WO2021260443A1

WO2021260443A1 - Combinations of 2,3-dihydroimidazo[1,2-c]quinazolines

Info

Publication number: WO2021260443A1
Application number: PCT/IB2021/000634
Authority: WO
Inventors: Ningshu Liu; Hong Wu; Zhi QI; Andreas Janzer
Original assignee: Bayer Aktiengesellschaft
Priority date: 2020-06-24
Filing date: 2021-06-17
Publication date: 2021-12-30

Abstract

The present invention relates to : * combinations of : component A : arylaminoalcohol‐substituted 2,3‐dihydroimidazo[1,2‐ c]quinolines of general formula (I) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; component B, which is: ▪ component B1 : anti-Programmed Cell Death Protein 1 (also referred to as „PD‐1" or „CD279" (cluster of differentiation 279)) antibody (anti-PD-1 mAb); or ▪ component B2: anti-Programmed death-ligand 1 (also referred to as "PD-L1", also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1)); or ▪ component B3: anti-Programmed death-ligand 2 (also referred to as "PD-L2", also known as cluster of differentiation 273 (CD273) or B7-DC homolog 1 (B7-H1)); and, optionally, component C : one or more further pharmaceutical agents; in which optionally some or all of the components are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially; independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route; * use of such combinations for the preparation of a medicament for the treatment or prophylaxis of a cancer; and * a kit comprising such a combination.

Description

COMBINATIONS OF 2,3-DIHYDROIMIDAZO[l,2-c]QUINAZOLINES

The present invention relates to combinations of :

• component A : one or more arylaminoalcohol-substituted 2,3- dihydroimidazo[l,2-c]quinolines, (hereinafter referred to as "compounds of general formula (I)") as described and defined hereinarylaminoalcohol- substituted 2,3-dihydroimidazo[l,2-c]quinolines of general formula (I), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; and

• component B, which is: o component B1 : anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti-PD-1 mAb) ; or o component B2: anti-Programmed death-ligand 1 (also referred to as "PD- VI" , also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1)); or o component B3: anti-Programmed death-ligand 2 (also referred to as "PD- L2", also known as cluster of differentiation 273 (CD273) or B7-DC homolog 1 (B7-H1)); and, optionally,

• component C : one or more further pharmaceutical agents ; in which optionally either or both of components A and B in any of the above- mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. Another aspect of the present invention relates to the use of such combinations as described supra for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly cancers with altered activation of PI3K pathway and/or particular PI3K isoform(s) induced modulation of immune response, which not only provide survival signaling to tumor cells but also cause impaired anti-tumor immunity and/or the resistance to the cancer immune therapies. The applicable cancer indications are, but not limited to, colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia, etc.

In a further aspect, the present invention relates to a kit comprising a combination of :

• component B, which is: o component B1 : anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti-PD-1 mAb) ; or o component B2: anti-Programmed death-ligand 1 (also referred to as "PD- VI" , also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1)); or o component B3: anti-Programmed death-ligand 2 (also referred to as "PD- L2", also known as cluster of differentiation 273 (CD273) or B7-DC homolog 1 (B7-H1)); and, optionally, · component C : one or more further pharmaceutical agents ; in which optionally either or both of said components A) and B) in any of the above- mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.

BACKGROUND OF THE INVENTION Combination of PI3K Inhibitors and anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibodies (anti-PD-1 mAb), or anti-PD-Ll/L2 antibodies :

Cancer is the second most prevalent cause of death in the United States, causing 450,000 deaths per year. While substantial progress has been made in identifying some of the likely environmental and hereditary causes of cancer, there is a need for additional therapeutic modalities that target cancer and related diseases. In particular there is a need for therapeutic methods for treating diseases associated with dysregulated growth / proliferation. Cancer is a complex disease arising after a selection process for cells with acquired functional capabilities like enhanced survival / resistance towards apoptosis and a limitless proliferative potential. Thus, it is preferred to develop drugs for cancer therapy addressing distinct features of established tumors. The PI3K signaling pathway is one of the prominent pathways that promote tumor cell survival. PI3K is activated by many cancer related receptor tyrosine kinases (e.g. VEGFR, PDGFR, EGFR, HER2/3, or IGF-1R), cell adhesion molecules, GPCR, and oncogenic proteins (such as Ras). The PI3K pathway activation by genetic alteration of PI3K (activation mutation and/or amplification) and/or loss-of-function of the tumour suppressor PTEN are frequently found in many tumors. Furthermore, activation of PI3K is one of the major mechanisms causing the resistance of tumors to radio-, chemo- and targeted therapeutics. Once PI3K is activated, it catalyzes the generation of PIP3 from PIP2. The biological active PIP3 binds to the pleckstrin homology (PH) domains of PDK-1, AKT, and other PH- domain containing proteins, such as Rho and PLC. As the consequence of binding to PIP3, these proteins are translocated to the cell membrane and are subsequently activated to induce tumor cell proliferation, survival, invation and migration.

In addition to the roles in tumor cells, PI3K also regulate the activity of the tumor stroma cells (cells that form part of the tumor mass but are not malignantly transformed). The stroma cells include (a) the vasculature, (b) infiltrating immune cells, (c) fibroblasts and (d) other connective tissue. Recent data indicate that the four class I PI3K isoforms have both redoundant and distinct roles in regulating the PI3K signalling in each of these stromal elements. The complexity and/or difficulty in predicting the final outcomes of PI3K inhibitors have been realized, particularly with regard to different isoform profiles and/or other technical properties of PI3K inhibitors. One of the major issues in clinical development of PI3K inhibitors in solid tumors is the difficulty to achieve sufficient therapeutic windows. The challenges are the off tumor toxicities observed with pan-PI3K inhibitors and lack of sustained efficacy with isoform selective inhibitors due to redundant and/or rebound activation of the pathway. New approaches are needed to tackle these issues. Programmed cell death protein 1, also known as PD-1 and CD279 (cluster of differentiation 279), is a protein that in humans is encoded by the PDCD1 gene [see: Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T (Oct 1994). "Structure and chromosomal localization of the human PD-1 gene (PDCD1)". Genomics 23 (S): 704-6. doi:10.1006/geno.1994.1562. PMID 7851902]; [see also: "Entrez Gene: PDCD1 programmed cell death 1"].

PD-1 is a cell surface receptor that belongs to the immunoglobulin superfamily and is expressed on T cells pro-B cells, macrophages [see: Entrez Gene: PDCD1 programmed cell death 1"]. PD-1 binds two ligands, PD-L1 and PD-L2. PD-1, functioning as an immune checkpoint, plays an important role in down regulating the immune system by preventing the activation of T-cells, which in turn reduces immunity and promotes tolerance. The inhibitory effect of PD-1 is accomplished through a dual mechanism of promoting apoptosis (programmed cell death) in antigen specific T-cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (suppressor T cells) [see: Francisco LM, Sage PT, Sharpe AH (Jul 2010). "The PD-1 pathway in tolerance and immunity". Immunological Reviews 236: 219-42. doi:10.1111/j 1600-

065X.2010.00923.x. PMC 2919275. PMID 20636820]; [see also: Fife BT, Pauken KE (Jan 2011). "The role of the PD-1 pathway in autoimmunity and peripheral tolerance". Annals of the New York Academy of Sciences 1217: 45-59. doi:10.1111/j 1749- 6632.2010.05919.x. PMID 21276005] Base on these rationale, recently, a new class of drugs that block PD-1, the PD-1 inhibitors, activate the immune system to attack tumors and are successfully developed for the treatment of some types of cancer [see: Weber J (Oct 2010). "Safety, activity, and immune correlates of anti-PD-1 antibody in cancer". The New England Journal of Medicine 366 (26): 2443-54] Treatment of patients with melanoma, lung cancer or bladder cancer induced objective responses(l-3). However, the majority of patients still fail to respond to T cell-mediated immunotherapy and cancer cure rate of anti-PD-1 mAb is still limited. Therefore there is need to understand the molecular mechanisms of intrinsic and acquired resistance and identify new therapies to overcome the resistance and/or increase the cure rate of anti-PD-1 mAb. In addition to aberrant activation in cancer cells, the PI3K pathway plays both positive and negative roles in immune response. Therefore, the overall outcome of PI3K inhibition on anti-tumor immunity and the combination strategy with aPD-1 and other immune checkpoint inhibitors (ICIs) are difficult to predict and should be carefully investigated.

In this invention, the effects of dosing schedules on the overall anti-tumor activity were evaluated systematically in the context of both direct anti-tumor activity and indirect regulation of anti-tumor immunity in various immune competent mouse tumor models. Different from conventional thought that constent inhibition of the oncogenic PI3K signaling pathway is required to achieve the best anti-tumor efficacy, suppressingly, we found that intermittent dosing of pan-PIBK inhibitor Cpd A achieved better antitumor efficacy even at lower total doses compared to the continuous treatment schedules. We found that the superior anti-tumor efficacy with intermittent treatment of Cpd A was due to differential immune modulation effects. Thus, continuous treatment of Cpd A led to overall suppression of CD4+ and CD8+ T cells in both tumors and normal lymphoid organs (spleen and bone marraw), which resulted in negative impact on anti tumor immunity. Unexpectedly, intermittent treatment of Cpd A merely had effects on CD8+ and CD4+ T cells in spleen and bone marrow, but preferentially inhibited immune suppressive Treg and meanwhile enhanced CD8+ T cells infiltration, proliferation and activation in tumor microenvironment (TME). As such, intermittent treatment of Cpd A lead to favorable immune modulation by converting immune suppressive TME into immune stimulating TME.

Tumors with PTEN-loss and/or PI3K pathway activation have been shown to associate with immune excluded phenotype and resistance to immune checkpoint inhibitors (ICIs, e.g. anti-PD-1 antibodies). It is of high interest to identify drugs that can break the physical barriers between immune and tumor cells in PTEN-loss tumors. We selected a genetic engineered PTEN-loss prostate tumor model and investigated if Cpd A can turn immune excluded phenotype into immne inflamed phenotype and therefore sensitize tumors to ICI treatment. Strikingly, Cpd A dosed intermittently not only resulted in stimulating CD8 T cell infiltration into tumors, but also enhanced CD8 T cell clonal expansion and activation and meanwhile suppressed Treg survival in prostate tumors. The treatment outcome in immune excluded tumor models is very similar to what observed in inflamed tumors with immune suppressive TME.

In light with favorable enhancement of anti-tumor immunity by intermittent treatment of Cpd A, we investigated combination effects of Cpd A and with anti-PD-1 antibody Cpd B in ICI-insensitive immune inflamed tumors as well as PTEN-loss, ICI-resistant immune excluded tumors. In both insensitive and resistant tumors, we found that intermittent treatment cpd A produced better anti-tumor efficacy, increased intratumoral CD8+ T cell vs Treg (regulatory T cell) ratio and generating long term anti-immunity via producing memory T cells. In addition, treatment of compound A with subsequent combination of Cpd B (interval could be from 1 day to 1 month or longer) could induced tumor regression compared to tumor progression observed with each monotherapy. Taken together, combination of intermittently dosed Cpd A with ICIs, e.g Cpd B, therefore is a promising strategy to overcome the therapeutic resistance induced by intratumoral oncogenic signaling and an immune suppressive tumor microenvironment, and to prevent tumor recurrence.

For detailed overviews of the PI3K signaling pathway, PI3K inhibitors, and ongoing clinical trials, we refer the reader to recent reviews (1-4, 7 ).

As described in the present invention, N-(8-{[(2R)-2-hydroxy-3-(morpholin-4- yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine- 3-carboxamide, (which displays a surprising balanced activity for the inhibition of phosphatidylinositol-3-kinase alpha- and beta- isoforms) and anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti-PD-1 mAb) as defined herein, were investigated as combination in inhibiting cancers with altered activation PI3K pathway and/or PI3K activation induced modulation of immune response, which not only provide survival signaling to tumor cells but also cause impaired anti-tumor immunity and the resistance to the cancer immune therapies. The applicable cancer indications are, but not limited to, colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia, etc. as single agent or in combination with immuno-checkpoint blockers and/or other targeted or chemo therapies.

Unexpectedly, and this represents a basis of the present invention, when combinations of: component A one or more arylaminoalcohol-substituted 2,3- dihydroimidazo[l,2-c]quinolines of general formula (I), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein; with component B : anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti-PD-1 mAb), as described and defined herein ; were evaluated for the treatment of (but not limited to) colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia, etc., synergistically increased anti-tumor activities were demonstrated with these combinations compared to each monotherapy, providing a fundamental rationale for the clinical combination therapy using PI3K inhibitors- anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antobody (anti-PD-1 mAb). To the Applicant's knowledge, no generic or specific disclosure or suggestion in the prior art is known that combinations of :

• component C : one or more further pharmaceutical agents ; in which optionally either or both of said components A and B of any of the above- mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially, would be effective in the treatment or prophylaxis of cancer, particularly (but not limited to) colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, endometrial cancer, pancreatic cancer, kidney cancer, lymphoma, leukemia, etc..

Based on the action of the testing compounds described in this invention, the combinations of the present invention as described and defined herein, show a beneficial effect in the treatment of cancer, particularly (but not limited to) colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, endometrial cancer, pancreatic cancer, kidney cancer, lymphoma, leukemia, etc..

Accordingly, in accordance with a first aspect, the present invention relates to combinations of: component A : one or more arylaminoalcohol-substituted 2,3-dihydroimidazo[l,2- c]quinoline compounds of general formula (I) :

(I) in which :

R¹ represents -(CH )n-(CHR⁴)-(CH )_m-N(R⁵)(R⁵') ; R² represents a heteroaryl of structure : optionally substituted with 1, 2 or 3 R⁶ groups, in which :

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

X represents N or C-R⁶,

X' represents O, S, NH, N-R⁶, N or C-R⁶, with the proviso that when X and X' are both C-R⁶, then one C-R⁶ is C-H ;

R³ is methyl ;

R⁴ is hydroxy ;

R⁵ and R^5' are the same or different and are, independently of each other, a hydrogen atom, or a Ci-C₆-alkyl, C₃-C₆-cycloalkyl-Ci-C₆-alkyl, or Ci-C₆-alkoxy-Ci-C₆-alkyl, or

R⁵ and R^5', taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R^6' groups ; each occurrence of R⁶ may be the same or different and is independently a hydrogen atom, a halogen atom, Ci-C₆-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6- cycloalkyl-Ci-C₆-alkyl, aryl, aryl-Ci-C₆-alkyl, heteroaryl, heteroaryl-Ci-C₆-alkyl, 3- to 8- membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-C₆-alkyl, -Ci-C₆-alkyl- OR⁷, -Ci-Ce-alkyl-SR⁷, -Ci-C₆-alkyl-N(R⁷)(R^7'), -Ci-C₆-alkyl-C(=0)R⁷,-CN, -C(=0)0R⁷, - C(=0)N(R⁷)(R⁷ ), -OR⁷, -SR⁷, -N(R⁷)(R⁷ ), or -NR⁷C(=0)R⁷ each of which may be optionally substituted with 1 or more R⁸ groups ; each occurrence of R^6' may be the same or different and is independently Ci-C₆-alkyl, C3-C6-cycloalkyl-Ci-C6-alkyl, or Ci-C₆-alkyl-OR⁷; each occurrence of R⁷ and R^7' may be the same or different and is independently a hydrogen atom, or a Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆- cycloalkyl-Ci-C₆-alklyl, C₃-C₆-cycloalkenyl, aryl, aryl-Ci-C₆-alkyl, heteroaryl, 3- to 8- membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-C₆-alkyl, or heteroaryl- Ci-C₆-alkyl ; each occurrence of R⁸ is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci-C₆-alkyl, Ci-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆- cycloalkyl, C₃-C₆-cycloalkyl-Ci-C₆-alkyl, Ci-C₆-cycloalkenyl, aryl, aryl-Ci-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-Ci-C₆-alkyl, or heteroaryl- Ci-C₆-alkyl ; n is an integer of 1 and m is an integer of 1 ; with the proviso that when :

- said R⁵ and R^5', taken together with the nitrogen atom to which they are bound, represent :

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

- said R² heteroaryl of structure :

is not : in which * represents the point of attachment with the rest of the structure of general formula (I). or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially ; component B, which is:

• component Bl: anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti-PD-1 mAb); or

• component B2: anti-Programmed death-ligand 1 (also referred to as "PD-L1", also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1)); or

• component B3: anti-Programmed death-ligand 2 (also referred to as "PD-L2", also known as cluster of differentiation 273 (CD273) or B7-DC homolog 1 (B7-H1)); and, optionally, component C : one or more further pharmaceutical agents. In an embodiment of the first aspect, the present invention relates to combinations wherein : said component A is an arylaminoalcohol-substituted 2,3-dihydroimidazo[l,2- c]quinoline compound of general formula (I) according to claim 1, wherein R¹ represents -(CH )n-(CHR⁴)-(CH )_m-N(R⁵)(R⁵') ;

R² represents a heteroaryl of structure :

in which :

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

R³ is methyl ;

R⁴ is hydroxy ;

R⁵ and R^5' are the same or different and are, independently of each other, a hydrogen atom, or a Ci-C₆-alkyl, C3-C6-cycloalkyl-Ci-C6-alkyl, or Ci-C₆-alkoxy-Ci-C₆-alkyl, or

R⁵ and R^5', taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R^6' groups ; each occurrence of R⁶ may be the same or different and is independently a hydrogen atom, a halogen atom, Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C3-C6-cycloalkyl, C3-C6- cycloalkyl-Ci-C₆-alkyl, aryl, aryl-Ci-C₆-alkyl, heteroaryl, heteroaryl-Ci-C₆-alkyl, 3- to 8- membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-C₆-alkyl, -Ci-C₆-alkyl- OR⁷, -Ci-Ce-alkyl-SR⁷, -Ci-C₆-alkyl-N(R⁷)(R^7'), -Ci-C₆-alkyl-C(=0)R⁷,-CN, -C(=0)0R⁷, - C(=0)N(R⁷)(R⁷ ), -OR⁷, -SR⁷, -N(R⁷)(R⁷ ), or -NR⁷C(=0)R⁷ each of which may be optionally substituted with 1 or more R⁸ groups ; each occurrence of R^6' may be the same or different and is independently Ci-C₆-alkyl, C₃-C₆-cycloalkyl-Ci-C₆-alkyl, or Ci-C₆-alkyl-OR⁷; each occurrence of R⁷ and R^7' may be the same or different and is independently a hydrogen atom, or a Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆- cycloalkyl-Ci-C₆-alkyl, C₃-C₆-cycloalkenyl, aryl, aryl-Ci-C₆-alkyl, heteroaryl, S- to 8- membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-C₆-alkyl, or heteroaryl- Ci-C₆-alkyl ; each occurrence of R⁸ is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci-C₆-alkyl, Ci-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆- cycloalkyl, C₃-C₆-cycloalkyl-Ci-C₆-alkyl, Ci-C₆-cycloalkenyl, aryl, aryl-Ci-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-Ci-C₆-alkyl, or heteroaryl- Ci-C₆-alkyl ; n is an integer of 1 and m is an integer of 1 ; with the proviso that when :

- said R² heteroaryl of structure : is not :

in which * represents the point of attachment with the rest of the structure of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.

In an embodiment of the first aspect, the present invention relates to combinations wherein : said component A is one or more arylaminoalcohol-substituted 2,3-dihydroimidazo[l,2- c]quinoline compounds of general formula (I) according to claim 1, which is selected from the list consisting of specific compound Examples 1 to 41 on pp. 66 to 91106, of International patent application PCT/EP2011/069637, published as WO 2012/062748 A1 on May 18, 2012; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.

In an embodiment of the first aspect, the present invention relates to combinations wherein : said component A is one or more arylaminoalcohol-substituted 2,3-dihydroimidazo[l,2- c]quinoline compounds of general formula (I) according to claim 1, which is selected from the list consisting of :

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

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

N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7-methoxy-

2,3-dihydroimidazo[l,2-c]quinazolin-5-yl]pyridine-3-carboxamide

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

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

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

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

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

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

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

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

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

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

2.3-dihydroimidazo[l,2-c]quinazolin-5-yl]-2-methylpyridine-3-carboxamide N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-l-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide N-(8-{[(2R)-2-hydroxy-3-(piperidin-l-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[l,2- c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide 6-amino-N-{8-[2-hydroxy-3-(morpholin-4-yl)propoxy]-7-methoxy-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl}pyridine-3-carboxamide 6-amino-N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-l-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide 2-amino-N-{8-[2-hydroxy-3-(morpholin-4-yl)propoxy]-7-methoxy-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide 2-amino-N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7- methoxy-2,3-dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide 2-amino-N-(8-{[(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)propyl]oxy}-7- methoxy-2,3-dihydroimidazo[l,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide dihydrochloride

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

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

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

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

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

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

N-(8-{[(2R)-2-Hydroxy-3-(pyrrolidin-l-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl)-4-methyl-l,3-thiazole-5-carboxamide

2-amino-N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl)-4-methyl-l,3-thiazole-5-carboxamide

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

N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl)-l,3-thiazole-5-carboxamide, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. In an embodiment of the first aspect, the present invention relates to combinations wherein : said component B is component Bl, which is anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti- PD-1 mAb) ; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. In an embodiment of the first aspect, the present invention relates to combinations wherein : said component B is component B2, which is anti-Programmed death-ligand 1 (also referred to as "PD-L1", also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1)); optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.

In an embodiment of the first aspect, the present invention relates to combinations wherein : said component B is component B3, which is anti-Programmed death-ligand 2 (also referred to as "PD-L2", also known as cluster of differentiation 273 (CD273) or B7-DC homolog 1 (B7-H1)); optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.

In an embodiment of the first aspect, the present invention relates to combinations wherein : said component A is N-(8-{[(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy}-7- methoxy-2,3-dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide.

In an embodiment, the present invention relates to combinations of a component A and a component B, wherein: said component A is N-(8-{[(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-

2,3-dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially ; and wherein: said component B is component Bl, which is anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti- PD-1 mAb); optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.

2,3-dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially ; and wherein: said component B is component B2, which is anti-Programmed death-ligand 1 (also referred to as "PD-L1", also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1)); optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. In an embodiment, the present invention relates to combinations of a component A and a component B, wherein: said component A is N-(8-{[(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy- 2,3-dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially ; and wherein: said component B is component B3, which is anti-Programmed death-ligand 2 (also referred to as "PD-L2", also known as cluster of differentiation 273 (CD273) or B7-DC homolog 1 (B7-H1)); optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.

In an embodiment, the present invention relates to combinations of a component A and a component B, wherein: said component A is N-(8-{[(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy- 2,3-dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide, and wherein: said component B is component Bl, which is anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti- PD-1 mAb).

In an embodiment, the present invention relates to combinations of a component A and a component B, wherein: said component A is N-(8-{[(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy- 2,3-dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide, and wherein: said component B is component B2, which is anti-Programmed death-ligand 1 (also referred to as "PD-L1", also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1)).

In an embodiment, the present invention relates to combinations of a component A and a component B, wherein: said component A is N-(8-{[(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy- 2,3-dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide, and wherein: said component B is component B3, which is anti-Programmed death-ligand 2 (also referred to as "PD-L2", also known as cluster of differentiation 273 (CD273) or B7-DC homolog 1 (B7-H1)).

In an embodiment, the present inventon relates to combinations, wherein said anti- Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti-PD-1 mAb) is pembrolizumab, nivolumab, pidilizumab, tislelizumab, cemiplimab, camrelizumab, sintilimab, or toripalimab.

In an embodiment, the present inventon relates to combinations, wherein said anti- Programmed death-ligand 1 (also referred to as "PD-L1", also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1)), is atezolizumab, durvalumab, avelumab, or any other anti-PD-Ll, in particular atezolizumab.

In an embodiment, the present inventon relates to combinations, wherein said anti- Programmed death-ligand 2 (also referred to as "PD-L2", also known as cluster of differentiation 273 (CD273) or B7-DC homolog 1 (B7-H1)), is CD273 (PD-L2) Monoclonal antibody.

In an embodiment, the present inventon relates to combinations, wherein: said anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti-PD-1 mAb) is pembrolizumab.

In an embodiment, the present inventon relates to combinations, wherein said anti- Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti-PD-1 mAb) is nivolumab.

In an embodiment, the present inventon relates to combinations, wherein: said component A is 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide, and wherein: said anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti-PD-1 mAb) is pembrolizumab.

In an embodiment, the present inventon relates to combinations, wherein: said component A is 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide, and wherein: said anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti-PD-1 mAb) is nivolumab.

In an embodiment, the present inventon relates to combinations, wherein: said anti-Programmed death-ligand 1 (also referred to as "PD-L1", also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1)), is atezolizumab.

In an embodiment, the present inventon relates to combinations, wherein: said component A is 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide, and wherein: said anti-Programmed death-ligand 1 (also referred to as "PD-L1", also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1)), is atezolizumab.

In an embodiment, the present inventon relates to combinations, wherein: said anti-Programmed death-ligand 2 (also referred to as "PD-L2", also known as cluster of differentiation 273 (CD273) or B7-DC homolog 1 (B7-H1)), is CD273 (PD-L2) Monoclonal antibody. In an embodiment, the present inventon relates to combinations, wherein: said component A is 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide, and wherein: said anti-Programmed death-ligand 2 (also referred to as "PD-L2", also known as cluster of differentiation 273 (CD273) or B7-DC homolog 1 (B7-H1)), is CD273 (PD-L2) Monoclonal antibody.

In a further aspect, the present invention relates to combinations as described and defined herein for use in the treatment or prophylaxis of a cancer, particularly colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia.

In a further aspect, the present invention relates to the use of combinations as described and defined herein in the treatment or prophylaxis of a cancer, particularly colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia.

In a further aspect, the present invention relates to the use of combinations as described and defined herein for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia.

In an embodiment, the present invention relates to the use of combinations as described and defined herein, wherein said cancer is colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia.

In an embodiment, the present invention relates to combinations as described and defined herein, wherein said cancer is colorectal cancer, particularly immune- checkpoint blockers insensitive or resistant colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia.

In an embodiment, the present invention relates to a method of treatment or prophylaxis of a cancer, particularly lung cancer, in particular colorectal cancer, particularly immune-checkpoint blockers insensitive or resistant colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia, etc., in subject, comprising administering to said subject a therapeutically effective amount of a combination as described and defined herein.

In a further aspect, the preent invnetion relates to kits comprising a combination as described and defined herein, in which optionally both or either of said components A) and B) are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. In some embodiments, the asymmetric carbon to which R⁴ is bonded has the (/?)- configuration in the compound of formula (I), as described herein. In other embodiments, the asymmetric carbon to which R⁴ is bonded has the (Sj-configuration in the compound of formula (I), as described herein.

In other embodiment, component A is selected from the group of PI3K inhibitors consisting of buparlisib, idelalisib, BYL-719, dactolisib, PF-05212384, pictilisib, copanlisib, copanlisib dihydrochloride, ZSTK-474, GSK-2636771, duvelisib, GS-9820, PF- 04691502, SAR-245408, SAR-245409, sonolisib, Archexin, GDC-0032, GDC-0980, apitolisib, pilaralisib, DLBS 1425, PX-866, voxtalisib, AZD-8186, BGT-226, DS-7423, GDC- 0084, GSK-2126458, INK-1117, SAR-260301, SF-1126, AMG-319, BAY-1082439, CH- 5132799, GSK-2269557, P-7170, PWT-33597, CAL-263, RG-7603, LY-3023414, RP-5264, RV-1729, taselisib, TGR-1202, GSK-418, INCB-040093, Panulisib, GSK-1059615, CNX-

1351, AMG-511, PQR-309, 17beta-Hydroxywortmannin, AEZS-129, AEZS-136, HM- 5016699, I PI-443, ONC-201, PF-4989216, RP-6503, SF-2626, X-339, XL-499, PQR-401, AEZS-132, CZC-24832, KAR-4141, PQR-311, PQR-316, RP-5090, VS-5584, X-480, AEZS- 126, AS-604850, BAG-956, CAL-130, CZC-24758, ETP-46321, ETP-47187, GNE-317, GS- 548202, HM-032, KAR-1139, LY-294002, PF-04979064, PI-620, PKI-402, PWT-143, RP-

6530,

3-HOI-BA-01, AEZS-134, AS-041164, AS-252424, AS-605240, AS-605858, AS-606839, BCCA-621C, CAY-10505, CH-5033855, CH-5108134, CUDC-908, CZC-19945, D-106669, D- 87503, DPT-NX7, ETP-46444, ETP-46992, GE-21, GNE-123, GNE-151, GNE-293, GNE-380, GNE-390, GNE-477, GNE-490, GNE-493, GNE-614, HMPL-518, HS-104, HS-106, HS-116,

HS-173, HS-196, IC-486068, INK-055, KAR 1141, KY-12420, Wortmannin, Lin-05, NPT- 520-34, PF-04691503, PF-06465603, PGNX-01, PGNX-02, PI 620, PI-103, PI-509, PI-516, PI-540, PIK-75, PWT-458, RO-2492, RP-5152, RP-5237, SB-2015, SB-2312, SB-2343, SHBM-1009, SN 32976, SR-13179, SRX-2523, SRX-2558, SRX-2626, SRX-3636, SRX-5000, TGR-5237, TGX-221, UCB-5857, WAY-266175, WAY-266176, El-201, AEZS-131, AQX- MN100, KCC-TGX, OXY-111A, PI-708, PX-2000, WJD-008.

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

The PI3K-inhibitors mentioned in the prior art as well as in the lists above have been disclosed for the treatment or prophylaxis of different diseases, especially cancer

The specific compounds of the lists as disclosed above are preferred as being component A of the combination, most preferred is the compound used in the experimental section. The synergistic behavior of a combination of the present invention is demonstrated herein with one of the PI3K inhibitors specifically disclosed in the Examples section, as Example 14, of WO 2012/062748, referrred to as compound A (or as cpd. A) below.

Said component A may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. The definitions used in relation to the structure (I) in this text are as follows :

The term "halogen atom" or "halo" is to be understood as meaning a fluorine, chlorine, bromine or iodine atom. The term "Ci-C₆-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso pentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3- dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1, 2 or 3 carbon atoms ("Ci-C3-alkyl"), methyl, ethyl, n- propyl- or iso-propyl.

The term "Ci-C₆-alkoxy" is to be understood as preferably meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl, in which the term "alkyl" is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso- butoxy, tert-butoxy, sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomer thereof.

The term "Ci-C₆-alkoxy-Ci-C₆-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a Ci-C₆-alkoxy group, as defined supra, e.g. methoxyalkyl, ethoxyalkyl, propyloxyalkyl, iso-propoxyalkyl, butoxyalkyl, iso-butoxyalkyl, tert-butoxyalkyl, sec-butoxyalkyl, pentyloxyalkyl, iso- pentyloxyalkyl, hexyloxyalkyl group, in which the term "Ci-C₆-alkyl" is defined supra, or an isomer thereof.

The term "C2-C6-alkenyl" is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3- alkenyl"), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other. Said alkenyl group is, for example, a vinyl, allyl, (E)-2-methylvinyl, (Z)- 2-methylvinyl, homoallyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-l-enyl, (Z)-but-l-enyl, pent-4-enyl, (E)-pent-B-enyl, (Z)-pent-B-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-

1-enyl, (Z)-pent-l-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)- hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-l-enyl, (Z)-hex-l-enyl, isopropenyl, 2- methylprop-2-enyl, l-methylprop-2-enyl, 2-methylprop-l-enyl, (E)-l-methylprop-l- enyl, (Z)-l-methylprop-l-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, l-methylbut-3- enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-l- methylbut-2-enyl, (Z)-l-methylbut-2-enyl, (E)-3-methylbut-l-enyl, (Z)-3-methylbut-l- enyl, (E)-2-methylbut-l-enyl, (Z)-2-methylbut-l-enyl, (E)-l-methylbut-l-enyl, (Z)-l- methylbut-l-enyl, l,l-dimethylprop-2-enyl, 1-ethylprop-l-enyl, 1-propylvinyl, 1- isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1- methylpent-4-enyl, 4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z)-3-methylpent-3- enyl, (E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl, (E)-l-methylpent-3-enyl, (Z)-l- methylpent-3-enyl, (E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl, (E)-3-methylpent-

2-enyl, (Z)-3-methylpent-2-enyl, (E)-2-methylpent-2-enyl, (Z)-2-methylpent-2-enyl, (E)- l-methylpent-2-enyl, (Z)-l-methylpent-2-enyl, (E)-4-methylpent-l-enyl, (Z)-4- methylpent-l-enyl, (E)-3-methylpent-l-enyl, (Z)-3-methylpent-l-enyl, (E)-2-methylpent- 1-enyl, (Z)-2-methylpent-l-enyl, (E)-l-methylpent-l-enyl, (Z)-l-methylpent-l-enyl, 3- ethylbut-3-enyl, 2-ethylbut-3-enyl, l-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl, (Z)-3- ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl, (E)-l-ethylbut-2-enyl, (Z)-l- ethylbut-2-enyl, (E)-3-ethylbut-l-enyl, (Z)-3-ethylbut-l-enyl, 2-ethylbut-l-enyl, (E)-l- ethylbut-l-enyl, (Z)-l-ethylbut-l-enyl, 2-propylprop-2-enyl, l-propylprop-2-enyl, 2- isopropylprop-2-enyl, l-isopropylprop-2-enyl, (E)-2-propylprop-l-enyl, (Z)-2- propylprop-l-enyl, (E)-l-propylprop-l-enyl, (Z)-l-propylprop-l-enyl, (E)-2- isopropylprop-l-enyl, (Z)-2-isopropylprop-l-enyl, (E)-l-isopropylprop-l-enyl, (Z)-l- isopropylprop-l-enyl, (E)-3,3-dimethylprop-l-enyl, (Z)-3,3-dimethylprop-l-enyl, 1-(1,1- dimethylethyl)ethenyl, buta-l,3-dienyl, penta-l,4-dienyl, hexa-l,5-dienyl, or methylhexadienyl group. Particularly, said group is vinyl or allyl. The term "C2-C6-alkynyl" is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2- C3-alkynyl"). Said C2-C6-alkynyl group is, for example, ethynyl, prop-l-ynyl, prop-2-ynyl, but-l-ynyl, but-2-ynyl, but-3-ynyl, pent-l-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-l-ynyl, hex-2-inyl, hex-3-inyl, hex-4-ynyl, hex-5-ynyl, l-methylprop-2-ynyl, 2- methylbut-3-ynyl, l-methylbut-3-ynyl, l-methylbut-2-ynyl, 3-methylbut-l-ynyl, 1- ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, l-methylpent-4-ynyl, 2- methylpent-3-ynyl, l-methylpent-3-ynyl, 4-methylpent-2-ynyl, l-methylpent-2-ynyl, 4- methylpent-l-ynyl, 3-methylpent-l-ynyl, 2-ethylbut-3-ynyl, l-ethylbut-3-ynyl, 1- ethylbut-2-ynyl, l-propylprop-2-ynyl, l-isopropylprop-2-ynyl, 2,2-dimethylbut-3-inyl, l,l-dimethylbut-3-ynyl, l,l-dimethylbut-2-ynyl, or 3,3-dimethylbut-l-ynyl group. Particularly, said alkynyl group is ethynyl, prop-l-ynyl, or prop-2-inyl.

The term "C3-C6-cycloalkyl" is to be understood as preferably meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5, or 6 carbon atoms. Said C3-C6-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, or a bicyclic hydrocarbon ring, e.g. a perhydropentalenylene or decalin ring. Said cycloalkyl ring can optionally contain one or more double bonds e.g. cycloalkenyl, such as a cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group, wherein the bond between said ring with the rest of the molecule may be to any carbon atom of said ring, be it saturated or unsaturated. The term "alkylene" is understood as preferably meaning an optionally substituted hydrocarbon chain (or "tether") having 1, 2, 3, 4, 5, or 6 carbon atoms, i.e. an optionally substituted -CH2- ("methylene" or "single membered tether" or, for example -C(Me)2-), -CH2-CH2- ("ethylene", "dimethylene", or "two-membered tether"), -CH2-CH2-CH2- ("propylene", "trimethylene", or "three-membered tether"), -CH2-CH2-CH2-CH2- ("butylene", "tetramethylene", or "four-membered tether"), -CH2-CH2-CH2-CH2-CH2- ("pentylene", "pentamethylene" or "five-membered ether"), or -CH2-CH2-CH2-CH2-CH2- CH2- ("hexylene", "hexamethylene", or six-membered tether") group. Particularly, said alkylene tether has 1, 2, 3, 4, or 5 carbon atoms, more particularly 1 or 2 carbon atoms.

The term "3- to 8-membered heterocycloalkyl", is to be understood as meaning a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 2, 3, 4, 5, 6 or 7 carbon atoms, and one or more heteroatom-containing groups selected from C(=0), O, S, S(=0), S(=0)₂, NRa, in which R^a represents a hydrogen atom, or a Ci-C₆-alkyl- or halo-Ci-C₆-alkyl- group ; it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, the nitrogen atom.

Particularly, said 3- to 8-membered heterocycloalkyl can contain 2, 3, 4, 5, 6 or 7 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "3- to 8-membered heterocycloalkyl"), more particularly said heterocycloalkyl can contain 4 or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "5- to 7-membered heterocycloalkyl").

Particularly, without being limited thereto, said heterocycloalkyl can be a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or a 7-membered ring, such as a diazepanyl ring, for example. Optionally, said heterocycloalkyl can be benzo fused. Said heterocyclyl can be bicyclic, such as, without being limited thereto, a 5,5- membered ring, e.g. a hexahydrocyclopenta[c]pyrrol-2(lH)-yl) ring, or a 5, 6-membered bicyclic ring, e.g. a hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl ring, or 8-oxa-3- azabicyclo[3.2.1]oct-3-yl ring, for example. As mentioned supra, said nitrogen atom-containing ring can be partially unsaturated, i.e. it can contain one or more double bonds, such as, without being limited thereto, a 2,5-dihydro-lH-pyrrolyl, 4H-[l,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[l,4]thiazinyl ring, for example, or, it may be benzo-fused, such as, without being limited thereto, a dihydroisoquinolinyl ring, for example.

The term "aryl" is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, mono-, or bi- or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (a "C6-Ci4-aryl" group), particularly a ring having 6 carbon atoms (a "C₆-aryl" group), e.g. a phenyl group; or a biphenyl group, or a ring having 9 carbon atoms (a "Cg-aryl" group), e.g. an indanyl or indenyl group, or a ring having 10 carbon atoms (a "Cio-aryl" group), e.g. a tetralinyl, dihydronaphthyl, or naphthyl group, or a ring having 13 carbon atoms, (a "Ci3-aryl" group), e.g. a fluorenyl group, or a ring having 14 carbon atoms, (a "Ci -aryl" group), e.g. an anthranyl group. A particular example of an aryl group is one of the following possible structures :

in which z represents O, S, NH or N(Ci-C₆-alkyl), and * indicates the point of attachment of said aryl group with the rest of the molecule.

The term "heteroaryl" is understood as preferably meaning a monovalent, monocyclic- , bicyclic- or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl" group), particularly 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur, and in addition in each case can be benzocondensed.

Particularly, said heteroaryl is of structure : optionally substituted with 1, 2 or 3 R⁶ groups, in which :

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

X represents N or C-R⁶,

X' represents O, S, NH, N-R⁶, N or C-R⁶,

- each occurrence of R⁶may be the same or different and is independently a hydrogen atom, a halogen atom, Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆- cycloalkyl-Ci-C₆-alkyl, aryl, aryl-Ci-C₆-alkyl, heteroaryl, heteroaryl-Ci-C₆-alkyl, 3- to 8- membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-C₆-alkyl, -Ci-C₆-alkyl- OR⁷, -Ci-Ce-alkyl-SR⁷, -Ci-C₆-alkyl-N(R⁷)(R^7'), -C C₆-alkyl-C(=0)R⁷,-CN, -C(=0)0R⁷, - C(=0)N(R⁷)(R⁷ ), -OR⁷, -SR⁷, -N(R⁷)(R⁷ ), or -NR⁷C(=0)R⁷ each of which may be optionally substituted with 1 or more R⁸ groups ; - each occurrence of R⁷ and R^7' may be the same or different and is independently a hydrogen atom, or a Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆- cycloalkyl-Ci-C₆-alklyl, C₃-C₆-cycloalkenyl, aryl, aryl-Ci-C₆-alkyl, heteroaryl, 3- to 8- membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-C₆-alkyl, or heteroaryl- Ci-C₆-alkyl ; - each occurrence of R⁸ is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci-C₆-alkyl, Ci-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆- cycloalkyl, C₃-C₆-cycloalkyl-Ci-C₆-alkyl, Ci-C₆-cycloalkenyl, aryl, aryl-Ci-C₆-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-Ci-C₆-alkyl, or heteroaryl- Ci-C₆-alkyl.

More particularly, said heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl etc., and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl, etc..

In general, and unless otherwise mentioned, the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof. Thus, for some illustrative non-restricting example, the term pyridinyl or pyridinylene includes pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene.

The term "Ci-Ce", as used throughout this text, e.g. in the context of the definition of "Ci-C₆-alkyl" or "Ci-C₆-alkoxy" is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term "Ci-Ce" is to be interpreted as any sub-range comprised therein, e.g. Ci-C₆, C₂-C₅, C₃-C , Ci-C₂, Ci-C₃, Ci-C₄, Ci-C5, Ci-C_{6 ;} particularly Ci-C₂, Ci-C₃, Ci-C₄, C1-C5, C1-C6 _; more particularly Ci-C₄; in the case of "Ci-C₆-haloalkyl" or "Ci-C₆-haloalkoxy" even more particularly Ci-C₂.

Similarly, as used herein, the term "C₂-Ce", as used throughout this text, e.g. in the context of the definitions of "C₂-C₆-alkenyl" and "C₂-C₆-alkynyl", is to be understood as meaning an alkenyl group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term "C₂- " is to be interpreted as any sub-range comprised therein, e.g. C₂-C₆, C₃-Cs, C₃-C₄, C₂- C₃, C₂-C , C₂-C_{5 ;} particularly C₂-C₃. Further, as used herein, the term "C3-C6", as used throughout this text, e.g. in the context of the definition of "C₃-C₆-cycloalkyl", is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of B to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term "C3-C6" is to be interpreted as any sub-range comprised therein, e.g. C3-C6, C4-C5 , C3-C5 , C3-C4, C4-C6, C5-C6 ; particularly C3- C6.

The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

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

Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system. As used herein, the term "one or more times", e.g. in the definition of the substituents of the compounds of the present invention (e.g. component A, B or C), is understood as meaning "one, two, three, four or five times, particularly one, two, three or four times, more particularly one, two or three times, even more particularly one or two times". Where the plural form of the word components, compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single component, compound, salt, polymorph, isomer, hydrate, solvate or the like. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

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

The compounds of this invention may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (/?)- and/or (Sj-configuration, resulting in racemic mixtures in the case of a single asymmetric center, and diastereomeric mixtures in the case of multiple asymmetric centers. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention. Preferred compounds are those, which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or 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.

Tautomers, sometimes referred to as proton-shift tautomers, are two or more compounds that are related by the migration of a hydrogen atom accompanied by the switch of one or more single bonds and one or more adjacent double bonds. The compounds of this invention may exist in one or more tautomeric forms. For example, a compound of Formula I may exist in tautomeric form la, tautomeric form lb, or tautomeric form lc, or may exist as a mixture of any of these forms. It is intended that all such tautomeric forms are included within the scope of the present invention. The present invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts, co-precipitates, metabolites, hydrates, solvates and prodrugs of all the compounds of examples. The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid. Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and chorine salts. Those skilled in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.

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

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

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

Constituents which are optionally substituted as stated herein, may be substi-tuted, unless otherwise noted, one or more times, independently from one another at any possible position. When any variable occurs more than one time in any constituent, each definition is independent.

The heteroarylic, or heterocyclic groups mentioned herein can be substituted by their given substituents or parent molecular groups, unless otherwise noted, at any possible position, such as e.g. at any substitutable ring carbon or ring nitrogen atom. Analogously it is being understood that it is possible for any heteroaryl or heterocyclyl group to be attached to the rest of the molecule via any suitable atom if chemically suitable. Unless otherwise noted, any heteroatom of a heteroarylic ring with unsatisfied valences mentioned herein is assumed to have the hydrogen atom(s) to satisfy the valences. Unless otherwise noted, rings containing quaternizable amino- or imino-type ring nitrogen atoms (-N=) may be preferably not quaternized on these amino- or imino- type ring nitrogen atoms by the mentioned substituents or parent molecular groups.

Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques already known in the art.

The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.

If in the context of the invention "embodiment" is mentioned it should be understood to include a plurality of possible combinations. In order to limit different types of isomers from each other reference is made to lUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium), C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷0, ¹⁸0, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁸F, ³⁶CI, ⁸²Br, ¹²³l, ¹²⁴l, ¹²⁹l and ¹³¹l, respectively. Certain isotopic variations of a compound of the invention, for example, those in which one or more radioactive isotopes such as ³H or ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.

The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example. The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.

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

Said component A may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.

Said component B may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.

In accordance with an embodiment, the present invention relates to a combination of any component A mentioned herein with any component B mentioned herein.

In a particular embodiment, the present invention relates to a combination of a component A with a component B, as mentioned in the Examples section herein.

Useful forms of components A and B of the combinations of the present invention

As mentioned supra, either or both of components A and B of any of the combinations of the present invention may be in a useful form, such as pharmaceutically acceptable salts, co-precipitates, metabolites, hydrates, solvates and prodrugs of all the compounds of examples. The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid. Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and chorine salts. Those skilled in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods. Representative salts of the compounds of this invention include the conventional non toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate.

Pharmaceutical formulations of components A and B of the combinations of the present invention

As mentioned supra, the components A or B may, independently from one another, be in the form of a pharmaceutical composition or formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.

Said compositions can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes combinations in which components A and B, independently of one another, are pharmaceutical formulations compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a said component. A pharmaceutically acceptable carrier is preferably a carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of component, and/or combination. A pharmaceutically effective amount of a combination is preferably that amount which produces a result or exerts an influence on the particular condition being treated. The combinations of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.

It is possible for the compounds according to the invention to have systemic and/or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent. For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms. For oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.

Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders. Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.

The compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia,

• fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel^®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos^®)),

• ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols),

• bases for suppositories (for example polyethylene glycols, cacao butter, hard fat),

• solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides, fatty oils, liquid polyethylene glycols, paraffins),

• surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette^®), sorbitan fatty acid esters (such as, for example, Span^®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween^®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor^®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic^®),

• buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine),

• isotonicity agents (for example glucose, sodium chloride),

• adsorbents (for example highly-disperse silicas),

• viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, CarbopoT); alginates, gelatine),

• disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab^®), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol^®)), · flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosif)),

• coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon^®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit^®)),

• capsule materials (for example gelatine, hydroxypropylmethylcellulose), • synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit^®), polyvinylpyrrolidones (such as, for example, Kollidon^®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),

• plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate),

• penetration enhancers,

• stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate),

• preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

• colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide),

• flavourings, sweeteners, flavour- and/or odour-masking agents.

The present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.

Method of treating cancer

Within the context of the present invention, the term "cancer" includes, but is not limited to, cancers of the breast, lung, brain, reproductive organs, digestive tract, urinary tract, liver, eye, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include multiple myeloma, lymphomas, sarcomas, and leukemias. Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.

Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.

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

Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.

Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma. Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.

Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

The present invention relates to a method for using the combinations of the present invention, in the treatment or prophylaxis of a cancer, particularly (but not limited to) colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia, etc.. Combinations can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis, in the treatment or prophylaxis of cancer, in particular (but not limited to) colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia, etc.. This method comprises administering to a mammal in need thereof, including a human, an amount of a combination of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc. which is effective for the treatment or prophylaxis of cancer, in particular (but not limited to) colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia, etc..

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

Based upon standard laboratory techniques known to evaluate compounds useful for the treatment or prophylaxis of cancer, in particular (but not limited to) colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia, etc., by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the combinations of this invention can readily be determined for treatment of the indication. The amount of the active ingredient to be administered in the treatment of the condition can vary widely according to such considerations as the particular combination and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be 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 ingredient, and can be administered one or more times per day or less than once a day.

The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The 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 combination employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a combination 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. Therapies using combinations of component A as described supra, component B as described supra, and component C: one or more further pharmaceutical agents.

The combinations of component A and component B of this invention can be administered as the sole pharmaceutical agent or in combination with one or more further pharmaceutical agents where the resulting combination of components A, B and C causes no unacceptable adverse effects. For example, the combinations of components A and B of this invention can be combined with component C, i.e. one or more further pharmaceutical agents, such as known anti-angiogenesis, anti-hyper- proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agents, and the like, as well as with admixtures and combinations thereof.

Component C, can be one or more pharmaceutical agents such as 1311-chTNT, abarelix, abemaciclib, abiraterone, acalabrutinib, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, alpharadin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, apalutamide, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, avelumab, axicabtagene ciloleucel, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, bosutinib, buserelin, brentuximab vedotin, brigatinib, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cemiplimab, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib , crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, durvalumab, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, enasidenib, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, inotuzumab ozogamicin, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, lutetium Lu 177 dotatate, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, midostaurin, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, mvasi, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neratinib, neridronic acid, netupitant/palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, niraparib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, ribociclib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, rucaparib, samarium (153Sm) lexidronam, sargramostim, sarilumab, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC- [Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tisagenlecleucel, tislelizumab, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin. Generally, the use of component C in combination with a combination of components A and B of the present invention will serve to:

(1) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone,

(2) provide for the administration of lesser amounts of the administered chemo therapeutic agents, (B) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies,

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

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

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

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

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

The following Examples describe the feasability of the present invention, but not restricting the invention to these Examples only. EXAMPLES

The following abbreviations are used in the Examples:

"Compound A" (or "cpd. A") means N-(8-{[(2R)-2-hydroxy-3-(morpholin-4- yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine- 3-carboxamide: it is published in international patent application PCT/EP2011/069637, published as WO 2012/062748 on May 18, 2012, (which is incorporated herein by reference in its entirety), as the compound of Example 14: : it may be synthesized according to the method given in said Example 14. N-(8-{[(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide is a compound of structure :

and is an example of component A as described and defined herein.

"Compound B" (or "cpd. B") means :

• compound B1 (or cpd. Bl), which is anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody blocking the interaction of PD-1 (said antibody being also referred as "anti-PD-1 mAb"). Said anti- Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti-PD-1 mAb) is anti-murine PD-1 antibody RMP-14 clone in the studies in mouse models and the corresponding anti-human PD-1 antibody is such as pembrolizumab, nivolumab, cemiplimab, camrelizumab, sintilimab, tislelizumab, toripalimab, etc. can be used for clinical studies in human. A anti-murine PD-1 antibody RMP-14 clone was used in this study: CD279 (PD-1) Monoclonal Antibody (clone RMP1-14) was obtained from Invivogen, bulk ordered, Reference Code mpdl-mabl5-10. One more source on anti-PD-1 used (the same clone, but different provider): Manufacturer: BioXcell; Clone No.: RMP1-14; Lot no.: 61461601.

The corresponding anti-human-PD-1 antibodies include but not limited to, pembrolizumab, nivolumab, cemiplimab, camrelizumab, sintilimab, tislelizumab, toripalimab, etc.; or

• compound B2 (or cpd. B2), which is a ligand of anti-Programmed Cell Death Protein 1 (said ligand being also referred to as "PD-L1") or "anti-mouse PD-1") ), such as atezolizumab, durvalumab, avelumab, or any other anti-PD-Ll, in particular atezolizumab; or

• compound B3 (or cpd. B3), which is a ligand of anti-Programmed Cell Death Protein 1 (said ligand being also referred to as "PD-L2") or "anti-mouse PD-2"), such as CD273 (PD-L2) Monoclonal antibody (TY25 BE0112) from BioXCell. Cat. #: BE0112; compound Bl, compound B2 and compound B3 being examples of component B as described and defined herein.

In re. compound Bl:

The anti-mouse PD-1 (CD279) was purchased from Bio X Cell, 10 Technology Dr., Suite 2B, West Lebanon, NH 03784-1671, U.S.A., as clone RMP1-14, Catalog#: BE0146. This mouse anti-PD-1 showed similar effects on blocking the interaction of PD-1 and PD- L1/L2, as well as functional consequence on immune system as what have been observed with antibodies or inhibitors blocking human PD-1 and its ligand PD-L1/L2 interaction, such as (but not limited to), nivolumab (Opdivo), Pembrolizumab (Keytruda, Merck) (DrugBank Accession Number = DB09037), Pidilizumab (CT-011) Medivation), Tislelizumab (BGB-A317, BeiGene and Celgene), MEDI4736, MPDL3280A, etc.

In re. pembrolizumab (Keytruda, Merck) (DrugBank Accession Number = DB09037):

US 8,354,509 (referred to as " '509"); US 8,900,587 (referred to as " '587"). The '509 and '587 patents cover pembrolizumab as a composition of matter.

EP 2,170,959 (referred to also as " '959"). EP 2,170,959 - UK, Germany, Spain, France, Italy. Keytruda (pembrolizumab) is indicated as monotherapy for the treatment of (1) advanced unresectable or metastatic melanoma and (2) locally advanced or metastatic non-small cell lung cancer in certain adults, and (3) relapsed or refractory classical Hodgkin lymphoma in certain adults. In July 2017, EMA's Committee for Medicinal Products for Human Use recommended approval for Keytruda for the treatment of certain patients with locally advanced or metastatic urothelial cancer. The '959 patent covers pembrolizumab as a composition of matter. In re. Nivolumab (Opdivo, Bristol-Myers Squibb) (DrugBank Accession Number = DB09035 (DB06132):

US 8,008,449 (referred to as " '449"). The '449 patent is the composition-of-matter patent for nivolumab. In re. anti-murine PD-1 antibody RMP-14 in the studies in mouse models: CD279 (PD-1) Monoclonal Antibody (clone RMP1-14) was obtained from Invivogen, bulk ordered, Reference Code mpdl-mabl5-10, or from BioXcell, Reference code BE0146. Experimental Methods

In vivo study

A20 B cell lymphoma model and CT26 colorectal cancer model were used in this invention. A20 and CT26 cells were maintained in vitro in cell cultural medium supplemented with serum (according to the instructions for each corresponding cell lines) at B7^C in an atmosphere of 5% C02 in air. The tumor cells were routinely subcultured twice weekly. The cells in an exponential growth phase were harvested and counted for tumor inoculation. To investigate anti-tumor efficacy and mechanisms of action in vivo, each mouse was inoculated subcutaneously at the right lower flank region with tumor cells (lxlO⁵- 2xl0⁶ depending on the cell lines) in 0.1 ml of PBS with or without metrigel for tumor development. Before commencement of treatment, all animals were weighed and the tumor sizes were measured using a caliper. Since the tumor size can affect the effectiveness of any given treatment, tumor size was used as numeric parameter to randomize selected animals into specified groups to minimize the systematic error. The randomization was performed using matched distribution method. The treatments were started when the mean tumor size reached a predefined volume.

Cpd A was formulated in 0.1 N HCL and orally administered. Control antibody 6.94 mg/ml rlgG2a and Cpd B were diluted with PBS to make 0.9 ml dosing solution for each use. For the tumor re-challenge study, mice with complete tumor remission from the previous treatment were re-challenged with A20 tumor cells after the tumors were completed regressed for > 4 weeks. Treatment naive mice were used as the control. The tumor cells were inoculated subcutaneously at the right upper flank region and tumor growth was followed for another 20 days after the re-challenge.

Generation of Pb-Cre⁺;Pten^L/L (C P) and Pb-Cre⁺;Pten^L/L;K-ras^G12D/w (C PK) prostate tumor mice was described in the previous publications²⁴'²⁵. Castration in CP mice was performed as described²⁴. Cpd A was administered either daily at a dose of 75mg/kg for 4 weeks, or intermittently at a dose of 180mg/kg with 2 days on/5 days off schedule for 4 weeks. Brdu was dissolved in PBS and dosed lOOmg/kg by i.p for 24h, Brdu positive rate was analyzed by Flow Cytometry (00-5525) using eBioscience™ Brdll Staining Buffer Set.

Sampling procedures: organ and tumor tissues were quickly removed and weighted 3h post the final dose for FACS, IHC (FFPE), and RNA/pretein expression analysis.

Histology and IHC Analysis

The following antibodies were used for IHC studies: CD8 (Cell Signaling Technology), Granzyme-b (Abeam), P-AKT (Cell Signaling Technology), Ki67 (Abeam). For immunofluorescence study, the following antibodies were used: CD8 (Cell Signaling Technology), TRITC anti-Rabbit IgG (ZSGB-BIO), Granzyme-b (ebioscience), FITC anti-rat IgG (abeam)

Tissue Dissociation, Single-cell Suspension and FACS analysis/sorting Tissues were minced in sterile tissue culture dishes and subjected to collagenase A (1 mg/ml; Roche) and DNase I (0.1 mg/ml; Roche) digestion for 1 h at 37°C with constant agitation. Undigested tissue was removed through pass a 70-miti filter, the total cell number was counted by cell counting chamber, the single-cell suspensions were firstly stained with Fixable Viability Stain 450 (BD) then stained with fluorescent-labeled antibody against CD45, CD3, CD8, CD4, CD25 (Biolegend). FOXP3 was stained by using eBioscience™ FOXP3 Staining Buffer Set. FACS analysis/sorting of each T cell population are then performed.

RNAseq analysis

For tissue RNAseq analysis, RNA from anterior lobe of prostate tumor was extracted by using RNAeasy mini kit (Qiagen 74106), the cDNA library was constructed by using NEBNext^® Poly(A) mRNA Magnetic Isolation Module (E7490) and NEBNext^® Ultra™ RNA Library Prep Kit for lllumina^® (E7530). For RNAseq analysis of tumor-associated immune cells, CD45+CD3+CD8+ or CD45+CD3+CD4+CD25+ T cell from single-cell suspension as sorted by FACS, RNA was extracted by using RNAeasy micro kit (Qiagen 74004). The cDNA library was constructed by SMART-SEQ 2 protocol(26). All RNA-seq data were aligned to the mmlO genome using Tophat (version v2.1.1) with the parameter --no- novel-juncs. Differentially expressed genes between samples were then identified by Cuffdiff (version v2.2.1)27. FPKM was used for following analysis and comparison. GSEA analysis was performed as software suggested. T cell clontype diversity analysis was performed by TRUST28.

Statistical Analysis: Summary statistics, including mean and the standard error of the mean (SEM), are provided for the tumor volume of each group at each time point. Statistical analysis of difference in tumor volume between the comparing groups was conducted using independent-samples T test. P-values were rounded to three decimal places, with the exception that raw P-values less than 0.001 were stated as P<0.001. All tests were two-sided. P<0.05 was considered to be statistically significant.

EXAMPLE 1: EFFECTS OF Cpd A DOSING SCHEDULE ON ANTI-TUMOR ACTIVITY AND IMMUNE MODULATION:

It has been thought that effective inhibition of tumor growth requires constant suppression of oncogenic signaling pathways, such as the PI3K pathway. So far, almost all the PISK inhibitors have been developed in clinic with oral continuous dosing regimens. This is largely because the anti-tumor activity of PISK inhibitors have been evaluated in xenograft tumor models in immune deficient mice. Considering the role of PI3K in regulation of various immune cells important for regulation of anti-tumor immunity, we firstly compared the anti-tumor efficacy of Cpd A dosed intermittently vs continuously in immune competent A20 syngeneic tumor model. Cpd A was dosed at 175, 125 and 75 mg/kg with intermittent schedule of 2 days on and 5 days off and at 50 mg/kg with continuous daily dosing schedule. The weekly total dose of continuous schedule (350 mg/kg) is equal to the high dose group (175 mg/kg) with intermittent schedule. Interestingly, tumor growth was inhibited more effectively by intermittent treatment of Cpd A with higher response rate (RR) in the 175 mg/kg group (30% and 50% RR on day 17 and day 30, respectively) than in the mice receiving 50 mg/kg daily dosing (only 10% RR on dayl7 and day 30, shown in Figure 1A). Intermittent treatment showed better efficacy even in the lower dose groups (125 mg/kg and 75 mg/kg equal to 71% and 43% of the total dose used in daily continuous treatment group, respectively). Similar results were also obtained in CT26 syngeneic model, where intermittent treatment led to better antitumor efficacy compared to daily continuous treatment with equal total dosage (Figure IB). These results promoted us to investigate if the better efficacy could be driven by better anti-tumor immune response with intermittent treatment of Cpd A. We measured TILs expressing interferon g (I FNy), an immue stimulatory cytokine secreted by activated innate and adaptive immune cells. Interestingly, significant increase in I FNy-i- TILs was observed ony in intermittent but not in continuous treatment group, indicating that Cpd A had differential effects on anti tumor immunity depending on the dosing schedule (Figure 1C).

Immune modulation by PI3K inhibition may have both acute and chronic effects on tumor and normal tissues. A prostate conditional knockout of Pten mouse model that closely mimics human prostate cancers wwa used to investigate long-term anti-tumor and immune modulation effects of Cpd A. CP mice developed prostate carcinoma at week 10 and were either received Cpd A daily at 75 mg/kg or at 180 mg/kg with 20n/50ff schedule. After 4 week treatment, intratumoral and spleno CD8+ and CD4+ T cells were analyzed by FACS and IHC. Strikingly, daily Cpd A treatment reduced both intratumoral and spleno CD8 and CD4+ T cells, while intermittent treatment of Cpd A increased intratumoral CD8+ and CD4+ T cells and revealed normal CD8+ and CD4+ T cells in normal tissues such as spleen, liver and lung (Figure ID and IE).

Taken together, testing Cpd A in immue competent mice in the context of evaluating its direact activity on tumor cells as well as indirect anti-tumor activity via modulation of anti-tumor immune response led to the discovery on schedule-dependent anti-tumor efficacy as well as immune related safety profile. These findings suggest that intermittent treatment of Cpd A may specifically enhance antitumor immunity, while have no impact on T cell components in normal tissues, such as spleen, liver and lung. In contrast, continuous daily treatment of Cpd A may obstruct anti-tumor immunity and cause immune suppressive side effects. EXAMPLE 2: INTERMETTENT TREATMENT OF Cpd A RESULTS IN FAVORABLE ANTITUMOR IMMUNITY BY TURNING NON-INFLAMED IMMUNE SUPPRESSIVE TME TO INFLAMED IMMUNE STIMULATING TME.

To investigate if Cpd A induced intratumoral CD8+ T cells are functioning, Tissue RNAseq analysis was conducted with sorted tumor infiltrating CD8+ T cells. Intermittent treatment of Cpd A increased the expression of immune stimulatory cytokine IFNy, T cell cytokine IL-2, T cell activation marker CD25, and T cell co-stimulatory molecule CD40L. GSEA analysis also revealed enrichment of IFNy response, IL-2/STAT5 signaling, and T cell receptor (TCR) signaling signatures (Figure 2A). Further analysis by IHC confirmed that intermittent, but not daily treatment of CpdA promoted an increase in intratumoral CD8+ T cells and granzyme B+ cells (Figure 2A). Tumor specific local expansion of CD8+ T cells unpone intermittent treatment of Cpd A was revealed by BrdU pulse labeling experiment and RNAseq analysis of TCR on CD8+ T cells. A significantly decreased clonotype diversity after intermittent Cpd A treatment observed on prostate tumoral CD8+ T cells but not on spleno CD8+ T cells (Fig. 2B) Furthermore, intermittent Cpd A treatment increased Brdu positive ratio in tumor infiltrating CD8+ T and CD4+ T cells but not those in spleen (Figure 2B).

Together, these results showed that intermittent treatment of Cpd A triggers a local, colonal expansion and activation of tumor infiltrating CD8+ T cells.

As regulatory T cell plays key role in mediating immune tolerance by suppressing effector CD8+ and CD4 T cells, we investigated the potential effect of Cpd A on tumor associated T_regs. In CRPC CP model, both daily and intermittent Cpd A treatment led to a significantly decreased total intratumoral T_reg number and tumor T_reg/CD4+ ratio (Figure 2C). However, intermittent treatment was far more efficient in breaking immune tolerance in tumors shown by increasing CD8⁺/T_reg ratio of 25-fold compared to only 1- fold with daily treatment (Figure 2C). Interestingly, daily but not intermittent treatment of Cpd A showed significant suppression of spleno T_regs in the same animals (Figure 2C), indicating intermittent treatment have a more tumor-specific T_reg depletion effects.

Together, these results suggest that intermittent treatment of Cpd A could effectively break immune tolerance mediated by T_regs specifically in tumors.

We next investigated how long prostate tumor could remain in T cell inflamed after release from intermittent treatment of Cpd A. We first treated CRPC mice with Cpd A with 20n/50ff schedule for 4 weeks to turn tumor microenvironment into T cell inflamed, thereafter the mice were released from Cpd A treatment for 4 weeks or 10 weeks. We found that both tumor size and weight decreased dramatically in Cpd A treatment-release group compare to vehicle group (Figure 2D). FACS analysis revealed that intratumoral CD8+ T cell increase (total number and ratio in CD45+ cells) remained at similar levels even after Cpd A release for 4 and 10 weeks (Figure 2D). Furthermore, increase in IL-2 expression and decreased clontype diversity were also maintained (Figure 2D). IHC also confirmed the increased CD8T cell infiltration into tumor tissue after Cpd A release for 4 weeks (Figure 2D).

Together, these results indicated that once tumors were turned into T cell inflamed by intermittent treatment of Cpd A, T cell inflamed status persisted even without continuous Cpd A treatment for months.

EXAMPLE 3: SYNERGISTIC COMBINATIONS OF COMPONENT A AND COMPONENT B WITH VARIOUS DOSING SCHEDULES OF THE PRESENT INVENTION

In clinic, immune-checkpoint blockers showed clinical benefits only in a small population of patients with inflamed tumor phenotype, e.g. melanoma, lung cancer, head and neck cancer, CRC, bladder cancer, gastric cancer, RCC, HCC, and Hodgkin's lymphoma (HL) with I FNy gene signature, PD-L1 expression, tumor mutation burden, and MSI-high and/or DDR. However, tumors with immune excluded (lack of effector T cell infiltration into tumor area) or immune desert (lack of functioning antigen presentation) tumor phenotypes do not respond well to the 1^st generation T cell-based immunotherapies. There are many possible mechanisms could cause the resistance to the current checkpoint inhibitors, therefore it is difficult to predict the therapeutic potential of a pathway, a cell type, and/or an asset without experiments to understanding anti-tumor efficacy and the corresponding MoA. Therefore, we investigated the combination of Cpd A and Cpd B (CD279 (PD-1) Monoclonal Antibody (clone RMP1-14) was obtained from Invivogen, bulk ordered, Reference Code mpdl- mabl5-10) with multiple doses and dosing schedules to understand how best the synergy of Cpd A and Cpd B (CD279 (PD-1) Monoclonal Antibody (clone RMP1-14) was obtained from Invivogen, bulk ordered, Reference Code mpdl-mabl5-10) could be generated. The first study was to compare continuous (QD, once daily) vs intermittent schedule (2 days on/5 days off, 20n/50ff) at the same weekly total dose (350 mg/kg) as well as to compare high (175 mg/kg) vs low (75 mg/kg) doses with intermittent 20n/50ff schedule. Anti-PD-1 Cpd B (CD279 (PD-1) Monoclonal Antibody (clone RMP1- 14) was obtained from Invivogen, bulk ordered, Reference Code mpdl-mabl5-10) was given on day B and day 6 of each week. As shown in Figure 3A, no responders were observed in vehicle and anti-PD-1 Cpd B (CD279 (PD-1) Monoclonal Antibody (clone RMP1-14) was obtained from Invivogen, bulk ordered, Reference Code mpdl-mabl5- 10) treatment groups with a tumor size over 150 mm² observed in the majority of animals (8/10) on day 17. Cpd A monotherapy treatment demonstrated dose- dependent anti-tumor efficacy where in favor of the two intermittent treatment groups at end (day 17) and post of the treatment (day 30 and day 65). However tumor regression observed in Cpd A monotherapy treatment seemed not sustainable, indicated by tumor recurrence. Combination treatment of Cpd A and Cpd B (CD279 (PD- 1) Monoclonal Antibody (clone RMP1-14) was obtained from Invivogen, bulk ordered,

Reference Code mpdl-mabl5-10) greatly enhanced response rates at Day 17 from 30% (Cpd A mono) to 60% in Cpd A intermittent high dose group, from 10% (Cpd A mono) to 50% in Cpd A intermittent low dose group, and from 10% (Cpd A mono) to 30% in Cpd A continuous treatment group. Supprisingly, intermittent low dose of Cpd A (75 mg/kg, total dose 450 mg) showed the best sustained tumor response (RR=50%) at 7 weeks post stopping treatment compared to intermittent high dose (RR=30%, 175 mg/kg/dose, total dose 1050 mg) and continuous treatment (RR=30%, 50 mg/kg/dose, total dose 1050 mg) groups. These results indicated that for 10 combination (e.g. with anti-PD-1), Cpd A can be effective at a dose below the MDT (e.g. 40% of MTD) and achieve even better long term combination efficacy and safety profile. Taken these results into consideration, Cpd A should be tested at doses below its MTD in the 10 (e.g. anti-PD-1) combination clinical trials.

To further exam if the long term anti-tumor activity observed in the combination treatment of Cpd A and Cpd B (CD279 (PD-1) Monoclonal Antibody (clone RMP1-14) was obtained from Invivogen, bulk ordered, Reference Code mpdl-mabl5-10) is through generation of adaptive immune memory, a tumor re-challenge study is performed in the same A20 tumor model. A20 tumor cells were inoculated into the mice with complete remission from the previous treatment of Cpd A and Cpd B (CD279 (PD-1) Monoclonal Antibody (clone RMP1-14) was obtained from Invivogen, bulk ordered, Reference Code mpdl-mabl5-10) combination 6 weeks after complete remission and 4 weeks post stopping treatment. Age-matched naive mice were used as a control. As shown in Figure 3B, no tumor growth could be observed in the mice previously treated with Cpd A and Cpd B (CD279 (PD-1) Monoclonal Antibody (clone RMP1-14) was obtained from Invivogen, bulk ordered, Reference Code mpdl-mabl5- 10), while the tumors in the control Cpd naive mice reached critical tumor mass (>1500 mm³). This result demonstrated that treatment of Cpd A in combination with Cpd B could generate long lasting anti-tumor immune response to prevent tumor recurrence.

We further examed if Cpd A could also sensitize PTEN-null immune excluded "cold" prostate GEM models to Cpd B (CD279 (PD-1) Monoclonal Antibody (clone RMP1-14) from BioXcell, Reference code BE0146) by stimulating CD8+ T cell infiltration and homing (Figure ID) and suppressing CD4+ Treg in the tumor microenvironment (TME) of prostate cancers. CP mice developed prostate carcinoma at week 10 and were received Cpd A at 180 mg/kg with 20n/50ff schedule (Dayl, Day2 each weekly cycle) and 200 pg/mice Cpd B (CD279 (PD-1) Monoclonal Antibody (clone RMP1-14) from BioXcell, Reference code BE0146) on Day B and Day 6 as monotherapy or in combination. After 4 week treatment, HE staining and CD3 IHC, as well as FACS analysis of CD8+ and CD4+ Treg cells were conducted. Strikingly, combination of Cpd A and Cpd B (CD279 (PD-1) Monoclonal Antibody (clone RMP1-14) from BioXcell, Reference code BE0146) treatment significantly enhanced tumor killing effects compared to each monotherapy shown by HE staining in Figure 3C. This potent anti-tumor activity in combination was associated with CD3 T cell infiltration, significant increase intratumoral CD8+ T cells and reduction of CD4+ Treg, and release PD-1/PD-L1 induced suppression of effector T cells.

Taking the result in Figure 3D into consideration where Cpd A could induce long lasting immune response even after stopping treatment for one month, we conducted a combination study with a sequential dosing schedule. Thus, CRPC mice were firstly treated with Cpd A for 4 weekly cycles, then dosed with PD-1 or isotype antibody (Figure 3D). Based on the assessment of HE staining, Cpd A following with Cpd B (CD279 (PD-1) Monoclonal Antibody (clone RMP1-14) was obtained from BioXcell, Reference code BE0146) treatment lead to a nearly "hollow" complete kill of prostate tumor cells particularly in anterior lobes. This result further expanded the potential options to achieve better efficacy and lower side effects when developing Cpd A and Cpd B combination therapy in clinic for the treatment of 10 therapy-resistant tumors.

Together, these results demonstrated preclinical beneficial effects of Cpd A and Cpd B combination therapy to overcome the resistance to the current immune checkpoint inhibitors in both "inflamed" and "cold" tumors. Furthermore, approaches for clinical evaluation of optimal dose, dosing schedule, and the corresponding PD and functional biomarkers (tumor and immune components in TME) for Cpd A and Cpd B combination therapy were identified and proposed.

Claims

1. A combination of component A : one or more arylaminoalcohol-substituted 2,3- dihydroimidazo[l,2-c]quinoline compounds of general formula (I) :

(I) in which :

R¹ represents -(CH₂)_n-(CHR⁴)-(CH₂)_m-N(R⁵)(R^5') ; R² represents a heteroaryl of structure :

optionally substituted with 1, 2 or 3 R⁶ groups, in which : * represents the point of attachment of said heteroaryl with the rest of the compound of general formula (I),

X represents N or C-R⁶,

X' represents O, S, NH, N-R⁶, N or C-R⁶, with the proviso that when X and X' are both C-R⁶, then one C-R⁶ is C-H ; R³ is methyl ;

R⁴ is hydroxy ;

R⁵ and R^5' are the same or different and are, independently of each other, a hydrogen atom, or a Ci-C₆-alkyl, C3-C6-cycloalkyl-Ci-C6-alkyl, or Ci-C₆-alkoxy-Ci-C₆-alkyl, or R⁵ and R^5', taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R^6' groups ; each occurrence of R⁶ may be the same or different and is independently a hydrogen atom, a halogen atom, Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆- cycloalkyl-Ci-C₆-alkyl, aryl, aryl-Ci-C₆-alkyl, heteroaryl, heteroaryl-Ci-C₆-alkyl, 3- to 8- membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-C₆-alkyl, -Ci-C₆-alkyl- OR⁷, -Ci-Ce-alkyl-SR⁷, -Ci-C₆-alkyl-N(R⁷)(R^7'), -Ci-C₆-alkyl-C(=0)R⁷,-CN, -C(=0)0R⁷, - C(=0)N(R⁷)(R⁷ ), -OR⁷, -SR⁷, -N(R⁷)(R⁷ ), or -NR⁷C(=0)R⁷ each of which may be optionally substituted with 1 or more R⁸ groups ; each occurrence of R^6' may be the same or different and is independently Ci-C₆-alkyl, C₃-C₆-cycloalkyl-Ci-C₆-alkyl, or Ci-C₆-alkyl-OR⁷; each occurrence of R⁷ and R^7' may be the same or different and is independently a hydrogen atom, or a Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆- cycloa I kyl-Ci-C₆-a I kly I, C₃-C₆-cycloalkenyl, aryl, a ry l-Ci-C₆-a I ky I, heteroaryl, 3- to 8- membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-C₆-alkyl, or heteroaryl- Ci-C₆-alkyl ; each occurrence of R⁸ is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci-C₆-alkyl, Ci-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆- cycloalkyl, C₃-C₆-cycloalkyl-Ci-C₆-alkyl, Ci-C₆-cycloalkenyl, aryl, a ry l-Ci-C₆-a I ky I, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-Ci-C₆-alkyl, or heteroaryl- Ci-C₆-alkyl ; n is an integer of 1 and m is an integer of 1 ; with the proviso that when :

- said R² heteroaryl of structure :

is not :

in which * represents the point of attachment with the rest of the structure of general formula (I). or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially ; and component B, which is: • component Bl: anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti-PD-1 mAb); or

• component B3: anti-Programmed death-ligand 2 (also referred to as "PD-L2", also known as cluster of differentiation 273 (CD273) or B7-DC homolog 1 (B7-H1)); and, optionally, component C : one or more further pharmaceutical agents.

2. The combination according to claim 1, wherein : said component A is an arylaminoalcohol-substituted 2,3-dihydroimidazo[l,2- c]quinoline compound of general formula (I) according to claim 1, wherein R¹ represents -(CH )n-(CHR⁴)-(CH )_m-N(R⁵)(R⁵') ;

R² represents a heteroaryl of structure :

in which :

R³ is methyl ;

R⁴ is hydroxy ; R⁵ and R^5' are the same or different and are, independently of each other, a hydrogen atom, or a Ci-C₆-alkyl, C₃-C₆-cycloalkyl-Ci-C₆-alkyl, or Ci-C₆-alkoxy-Ci-C₆-alkyl, or

R⁵ and R^5', taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R^6' groups ; each occurrence of R⁶ may be the same or different and is independently a hydrogen atom, a halogen atom, Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆- cycloalkyl-Ci-C₆-alkyl, aryl, aryl-Ci-C₆-alkyl, heteroaryl, heteroaryl-Ci-C₆-alkyl, 3- to 8- membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-C₆-alkyl, -Ci-C₆-alkyl- OR⁷, -Ci-Ce-alkyl-SR⁷, -Ci-C₆-alkyl-N(R⁷)(R^7'), -Ci-C₆-alkyl-C(=0)R⁷,-CN, -C(=0)OR⁷, - C(=0)N(R⁷)(R^7'), -OR⁷, -SR⁷, -N(R⁷)(R^7'), or -NR⁷C(=0)R⁷ each of which may be optionally substituted with 1 or more R⁸ groups ; each occurrence of R^6' may be the same or different and is independently Ci-C₆-alkyl, C₃-C₆-cycloalkyl-Ci-C₆-alkyl, or Ci-C₆-alkyl-OR⁷; each occurrence of R⁷ and R^7' may be the same or different and is independently a hydrogen atom, or a Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₃-C₆- cycloalkyl-Ci-C₆-alkyl, C₃-C₆-cycloalkenyl, aryl, aryl-Ci-C₆-alkyl, heteroaryl, 3- to 8- membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-C₆-alkyl, or heteroaryl- Ci-C₆-alkyl ; each occurrence of R⁸ is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci-C₆-alkyl, Ci-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆- cycloalkyl, C₃-C₆-cycloalkyl-Ci-C₆-alkyl, Ci-C₆-cycloalkenyl, aryl, a ry l-Ci-C₆-a I ky I, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-Ci-C₆-alkyl, or heteroaryl- Ci-C₆-alkyl ; n is an integer of 1 and m is an integer of 1 ; with the proviso that when : - said R⁵ and R^5', taken together with the nitrogen atom to which they are bound, represent :

- said R² heteroaryl of structure :

is not :

3. The combination according to claim 1 or 2, wherein : said component A is one or more arylaminoalcohol-substituted 2,3-dihydroimidazo[l,2- c]quinoline compounds of general formula (I) according to claim 1, which is selected from the list consisting of specific compound Examples 1 to 41 on pp. 66 to 91106, of International patent application PCT/EP2011/069637, published as WO 2012/062748 A1 on May 18, 2012; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.

4. The combination according to any one of claims 1 to 3, wherein : said component A is one or more arylaminoalcohol-substituted 2,3-dihydroimidazo[l,2- c]quinoline compounds of general formula (I) according to claim 1, which is selected from the list consisting of :

2,3-dihydroimidazo[l,2-c]quinazolin-5-yl]pyridine-3-carboxamide

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

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

2,3-dihydroimidazo[l,2-c]quinazolin-5-yl]-2-methylpyridine-3-carboxamide

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

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

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

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

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

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

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

2-amino-N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7- methoxy-2,3-dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide 2-amino-N-(8-{[(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)propyl]oxy}-7- methoxy-2,3-dihydroimidazo[l,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide dihydrochloride

2,3-dihydroimidazo[l,2-c]quinazolin-5-yl]-l,3-thiazole-5-carboxamide

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

N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl)-l,3-thiazole-5-carboxamide, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.

5. The combination according to any one of claims 1 to 4, wherein: said component B is component Bl, which is anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti- PD-1 mAb) ; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially

6. The combination according to any one of claims 1 to 4, wherein: said component B is component B2, which is anti-Programmed death-ligand 1 (also referred to as "PD-L1", also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1)); optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.

7. The combination according to any one of claims 1 to 4, wherein: said component B is component B3, which is anti-Programmed death-ligand 2 (also referred to as "PD-L2", also known as cluster of differentiation 273 (CD273) or B7-DC homolog 1 (B7-H1)); optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.

8. The combination according to any one of claims 1 to 7, wherein said component A is N-(8-{[(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide.

9. A combination of a component A and a component B, wherein: said component A is N-(8-{[(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-

10. A combination of a component A and a component B, wherein: said component A is N-(8-{[(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-

2,3-dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially ; and wherein: said component B is component B2, which is anti-Programmed death-ligand 1 (also referred to as "PD-L1", also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1)); optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.

11. A combination of a component A and a component B, wherein: said component A is N-(8-{[(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-

2,3-dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially ; and wherein: said component B is component B3, which is anti-Programmed death-ligand 2 (also referred to as "PD-L2", also known as cluster of differentiation 273 (CD273) or B7-DC homolog 1 (B7-H1)); optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.

12. The combination according to claim 9, wherein: said component A is N-(8-{[(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy- 2,B-dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine-B-carboxamide, and wherein: said component B is component Bl, which is anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti- PD-1 mAb).

13. The combination according to claim 10, wherein: said component A is N-(8-{[(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy- 2,3-dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide, and wherein: said component B is component B2, which is anti-Programmed death-ligand 1 (also referred to as "PD-L1", also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1)).

14. The combination according to claim 11, wherein: said component A is N-(8-{[(2R)-2-Hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy- 2,3-dihydroimidazo[l,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide, and wherein: said component B is component B3, which is anti-Programmed death-ligand 2 (also referred to as "PD-L2", also known as cluster of differentiation 273 (CD273) or B7-DC homolog 1 (B7-H1)).

15. The combination according to claim 9 or 12, wherein said anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti-PD-1 mAb) is pembrolizumab, nivolumab, pidilizumab, tislelizumab, cemiplimab, camrelizumab, sintilimab, or toripalimab.

16. The combination according to claim 10 or 13, wherein said anti-Programmed death- ligand 1 (also referred to as "PD-L1", also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1)), is atezolizumab, durvalumab, avelumab, or any other anti-PD-Ll, in particular atezolizumab.

17. The combination according to claim 11 or 14, wherein said anti-Programmed death- ligand 2 (also referred to as "PD-L2", also known as cluster of differentiation 273 (CD273) or B7-DC homolog 1 (B7-H1)), is CD273 (PD-L2) Monoclonal antibody.

18. The combination according to claim 15, wherein: said anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti-PD-1 mAb) is pembrolizumab.

19. The combination according to claim 15, wherein said anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti-PD-1 mAb) is nivolumab.

20. The combination according to claim 15 or 18, wherein: said component A is 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide, and wherein: said anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti-PD-1 mAb) is pembrolizumab.

21. The combination according to claim 15 or 19, wherein: said component A is 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide, and wherein: said anti-Programmed Cell Death Protein 1 (also referred to as „PD-1" or „CD279" (cluster of differentiation 279)) antibody (anti-PD-1 mAb) is nivolumab.

22. The combination according to claim 16, wherein: said anti-Programmed death-ligand 1 (also referred to as "PD-L1", also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1)), is atezolizumab.

23. The combination according to claim 16 or 22, wherein: said component A is 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide, and wherein: said anti-Programmed death-ligand 1 (also referred to as "PD-L1", also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1)), is atezolizumab.

24. The combination according to claim 17, wherein: said anti-Programmed death-ligand 2 (also referred to as "PD-L2", also known as cluster of differentiation 273 (CD273) or B7-DC homolog 1 (B7-H1)), is CD273 (PD-L2) Monoclonal antibody.

25. The combination according to claim 17 or 24, wherein: said component A is 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide, and wherein: said anti-Programmed death-ligand 2 (also referred to as "PD-L2", also known as cluster of differentiation 273 (CD273) or B7-DC homolog 1 (B7-H1)), is CD273 (PD-L2) Monoclonal antibody.

26. A combination according to any one of claims 1 to 25 for use in the treatment or prophylaxis of a cancer, particularly colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia.

27. Use of a combination according to any one of claims 1 to 25 in the treatment or prophylaxis of a cancer, particularly colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia.

28. Use of a combination according to any one of claims 1 to 25 for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia.

29. Use according to any one of claims 26 to 28, wherein said cancer is colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia.

30. Use according to claim 28 or 29, wherein said cancer is colorectal cancer, particularly immune-checkpoint blockers insensitive or resistant colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia.

31. A method of treatment or prophylaxis of a cancer, particularly lung cancer, in particular colorectal cancer, particularly immune-checkpoint blockers insensitive or resistant colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, ovarian cancer, pancreatic cancer, kidney cancer, endometrial cancer, lymphoma, leukemia, etc., in subject, comprising administering to said subject a therapeutically effective amount of a combination accoring to any one of claims 1 to 25.

32. A kit comprising a combination according to any one of claims 11 to 26, in which optionally both or either of said components A) and B) are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.