The present invention relates to combinations of : component A : one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Al) or (A2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ;

and

component B : one or more dihydroorotate dehydrogenase (DHODH)-inhibiting 2,4,5- trisubstituted 1,2,4-triazolone compounds of general formula (B-l) as defined herein, or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxide thereof ;

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 independently 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 lymphomas, such as AIDS-related lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, lymphoma of the central nervous system, or non-Hodgkin's lymphoma (hereinafter abbreviated to "NHL"), particularly 1st line, 2nd line, relapsed, refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukaemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), mantle cell lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL").

In a further aspect, the present invention relates to a kit comprising a combination of : component A : one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Al) or (A2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ;

and

component B : one or more dihydroorotate dehydrogenase (DHODH)-inhibiting 2,4,5- trisubstituted 1,2,4-triazolone compounds of general formula (B-l) as defined herein, or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxide thereof ;

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 independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.

BACKGROUND OF THE INVENTION

Combinations of PI3K Inhibitors and dihydroorotate dehydrogenase (DHODH)-inhibitors:

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. 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 I oss-of-f unction 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. DHODH is a mitochondrial membrane located protein and the fourth and rate limiting enzyme in the de novo pyrimidine synthesis, converting dihydroorotate (DHO) to orotate. A cell has normally two options to produce pyrimidines -via the de novo pathway and the salvage pathway. While the de novo pathway has the higher capability to produce pyrimidines per given time the salvage pathway is more energy efficient. Therefore cells in a physiological setting often switch between the pathways dependent on their need. Resting B and T cells rely mainly on the salvage pathway while activated lymphocytes - due to their increased pyrimidine needs by around 8-10 times - highly depend on the de novo pathway. Cells with high pyrimidine need are dependent on the de novo pathway. It was recently shown that DHODH plays a crucial role in acute myeloid leukemia (Sykes et al Cell 2016) and the enzyme has been previously described in other malignancies.

The prior art discloses a multitude of DHODH inhibitors (see, for example, H. Munier-Lehmann et al J Med Chem 2013, 56 (8) pp 3148 - 3167. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive Non-Hodgkin Lymphoma (NHL). DLBCL can be classified into three different molecular cell-of-origin subtypes: germinal centre B-cell (GCB), activated B-cell (ABC) and primary mediastinal B-cell lymphoma (PMBL). GCB DLBCL frequently has Bcl2 translocations and most result in activation of Bcl6. Mutations of EZH2 (21%) are specific for this subtype. Loss-of-PTEN (55% of GCB-DLBCL cases) results in activation of the PI3K pathway. Constitutive activation of the NF-kB (NF-kappaB) and BCR oncogenic signalling pathways by mutations in Myd88, CARD11 and CD79 are the hallmark of ABC DLBCL. Thus, DLBCL has significant molecular heterogeneity (Table 1) and shows diverse prognosis. Therefore, identification of combinations of novel agents targeting the driver oncogenic signalling pathways is needed for increasing the cure rate of DLBCL

Table 1 Oncogenic signalling pathways in DLBCL

As described in the present invention, 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamid e dihydrochloride, (a highly selective pan-Class I PI3K inhibitor with predominant activity against PI3Ka and PI3K6) and dihydroorotate dehydrogenase (DHODH)-inhibiting 2,4,5-trisubstituted 1,2,4-triazolone compounds of general formula (B-l) as defined herein, were investigated as combination in inhibiting tumor growth of a DLBCL xenograft model in vivo compared to each single agent.

Unexpectedly, and this represents a basis of the present invention, when combinations of: component A : one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Al) or (A2), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein; with - component B : one or more dihydroorotate dehydrogenase (DHODH)-inhibiting 2,4,5- trisubstituted 1,2,4-triazolone compounds of general formula (B-l) as defined herein, or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxide thereof, as described and defined herein ; were evaluated for the treatment of non-Hodgkin's lymphoma (hereinafter abbreviated to "NHL"), particularly 1st line, 2nd line, relapsed, refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukaemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), mantle cell lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL"), 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-DHODH inhibitors.

To the Applicant's knowledge, no generic or specific disclosure or suggestion in the prior art is known that either combinations of: component A : one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Al) or (A2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; component B : one or more dihydroorotate dehydrogenase (DHODH)-inhibiting 2,4,5- trisubstituted 1,2,4-triazolone compounds of general formula (B-l) as defined herein, or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxide thereof ; 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 cancer, particularly lymphomas, such as AIDS-related lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, lymphoma of the central nervous system, or non-Hodgkin's lymphoma (hereinafter abbreviated to "NHL"), particularly 1st line, 2nd line, relapsed, refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukaemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), mantle cell lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL").

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 cancer, particularly lymphomas, such as AIDS-related lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, lymphoma of the central nervous system, or non- Hodgkin's lymphoma (hereinafter abbreviated to "NHL"), particularly 1st line, 2nd line, relapsed, refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukaemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), mantle cell lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL").

Accordingly, in accordance with a first aspect, the present invention relates to combinations of : component A : one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Al) or (A2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; component B : one or more dihydroorotate dehydrogenase (DHODH)-inhibiting 2,4,5- trisubstituted 1,2,4-triazolone compounds of general formula (B-l) as defined herein, or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxide thereof ; 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. The components may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.

In accordance with a second aspect, of the present invention relates to the use of any of such combinations as described supra for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly lymphomas, such as AIDS-related lymphoma, cutaneous T- cell lymphoma, Burkitt lymphoma, Hodgkin's disease, lymphoma of the central nervous system, or non-Hodgkin's lymphoma (hereinafter abbreviated to "NHL"), particularly 1st line, 2nd line, relapsed, refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukaemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), mantle cell lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL").

Further, in accordance with a third aspect, the present invention relates to a kit comprising a combination of : component A : one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Al) or (A2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; component B : one or more dihydroorotate dehydrogenase (DHODH)-inhibiting 2,4,5- trisubstituted 1,2,4-triazolone compounds of general formula (B-l) as defined herein, or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxide thereof ; 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 independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.

Detailed description of the Invention

In accordance with an embodiment of the above-mentioned aspects of the present invention, said combinations are of: component A : wh ich is one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Al) :

wherein

X represents CR ⁵ R ⁶ or NH;

Y ¹ represents CR ³ or N; Chemical bond between y ² — y ³ represents a single bond or double bond, with the proviso that when theY ² — Y ³ represents a double bond,

Y ² and Y ³ independently represent CR ⁴ or N, and when Y ² — Y ³ represents a single bond, Y ² and Y ³ independently represent CR ³ R ⁴ or N R ⁴ ;

Z ¹ , Z ² , Z ³ and Z ⁴ independently represent CH , CR ² or N; R ¹ represents aryl optionally having 1 to 3 substituents selected from R , C cycloalkyl optionally having 1 to 3 substituents selected from R ,

C alkyl optionally substituted by

aryl, heteroaryl, Ci- ₆ alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,

C alkoxy optionally substituted by

carboxy, aryl, heteroaryl, Ci- ₆ alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen, or

a 3 to 15 membered mono- or bi-cyclic heterocyclic ring that is saturated or unsaturated, and contains 1 to 3 heteroatoms selected from the group consisting of N,

O and S, and optionally having 1 to 3 substituents selected from R

wherein

R represents

halogen, nitro, hydroxy, cyano, carboxy, amino, N-(Ci- ₆ alkyl)amino, N-(hydroxyCi- 6alkyl)amino, N,N-di(Ci- ₆ alkyl)amino, N-(Ci- ₆ acyl)amino, N-(formyl)-N-(Ci- ₆ alkyl)amino, N-

(Ci- ₆ alkanesulfonyl) amino, N-(carboxyCi- ₆ alkyl)-N-(Ci- ₆ alkyl)amino, N-(Ci- 6alkoxycabonyl)amino, N-[N,N-di(Ci- ₆ alkyl)amino methylene]amino, N-[N,N-di(Ci- 6alkyl)amino (Ci- ₆ alkyl)methylene]amino, N-[N,N-di(Ci- ₆ alkyl)amino C _2-6 alkenyl]amino, aminocarbonyl, N-(Ci- ₆ alkyl)aminocarbonyl, N,N-di(Ci- ₆ alkyl)aminocarbonyl, C _3. scycloalkyl, Ci- ₆ alkylthio, Ci- ₆ alkanesulfonyl, sulfamoyl, Ci- ₆ alkoxycarbonyl,

N-arylamino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R ¹⁰¹ , N-(aryl Ci- ₆ alkyl)amino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R ¹⁰¹ , aryl Ci- ₆ alkoxycarbonyl wherein said aryl moiety is optionally having 1 to 3 substituents selected from R ¹⁰¹ ,

Ci-galkyl optionally substituted by

mono-, di- or tri- halogen, amino, N-(Ci- ₆ alkyl)amino or N,N-di(Ci- ₆ alkyl)amino,

Ci-galkoxy optionally substituted by

mono-, di- or tri- halogen, N-(Ci- ₆ alkyl)sulfonamide, or N-(aryl)sulfonamide, or

a 5 to 7 membered saturated or unsaturated ring having 1 to 3 heteroatoms selected from the group consisting of O, S and N, and optionally having 1 to 3 substituents selected from R ¹⁰¹

wherein R ¹⁰¹ represents

halogen, carboxy, amino, N-(C _I-6 alkyl)amino, N,N-di(Ci- ₆ alkyl)amino, aminocarbonyl, N- (Ci- ₆ alkyl)aminocarbonyl, N,N-di(Ci- ₆ alkyl)aminocarbonyl, pyridyl,

Ci- ₆ alkyl optionally substituted by cyano or mono- di- or tri- halogen,

or

Ci- ₆ alkoxy optionally substituted by cyano, carboxy, amino, N-(C _I-6 alkyl)amino, N,N- di(Ci- ₆ alkyl)amino, aminocarbonyl, N-(Ci- ₆ alkyl)aminocarbonyl, N,N-di(Ci- 6alkyl)aminocarbonyl or mono-, di- or tri- halogen; R ² represents hydroxy, halogen, nitro, cyano, amino, N-(Ci- ₆ alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(hydroxyCi- ₆ alkyl)amino, N-(hydroxyCi- ₆ alkyl)-N-(Ci- ₆ alkyl)amino, Ci- ₆ acyloxy, aminoCi- ₆ acyloxy, C _2-6 alkenyl, aryl,

a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by hydroxy, Ci- ₆ alkyl, Ci- ₆ alkoxy, oxo, amino, amino Ci _-6 alkyl, N-(Ci- ₆ alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(C _I-6 acyl)amino, N-(Ci- ₆ alkyl)carbonylamino, phenyl, phenyl Ci- ₆ alkyl, carboxy, Ci- ₆ alkoxycarbonyl, aminocarbonyl, N-(Ci- ₆ alkyl)aminocarbonyl, or N,N-di(Ci- 6alkyl)amino,

-C(O)- R ²⁰

wherein

R ²⁰ represents Ci- ₆ alkyl, Ci- ₆ alkoxy, amino, N-(Ci- ₆ alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(C _I-6 acyl)amino, or a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by

Ci- ₆ alkyl, Ci- ₆ alkoxy, oxo, amino, N-(Ci- ₆ alkyl)amino, N,N-di(Ci- ₆ alkyl)amino, N- (Ci- ₆ acyl)amino, phenyl, or benzyl,

Ci- ₆ alkyl optionally substituted by R ²¹

or

Ci- ₆ alkoxy optionally substituted by R ²¹

wherein

R ²¹ represents cyano, mono-, di or tri- halogen, hydroxy, amino, N-(Ci- ₆ alkyl)amino, N,N-di(Ci- ₆ alkyl)amino, N-(hydroxyCi- ₆ alkyl)amino, N-(halophenylCi- ₆ alkyl)amino, aminoC alkylenyl, Ci- ₆ alkoxy, hydroxyCi- ₆ alkoxy, -C(O)- R ²⁰¹ , -

NHC(O)- R ²⁰¹ , C -scycloalkyl, isoindolino, phthalimidyl, 2-oxo-l,3-oxazolidinyl, aryl or a 5 or membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N optionally substituted by

hydroxy, Ci alkyl, Ci alkoxy, Ci alkoxycarbonyl, hydroxyCi alkoxy, oxo, amino, aminoCi- alkyl, N-(Ci- alkyl)amino, N,N-di(Ci- alkyl)amino, N-(C _I acyl)amino, or benzyl, wherein

represents hydroxy, amino, N-(Ci- alkyl)amino, N,N-di(Ci- alkyl)amino, N- (halophenylCi alkyl) amino, Ci_ al kyl, aminoCi-g alkyl, aminoC alkylenyl, Ci alkoxy, a 5 or membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N optionally substituted by

hydroxy, Ci alkyl, Ci alkoxy, Ci alkoxycarbonyl, hydroxyCi alkoxy, oxo, amino, N-(Ci- alkyl)amino, N,N-di(Ci- alkyl)amino, N-(C _I acyl)amino or benzyl;

R represents hydrogen, halogen, aminocarbonyl, or Ci alkyl optionally substituted by aryl Ci alkoxy or mono-, di- or tri- halogen;

R represents hydrogen or Ci alkyl;

R represents hydrogen or Ci alkyl; and

R represents halogen, hydrogen or Ci alkyl ; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; said compounds are published as compounds of general formulae I, l-a, and l-b in International patent application PCT/EP2003/010377, published as WO 04/029055 A1 on April 08, 2004, which is incorporated herein by reference in its entirety. In WO 04/029055, said compounds of general formula I, l-a and l-b are described on pp. et seq., they may be synthesized according to the methods given therein on pp. 26 et seq., and are exemplified as specific compound Examples 1-1 to 1-210 on pp. 47 to 106, specific compound Examples 2-1 to 2-368 on pp. 107 to 204, specific compound Examples 3-1 to 3-2 on pp. 205 to 207, and as specific compound Examples 4-1 to 4-2 on pp. 208 to 210, therein.

Such a compound, 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydro imid- azo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride, (which is hereinafter referred to as "compound A" or "cpd. A") is published in international patent application PCT/EP2012/055600, published as WO 2012/136553 on October 11, 2012, (which is incorporated herein by reference in its entirety), as the compound of Examples 1 and 2 : 2- amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroim idazo[l,2-c]quinazolin-5- yl] pyrimidine-5-carboxamide dinydrochloride: it may be synthesized according to the methods given in said Examples 1 and 2. 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 independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. In accordance with another embodiment of the above-mentioned aspects of the present invention, said combinations are of : component A : which is one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Al), supra, which is selected from the list consisting of specific compound Examples 1-1 to 1-210 on pp. 47 to 106, specific compound Examples 2-1 to 2-368 on pp. 107 to 204, specific compound Examples 3-1 to 3-2 on pp. 205 to 207, and specific compound Examples 4-1 to 4-2 on pp. 208 to 210, of in International patent application PCT/EP2003/010377, published as WO 04/029055 Al on April 08, 2004, which is incorporated herein by reference in its entirety; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof. Such a component A may be : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimid-azo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxami de dihydrochloride, (which is hereinafter referred to as "compound A" or "cpd. A") is published in international patent application PCT/EP2012/055600, published as WO 2012/136553 on October 11, 2012, (which is incorporated herein by reference in its entirety), as the compound of Examples 1 and 2 : 2- amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroim idazo[l,2-c]quinazolin-5- yl] pyrimidine-5-carboxamide dihydrochloride: it may be synthesized according to the methods given in said Examples 1 and 2. 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 independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. As mentioned supra, said specific compound Examples may be synthesized according to the methods given in WO 04/029055 A1 on pp. 26 et seq..

As mentioned supra, 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydro imid- azo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride, (which is hereinafter referred to as "compound A" or "cpd. A") may be synthesized as described in Examples 1 and 2 of international patent application PCT/EP2012/055600, published as WO 2012/136553 on October 11, 2012, (which is incorporated herein by reference in its entirety).

In accordance with another embodiment of the above-mentioned aspects of the present invention, said combinations are of : component A : which is one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (A2) :

in which :

X represents CR ⁵ R ⁶ or NH;

Y ¹ represents CR ³ or N; the chemical bond between y ² — y ³ represents a single bond or double bond,

with the proviso that when theY ² — Y ³ represents a double bond, Y ² and Y ³ independently represent CR ⁴ or N, and

when Y ² — Y ³ represents a single bond, Y ² and Y ³ independently represent CR ³ R ⁴ or NR ⁴ ;

Z ¹ , Z ² , Z ³ and Z ⁴ independently represent CH , CR ² or N;

R ¹ represents aryl optionally having 1 to 3 substituents selected from R , C ₃ -s cycloalkyl optionally having 1 to 3 substituents selected from R , Ci- ₆ alkyl optionally substituted by aryl, heteroaryl, Ci- ₆ alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,

Ci- ₆ alkoxy optionally substituted by carboxy, aryl, heteroaryl, Ci- ₆ alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,

or

a 3 to 15 membered mono- or bi-cyclic heterocyclic ring that is saturated or unsaturated, optionally having 1 to 3 substituents selected from R , and contains 1 to 3 heteroatoms selected from the group consisting of N, O and S, wherein

R represents halogen, nitro, hydroxy, cyano, carboxy, amino, N- (Ci- ₆ alkyl)amino, N-(hydroxyCi- ₆ alkyl)amino, N,N-di(Ci- ₆ alkyl)amino, N-(Ci- ₆ acyl)amino, N-(formyl)-N-(Ci- ₆ alkyl)amino, N-(Ci- ₆ alkanesulfonyl) amino, N- (carboxyCi- ₆ alkyl)-N-(Ci- ₆ alkyl)amino, N-(Ci- ₆ alkoxycabonyl)amino, N-[N,N-di(Ci- ₆ alkyl)amino methylene]amino, N-[N,N-di(Ci- ₆ alkyl)amino (Ci_ ₆ alkyl)methylene]amino, N-[N,N-di(Ci- ₆ alkyl)amino C _2-6 alkenyl]amino, aminocarbonyl, N-(Ci- ₆ alkyl)aminocarbonyl, N,N-di(Ci- ₆ alkyl)aminocarbonyl, C _3-8 cycloalkyl, Ci- ₆ alkylthio, Ci- ₆ alkanesulfonyl, sulfamoyl, Ci- ₆ alkoxycarbonyl, N-arylamino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R ¹⁰¹ , N-(aryl Ci- ₆ alkyl)amino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R ¹⁰¹ , aryl Ci- ₆ alkoxycarbonyl wherein said aryl moiety is optionally having 1 to 3 substituents selected from R ¹⁰¹ ,

Ci- ₆ al kyl optionally substituted by mono-, di- or tri- halogen, amino, N-(Ci- ₆ alkyl)amino or N,N-di(Ci- ₆ alkyl)amino,

Ci- ₆ alkoxy optionally substituted by mono-, di- or tri- halogen, N- (Ci- ₆ alkyl)sulfonamide, or N-(aryl)sulfonamide,

or

a 5 to 7 membered saturated or unsaturated ring having 1 to 3 heteroatoms selected from the group consisting of O, S and N, and optionally having 1 to 3 substituents selected from R ¹⁰¹ wherein

R ¹⁰¹ represents halogen, carboxy, amino, N-(C _I-6 alkyl)amino, N,N-di(Ci- 6alkyl)amino, aminocarbonyl, N-(Ci- ₆ alkyl)aminocarbonyl, N,N-di(Ci- 6alkyl)aminocarbonyl, pyridyl,

Ci- ₆ alkyl optionally substituted by cyano or mono- di- or tri- halogen, and

Ci- ₆ alkoxy optionally substituted by cyano, carboxy, amino, N-(C _I-6 alkyl)amino, N,N-di(Ci- ₆ alkyl)amino, aminocarbonyl, N-(Ci- ₆ alkyl)aminocarbonyl, N,N-di(Ci- ₆ alkyl)aminocarbonyl or mono-, di- or tri- halogen;

R ² represents hydroxy, halogen, nitro, cyano, amino, N-(Ci- ₆ alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(hydroxyCi- ₆ alkyl)amino, N-(hydroxyCi- ₆ alkyl)-N-(Ci- ₆ alkyl)amino,

Ci- ₆ acyloxy, aminoCi- ₆ acyloxy, C _2-6 alkenyl, aryl, a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by hydroxy, Ci- ₆ alkyl, Ci- ₆ alkoxy, oxo, amino, amino Ci_ ₆ al kyl, N-(Ci- ₆ alkyl)amino, N,N-di(Ci- ₆ alkyl)amino, N-(C _I-6 acyl)amino, N-(Ci- ₆ alkyl)carbonylamino, phenyl, phenyl Ci- ₆ alkyl, carboxy, Ci- ₆ alkoxycarbonyl, aminocarbonyl, N-(Ci- 6alkyl)aminocarbonyl, or N,N-di(Ci- ₆ alkyl)amino, -C(O)- R ²⁰

wherein

R ²⁰ represents Ci- ₆ alkyl, Ci- ₆ alkoxy, amino, N-(Ci- ₆ alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(C _I-6 acyl)amino, or a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by Ci- ₆ alkyl,

Ci- ₆ alkoxy, oxo, amino, N-(Ci- ₆ alkyl)amino, N,N-di(Ci- ₆ alkyl)amino, N-(Ci- 6 acyl)amino, phenyl, or benzyl,

Ci- ₆ alkyl optionally substituted by R ²¹ ,

or

Ci- ₆ alkoxy optionally substituted by R ²¹ ,

wherein

R ²¹ represents cyano, mono-, di or tri- halogen, hydroxy, amino, N- (Ci- ₆ alkyl)amino, N,N-di(Ci- ₆ alkyl)amino, N- (hydroxyCi-s alkyl) amino, N- (halophenylCi-s alkyl) amino, amino C _2.6 alkylenyl, Ci- ₆ alkoxy, hydroxyCi- ₆ alkoxy, -C(O)- R ²⁰¹ , -NHC(O)- R ²⁰¹ , C ₃ - scycloalkyl, isoindolino, phthalimidyl, 2-oxo-l,3-oxazolidinyl, aryl or a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N, and optionally substituted by hydroxy, Ci- ₆ alkyl, Ci- ₆ alkoxy, Ci- ₆ alkoxycarbonyl, hydroxyCi- ₆ alkoxy, oxo, amino, aminoCi- ₆ alkyl, N-(Ci- ₆ alkyl)amino, N,N- di(Ci- ₆ alkyl)amino, N-(C _I-6 acyl)amino, or benzyl, wherein

_R ° ^I represents hydroxy, amino, N-(Ci- ₆ alkyl)amino, N,N-di(Ci- 6alkyl)amino, N- (halophenylCi- ₆ alkyl) amino, Ci- ₆ alkyl, aminoCi- ₆ alkyl, aminoC _2-6 alkylenyl, Ci- ₆ alkoxy, a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N, and optionally substituted by hydroxy, Ci- ₆ alkyl, Ci- ₆ alkoxy, Ci- ₆ alkoxycarbonyl, hydroxyCi- ₆ alkoxy, oxo, amino, N-(Ci- ₆ alkyl)amino, N,N- di(Ci- ₆ alkyl)amino, N-(C _I-6 acyl)amino or benzyl;

R ³ represents hydrogen, halogen, aminocarbonyl, or Ci- ₆ alkyl optionally substituted by aryl Ci- ₆ alkoxy or mono-, di- or tri- halogen;

R ⁴ represents hydrogen or Ci- ₆ alkyl;

R ⁵ represents hydrogen or Ci- ₆ alkyl; and

R ⁶ represents halogen, hydrogen or Ci- ₆ alkyl ; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; said compounds are published as compounds of general formulae I, la, lb, lc, Id and le in International patent application PCT/US2007/024985, published as WO 2008/070150 A1 on June 12, 2008, which is incorporated herein by reference in its entirety. In WO 2008/070150, said compounds of general formula I, la, lb, lc, Id and le are described on pp. 9 et seq., they may be synthesized according to the methods given therein on pp. 42, et seq., and are exemplified as specific compound Examples 1 to 103 therein on pp. 65 to 101. Biological test data for certain of said compounds are given therein on pp. 101 to 107.

2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihy droimid-azo[l,2-c]quinazolin-5- yl] pyrimidine-5-carboxamide dihydrochloride, (which is hereinafter referred to as "compound A" or "cpd. A") is published in international patent application PCT/EP2012/055600, published as WO 2012/136553 on October 11, 2012, (which is incorporated herein by reference in its entirety), as the compound of Examples 1 and 2 : 2-amino-N-[7-methoxy-8-(3-morpholin-4- ylpropoxy)-2,3-dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidi ne-5-carboxamide

dihydrochloride : it may be synthesized according to the methods given in said Examples 1 and 2. The definitions used in relation to the structure (A) in this text are as follows :

The term 'alkyl' refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, such as illustratively, methyl, ethyl, n-propyl 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).

The term "alkenyl " refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched or branched chain having about 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l-propenyl, 1- butenyl, 2-and butenyl.

The term "alkynyl" refers to a straight or branched chain hydrocarbonyl radicals having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms (with radicals having in the range of about 2 up to 10 carbon atoms presently being preferred) e.g., ethynyl. The term "alkoxy" denotes an alkyl group as defined herein attached via oxygen linkage to the rest of the molecule. Representative examples of those groups are methoxy and ethoxy.

The term "alkoxyakyl" denotes an alkoxy group as defined herein attached via oxygen linkage to an alkyl group which is then attached to the main structure at any carbon from alkyl group that results in the creation of a stable structure the rest of the molecule. Representative examples of those groups are -CH ₂ OCH ₃ and --CH OC H .

The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and examples of multicyclic cycloalkyl groups include perhydronapththyl, adamantyl and norbornyl groups bridged cyclic group or sprirobicyclic groups e.g sprio (4,4) non-2-yl.

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

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

The term "arylalkyl" refers to an aryl group as defined herein directly bonded to an alkyl group as defined herein which is then attached to the main structure at any carbon from alkyl group that results in the creation of a stable structure the rest of the molecule, e.g., --CH C H ₅ , -- C H C H .

The term "heterocyclic ring" refers to a stable 3- to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heteroaromatic or heteroaryl aromatic). Examples of such heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl cinnolinyl dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazil, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl tetrahydroisouinolyl, piperidinyl, piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4- piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl pyridazinyl, oxazolyl oxazolinyl oxasolidinyl, triazolyl, indanyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, isochromanyl . The term "heteroaryl" refers to heterocyclic ring radical as defined herein which are aromatic. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

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

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

The term "heterocyclyl" refers to a heterocylic ring radical as defined herein. The heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. The term "heterocyclylalkyl" refers to a heterocylic ring radical as defined herein directly bonded to alkyl group. The heterocyclylalkyl radical may be attached to the main structure at carbon atom in the alkyl group that results in the creation of a stable structure. The term "carbonyl" refers to an oxygen atom bound to a carbon atom of the molecule by a double bond.

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

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 independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.

In accordance with an embodiment of the above-mentioned aspects of the present invention, said combinations are of : component B : which is one or more dihydroorotate dehydrogenase (DHODH)-inhibiting 2,4,5- trisubstituted 1,2,4-triazolone compound(s) of general formula (B-l) :

in which

R ¹ represents a group selected from

a C ₅ -Cs-alkyl group,

a C -Cs-haloalkyl group,

a C ₄ -C ₈ -cycloalkyl group,

which is optionally partially unsaturated and which is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from

hydroxy, phenyl and -N(R ⁷ )(R ⁸ ), and wherein said phenyl substituent is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from Ci-C ₃ -alkyl, Ci-C ₄ -haloalkyl, Ci-C ₃ -alkoxy and hydroxy,

a Ci-Cg-alkyl group which is substituted with a C ₃ -C ₈ -cycloalkyl group,

a C ₂ -C ₆ -alkyl group which is substituted with a cyano group, a hydroxy group, a phenyl group or a C ₃ -C ₈ -heterocycloalkyl group,

a C ₃ -C ₆ -alkyl group which is substituted with a monocyclic - or bicyclic heteroaryl group, a (C ₂ -C ₆ -hydroxyalkyl)-0-(C ₂ -C ₆ -alky)- group,

a -(C ₃ -C ₆ -alkyl)-N(R ⁷ )(R ⁸ ) group,

a -(C ₃ -C ₈ -cycloalkyl)-N(R ⁷ )(R ⁸ ) group,

a -(C ₃ -C ₆ -alkyl)-C(=0)N(R ⁷ )(R ⁸ ) group,

a 4-7-membered heterocycloalkyl group, a 5- to 7-membered heterocycloalkenyl group, wherein said 4-7-membered heterocycloalkyl group and said 5- to 7-membered heterocycloalkenyl group are connected to the rest of the molecule via a carbon atom, and which is optionally substituted one or two times, each substituent independently selected from a group selected from

Ci-C ₃ -alkyl, 5- to 6-membered heteroaryl, -C(=0)0(Ci-C ₄ -alkyl),

-C(=0)(Ci-C ₆ -alkyl), -C(=0)(C ₃ -C ₆ -cycloaikyl), -S(=0) ₂ (Ci-C ₆ -alkyl) and oxo (=0),

wherein said 5- to 6-membered heteroaryl substituent is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from Ci-C ₃ -alkyl, Ci-C ₄ -haloalkyl, Ci-C ₃ -alkoxy and hydroxy, a phenyl group,

which is optionally substituted, one, two, three, four or five times, each substituent independently selected from a halogen atom or a group selected from

Ci-Cg-alkyl, C ₃ -C ₈ -cycloalkyl, Ci-C ₆ -haloalkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, aryl, -(Ci-Ce-a I ky I )-a ryl, -aryl-(Ci-C ₆ -alkyl), hydroxy, cyano, Ci-Cg-hydroxyalkyl,

Ci-Cg-alkoxy, -0(C ₂ -C ₆ -alkenyl), Ci-Cg-haloalkoxy, C ₃ -C ₈ -cycloalkoxy, aryl,

-O-aryl, cyano, -C(=0)0R ⁶ , -C(=0)N(R ⁷ )(R ⁸ ), -N(R ⁷ )(R ⁸ ),

-(Ci-C ₆ -alkyl))-N(R ⁷ )(R ⁸ ), -(C ₁ -C ₃ -alkyl)-C(=0)0R ⁶ , -(C ₁ -C ₆ -alkyl)-C(=0)N(R ⁷ )(R ^s ), -0-C(=0)-(Ci-C ₆ -alkyl)-, -SH, -S-(Ci-C ₆ -alkyl),

-S-(C ₂ -C ₆ -alkenyl), -S(=0) ₂ N(R ⁷ )(R ⁸ ), -S(=0) ₂ (Ci-C ₆ -alkyl),

-S(=0) ₂ -(C ₂ -C ₆ -alkenyl), -S(=0)(=NR )(Ci-C ₃ -alkyl), -N(0) ₂ ,

-P(=0)(Ci-C ₃ -alkyl) ₂ and SF ₅ ,

or

wherein two vicinal substituents may form together a 5- or 6-membered, optionally heterocyclic, aromatic or non-aromatic ring, having optionally 1-3 heteroatoms independently selected from -N=, -NH-, -N(R ⁷ )-, -0-, -S-, and optionally containing a C(=0) group, and wherein the so formed ring is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from

Ci-Cg-alkyl, Ci-C ₆ -haloalkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, aryl, -(Ci-C ₆ -a I kyl )-a ryl, -aryl-(Ci-C ₆ -alkyl), C ₃ -C ₈ -cycloalkyl, Ci-C ₆ -alkoxy, -0(C ₂ -C ₆ -alkenyl), Ci-C ₆ - haloalkoxy, C ₃ -C ₈ -cycloalkoxy, aryl, -O-aryl, cyano, -C(0)OH, hydroxy, -SH, -S-(Ci-C ₆ -alkyl), -S-(C ₂ -C ₆ -alkenyl), -S(=0) ₂ (C ₁ -C ₆ -alkyl), -N(0) ₂ , and -N(R ⁷ )(R ⁸ ) and

a bicyclic aryl group,

a partially saturated mono- or bicyclic aryl- or heteroaryl group,

a monocyclic- or bicyclic heteroaryl group,

which is optionally substituted one, two or three times, each substituent independently selected from a halogen atom or a group selected from Ci-Cg-alkyl, Ci-C ₆ -haloalkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, -(Ci-C ₆ -alkyl)-aryl, -aryl- (Ci-Cg-alkyl), C ₃ -C ₈ -cycloalkyl, Ci-C ₆ -alkoxy, Ci-C ₆ -haloalkoxy, -0(C ₂ -C ₆ -alkenyl), C ₃ -C ₈ -cycloalkoxy, aryl, -O-aryl, cyano, C(=0)0R ⁶ , hydroxy, -SH, -S-(Ci-C ₆ -alkyl), -S-(C ₂ -C ₆ -alkenyl), -S(=0) ₂ (Ci-C ₆ -alkyl), -S(=0) ₂ -(C ₂ -C ₆ -alkenyl), -N(0) ₂ , and - N(R ⁷ )(R ⁸ ),

R ² represents a hydrogen atom or a halogen atom, R ³ represents a group selected from,

a Ci-Cg-alkyl group,

which is optionally substituted with a C ₃ -C ₈ -cycloalkyl group, a C ₃ -C ₈ -cycloalkyl group, a Ci-Cg-haloalkyl group,

a Ci-Cg-hydroxyalkyl group,

a C ₂ -C ₆ -alkenyl group,

a C ₂ -C ₆ -alkynyl group,

a C ₄ -C ₈ -cycloalkenyl group,

a (Ci-C ₆ -alkyl)-N(R ⁷ )R ⁸ group,

a -(Ci-C ₆ -alkyl)-(4- to 7-membered nitrogen containing heterocycloalkyl) group,

wherein said 4- to 7-membered nitrogen containing heterocycloalkyl group is connected to the alkyl group via a carbon atom of the heterocycloalkyl group and which is optionally substituted with a Ci-C ₃ -alkyl group, and a phenyl group,

which is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from

Ci-Cg-alkyl, Ci-C ₆ -haloalkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, aryl, -(Ci-C ₆ -a I kyl )-a ryl, -aryl-(Ci-C ₆ -alkyl), C ₃ -C ₈ -cycloalkyl, Ci-C ₆ -alkoxy, -0(C ₂ -C ₆ -alkenyl), Ci-C ₆ - haloalkoxy, C ₃ -C ₈ -cycloalkoxy, aryl, -O-aryl, cyano, -C(0)0H, hydroxy, -SH, -S-(Ci-C ₆ -alkyl), -S-(C ₂ -C ₆ -alkenyl), -S(=0) ₂ (Ci-C ₆ -alkyl), -S(=0) ₂ -(C ₂ -C ₆ -alkenyl), -N(0) ₂ , and -N(R ⁷ )(R ⁸ )

R ⁴ represents a group selected from,

a Ci-Cg-alkyl group,

which is optionally substituted with a group selected from

C ₃ -C ₈ -cycloalkyl and phenyl,

wherein said phenyl group is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from

Ci-Cg-alkyl, Ci-Cg-haloalkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, aryl, -(Ci-C ₆ - alkyl)-aryl, -aryl-(Ci-C ₆ -alkyl), C ₃ -C ₈ -cycloalkyl, Ci-C ₆ -alkoxy, -0(C ₂ -C ₆ - alkenyl), Ci-C ₆ -haloalkoxy, C ₃ -C ₈ -cycloalkoxy, aryl, -O-aryl, cyano, -C(=0)0R ⁶ , hydroxy, -SH, -S-(Ci-C ₆ -alkyl), -S-(C ₂ -C ₆ -alkenyl), S(=0) ₂ (Ci-C ₆ - al kyl), -S(=0) ₂ -(C ₂ -C ₆ -alkenyl),-N(0) ₂ , and -N(R ⁷ )(R ⁸ )

a C ₂ -C ₆ -alkenyl group,

a C ₃ -C ₈ -cycloalkyl group, a C ₂ -C ₆ -haloalkyl group,

a C ₂ -C ₆ -hydroxyalkyl group,

a-(C ₂ -C ₆ -alkyl)-N(R ⁷ )(R ⁸ ) group, R ⁵ represents a halogen atom or a group selected from

a Ci-Cg-alkyl group,

a C ₃ -C ₈ -cycloalkyl group,

a Ci-Cg-haloalkyl group, which is optionally substituted with a hydroxy group, a Ci-Cg-hydroxyalkyl group,

a -(Ci-C ₆ -alkyl)-N(R ⁷ )(R ⁸ ) group,

a -(Ci-C ₆ -alkyl)-0-(Ci-C ₆ -alkyl) group,

a C ₂ -C ₆ -alkenyl group,

a C ₂ -C ₆ -alkynyl group,

a Ci-Cg-alkoxy group,

a Ci-Cg-alkylsulfanyl group,

a -N(R ⁷ )(R ⁸ ) group,

a -C(=0)0R ⁶ group,

a -C(=0)N(R ⁷ )(R ⁸ ) group,

a -S(=0)(=NR )(Ci-C ₃ -alkyl) group, and

a phenyl group

which is optionally substituted one, two or three times, each substituent independently selected from a halogen atom or a group selected from Ci-C ₆ -alkyl, Ci-Cg-haloalkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, aryl, -(Ci-C ₆ -alkyl)-aryl, -aryl-(Ci-C ₆ - alkyl), C ₃ -C ₈ -cycloalkyl, Ci-C ₆ -alkoxy, -0(C ₂ -C ₆ -alkenyl), Ci-C ₆ -haloalkoxy,

C ₃ -C ₈ -cycloalkoxy, aryl, -O-aryl, cyano, -C(=0)0R ⁶ , hydroxy, -SH, -S-(Ci-C ₆ -alkyl), -S-(C ₂ -C ₆ -a Ikenyl ), S(=0) ₂ (Ci-C ₆ -aikyl), -S(=0) ₂ -(C ₂ -C ₆ -aikenyl),-N(0) ₂ , and -N(R ⁷ )(R ⁸ )

R ¹ represents a hydrogen atom or a group selected from

a Ci-Cg-alkyl group and a benzyl group,

R ⁷ and R ⁸ represent, independently for each occurrence, a hydrogen atom or a grou p selected from a Ci-Cg-alkyl group, a C -C ₆ -hydroxyalkyl group, a C ₃ -C ₆ -cycloalkyl group, and a -(C ₂ -C ₆ - alkyl)-N(R ⁹ )(R ¹⁰ ) group,

or

R ⁷ and R ⁸ together with the nitrogen to which they are attached represent a nitrogen containing 4- to 7-membered heterocycloalkyl group,

which is optionally substituted with a group selected from

Ci-Cs-alkyl, -S(=0) ₂ (C ₁ -C ₃ -alkyl) and -C(=0)0(Ci-C ₄ -alkyl),

R ⁹ and R ¹⁰ represent, independently for each occurrence, a hydrogen atom or

a Ci-C ₃ -alkyl group,

or

R ⁹ and R ¹⁰ together with the nitrogen to which they are attached represent a

nitrogen containing 4- to 7-membered heterocycloalkyl group, R ¹¹ represents a hydrogen atom or a group selected from

a cyano group and a -C(=0)(Ci-C ₃ -haloaikyl) group, or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxid thereof. The definitions of the substituents in said dihydroorotate dehydrogenase (DHODH)-inhibiting 2,4,5-trisubstituted 1,2,4-triazolone compounds of general formula (B-l) of the inventive combinations of the present invention, unless specified otherwise, are defined as follows:

The term "substituted" means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.

The term "optionally substituted" means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, it is possible for the number of optional substituents, when present, to be 1, 2, 3, 4 or 5, in particular 1, 2 or 3. As used herein, the term "one or more", e.g. in the definition of the substituents of the compounds of general formula (B-l) of the present invention, means "1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, more particularly 1, 2 or 3, even more particularly 1 or 2".

As used herein, an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.

The term "ring substituent" means a substituent attached to an aromatic or nonaromatic ring which replaces an available hydrogen atom on the ring.

Should a composite substituent be composed of more than one parts, e.g. (Ci-C3-alkoxy)-(Ci-C ₆ -alkyl)-, it is possible for the position of a given part to be at any suitable position of said composite substituent, i.e. the Ci-C ₃ -alkoxy part can be attached to any carbon atom of the Ci-C ₆ -alkyl part of said (Ci-C3-alkoxy)-(Ci-C ₆ alkyl)- group. A hyphen at the beginning or at the end of such a composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule. Should a ring, comprising carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen or sulfur atoms for example, be substituted with a substituent, it is possible for said substituent to be bound at any suitable position of said ring, be it bound to a suitable carbon atom and/or to a suitable heteroatom.

The term "comprising" when used in the specification includes "consisting of".

If within the present text any item is referred to as "as mentioned herein", it means that it may be mentioned anywhere in the present text.

The terms as mentioned in the present text have the following meanings:

The term "halogen atom" means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.

The term "Ci-C ₈ -alkyl" means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert- butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl,

1.2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl,

2.2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, heptyl or octyl group, or an isomer thereof. Particularly, said group has 1, 2, 3, 4, 5 or 6 carbon atoms ("Ci-Cg-alkyl"), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert- butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or 1,3-dimethylbutyl group. Particularly, said group has 1, 2, 3 or 4 carbon atoms ("Ci-C ₄ -alkyl"), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or tert- butyl group, more particularly 1, 2 or 3 carbon atoms ("Ci-C ₃ -alkyl"), e.g. a methyl, ethyl, n-propyl or isopropyl group.

The term "Ci-C ₆ -hydroxyalkyl" means a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C ₆ -alkyl" is defined supra, and in which 1 or 2 hydrogen atoms are replaced with a hydroxy group, e.g. a hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,

1.2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, l-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 2,3-dihydroxypropyl, l,3-dihydroxypropan-2-yl, 3-hydroxy-2- methylpropyl, 2-hydroxy-2-methyl-propyl, l-hydroxy-2-methyl-propyl group. Particularly, said group has 1, 2 or 3 carbon atoms ("Ci-C ₃ -hydroxyalkyl"), e.g. a hydroxymethyl, 1-hydroxyethyl,

2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, l-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 2,3-dihydroxypropyl or l,3-dihydroxypropan-2-yl group.

The term "Ci-C ₆ -cyanoalkyl" means a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-Cg-alkyl" is defined supra, and in which 1 or 2 hydrogen atoms are replaced with a cyano group, e.g. a cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 1,2-dicyanoethyl,

3-cyanopropyl, 2-cyanopropyl, 1-cyanopropyl, l-hydroxypropan-2-yl, 2-cyanopropan-2-yl,

2.3-dicyanopropyl, l,3-dicyanopropan-2-yl, 3-cyano-2-methylpropyl, 2-cyano-2-methyl-propyl, l-cyano-2-methyl-propyl group. Particularly, said group has 1, 2 or 3 carbon atoms

("Ci-C ₃ -cyanoalkyl"), e.g. a cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 1,2-dicyanoethyl, 3-cyanopropyl, 2-cyanopropyl, 1-cyanopropyl, l-cyanopropan-2-yl, 2-cyanopropan-2-yl,

2.3-dicyanopropyl or l,3-dicyanopropan-2-yl group, more particularly, said group has 1, 2 or 3 carbon atoms ("Ci-C ₃ -cyanoalkyl"), e.g. a cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyl, 2-cyanopropyl, 1-cyanopropyl, l-cyanopropan-2-yl or 2-cyanopropan-2-yl group. The term "Ci-C ₆ -alkylsulfanyl" means a linear or branched, saturated, monovalent group of formula (Ci-C ₆ -alkyl)-S-, in which the term "Ci-C ₆ -alkyl" is as defined supra, e.g. a methylsulfanyl, ethylsu Ifanyl, propylsulfanyl, isopropylsulfanyl, butylsu Ifanyl, sec-butylsulfanyl, isobutylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, isopentylsulfanyl, hexylsulfanyl group.

The term "C2-C ₈ -haloalkyl" means a linear or branched, saturated, monovalent hydrocarbon group in which the term "C ₂ -C ₃ -al kyl" is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said C ₂ -C ₈ -haloalkyl group is, for example, 2-fluoroethyl, 2.2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or

1.3-difluoropropan-2-yl. Particularly, said group has 2, 3, 4 5 or 6 carbon atoms ("C ₂ -C ₆ -haloalkyl") .

The term "Ci-Cg-haloalkyl" means a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C ₆ -alkyl" is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said Ci-C ₆ -haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or l,3-difluoropropan-2-yl. Particularly, said group has 1, 2, 3 or 4 carbon atoms ("Ci-C ₄ -haloalkyl"), more particularly 1, 2 or 3 carbon atoms

("Ci-C ₃ -haloalkyl"), e.g. fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,

2.2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or

1.3-difluoropropan-2-yl.

For any alkyl group being substituted the position of the substitutent may be at any position of the alkyl group indenpendently whether the alkyl group is defined as "an alkyl group which is substituted by [substituent X]" or " a [substituent X]-Ci-C ₆ -alkyl" group.

The term "Ci-C ₆ -alkoxy" means a linear or branched, saturated, monovalent group of formula (Ci-C ₆ -alkyl)-0-, in which the term "Ci-C ₆ -alkyl" is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert- butoxy, pentyloxy, isopentyloxy or n-hexyloxy group, or an isomer thereof. Particularly, said group has 1, 2 or 3 carbon atoms ("Ci-C3-alkoxy"), e.g. a methoxy, ethoxy, n-propoxy or isopropoxy group.

The term "Ci-C ₆ -haloalkoxy" means a linear or branched, saturated, monovalent Ci-C ₆ -alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said Ci-Cg-haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy. Particularly, said group has 1, 2 or 3 carbon atoms ("Ci-C3-haloalkoxy"), e.g. a fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoro ethoxy or pentafluoroethoxy group.

The term "C2-C ₆ -alkenyl" means a linear or branched, monovalent hydrocarbon group, which contains one double bond, 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 it is possible for said double bonds to be isolated from, or conjugated with, each other. Said alkenyl group is, for example, an ethenyl (or "vinyl"), prop-2-en-l-yl (or "allyl"), prop-l-en-l-yl, but-3-enyl, but-2-enyl, but-l-enyl, pent-4-enyl, pent-3-enyl, pent-2-enyl, pent-l-enyl, hex-5-enyl, hex-4-enyl, hex-3-enyl, hex-2-enyl, hex-l-enyl, prop-l-en-2-yl (or "isopropenyl"), 2-methylprop-2-enyl, l-methylprop-2-enyl,

2-methylprop-l-enyl, 1-methylprop-l-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, l-methylbut-3-enyl, 3-methylbut-2-enyl, 2-methylbut-2-enyl, l-methylbut-2-enyl,

3-methylbut-l-enyl, 2-methylbut-l-enyl, 1-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, l-methylpent-4-enyl, 4-methylpent-3-enyl, 3-methylpent-3-enyl,

2-methylpent-3-enyl, l-methylpent-3-enyl, 4-methylpent-2-enyl, 3-methylpent-2-enyl, 2-methylpent-2-enyl, l-methylpent-2-enyl, 4-methylpent-l-enyl, 3-methylpent-l-enyl,

2-methylpent-l-enyl, 1-methylpent-l-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl,

1-ethylbut-3-enyl, 3-ethylbut-2-enyl, 2-ethylbut-2-enyl, l-ethylbut-2-enyl, 3-ethylbut-l-enyl,

2-ethylbut-l-enyl, 1-ethylbut-l-enyl, 2-propylprop-2-enyl, l-propylprop-2-enyl,

2-isopropylprop-2-enyl, l-isopropylprop-2-enyl, 2-propylprop-l-enyl, 1-propylprop-l-enyl, 2-isopropylprop-l-enyl, 1-isopropylprop-l-enyl, 3,3-dimethylprop-l-enyl, or l-(l,l-dimethylethyl)ethenyl group. Particularly, said group is allyl.

The term "C -C ₆ -alkynyl" means a linear or branched, monovalent hydrocarbon group which contains one triple bond, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C -C ₃ -alkynyl"). Said C ₂ -C ₆ -alkynyl group is, for example, ethynyl, prop-l-ynyl, prop-2-ynyl (or "propargyl"), 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-ynyl, hex-3-ynyl, 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, l-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methyl- pent-4-ynyl, 2-methylpent-3-ynyl, l-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methyl- pent-2-ynyl, 4-methylpent-l-ynyl, 3-methylpent-l-ynyl, 2-ethylbut-3-ynyl, l-ethylbut-3-ynyl, l-ethylbut-2-ynyl, l-propylprop-2-ynyl, l-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, l,l-dimethylbut-3-ynyl, l,l-dimethylbut-2-ynyl or 3,3-dimethylbut-l-ynyl group.

The term "bicyclic aryl group means an aromatic ring system selected from naphthyl, indenyl.

The term "partially saturated mono- or bicyclic aryl- or heteroaryl" includes dihydrophenyl, tetrahydrophenyl, 5- to 7-membered heterocycloalkenyl (as further defined below), indanyl, tetralinyl, tetralonyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, dihydrocinnolinyl, tetrahydrocinnolinyl, dihydrophthalazinyl, tetrahydrophthalazinyl, dihydroquinoxalinyl, tetrahydroquinoxalinyl, dihydropteridinyl or tetrahydropteridinyl, dihydroindolyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzimidazolyl dihydrobenzoxazolyl, dihydrobenzisoxazolyl, dihydrobenzimidazolyl, dihydrobenzothiazolyl, dihydrobenzotriazolyl, dihydroindazolyl, dihydroisoindolyl, dihydroindolizinyl or dihydropurinyl.

The term "C3-C ₈ -cycloalkyl" means a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms ("C3-C ₈ -cycloalkyl"). Said C3-Cs-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[4.2.0]octyl or octahydropentalenyl. Particularly, said group contains 3, 4, 5 or 6 carbon atoms ("C3-C ₆ -cycloalkyl"), e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group. Particularly, said group contains 4, 5, 6, 7 or 8 carbon atoms ("C4-C8-cycloalkyl"), e.g. a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group.

The term "C ₄ -C ₈ -cycloalkenyl" means a monovalent, mono- or bicyclic hydrocarbon ring which contains 4, 5, 6, 7 or 8 carbon atoms and one double bond. Particularly, said ring contains 4, 5 or 6 carbon atoms ("C4-C6-cycloalkenyl"). Said C ₄ -C ₈ -cycloalkenyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[2.2.1]hept-2-enyl or bicyclo[2.2.2]oct-2-enyl.

The term "C ₃ -C ₈ -cycloalkoxy" means a saturated, monovalent, mono- or bicyclic group of formula (C ₃ -C ₈ -cycloalkyl)-0-, which contains 3, 4, 5, 6, 7 or 8 carbon atoms, in which the term "C ₃ -C ₈ -cycloalkyl" is defined supra, e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy group. Particularly, said group has 3, 4, 5 or 6 carbon atoms ("C ₃ -C ₆ -cycloalkoxy"), e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy group.

The terms "4- to 7-membered heterocycloalkyl" and "4- to 6-membered heterocycloalkyl" mean a monocyclic, saturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S 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 and not excluded otherwise, a nitrogen atom. Said heterocycloalkyl group, without being limited thereto, can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolid inyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazinanyl, for example, or a 7-membered ring, such as azepanyl, 1,4-diazepanyl or 1,4-oxazepanyl, for example.

The terms "4- to 7-membered nitrogen containing heterocycloalkyl" and "4- to 6-membered nitrogen containing heterocycloalkyl" mean a monocyclic, saturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring atoms in total, containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O, S atom.

Said nitrogen containing heterocycloalkyl group, without being limited thereto, can be a 4- membered ring, such as azetidinyl for example; or a 5-membered ring, such as pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolidinyl, for example; or a 6-membered ring, such as piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl or 1,2-oxazinanyl, for example, or a 7-membered ring, such as azepanyl, 1,4-diazepanyl or 1,4-oxazepanyl, for example.

The term "5- to 7-membered heterocycloalkenyl" means a monocyclic, unsaturated, non- aromatic heterocycle with 5, 6 or 7 ring atoms in total, which contains one or two double bonds and one or two ring heteroatoms independently selected from the series: N, O, S.

Said heterocycloalkenyl group is, for example, 4H pyranyl, 2H pyranyl, 2,5 dihydro 1H pyrrolyl, [l,3]dioxolyl, 4H [l,3,4]thiadiazinyl, 2,5 dihydrofuranyl, 2,3 dihydrofuranyl, 2,5 dihydrothio-phenyl, 2,3 dihydrothiophenyl, 4,5 dihydrooxazolyl or 4H [l,4]thiazinyl.

The term "4-7-membered, optionally unsaturated, heterocyclic group" includes the terms "4- to 7-membered heterocycloalkyl" and "5- to 7-membered heterocycloalkenyl".

The term "aryl" means phenyl and naphthyl.

The term "phenyl groups of which two vicinal substituents may form together a 5- or 6- membered, optionally aromatic or non-aromatic ring, and optionally containing a C(=0) group" includes naphthalinyl, indanyl and tetralinyl.

The term "heteroaryl" means a monovalent, monocyclic or bicyclic aromatic ring having 5, 6, 8, 9 or 10 ring atoms (a "5- to 10-membered heteroaryl" group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).

Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a 9-membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolizinyl or purinyl; or a 10- membered heteroaryl group, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl or pteridinyl.

In general, and unless otherwise mentioned, the heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g. \ tautomers and positional isomers with respect to the point of linkage to the rest of the molecule. Thus, for some illustrative non-restricting examples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.

The term "Ci-C ₆ ", as used in the present text, e.g. in the context of the definition of "Ci-Cg-alkyl", "Ci-C ₆ -haloalkyl", "Ci-C ₆ -hydroxyalkyl", "Ci-C ₆ -alkoxy" or "Ci-C ₆ -haloalkoxy" means 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.

Further, as used herein, the term "C ₃ -C ₈ ", as used in the present text, e.g. in the context of the definition of "C ₃ -C ₈ -cycloalkyl", means a cycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e. 3, 4, 5, 6, 7 or 8 carbon atoms.

When a range of values is given, said range encompasses each value and sub-range within said range.

For example:

"Ci-C ₈ " encompasses Ci, C ₂ , C ₃ , C ₄ , C ₅ , Cs, C ₇ , C ₈ , Ci-C ₈ , C ₁ -C ₇ , C ₁ -C ₆ , C ₁ -C ₅ , C ₁ -C ₄ , Ci-C ₃ , C ₁ -C ₂ , C ₂ - C ₈ , C ₂ -C ₇ , C ₂ -C ₆ , C ₂ -C ₅ , C ₂ -C ₄ , C ₂ -C ₃ , C ₃ -C ₈ , C ₃ -C ₇ , C ₃ -C ₆ , C ₃ -C ₅ , C ₃ -C ₄ , C ₄ -C ₈ , C ₄ -C ₇ , C ₄ -C ₆ , C ₄ -C ₅ , Cs-Cg, C ₅ -C ₇ , C ₅ -C ₆ , Cg-Cg, C ₆ -C ₇ and C ₇ -C ₈ ;

"Ci-Cs" encompasses Ci, C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₁ -C ₆ , C ₁ -C ₅ , C ₁ -C ₄ , Ci-C ₃ , C ₁ -C ₂ , C ₂ -C ₆ , C ₂ -C ₅ , C ₂ -C ₄ , C ₂ -C ₃ , C ₃ -Cs, C ₃ -C ₅ , C ₃ -C ₄ , C4-C6, C4-C5, and C5-C6;

"C1-C4" encompasses Ci, C2, C ₃ , C ₄ , C1-C4, Ci-C ₃ , C1-C2, C2-C4, C2-C ₃ and C ₃ -C ₄ ;

"Ci-C ₃ " encompasses Ci, C2, C ₃ , Ci-C ₃ , C1-C2 and C2-C ₃ ;

l ^l C ₂ -C ₆ ¹¹ encompasses C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₂ -C ₆ , C ₂ -C ₅ , C ₂ -C ₄ , C ₂ -C ₃ , C ₃ -C ₆ , C ₃ -Cs,

C ₃ -C ₄ , C ₄ -C ₆ , C ₄ -C ₅ , and C -C _: :

"C ₃ -C ₈ " encompasses C ₃ , C ₄ , C ₅ , Ce, C ₇ , C ₈ , C ₃ -C ₈ , C ₃ -C ₇ , C ₃ -C ₆ , C ₃ -Cs, C ₃ -C ₄ , C ₄ -C ₈ , C ₄ -C ₇ , C ₄ -C ₆ , C ₄ -C ₅ ,

Cs-Cg, C ₅ -C ₇ , C ₅ -C ₆ , Cs-Cg, C ₆ -C ₇ and Cj-Cs,'

"Cg-Cs" encompasses C ₃ , C ₄ , C ₅ , C ₆ , C ₃ -C ₆ , C ₃ -Cs, C ₃ -C ₄ , C ₄ -C ₆ , C ₄ -C ₅ , and C ₅ -C ₆ J "C^Cg" encompasses C ₄ , C ₅ , C ₇ , Cs, C ₄ -C ₈ , C ₄ -C ₇ , C ₄ -C ₆ , C ₄ -C ₅ , C ₅ -C ₈ , C ₅ -C ₇ ,

C ₅ -C ₆ , C ₆ -C8, C ₆ -C ₇ and C ₇ -C8;

^M C ₄ -C ₇ ^M encompasses C ₄ , C ₅ , C _& C ₇ , C ₄ -C ₇ , C ₄ -C ₆ , C ₄ -C ₅ , C ₅ -C ₇ , C ₅ -C ₆ and C^-C ,'

"C ₄ -C ₆ " encompasses C ₄ , C ₅ , C ₆ , C ₄ -C ₆ , C ₄ -C ₅ and C ₅ -C ₆ ;

"C ₅ -C ₁₀ " encompasses C ₅ , Ce, C ₇ , Cs, Cg, C ₁₀ , C ₅ -C ₁₀ , C ₅ -C ₉ , Cs-Cs, C ₅ -C ₇ , C ₅ -C ₆ , C ₆ -Cio _;

Cg-Cg, Cg-Cg, C ₅ -C ₇ , C ₇ -C ₁₀ , C ₇ -C ₉ , C- _/~ Cg, C _g -Cio, Cs-Cg and C _g -Cio;

"C ₆ -C ₁₀ " encompasses C _g , C ₇ , Cs, C _g , C ₁₀ , C _g -Cio, C _g -Cg, C _g -C _g , Cg-Cj, C ₇ -C ₁₀ , C ₇ -C ₉ , C- _/ -Cg, Cg-Cio, Cg-C _g and C ₉ -C ₁₀ . The term "substituent" refers to a group "substituted" on, e.g., an alkyl, haloalkyl, cycloalkyl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, aryl, or heteroaryl group at any atom of that group, replacing one or more hydrogen atoms therein. In one aspect, the substituent(s) on a group are independently any one single, or any combination of two or more of the permissible atoms or groups of atoms delineated for that substituent. In another aspect, a substituent may itself be substituted with any one of the above substituents. Further, as used herein, the phrase "optionally substituted" means unsubstituted (e.g., substituted with an H) or substituted.

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 independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.

In accordance with an embodiment, the present invention relates to combinations of component A and component B, 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, or 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydro imid-azo[l,2-c]quinazolin-5- yl] pyrimidine-5-carboxamide dihydrochloride; or a 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 accordance with an embodiment, the present invention relates to combinations of component A and component B, wherein said component B is N-(2-chloro-6-fluorophenyl)-4-[4- ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l -yl]-5-fluoro-2-{[(2S)-l,l,l- trifluoropropan-2-yl]oxy}benzamide; or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxide thereof; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.

In accordance with an embodiment, the present invention relates to combinations of component A and component B, 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-carboxamid e, or 2-amino-N-[7-methoxy-8- (3-morpholin-4-ylpropoxy)-2,3-dihydroimid-azo[l,2-c]quinazol in-5-yl]pyrimidine-5-carboxamide dihydrochloride; or a 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 N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-o xo-4,5- dihydro-lH-l,2,4-triazol-l-yl]-5-fluoro-2-{[(2S)-l,l,l-trifl uoropropan-2-yl]oxy}benzamide; or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxide thereof; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. In accordance with an embodiment, the present invention relates to combinations of component A and component B, 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-carboxamid e, and wherein: said component B is N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-o xo-4,5- dihydro-lH-l,2,4-triazol-l-yl]-5-fluoro-2-{[(2S)-l,l,l-trifl uoropropan-2-yl]oxy}benzamide.

In accordance with an embodiment, the present invention relates to combinations of component A and component B, 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-carboxamid e dihydrochloride, and wherein: said component B is N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-o xo-4,5- dihydro-lH-l,2,4-triazol-l-yl]-5-fluoro-2-{[(2S)-l,l,l-trifl uoropropan-2-yl]oxy}benzamide.

In accordance with an embodiment, the present invention relates to combinations of component A and component B, 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-carboxamid e dihydrochloride, or a solvate, hydrate or stereoisomer thereof ; and wherein: said component B is N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-o xo-4,5- dihydro-lH-l,2,4-triazol-l-yl]-5-fluoro-2-{[(2S)-l,l,l-trifl uorOpropan-2-yl]oxy}benzamide or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxide thereof.

In accordance with an embodiment, the present invention relates to combinations of component A and component B, 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-carboxamid e, or a pharmaceutically acceptable salt, a solvate, hydrate or stereoisomer thereof ; and wherein: said component B is N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-o xo-4,5- dihydro-lH-l,2,4-triazol-l-yl]-5-fluoro-2-{[(2S)-l,l,l-trifl uoropropan-2-yl]oxy}benzamide or a tautomer, an N-oxide, a salt, a salt of a tautomer or a salt of an N-oxide thereof.

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.

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.

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 independently 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 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, hydroxypropyl- cellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol ^* ); 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, AcDiSof )),

• flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil ^* )),

• 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, hydroxypropyl- methylcellulose 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 gal late), · 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 pharmaceutical compositions which comprise at least a combination of component A and component B 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

As mentioned supra, the present invention also relates to : • the use of any combinations as described herein in the treatment or prophylaxis of a cancer,

• the use of any combinations as described herein for the preparation of a medicament for the treatment or prophylaxis of a cancer, and

· a method of treatment or prophylaxis of a cancer, comprising administering to a mammal in need thereof, including a human, an amount of a combination as described herein, which is effective for the treatment or prophylaxis of cancer.

Within the context of the present invention, the term "cancer" includes, but is not limited to the following :

Breast cancers, examples of which include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. Cancers of the respiratory tract, example of which include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma. Brain cancers, examples of which include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.

Tumours of the male reproductive organs, examples of which include, but are not limited to, prostate and testicular cancer.

Tumours of the female reproductive organs, examples of which include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.

Tumours of the digestive tract, examples of which include, but are not limited to, anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers. Tumours of the urinary tract, examples of which include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.

Eye cancers, examples of which include, but are not limited to, intraocular melanoma and retinoblastoma. Liver cancers, examples of which 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, examples of which 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, examples of which include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.

Lymphomas, examples of which include, but are not limited to, AIDS-related lymphoma, chronic lymphocytic lymphoma (CLL), non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T- NHL), subtypes of NHL such as Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell lymphoma DLBCL, double-hit lymphoma and double-expressor lymphoma; anaplastic large cell lymphoma, B-cell lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, hairy cell lymphoma, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoma of the central nervous system, small lymphocytic lymphoma and chronic lymphocytic lymphoma and Sezary syndrome.

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

Leukemias, examples of which include, but are not limited to acute lymphoblastic leukemia, acute myeloid leukemia, (acute) T-cell leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia (ALL) , acute monocytic leukemia (AML), acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and also myelodysplastic syndrome (MDS), which can develop into an acute myeloid leukemia. In particular, the present invention relates to a method for using the combinations of the present invention, in the treatment or prophylaxis of a cancer, particularly lymphomas, such as AIDS-related lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, lymphoma of the central nervous system, or non-Hodgkin's lymphoma (hereinafter abbreviated to "NHL"), particularly 1st line, 2nd line, relapsed, refractory, indolent or aggressive non- Hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukaemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), mantle cell lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL"). 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 non-Hodgkin's lymphoma (hereinafter abbreviated to "NHL"), particularly 1st line, 2nd line, relapsed, refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukaemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), mantle cell lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL"). 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 non- Hodgkin's lymphoma (hereinafter abbreviated to "NHL"), particularly 1st line, 2nd line, relapsed, refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukaemia

(hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), mantle cell lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL").

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 non-Hodgkin's lymphoma (hereinafter abbreviated to "NHL"), particularly 1st line, 2nd line, relapsed, refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukaemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), mantle cell lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL"), 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 cancer. 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, 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, 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 glycid idazole, 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, 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 chemotherapeutic agents, (3) 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 Example describes the feasability of the present invention, but not restricting the invention to this Example only.

EXAMPLES

The following abbreviations are used in the Examples: "Compound A" (or "cpd. A" or "copanlisib") means 2-amino-N-[7-methoxy-8-(3-morpholin-4- ylpropoxy)-2,3-dihydroimid-azo[l,2-c]quinazolin-5-yl]pyrimid ine-5-carboxamide

dihydrochloride: it is published in international patent application PCT/EP2012/055600, published as WO 2012/136553 on October 11, 2012, (which is incorporated herein by reference in its entirety), as the compound of Examples 1 and 2 : 2-amino-N-[7-methoxy-8-(3-morpholin- 4-ylpropoxy)-2,3-dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimi dine-5-carboxamide

dinydrochloride: it may be synthesized according to the methods given in said Examples 1 and

2.

2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydro imidazo[l,2-c]quinazolin-5- yl] pyrimidine-5-carboxamide dihydrochloride is a compound of structure :

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

"Compound B" (or "cpd. B" or "DHODH In h") means N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3- (hydroxymethyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl]-5-f luoro-2-{[(2S)-l,l,l- trifluoropropan-2-yl]oxy}benzamide: it is exemplified in international patent application PCT/EP2017/077252, (which is incorporated herein by reference in its entirety), as the compound of Example 121.

N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)- 5-oxo-4,5-dihydro-lH-l,2,4-triazol-l- yl]-5-fluoro-2-{[(2S)-l,l,l-trifluoropropan-2-yl]oxy}benzami de is a compound of structure :

and is an example of component B as described and defined herein. The synthesis of N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-o xo-4, 5-dihydro- lH-l,2,4-triazol-l-yl]-5-fluoro-2-{[(2S)-l,l,l-trifluoroprop an-2-yl]oxy}benzamide is described in Internation patent application PCT/EP2017/077252 and is described below :

Synthesis of compound B : N-(2-chloro-6-fluorophenyl)-4-f4-ethyl-3-(hvdroxymethyl)-5-o xo- 4.5-dihvdro-lH-1.2.4-triazol-l-vn-5-fluoro-2-{f -l.l.l-trifluoropropan-2- benzamide :

NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. The ^-NMR data are listed in the form of ^-NMR peaklists. For each signal peak the d value in ppm is given, followed by the signal intensity, reported in round brackets. The d value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: di (intensityi), d ₂ (intensity ₂ ), ... , d, (intensity,), ... , d _h (intensity,,). The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A ^-NMR peaklist is similar to a classical ^-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical ^-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of target compounds (also the subject of the invention), and/or peaks of impurities. The peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compounds (e.g., with a purity of >90%).

Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify the reproduction of our manufacturing process on the basis of "by-product fingerprints". An expert who calculates the peaks of the target compounds by known methods (MestReC, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of target compounds as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical ¹ H- NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. Research Disclosure Database Number 605005, 2014, 01 Aug 2014, or http://www.researchdisclosure.com/searching-disclosures). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1% and 4%. Depending on the chemical structure and/or depending on the concentration of the measured compound it may be reasonable to set the parameter "MinimumHeight" <1%.

Chemical names were generated using the ACD/Name software from ACD/Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD/Name generated names. The following table 1 lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person. Table 1: Abbreviations

Other abbreviations have their meanings customary per se to the skilled person.

All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.

The compound and intermediates produced according to the methods described herein may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-SiT or KP-NH ^e in combination with a Biotage autopurifier system (SP4 ^* or Isolera Four”) and eluents such as gradients of hexane/ethyl acetate or DCM/methanol. In some cases, the compound and the intermediates may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

UPLC-MS Standard Procedures

Analytical UPLC-MS was performed as described below. The masses (m/z) are reported from the positive mode electrospray ionisation unless the negative mode is indicated (ESI-).

Method A (HPLC-MS):

Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 pm, 50x2. lmm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm.

Method B (HPLC-MS):

Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 pm, 50x2. lmm; eluent A: water + 0.2 Vol-% aq. ammonia (32%), eluent B: acetonitrile; gradient: 0-

1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm.

Preparation of Intermediate 1 : 4-Ethyl-5-(hvdroxymethyl)-2.4-dihvdro-3H-1.2.4-triazol-3-one

2-hydroxyacetohydrazide (50.0 g, 555 mmol) was dissolved in water (125 mL) and cooled to 0°C. Ethyl isocyanate (44 ml, 560 mmol) was added (very exotherm !) and the resulting mixture was stirred at room temperature overnight. The resulting suspension was treated with sodium hydroxide solution (64g, 50 wt% in water) (exotherm). The resulting solution was heated to 95 2C overnight. The yellow reaction mixture was neutralized with concentrated hydrochloric acid and the resulting cloudy solution was concentrated to dryness. The solids were triturated with a mixture of dichloromethane and isopropanol (4:1, 750 mL), the solution was filtered off and concentrated to dryness again to yield ~78g of crude product. The product was recrystallized from ethyl acetate to yield the desired product (56.2g, 71% yield).

'H-NMR (400 MHz, DMSO-d6) d [ppm] : 1.156 (6.88), 1.174 (16.00), 1.192 (7.02), 2.518 (0.48), 3.606 (2.02), 3.623 (6.84), 3.641 (6.79), 3.659 (1.96), 4.316 (4.51), 5.540 (0.94).

Preparation of Intermediate 2 : 4-Bromo-5-fluoro-2-{[(2S)-l,l,l-trifluoropropan-2- ylloxylbenzonitrile

To a stirred suspension of 4-bromo-2,5-difluorobenzonitrile (91 g, 417 mmol) and potassium carbonate (173 g, 1.25 mol) in N,N-dimethylformamide (910 ml) was added (S)-l,l,l- trifluoropropanol [CAS 3539-97-7] dropwise (52.4 g, 460 mmol). The resulting mixture was heated at 70 °C for for 15 hours and cooled to room temperature. The reaction was concentrated and the residue was diluted with water. The aqueous solution was extracted with DCM (3x). The combined organic washes were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give an oil (136.6 g). The residue was triturated with a mixture of hexanes and toluene (9:1, 200 mL) to give the desired product as a white solid (90.3 g, 93% purity, 64% yield). LC-MS (Method A): R, = 1.29 min; MS (ESIpos): m/z = 312.0 [M+H] ⁺ .

¹ H-NMR (400 MHz, CHLOROFORM-d) d [ppm] : 1.511 (4.41), 1.531 (15.64), 1.533 (16.00), 1.548 (15.84), 1.550 (15.83), 4.566 (1.08), 4.581 (2.68), 4.597 (3.18), 4.612 (2.62), 4.626 (1.01), 7.194 (5.27), 7.207 (7.60), 7.220 (7.57).

Preparation of Intermediate 3 : 4-Bromo-5-fluoro-2-{[(2S)-l.l.l-trifluoropropan-2- ylloxylbenzoic acid

To a solution of 4-bromo-5-fluoro-2-{[(2S)-l,l,l-trifluoropropan-2-yl]oxy}ben zonitrile (Intermediate 2, 27.4 g, 87.9 mmol) in ethanol (90 ml) was added aqueous sodium hydroxide (2 N, 140 ml) and the resulting mixture was heated to 90 °C for 20 hours. The resulting solution was cooled to room temperature, diluted with water, and extracted with dichloromethane. The aqueous phase was acidified with 2 N aqueous hydrochloric acid (pH 2) upon which a white solid precipitated. The suspension was stirred for further 15 minutes, the solid was filtered off, washed with water and dried in vacuo to yield an off-white solid (25.97 g, 89 %), which was used for the next step without further purification.

LC-MS (Method A): R, = 1.16 min; MS (ESIpos): m/z = 331 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) d [ppm] : 1.396 (15.96), 1.411 (16.00), 1.469 (0.69), 1.484 (0.45), 2.518 (3.48), 2.523 (2.36), 5.288 (1.19), 5.304 (2.89), 5.320 (3.73), 5.336 (2.70), 5.352 (1.05),

7.612 (11.35), 7.634 (11.12), 7.743 (7.88), 7.757 (7.91).

Preparation of Intermediate 4 : 4-Bromo-5-fluoro-2-{[(2S)-l,l,l-trifluoropropan-2- ylloxylbenzoyl chloride

To a solution of 4-bromo-5-fluoro-2-{[(2S)-l,l,l-trifluoropropan-2-yl]oxy}ben zoic acid (Intermediate 3, 15.0 g, 45.3 mmol) in dichloromethane (230 ml) was added N,N- dimethylformamide (350 mI), followed by dropwise addition of ethanedioyl dichloride (4.7 ml, 54 mmol). The reaction mixture was stirred at room temperature for one hour, and concentrated under reduced pressure. The title compound was obtained as brown oil (15.84 g, quantitative), which was used for the next step without purification. For analytic, a small amount of the product was treated with methanol, to yield the corresponding methyl ester, which was detected by LC-MS.

LC-MS (Method A) [methyl ester]: R _t = 1.36 min; MS (ESIpos): m/z = 345 [M+H] ⁺ . Preparation of Intermediate 5 : 4-Bromo-N-(2-chloro-6-fluorophenyl)-5-fluoro-2-{[(2S)-l.l.l- trifluoropropan-2-ylloxylbenzamide

4-Bromo-5-fluoro-2-{[(2S)-l,l,l-trifluoropropan-2-yl]oxy} benzoyl chloride (Intermediate 4, 31.9 g, 91.3 mmol) was dissolved in DCM (300 mL) and added to a solution of 2-chloro-6- fluoroaniline (14.6 g, 100.4 mmol) and triethylamine (14 ml, 100 mmol) in DCM (400 mL).The mixture was stirred at room temperature for 30 min. The mixture was concentrated to yield 47.9g of crude product. The crude product was dissolved in ethanol (250 mL) and water (500 mL) was added slowly. The resulting precipitate was filtered off, the solids were washed with water and dried to yield the desired product (39.3 g, 84.5 % yield).

LC-MS (Method A): R, = 1.44 min; MS (ESIpos): m/z = 458 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) d [ppm] : 1.343 (1.46), 1.359 (1.66), 1.387 (0.50), 1.437 (16.00), 1.452 (15.88), 1.475 (0.73), 1.495 (0.82), 1.513 (0.53), 1.907 (0.67), 2.332 (1.23), 2.518 (7.59), 2.523 (4.64), 2.673 (1.20), 5.400 (1.28), 5.416 (2.77), 5.432 (3.47), 5.448 (2.51), 5.464 (1.02),

7.323 (1.55), 7.328 (1.69), 7.347 (3.94), 7.354 (2.01), 7.363 (2.31), 7.371 (2.98), 7.383 (2.19),

7.395 (1.78), 7.402 (3.88), 7.416 (5.31), 7.425 (9.08), 7.431 (9.78), 7.445 (2.16), 7.481 (0.67),

7.502 (0.44), 7.528 (6.83), 7.549 (6.80), 7.665 (0.44), 7.680 (0.70), 7.694 (0.41), 7.820 (5.90),

7.833 (5.87), 9.977 (11.65). Preparation of compound B : N-(2-Chloro-6-fluorophenyl)-4-[4-ethyl-3-(hvdroxymethyl)-5-o xo-

4.5-dihvdro-lH-1.2.4-triazol-l-yl1-5-fluoro-2-{[(2S)-l.l. l-trifluoropropan-2-yl1oxy}benzamide

4-Bromo-N-(2-chloro-6-fluorophenyl)-5-fluoro-2-{[(2S)-l,l ,l-trifluoropropan-2- yl]oxy}benzamide (Intermediate 5, 100 mg, 218 pmol), 4-ethyl-5-(hydroxymethyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one (Intermediate 1, 46.8 mg, 327 pmol), tris(dibenzylideneacetone)dipailadium(0) (20 mg, 22 pmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (38 mg, 65 pmol), and cesium carbonate (142 mg, 436 pmol) were loaded into a microwave vial. The vial was purged with argon, dioxane (2 mL, degassed) was added, and the vial was sealed. The mixture was stirred for 17h at 110°C. The resulting suspension was filtered over Celite, washed with ethyl acetate and concentrated. Mass triggered preparative chromatography yielded the desired product (47.0 mg, 40 % yield).

LC-MS (Method A): R, = 1.16 min; MS (ESIpos): m/z = 521 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) d [ppm] : 1.137 (0.43), 1.233 (0.49), 1.264 (6.16), 1.282 (13.73), 1.300 (6.05), 1.436 (9.08), 1.451 (8.92), 2.084 (8.00), 2.322 (2.38), 2.326 (3.08), 2.331 (2.22),

2.518 (16.00), 2.522 (10.27), 2.664 (2.43), 2.669 (3.14), 2.673 (2.27), 3.764 (1.73), 3.782 (5.24),

3.800 (5.08), 3.818 (1.51), 4.479 (8.00), 4.493 (8.00), 5.331 (0.59), 5.347 (1.41), 5.363 (1.78),

5.380 (1.24), 5.396 (0.49), 5.759 (1.24), 5.789 (2.65), 5.803 (5.89), 5.817 (2.38), 7.337 (0.97), 7.356 (2.16), 7.372 (1.35), 7.380 (1.62), 7.388 (1.14), 7.408 (2.00), 7.422 (2.43), 7.433 (4.54),

7.439 (5.08), 7.453 (1.14), 7.550 (3.41), 7.575 (3.57), 7.588 (3.19), 7.602 (2.92), 10.065 (7.03). EXAMPLE 1: IN VIVO B CELL LYMPHOMA XENOGRAFT MODEL

Anti-tumor activity of compound B (DHODH Inh) in combination with copanlisib has been analyzed in murine xenograft models. For that purpose DLBCL cell line TMD8 was inoculated in the flank of female SCID mice. Each mouse was inoculated subcutaneously at the right flank with TMD8 cells for tumor development in 50% Medium and 50% Matrigel. The treatment was started when the average tumor reached about a size of above 100 mm ³ . Mice were allocated randomly into experimental groups according to their tumor sizes, 10 mice per group. This happened at day 20 post inocculation. Treatments were administrated to tumor-bearing mice from day 21 through day 86. Treatment groups were: vehicle control, copanlisib monotherapy, compound B (DHODH Inh) monotherapy in 2 doses and combination of copanlisib and compound B (DHODH Inh) (Table C). Tumor sizes were measured in two dimensions using a caliper, and the volume is expressed in mm ³ using the formula: V = 0.5 a x b ² , where a and b are the long and short diameters of the tumor, respectively. The T/C value is an indicator of tumor response to treatment and commonly used as anti-tumor activity endpoint. T and C are the mean tumor volume of the treated and control groups, respectively. Statistical analysis of difference in tumor volume among the groups was evaluated using one-way ANOVA on log transformed samples followed by multiple comparison procedures (Tukey ^' s method). P < 0.05 was considered to be statistically significant.

Figure 1 shows activity of compound B (DHODH Inh) in monotherapy and combination therapy with copanlisib during treatment of human TMD-8-DLBCL tumors. Compound B (DHODH Inh) has been applied orally at doses of 2 and 4 mg/kg once daily. Copanlisib was applied intraveneously for 2 days followed by a 5 day treatment break upon a dose of 14 mg/kg.

Compound B (DHODH Inh) exhibits a dose dependent any anti-tumor activity in vivo in monotherapy. Copanlisib shows tumor growth delay in this experiment. Combination of compound B (DHODH Inh) with copanlisib leads to tumoral regression and complete responses in 70% of the animals in this group indicating synergistic activity of compound B (DHODH Inh) and copanlisib. The combination group shows significant difference to the monotherapy compound B (DHODH Inh) and monotherapy copanlisib groups. In summary, this study demonstrates that combination of compound B (DHODH Inh) with PI3K inhibitor copanlisib can significantly improve the respective monotherapy efficacies in a model of DLBCL. TABLE C: Anti-Tumor activity of compound B in monotherapy and combination with compound

A in TMD-8 xenograft model in SCID mice.

* P<0.05 (statistically significant vs. Vehicle)

a) T/C= Treatment/ Control ratio, calculated from mean tumor volume at termination of control.

b) Response: PD = progressive disease, the number of tumors exhibiting >20% tumor increase; SD = stable disease, the number of tumors exhibiting <30% tumor shrinkage and <20% tumor increase; PR = partial response, the number of tumors exhibiting >30% tumor shrinkage; CR = complete response, the number of not measureable tumors.