods.

W0 2014/166820 Representative salts of the nds of this invention include the conventional non— toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For e, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, Z-hydroxyethanesulfonate, itaconate, e, maleate, ate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, ate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate.

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

A solvate for the purpose of this ion is a complex ofa 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. es are a specific form of solvate n the t is water.

The synthesis of the compounds listed above is described in International Patent Application No. 2003/010377, published as WO 2004/029055 A1, and in International Patent Application No. PCT/USZOO7/024985, published as W0 2008/070150, both of which are hereby incorporated herein in their entirety by reference.

W0 2014/166820 In accordance with another embodiment, the present invention relates to a 2,3— oimidazo[1,2—c]quinazo|ine compound as defined herein, in particular Z-amino—N- [7-methoxy-8—(3-morpholin-4—ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin yl]pyrimidinecarboxamide, or a physiologically able salt, e, hydrate or stereoisomer f, as a sole agent, for the treatment of non—Hodgkin’s lymphoma (NHL), particularly 1st line, 2nd line, relapsed, refractory, indolent or agressive non- Hodgkin’s ma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B—cell lymphoma (DLBCL), mantle cell ma (MCL), transformed lymphoma (TL), or peripheral T—cell lymphoma (PTCL).

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said cancer is non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive dgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell ma (DLBCL), mantle cell lymphoma (MCL), transformed ma (TL), or peripheral T-cell lymphoma (PTCL).

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; b) one or more further active agents, in particular an active agent selected from an anti- enesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or W0 2014/166820 antiviral agent, more ularly one or more further active agents selected from the group consisting of : — Pl3K6—selective tor GS—1101, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766 (RDEA-119)).

In a preferred embodiment, the invention encompasses combinations of: a) o—N-[7-methoxy-8—(3-morpholinylpropoxy)-2,3-dihydroimidazo[1,2— azolinyl]pyrimidine—S-carboxamide, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; or pharmaceutical compositions containing such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof b) one or more further active agents, in particular an active agent selected from an anti- angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, ic, antiarrhytmic, anti—hypercholsterolemia, anti—dyslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : — Pi3K6—selective tor GS-1101, BTK tor nib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766 (RDEA-119)).

In a preferred embodiment, the invention encompasses combinations of: a) 2—amino—N—[7—methoxy-8—(3—morpholin—4-ylpropoxy)-2,3-dihydroimidazo[1,2— c]quinazolin-S-yl]pyrimidine-S-carboxamide, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; or pharmaceutical compositions containing such a compound or a physiologically acceptable salt, solvate, e or stereoisomer thereof W0 66820 b) one or more further active agents selected from the group consisting of : PI3K5— selective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766 (RDEA-119)).

In a preferred embodiment, the invention encompasses combinations of: a) 2-amino—N-[7-methoxy-8—(3—morpholinylpropoxy)-2,3-dihydroimidazo[1,2— clquinazolin—S-yl]pyrimidine-5—carboxamide, 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 isomer thereof and b) a further active agent which is PI3K6—selective inhibitor 65-1101.

In a preferred embodiment, the ion encompasses combinations of: a) 2-amino—N-[7-methoxy—8—(3-morpholin-4—ylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazolin—S-yl]pyrimidine—S-carboxamide, or a physiologically able salt, solvate, hydrate or stereoisomer thereof; or pharmaceutical compositions containing such a compound or a physiologically acceptable salt, solvate, e or stereoisomer thereof b) a further active agent which is BTK inhibitor ibrutinib.

In a preferred embodiment, the invention encompasses combinations of: W0 2014/166820 2014/056768 a) 2—amino—N—[7—methoxy—8—(3—morpholin-4—ylpropoxy)—2,3—dihydroimidazo[1,2- c]quinazolinyl]pyrimidine-S-carboxamide, or a physiologically acceptable salt, solvate, hydrate or stereoisomer f; or pharmaceutical compositions containing such a compound or a physiologically acceptable salt, e, hydrate or stereoisomer thereof b) a further active agent which is IKK inhibitor BAY Compound B.

In a preferred embodiment, the invention asses combinations of : a) 2-amino—N-[7-methoxy(3-morpholin—4-ylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazolinyl]pyrimidinecarboxamide, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; or pharmaceutical compositions containing such a nd or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof b) a further active agent which is REFAMETINIB (BAY 86-9766 (RDEA-119)).

In a preferred embodiment, the invention encompasses the use of combinations of : a) 2-amino-N-[7-methoxy-8—(3-morpholin-4—ylpropoxy)-2,3—dihydroimidazo[1,2- c]quinazo|in—5-yl]pyrimidine—5-carboxamide, or a logically acceptable salt, solvate, hydrate or stereoisomer thereof; or pharmaceutical compositions containing such a compound or a physiologically acceptable salt, e, hydrate or stereoisomer thereof b) a further active agent which is Pl3K6-selective inhibitor 65-1101.

W0 2014/166820 In a preferred embodiment, the invention asses the use of combinations of: a) 2-amino—N-[7-methoxy—8—(3—morpholin-4—ylpropoxy)-2,3—dihydroimidazo[1,2- c]quinazo|inyl]pyrimidinecarboxamide, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; or pharmaceutical compositions ning such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof and b) a further active agent which is BTK tor ibrutinib.

In a preferred embodiment, the invention encompasses the use of combinations of: a) Z-amino-N-[7-methoxy—8—(3—morpholinylpropoxy)-2,3-dihydroimidazo[1,2- c]quinazo|inyl]pyrimidinecarboxamide, or a logically acceptable salt, solvate, hydrate or stereoisomer thereof; or pharmaceutical compositions containing such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof I b) a further active agent which is IKK inhibitor BAY Compound B.

In a preferred embodiment, the invention encompasses the use of combinations of : a) o-N-[7-methoxy-8—(3—morpholin-4—ylpropoxy)—2,3—dihydroimidazo[1,2— azo|inyl]pyrimidinecarboxamide, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; or pharmaceutical compositions containing such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof W0 2014/166820 b) a further active agent which is REFAMETINIB (BAY 86—9766 (RDEA—119)).

The compounds of this invention can be stered as the sole pharmaceutical agent or in ation with one or more other pharmaceutical agents (or "further active agents”) 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, rhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agents, and the like, as well as with admixtures and combinations f.

The additional pharmaceutical agent or agents (or ”further active agent”) can be, but are not limited to 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole, arglabin, c de, asparaginase, azacitidine, basiliximab, BAY 1000394, refametinib (BAY 86-9766 (RDEA 119)), belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, calcium levofolinate, capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cetuximab, chlorambucil, chlormadinone, ethine, cisplatin, bine, clodronic acid, clofarabine, crisantaspase, cyclophosphamide, cyproterone, cytarabine, azine, omycin, darbepoetin alfa, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, deslorelin, dibrospidium chloride, docetaxel, uridine, doxorubicin, doxorubicin + estrone, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, epirubicin, epitiostanol, epoetin alfa, epoetin beta, eptaplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, flutamide, formestane, fotemustine, fulvestrant, gallium nitrate, lix, gefitinib, gemcitabine, gemtuzumab, glutoxim, goserelin, histamine dihydrochloride, histrelin, hydroxycarbamide, |-125 seeds, onic acid, momab tiuxetan, icin, ifosfamide, imatinib, imiquimod, improsulfan, eron alfa, interferon beta, interferon gamma, ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, lenograstim, lentinan, letrozole, W0 66820 relin, levamisole, lisuride, lobaplatin, lomustine, Ionidamine, masoprocol, medroxyprogesterone, megestrol, melphalan, mepitiostane, mercaptopurine, methotrexate, methoxsalen, Methyl aminolevulinate, testosterone, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, ntrone, nedaplatin, nelarabine, nilotinib, nilutamide, nimotuzumab, nimustine, nitracrine, obinutuzumab, ofatumumab, omeprazole, ekin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, pamidronic acid, mumab, pazopanib, pegaspargase, PEG-epoetin beta (methoxy oetin beta), pegfilgrastim, peginterferon alfa-Zb, pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide, picibanil, pirarubicin, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polysaccharide—K, porfimer sodium, pralatrexate, mustine, procarbazine, quinagolide, raloxifene, raltitrexed, ranimustine, razoxane, regorafenib, risedronic acid, rituximab, psin, romiplostim, mostim, sipuleucel—T, ran, sobuzoxane, sodium glycididazole, sorafenib, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tasonermin, teceleukin, tegafur, tegafur + gimeracil + oteracil, rfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, pa, thymalfasin, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin, trilostane, triptorelin, trofosfamide, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, nine, vinorelbine, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, atin amer, zoledronic acid, zorubicin, or a combination thereof.

The additional pharmaceutical 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, ine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin, S—azacytidine, azathioprine, ECG or tice BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, ome, decadron, decadron phosphate, delestrogen, denileukin ox, depo-medrol, deslorelin, W0 2014/166820 dexomethasone, dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine, doxorubicin, dronabinol, DW—166HC, eligard, elitek, ellence, emend, epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, e, estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyol, etidronic acid, etopophos, etoposide, fadrozole, farston, filgrastim, finasteride, fligrastim, floxuridine, fluconazole, fludarabine, 5- fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, tane, fosteabine, fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron HCl, tin, histrelin, hycamtin, ortone, eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan, icin, ifosfamide, eron alpha, interferon-alpha 2, interferon alfa-ZA, interferon B, interferon alfa-nl, interferon alfa-n3, interferon beta, interferon gamma-1a, interleukin-2, intron A, iressa, irinotecan, , Iapatinib, lentinan sulphate, letrozole, orin, leuprolide, leuprolide acetate, Ienalidomide, levamisole, Ievofolinic acid calcium salt, Ievothroid, levoxyl, Iomustine, lonidamine, marinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, menest, 6-mercaptopurine, Mesna, methotrexate, metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, Modrenal, Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide, nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCI, orapred, oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin, picibanil, pilocarpine HCI, pirarubicin, plicamycin, porfimer sodium, prednimustine, prednisolone, prednisone, premarin, procarbazine, procrit, tinib (BAY 86-9766 (RDEA 119)), raltitrexed, rebif, rhenium—186 etidronate, rituximab, roferon-A, ide, salagen, sandostatin, sargramostim, semustine, sizofiran, sobuzoxane, solu—medrol, sparfosic acid, ell therapy, streptozocin, strontium-89 chloride, sunitinib, synthroid, fen, tamsulosin, tasonermin, tastolactone, taxotere, teceleukin, temozolomide, side, testosterone nate, testred, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, tretinoin, trexall, hylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, stine, vincristine, ine, lbine, virulizin, zinecard, zinostatin stimalamer, , ABI— 007, acolbifene, actimmune, affinitak, aminopterin, arzoxifene, asoprisnil, atamestane, atrasentan, BAY 43-9006 (sorafenib), n, CCI-779, CDC-501, celebrex, cetuximab, crisnatol, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLlM, W0 2014/166820 eride, edotecarin, eflornithine, exatecan, inide, histamine dihydrochloride, histrelin hydrogel t, holmium-166 DOTMP, ibandronic acid, interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, Ianreotide, lasofoxifene, libra, Ionafarnib, miproxifene, minodronate, MS—209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, pamidronate disodium, PN—401, QS—Zl, quazepam, R-1549, raloxifene, ranpirnase, 13-cis —retinoic acid, satraplatin, seocalcitol, T—138067, tarceva, taxoprexin, thalidomide, thymosin alpha 1, tiazofurine, tipifarnib, tirapazamine, TLK-286, toremifene, TranleD-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z- 100, onic acid or combinations f.

In accordance with an embodiment, the additional pharmaceutical agent or agents (or ”further active agent”) is selected from the group consisting of : 131l-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, tinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY 1000394, refametinib (BAY 86-9766 (RDEA 119)), belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, m folinate, calcium levofolinate, capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cetuximab, chlorambucil, chlormadinone, ethine, cisplatin, cladribine, clodronic acid, clofarabine, crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, nib, daunorubicin, decitabine, degarelix, denileukin diftitox, mab, elin, dibrospidium chloride, xel, doxifluridine, doxorubicin, doxorubicin + estrone, eculizumab, edrecolomab, elliptinium acetate, bopag, endostatin, abine, icin, epitiostanol, epoetin alfa, epoetin beta, eptaplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, flutamide, formestane, fotemustine, trant, gallium e, ganirelix, gefitinib, gemcitabine, umab, glutoxim, goserelin, histamine dihydrochloride, histrelin, hydroxycarbamide, l-125 seeds, ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferon alfa, eron beta, interferon gamma, ipilimumab, ecan, ixabepilone, lanreotide, Iapatinib, lenalidomide, astim, lentinan, letrozole, leuprorelin, levamisole, lisuride, lobaplatin, lomustine, W0 2014/166820 lonidamine, masoprocol, yprogesterone, megestrol, melphalan, mepitiostane, mercaptopurine, methotrexate, methoxsalen, Methyl aminolevulinate, methyltestosterone, mifamurtide, osine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide, nimotuzumab, nimustine, nitracrine, ofatumumab, omeprazole, ekin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin, ium—103 seed, pamidronic acid, panitumumab, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pegfilgrastim, peginterferon alfa—Zb, pemetrexed, pentazocine, tatin, peplomycin, perfosfamide, picibanil, pirarubicin, plerixafor, plicamycin, poliglusam, polyestradiol ate, polysaccharide-K, porfimer sodium, rexate, mustine, procarbazine, quinagolide, raloxifene, raltitrexed, ranimustine, razoxane, regorafenib, risedronic acid, rituximab, psin, romiplostim, sargramostim, sipuleucel—T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tasonermin, teceleukin, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin, tane, triptorelin, trofosfamide, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, ine, vinflunine, vinorelbine, vorinostat, vorozole, yttrium-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, , U0126, insulin, an insulin derivative, a PPAR ligand, a sulfonylurea drug, an a-glucosidase tor, a biguanide, a PTP-lB inhibitor, a DPP-IV inhibitor, a a-HSD inhibitor, GLP-l, a GLP-l derivative, GIP, a GIP derivative, PACAP, a PACAP derivative, secretin or a secretin tive.

Optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11‘h Edition of the Merck Index, (1996), which is hereby incorporated by reference, W0 2014/166820 such as ginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), icin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, orin, ine, mechlorethamine, 6— mercaptopurine, mesna, rexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanlne, topotecan, stine, vincristine, and vindesine.

Other anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman’s The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw—Hill, pages 1225-1287, (1996), which is hereby orated by reference, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, an, diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, abine phosphate, fluoxymesterone, ide, hydroxyprogesterone caproate, icin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacety|-L—aspartate (PALA), ycin, 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 ancer agents such as epothilone and its derivatives, irinotecan, raloxifen and topotecan.

Generally, the use of cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will serve to: (1) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone, W0 2014/166820 (2) provide for the administration of lesser amounts of the administered chemo— therapeutic agents, (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, ally humans, (5) provide for a higher se rate among treated patients, (6) provide for a longer survival time among d patients compared to standard chemotherapy treatments, (7) provide a longer time for tumor progression, and/or (8) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.

In accordance with an embodiment, the invention relates to combinations n said 2,3-dihydroimidazo[1,2-c]quinazoline compound is 2-amino-N-[7-methoxy-8—(3- morpholinylpropoxy)-2,3—dihydroimidazo[1,2—c}quinazolin-S-yl]pyrimidine—5- carboxamide.

In accordance with an embodiment, the ion relates to combinations wherein said 2,3-dihydroimidazo[1,2-c]quinazoline nd is o—N-[7—methoxy—8-(3— morpholinylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-S-yl]pyrimidine carboxamide dihydrochloride.

In accordance with an embodiment, the ion relates to combinations wherein said 2,3-dihydroimidazo[1,2-c]quinazoline compound is 2-amino-N-[7-methoxy-8—(3- W0 2014/166820 morpholin—4—yl propoxy)—2,3—dihyd roimidazo[1,2—c]quinazolin—S—yl]pyrimidine—5- carboxamide and said further active agent is PI3K6-selective inhibitor GS-1101.

In accordance with an embodiment, the invention relates to combinations wherein said 2,3-dihydroimidazo[1,2-c]quinazoline compound is Z-amino-N-[7-methoxy-8—(3- morpholinylpropoxy)—2,3—dihydrolmidazo[1,2—c]quinazolin—S—yl]pyrimidine-5— carboxamide and said further active agent is BTK inhibitor ibrutinib.

In accordance with an embodiment, the invention relates to ations wherein said 2,3'dihydroimidazo[1,2—c]quinazoline compound is Z-amino-N-[7-methoxy(3- morpholin—4—ylpropoxy)-2,3-dihydroimidazo[1,2—c]quinazolin-S-yl]pyrimidine—5- carboxamide and said further active agent is REFAMETINIB (BAY 86—9766 (RDEA-119)).

In accordance with an embodiment, the ion relates to ations wherein said 2,3-dihydroimidazo[1,2-c]quinazoline compound is 2-amino-N-[7-methoxy-8—(3- morpholinylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-S-yl]pyrimidine carboxamide dihydrochloride and said further active agent is PI3K5-selective inhibitor GS-llOl.

In accordance with an embodiment, the invention relates to combinations wherein said hydroimidazo[1,2-c]quinazoline compound is 2-amino-N-[7—methoxy-8—(3- morpholinylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-S-yl]pyrimidine carboxamide ochloride and said further active agent is BTK inhibitor ibrutinib.

In ance with an embodiment, the invention relates to combinations wherein said 2,3-dihydroimidazol1,2-c]quinazoline compound is o—N-[7-methoxy-8—(3— morpholinylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-S-yl]pyrimidine carboxamide dihydrochloride and said further active agent is IKK inhibitor BAY Compound B.

In accordance with an embodiment, the invention s to combinations wherein said hydroimidazo[1,2-c]quinazo|ine compound is 2-amino—N-[7—methoxy—8—(3— morpholinyl propoxy)-2,3-dihyd roimidazo[1,2-c]quinazolinyl]pyrimidine W0 66820 carboxamide dihydrochloride and said further active agent is REFAMETINIB (BAY 86— 9766 119)).

Pharmaceutical compositions of the compounds of the invention As mentioned supra, the present invention relates to ceutical compositions : - sing a 2,3—dihydroimidazo[1,2-c]quinazoline compound, or a physiologically acceptable salt, solvate, hydrate or stereoisomer f, as a sole active agent, for the treatment of non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non- Hodgkin‘s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic mia (CLL), marginal zone lymphoma (MZL), diffuse large B- cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL), and - comprising a pharmaceutical composition which comprises a combination of: a) 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 an 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: — Pl3K6-selective inhibitor GS—llOl, BTK inhibitor ibrutinib, lKK inhibitor BAY Compound B, and REFAMETlNIB (BAY 86-9766 (RDEA-119)).

In accordance with another embodiment, the present invention relates to pharmaceutical compositions which comprise a 2,3-dihydroimidazo[1,2—c]quinazoline nd as defined herein, in particular 2-amino-N—[7-methoxy-8—(3-morpholin—4- ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-S-yl]pyrimidinecarboxamide, or a physiologically acceptable salt, solvate, e or stereoisomer thereof, as a sole agent, W0 2014/166820 for the treatment of non—Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic cytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B—cell ma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma .

In accordance with another embodiment, the present invention relates to ceutical compositions which comprise Z-amino-N-[7-methoxy—8-(3—morpholin ylpropoxy)—2,3-dihydroimidazo[1,2-c]quinazolin—S-yl]pyrimidine-S-carboxamide dihydrochloride, as a sole agent, for the treatment of non-Hodgkin's lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, nt or ive non-Hodgkin’s lymphoma (NHL), in particular ular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell ma (MCL), transformed lymphoma (TL), or eral T—cell lymphoma (PTCL) In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said cancer is non—Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular ma (FL), chronic lymphocytic mia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T—cell lymphoma (PTCL) In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said cancer is non-Hodgkin’s lymphoma (NHL), ularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL).

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said cancer is follicular lymphoma (FL).

W0 2014/166820 In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said cancer is chronic lymphocytic mia (CLL).

In accordance a particular embodiment of any of the above s, or embodiments thereof, of the present invention, said cancer is marginal zone lymphoma (MZL).

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said cancer is diffuse large B-cell lymphoma (DLBCL).

In ance a particular embodiment of any of the above aspects, or ments thereof, of the present invention, said cancer is mantle cell lymphoma (MCL).

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said cancer is transformed lymphoma (TL).

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said cancer is peripheral T-cell ma (PTCL).

Said pharmaceutical compositions contain one or more compounds. These compositions can be utilized to achieve the desired pharmacological effect by administration to a patient in need f. A patient, for the purpose of this invention, is a , including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a nd, 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 trations 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 ive amount of compound is preferably that amount which es a result or exerts an influence on the particular condition being treated.

The compounds of the present invention can be stered with pharmaceutically- acceptable carriers well known in the art using any effective conventional dosage unit W0 2014/166820 forms, including ate, slow and timed release preparations, orally, parenterally, topically, nasally, lmicaliy, optically, sublingually, rectally, vaginally, and the like.

For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, s, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared ing to methods known to the art for the manufacture of pharmaceutical itions. The solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.

In r 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 administration such as potato , alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to t the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, 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 ate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and hylene alcohols, either with or without the addition of a pharmaceutically able surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both. sible powders and granules are suitable for the preparation of an aqueous suspension. They provide 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 mentioned above.

W0 2014/166820 2014/056768 Additional ents, for example those sweetening, flavoring and coloring agents described above, may also be present.

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 e of ble 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 hexitol anhydrides, for example, sorbitan monooleate, (4) condensation ts of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate, The emulsions may also contain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active agent in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily sions may n 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 flavoring agents; and one or more sweetening agents such as SUCFOSB or saccharin.

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

The compounds of this ion may also be stered erally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectabie dosages of the compound in preferably a physiologically acceptable diluent with a ceutical 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 cyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4—methanoi, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty W0 2014/166820 2014/056768 acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically able surfactant such as a soap or a detergent, suspending agent such as pectin, ers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying 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 e, ethyl oleate and isopropyl ate. le soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable ents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, , ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic ents, for example, fatty amine oxides, fatty acid alkanolamides, and xyethy|ene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta— ropionates, and 2—alkylimidazoline quarternary ammonium salts, as well as mixtures.

The parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active agent in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile- lipophile balance (HLB) preferably of from about 12 to about 17. The ty of surfactant in such formulation preferably ranges from about 5% 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 formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of ene oxide with propylene glycol.

W0 2014/166820 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 ymethylcellulose, methylcellulose, ypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth 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 d form a fatty acid and a hexitol such as yethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectable on or sion in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer’s solution, isotonic sodium chloride solutions and isotonic glucose ons. In addition, e fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed ing synthetic mono— or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be ed 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 .

Another formulation employed in the methods of the present invention employs transdermal delivery devices (”patches"). Such transdermal patches may be used to provide continuous or discontinuous on of the nds of the present invention in lled amounts. The construction and use of transdermal patches for W0 2014/166820 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, pulsatile, or on demand delivery of pharmaceutical agents.

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

It may be desirable or necessary to uce the ceutical composition to the patient via a mechanical 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 y involve placement of a drug delivery catheter into the patient’s ventricular system to bypass the brain barrier. One such implantable delivery , used for the transport of agents to ic anatomical regions of the body, is described in US Patent No. ,011,472, issued April 30, 1991.

The compositions of the invention can also contain other conventional pharmaceutically able 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 nces, each of which is incorporated herein by reference: Powell, M.F. et ai, "Compendium of Excipients for Parenteral ations" PDA Journal of Pharmaceutical Science 8: Technology 1998, 52(5), 238-311; Strickley, R.G ”Parenteral Formulations of Small Molecule Therapeutics ed in the United States (1999)—Part—1" PDA Journal of ceutical Science & Technology 1999, 53(6), 324- 349; and Nema, S. et al, ”Excipients and Their Use in Injectable Products” PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166—171.

Commonly used pharmaceutical ingredients that can be used as appropriate to formulate the composition for its intended route of administration include: W0 2014/166820 acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); nizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, ium hydroxide, sodium , sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered ose and activated charcoal); aerosol propellants (examples include but are not limited to carbon e, CClez, F2ClC‘CCl F2 and CCl F3) 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 benzoate); antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium de, benzyl alcohol, cetylpyridinium chloride, butanol, phenol, phenylethyl l, phenylmercuric nitrate and thimerosal); idants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding als (examples include but are not limited to block polymers, natural and tic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene- butadiene copolymers); W0 2014/166820 buffering agents (examples include but are not limited to potassium metaphosphate, dipotassium ate, sodium acetate, sodium e anhydrous and sodium e dihyd rate) carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride ion and bacteriostatic water for injection) ing agents les include but are not limited to edetate 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.5, 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 alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate); encapsulating agents (examples include but are not d to gelatin and cellulose acetate phthalate) flavorants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants les include but are not limited to glycerol, propylene glycol and sorbitol); levigating agents (examples include but are not limited to mineral oil and glycerin); W0 2014/166820 oils (examples include but are not limited to arachis oil, l oil, olive oil, peanut oil, sesame oil and ble oil); ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal delivery) (examples include but are not limited to droxy or droxy alcohols, mono-or polyvalent ls, ted or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, in, 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, seed 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, paraffin, stearyl alcohol, white wax and yellow wax); suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures)); tants (examples include but are not limited to konium chloride, nol , oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono—palmitate); suspending agents (examples include but are not d to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); W0 2014/166820 sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (examples include but are not limited to magnesium stearate and talc); tablet binders (examples include but are not d to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, cellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch); tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, ol, rystalline ose, powdered cellulose, itated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, ypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (examples include but are not limited to dibasic m phosphate); tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross— linked nylpyrrolidone, sodium alginate, sodium starch glycollate and starch); tablet glidants (examples include but are not limited to colloidal , corn starch and talc); tablet lubricants (examples include but are not limited to calcium stearate, magnesium te, mineral oil, stearic acid and zinc stearate); W0 2014/166820 2014/056768 tablet/capsule opaquants (examples include but are not limited to titanium dioxide); tablet polishing agents les include but are not d to carnuba wax and white wax); thickening agents (examples include but are not limited to beeswax, cetyl alcohol and paraffin); tonicity 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, cellulose, nyl pyrrolidone, sodium alginate and tragacanth); and wetting agents (examples e but are not limited to heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can be illustrated as follows: Sterile IV Solution: 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 gowder for IV administration: A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a ized powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 — 3000 mg Dextran 40. The formulation is reconstituted with e, able 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 on over 15 — 60 minutes.

W0 2014/166820 Intramuscular suspension: The following solution or suspension can be prepared, for intramuscular injection: 50 mg/mL of the desired, water-insoluble compound of this invention mg/mL sodium carboxymethylcellulose 4 mg/mL TWEEN 80 9 mg/mL sodium chloride 9 mg/mL benzyl l Hard Shell Capsules: A large number of unit capsules are prepared by filling rd two-piece hard galantine capsules each with 100 mg of ed active agent, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft n 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 cement pump into molten gelatin to form soft n 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 medicine 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 dal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate s and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.

Immediate Release Tabletleaqules: These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active agent is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are fied 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 escent components to produce porous matrices intended for immediate release, without the need of water.

W0 2014/166820 Method of n d kin's | m homa NHL articularl lst line 2nd line rela sed refractor indolent or a ressive non-Hod kin’s l m homa NHL in articular follicular l m homa FL chronic | m hoc ic leukaemia CLL mar inal zonel m homa MZL diffuse lar e B—celll m homa DLBCL mantle celll m homa (MCL), ormed lymphoma (TL)I or peripheral T-cell lymphoma (PTCL) The t invention also relates to a method of treating or prophylaxis of non- Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular ma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B- cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T—cell lymphoma (PTCL), in a mammal, said method comprising administering a 2,3-dihydroimidazo[1,2-c]quinazoline compound as defined herein, or a pharmaceutical composition containing same, as a sole active agent, or administering a combination of a) said compound or a pharmaceutical composition ning 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 present invention, said cancer is non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular ular ma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma ), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T—cell lymphoma (PTCL).

The ments of the methods of treating or prophylaxis of cancer, e.g. non- Hodgkin’s ma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic cytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B- cell lymphoma ), mantle cell ma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL), as defined supra, are as described in the embodiments of the use of the compounds/combinations, as described supra.

W0 2014/166820 The present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat mammalian non—Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or ive non- Hodgkin’s ma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B—cell lymphoma ), mantle cell ma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL). nds can be utilized to t, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce sis, in the treatment or prophylaxis of non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or eral T-cell lymphoma . 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, , rph, metabolite, hydrate, solvate or ester thereof; etc. which is effective for the treatment or prophylaxis of non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non—Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), al zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or eral T-cell lymphoma (PTCL).

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

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

Dose and administration W0 2014/166820 Based upon standard laboratory techniques known to te compounds useful for the treatment or prophylaxis of non—Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B—cell lymphoma (DLBCL), mantle cell lymphoma (MCL), ormed lymphoma (TL), or peripheral T-cell lymphoma (PTCL), 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 ions, the effective dosage of the compounds of this invention can readily be determined for treatment of the indication. The amount of the active agent to be administered in the treatment of the ion 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 t treated, and the nature and extent of the condition treated.

The total amount of the active agent to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and ably 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 . In addition, ”drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial 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 l 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 ermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The W0 2014/166820 2014/056768 average daily inhalation 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 patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The d mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.

Biomarkers used for t fication are e.g. the expression of P|3K isoforms, BTK and lKK, BCR activation, BCR downstream activation of NFKB pathway, c-Myc, EZH2, for predicting the sensitivity and/or resistance of a cancer t to said nd, thus providing rationale-based synergistic combination as defined herein to overcome the resistance.

W0 2014/166820 COMPOUNDS USED Throughout the whole of this text, including in the Examples which follow: 1. “compound of formula III refers to 2—amino-N-[7-methoxy-8—(3-morpho|in—4— yipropoxy)-2,3-dihydroimidazo[1,2—c]quinazo|in—5-yl]pyrimidine-S—carboxamide, of ure : flNMO/La NKAN ON) H \Cm KN? NW, or a solvate, hydrate or stereoisomer thereof. 2. ”compound A” refers to 2-amino-N—[7-methoxy-8—(3-morphoiinylpropoxy)-2,3- dihydroimidazo[1,2—c]quinazolin-S-yl]pyrimidine-S-carboxamide dihydrochioride, of Structure: N/\\ (/\N/\v/\o)£f? NZKNJKX/xN O / H “““ o“*3 lN/‘xNHzin, W0 2014/166820 or a solvate, hydrate or stereoisomer thereof.

The synthesis of compound A is bed in European patent application number EP 11 161 111.7, and in PCT application number published under WO 2012/136553, both of which are hereby incorporated herein in their 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 ethanol (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 closed within 5 hwas added into the mixture over 5 h, which isand the resulting mixture was subsequently stirred for 1 h. The sion is filtered and the residue is washed first with a mixture of 130 g water and 215 g ethanol, ly with a e of 80 g water and 255 g ethanol 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: The chemical structure of compound A has been confirmed using the described s of structural analysis.

IR and Raman spectroscopy Apparatus and measuring conditions FT-IR / FT—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 W0 2014/166820 Laser power / 350mW Sample preparation KBr pellet / solid in test tube Assignment ofthe characteristic bands Table: Assignment of the characteristic active ions to the spectrum with V E stretching vibrations; 8 E bending vibrations; o.o.p. E out of plane.

Assigned Structure IR Band on [cm'l] Raman Band position [cm'l] 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 ll 1618 —- 1477 1619 — 1476 v C-0 1285 1291 6 =C-H 0.0.p. 812 v E stretching vibrations; 5 E bending vibrations; o.o.p. E out of plane The IR spectrum is given in Figure 7.

The Raman spectrum is given in Figure 8.

UVlVIS spectroscopy tus and measuring conditions UV/VIS spectrometer Varian Cary4 Cuvette Quartz, 1 cm Wave number range 200-800 nm W0 2014/166820 Sample preparation 4.67 mg / 500 mL water Bands 309 nm The UV/vis spectrum is given in Figure 9.

NMR spectroscopy lH-NMR-spectroscogx Equipment and experimental parameters: NMR ometer , model Avance Working frequency 500.13 MHZ Solvent Dimethylsulfoxide d6) 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 Digital resolution 0.079 Hz/Pt Pulse length 4.5 usec, 30° Pulse flip angle Acquisition time 6.34sec Relaxation time 0.55ec No. of free induction decays 32 Structural Formula for the assignment of NMR signals W0 2014/166820 HCI HCI 2 9 [77> 3 29 3 ea‘N/s“in O 30 (\N/ZrEE/ZEQ Ill 13 O\/I 33 7 |14\N 17 /O H 19 N/ NH 32 23 al shift, signal multiplicity, relative number of nuclei: H-atoms(a) Chemical shift Multiplicity and no. of nuclei (ppm) coupling constants (b) H/molecule 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 NH2 7.54 S 2 H-10 8.21 D 1 H-16; H—20 8.97 S 1; 1 HCI 11.1; 12.6 b5; b5 1; 1 H-12 13.4 b5 1 a) Numbering refers to the structural formula for the assignment of NMR— signals.

W0 2014/166820 b) S = t bS = broad Singlet D = Doublet T = Triplet M = Multiplet The 1H—NMR Spectrum of nd A is given in Figure 10. 13C-NMR-sgectroscom Equipment and experimental parameters NMR spectrometer Bruker, model Avance Working frequency 125.76 MHz Solvent Dimethylsulfoxide-ds (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 l resolution 0.4624 Hz/Pt Pulse length 11.0 usec, 90° Pulse flip angle Acquisition time 1.08 sec Relaxation time 4 sec No. of free induction decays 256 W0 2014/166820 Chemical shift, signal multiplicity, rel. no. ofnuclei: C-atoms(a) Chemical shift Multiplicity and no. of nuclei (ppm) coupling constants (b) C/molecule C-26 22.73 T 1 C—2; C—3 44.96; 45.65 T; T 1; 1 C—29; C-33 50.84 T 1; 1 C-27 53.01 T 1 OCH3 61.24 Q 1 C-30; C-32 63.03 T 1; 1 C-25 66.81 T 1 C-lOa 100.79 S 1 C-9 112.17 D 1 015 118.16 S 1 C-10 123.86 D 1 C—6a 132.43 S 1 C-7 133.95 S 1 C-5 148.58 S 1 C-ll 156.29 S 1 C-8 156.89 S 1 C-16; C-20 160.20 D 1; 1 C-18 164.61 S 1 C=O 175.65 S 1 a) Numbering refers to the structural formula for the ment of NMR-signals. b) S = Single (C) D = Doublet (CH) T = Triplet (CH2) Q = Quadruplet (CH3) W0 2014/166820 The l3C—NMR Spectra of compound A are given in Figures 11 and 12.

Mass Spectrometry Instrumental Parameters Mass ometer Waters ZQ Ionization mode ESI (Eiectrospray-lonization) Solvent CchN/Hzo Interpretation of the Spectrum “Ms—WW Rel- Intensit % mm (M + H) (C16 H16 N7 03)+ (M + 2H + CH3CN)+2 The Mass Spectrum of compound A is given in Figure 13. Refer to the spectrum for ve peak intensities.

W0 2014/166820 2014/056768 Elemental Analysis Elemental analysis was conducted by Bayer Industry Services, Leverkusen, Germany.

Results Element Measured Calculated ated 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 CI 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. r method of greparation of comgound “A” To a suspension of 366 g of compound of formula (I) in 1015 g water, 183 g of an aqueous hloric acid solution (32%) were added while maintaining the temperature at 20 °C (+-2°) until a pH of 3 to 4 was reached. The resulting 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 ature, 146g of ethanol (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, washed with a water—ethanol e and dried in vacuo to give 410 g (97%) of compound A of a purity >99% according to HPLC.

W0 66820 2. “Pl3K5—selective inhibitor GS—1101” refers to Pl3|<5~se|ective inhibitor CAL-101 (GS— 1101), was purchased from ChemieTec and is of structure shown below: IR ‘N 2/ N1” I.O\ HN, N | 3 ‘e—NH Pl3K6—selective inhibitor CAL—101(GS-1101) W0 2014/166820 3. ”BTK inhibitor ibrutinib” refers to the BTK inhibitor lbrutinib (P032765), which was purchased from enamine and is of structure shown below: ’ 7 $47- \ ,,I N? T ,9: \f \E NH; (7‘\\\\ 7“ fx 0 V \KL/ 4. ”lKK inhibitor BAY Compound B” is the free base (-)-S-enantiomer under Example 2 of PCT ation published under and is of structure : W0 2014/166820 EXAMPLES The invention is trated in the following examples which are not meant to limit the ion in any way: Mutation and protein expression analysis of DLBCL cell lines Table 1. Genetic characteristics of DLBCL cell lines Subtype ABC-DLBCL BCL Mutation HBL— TMD- OCI- 0C!- 1 8 Ly3 Ly19 I...

WT WT ABC, activated B—cell—like; GCB, germinal B-cell—like; mut, mutant Example 1 : Figure 1 shows signaling pathways downstream of receptors on B- cells.(see reference 5A) 0 COMPOUND A demonstrated 6/6 PR in follicular NHL with partial response observed at the end of cycle 2 at doses % mg/kg except in one case where the PR was d at the end of cycle 4 at 0.6 mg/kg. 0 In contrast to P|3Kde|ta-selective inhibitor GS-1101 (9/9 PD in DLBCL patients), 1/3 SD with 39% tumor reduction was observed in DLBCL patients.

W0 2014/166820 Example 2 : Figure 2 shows activity of COMPOUND A in NHL patients.

Initial clinical cy of the pan-PI3K inhibitor COMPOUND A in NHL (see reference 6A) PD, progression of e; PR, partial response; SD, stable disease; WT, wild type for PlK3CA. o COMPOUND A demonstrated 6/6 PR in follicular NHL with partial response observed at the end of cycle 2 at doses % mg/kg except in one case where the PR was reached at the end of cycle 4 at 0.6 mg/kg. 0 In contrast to Pl3Kde|ta-selective inhibitor GS-1101 (9/9 PD in DLBCL patients), 1/3 SD with 39% tumor reduction was observed in DLBCL ts.

Example 3 : Figure 3 shows differential expression of PI3K isoforms, BTK, and IKK in DLBCL cell lines Methods: The mutation status was obtained from public database. n expression was analyzed by western blot with antibodies against PI3K p1100i (#4249, Cell Signaling); P|3K (011013 (#3011, Cell ing) Pl3K p110y (#5405, Cell Signaling),Pl3K p1106 (#ab1678, Abcam), BTK (#3533, Cell Signaling), IKKB (#2370, Cell Signaling).

Conclusions 0 The expression of PI3KOL, PI3KB, and PI3Ky isoforms was similar in all 8 DLBCL cell lines tested, while the expression of PI3K6 varied W0 2014/166820 o IKKB was expressed across all DLBCL cell lines, while BTK was ively expressed Example 4 Anti-proliferative activity of PI3K, BTK, and IKK inhibitors in DLBCL cell lines Figure 4 shows differential anti-proliferative profile of pan-PI3K inhibitor COMPOUND A, Pl3K5-selective inhibitor GS-1101, BTK inhibitor ibrutinib, and IKK inhibitor BAY nd B in DLBCL cell lines *>1.0E-05 (M) Method: Anti-proliferative effects were assessed by a 72-h CellTiter—Glo® assay (Promega, Cat.#G7573). Briefly, cells were plated at 250-2000 cells/well of 384—well plates (based on cell lines) in 20 ML of growth medium. For each cell line assayed, cells were plated into a separate plate for determination of luminescence at the t = 0 hours and t = 72 hour time points. Following ght incubation at 37 °C, luminescence values for the t = 0 samples were determined by adding 20 uL of Cell Glo solution per well, transferring the plates to an orbital shaker for 10 minutes at room temperature, and then reading the plates on a Wallac Victor2 1420 Multilabel HTS Counter using the luminometry window (maximum light detection is measured at 428 nM). Dose plates for t = 72 hour time points were treated with compounds diluted into growth medium in a final volume of 30 uL. Cells were then incubated for 72 hours at 37 °C. Luminescence values for the t = 72 hour samples were ined by adding 30 uL of Promega ter—Glo solution, placing the cells on a shaker for 10 minutes at room temperature, and then reading the luminescence using a Victor luminometer. For data processing, t = O values are subtracted from those determined for the t = 72 hour time points, for both the treated and untreated samples. Percent differences in luminescence between drug treated and controls are used to determine percent inhibition of growth.

Conclusions: l, the potent activity of PI3K, BTK, and IKK tors in a subset of cell lines ated with the high expression of the targets W0 2014/166820 2014/056768 Pan—PI3K inhibitor COMPOUND A was particularly active in the cells with activated BCR signaling (TMD—8 and HBL-l). It was also effective in DLBCL cells with activating NFKB pathway (HBL—l and OCl-Ly3), but required higher concentrations to reach complete tumor growth inhibition (assessed by ngo), indicating that combination treatment might be needed to induce tumor stasis and tumor regression PI3K6-selective inhibitor 1 was active only in BCR-mutant cell lines without ream mutations. Any mutations ream of BCR led to >100-fold decreased activity with respect to iCso values o BTK inhibitor ibrutinib was active in BCR—mutant cell lines even in the presence of activating NFKB y (ICSQ <30 nM). Cell lines without BCR-activating ons showed a dramatically increased ngo value (>1 uM) or complete inactivity IKKB inhibitor BAY compound B was more active in ABC-DLBCL compared with BCL cell lines Example 5 : In vivo efficacy of COMPOUND A and ibrutinib in TMD-8 xenograft model in C317 scid mice Methods: Untreated female 5-6 week old CBl7.Scid mice are inoculated with 10 x 106 TMD-8 tumor cells (suspended in 50% Matrigel and 50% Medium) subcutaneously into the flank. Animals are randomized to ent groups when tumors reach a tumor area of 30-35 mmz. Treatment is conducted as described in Figure 5 legend. Tumor area and animal body are recorded three times per week.

Conclusions: P|3K inhibitor compound A achieved good tumor growth inhibition in the TMD-8 model upon treatment with 14 mg/kg every 2 days, reaching TGI (tumor growth inhibition) based on ve tumor area (rel TA) at the end of the study of 75%. BTK inhibitor ibrutinib did also show good tumor growth inhibition in TMD-8 tumors upon treatment with 20 mg/kg once daily, reaching TGI (rem) of 70%. All treatments were well tolerated.

W0 2014/166820 Overall, PI3K inhibitor COMPOUND A shows potent anti—tumor activity in the human ABC-DLBCL model TMD-8, able to BTK inhibitor nib,.

See Figure 5. Effect of COMPOUND A and ibrutinib on tumor growth in vivo.

COMPOUND A was administered iv once every 2 days (Q2D) at 10 and 14 mg/kg and ibrutinib was dosed po at 12 and 20 mg/kg. Tumor growth was monitored by determination of the tumor area using caliper measurement 3 times weekly. QD, once daily; SD, standard deviation of the mean; TGI, relative tumor growth inhibition vs control (%, tumor area at the end ofthe study on day 29) Example 6 : Combination effects of PI3K inhibitor with BTK, IKK, and MEK inhibitors in DLBCL cells Methods: Combination study: The combination effects were evaluated using combination index isobologram analysis. The efficacy parameters were the median effect in a r cell proliferation assay. Briefly, cells were plated in 384-well plate with 25 ul medium. After 24 hours, 5 uL of experimental media containing either compound A (D1), or combination partner D2 (Ibrutinib, BAY Compound B, or REFAMETINIB (BAY 86-9766 (RDEA-119))), or the combination of compound A plus D2 at different ratios (O.8xD1+O.2xD2, +0.4XD2, O.4xD1+0.6xD2, 0.2xD1+0.8xD2, 0.1xD1+0.9xD2) were used to make serial three-fold ons to generate 7-dose curves. Experiments were conducted in triplicates. The mapping ECso/leo and C90 were ated using AnalyzeS computer program. The ponding component doses of D1 and D2 at the E(|)Cso/ E(l)C90 were calculated and used for plotting isobolograms. Multiple drug effect was analyzed as described by Chou (see nce 7A) and the combination index was calculated using the formula: Combination Index = [D1x]/ D1’ + [D2x]/ D2' W0 2014/166820 [Dlx] and [D2x] refer to the Drug 1 and Drug 2 concentration at CSO or EC90/lC90, tively, in combination. D1’ and D2’ refer to the ECsO/lCSo or EC90/lC90 values of D1 and D2, respectively, as a single agent. In this analysis, values less than 1.0 indicate synergistic interactions, values greater than 1.0 indicate antagonistic interactions, and values around 1.0 indicate additive ctions.

Western Blot: Modulation of intracellular pathways were assessed by Western blots at 24h post treatment with indicated compounds either as single agent or in combination.

Antibodies used in this study are AKT (#4685, Cell Signaling), p-AKT (#4060, Cell Signaling), ERK (#4695, Cell Signaling), p-ERK , Cell Signaling), BTK (#3533, Cell Signaling), p-BTK (#5082, Cell Signaling), IKBOL (#4812, Cell Signaling), p-IKBOL (#AF4809, R&D), c/B (#2078, Cell Signaling), IKKB (#2370, Cell Signaling).

W0 2014/166820 Conclusions: Combination of pan—PI3K inhibitor compound A with BTK inhibitor ibrutinib: o Synergistic antitumor effect observed in the tumor cell lines responding to BTK inhibition o Antagonistic effect observed in BTK inhibitor-resistant tumor cell lines o No synergistic s on complete tumor growth inhibition in the cell lines with activated NFKB pathway (MyD88 or CARDll mutation), even in the presence of BCR activation 0 Combination of pan-PI3K inhibitor COMPOUND A with IKK tor BAY Compound B: o Synergistic antitumor effect observed in ABC-DLBCL cells 0 In BCL cells, the combination had both moderate synergistic and antagonistic effects 0 Feedback activations by inhibition of Pl3K6, BTK, and IKK : 0 Activation of p-ERK by BTK inhibitor ibrutinib in both HBL-l and OCl-Ly3 cells 0 Activation of /B by IKK inhibitor BAY nd B in both HBL—l and OCl—Ly3 cells 0 Activation of p-ERK by P|3K6 inhibitor GS-1101 in HBL-l cells 0 Very strong synergistic combination with the MEK inhibitor TINIB (BAY 86- 9766 (RDEA-119)) was demonstrated in MyD88- and CARDll—mutant OCl-Ly3 DLBCL cell lines W0 2014/166820 2014/056768 Figure 6 shows the combination effect of P|3K inhibitor nd A with BTK inhibitor ibrutinib or lKK inhibitor BAY Compound B in DLBCL cell lines Figure 6A shows the anti-proliferative effect was investigated using a 72-h CellTiter-Glo assay. The results were analyzed as previously described (see reference 7A). Each combination study was conducted with 5 different concentration ratios of 2 compounds and ICSO values were determined using a series of 7-dose dilution. The differential combination effects of BTK v5 IKK inhibitor were further investigated by analyzing the modulation of signaling pathways using n blots with indicated anti-phospho and anti—total target proteins in OCl-Ly3 (Figure 6B) and HBL—1 (Figure 6C) cells. Figure 6D shows the strong synergistic combination with MEK inhibitor REFAMETINIB (BAY 86- 9766 (RDEA-119)) in MyD88— and CARD11-mutant OCl-Ly3 DLBCL cells Cl, combination index; NA, not achievable at a concentration of 10 (AM of the 2 compounds.

Example 7: Phase II study of single agent ND 0F A I in patients with lst line, 2nd line, ed, refractory, indolent or aggressive lymphoma A phase I dose-escalation study (Patnaik et al, ASH 2012) established the maximum tolerated dose of ND OF FORMULA | (0.8 mg/kg) and reported promising activity (6/6 PR) in follicular lymphoma. In the present study we further investigated the activity and safety of COMPOUND OF FORMULA l in patients with indolent or aggressive lymphoma subtypes that have progressed after standard y.

In this Phase II study, patients with histologically confirmed indolent or aggressive lymphoma relapsed or refractory to 22 prior lines of treatment were eligible. Patients received COMPOUND OF FORMULA | at a dose of 0.8 mg/kg as a 1 hour infusion on days 1, 8 and 15 of a 28-day cycle. Patients continued on therapy until disease progression or unacceptable toxicity. Responses were assessed every two cycles according to the se criteria for lymphoma (Cheson et al., JCO 17:1244,1999) or the guidelines for diagnosis and ent of chronic lymphocytic ia (CLL; Hallek et al., Blood 111:5446-56, 2008).

W0 2014/166820 Results: As of May 31, 2013, a total of 61 lymphoma patients (27 nt and 34 aggressive) were enrolled and 56 started study treatment. Patients were similarly distributed among nt and aggressive cohorts with respect to gender (52% female), median age (68 yr, range 22-90) and ethnicity (76% Caucasian) and were heavily ated (median number of prior therapies: 3; prior Rituximab: 84%; prior ASCT: %). Other characteristics included advanced stage III-IV in 85% and B symptoms in 17%. The following entities were represented: follicular (FL; n=13); CLL (n= 11); marginal zone (MZL; n=3; none re-staged); diffuse large B-cell (DLBCL; n=17); mantle cell (MCL; n=7); transformed (n=5); and peripheral T-cell (PTCL; n=4). At the time of is patients had received between 1 and 5 cycles of ent. Objective responses were seen across histologic subtypes (Table 1). At the time of this interim analysis, the overall response rate (RR) and complete RR were 44% and 22% in FL, 83% and 17% in MCL, and 50% and 0% in PTCL, respectively.

Table 1. Best response by lymphoma subtype in staged patients ”VCR“ -IIII-—II EIIEH—II PD 0 1 8 1 2 2 CR — complete response; CRu — CR irmed; PR — partial response; SD — stable disease; PD — progressive disease Grade 3 adverse events (AE) were reported in 49% of patients, and grade 4 AE (all neutropenia) occurred in 15% of patients. Grade 3/4 AEs occurring in 25% of patients included hypertension (31%), penia (16%), lycemia (13%), diarrhea (5%) W0 2014/166820 and fatigue (5%). Hyperglycemia of any grade occurred in 47%. Four patients required insulin therapy, but no grade 4 hyperglycemia was observed. Hypertension of any grade occurred in 46% of patients. Eight patients ed antihypertensive treatment, but no grade 4 hypertension was reported. Diarrhea of any grade occurred in 25% of cases. No case of colitis was reported. There were two cases of titial pneumonitis, with both cases resolved following corticosteroid administration. Withdrawal of study drug due to AEs occurred in 10 patients (16%), and 4 patients required a dose reduction. Four deaths ed; 1 due to progressive disease, 1 due to acute respiratory insufficiency, 1 due to Cryptococcal meningitis and 1 due to sepsis after start of a salvage chemotherapy regimen.

Conclusions: The novel P|3K inhibitor COMPOUND OF FORMULA | is clinically active as a single agent and s to have an acceptable toxicity profile in lst line, 2nd line, relapsed, refractory lymphoma. Preliminary efficacy results are encouraging, as ing activity has been observed in FL, MCL, and PTCL. The safety profile was consistent with prior studies.

Summary 0 All 4 PI3K isoforms are expressed in a panel of 8 DLBCL cell lines o The pan-PI3K inhibitor COMPOUND A, selective inhibitor 65-1101, BTK inhibitor lbrutinib and IKK inhibitor BAY compound B demonstrate ential profiles of anti-proliferative activity 0 Broader and greater antitumor activity is observed with pan—PI3K inhibitor COMPOUND A compared with PI3K5-selective inhibitor GS-1101, BTK inhibitor ibrutinib, and IKK inhibitor BAY compound B o COMPOUND A administered iv QZD (Tl/2‘1 h in mice) at 14 mg/kg demonstrated marked mor activity comparable to lbrutinib in CD79 mutant TMD-8 DLBCL xenograft model 0 A cell-specific synergistic effect was ed for COMPOUND A in ation with an IKK inhibitor, BTK inhibitor, and MEK inhibitor BAY 86-9766 W0 2014/166820 0 Potential biomarkers to be considered for both monotherapy and combination therapy: 0 Target sion 0 BCR activation o BCR downstream activation of NFKB y 0 c-Myc, EZHZ 0 Further studies may reveal more effective combination partners for COMPOUND These findings provide a retionale to develop personalized therapies for the treatment of non-Hodgkin’s ma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic mia (CLL), al zone lymphoma (MZL), diffuse large B-cell ma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL).

Hence, as mentioned supra, the present invention relates to the use of biomarkers ed in the modification of the expression of P|3K isoforms, BTK and IKK, BCR activation, BCR downstream tion of NFKB pathway, c-Myc, EZHZ, for predicting the sensitivity and/or resistance of a patient with non-Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B—cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell ma , to a 2,3-dihydroimidazo[1,2-c]quinazoline compound as defined herein, thus providing ale-based synergistic 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 the expression of P|3K isoforms, BTK and IKK, W0 2014/166820 BCR activation, BCR ream activation of NFKB pathway, c—Myc, EZHZ, for predicting the sensitivity and/or resistance of a patient with non—Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non— Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T—cell lymphoma , to a 2,3—dihydroimidazo[1,2-c]quinazoline nd as defined herein, thus ing a rationale—based synergistic combination as defined herein to overcome the resistance (patient stratification).

In accordance with an embodiment, the present invention relates to a method of determining the level of a component ofone or more of the expression of PI3K ms, BTK and |KK,, BCR activation, BCR downstream activation of NFKB y, c—Myc, EZHZ.

Further, as mentioned supra, the present invention thus relates to combinations of : a) a 2,3—dihydroimidazo[1,Z-c]quinazoline compound as d supra, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; or pharmaceutical compositions containing such a compound or a physiologically able salt, solvate, hydrate or stereoisomer thereof; b) one or more further active agents, in particular an active agent selected from an anti— angiogenesis, anti-hyper-proliferative, flammatory, analgesic, immunoregulatory, ic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agent, more particularly one or more further active agents selected from the group consisting of : - Pl3K6—selective inhibitor GS-1101, BTK inhibitor nib, IKK inhibitor BAY Compound B, and REFAMETINIB (BAY 86-9766 (RDEA-119)), as defined supra.

W0 2014/166820 In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the t invention, said cancer is non—Hodgkin’s lymphoma (NHL), particularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular ma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B—cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL).

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said cancer is non-Hodgkin’s lymphoma (NHL), ularly lst line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL).

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said cancer is ular lymphoma (FL).

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said cancer is chronic lymphocytic leukaemia (CLL).

In ance a particular embodiment of any of the above aspects, or embodiments thereof, of the t invention, said cancer is marginal zone lymphoma (MZL).

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said cancer is e large B-cell lymphoma (DLBCL).

In accordance a ular embodiment of any of the above aspects, or embodiments thereof, of the present ion, said cancer is mantle cell lymphoma (MCL).

In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said cancer is transformed lymphoma (TL).

W0 2014/166820 In accordance a particular embodiment of any of the above aspects, or embodiments thereof, of the present invention, said cancer is peripheral T-cell lymphoma (PTCL).

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Claims (11)

1. Use of a 2,3-dihydroimidazo[1,2-c]quinazoline compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof as a sole active agent, 5 or of a pharmaceutical composition containing the nd or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, for the preparation of a medicament for the treatment or prophylaxis of dgkin’s lymphoma (NHL), ularly 1st line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), c lymphocytic leukaemia 10 (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed ma (TL), or peripheral T-cell lymphoma (PTCL), wherein said 2,3-dihydroimidazo[1,2-c]quinazoline compound is o-N-[7-methoxy- 8-(3morpholinylpropoxy)-2.3-dihydroimidazo[1,2-c]quinazolineyl]pyrimidine 15 carboxamide.

2. Use according to claim 1, wherein said salt is 2-amino-N-[7-methoxy(3-morpholin- 4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide dihydrochloride.

3. A combination drug of: a) a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a logically acceptable salt, solvate, hydrate or stereoisomer thereof; or a ceutical composition 25 containing the compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, 30 b) one or more further active agents selected from the group consisting of: PI3Kδselective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B of the formula 128 BHC 133020 FC , and TINIB (BAY 86-9766 119)), for the treatment of prophylaxis of non-Hodgkins’s lymphoma (NHL), particularly 1st line, 2nd line, relapsed, refractory, indolent or aggressive non-Hodgkins’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone 5 lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL), wherein said 2,3- dihydroimidazo[1,2-c]quinazoline compound is 2-amino-N-[7-methoxy(3-morpholin-

4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide. 10 4. The combination drug according to claim 3, comprising 2-amino-N-[7-methoxy(3- morpholinylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolinyl]pyrimidine carboxamide.

5. The combination drug according to claim 3, comprising 2-amino-N-[7-methoxy(3- 15 linylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolinyl]pyrimidine carboxamide dihydrochloride.

6. The combination drug according to claim 4 or 5, wherein said further active agent is selective inhibitor GS-1101.

7. The combination drug according to claim 4 or 5, wherein said further active agent is BTK inhibitor ibrutinib.

8. The combination drug according to claim 4 or 5, wherein said r active agent is 25 IKK inhibitor BAY nd B of the formula 129 BHC 133020 FC

9. The combination drug according to claim 4 or 5, wherein said further active agent is REFAMETINIB (BAY 86-9766 (RDEA-119)).

10. 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 thereof; and b) one or more further active agents selected from the group consisting of: elective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B of the , and REFAMETINIB (BAY 86-9766 (RDEA-119)), for 15 the treatment or prophylaxis of non-Hodgkin’s lymphoma (NHL), particulary 1st line, 2nd line, relapsed, refractory, indolent or agressive dgkin’s lymphoma (NHL), in particular ular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma , n said 2,3- 20 dihydroimidazo[1,2-c]quinazoline compound is 2-amino-N-[7-methoxy(3-morpholin- 4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolinyl]pyrimidinecarboxamide. 130 BHC 133020 FC

11. U se of a combination or a pharmaceutical composition containing the combination for the preparation of a medicament for the treatment or prophylaxis of non-Hodgkin’s lymphoma (NHL), particulary 1st line, 2nd line, relapsed, tory, indolent or agressive non-Hodgkin’s lymphoma (NHL), in particular follicular lymphoma (FL), chronic 5 lymphocytic mia (CLL), al zone lymphoma (MZL), diffuse large B-cell ma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL), wherein the combination comprises: 10 a) a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; or of a pharmaceutical composition containing such a compound or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, 15 and b) one or more further active agents selected from the group consisting of: PI3Kδselective inhibitor GS-1101, BTK inhibitor ibrutinib, IKK inhibitor BAY Compound B of the formula 20 , and TINIB (BAY 86-9766 119)); wherein said 2,3-dihydroimidazo[1,2-c]quinazoline nd is 2-amino-N-[7- methoxy(3-morpholinylpropoxy)-2,3 dihydroimidazo[1,2-c]quinazolin yl]pyrimidinecarboxamide.