WO2019243236A1

WO2019243236A1 - New anticancer drug combinations

Info

Publication number: WO2019243236A1
Application number: PCT/EP2019/065841
Authority: WO
Inventors: Vicente José FRESQUET ARNAU; José Angel MARTÍNEZ CLIMENT; Julen Oyarzabal Santamarina; Felipe PRÓSPER CARDOSO; Xabier Aguirre Ena; Marta DUEÑAS PORTO; Jesús M PARAMIO GONZÁLEZ
Original assignee: Fundación Para La Investigación Médica Aplicada; Universidad De Navarra; Centro De Investigaciones Energéticas, Medioambientales Y Tecnológicas, O.A., M.P.
Priority date: 2018-06-18
Filing date: 2019-06-17
Publication date: 2019-12-26

Abstract

It relates to a combination comprising: A) a compound of formula (I), or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of any of its pharmaceutically or veterinary acceptable salts, wherein L, X, R1, R2, R3, and R4 are as defined herein; and B) a drug selected from the group consisting of: i) an immune checkpoint inhibitor, ii) an inhibitor of an anti-apoptotic protein, and iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor; and to pharmaceutical or veterinary compositions, and package or kit of parts comprising it. It also relates to the combination, the composition or a package or kit of parts for use in the treatment and/or prevention of cancer.

Description

New anticancer drug combinations

This application claims the benefit of European Patent Application EP18382435.8 filed on 18.06.2018.

Technical Field

The present invention relates to anticancer drug combinations of quinoline derivatives, which are epigenetic inhibitors, and other anticancer agents. It also relates to pharmaceutical or veterinary compositions and kits containing them, and to their use in medicine, in particular as anticancer agents.

Background Art

Cancer is among the leading causes of death worldwide. There are currently a number of methods to treat the cancer disease including surgery, radiotherapy, chemotherapy and molecular-targeted therapy.

Hematological tumors and some solid tumors such as breast, bladder, prostate and colorectal cancer are treated mainly by chemotherapy. However, chemotherapeutic agents are not effective for all types of cancer. Furthermore, one of the major problems in chemotherapy is multidrug resistance. Therefore, complementary treatment modalities have been explored in recent years.

Epigenetic therapy is a novel tumor therapeutic method based on the targeting the aberrant epigenetic modifications present in cancer cells. Despite the clinical approval of various epigenetic drugs as anti-cancer agents, their molecular mechanisms of action are not completely understood. Epigenetic drugs impair survival of tumor cells by either selectively reactivating the transcription of tumor suppressor genes silenced in cancer cells, by globally targeting the typical hypomethylation pattern of cancer cells, or by inhibiting gain-of-function mutations of epigenetic enzymes. Understanding the mechanistic basis of epigenetic therapies that can explain their ample anti-tumor effects remains as an enormous scientific and clinical challenge.

Apart from epigenetic alternations, cancer cells present many other atypical characteristics, such as the blockade of the physiologically regulated programmed cell death (apoptosis), which is one of the major hallmarks of all cancer cells. Cancer cells exhibit many abnormal phenotypes to suppress apoptotic signaling via the intrinsic (or mitochondrial) pathway. Indeed, extensive studies during the last decades have revealed that most cancer cells select different mechanisms to block mitochondrial apoptosis and survive. Using a strategy termed BH3 profiling, most cancer cells can be classified as addicted to three specific anti-apoptotic molecules of the BCL-2 family (namely BCL-2, MCL-1 and BCL-XL), which are commonly over-expressed in tumor cells. As such, it is accepted that survival of almost every tumor relies on each of these hyper-activated pro-apoptotic molecules (in other words, every tumor is“addicted” either to BCL2, MCL1 or BCL-XL for survival). Because of these data, targeting the mitochondrial apoptosis pathway to induce cancer cell death has been a high-priority goal for cancer therapy. However, the results obtained so far in preclinical and clinical settings show that cancer cells readily develop resistance to drugs targeting these pathways. Accordingly, a deeper understanding of their mechanisms of action, alone and in combination with various potential targeted agents, constitutes a major challenge in clinical oncology.

On the other hand, increased understanding of tumor immunology has led to the development of effective targeted therapies. The immune system is regulated, among others, by particular immune checkpoints that avoid the development of auto-immune responses by attacking cells indiscriminately. Immune checkpoint mechanisms are often activated in cancer to suppress the nascent anti-tumor immune response. Accordingly, the development of several checkpoint inhibitors, mainly antibodies, has been proposed for the treatment of a number of cancers. However, many tumor types are resistant to this type of therapies.

The development of additional therapies for the treatment of cancer is of utmost importance. Thus, there is still a need of developing new therapies which show improved activity in the treatment and/or prevention of cancer.

Summary of Invention

Inventors have found that combinations that comprise a quinoline derivative and a drug selected from an immune checkpoint inhibitor, an inhibitor of an anti-apoptotic protein, or a chemotherapeutic agent, act synergistically against cancer. The quinoline derivatives of the invention are epigenetic inhibitors. As illustrated in the examples below, the synergistic effect has been shown in multiple hematological malignancies, as well as in solid tumors, both in vitro and in vivo.

According to the results, the inventors surprisingly found that the quinoline derivatives of the invention are able to trigger widespread transcription of normally-silenced endogenous retroviral genes (ERVs) in cancer cells, thereby inducing an antiviral immune cellular response that promotes an anti-proliferative state, reactivates tumor immunogenicity, and alters cell signaling pathways leading to cell death.

Without being bound to theory, it is thought that the IFN response triggered by the quinoline derivatives of the invention depletes energetic ATP, which blocks the apoptotic pathway while promoting caspase-independent necroptotic cell death. Subsequently, ATP depletion triggers compensatory mitochondria respiration that generate oxidative metabolic stress and decreases mitochondrial apoptotic thresholds, rendering tumor cells susceptible to caspase-dependent apoptosis through selective BCL2, MCL1 or BCL-XL inhibition.

Furthermore, the interferon (IFN) cellular response reduces the tumor immune suppressive microenvironment and improves anti-tumor efficacy of checkpoint inhibitors.

In summary, through the activation of ERV-mediated innate immune responses the quinoline derivatives of the invention are able to i) induce necroptosis in tumor cells; ii) perturb energetic metabolism and render tumor cells addicted to mitochondrial apoptosis; iii) sensitize tumor cells to standard chemotherapeutic agents, and iv) increase IFN-mediated immunogenicity of tumor cells that sensitizes them to immunotherapy in vivo.

Therefore, a first aspect of the invention relates to a combination comprising: A) a compound of formula (I), or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of any of its pharmaceutically or veterinary acceptable salts; and

B) a drug selected from the group consisting of:

i) an immune checkpoint inhibitor,

ii) an inhibitor of an anti-apoptotic protein, and

iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor; wherein:

X is a biradical selected from -NR^a’-, -0-, -CR^bR^c- and

wherein B is a known ring system which is attached to the quinoline ring through the N atom, and which comprises a 3- to 7-membered saturated or partially unsaturated heterocyclic monocyclic ring, which is optionally fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring; wherein the ring system B is optionally substituted with: a) one Cy¹; and/or

b) one or more substituents R^d, and/or

c) one or more substituents Z¹ optionally substituted with one or more substituents R^d and/or one Cy²; wherein Cy¹ and Cy² are optionally substituted with one or more substituents independently selected from R^d, and Z² optionally substituted with one or more substituents R^d;

L is a biradical selected from Cy³, and Z³ optionally substituted with one or more substituents R^d and/or one or more Cy⁴; wherein Cy³ and Cy⁴are independently optionally substituted with:

a) one Cy⁵; and/or

b) one or more substituents R^d, and/or

c) one or more substituents Z⁴ optionally substituted with one or more substituents R^d and/or one Cy⁶; wherein Cy⁵ and Cy⁶ are independently optionally substituted with one or more substituents independently selected from R^d, and Z⁵ optionally substituted with one or more substituents R^d;

wherein L is attached to X through Cy³or Z³; and L is attached to -R₄ through either Cy³or Z³, or alternatively, through any of the substituents of Cy³ or Z³;

Ri is selected from the group consisting of R^e, Cy⁷, halogen, -NO2, -CN, -OR^e, -0C(0)R^e’, -0C(0)0R^e’,

R₂ is selected from the group consisting of H, R^a, halogen, -N0₂, -CN, -OR^3’, -0C(0)R^a’, -0C(0)0R^a’,

R3 is selected from the group consisting of R^f, -OR^f, -NR^a’R^f, and -NR^a’COR^f;

R₄ is independently selected from H, halogen, -N0₂, -CN, -OR^a’, -OC(Y)R^a’, -OC(Y)OR^a’, -OC(Y)NR^a’R^a’,

each R^a’ is independently H or R^a; each R^a is independently selected from the group consisting of (Ci-Ce)al kyl, (C₂-C6)al kenyl, (C₂-C6)alkynyl, (C₂-C6)hydrocarbon chain having one or more double bonds and one or more triple bonds, and Cy⁸, wherein each R^a is optionally substituted with one or more halogen atoms,

R^b and R^c are independently selected from the group consisting of H, halogen, (Ci-Cejalkyl, (C₂-Ce)al kenyl, (C₂-C6)alkynyl, (C₂-C6)hydrocarbon chain having one or more double bonds and one or more triple bonds, and a Cy⁹; wherein (Ci-Cejalkyl, (C₂-C6)al kenyl, (C₂-C6)alkynyl, (C₂-C6)hydrocarbon chain and Cy⁹ are independently optionally substituted with one or more halogen atoms; or alternatively

R^b and R^c, together with the carbon atom to which they are attached, form a known ring system comprising a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is optionally fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring; wherein the ring system is optionally substituted with: a) one Cy¹⁰; and/or

b) one or more substituents R^d, and/or c) one or more substituents Z⁶ optionally substituted with one or more substituents R^d and/or one Cy¹¹; wherein Cy¹⁰ and Cy¹¹ are optionally substituted with one or more substituents independently selected from R^d, and Z⁷ optionally substituted with one or more substituents R^d; each R^d is independently selected from halogen, -NO2, -CN, -OR^3’, -OC(Y)R^a’, -OC(Y)OR^a’, -OC(Y)NR^a’R^a’, -NR^aR^a’, -NR^aC(Y)R^a’, -NR^aC(Y)OR^a’, -NR^aC(Y)NR^aR^a’, -NR^aS(0)₂R^a’, -NR^SCWR^3’, -SR^a’, -S(0)R^a’, -S(0)0R^a’, -S0₂R^a’, -S0₂(0R^a), -S0₂NR^a R^a’, -SC(Y)NR^aR^a’, -C(Y)R^a’, -C(Y)OR^a’, -C(Y)NR^aR^a’,

-C(Y)NR^aOR^a’, and -C(0)NR^aS0₂R^a’; each Y is independently 0, S, or NR^a’; each R^e’ is independently H or R^e; each R^e is independently selected from the group consisting of (Ci-C₆)alkyl, (C2-C6)al kenyl, (C2-C6)alkynyl, (C2-Ce)hydrocarbon chain having one or more double bonds and one or more triple bonds, wherein each R^e is optionally substituted with one or more substituents R^b and/or one Cy¹²; wherein Cy¹² is optionally substituted with:

a) one Cy¹³, and/or

b) one or more substituents R^d, and/or

c) one or more substituents Z⁸ optionally substituted with one or more substituents R^d and/or one Cy¹³; wherein Cy¹³ is optionally substituted with one or more substituents independently selected from R^d, and Z¹³ optionally substituted with one or more substituents R^d; each R^f is independently Cy¹⁴, or Z⁹ optionally substituted with one or more substituents R^d and/or one Cy¹⁵; wherein Cy¹⁴ or Cy¹⁵are independently optionally substituted with:

a) one Cy¹⁶; and/or

b) one or more substituents R^d, and/or

c) one or more substituents Z⁹ optionally substituted with one or more substituents R^d and/or one Cy¹⁷; wherein Cy¹⁶and Cy¹⁷ is optionally substituted with one or more substituents independently selected from R^d, and Z¹⁰ optionally substituted with one or more substituents R^d; and

Cy⁷ is a known ring system selected from the group consisting of:

(i) phenyl;

(ii) 5- or 6-membered heteroaromatic ring;

(iii) 3- to 7-membered carbocyclic or heterocyclic monocyclic ring, which is saturated or partially

unsaturated;

(iv) 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic

monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring; (v) phenyl fused to a 6- to 14-membered saturated or partially unsaturated carbocyclic or heterocyclic bicyclic ring, wherein the rings of the bicyclic ring are spiro-fused; and

(vi) 5- to 6-membered heteroaromatic ring fused to a 6- to 14-membered saturated or partially

unsaturated carbocyclic or heterocyclic bicyclic ring, wherein the rings of the bicyclic ring are spiro- fused;

wherein Cy⁷ is optionally substituted with:

a) one Cy¹⁸, and/or

b) one or more substituents R^d, and/or

c) one or more substituents Z¹¹ optionally substituted with one or more substituents R^d and/or one Cy¹⁹; wherein Cy¹⁸ or Cy¹⁹ are optionally substituted with one or more substituents independently selected from R^d, and Z¹² optionally substituted with one or more substituents R^d;

Z¹-Z¹³ are independently selected from the group consisting of (Ci-Ci2)alkyl, (C2-Ci2)al kenyl, (C2-Ci2)alkynyl, and (C2-Ci2)hydrocarbon chain having one or more double bonds and one or more triple bonds, wherein any carbon atom of Z¹-Z¹³ is optionally a spiro atom substituted with R^h and R', and R^h and R', together with the spiro carbon atom, form a known ring system comprising a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring;

Cy¹-Cy⁴, Cy¹²-Cy¹⁵, and Cy¹⁸are independently a known ring system selected from the group consisting of phenyl; 5- or 6-membered heteroaromatic ring; 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7- membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring; Cy⁵-Cy⁶, Cy⁸-Cy¹¹, Cy¹⁶-Cy¹⁷, and Cy¹⁹are independently a known ring system selected from the group consisting of phenyl; 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 5- or 6-membered heteroaromatic ring; wherein in the carbocyclic rings all ring members are carbon atoms; and in the heterocyclic and

heteroaromatic rings one or more ring members are selected from N, 0, and S; and wherein in all saturated or partially unsaturated rings one or two members of the rings are optionally C(O) and/or C(NH) and/or C [N (Ci -C₄)al ky I ] .

The compounds of the invention may be formulated in different types of compositions/kits of parts. Thus, a second aspect of the invention relates to a single pharmaceutical or veterinary composition which comprises a therapeutically effective amount of:

a) a compound of formula (I) as defined above, or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically or veterinary acceptable salt; and b) a drug selected from the group consisting of: i) an immune checkpoint inhibitor, ii) an inhibitor of an anti-apoptotic protein, and iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor;

together with one or more pharmaceutically or veterinary acceptable excipients or carriers.

A third aspect of the invention relates to a package or kit of parts comprising:

a) a first pharmaceutical or veterinary composition which comprises a therapeutically effective amount of a compound of formula (I) as defined above, or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically or veterinary acceptable salt, together with one or more pharmaceutically or veterinary acceptable excipients or carriers; and

b) a second pharmaceutical or veterinary composition which comprises a therapeutically effective amount of a drug selected from the group consisting of: i) an immune checkpoint inhibitor, ii) an inhibitor of an anti-apoptotic protein, and iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor; together with one or more

pharmaceutically or veterinary acceptable excipients or carriers;

wherein compositions a) and b) are separate compositions.

Further, as mentioned above, the combination of the invention may be used in cancer. Thus, a fourth aspect of the invention relates to the combination, the single pharmaceutical or veterinary composition, or the package or kit of parts as previously defined, for use in the treatment and/or prevention of cancer.

A fifth aspect of the invention relates to a compound of formula (I) as defined above, or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically or veterinary acceptable salt, together with one or more

pharmaceutically or veterinary acceptable excipients or carriers, for administration in combination with a drug selected from the group consisting of: i) an immune checkpoint inhibitor, ii) an inhibitor of an anti-apoptotic protein, and iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor; together with one or more pharmaceutically or veterinary acceptable excipients or carriers, for simultaneous, concurrent, separate or sequential use in the treatment and/or prevention of cancer.

A sixth aspect of the invention relates to a drug selected from the group consisting of: i) an immune checkpoint inhibitor, ii) an inhibitor of an anti-apoptotic protein, and iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor; together with one or more pharmaceutically or veterinary acceptable excipients or carriers, for administration in combination with a compound of formula (I) as defined above, or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically or veterinary acceptable salt, together with one or more pharmaceutically or veterinary acceptable excipients or carriers, for simultaneous, concurrent, separate or sequential use in the treatment and/or prevention of cancer.

Brief Description of Drawings

Fig. 1 shows the cellular effects of treatment with compound 1-3-04. A) Annexin positive cell staining and cell cycle upon 1-3-04 therapy in four representative DLBCL cell lines. The y-axis represents the % of annexin V positive cells, and the x-axis represents the concentration of 1-3-04 used, as follows OcilylO: 0, 1 and 2 mM; DB and K422: 0, 2 and 4 mM; and HBL1 : 0, 4 and 6 mM. B) Western blot for PARP and caspases 8, 9 and 3, BCL2, MCL1 , BCL-XL, BIM, NOXA, BAX, BAK (apoptosis), beclin, LC3B, p62 (autophagy), phospho-RIPK1 and RIPK3 (necroptosis) after 1-3-04 treatment of cells at the following increasing concentrations: OcilylO: 0, 0.5, 1 and 2 mM; DB and K422: 0, 1 , 2 and 4 mM; and HBL1 : 0, 2, 4 and 6 mM.

Fig. 2 shows the ERV response of cancer cells upon 1-3-04 treatment. qRT-PCR of ERV transcripts (A), RIG1 and MDA5 genes (B), and IFN genes (C) induced by compound 1-3-04 in DLBCL cells. The y-axis represents the expression fold change (FC). The first column corresponds to K422 cells treated with 1-3-04 at 2mM; the second column to DB cells treated with 1-3-04 at 2mM; the thirds column to HBL1 cells treated with 1-3-04 at 4mM; and the fourth column to OCILylO cells treated with 1-3-04 at 2mM.

Fig. 3 shows a Western blot for MAVS after treatment of cells with compound 1-3-04 at increasing concentrations, as follows: OcilylO: 0, 0.5, 1 and 2 mM; DB and K422: 0, 1 , 2 and 4 mM; and HBL1 : 0, 2, 4 and 6 mM. The upper panels represent the oligomeric form of MAVS, and the lower pannels the monomeric form of MAVS.

Fig. 4 shows the in vivo therapeutic effect of the combination of compound 1-3-04 and ABT199 in Karpas422 and HBL1 malignant cells xenographs. The y-axis represents the tumor size in mm³, and the x-axis represents the time after treatment in days.“A” corresponds to control mice (not treated);“B” corresponds to mice treated with compound 1-3-04 at 2.5 mg/Kg;“C” corresponds to mice treated with ABT199 at 26 mg/Kg; and“D” corresponds to mice treated with a combination of compound 1-3-04 at 2.5 mg/Kg with ABT199 at 26 mg/Kg.

Fig. 5 shows the in vivo therapeutic effect of the combination of compound 1-3-04 and cisplatin in two models of bladder cancer (BC). A) Tumour volume (mm³) of RT 112 cells subcutaneously implanted in the flanks of nude mice and treated with vehicle (1), compou nd 1 -3-04 at 5 mg/kg i - p . five days per week (2), Cisplatin a t 6mg/kg i . p . once per week (4), or both compounds (3). Tumor volume was related to baseline volume before treatment. ^*p-value < 0.05, ^**p-value < 0.01 ^**** value < 0.0001 determined by the Mann-Whitney t-test. B) shows a Kaplan-Meier curve of a transgenic quadruple knockout

mouse model of metastatic bladder cancer and treated (A) with the compound 1-3- 04 (5mg/kg, i.p.) + cisplatin (3 mg/kg, i.p.) in combination (n=14); (B) the compound 1-3-04 (5mg/kg, i.p.) (n=20), (C) cisplatin (3 mg/kg, i.p.) (n=15), or (D) treated with the vehicle (n=15). The p-value was obtained using the log-rank test. Arrow denotes the treatment period. The y-axis represents the % of tumor free. The x-axis represents days after inoculation. C) Percentage of mice displaying overt or microscopic metastases in the two cohorts of mice. In C), A represents control mice; B represents mice treated with 1-3-04+CDDP; C represents mice treated with 1-3-04; and D represents mice treated with CDDP..

Fig. 6 shows that the epigenetic inhibitor 1-3-04 sensitizes an immunocompetent model of acute myeloid leukemia (AML) to anti-PD1 anticancer therapy. The y-axis represents the fold change (FC) of the treated mice tumour bulk in relation to the one of mice treated with the vehicle. Fig. 7 shows that G9a/DNMT inhibition enhances responses to PD-L1 blockade and induces tumor regression. A) Scheme of different protocols used to monitor the effect of the cited treatments in the QKO mouse model at different time points. The cohorts included untreated mice (n=15, sacrificed at the mid treatment time point (16 days, n=9) and at the end of treatment (day 28, n=6), mice treated with anti PD-L1 (n=16, sacrificed at the mid-treatment time point (16 days, n=8) and at the end of treatment (day 28, n=8)), mice treated with 1-3-04 and CDDP (n=20, sacrificed at the mid-treatment time point (16 days, n=10) and end of treatment (day 28, n=10)), mice treated with 1-3-04 and anti-PD-L1 (n=21 , sacrificed at the mid-treatment time point (16 days, n=10), end of treatment (day 28, n=5) and 28 days after the end of the treatment (n=6)), and mice treated with 1-3-04, CDDP and anti-PD-L1 (n=26, sacrificed at the mid-treatment time point (16 days, n=7), end of treatment (day 28, n=11) and 28 days after the end of the treatment (n=8)). B) Summary of the incidence of tumors and metastases in the different cohorts of transgenic mice at the End of treatment (28 days). A represents untreated mice; B represents mice treated with anti-PD-L1 ; C represents mice treated with 1-3-04+CDDP; D represents mice treated with 1-3-04+anti-PD-L1 ; and E represents mice treated with 1- 3-04+CDDP+ anti-PD-L1. p values were determined by the F Fischer test including all animals of the different cohorts. C) Summary of the incidence of tumors and metastases in the different cohorts of transgenic mice at Post treatment (28 days after end of treatment). A represents mice treated with 1-3-04+anti-PD-L1 ; and B represents mice treated with 1-3-04+CDDP+ anti-PD-L1. In B) and C) black bars correspond to tumors and grey bars correspond to metastases.

Detailed description of the invention

All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly through-out the specification and claims unless an otherwise expressly set out definition provides a broader definition. For the purposes of the invention, the term“inhibitor” refers to an agent or compound that is able to block, partially block, interfere, decrease, suppress, reduce or deactivate a target protein (i.e. a checkpoint protein or an anti-apoptotic protein).

The term "synergy" or“synergistic” is used herein to mean an effect greater than the sum of the effects obtained independently with each one of the components of the drug combination. The synergy can be determined e.g. by the Chou-Talalay method for drug combination as described in Chou, T.C., Cancer research 2010, 70, pp. 440-446.

"Protective group" (PG) refers to a group of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity.

The expression“substituted with one or more" means that a group can be substituted with one or more, preferably with 1 , 2, 3 or 4 substituents, provided that this group has enough positions susceptible of being substituted.

The term“carbocyclic” ring system refers to a known ring system wherein all the ring members contain carbon atoms. The term“heterocyclic” ring system refers to a known ring system wherein one or more of the ring members, preferably 1 , 2, 3, or 4 ring members, are selected from NH, N, O, and S, where chemically possible. The remaining ring members of the heterocyclic ring are independently selected from C, CH, CH2,

O, N, NH, and S. Unless otherwise specified, the“heterocyclic” ring system may be attached to the rest of the molecule through a C or a N atom of the ring system. Both the carbocyclic and heterocyclic rings can be saturated, partially unsaturated, or aromatic and may be unsubstituted or substituted as described herein, being the substituents placed on any available position. Thus, in a ring member of a carbocyclic ring that is CH or CH2 or in a ring member of a heterocyclic ring that is CH, CH2 or NH, one or more of the H atoms of these ring members may be substituted by another moiety as herein disclosed.

For the purposes of the present invention, in "fused" rings the fusion occurs through one bond which is common to two adjoining rings; in "bridged-fused" rings the fusion occurs through a sequence of atoms (bridgehead) which is common to two rings; and in "spiro-fused" rings, the fusion occurs through only one atom (spiro atom), preferably a carbon atom, which is common to two adjoining rings (including bridged rings).

The term "heteroaromatic" ring refers to a known aromatic ring system, wherein one or more of the ring members, preferably 1 , 2, 3, or 4 ring members, are selected from NH, N, O, and S, where chemically possible. The remaining ring members of the heteroaromatic ring are independently selected from C, CH, O, N, NH, and S. The heteroaromatic ring may be unsubstituted or substituted as described herein, being the substituents placed on any available position. Thus, in a ring member of the heteroaromatic ring which is CH or NH the H atom may be substituted by another moiety, as herein disclosed.

In the present invention any of the substituents“Cy”,“Cy_A”,“Cy_B” or“Z”,“ZA”,“ZB” may be attached to the rest of the molecule through any available position.

As it will be explained below, it forms part of the invention not only the combination comprising: A) a compound of formula (I) as previously defined; and B) a drug selected from the group consisting of: i) an immune checkpoint inhibitor, ii) an inhibitor of an anti-apoptotic protein, and iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor; but also a combination comprising: A) a compound selected from the group consisting of a compound of formula (III), a compound of formula (IV), and a compound of formula (V); and B) a drug selected from the group consisting of: i) an immune checkpoint inhibitor, ii) an inhibitor of an anti-apoptotic protein, and iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor.

The present invention also includes the tautomeric forms of the compounds of formula (I), (III), (IV), or (V) as defined herein. The term "tautomeric isomers" means isomers, the structures of which differ in the position of an atom, generally a hydrogen atom, and of one or more multiple bonds, and which are capable of easily and reversibly changing from one to another. The tautomers are used indistinctly in the present application. Thus, as an example, a hydroxyphenyl group has to be considered equivalent to its tautomeric form: cyclohexa-2,4- dienone. All tautomers are to be considered equivalent for the purposes of the invention.

The term "known ring system" as used herein refers to a ring system which is chemically feasible and is known in the art and so intends to exclude those ring systems that are not chemically possible.

For the purposes of the present invention, in all saturated or partially unsaturated rings, one or two members of the rings are optionally C(O) and/or C(NH) and/or C[N(Ci-C4)alkyl],

The term (Ci-C_n)alkyl refers to a saturated branched or linear hydrocarbon chain which contains from 1 to n carbon atoms and only single bonds. The term (C2-C_n)alkenyl refers to an unsaturated branched or linear hydrocarbon chain which comprises from 2 to n carbon atoms and at least one or more double bonds. The term (C2-C_n)alkynyl refers to a saturated branched or linear hydrocarbon chain which comprises from 2 to n carbon atoms and at least one or more triple bonds. For the purposes of the invention, the

(C2-C_n)hydrocarbon chain having one or more double bonds and one or more triple bonds is a branched or linear hydrocarbon chain which contains from 2 to n carbon atoms.

In the (Ci-C_n)alkyl chains, (C2-C_n)alkenyl chains, (C2-C_n)alkynyl chains, and (C2-C_n)hydrocarbon chains having one or more double bonds and one or more triple bonds, it is contemplated that any carbon of the chain is optionally a spiro atom substituted as defined herein.

A halogen substituent means fluoro, chloro, bromo or iodo.

For the purposes of the invention, room temperature is 20-25 °C.

In the embodiments of the invention referring to the compounds of formula (I), (III), (IV), or (V), where the substitution or unsubstitution of a certain group is not specified, e.g. either because it is not indicated a certain substitution for that group, or that the group is unsubstituted, it has to be understood that the possible substitution of this group is the one as in the broadest definition of the formula (I), (III), (IV), or (V), respectively. The same applies when in specific group is said to be“optionally substituted” without specifically indicating the substitution.

There is no limitation on the type of salt of the compounds of the invention that can be used, provided that these are pharmaceutically or veterinary acceptable when they are used for therapeutic purposes. The term "pharmaceutically or veterinary acceptable salts", embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.

The preparation of pharmaceutically or veterinary acceptable salts of the compounds of formula (I), (III), (IV), or (V) can be carried out by methods known in the art. For instance, they can be prepared from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate pharmaceutically or veterinary acceptable base or acid in water or in an organic solvent or in a mixture of them. The compounds of formula (I), (III), (IV), or (V) and their respective salts may differ in some physical properties, but they are equivalent for the purposes of the present invention.

The compounds of the invention may be in crystalline form either as free solvation compounds or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art. In general, the solvated forms with pharmaceutically, cosmetically or veterinary acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated form for the purposes of the invention.

Some compounds of the invention can have chiral centres that can give rise to various stereoisomers. As used herein, the term "stereoisomer" refers to all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or syn/anti or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers). The present invention relates to each of these stereoisomers and also mixtures thereof.

Diastereoisomers and enantiomers can be separated by conventional techniques such as chromatography or fractional crystallization. Optical isomers can be resolved by conventional techniques of optical resolution to give optically pure isomers. This resolution can be carried out on any chiral synthetic intermediates or on compounds of the invention. Optically pure isomers can also be individually obtained using enantiospecific synthesis.

In all embodiments of the invention referring to the compounds of formula (I), (III), (IV), or (V), the pharmaceutically, cosmetically or veterinary acceptable salts thereof and the stereoisomers or mixtures of stereoisomers, either of any of the compounds of formula (I), (III), (IV), or (V) or of any of their respective pharmaceutically acceptable salts are always contemplated even if they are not specifically mentioned.

Compounds of formula (I)

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

A) a compound of formula (I), or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of any of its pharmaceutically or veterinary acceptable salts

as previously defined, and

B) a drug selected from the group consisting of: i) an immune checkpoint inhibitor, ii) an inhibitor of an anti- apoptotic protein, and iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor.

Compounds of formula (I) include compounds of formulas (la), (lb), (lc) and (Id) as shown below:

In embodiment 1 , optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, X is a biradical -NR^a- (i.e. a compound (la)). More particularly, R^a’ in (la) is H, (Ci-Ce)al kyl optionally substituted with one or more halogen atoms, or a 3- to 7-membered saturated or partially unsaturated carbocyclic monocyclic ring optionally substituted with one or more halogen atoms. Even more particularly, R^a’ in (la) is H or (Ci-Cejalkyl optionally substituted with one or more halogen atoms; even more particularly is H or-Ch ; and even more particularly H. In embodiment 1a, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, X is a biradical -NH- and R₄ is H (i.e. a compound (la’)):

The compounds of formula (la’) are capable to inhibit both histone methyltransferase G9a and DNA methyltransferases (DNMTs), i.e. they are G9a/DNMT dual inhibitors. For the purposes of the invention, this means that they are capable of inhibiting G9a with an IC50 value £ 10 mM, preferably £ 1 mM, more preferably £ 500 nM, and also capable of inhibiting one or more DNMTs selected from the group consisting of DNMT1, DNMT3A and DNMT3B with an IC50 value < 10 mM, preferably £ 1 mM, more preferably £ 500 nM, when the inhibition of G9a and DNMTs is measured in enzymatic assays as the ones described in

WO2015192981.

In embodiment 2, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, X is a biradical

(i.e. a compound (lb)). More particularly, ring B is a known ring system comprising a 3- to 7-membered saturated or partially unsaturated heterocyclic monocyclic ring optionally substituted as previously defined. More particularly, ring B is optionally substituted with: a) one or more substituents R^d, and/or b) one or more substituents Z¹ optionally substituted as previously defined. Even more particularly, Z¹ in ring B is (Ci-Cejalkyl optionally substituted with one or more substituents R^d.

In embodiment 3, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, X is a biradical -O- (i.e. a compound (lc)).

In embodiment 4, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, X is a biradical -CR^bR^c- (i.e. a compound (Id)). More particularly, R^b and R^c in (Id) are independently H, (Ci-Cejalkyl optionally substituted with one or more halogen atoms, or R^b and R^c together with the carbon atom to which they are attached, form a 3- to 7-membered saturated or partially unsaturated carbocyclic monocyclic ring optionally substituted with one or more halogen atoms. Even more particularly, R^band R^c in (Id) are independently H or (Ci-Cejalkyl optionally substituted with one or more halogen atoms; even more particularly are H or -Chh; and even both R^b and R^c are H.

In the compounds of formula (I), the biradical L is attached to X through Cy³ or Z³; and L is attached to -R₄ through either Cy³ or Z³, or alternatively, through any of the possible substituents of Cy³ or Z³. Thus, some illustrative examples of L-R₄ moieties when L is attached to -R₄ through Cy³ include, without limitation:

On the other hand, some illustr p exa^*m· of L-R₄ moieties when L is attached to -R₄ through a substituent of Cy³ or Z³ include, without limitation:

In embodiment 5, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, L is a biradical selected from the list consisting of:

1) -Cy³-; 2) -Cy³-Cy⁵-; 3) -Cy³-Cy⁵-Z⁵-; 4) -Cy³-Z⁴-; 5) -Cy³-Z⁴-Cy⁶-; 6) -Cy³-Z⁴-Cy⁶-Z⁵-; 7) -Z³-;

8) -Z³-Cy⁴-; 9) -Z³-Cy⁴-Cy⁵-; 10) -Z³-Cy⁴-Cy⁵-Z⁵-; 11) -Z³-Cy⁴-Z⁴-; 12) -Z³-Cy⁴-Z⁴-Cy⁶-; and

13) -Z³-Cy⁴-Z⁴-Cy⁶-Z⁵-;

wherein:

the left part of the biradicals 1) to 13) as drawn above is attached to X, and the right part is attached to -R₄;

Z³ is unsubstituted or substituted with one or more substituents R^d and/or one or more additional Cy⁴;

Cy³ and each Cy⁴, wherein Cy⁴ either forms part of the linker or is a substituent of Z³, are unsubstituted or independently substituted with:

a) one additional Cy⁵; and/or

b) one or more substituents R^d, and/or

c) one additional Z⁴ optionally substituted with one or more substituents R^d and/or one additional Cy⁶; each Cy⁵ and Cy⁶, either when forming part of the linker or as substituents, are independently optionally substituted with one or more substituents independently selected from R^d, and additional Z⁵ optionally substituted with one or more substituents R^d. In embodiment 6, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, L is a moiety of formula (XXI):

wherein:

m and n are independently a value selected from 0 to 2; p is a value selected from 0 to 1 ;

Ri and R^kare independently selected from the group consisting of H, halogen, and (Ci-C3)alkyl optionally substituted with one or more halogen atoms; or alternatively

Ri and R^k, together with the spiro carbon atom to which they are attached, form a known ring system comprising a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; Cy²⁰ is a known ring system selected from the group consisting of phenyl; 5- or 6-membered heteroaromatic ring; 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring; and Cy²⁰ is optionally substituted with one or more substituents selected from halogen and (Ci-C3)alkyl optionally substituted with one or more halogen atoms,

Cy²¹ is a known ring system selected from the group consisting of phenyl; 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 5- or 6-membered heteroaromatic ring; and Cy²¹ is optionally substituted with one or more substituents selected from halogen and (Ci-C3)alkyl optionally substituted with one or more halogen atoms.

In the compound of formula (I), the moiety of formula (XXI) is attached to X through -(CRjRk)_m, and is attached to - R₄ through (Cy²¹)_p. For example, when L is a moiety of formula (XXI) as defined above wherein m, n, p = 0, then L is attached to -R₄ through Cy²⁰ (corresponding to Cy³ in the definition of the compounds of formula (I) as indicated above). When L is a moiety of formula (XXI) as defined above wherein m is 0 and one or both of m and p are other than 0, then L is attached to -R₄ through a substituent of the cycle Cy²⁰, which is and embodiment of Cy³ in the definition of the compounds of formula (I) as indicated above. When L is a moiety of formula (XXI) as defined above wherein m is other than 0, then L is attached to -R₄ through a substituent of the moiety -(CRiR^k)_m-, e.g. through Cy²⁰ when n, p = 0, which is and embodiment of Z³ in the definition of the compounds of formula (I) as indicated above).

Thus, in this embodiment 6, the compound of formula (I) has the formula (I¹):

O')

wherein Ri, R₂, R₃, R₄, X, R^j and R^k, Cy²⁰, Cy²¹, m, n, and p are as previously defined. Compounds of formula (G) include compounds of formulas (I'a), (I'b), (I'c) and (I'd) as shown below:

More particularly, R^a’ on the N atom at position 4 of the quinoline ring of formula (I’a) is H or (Ci-Cejalkyl optionally substituted with one or more halogen atoms; even more particularly is H or -CI-13; and even more particularly is H.

In embodiment 7, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, the moiety -L-R₄ is selected from the group consisting of the following moieties:

In one more particular embodiment of embodiment 7, in the compound of formula (I) of the combination of the invention as previously described, the moiety -L-R₄ is selected from the group consisting of the following moieties:

wherein f¾ is independently selected from H, and -C(Y)NR^a’0R^a’, more particuarly R4 is -C(0)NH0H.

In another more particular embodiment of embodiment 7, in the compound of formula (I) of the combination of the invention as previously described, the moiety -L-R₄ is selected from the group consisting of the following moieties:

wherein R₄ is independently selected from H, methyl, isopropyl and cyclopropyl.

In embodiment 8, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, R₁ is selected from the group consisting of R^e, Cy⁷, -OR^e, -NR^e’R^e’, -NR^e’C(0)R^e’, -NR^e’S(0)₂R^e’, -S0₂NR^e’R^e’, and -C(0)NR^e’R^e’; wherein Cy⁷ is optionally substituted as previously defined.

In embodiment 9, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, R₁ is Cy⁷ optionally substituted as previously defined. More particularly, Cy⁷ is a known ring system selected from the group consisting of:

(i) phenyl;

(ii) 5- or 6-membered heteroaromatic ring;

unsaturated;

monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring;

and even more particularly, R₁ is Cy⁷ optionally substituted as previously defined, wherein Cy⁷ is a known ring system selected from the group consisting of (i), (ii), and (iii), as defined above.

In embodiment 10, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, R₁ is Cy⁷ optionally substituted as previously defined and is attached to the quinoline through a carbon atom. In embodiment 11 , optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, Ri is selected from the group consisting of the following moieties:

wherein Ri is optionally substituted as previously defined.

In embodiment 12, optionally in combination with one or more features of the various embodiments described above or below, the invention relates to a compound of formula (I) as previously described, wherein Ri is methyl.

In embodiment 13, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, R₂ is selected from halogen, -CN and -OR^3’, more particularly, R₂ is selected from halogen and -OR^3’; even more particularly, R₂ is -OR³; wherein R is (Ci-C₆)alkyl optionally substituted with one or more halogen atoms, and even more particularly R₂ is -OCH₃.

In embodiment 13a, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the compound of formula (I) of the combination of the invention as previously described is a compound of formula (I"):

wherein R₃, R₄, X, R^3’, R^j and R^k, Cy⁷, Cy²⁰, Cy²¹, m, n, and p are as previously defined. Compounds of formula (I") include compounds of formulas (l"a), (l"b), (l"c) and (l"d) as shown below:

More particularly, R^a’ on the N atom at position 4 of the quinoline ring of formula (l"a) is H or (Ci-Cejalkyl optionally substituted with one or more halogen atoms; even more particularly is H or -CI-1₃; and even more particularly is H. In embodiment 14, optionally in combination with one or more features of the various embodiments described above or below, the invention relates to a compound of formula (I) as previously described, wherein is methyl.

In embodiment 15, optionally in combination with one or more features of the various embodiments described above or below, the invention relates to a compound of formula (I) as previously described, wherein R₃ is methyl.

In embodiment 16, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, R₃ is selected from the group consisting of -0R^f, and -NR^a’R^f. More particularly, R₃ is -0R^f. Even more particularly, R^f is Z⁹ optionally substituted as previously defined.

In embodiment 17, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, R₃ is methoxy. In embodiment 18, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, in R₃, R^f contains at least one N atom.

In embodiment 19, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, R₃ is a moiety of formula (XX):

wherein

Cy²² is a known ring system selected from the group consisting of phenyl; 5- or 6-membered heteroaromatic ring; 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring; and Cy²² is optionally substituted with one or more substituents selected from halogen and (Ci-C₃)alkyl optionally substituted with one or more halogen atoms, X¹ and X²are independently H or halogen, and r is a value selected from 0 to 6. More particularly, R₃ is a moiety of formula (XX) wherein Cy²² is a 3- to 7-membered saturated heterocyclic monocyclic ring or a 3- to 7-membered saturated carbocyclic or heterocyclic monocyclic ring, which is spiro-fused to a 3- to 7-membered saturated carbocyclic or heterocyclic monocyclic ring, and Cy²² is optionally substituted as previously defined, X¹ and X² are H, and r is a value selected from 0 to 6.

Thus, in this embodiment 19, the compound of formula (I) has the formula (I'"):

wherein R-i, R₂, L, X, R₄, X¹, X², Cy²², and r are as previously defined.

In embodiment 19a, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the compound of formula (I) of the combination of the invention as previously described is a compound of formula (l^lv):

10 wherein Ri, R2, R₄, X, R^j and R^k, Cy²⁰, Cy²¹, X¹, X², Cy²², r, m, n, and p are as previously defined. Compounds of formula (l^lv) include compounds of formulas (l^lva), (l^lvb), (l^lvc) and (l^lvd) as shown below:

More particularly, R^a’ on the N atom at position 4 of the quinoline ring of formula (l^lva) is H or (Ci-Cejalkyl optionally substituted with one or more halogen atoms; even more particularly is H or -CI-13; and even more 15 particularly is H.

In embodiment 19b, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the compound of formula (I) of the combination of the invention as previously described is a compound of formula (l^v):

20

0 (l^v)

wherein R₄, X, R^a’, R^j and R^k, Cy⁷, Cy²⁰, Cy²¹, X¹, X², Cy²², r, m, n, and p are as previously defined.

Compounds of formula (l^v) include compounds of formulas (l^va), (l^vb), (l^vc) and (l^vd) as shown below:

More particularly, R^a’ on the N atom at position 4 of the quinoline ring of formula (l^va) is H or (Ci-C₆)alkyl 5 optionally substituted with one or more halogen atoms; even more particularly is H or -CH₃; and even more particularly is H.

In embodiment 20, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the0 invention as previously described, R₃ is selected from the group consisting of the following moieties:

In embodiment 21 , optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, R4 is independently selected from H, and -C(Y)NR^aOR^a’, more particuarly -C(0)NH0H.

In embodiment 22, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (I) of the combination of the invention as previously described, R4 is -C(0)NH0H. i.e. a compound of formula (II):

Even more particularly, in embodiment 22, R3 is selected from the group consisting of -OR^f, and -NR^a’R^f. Even more particularly, R3 is -ORf Even more particularly, R^f is Z⁹ optionally substituted as previously defined; and even more particularly, R3 is methoxy. In embodiment 23, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the compound of formula (I) of the combination of the invention as previously described, is selected from the group consisting of:

1 3-07 1 3-08 1 3-09

-19 13-20 13-21

-34 13-35 13-36

-02 14-03 15-01

-05 18-01 18-02

38

4-2-06 4-2-07

4-2-05

-01 32-02 32-03

3 4-03 3 4-04

Regarding the compounds indicated as“cis isomer” or“trans isomer”, an aleatory absolute configuration of the cis or trans isomers is shown. In the examples it is clearly indicated which of the isomers is concerned in relative terms by differentiating unambiguously between cis and trans isomers by their physical and/or spectroscopic properties.

Compounds of formula (III)

In a seventh aspect, it also forms part of the invention a combination comprising:

A) a compound of formula (III), or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (III) or of any of its pharmaceutically or veterinary acceptable salts; and

B) a drug selected from the group consisting of: i) an immune checkpoint inhibitor, ii) an inhibitor of an anti- apoptotic protein, and iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor; wherein the compound of formula (III) is selected from the group consisting of compounds of formula (Ilia), (lllb), (lllc), and (llld):

wherein

RAI is selected from the group consisting of RA³, CyA¹, halogen, -NO2, -CN, -ORA⁶, -0C(0)RA^b’, -0C(0)0RA^b’, -0C(0)NR_A ^bR_A ^b, -NRA^b’R_A ^b’, -NR_A ^bC(0)R_A ^b, -NR_A ^bC(0)0R_A ^b , -NR_A ^b,C(0)NRA^b RA^b , -NRA^b’S(0)₂RA^b’, -NRA^b’S0₂NRA^b’RA^b’, -SR_A ^b’, -S(0)R_A ^b’, -S(0)0R_A ^b’, -SOW, -S0₂(0R_A ^b’), -S0₂NR_A ^bR_A ^b, -SC(0)NR_A ^bR_A ^b , -C(0)R_A ^b’, -C(0)0R_A ^b, -C(0)NR_A ^bR_A ^b , -C(0)NR_A ^bOR_A ^b , and -C(0)NR_A ^b,S0₂RA^b’;

Cy_A ¹ is a known ring system selected from the group consisting of:

(i) phenyl;

(ii) 5- or 6-membered heteroaromatic ring;

unsaturated;

(v) phenyl fused to a 6- to 14-membered saturated or partially unsaturated carbocyclic or heterocyclic bicyclic ring, wherein the rings of the bicyclic ring are spiro-fused; and

unsaturated carbocyclic or heterocyclic bicyclic ring, wherein the rings of the bicyclic ring are spiro- fused; wherein Cy_A ¹ is optionally substituted with:

a) one Cy_A ² or one Cy_A ³, and/or

b) one or more substituents R_A ^c, and/or

c) one or more substituents Z_A ¹ optionally substituted with one or more substituents R_A ^C and/or one Cy_A ²;

wherein Cy_A ² or Cy_A ³ are optionally substituted with one or more substituents independently selected from R_A ^c, and Z_A ² optionally substituted with one or more substituents R_A ^c;

RA2 is selected from the group consisting of H, RA⁹, halogen, -NO2, -CN, -ORA^9’, -0C(0)RA^9’, -0C(0)0RA^9’, -0C(0)NRA⁹ RA⁹ , -NRA⁹ RA⁹ , -NRA⁹ C(0)RA⁹ , -NRA⁹ C(0)0RA⁹ , -NRA⁹ C(0)NRA⁹ RA⁹ , -NRA⁹ S(0)2RA⁹ ,

-NRA⁹ S02NRA⁹ RA⁹ , -SRA⁹ , -S(0)RA⁹ , -S(0)0RA⁹ , -SO2RA⁹ , -S02(0RA⁹), -S02NRA⁹ RA⁹ , -SC(0)NRA⁹ RA⁹ , -C(0)RA⁹ , -C(0)0RA⁹ , -C(0)NRA⁹ RA⁹ , and -C(0)NRA⁹0RA⁹ , and -C(0)NRA⁹ S02RA⁹ ;

RA3 is selected from the group consisting of RA^d, -ORA^d, -NRA^A^9’, and -NRA^a,CORA^d; wherein RA3 contains at least one atom selected from N, 0, S, and F;

RA4, RA7, RAI7, RAI8 are independently H or RA^d;

RA5, RA8, RAID, RAM, RAIS are independently selected from the group consisting of H, RA*⁵, -ORA', -NR RA^9’, -NR_A ^a'CORA^f, and R_A ^f;

RA6, RA9, RAH, RAI2, RAI3, RAI6 are independently selected from the group consisting of H, RA³, and one or more halogen atoms; each R_A ³ is independently selected from the group consisting of (Ci-Cejalkyl, (C2-Ce)alkenyl, (C2-Ce)alkynyl, (C2-Ce)hydrocarbon chain having one or more double bonds and one or more triple bonds, wherein each R_A ³ is optionally substituted with one or more halogen atoms, each R_A ^3’ is independently H or R_A ³; each R_A ^b is independently selected from the group consisting of (Ci-Cejalkyl, (C2-Ce)alkenyl, (C2-Ce)alkynyl, (C2-Ce)hydrocarbon chain having one or more double bonds and one or more triple bonds, wherein any of these groups is optionally substituted with one or more halogen atoms, and Cy_A ⁴ optionally substituted with one or more substituents R_A ^c; each R_A ^b’ is independently H or R_A ^b; each RA^C is independently selected from halogen, -NO2, -CN, -ORA^9’, -OC(YA)RA^9’, -OC(YA)ORA^9’,

-OC(YA)NRA⁹ RA⁹ , -NRA⁹ RA⁹ , -NRA⁹ C(YA)RA⁹ , -NRA⁹ C(YA)ORA⁹ , -NRA⁹ C(YA)NRA⁹ RA⁹ , -NRA⁹ S(0)2RA⁹ , -NRA^gSC>2NRA^g RA^g , -SRA⁹ , -S(0)RA^g , -S(0)0RA^g , -S02RA^g , -S02(0RA^g), -S02NRA^g RA^g ,

-SC(YA)NRA^g,R_A ^g’, -C(Y_A)RA^g’, -C(Y_A)ORA^g’, -C(YA)NRA^g,R_A ^g’, -C(Y_A)NRA^gORA^g’, and -C(0)NR_A ^g,S0₂RA^g’; each R_A ^d is independently R_A ^eor R_A ¹; each R_A ^e is independently Cy_A ⁵ optionally substituted with:

a) one Cy_A ⁷; and/or

b) one or more substituents R_A ^c, and/or

c) one or more substituents Z_A ⁴ optionally substituted with one or more substituents R_A ^C and/or one

Cy_A ⁷;

wherein Cy_A ⁷ is optionally substituted with one or more substituents independently selected from R_A ^c, and Z_A ⁵ optionally substituted with one or more substituents R_A ^c; and each R_A ¹ is independently Z_A ³ optionally substituted with one or more substituents R_A ^C and/or one Cy_A ⁶;

wherein Cy_A ⁶ is optionally substituted with:

a) one Cy_A ⁸; and/or

b) one or more substituents R_A ^c, and/or

c) one or more substituents Z_A ⁶ optionally substituted with one or more substituents R_A ^C and/or one

Cy_A ⁸;

wherein Cy_A ⁸ is optionally substituted with one or more substituents independently selected from R_A ^c, and Z_A ⁷ optionally substituted with one or more substituents R_A ^c; each R is independently H or R_A ¹; each R_A ⁹ is independently selected from the group consisting of (Ci-Cejalkyl, (C2-C6)alkenyl, (C2-Ce)alkynyl, (C2-Ce)hydrocarbon chain having one or more double bonds and one or more triple bonds, and 3- to 7- membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, wherein each R_A ⁹ is optionally substituted with one or more halogen atoms, each R_A ^9’ is independently H or R_A ⁹;

Y_A is 0, S, or NR_A ^9’;

ZA¹- Z_A ⁷are independently selected from the group consisting of (Ci-Ci2)alkyl, (C2-Ci2)alkenyl, (C2-Ci2)alkynyl, and (C2-Ce)hydrocarbon chain having one or more double bonds and one or more triple bonds;

Cy_A ², Cy_A ⁷ and Cy_A ⁸ are independently a known ring system selected from the group consisting of phenyl; 3- to 7-membered carbocyclic or heterocyclic monocyclic ring, saturated or partially unsaturated; and 5- or 6- membered heteroaromatic ring; Cy_A ³, Cy_A ⁴, Cy_A ⁵and Cy_A ⁶ are independently a known ring system selected from group consisting of phenyl; 5- or 6-membered heteroaromatic ring; 3- to 7-membered carbocyclic or heterocyclic monocyclic ring, which is saturated or partially unsaturated; and 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7- membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring; wherein in the carbocyclic rings all ring members are carbon atoms; and in the heterocyclic and

heteroaromatic rings one or more ring members are selected from N, 0, and S; and wherein in all saturated or partially unsaturated rings one or two members of the rings are optionally C(0) and/or C(NH) and/or C[N(Ci-C₄)alkyl],

In embodiment 24, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the compound of formula (III) of the combination of the invention as previously described is a compound of formula (Ilia).

In embodiment 25, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the compound of formula (III) of the combination of the invention as previously described is a compound of formula (lllb).

In embodiment 26, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the compound of formula (III) of the combination of the invention as previously described is a compound of formula (lllc). In embodiment 27, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the compound of formula (III) of the combination of the invention as previously described is a compound of formula (Hid).

In embodiment 28, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, R_AI is selected from the group consisting of R_A ³, Cy_A ¹, -OR_A ⁶, -NR_A ^b’R_A ^b’, -NRA^b’C(0)RA^b’, -NRA^b’S(0)2RA^b’, -S02NRA^b’RA^b’, and -C(0)NRA^b’RA^b’; wherein CyA¹ is optionally substituted as previously defined. In embodiment 29, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, R_AI is Cy_A ¹ optionally substituted as previously defined. More particularly, Cy_A ¹ is a known ring system selected from the group consisting of:

(i) phenyl; (ii) 5- or 6-membered heteroaromatic ring;

unsaturated;

and even more particulaly, R_AI is Cy_A ¹ optionally substituted as previously defined, wherein Cy_A ¹ is a known ring system selected from the group consisting of (i), (ii), and (iii), as defined above. In embodiment 30, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, R_AI is Cy_A ¹ optionally substituted as previously defined and is attached to the quinoline through a carbon atom.

In embodiment 31 , optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, R_AI is selected from the group consisting of phenyl, 5- to 6-membered heteroaromatic monocyclic ring, and 4- to 6-membered saturated carbocyclic or heterocyclic monocyclic ring, being R_AI optionally susbtituted as previously defined. More particulary, R_AI is a 5- to 6-membered heteroaromatic monocyclic ring attached to the quinoline through a carbon atom and optionally substituted as previously defined, and even more particularly, R_AI is selected from the group consisting of 2-thiophene, 3- thiophene, 2-pyrrol, 3-pyrrol, 2-furan and 3-furan. In a more particular embodiment, R_AI is selected from the group consisting of 2-thiophene, 3-thiophene, 2-pyrrol, 3-pyrrol, 2-furan and 3-furan, wherein R_AI is optionally substituted with one or more groups (Ci-Cejalkyl.

In embodiment 32, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, wherein R_AI is selected from the group consisting of the following moieties:

In embodiment 33, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, RA2 is selected from H, halogen, -CN and -ORA⁹’, more particularly, RA2 is selected from H, halogen and -ORA⁹’; even more particularly, RA2 IS H OG -ORA⁹; and even more particularly RA2 is -ORA⁹ wherein RA⁹ is (Ci-Cejalkyl optionally substituted with one or more halogen atoms. Even more particularly, R_A2 is -OCH₃. In embodiment 34, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, R_A3 is selected from the group consisting of -OfV and -ISHVR_A ^9’. More particularly, R_A3 is -OR_A ^d, and even more particularly R_A ^d in R_A3 is a moiety which contains at least one N atom.

In embodiment 35, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, R_A ^d in RA3 is ZA³, wherein It? is (Ci-C₆)alkyl substituted with one or more substituents as previously defined, more particularly in the latter embodiment, It? is (Ci-C₆)alkyl substituted with Cy_A ⁶, wherein Cy_A ⁶ is optionally substituted as previously defined; even more particularly, in the latter embodiment, Cy_A ⁶ is a 3- to 7-membered carbocyclic or heterocyclic monocyclic ring, saturated or partially unsaturated. In embodiment 36, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, R_A3 is a moiety of formula (XIV):

wherein

Cy_A ⁹ is a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring or a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, and Cy_A ⁹ is optionally substituted with one or more substituents selected from halogen and (Ci-C3)alkyl optionally substituted with one or more halogen atoms, X_A ¹ and X_A ²are independently H or halogen, and G_A is a value selected from 0 to 6. More particularly, R_A3 is a moiety of formula (XIV) wherein Cy_A ⁹ is a 3- to 7-membered saturated heterocyclic monocyclic ring or a 3- to 7-membered saturated carbocyclic or heterocyclic monocyclic ring, which is spiro- fused to a 3- to 7-membered saturated carbocyclic or heterocyclic monocyclic ring, and Cy_A ⁹ is optionally substituted as previously defined, X_A ¹ and X_A ²are H, and G_A is a value selected from 0 to 6.

In embodiment 37, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, R_A3 is selected from the group consisting of the following moieties:

In embodiment 38, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, RAS, RAS, RAIO, RAM, RAM are independently selected from the group consisting of H, R_A ^e, and RA.

In embodiment 39, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, RAS is H and RA-IO is RA⁶ or RA^j, or alternatively, RAS is RA⁶ or RA^j, and RA-IO is

H.

In embodiment 40, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, R_AM is H and R_AM is R_A ⁶ or R_A ^j, or alternatively, R_AM is R_A ⁶ or R_A ^j, and R_AM is H.

In embodiment 41 , optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, RA6, RA9, RAM, RAM, RAM, and RAM are H.

In embodiment 42, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, R_A4 and R_A7 are H.

In embodiment 43, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, R_AM is H and R_AM is R_AA or alternatively, R_AM is R_A ^d and R_AM is H. In embodiment 44, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, R_A4-R_AI8 are H.

In embodiment 45, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, one of R_A4-R_A6 is other than H and the others of R_A4-R_A6 are H; or one of RA7-RAI3 is other than H and the others of R_A7-R_Ai3are H; or one of RA-M-RI6 is other than H and the others of R_Ai4-R_Ai6are H; or one of R^ and RA-IS is other than H and the other of RAI7 and RA-IS is H.

In embodiment 46, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (III) of the combination of the invention as previously described, RA6, RA9, RAn-RAi3 and Rwe are H; one of RA4-RAS is other than H and the other of RA4-RAS is H; one of RA7, RAS and RA-IO is other than H and the others of RA7, RAS and RAioare H; one of RAI4-RAI5 is other than H and the other of RAM-RAM is H; and one of RAI7 and RA-IS is other than H and the other of RAI7 and RA-IS is H. More particularly, R_A4, RA6, RA7, RA9-RAi3and Rws-RA^are H; and RAS, RAS, RAM and Rwe are other than H. More particularly, in embodiment 47, the substituents R_A4-R_AI8 that are other than H in the latter two embodiments 45 and 46 are independently a (Ci-Ci2)alkyl optionally substituted with one o more substituents selected from the group consisting of:

halogen,

-NRA⁹ RA⁹ ,

-NRA^g’C(0)RA^g’, and

Cy_A ⁶ optionally substituted with one o more substituents selected from the group consisting of:

halogen,

-NRA⁹ RA⁹ ,

-NRA⁹ C(0)RA⁹ ,

-C(0)RA^9’,

-(Ci-Cejalkyl optionally substituted with one or more halogen atoms; and

a 3- to 7-membered carbocyclic or heterocyclic monocyclic ring, which is saturated or partially unsaturated;

wherein Cy_A ⁶ is a 3- to 7-membered carbocyclic or heterocyclic saturated or partially unsaturated monocyclic ring; or a 3- to 7-membered saturated carbocyclic or heterocyclic monocyclic ring, which is spiro-fused to a 3- to 7-membered saturated carbocyclic or heterocyclic monocyclic ring, and

each RA⁹’ is independently selected from H or (Ci-C6)alkyl optionally substituted with one or more halogen atoms. Even more particularly, in this embodiment 47, the substituents R_A4-R_Aiethat are other than H, preferably RAS, RA8, RAM and RAIS, are independently a (Ci-Ci2)alkyl substituted with Cy_A ⁶ optionally substituted with one o more substituents selected from the group consisting of:

halogen,

-C(0)R_A ^9’,

-(Ci-C₆)alkyl optionally substituted with one or more halogen atoms; and

a 3- to 7-membered saturated carbocyclic monocyclic ring;

RA⁹’ is H or (Ci-Ce)al kyl optionally substituted with one or more halogen atoms.

Even more particularly, in this embodiment 47, the substituents RA4-RAIS that are other than H, preferably RAS, RA8, RAM and RAIS, are selected from the group consisting of methyl and a moiety selected from the following ones:

In embodiment 48, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the compound of formula (III) of the combination of the invention is selected from the group consisting of:

Compounds of formula (IV)

In an eighth aspect, it also forms part of the invention a combination comprising:

A) a compound of formula (IV), or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (IV) or of any of its pharmaceutically or veterinary acceptable salts; and

B) a drug selected from the group consisting of: i) an immune checkpoint inhibitor, ii) an inhibitor of an anti- apoptotic protein, and iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor;

wherein the compound of formula (IV) is selected from the group consisting of compounds of formula (IVa), and (IVb):

wherein

RAI9 is selected from the group consisting of fV, CyA¹⁰, halogen, -NO2, -CN, -ORA', -0C(0)RA'^’, -0C(0)0RA'^’,

Cy_A ¹⁰ is a known ring system selected from the group consisting of:

(i) phenyl;

(ii) 5- or 6-membered heteroaromatic ring;

unsaturated;

(v) phenyl fused to a 6- to 14-membered saturated or partially unsaturated carbocyclic or heterocyclic bicyclic ring, wherein the rings of the bicyclic ring are spiro-fused; and (vi) 5- to 6-membered heteroaromatic ring fused to a 6- to 14-membered saturated or partially unsaturated carbocyclic or heterocyclic bicyclic ring, wherein the rings of the bicyclic ring are spiro- fused; wherein Cy_A ¹⁰ is optionally substituted with:

a) one CyA¹¹ or one CyA¹², and/or

b) one or more substituents R_A ¹, and/or

c) one or more substituents Z_A ⁸ optionally substituted with one or more substituents R_A ¹ and/or one Cy_A ¹¹;

wherein Cy_A ¹¹ or Cy_A ¹² are optionally substituted with one or more substituents independently selected from R_AI, and Z_A ⁹ optionally substituted with one or more substituents R_A ¹;

RA2O is selected from the group consisting of RA", halogen, -NO2, -CN, -ORA"^’, -0C(0)RA"^’, -0C(0)0RA"^’,

RA2I is selected from the group consisting of RA^k, -ORA¹⁵, -NRA^A"^’, and -NRA^h’CORA^k; wherein RA21 contains at least one atom selected from N, 0, S, and F;

RA22 and RA24 are independently selected from the group consisting of H, RA', -ORA¹¹¹, -NRA^RA"^’, - IWCORA¹¹¹, and R_A ^m;

R_A23 and R_A25 are independently selected from the group consisting of H, R_A ¹¹, and one or more halogen atoms; each R_A ¹¹ is independently selected from the group consisting of (Ci-Cejalkyl, (C2-Ce)alkenyl, (C2-Ce)alkynyl, (C2-Ce)hydrocarbon chain having one or more double bonds and one or more triple bonds, wherein each R_A ¹¹ is optionally substituted with one or more halogen atoms, each R_A ^11’ is independently H or R_A ¹¹; each R_A' is independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Ce)alkenyl, (C2-Ce)alkynyl, (C2-Ce)hydrocarbon chain having one or more double bonds and one or more triple bonds, wherein any of these groups is optionally substituted with one or more halogen atoms, and Cy_A ¹³ optionally substituted with one or more substituents R_A ¹; each R_A'¹ is independently H or R_A'; each RA¹ is independently selected from halogen, -NO2, -CN, -ORA"^', -OC^A^RA"^’, -OC(YA¹)ORA^n’, -OC(YA¹)NRA"^’RA"^’, -NRA"^’RA"^’, -NRA"^’C(YA¹)RA"^’, -NRA"^’C(YA¹)ORA"^’, -NRA"^’C(YA¹)NRA"^’RA"^’, -NRA"^’S(0)₂RA"^’, -NR SC^NR RA"^', -SRA"^’, -S(0)RA"^’, -S(0)0R_a"^’, -SCW, -S0₂(0RA"^’), -SC^NR RA"^', -SC(YA¹)NRA"^’R_a"^’, -C(Y_A ¹)RA"^’, -C(YA¹)ORA"^’, -C(YA¹)NRA"^’RA"^’, -C(YA¹)NR_A"ORA"^’, and -C(0)NRA"^’S0₂RA"^’; each R_A S independently R_A'or R_A ¹¹¹; each R_A ¹ is independently Cy_A ¹⁴ optionally substituted with:

a) one Cy_A ¹⁶; and/or

b) one or more substituents R_A ^j, and/or

c) one or more substituents Z_A ¹¹ optionally substituted with one or more substituents R_A ¹ and/or one Cy_A ¹⁶;

wherein Cy_A ¹⁶ is optionally substituted with one or more substituents independently selected from RA¹, and ZA¹² optionally substituted with one or more substituents RA¹; and each RA¹¹¹ is independently ZA¹⁰ optionally substituted with one or more substituents RA¹ and/or one Cy_A ¹⁵; wherein Cy_A ¹⁵ is optionally substituted with:

a) one Cy_A ¹⁷; and/or

b) one or more substituents R_A ¹, and/or

c) one or more substituents Z_A ¹³ optionally substituted with one or more substituents R_A ¹ and/or one

Cy_A ¹⁷;

wherein Cy_A ¹⁷ is optionally substituted with one or more substituents independently selected from RA¹, and ZA¹⁴ optionally substituted with one or more substituents RA¹; each R_A ^111’ is independently H or R_A ¹¹¹; each R_A" is independently selected from the group consisting of (Ci-Cejalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₂-C₆)hydrocarbon chain having one or more double bonds and one or more triple bonds, and 3- to 7- membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, wherein each R_A" is optionally substituted with one or more halogen atoms, each R_A"^’ is independently H or R_A";

YA¹ is O, S, or NRA"^’;

ZA⁸- Z_A ¹⁴are independently selected from the group consisting of (Ci-Ci₂)alkyl, (C₂-Ci₂)al kenyl,

(C₂-Ci₂)al kynyl, and (C₂-C₆)hydrocarbon chain having one or more double bonds and one or more triple bonds; Cy_A ¹¹, Cy_A ¹⁶ and Cy_A ¹⁷ are independently a known ring system selected from the group consisting of phenyl;

3- to 7-membered carbocyclic or heterocyclic monocyclic ring, saturated or partially unsaturated; and 5- or 6- membered heteroaromatic ring;

Cy_A ¹², Cy_A ¹³, Cy_A ¹⁴ and Cy_A ¹⁵ are independently a known ring system selected from group consisting of phenyl; 5- or 6-membered heteroaromatic ring; 3- to 7-membered carbocyclic or heterocyclic monocyclic ring, which is saturated or partially unsaturated; and 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7- membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring; wherein in the carbocyclic rings all ring members are carbon atoms; and in the heterocyclic and

heteroaromatic rings one or more ring members are selected from N, 0, and S; and wherein in all saturated or partially unsaturated rings one or two members of the rings are optionally C(O) and/or C(NH) and/or C[N(Ci-C₄)alkyl],

In embodiment 49, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the compound of formula (IV) of the combination of the invention is a compound of formula (IVa).

In embodiment 50, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the compound of formula (IV) of the combination of the invention is a compound of formula (IVb).

In embodiment 51 , optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (IV) of the combination of the invention, RAI9 is selected from the group consisting of fV, CyA¹⁰, -ORA', -NR/RA'^’, -NR/C^RA' ,

-I S^RA' , -SC^IWRA' , and -C^I RA'; wherein CyA¹⁰ is optionally substituted as previously defined. More particularly, R_A-I_Q is Cy_A ¹⁰ optionally substituted as previously defined. Even more particularly, Cy_A ¹⁰ is a known ring system selected from the group consisting of:

(i) phenyl;

(ii) 5- or 6-membered heteroaromatic ring;

unsaturated;

wherein Cy_A ¹⁰ is optionally substituted as previously defined.

In embodiment 52, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (IV) of the combination of the invention, R_A-I_Q is Cy_A ¹⁰ and is attached to the quinoline through a carbon atom and is optionally substituted as previously defined. In embodiment 53, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (IV) of the combination of the invention, R_AI9 is a 5- to 6-membered heteroaromatic monocyclic ring.

In embodiment 54, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (IV) of the combination of the invention, R_AI9 is selected from the group consisting of 2-thiophene, 3-thiophene, 2-pyrrol, 3-pyrrol, 2-furan and 3-furan and is optionally substituted as defined in embodiment 36.

In embodiment 55, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (IV) of the combination of the invention, R_A2_O IS selected from halogen, -CN and -OR_A"^’. More particularly, R_A2_O IS -OR_A". In embodiment 56, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (IV) of the combination of the invention, R_A2I is selected from the group consisting of -OR_A ¹⁵ and -NR_A ^kR_A ^n’. More particularly, R_A2I is -OR_A ¹⁵. Even more particularly, R_A ^K is a moiety which contains at least one N atom. In embodiment 57, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (IV) of the combination of the invention, RA^K in RA2I is ZA¹⁰, wherein ZA¹⁰ is (Ci-Ce)al kyl substituted with one or more substituents as previously defined. In embodiment 58, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (IV) of the combination of the invention, R_A2I is a moiety of formula (XV):

Cy_A ¹⁸— (CX_A ³X_A ⁴)r_A ¹— O—

(XV)

wherein

Cy_A ¹⁸ is a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring or a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, and Cy_A ¹⁸ is optionally substituted with one or more substituents selected from halogen and (Ci-C3)alkyl optionally substituted with one or more halogen atoms, X_A ³ and X_A ⁴are independently H or halogen, and G_A ¹ is a value selected from 0 to 6. More particularly, Cy_A ¹⁸ is a 3- to 7-membered saturated heterocyclic monocyclic ring or a 3- to 7- membered saturated carbocyclic or heterocyclic monocyclic ring, which is spiro-fused to a 3- to 7-membered saturated carbocyclic or heterocyclic monocyclic ring, and Cy_A ¹⁸ is optionally substituted as previously defined, X_A ³ and X_A ⁴are H, and G_A ¹ is a value selected from 0 to 6.

In embodiment 59, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (IV) of the combination of the invention, R_A2I is selected from the group consisting of the following moieties:

In embodiment 60, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (IV) of the combination of the invention, R_A22 and R_A24 are selected from the group consisting of H, R_A', and R_A ¹¹¹.

In embodiment 61 , optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (IV) of the combination of the invention, RA23 and RA25 are H.

In embodiment 62, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (IV) of the combination of the invention, RA22-RA25 are H.

In embodiment 63, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (IV) of the combination of the invention, one of R_A22-R_A23 is other than H and the other of R_A22-R_A23 is H; or one of R_A24-R_A25 is other than H, and the other of RA24-RA25 is H.

In embodiment 64, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (IV) of the combination of the invention, the substituents R_A22-R_A25 that are other than H are independently a (Ci-Ci₂)alkyl optionally substituted with one o more substituents selected from the group consisting of: halogen,

Cy_A ¹⁵ optionally substituted with one o more substituents selected from the group consisting of:

halogen,

-(Ci-C₆)alkyl optionally substituted with one or more halogen atoms; and

wherein Cy_A ¹⁵ is a 3- to 7-membered carbocyclic or heterocyclic saturated or partially unsaturated monocyclic ring; or a 3- to 7-membered saturated carbocyclic or heterocyclic monocyclic ring, which is spiro-fused to a 3- to 7-membered saturated carbocyclic or heterocyclic monocyclic ring, and

each R_A ^9’ is independently selected from H or (Ci-Ce)alkyl optionally substituted with one or more halogen atoms. More particularly, the substituents R_A22-R_A25 that are other than H are independently a (Ci-Ci2)alkyl substituted with Cy_A ¹⁵ optionally substituted with one o more substituents selected from the group consisting of:

halogen,

-(Ci-C₆)alkyl optionally substituted with one or more halogen atoms; and

a 3- to 7-membered saturated carbocyclic monocyclic ring;

R_A ^9’ is H or (Ci-Ce)alkyl optionally substituted with one or more halogen atoms.

In embodiment 65, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (IV) of the combination of the invention, the substituents R_A22-R_A25 that are other than H are independently selected from the group consisting of methyl and a moiety selected from the following ones:

Compounds of formula (V)

In a ninth aspect, it also forms part of the invention a combination comprising:

A) a compound of formula (V), or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (V) or of any of its pharmaceutically or veterinary acceptable salts; and

wherein

RB is a radical selected from the group consisting of formula (a), formula (b), formula (c), formula (d), and formula (e):

(a) (b) (c) (d) (e)

RBI is a known ring system selected from the group consisting of:

(i) phenyl;

(ii) 5- or 6-membered heteroaromatic ring;

(iii) 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring;

wherein RBI is optionally substituted with:

a) one Cye¹ or one Cye², and/or b) one or more substituents RB³, and/or

c) one or more substituents ZB¹ optionally substituted with one or more substituents RB³ and/or one Cys¹;

wherein Cye¹ or Cye²are optionally substituted with one or more substituents independently selected from RB³, and ZB² optionally substituted with one or more substituents RB³;

RB2 is selected from the group consisting of Re^b, halogen, -NO2, -CN, -(W, -0C(0)RB^b’, -0C(0)0RB^b’, -0C(0)NR_B ^bR_B ^b, -NR_B ^b,R_B ^b’, -NR_B ^b,C(0)R_B ^b’, -NR_B ^bC(0)0RB^b’, -NR_B ^b,C(0)NRB^b,RB^b’, -NR_B ^b,S(0)₂RB^b’, -NR_B ^b,S02NRB^b,RB^b’, W, -S(0)R_B ^b’, -S(0)0R_B ^b’, -S0₂RB^b’, -S0₂(0R_B ^b’), -SC^NRBW, -SC(0)NR_B ^bR_B ^b , -C(0)R_B ^b’, -C(0)0R_B ^b’, -C(0)NR_B ^b,R_B ^b’, -C(0)NR_B ^bOR_B ^b’, and -CiOJWSCW;

RB3 is selected from the group consisting of RB^c, -ORB^d, -ORB³, -NRB^b’RB^d, -NRB^b’RB^e, -NRB^fCORB^d, and -NRB'CORB³;

RB4 and RB6 are independently selected from the group consisting of Cye¹, and ZB¹ optionally substituted with one or more substituents RB³ and/or one Cye³;

wherein Cye¹ is optionally substituted with:

a) one Cye²; and/or

b) one or more substituents RB³, and/or

c) one or more substituents ZB² optionally substituted with one or more substituents RB³ and/or one

Cy_B ²;

wherein Cye² and Cye³ are optionally substituted with one or more substituents independently selected from RB³, and ZB³ optionally substituted with one or more substituents RB³; Res is (Ci-C₆)alkyl optionally substituted with one or more halogen atoms or a 3- to 7-membered saturated or partially unsaturated carbocyclic monocyclic ring optionally substituted with one or more halogen atoms; the dotted line means the presence or absence of a ring system B¹ or B³; RB7 is absent or is selected from the group consisting of H, RB³, Cye¹, and ZB¹ optionally substituted with one or more substituents RB³ and/or one Cye³;

wherein Cye¹ is optionally substituted with:

a) one Cye²; and/or

b) one or more substituents RB³, and/or

Cy_B ²;

wherein Cye² and Cye³ are optionally substituted with one or more substituents independently selected from RB³, and ZB³ optionally substituted with one or more substituents RB³; RB₈ and RB9 are independently selected from the group consisting of H, halogen, (Ci-Cejalkyl optionally substituted with one or more halogen atoms, and a 3- to 7-membered saturated or partially unsaturated carbocyclic monocyclic ring optionally substituted with one or more halogen atoms; or alternatively

RB₈ and RB9, together with the carbon atom to which they are attached, form a known ring system B¹ comprising a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is optionally fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring; wherein the ring system B¹ is optionally substituted with:

a) one Cye¹; and/or

b) one or more substituents RB³, and/or

c) one or more substituents ZB¹ optionally substituted with one or more substituents RB³ and/or one Cy_B ³;

wherein Cye¹ and Cye³ are optionally substituted with one or more substituents independently selected from RB³, and ZB² optionally substituted with one or more substituents RB³;

RB-I_O and RBH are independently selected from the group consisting of H, and ZB¹ optionally substituted with one or more substituents RB³ and/or one Cye³; wherein Cye³ are optionally substituted with one or more substituents independently selected from RB³, and ZB³ optionally substituted with one or more substituents RB³; or alternatively

RB-I_O and RBH, together with the carbon atom to which they are attached, form a known ring system B³ comprising a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is optionally fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring; wherein the ring system B³ is optionally substituted with:

a) one Cye¹; and/or

b) one or more substituents RB³, and/or

B² is a known ring system comprising a 3- to 7-membered saturated or partially unsaturated heterocyclic monocyclic ring, which is optionally fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring; wherein the ring system B² is optionally substituted with:

a) one Cye¹; and/or

b) one or more substituents RB³, and/or c) one or more substituents ZB¹ optionally substituted with one or more substituents RB³ and/or one Cy_B ³;

wherein Cy_B ¹ and Cye³ are optionally substituted with one or more substituents independently selected from RB³, and ZB² optionally substituted with one or more substituents RB³; each RB³ is independently selected from the group consisting of halogen, -NO2, -CN, -OR_B ^b’, -OC(Y_B)R_B ^b’,

each R_B ^b’ is independently H or Re^b; each Re^b is independently selected from the group consisting of (Ci-Cejalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₂-C₆)hydrocarbon chain having one or more double bonds and one or more triple bonds, and 3- to 7- membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, wherein each Re^b is optionally substituted with one or more halogen atoms,

RB^C is Re^d or RB⁹; with the proviso that RB^C is a moiety comprising at least one heteroatom selected from N, 0, S, and F;

Re^d is Cy_B ¹ optionally substituted with:

a) one Cye²; and/or

b) one or more substituents RB³, and/or

c) one or more substituents ZB¹ optionally substituted with one or more substituents RB³ and/or one Cy_B ²;

wherein Cye² is optionally substituted with one or more substituents independently selected from RB³, and ZB² optionally substituted with one or more substituents RB³;

RB³ is a moiety comprising at least 4 carbon atoms which is selected from the group consisting of

(Ci-Ci₂)alkyl, (C₂-Ci₂)alkenyl, (C₂-Ci₂)alkynyl, and (C₂-C₆)hydrocarbon chain having one or more double bonds and one or more triple bonds; wherein Re^e is optionally substituted with one or more substituents RB³ and/or one Cye³; wherein Cye³ is optionally substituted with:

a) one Cye⁴; and/or

b) one or more substituents RB³, and/or

c) one or more substituents ZB³ optionally substituted with one or more substituents RB³ and/or one

Cy_B ⁴;

wherein Cye⁴ is optionally substituted with one or more substituents independently selected from RB³, and ZB⁴ optionally substituted with one or more substituents RB³; f is H or RB¹;

RB¹ is selected from the group consisting of (Ci-Cejalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C2-Ce)hydrocarbon chain having one or more double bonds and one or more triple bonds, wherein each RB¹ is optionally substituted with one or more halogen atoms;

RB⁹ is selected from the group consisting of (Ci-Ci2)alkyl, (C2-Ci2)al kenyl, (C2-Ci2)alkynyl, and

(C2-Ce)hydrocarbon chain having one or more double bonds and one or more triple bonds; wherein RB⁹ is optionally substituted with one or more substituents RB³ and/or one Cye³; wherein Cye³ is optionally substituted with:

a) one Cye⁴; and/or

b) one or more substituents RB³, and/or

c) one or more substituents ZB³ optionally substituted with one or more substituents RB³ and/or one Cy_B ⁴;

wherein Cye⁴ is optionally substituted with one or more substituents independently selected from RB³, and ZB⁴ optionally substituted with one or more substituents RB³;

YB is 0, S, or NR_B ^b’; ZB¹, ZB², ZB³ and ZB⁴ are independently selected from the group consisting of (Ci-Ci2)alkyl, (C2-Ci2)al kenyl, (C2-Ci2)al kynyl, and (C2-Ce)hydrocarbon chain having one or more double bonds and one or more triple bonds;

Cy_B ¹ and Cye³ are independently a known ring system selected from the group consisting of phenyl; 5- or 6- membered heteroaromatic ring; 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring; Cy_B ², Cy_B ⁴ are independently a known ring system selected from the group consisting of phenyl; 3- to 7- membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 5- or 6- membered heteroaromatic ring; wherein in the carbocyclic rings all ring members are carbon atoms; and in the heterocyclic and

heteroaromatic rings one or more ring members are selected from N, 0, and S; and wherein in all saturated or partially unsaturated rings one or two members of the rings are optionally C(O) and/or C(NH) and/or C[N(Ci-C₄)alkyl], In embodiment 66, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, f is a moiety comprising at least 5 carbon atoms. In embodiment 67, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical selected from the group consisting of formula (a) (i.e. a compound (Va)) and formula (b) (i.e. a compound (Vb)):

In embodiment 68, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (a) (i.e. a compound (Va)), and RB4 is Cye¹ optionally substituted with one or more substituents ZB² optionally substituted as previously defined. More particularly, Cye¹ in RB4 is a known ring system selected from group consisting of 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused, more particularly bridged-fused or spiro-fused, to a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein Cye¹ is optionally substituted as previously defined. Even more particularly, ZB² in RB4 is (Ci-Cejalkyl optionally substituted with one or more substituents RB³.

In embodiment 69, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (a) (i.e. a compound (Va)), and RB4 is ZB¹; more particularly ZB¹ is

(Ci-Cejalkyl, optionally substituted as previously defined. Even more particularly, ZB¹ in RB4 is substituted with Cye³, wherein Cye³ is optionally substituted as previously defined. Even more particularly, Cye³ in RB4 is a known ring system selected from phenyl; 5- or 6-membered heteroaromatic ring; 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein Cye³ is optionally substituted as previously defined. Even more particularly, Cye³ in RB4 is selected from 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7- membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused, more particularly bridged-fused or spiro-fused, to a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein Cy_B ³ is optionally substituted as previously defined. Even more particularly, Cy_B ³ is optionally substituted with one or more substituents ZB³ optionally substituted as previously defined. More particularly, ZB³ in RB4 is (Ci-Cejalkyl optionally substituted with one or more substituents RB³.

In embodiment 70, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (a) (i.e. a compound (Va)), and RB4 is ZB¹; more particularly ZB¹ is (Ci-C₆)alkyl, optionally substituted with one or more halogen atoms.

In embodiment 71 , optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (a) (i.e. a compound (Va)), and RB_S is (Ci-Ce)alkyl optionally substituted with one or more halogen atoms, or a 3- to 7-membered saturated or partially unsaturated carbocyclic monocyclic ring optionally substituted with one or more halogen atoms. More particularly, RB_S is (Ci-Cejalkyl optionally substituted with one or more halogen atoms, even more particularly is -CH₃.

In embodiment 72, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (a) (i.e. a compound (Va)) selected from the group consisting of the following moieties:

wherein RBI3 is selected from the group consisting of H, methyl, isopropyl and cyclopropyl. In embodiment 73, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (b) (i.e. a compound (Vb)), and ring B² is a known ring system comprising a 3- to 7-membered saturated or partially unsaturated heterocyclic monocyclic ring optionally substituted as previously defined or a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused, more particularly bridged-fused or spiro-fused, to a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring optionally substituted as previously defined. More particularly, ring B² is optionally substituted with: a) one or more substituents RB³, and/or b) one or more substituents ZB¹ ; wherein ZB¹ in ring B² is optionally substituted as previously defined. Even more particularly, ZB¹ in ring B² is (Ci-Ce)alkyl optionally substituted with one or more substituents RB³.

In embodiment 74, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (b) (i.e. a compound (Vb)) selected from the group consisting of the following moieties:

In embodiment 75, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (c) (i.e. a compound (Vc)):

and RB6 is Cy_B ¹ optionally substituted with one or more substituents ZB² optionally substituted as previously defined. Even more particularly, Cy_B ¹ in RB₆ is a known ring system selected from group consisting of 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7- membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused, more particularly bridged-fused or spiro-fused, to a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein Cy_B ¹ is optionally substituted as previously defined. Even more particularly, ZB² is (Ci-Cejalkyl optionally substituted with one or more substituents RB³.

In embodiment 76, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (c) (i.e. a compound (Vc)), and RB6 is ZB¹; more particularly, ZB¹ is (Ci-C₆)alkyl, optionally substituted as previously defined. Even more particularly, ZB¹ is substituted with Cye³, wherein Cye³ is optionally substituted as previously defined. Even more particularly, Cye³ is optionally substituted with one or more substituents ZB³ optionally substituted as previously defined. Even more particularly, Cye³ in RB₆ is a known ring system selected from group consisting of phenyl; 5- or 6-membered heteroaromatic ring; 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein Cye³ is optionally substituted as previously defined. Even more particularly, Cye³ in RB₆ is selected from 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused, more particularly bridged-fused or spiro-fused, to a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein Cye³ is optionally substituted as previously defined. Even more particularly, ZB³ in RB6 is (Ci-Cejalkyl optionally substituted with one or more substituents RB³.

In embodiment 77, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (c) (i.e. a compound (Vc)) selected from the group consisting of the following moieties:

wherein RBI3 is selected from the group consisting of H, methyl, isopropyl and cyclopropyl.

In embodiment 78, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (d) (i.e. a compound (Vd)):

the dotted line means the absence of a ring system B¹; RB7 is Cye¹ optionally substituted with one or more substituents ZB² optionally substituted as previously defined; and RBS and RB9 are independently selected from the group consisting of H, halogen, (Ci-Cejalkyl optionally substituted with one or more halogen atoms, and a 3- to 7-membered saturated or partially unsaturated carbocyclic monocyclic ring optionally substituted with one or more halogen atoms. Even more particularly, Cye¹ in RB7 is a known ring system selected from group consisting of 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused, more particularly bridged-fused or spiro-fused, to a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein Cye¹ is optionally substituted as previously defined. Even more particularly, Cye¹ in RB7 is 3- to 7-membered saturated or partially unsaturated heterocyclic monocyclic ring, wherein Cye¹ is optionally substituted as previously defined. Even more particularly, ZB² in RB⁷ is (Ci-Cejalkyl optionally substituted with one or more substituents RB³.

Even more particularly, RB_S and RB9 are independently selected from the group consisting of H, halogen, and (Ci-C₆)alkyl optionally substituted with one or more halogen atoms. Even more particularly, RB_S and RB9 are independently H or halogen. Even more particularly, RB_S and RB9 are independently H or F.

In embodiment 79, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (d) (i.e. a compound (Vd)), the dotted line means the absence of a ring system B¹; RB7 is ZB¹ ; more particularly, ZB¹ is (Ci-Cejalkyl, optionally substituted as previously defined; and RB₈ and RB9 are independently selected from the group consisting of H, halogen, (Ci-Cejalkyl optionally substituted with one or more halogen atoms, and a 3- to 7-membered saturated or partially unsaturated carbocyclic monocyclic ring optionally substituted with one or more halogen atoms. Even more particularly,

ZB¹ in RB7 is substituted with Cye³, wherein Cye³ is optionally substituted as previously defined. Even more particularly, Cye³ is optionally substituted with one or more substituents ZB³ optionally substituted as previously defined. Even more particularly, Cye³ in RB7 is a known ring system selected from group consisting of phenyl; 5- or 6-membered heteroaromatic ring; 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7- membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein Cye³ is optionally substituted as previously defined. Even more particularly, Cye³ in RB7 is selected from 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7- membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused, more particularly bridged-fused or spiro-fused, to a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein Cye³ is optionally substituted as previously defined. Even more particularly, ZB³ in RB7 is (Ci-C₆)alkyl optionally substituted with one or more substituents RB³. Even more particularly, ZB³ in RB7 is (Ci-Cejalkyl optionally substituted with one or more substituents RB³. Even more particularly, RBS and RB9 are independently selected from the group consisting of H, halogen, and (Ci-Cejalkyl optionally substituted with one or more halogen atoms. Even more particularly, RB₈ and RB9 are independently H or halogen. Even more particularly, RB_S and RB9 are independently H or F. Even more particularly, RB_S and RB9 are H.

In embodiment 80, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (d) (i.e. a compound (Vd)); the dotted line means the presence of a ring system B¹; RB⁷ is absent; and RBS and RB9, together with the carbon atom to which they are attached, form a known ring system B¹ comprising a 3- to 7-membered partially unsaturated carbocyclic or heterocyclic monocyclic ring, more particularly a 3- to 7-membered heterocyclic monocyclic ring, wherein the ring B¹ is saturated or it contains at least one unsaturation between the carbon atom to which R_SB and Rge are attached and the contiguous carbon atom; and the ring system is optionally substituted with one or more substituents RB³, and/or one or more substituents ZB¹ optionally substituted as previously defined. Even more particularly, ZB¹ is (Ci-C₆)alkyl optionally substituted with one or more substituents RB³.

In embodiment 81 , optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (d) (i.e. a compound (Vd)); the dotted line means the presence of a ring system B¹; RB7 is Cye¹ optionally substituted with one or more substituents ZB² optionally substituted as previously defined; and RB_S and RB9, together with the carbon atom to which they are attached form a known ring system B¹ comprising a 3- to 7-membered saturated or partially unsaturated carbocyclic monocyclic ring optionally substituted as previously defined, more particularly substituted with one or more substituents ZB¹ , wherein ZB¹ in ring B¹ is optionally substituted as previously defined. Even more particularly, Cye¹ in RB7 is a known ring system selected from group consisting of 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused, more particularly bridged-fused or spiro-fused, to a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein Cye¹ is optionally substituted as previously defined. Even more particularly, Cye¹ in RB7 is 3- to 7-membered saturated or partially unsaturated heterocyclic monocyclic ring, wherein Cye¹ is optionally substituted as previously defined. Even more particularly, ZB² in RB⁷ is (Ci-Cejalkyl optionally substituted with one or more substituents RB³.

In embodiment 82, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (d) (i.e. a compound (Vd)), the dotted line means the presence of a ring system B¹; RB7 is ZB¹ ; more particularly, ZB¹ is (Ci-Cejalkyl, optionally substituted as previously defined; and RB₈ and RB9, together with the carbon atom to which they are attached form a known ring system B¹ comprising a 3- to 7-membered saturated or partially unsaturated carbocyclic monocyclic ring optionally substituted as previously defined, more particularly substituted with one or more substituents ZB¹, wherein ZB¹ in ring B¹ is optionally substituted as previously defined. Even more particularly, ZB¹ in RB7 is substituted with Cye³, wherein Cye³ is optionally substituted as previously defined. Even more particularly, Cye³ is optionally substituted with one or more substituents ZB³ optionally substituted as previously defined. Even more particularly, Cye³ in RB7 is a known ring system selected from group consisting of phenyl; 5- or 6-membered heteroaromatic ring; 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein Cye³ is optionally substituted as previously defined. Even more particularly, Cye³ in RB7 is selected from 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused, more particularly bridged-fused or spiro-fused, to a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein Cye³ is optionally substituted as previously defined. Even more particularly, ZB³ in RB7 is (Ci-Cejalkyl optionally substituted with one or more substituents RB³. Even more particularly, ZB³ in RB7 is (Ci-Cejalkyl optionally substituted with one or more substituents RB³.

In embodiment 83, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (d), and the dotted line means the presence of a ring system B¹; RB7 is selected from the group consisting of H, RB³, and ZB¹ optionally substituted with one or more substituents RB³; and RB₈ and RB9, together with the carbon atom to which they are attached form a known ring system B¹ as previously defined. More particularly, ZB¹ in f is (Ci-C3)alkyl optionally substituted with one or more substituents RB³, and RB³ in RB7 is selected from halogen, -OR_B ^b' (in particular wherein RB is H or

(Ci-C3)alkyl), and -CN. Even more particularly, RB_S and RB9, together with the carbon atom to which they are attached form a known ring system B¹ comprising a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring optionally substituted with one or more substituents ZB¹ , wherein ZB¹ in ring B¹ is optionally substituted as previously defined, more particularly ZB¹ in ring B¹ is (Ci-Cejalkyl optionally substituted with one or more substituents RB³.

In embodiment 84, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (d) (i.e. a compound (Vd)) selected from the group consisting of the following moieties:

wherein RBI3 is selected from the group consisting of H, methyl, isopropyl and cyclopropyl. In embodiment 85, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (e) (i.e. a compound (Ve)):

the dotted line means the presence of a ring system B³; RBIO and RBH, together with the carbon atom to which they are attached, form a known ring system B³ comprising a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is optionally fused, bridged-fused or spiro- fused, more particularly bridged-fused or spiro-fused, to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring; wherein the ring system B³ is optionally substituted as previously defined. More particularly, RBIO and RBH , together with the carbon atom to which they are attached, form a known ring system B³ comprising a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein the ring system B³ is optionally substituted as previously defined. Even more particularly, ring B³ is optionally substituted with one or more substituents RB³ and/or ZB¹ , more particularly ZB¹ is (Ci-C₆)alkyl, optionally substituted with one or more substituents RB³.

In embodiment 86, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB is a radical of formula (e) (i.e. a compound (Ve)) selected from the group consisting of the following moieties:

In embodiment 87, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RBI is a known ring system selected from the group consisting of:

(i) phenyl;

(ii) 5- or 6-membered heteroaromatic ring;

(iii) 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and (iv) 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic

wherein RBI is optionally substituted as previously defined. In embodiment 88, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, f is a known ring system selected from the group consisting of:

ii) 5- or 6-membered heteroaromatic ring;

iii) 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; more particularly 3- to 7-membered saturated or partially unsaturated heterocyclic monocyclic ring; even more particularly 3- to 7-membered saturated heterocyclic monocyclic ring;

iv) 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring; more particularly 5- to 6-membered aromatic carbocyclic or heterocyclic monocyclic ring, which is fused to a 5- to 6- membered aromatic carbocyclic or heterocyclic monocyclic ring;

wherein RBI is optionally substituted as previously defined.

In embodiment 89, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, f is a known ring system selected from the group consisting of:

ii) 5- or 6-membered heteroaromatic ring; and

wherein RBI is optionally substituted as previously defined.

In embodiment 90, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RBI is attached to the quinoline through a carbon atom.

In embodiment 91 , optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RBI is a 5- to 6-membered heteroaromatic monocyclic ring, in particular attached to the quinoline through a carbon atom, and optionally substituted as previously defined. More particularly, RBI is optionally substituted with one or more substituents ZB¹, more particularly ZB¹ is (Ci-Ci2)alkyl, optionally substituted as previously defined.

In embodiment 92, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RBI is selected from the group consisting of the following moieties:

In embodiment 93, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, f is selected from halogen, -CN and -OR_B ^b’, more particularly f¾ is selected from halogen and -OR_B ^b; even more particularly RB2 is -OR_B ^b; and even more particularly Re^b in RB2 is (Ci-Cejalkyl optionally substituted with one or more halogen atoms.

In embodiment 94, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB3 is selected from the group consisting of -ORB^d, -ORB⁶, -NRB^dRB^b’, and -NRB^eRB^b’. More particularly, RB3 is -OR_B ^d or -ORB⁶, and even more particularly R_B ^d or Re^e in RB3 contains at least one N atom.

In embodiment 95, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB3 is -ORB⁶. More particularly, Re^e is (Ci-Cejalkyl substituted as previously defined. Even more particularly Re^e in -ORB⁶ contains at least one N atom. Even more particularly, Re^e is substituted with Cy_B ³as previously defined. Even more particularly, Cye³ in Re^e is a known ring system selected from group consisting of a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused, more particularly bridged-fused or spiro-fused, to a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein Cye³ is optionally substituted as previously defined. Even more particularly, Cye³ is a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, and is optionally substituted as previously defined. Even more particularly, Cye³ is a 3- to 7-membered heterocyclic monocyclic ring and is optionally substituted with one or more substituents ZB³ optionally substituted as previously defined.

Even more particularly, ZB³ in Re^e is (Ci-Cejalkyl substituted with one or more substituents RB³. In embodiment 96, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, f is -Of , and f is Cy_B ¹ optionally substituted with one or more substituents ZB¹ optionally substituted as previously defined. More particularly, Cy_B ¹ in f is a known ring system selected from group consisting of a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused, more particularly bridged-fused or spiro-fused, to a 3- to 7- membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein Cy_B ¹ is optionally substituted as previously defined. Even more particularly, ZB¹ in R_B ^d is (Ci-Cejalkyl substituted with one or more substituents RB³.

In embodiment 97, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB3 is -NR_B ^b’R_B ^e. More particularly, Re^e is (Ci-Cejalkyl substituted as previously defined. Even more particularly Re^e in -NR_B ^b’R_B ^e contains at least one N atom. Even more particularly, Re^e is substituted with Cye³ as previously defined. Even more particularly, Cye³ in Re^e is a known ring system selected from group consisting of a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused, more particularly bridged-fused or spiro-fused, to a 3- to 7- membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein Cye³ is optionally substituted as previously defined. Even more particularly, Cye³ is a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, and is optionally substituted as previously defined. Even more particularly, Cye³ is a 3- to 7-membered heterocyclic monocyclic ring, and is optionally substituted with one or more substituents ZB³ optionally substituted as previously defined. Even more particularly, ZB³ in Re^e is (Ci-Cejalkyl substituted with one or more substituents RB³.

In embodiment 98, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB3 is -NR_B ^b’R_B ^d, and R_B ^d is Cy_B ¹ optionally substituted with one or more substituents ZB¹ optionally substituted as previously defined. More particularly, Cy_B ¹ in R_B ^d is a known ring system selected from group consisting of a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused, more particularly bridged-fused or spiro-fused, to a 3- to 7- membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, wherein Cy_B ¹ is optionally substituted as previously defined. Even more particularly, ZB¹ in R_B ^d is (Ci-Cejalkyl substituted with one or more substituents RB³.

In embodiment 99, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, RB3 is a moiety of formula (XXVI):

wherein

Cy_B ⁵ is a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring or a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, and Cy_B ⁵ is optionally substituted with one or more substituents selected from halogen and (Ci-C3)alkyl optionally substituted with one or more halogen atoms, XB¹ and Xe²are independently H or halogen, and re is a value selected from 0 to 6. More particularly, f is a moiety of formula (XXVI) wherein Cye⁵ is a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring or a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring, and Cye⁵ is optionally substituted with one or more substituents selected from halogen and (Ci-C3)alkyl optionally substituted with one or more halogen atoms, XB¹ and Xe²are independently H or halogen, and re is a value selected from 0 to 6. More particularly, f is a moiety of formula (XXVI) wherein Cye⁵ is a 3- to 7-membered saturated heterocyclic monocyclic ring or a 3- to 7-membered saturated carbocyclic or heterocyclic monocyclic ring, which is spiro-fused to a 3- to 7-membered saturated carbocyclic or heterocyclic monocyclic ring, and Cye⁵ is optionally substituted as previously defined, XB¹ and Xe²are H, and re is a value selected from 0 to 6.

In embodiment 100, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, in the compound of formula (V) of the combination of the invention, f is selected from the group consisting of the following moieties:

In embodiment 101 , optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the compound of formula (V) of the combination of the invention is selected from the group consisting of:

Synthesis of the compounds of formula (I), (III), (IV), and (V)

Compounds of formula (I) can be prepared as disclosed in the patent applications WO2015192981 ,

WO2017102677, and EP17382365.9 (not published). Compounds of formula (III) and (IV) can be prepared as disclosed in the patent application WO2017085053. Compounds of formula (V) can be prepared as disclosed in the patent application WO2017102677.

Besides, the compounds of formula (II) as defined above may be obtained generally by reacting a compound of formula (VI) as shown in the scheme below:

Scheme 1

wherein R’ is an hydroxamic acid protective group, more particularly an hydroxamic acid protective group selected from the group consisting of tetrahydro-2H-pyran-2-yloxy (THP), benzyl, 1-naphthylmethyl and dimethyloxybenzyl (DMB); R₅ is hydrogen, and R₁-R₃, X and L are as previously defined.

The removal of the protective group of the hydroxamic acid is carried out by standard methods well-known in the art as described for example in T. W. Green and P. G. M. Wuts, Protective Groups in Organic Chemistry (Wiley, 3rd ed. 1999, Chapter 2, pp. 17-200). Representative hydroxy protective groups include those where the hydroxy group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers. When the hydroxamic acid protective group is THP, the deprotection is carried out in acidic medium, for example with HCI, in a suitable solvent such as dioxane, ethyl acetate or methanol.

A compound of formula (XXII) may be obtained from a compound of formula (VI) wherein R₅ is H by reaction with a hydroxylamine of formula (XXIII), wherein R’ is an hydroxamic acid protective group as defined above, more particularly an hydroxamic acid protective group selected from the group consisting of tetrahydro-2H- pyran-2-yloxy (THP), benzyl, 1-naphthylmethyl and dimethyloxybenzyl (DMB). This conversion can be carried out in the presence of an activating agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCI) and Hydroxybenzotriazole (HOBt), preferably in the presence of a base, such as N- methyl morpholine (NMM) or diisopropylethylamine (DIEA), in a suitable solvent, such as dichloromethane, chloroform or dimethylformamide, at a temperature comprised from room temperature to the temperature of the boiling point of the solvent, preferably at room temperature.

A compound of formula (VI) wherein R₅ is H can be obtained from a compound of formula (VI) wherein R₅ is a carboxy protective group such as (Ci-C₆)alkyl, benzyl, p-methoxyphenyl, trimethylsilyl, or [2-(T rimethylsilyl)- ethoxy]methyl (SEM). The deprotection reaction can be carried out by standard methods well-known in the art as described for example in T. W. Green and P. G. M. Wuts, Protective Groups in Organic Chemistry (Wiley, 3rd ed. 1999, Chapter 5, pp. 369-451). When the carboxy protective group is (Ci-Cejalkyl, the deprotection is carried out in basic medium, for example with LiOH in a suitable solvent such as tetrahydrofuran, methanol, water or mixtures thereof.

Moreover, a compound of formula (II) which is a compound of formula (lla) or a compound formula (lib) as defined below can be obtained from a compound of formula (VII) by reacting it with a compound of formula (VIII) or a compound of formula (IX), respectively, as shown in the scheme below:

Scheme 2 wherein X3 is a halogen atom, preferably Cl, Q is -LCONHOH or a group capable of being converted to a group -LCONHOH, and R₁-R₃, R^a’, and ring B are as previously defined. In both cases the reactions for obtaining a compound of formula (lla) or a compound of formula (lib) are carried out optionally in the presence of p-toluenesulfonic acid (PTSA), in a suitable solvent, such as tert-butanol at a suitable temperature, preferably heating at a temperature around 100-120 °C.

Alternatively, the reactions for obtaining a compound of formula (lla) or a compound of formula (lib) can be carried out in the presence of a palladium catalyst, such as e.g. Tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), an organophosphorus compound, such as e.g. Biphenyl-2-yl-dicyclohexyl-phosphane, (2,2'- bis(diphenylphosphino)-1 ,1'-binaphthyl) (BINAP) or 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

(Xantphos), and a base, such as e.g. CS₂CO₃, sodium tert-butoxide or K₃PO₄. The reaction is performed in a suitable solvent, such as e.g. dimethyl ether (DME), toluene or dioxane, at a suitable temperature, preferably heating. A compound of formula (II) which is a compound of formula (lie) as defined below can be obtained from a compound of formula (VII), which is firstly converted into a compound of formula (X) and then subsequently reacted with a compound of formula (XI) as shown in the scheme below:

Scheme 3

wherein X₃ is a halogen atom, preferably Cl, Q is -LCONHOH or a group capable of being converted to a group -LCONHOH, LG is a leaving group, such as a methanesulfonate (Ms), and R₁-R₃ are as previously defined.

The first conversion is carried out with a boronic derivative such as 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 ,3,2-dioxaborolane, in the presence of a palladium catalyst, such as e.g. [1 ,1'-

Bis(diphenylphosphino)ferrocene]palladium(ll) dichloride (Pd(dppf)Cl2) and KOAc, in a suitable solvent, such as e.g. dioxane, at a suitable temperature, preferably heating at a temperature around 100-120 °C; and then by reacting the intermediate obtained with hydrogen peroxide in a suitable solvent, such as dichloromethane. The second conversion is carried out in the presence of a base, such as CS2CO3, in a suitable solvent such as N,N-dimethylformamide (DMF) preferably heating at a temperature around 80-120 °C.

Alternatively, a compound of formula (VII) can be directly converted into a compound of formula (IICc) by reaction with a compound of formula (CG) HO-Q, optionally in the presence of p-toluenesulfonic acid (PTSA) or a base such as NaH in DMF at a suitable temperature, preferably heating at a temperature around 100-120 °C (PTSA) or 20°C (NaH).

A compound of formula (II) which is a compound of formula (lid) as defined below can be obtained by reacting a compound of formula (VII) with a boronic derivative of formula (XII), as shown in the scheme below:

Scheme 4

wherein X3 is a halogen atom, preferably Cl, Q is -LCONHOH or a group capable of being converted to a group -LCONHOH, each R is H, (Ci-C6)alkyl or, alternatively, two R groups together with the B atom to which they are attached may form a cycle, and R₁-R₃, R^b and R^c are as previously defined.

For either R^b or R^c being hydrogen, this conversion is carried out in the presence of a palladium catalyst, such as e.g. Tetrakis(triphenylphosphine)-pailadium(0) (Pd(PPh3)4) and KOAc or K₂CO₃, in a suitable solvent, such as e.g. dioxane optionally mixed with water, at a suitable temperature, preferably heating at a temperature around 100-120 °C.

In the compounds (lla), (lib), (lie) and (lid) above, when Q is other than -LCONHOH, it is a group capable of being converted to a group -LCONHOH. For example, Q may be a group -LCO2R” wherein R” is H or a carboxylic acid protective group that is converted into an hydroxamic acid as decribed above. Further conversions of a Q moiety other than -LCONHOH into a Q moiety which is -LCONHOH are exemplified in the examples below.

A compound of formula (VII) can be obtained from a quinoline of formula (XIII) which is firstly converted into a compound of formula (XIV). This compound is then reacted with a compound of formula (XV) to give a compound of formula (XVI) which is converted into a compound (VII) as shown in the scheme below:

Scheme 5

wherein X3 is a halogen atom, preferably Cl, and Ri-Rsare as previously defined.

The reduction of the compound of formula (XIII) into a compound of formula (XIV) is carried out by hydrogenation, e.g. in the presence of Pd/C in a suitable solvent such as methanol, whereas the conversion of a compound of formula (XIV) into a compound of formula (XVI) is carried out in the presence of a halogenating agent, such as e.g. POCI₃, at a suitable temperature, preferably heating.

When Ri is R^e or Cy⁷, the conversion of a compound of formula (XVI) into a compound of formula (VII) may be carried out with a boronic derivative of formula RIB(OR)2 (XVII), wherein Ri is R^e or Cy⁷; and R is H, (Ci-C₆)alkyl or, alternatively, two R groups together with the B atom to which they are attached may form a cycle, in the presence of a palladium catalyst, such as e.g. Tetrakis(triphenylphosphine)-pailadium(0) (Pd(PPti3)4) and a base, such as e.g. K2C03or Na₂CC>₃, in a suitable solvent, such as e.g. dioxane optionally mixed with water, at a suitable temperature, preferably heating, particularly at about 100-120 °C. Alternatively, this conversion may be carried out with a stannate derivative in the presence of a palladium catalyst, such as e.g. Bis(triphenylphosphine)-palladium(ll) dichloride (Pd(PPhi₃)Cl₂) in a suitable solvent, such as e.g.

dimethylformamide, at a suitable temperature, preferably heating.

When Ri is -OR^e, the conversion of a compound of formula (XVI) into a compound of formula (VII) may be carried out with an alcohol of formula R^eOH (XVIII) in the same conditions described above when Ri is R^e or Cy⁷. When Ri is -NR^e’R^e’, the conversion of a compound of formula (XVI) into a compound of formula (VII) may be carried out with an amine of formula HNR^e,R^e’ (XIX) in the same conditions described above when Ri is R^e or Cy⁷· Alternatively, the reactions described above can be carried out in a different order. Thus, for example the above described reactions carried out on intermediates already containing substituents R₁-R₃ can also be performed on analogue intermediates containing one or more precursors of substituents R₁-R₃, which are subsequently transformed into groups R₁-R₃.

Compounds of formula (II) may also be converted into other compounds of formula (II) by reactions well known in the art. The compounds of formulas (XXIII), (VIII), (IX), (XI), (CG), (XII), (XIV), (XV), (XVII), (XVIII), and (XIX) are commercially available or can be obtained by conventional synthetic processes.

Inhibitors of an anti-apoptotic protein

As mentioned before, it forms part of the invention a combination either comprising or consisting of A) a compound selected from the group consisting of a compound of formula (I), a compound of formula (III), a compound of formula (IV), and a compound of formula (V) as defined above (i.e. including all possible pharmaceutically or veterinary acceptable salt thereof, stereoisomer or mixtures of stereoisomers as previously indicated); and B) an inhibitor of an anti-apoptotic protein.

For the purposes of the present invention an“inhibitor of an anti-apoptotic protein” is a compound or agent which is able to induce apoptosis in a cell by totally or partially reducing, inhibiting, interfering with or modulating one or more anti-apoptotic mechanisms of the cell. Thus, the inhibitor of an anti-apoptotic protein acts as a proapoptotic drug. The term“propaptotic"’ refers to the ability of the inhibitor to promote or enhance the induction and/or progression of apoptosis in a cell in vitro or in vivo. As used herein this inhibitor is capable of inhibiting one anti-apoptotic protein with an affinity (K_d or K,) value < 10 mM, preferably < 1 mM, more preferably < 500 nM, when the inhibition of the anti-apoptotic protein is measured in enzymatic assays as described in Ashkenazi A et al. (Nat Rev Drug Discov. 2017, 16(4), pp. 273-284), and Souers AJ et al. (Nat Med. 2013, 19(2), pp. 202-8).

The anti-apoptotic protein may be a member of the anti-apoptotic BCL-2 family. The term anti-apoptotic BCL-2 family members include any known members of the BCL-2 family of proteins which has anti-apoptotic activity. More particularly, the anti-apoptotic BCL-2 family members are selected from the group consisting of B-cell lymphoma-2 (BCL-2), BCL-XL, myeloid cell leukemia-1 (MCL-1), AI/BFL-1 , BOO- DIVA, BCL-w, and combinations thereof; even more particularly, are selected from the group consisting of BCL-2, BCL-XL, MCL- 1 , BCL-w, and combinations thereof.

Non limiting examples of inhibitors of an anti-apoptotic protein include the ones shown in table 1 below: Table 1 : Examples of inhibitors of an anti-apoptotic protein

In embodiment 102, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the inhibitor of an anti-apoptotic protein of the combination of the invention is an inhibitor of the anti-apoptotic BCL-2 family members; more particularly, the anti-apoptotic BCL-2 family members being selected from the group consisting of B-cell lymphoma-2 (BCL-2), BCL-XL, myeloid cell leukemia-1 (MCL-1), AI/BFL-1 , BOO- DIVA, BCL-w, and combinations thereof; and even more particularly, the anti-apoptotic BCL-2 family members being selected from the group consisting of BCL- 2, BCL-XL, MCL-1 , BCL-w and combinations thereof.

In embodiment 103, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the inhibitor of an anti-apoptotic protein of the combination of the invention is selected from the group consisting of ABT199, A855071.0, AT 101 , GX15-070, (R)-Gossypol, S55746, S63845, A1210477, UMI77, BL193, APG1252, WEHI539, A1331852, BM1197,

A1155463, Beclanorsen, Apogossypolone, TW37, ABT737, Augmerosen, and Cheleritrine.

In embodiment 104, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the invention relates to each of the individual specific binary combinations formed by A) a compound selected from the group consisting of a compound of formula (I), a compound of formula (III), a compound of formula (IV), and a compound of formula (V) as defined above (i.e. including all possible pharmaceutically or veterinary acceptable salt thereof, stereoisomer or mixtures of stereoisomers as previously indicated); which is selected from the group consisting of: 1-1-01, 1-1-02, 1-2-01 , 1-3-01, 1-3-02, 1-3-03, 1-3-04, 1-3-05, 1-3-06, 1-3-07, 1-3-08, 1-3-09, 1-3-10, 1-3-11, 1-3-12, 1-3-13, 1-3-14, 1-3-15, 1-3-16, 1-3-17, 1-3-18, 1-3-19, 1-3-20, 1-3-21, 1-3-22, 1-3-23, 1-3-24, 1-3-25, 1-3-26, 1-3-27, 1-3-28, 1-3-29, 1-3-30, 1-3-31, 1-3-32, 1-3-33, 1-3-34, 1-3-35, 1-3-36, 1-3-37, 1-3-38, 1-3-39, 1-3-40, 1-3-41, 1-3-42, 1-3-43, 1-3-44, 1-3-45, 1-3-46, 1-3-47, 1-3-48, 1-3-49, 1-3-50, 1-3-51, 1-3-52, 1-3-53, 1-3-54, 1-3-55, 1-3-56, 1-4-01, 1-4-02, 1-4-03, 1-5-01, 1-5-02, 1-5-03, 1-5-04, 1-5-05, 1-5-06, 1-5-07, 1-5-08, 1-6-01, 1-6-02, 1-7-01 , 1-7-02, 1-7-04, 1-7-05, 1-8-01, 1-8-02, 1-9-01, 1-10-01, 1-11-01, 1-11-02, 1-11-03, 1-11-04, 1-11-05, 1-11-06, 1-11-07, 1-11-08, 1-11-09, 1-11-10, 1-11-11, 1-11-12, 1-11-13, 1-12-01, 1-12-02, 1-12-03, 1-12-04, 1-12-05, 1-12-06, 1-13-01, 1-14-01, 1-15-01, 1-16-01, 1-16-02, 1-17-01 , 1-17-02, 1-18-01, 1-18-02, 1-19-01, 1-19-02, 1-19-03, 4-1-01 , 4-1-02, 4-1-03, 4-1-04, 4-1-05, 4-1-06, 4-1-07, 4-1-08, 4-1-09, 4-1-10, 4-1-11 , 4-1-12, 4-1-13, 4-1-14, 4-2-01, 4-2-02, 4-2-03, 4-2-04, 4-2-05, 4-2-06, 4-2-07, 4-2-08, 4-2-09, 4-2-10, 4-2-11, 4-2-12, 4-2-13, 4-2-14, 4-2-15, 4-2-16, 4-2-17, 4-2-18, 4-2-19, 4-2-20, 4-2-21 , 4-2-22, 4-3-01, 4-3-02, 4-3-03, 4-3-04, 4-3-05, 4-3-06, 4-3-07, 4-3-08, 4-3-09, 4-3-10, 4-3-11, 4-3-12, 4-3-13, 4-3-14, 4-3-15, 4-3-16, 4-3-17, 4-3-18, 4-3-19, 4-3-20, 4-3-21, 4-3-22, 4-3-23, 4-3-24, 4-3-25, 4-4-01, 4-5-01 , 4-6-01, 4-7-01 , 4-8-01, 4-9-01, 4-10-01 , 4-10- 02, 2-1-01, 2-1-02, 2-1-03, 2-1-04, 2-1-05, 2-1-06, 2-2-01, 2-2-02, 2-2-03, 2-2-04,2-2-05,2-2-06, 2-2-07, 2-2- 08, 2-2-09, 2-2-10, 2-2-11 , 2-2-12, 2-2-13, 2-3-01 , 2-3-02, 2-3-03, 2-3-04, 2-4-01 , 2-4-02, 2-4-03, 2-4-04, 2-4-

05, 3-1-01, 3-1-02, 3-1-03, 3-1-04, 3-1-05, 3-1-06, 3-1-07, 3-1-08, 3-1-09, 3-1-10, 3-1-11, 3-1-12, 3-1-13, 3-1-

14, 3-1-15, 3-1-16, 3-1-17, 3-1-18, 3-1-19, 3-1-20, 3-1-21, 3-1-22, 3-1-23, 3-2-01, 3-2-02, 3-2-03, 3-2-04, 3-2-

05, 3-2-06, 3-2-07, 3-2-08, 3-2-09, 3-3-01, 3-3-02, 3-3-03, 3-3-04, 3-3-05, 3-3-06, 3-3-07, 3-4-01, 3-4-02, 3-4-

03, 3-4-04, 3-5-01 , and 3-5-02; and B) an inhibitor of an anti-apoptotic protein selected from the group consisting of: ABT199, A855071.0, AT101 , GX15-070, (R)-Gossypol, BL193, S55746, S63845, A1210477, UMI77, APG1252, WEHI539, A1331852, BM1197, A1155463, Beclanorsen, Apogossypolone, TW37, ABT737, Augmerosen, and Cheleritrine.

In embodiment 105, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the combination of the invention, which comprises A) a compound selected from the group consisting of a compound of formula (I), a compound of formula (III), a compound of formula (IV), and a compound of formula (V) as defined above (i.e. including all possible pharmaceutically or veterinary acceptable salt thereof, stereoisomer or mixtures of stereoisomers as previously indicated), and B) an inhibitor of an anti-apoptotic protein, is selected from the group consisting of:

Immune checkpoint inhibitors

As mentioned before, it forms part of the invention a combination either comprising or consisting of A) a compound selected from the group consisting of a compound of formula (I), a compound of formula (III), a compound of formula (IV), and a compound of formula (V) as defined above (i.e. including all possible pharmaceutically or veterinary acceptable salt thereof, stereoisomer or mixtures of stereoisomers as previously indicated); and B) an immune checkpoint inhibitor.

The term“immune checkpoint inhibitor” as used herein refers to any binding agent or compound that totally or partially inhibit, interfere with or modulate one or more immune checkpoint proteins, such as programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), indoleamine 2,3-dioxygenase (IDO), T-cell membrane protein-3 (TIM3), lymphocyte activation gene-3 (LAG3), T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT), B- and T-lymphocyte attenuator (BTLA), V-domain Ig suppressor of T-cell activation (VISTA), inducible T-cell COStimulator (ICOS), killer immunoglobulin-like receptors (KIRs), or CD39.

Non limiting examples of immune checkpoint inhibitors include the ones shown in table 2 below:

Table 2: Examples of immune checkpoint inhibitors

In embodiment 106, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the immune checkpoint inhibitor of the combination of the invention is suitable to act against immune checkpoint proteins selected from the group consisting of PD- 1/PD-L1 , CTLA-4, IDO, TIM3, LAG 3, TIGIT, BTLA, VISTA, ICOS, KIRs, CD39, and combinations thereof.

In embodiment 107, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the immune checkpoint inhibitors of the combination of the invention is selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, ipilimumab, tremelimumab, spartalizumab, pidilizumab, dostarlimab, cemiplimab, SHR-1210, LY3300054, CK-301 , BMS-936559, 3D-2-02-0015, STI-1014, Indoximod, epacadostat, BMS-986205, navoximod free base, navoximod phosphate, 3-(5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione, LY3321367, TSR-022, OREG-103, MEDI-570, GSK3359609, JTX-2011 , lirilumab, LAG525, relatlimab, TSR-033, IMP321 , REGN3767, GSK2831781 , KD033, RG6058, OMP-313M32, PF-06688992, FAZ053, HTI-1316, KHK2455, STI-600, ENUM005, MK-4280, B I 754111 , BMS-986207, and AB154. More particularly, the immune checkpoint inhibitors of the combination of the invention is selected from the group consisting of

pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, ipilimumab, tremelimumab, spartalizumab, pidilizumab, dostarlimab, cemiplimab, SHR-1210, LY3300054, CK-301 , BMS-936559, 3D-2-02-0015, STI- 1014, Indoximod, epacadostat, BMS-986205, navoximod free base, navoximod phosphate, 3-(5-fluoro-1 H- indol-3-yl)pyrrolidine-2,5-dione, LY3321367, TSR-022, OREG-103, MEDI-570, GSK3359609, JTX-2011 , lirilumab, LAG525, relatlimab, TSR-033, IMP321 , REGN3767, GSK2831781 , KD033, RG6058, and OMP- 313M32.

In embodiment 108, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the invention relates to each of the individual specific binary combinations formed by A) a compound selected from the group consisting of a compound of formula (I), a compound of formula (III), a compound of formula (IV), and a compound of formula (V) as defined above (i.e. including all possible pharmaceutically or veterinary acceptable salt thereof, stereoisomer or mixtures of stereoisomers as previously indicated); which is selected from the group consisting of: 1-1-01, 1-1-02, 1-2-01 , 1-3-01, 1-3-02, 1-3-03, 1-3-04, 1-3-05, 1-3-06, 1-3-07, 1-3-08, 1-3-09, 1-3-10, 1-3-11, 1-3-12, 1-3-13, 1-3-14,

1-3-15, 1-3-16, 1-3-17, 1-3-18, 1-3-19, 1-3-20, 1-3-21, 1-3-22, 1-3-23, 1-3-24, 1-3-25, 1-3-26, 1-3-27, 1-3-28, 1-3-29, 1-3-30, 1-3-31, 1-3-32, 1-3-33, 1-3-34, 1-3-35, 1-3-36, 1-3-37, 1-3-38, 1-3-39, 1-3-40, 1-3-41, 1-3-42, 1-3-43, 1-3-44, 1-3-45, 1-3-46, 1-3-47, 1-3-48, 1-3-49, 1-3-50, 1-3-51, 1-3-52, 1-3-53, 1-3-54, 1-3-55, 1-3-56, 1-4-01, 1-4-02, 1-4-03, 1-5-01, 1-5-02, 1-5-03, 1-5-04, 1-5-05, 1-5-06, 1-5-07, 1-5-08, 1-6-01, 1-6-02, 1-7-01 , 1-7-02, 1-7-04, 1-7-05, 1-8-01, 1-8-02, 1-9-01, 1-10-01, 1-11-01 , 1-11-02, 1-11-03, 1-11-04, 1-11-05, 1-11-06,

1-11-07, 1-11-08, 1-11-09, 1-11-10, 1-11-11, 1-11-12, 1-11-13, 1-12-01, 1-12-02, 1-12-03, 1-12-04, 1-12-05, 1-12-06, 1-13-01, 1-14-01, 1-15-01, 1-16-01, 1-16-02, 1-17-01 , 1-17-02, 1-18-01, 1-18-02, 1-19-01, 1-19-02, 1-19-03, 4-1-01, 4-1-02, 4-1-03, 4-1-04, 4-1-05, 4-1-06, 4-1-07, 4-1-08, 4-1-09, 4-1-10, 4-1-11 , 4-1-12, 4-1-13, 4-1-14, 4-2-01, 4-2-02, 4-2-03, 4-2-04, 4-2-05, 4-2-06, 4-2-07, 4-2-08, 4-2-09, 4-2-10, 4-2-11, 4-2-12, 4-2-13, 4-2-14, 4-2-15,4-2-16, 4-2-17, 4-2-18, 4-2-19, 4-2-20, 4-2-21 , 4-2-22, 4-3-01, 4-3-02, 4-3-03, 4-3-04, 4-3-05, 4-3-06, 4-3-07, 4-3-08, 4-3-09, 4-3-10, 4-3-11, 4-3-12, 4-3-13, 4-3-14, 4-3-15, 4-3-16, 4-3-17, 4-3-18, 4-3-19,

4-3-20, 4-3-21, 4-3-22, 4-3-23, 4-3-24, 4-3-25, 4-4-01 , 4-5-01 , 4-6-01, 4-7-01 , 4-8-01, 4-9-01, 4-10-01 , 4-10- 02, 2-1-01, 2-1-02, 2-1-03, 2-1-04, 2-1-05, 2-1-06, 2-2-01, 2-2-02, 2-2-03, 2-2-04,2-2-05,2-2-06, 2-2-07, 2-2-

08, 2-2-09, 2-2-10, 2-2-11, 2-2-12, 2-2-13, 2-3-01, 2-3-02, 2-3-03, 2-3-04, 2-4-01, 2-4-02, 2-4-03, 2-4-04, 2-4-

05, 3-1-01, 3-1-02, 3-1-03, 3-1-04, 3-1-05, 3-1-06, 3-1-07, 3-1-08, 3-1-09, 3-1-10, 3-1-11, 3-1-12, 3-1-13, 3-1- 14, 3-1-15, 3-1-16, 3-1-17, 3-1-18, 3-1-19, 3-1-20, 3-1-21, 3-1-22, 3-1-23, 3-2-01, 3-2-02, 3-2-03, 3-2-04, 3-2-

05, 3-2-06, 3-2-07, 3-2-08, 3-2-09, 3-3-01, 3-3-02, 3-3-03, 3-3-04, 3-3-05, 3-3-06, 3-3-07, 3-4-01, 3-4-02, 3-4- 03, 3-4-04, 3-5-01 , and 3-5-02; and B) an immune checkpoint inhibitor selected from the group consisting of: pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, ipilimumab, tremelimumab, spartalizumab, pidilizumab, dostarlimab, cemiplimab, SHR-1210, LY3300054, CK-301 , BMS-936559, 3D-2-02-0015, STI- 1014, Indoximod, epacadostat, BMS-986205, navoximod free base, navoximod phosphate, 3-(5-fluoro-1 H- indol-3-yl)pyrrolidine-2,5-dione, LY3321367, TSR-022, OREG-103, MEDI-570, GSK3359609, JTX-2011 , lirilumab, LAG525, relatlimab, TSR-033, IMP321 , REGN3767, GSK2831781 , KD033, RG6058, and OMP- 313M32. In embodiment 109, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the combination of the invention, which comprises A) a compound selected from the group consisting of a compound of formula (I), a compound of formula (III), a compound of formula (IV), and a compound of formula (V) as defined above (i.e. including all possible pharmaceutically or veterinary acceptable salt thereof, stereoisomer or mixtures of stereoisomers as previously indicated) and B) the immune checkpoint inhibitor, is selected from the group consisting of:

Chemotherapeutic agent

As mentioned before, it forms part of the invention a combination either comprising or consisting of A) a compound selected from the group consisting of a compound of formula (I), a compound of formula (III), a compound of formula (IV), and a compound of formula (V) as defined above (i.e. including all possible pharmaceutically or veterinary acceptable salt thereof, stereoisomer or mixtures of stereoisomers as previously indicated); and B) an chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor. The term "chemotherapeutic agent" is used herein refers to an agent or drug that inhibits tumor cell growth and/or induces tumor cell death and is other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor.

Non limiting examples of inhibitors of chemotherapeutic agents used in the combinations of the invention include the ones shown in table 3 below:

Table 3: Examples of chemotherapeutic agents

In embodiment 110, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor is selected from the group consisting of platin compounds (such as carboplatin, cisplatin, oxaliplatin), alkylating agents other than platin compounds (such as busulfan, melfalan, temozolomide), topoisomerase inhibitors (such as mitoxantrone, idarubicin, vosaroxin, topotecan, etoposide), histone deacetylase inhibitors (such as panobinostat, vorinostat, romidepsin, belinostat, valproic Acid, AR-42, pracinostat, mocetinostat, entinostat, belinostat), anti-CD33 antibodies (such as gemtuzumab, vadastuximab, lintuzumab), protein cereblon binders (such as lenalidomide, pomalidomide, thalidomide), proteasome inhibitors (bortezomib, ixazomib, carfilzomib), kinase inhibitors (such as ruxolitinib, pacritinib, imatinib, dasatinib, nilotinib, ponatinib, bosutinib, midostaurin, volasertib, vemurafenib, cobimetinib, selumetinib, PCM-075, imatinib, sirolimus, panitumumab, bemcentinib, palbociclib, entospletinib, HMPL-523, ibrutinib, rigosertib, erlotinib, bevacizumab, CC-223, gilteritinib, quizartinib, ilorasertib, crenolanib, sorafenib, regorafenib), DNA intercalating agents (such as doxorubicin), antimetabolites (such as methotrexate).

As used herein,“protein cereblon binders” refers to proteins that bind and totally or partially reduce, inhibit, interfere with or modulate the cereblon ubiquitin ligase, thereby hindering the DNA damage response of the cell.

As used herein,“topoisomerase inhibitors” refers to compounds that totally or partially reduce, inhibit, interfere with or modulate the action of topoisomerase enzymes, including topoisomerase I and topoisomerase II.

The term“alkylating agents other than platin compounds” refers to any antineoplastic compound that irreversibly binds to a variety of susceptible biomolecules such as nucleic acids, proteins, amino acids, and nucleotides, in particular DNA. This covalent interaction mediates cell death through interference with DNA structure and function, inactivation of DNA repair enzymes, or cell membrane damage.

“Proteasome inhibitors” is meant to encompass compounds that totally or partially reduce, inhibit, interfere with or modulate at least one enzymatic activity of the proteasome. Exemplary enzymatic activities of the proteasome include tryptic activity (i.e., cleaving after basic residues) present in the b2 subunit; chymotryptic activity (i.e., cleaving after hydrophobic residues) present in the b5 subunit; and“caspase-like” or“post-acidic” activity present in the b1 subunit.

The term“platin compounds” refers to anticancer coordination complexes of platinum that bind DNA, resulting in ineffective DNA damage repair and, ultimately, the death of the cancer cell.

As used herein,“kinase inhibitors” refers to compounds that totally or partially reduce, inhibit, interfere with or modulate the action of one or more protein kinases. In particular, the kinase inhibitors of the invention are directed against protein kinases that contribute to tumor growth and/or survival, such as JAK kinase,

BCR/ABL kinases, Src family tyrosine kinase, PLK1 , MEK, mTOR, Syk, BTK, Aurora Kinases and Tyrosine kinase receptors, among others.

In embodiment 111 , optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor is selected from the group consisting of Mitoxantrone, Doxorubicin, Daunorubicin, Idarubicin, Epirubicin, Topotecan, Vosaroxin, Gemcitabine, Hydroxyurea, Fludarabine, Busulfan, Melphalan, Bendamustine, Cytarabine, Temozolomide, Carboplatin, Cisplatin, Oxaliplatin, Vinorelbine, Cyclophosphamide, Methotrexate, Fluorouracil, Doxetacel, Pad itaxel, Bleomycin, Dacarbazine, Procarbazine, Chlormethine, Vincristine, Vinblastine, Etoposide, Capecitabine, Irinotecan, talacotuzumab, Talazoparib, Tamoxifen, Pevonedistat, Plerixafor, AMG-232, Selinexor,

Lenalidomide, Pomalidomide, Thalidomide, GO 203 2c, APR-246, Gemtuzumab, Lintuzumab, Vadastuximab, Bl 836858, Birinapant, Alemtuzumab, Fulvestrant, Pioglitazone, PF-04518600, Utomilumab, Daratumumab, Rituximab, Hu5F9-G4, Brentuximab, SL-401 , Bortezomib, ixazomib, Carfilzomib, Ruxolitinib, Pacritinib, Imatinib, Dasatinib, Nilotinib, Ponatinib, bosutinib, Midostaurin, Volasertib, Vemurafenib, Cobimetinib, Selumetinib, Sirolimus, Panitumumab, Bemcentinib, Palbociclib, Entospletinib, Ibrutinib, rigosertib, Erlotinib, Bevacizumab, CC-223, Gilteritinib, Quizartinib, llorasertib, Crenolanib, Sorafenib, Regorafenib, Panobinostat, Vorinostat, Romidepsin, Pracinostat, Mocetinostat, Entinostat, Belinostat, Sonidegib, Vismodegib, Glasdegib, Tosedostat, Celecoxib, Enasidenib, Ivosidenib, GSK2879552, INCB057643, INCB59872, P505-15,

Alvespimycin, PF-06747143, and PCM-075. More particularly, the chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor is selected from the group consisting of Mitoxantrone, Doxorubicin, Daunorubicin, Idarubicin, Epirubicin, Topotecan, Vosaroxin, Gemcitabine, Hydroxyurea, Fludarabine, Busulfan, Melphalan, Bendamustine, Cytarabine, Temozolomide, Carboplatin, Cisplatin, Oxaliplatin, Vinorelbine, Cyclophosphamide, Methotrexate, Fluorouracil, Doxetacel, Pad itaxel, Bleomycin, Dacarbazine, Procarbazine, Chlormethine, Vincristine, Vinblastine, Etoposide, Capecitabine, Irinotecan, talacotuzumab, Talazoparib, Tamoxifen, Pevonedistat, Plerixafor, AMG-232, Selinexor,

Lenalidomide, Pomalidomide, Thalidomide, GO 203 2c, APR-246, Gemtuzumab, Lintuzumab, Vadastuximab, Bl 836858, Birinapant, Alemtuzumab, Fulvestrant, Pioglitazone, PF-04518600, Utomilumab, Daratumumab, Rituximab, Hu5F9-G4, Brentuximab, SL-401 , Bortezomib, ixazomib, Carfilzomib, Ruxolitinib, Pacritinib, Imatinib, Dasatinib, Nilotinib, Ponatinib, bosutinib, Midostaurin, Volasertib, Vemurafenib, Cobimetinib, Selumetinib, Sirolimus, Panitumumab, Bemcentinib, Palbociclib, Entospletinib, Ibrutinib, rigosertib, Erlotinib, Bevacizumab, CC-223, Gilteritinib, Quizartinib, llorasertib, Crenolanib, Sorafenib, Regorafenib, Panobinostat, Vorinostat, Romidepsin, Pracinostat, Mocetinostat, Entinostat, Belinostat, Sonidegib, Vismodegib, Glasdegib, Tosedostat, Celecoxib, Enasidenib, Ivosidenib, GSK2879552, INCB057643, INCB59872, P505-15, and Alvespimycin.

In embodiment 112, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the invention relates to each of the individual specific binary combinations formed by A) a compound selected from the group consisting of a compound of formula (I), a compound of formula (III), a compound of formula (IV), and a compound of formula (V) as defined above (i.e. including all possible pharmaceutically or veterinary acceptable salt thereof, stereoisomer or mixtures of stereoisomers as previously indicated); which is selected from the group consisting of: 1-1-01, 1-1-02, 1-2-01 , 1-3-01, 1-3-02, 1-3-03, 1-3-04, 1-3-05, 1-3-06, 1-3-07, 1-3-08, 1-3-09, 1-3-10, 1-3-11, 1-3-12, 1-3-13, 1-3-14, 1-3-15, 1-3-16, 1-3-17, 1-3-18, 1-3-19, 1-3-20, 1-3-21, 1-3-22, 1-3-23, 1-3-24, 1-3-25, 1-3-26, 1-3-27, 1-3-28, 1-3-29, 1-3-30, 1-3-31, 1-3-32, 1-3-33, 1-3-34, 1-3-35, 1-3-36, 1-3-37, 1-3-38, 1-3-39, 1-3-40, 1-3-41, 1-3-42, 1-3-43, 1-3-44, 1-3-45, 1-3-46, 1-3-47, 1-3-48, 1-3-49, 1-3-50, 1-3-51, 1-3-52, 1-3-53, 1-3-54, 1-3-55, 1-3-56, 1-4-01, 1-4-02, 1-4-03, 1-5-01, 1-5-02, 1-5-03, 1-5-04, 1-5-05, 1-5-06, 1-5-07, 1-5-08, 1-6-01, 1-6-02, 1-7-01 , 1-7-02, 1-7-04, 1-7-05, 1-8-01, 1-8-02, 1-9-01, 1-10-01, 1-11-01, 1-11-02, 1-11-03, 1-11-04, 1-11-05, 1-11-06, 1-11-07, 1-11-08, 1-11-09, 1-11-10, 1-11-11, 1-11-12, 1-11-13, 1-12-01, 1-12-02, 1-12-03, 1-12-04, 1-12-05, 1-12-06, 1-13-01, 1-14-01, 1-15-01, 1-16-01, 1-16-02, 1-17-01 , 1-17-02, 1-18-01, 1-18-02, 1-19-01, 1-19-02,

1-19-03, 4-1-01, 4-1-02, 4-1-03, 4-1-04, 4-1-05, 4-1-06, 4-1-07, 4-1-08, 4-1-09, 4-1-10, 4-1-11 , 4-1-12, 4-1-13, 4-1-14, 4-2-01, 4-2-02, 4-2-03, 4-2-04, 4-2-05, 4-2-06, 4-2-07, 4-2-08, 4-2-09, 4-2-10, 4-2-11, 4-2-12, 4-2-13, 4-2-14, 4-2-15, 4-2-16, 4-2-17, 4-2-18, 4-2-19, 4-2-20, 4-2-21 , 4-2-22, 4-3-01, 4-3-02, 4-3-03, 4-3-04, 4-3-05, 4-3-06, 4-3-07, 4-3-08, 4-3-09, 4-3-10, 4-3-11, 4-3-12, 4-3-13, 4-3-14, 4-3-15, 4-3-16, 4-3-17, 4-3-18, 4-3-19, 4-3-20, 4-3-21 , 4-3-22, 4-3-23, 4-3-24, 4-3-25, 4-4-01 , 4-5-01 , 4-6-01 , 4-7-01 , 4-8-01 , 4-9-01 , 4-10-01 , 4-10-

02, 2-1-01, 2-1-02, 2-1-03, 2-1-04, 2-1-05, 2-1-06, 2-2-01, 2-2-02, 2-2-03, 2-2-04,2-2-05,2-2-06, 2-2-07, 2-2-

14, 3-1-15, 3-1-16, 3-1-17, 3-1-18, 3-1-19, 3-1-20, 3-1-21, 3-1-22, 3-1-23, 3-2-01, 3-2-02, 3-2-03, 3-2-04, 3-2- 05, 3-2-06, 3-2-07, 3-2-08, 3-2-09, 3-3-01 , 3-3-02, 3-3-03, 3-3-04, 3-3-05, 3-3-06, 3-3-07, 3-4-01 , 3-4-02, 3-4-

03, 3-4-04, 3-5-01 , and 3-5-02; and B) a chemotherapeutic agent selected from the group consisting of Mitoxantrone, Doxorubicin, Daunorubicin, Idarubicin, Epirubicin, Topotecan, Vosaroxin, Gemcitabine, Hydroxyurea, Fludarabine, Busulfan, Melphalan, Bendamustine, Cytarabine, Temozolomide, Carboplatin, Cisplatin, Oxaliplatin, Vinorelbine, Cyclophosphamide, Methotrexate, Fluorouracil, Doxetacel, Paclitaxel, Bleomycin, Dacarbazine, Procarbazine, Chlormethine, Vincristine, Vinblastine, Etoposide, Capecitabine,

Irinotecan, talacotuzumab, Talazoparib, Tamoxifen, Pevonedistat, Plerixafor, AMG-232, Selinexor,

Lenalidomide, Pomalidomide, Thalidomide, GO 203 2c, APR-246, Gemtuzumab, Lintuzumab, Vadastuximab, Bl 836858, Birinapant, Alemtuzumab, Fulvestrant, Pioglitazone, PF-04518600, Utomilumab, Daratumumab, Rituximab, Hu5F9-G4, Brentuximab, SL-401 , Bortezomib, ixazomib, Carfilzomib, Ruxolitinib, Pacritinib, Imatinib, Dasatinib, Nilotinib, Ponatinib, bosutinib, Midostaurin, Volasertib, Vemurafenib, Cobimetinib,

Selumetinib, Sirolimus, Panitumumab, Bemcentinib, Palbociclib, Entospletinib, Ibrutinib, rigosertib, Erlotinib, Bevacizumab, CC-223, Gilteritinib, Quizartinib, llorasertib, Crenolanib, Sorafenib, Regorafenib, Panobinostat, Vorinostat, Romidepsin, Pracinostat, Mocetinostat, Entinostat, Belinostat, Sonidegib, Vismodegib, Glasdegib, Tosedostat, Celecoxib, Enasidenib, Ivosidenib, GSK2879552, INCB057643, INCB59872, P505-15, and Alvespimycin.

In embodiment 113, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the combination of the invention, which comprises A) a compound selected from the group consisting of a compound of formula (I), a compound of formula (III), a compound of formula (IV), and a compound of formula (V) as defined above (i.e. including all possible pharmaceutically or veterinary acceptable salt thereof, stereoisomer or mixtures of stereoisomers as previously indicated) and B) the chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor, is selected from the group consisting of:

It also forms part of the invention a ternary combination either comprising or consisting of A) a compound selected from the group consisting of a compound of formula (I), a compound of formula (III), a compound of formula (IV), and a compound of formula (V) as defined above (i.e. including all possible pharmaceutically or veterinary acceptable salt thereof, stereoisomer or mixtures of stereoisomers as previously indicated), B) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor; and C) an immune checkpoint inhibitor.

In embodiment 114, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the immune checkpoint inhibitor of the ternary combination of the invention as defined in any of the embodiments 106 and 107.

In embodiment 115, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the invention relates to each of the individual specific ternary combinations formed by A) a compound selected from the group consisting of a compound of formula (I), a compound of formula (III), a compound of formula (IV), and a compound of formula (V) as defined above (i.e. including all possible pharmaceutically or veterinary acceptable salt thereof, stereoisomer or mixtures of stereoisomers as previously indicated); which is selected from the group consisting of: 1-1-01, 1-1-02, 1-2-01 , 1-3-01, 1-3-02, 1-3-03, 1-3-04, 1-3-05, 1-3-06, 1-3-07, 1-3-08, 1-3-09, 1-3-10, 1-3-11, 1-3-12, 1-3-13, 1-3-14, 1-3-15, 1-3-16, 1-3-17, 1-3-18, 1-3-19, 1-3-20, 1-3-21 , 1-3-22, 1-3-23, 1-3-24, 1-3-25, 1-3-26, 1-3-27, 1-3-28, 1-3-29, 1-3-30, 1-3-31, 1-3-32, 1-3-33, 1-3-34, 1-3-35, 1-3-36, 1-3-37, 1-3-38, 1-3-39, 1-3-40, 1-3-41, 1-3-42, 1-3-43, 1-3-44, 1-3-45, 1-3-46, 1-3-47, 1-3-48, 1-3-49, 1-3-50, 1-3-51, 1-3-52, 1-3-53, 1-3-54, 1-3-55, 1-3-56, 1-4-01, 1-4-02, 1-4-03, 1-5-01 , 1-5-02, 1-5-03, 1-5-04, 1-5-05, 1-5-06, 1-5-07, 1-5-08, 1-6-01, 1-6-02, 1-7-01 , 1-7-02, 1-7-04, 1-7-05, 1-8-01, 1-8-02, 1-9-01, 1-10-01, 1-11-01, 1-11-02, 1-11-03, 1-11-04, 1-11-05, 1-11-06, 1-11-07, 1-11-08, 1-11-09, 1-11-10, 1-11-11 , 1-11-12, 1-11-13, 1-12-01, 1-12-02, 1-12-03, 1-12-04, 1-12-05, 1-12-06, 1-13-01, 1-14-01, 1-15-01, 1-16-01 , 1-16-02, 1-17-01 , 1-17-02, 1-18-01, 1-18-02, 1-19-01 , 1-19-02, 1-19-03, 4-1-01, 4-1-02, 4-1-03, 4-1-04, 4-1-05, 4-1-06, 4-1-07, 4-1-08, 4-1-09, 4-1-10, 4-1-11 , 4-1-12, 4-1-13,

4-1-14, 4-2-01, 4-2-02, 4-2-03, 4-2-04, 4-2-05, 4-2-06, 4-2-07, 4-2-08, 4-2-09, 4-2-10, 4-2-11, 4-2-12, 4-2-13, 4-2-14, 4-2-15, 4-2-16, 4-2-17, 4-2-18, 4-2-19, 4-2-20, 4-2-21 , 4-2-22, 4-3-01, 4-3-02, 4-3-03, 4-3-04, 4-3-05, 4-3-06, 4-3-07, 4-3-08, 4-3-09, 4-3-10, 4-3-11, 4-3-12, 4-3-13, 4-3-14, 4-3-15, 4-3-16, 4-3-17, 4-3-18, 4-3-19, 4-3-20, 4-3-21, 4-3-22, 4-3-23, 4-3-24, 4-3-25, 4-4-01, 4-5-01 , 4-6-01, 4-7-01 , 4-8-01, 4-9-01, 4-10-01 , 4-10- 02, 2-1-01, 2-1-02, 2-1-03, 2-1-04, 2-1-05, 2-1-06, 2-2-01, 2-2-02, 2-2-03, 2-2-04,2-2-05,2-2-06, 2-2-07, 2-2-

05, 3-1-01 , 3-1-02, 3-1-03, 3-1-04, 3-1-05, 3-1-06, 3-1-07, 3-1-08, 3-1-09, 3-1-10, 3-1-11 , 3-1-12, 3-1-13, 3-1-

14, 3-1-15, 3-1-16, 3-1-17, 3-1-18, 3-1-19, 3-1-20, 3-1-21 , 3-1-22, 3-1-23, 3-2-01 , 3-2-02, 3-2-03, 3-2-04, 3-2-

05, 3-2-06, 3-2-07, 3-2-08, 3-2-09, 3-3-01 , 3-3-02, 3-3-03, 3-3-04, 3-3-05, 3-3-06, 3-3-07, 3-4-01 , 3-4-02, 3-4- 03, 3-4-04, 3-5-01 , and 3-5-02; B) a chemotherapeutic agent selected from the group consisting of

Mitoxantrone, Doxorubicin, Daunorubicin, Idarubicin, Epirubicin, Topotecan, Vosaroxin, Gemcitabine, Hydroxyurea, Fludarabine, Busulfan, Melphalan, Bendamustine, Cytarabine, Temozolomide, Carboplatin, Cisplatin, Oxaliplatin, Vinorelbine, Cyclophosphamide, Methotrexate, Fluorouracil, Doxetacel, Paclitaxel, Bleomycin, Dacarbazine, Procarbazine, Chlormethine, Vincristine, Vinblastine, Etoposide, Capecitabine, Irinotecan, talacotuzumab, Talazoparib, Tamoxifen, Pevonedistat, Plerixafor, AMG-232, Selinexor,

Lenalidomide, Pomalidomide, Thalidomide, GO 203 2c, APR-246, Gemtuzumab, Lintuzumab, Vadastuximab, Bl 836858, Birinapant, Alemtuzumab, Fulvestrant, Pioglitazone, PF-04518600, Utomilumab, Daratumumab, Rituximab, Hu5F9-G4, Brentuximab, SL-401 , Bortezomib, ixazomib, Carfilzomib, Ruxolitinib, Pacritinib, Imatinib, Dasatinib, Nilotinib, Ponatinib, bosutinib, Midostaurin, Volasertib, Vemurafenib, Cobimetinib, Selumetinib, Sirolimus, Panitumumab, Bemcentinib, Palbociclib, Entospletinib, Ibrutinib, rigosertib, Erlotinib, Bevacizumab, CC-223, Gilteritinib, Quizartinib, llorasertib, Crenolanib, Sorafenib, Regorafenib, Panobinostat, Vorinostat, Romidepsin, Pracinostat, Mocetinostat, Entinostat, Belinostat, Sonidegib, Vismodegib, Glasdegib, Tosedostat, Celecoxib, Enasidenib, Ivosidenib, GSK2879552, INCB057643, INCB59872, P505-15, and Alvespimycin; and C) an immune checkpoint inhibitor selected from the group consisting of: pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, ipilimumab, tremelimumab, spartalizumab, pidilizumab, dostarlimab, cemiplimab, SHR-1210, LY3300054, CK-301 , BMS-936559, 3D-2-02-0015, STI-1014,

Indoximod, epacadostat, BMS-986205, navoximod free base, navoximod phosphate, 3-(5-fluoro-1 H-indol-3- yl)pyrrolidine-2,5-dione, LY3321367, TSR-022, OREG-103, MEDI-570, GSK3359609, JTX-2011 , lirilumab, LAG525, relatlimab, TSR-033, IMP321 , REGN3767, GSK2831781 , KD033, RG6058, and OMP-313M32.

In embodiment 116, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the ternary combination of the invention, which comprises A) a compound selected from the group consisting of a compound of formula (I), a compound of formula (III), a compound of formula (IV), and a compound of formula (V) as defined above (i.e. including all possible pharmaceutically or veterinary acceptable salt thereofs, stereoisomer or mixtures of stereoisomers as previously indicated), B) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor; and C) the immune checkpoint inhibitor, is selected from the group consisting of:

Pharmaceutical and veterinary compositions, package or kit of parts

The present invention also relates to pharmaceutical and veterinary compositions, or packages or kit of parts comprising A) a compound selected from the group consisting of a compound of formula (I), a compound of formula (III), a compound of formula (IV), and a compound of formula (V) as defined above (i.e. including all possible pharmaceutically or veterinary acceptable salt thereofs, stereoisomer or mixtures of stereoisomers as previously indicated); and B) a drug selected from the group consisting of i) an immune checkpoint inhibitor, ii) an inhibitor of an anti-apoptotic protein, and iii) a chemotherapeutic agent other than an inhibitor of an anti- apoptotic protein and an immune checkpoint inhibitor; form part of the invention.

The expression "therapeutically effective amount" as used herein, refers to the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed. The specific dose of the compound of the invention to obtain a therapeutic benefit may vary depending on the particular circumstances of the individual patient including, among others, the size, weight, age and sex of the patient, the nature and stage of the disease, the aggressiveness of the disease, and the route of administration. For example, a dose of from about 0.01 to about 500 mg/kg may be used.

The expression "pharmaceutically or veterinary acceptable excipients or carriers" refers to pharmaceutically or veterinary acceptable materials, compositions or vehicles. Each component must be pharmaceutically or veterinary acceptable in the sense of being compatible with the other ingredients of the pharmaceutical or veterinary composition. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio.

Thus, in embodiment 117, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the invention relates to a single pharmaceutical or veterinary composition which comprises a therapeutically effective amount of:

a) a compound selected from the group consisting of a compound of formula (I), (III), (IV), and (V) as defined above, or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I), (III), (IV), or (V), respectively, or of its pharmaceutically or veterinary acceptable salt, together with one or more pharmaceutically or veterinary acceptable excipients or carriers; and

b) a drug selected from the group consisting of:

i) an immune checkpoint inhibitor;

ii) an inhibitor of an anti-apoptotic protein; and

iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor; together with one or more pharmaceutically or veterinary acceptable excipients or carriers, wherein the compound A) and the drug B) are as previously defined.

In embodiment 118, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the invention also relates to a package or kit of parts comprising:

a) a first pharmaceutical or veterinary composition which comprises a therapeutically effective amount of a compound selected from the group consisting of a compound of formula (I), (III), (IV), and (V) as defined above, or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I), (III), (IV), or (V), respectively, or of its pharmaceutically or veterinary acceptable salt, together with one or more pharmaceutically or veterinary acceptable excipients or carriers, as defined above; and

b) a second pharmaceutical or veterinary composition which comprises a therapeutically effective amount of a drug selected from the group consisting of:

i) an immune checkpoint inhibitor;

ii) an inhibitor of an anti-apoptotic protein; and

iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor;

as defined above, together with one or more pharmaceutically or veterinary acceptable excipients or carriers;

wherein compositions a) and b) are separate compositions.

The election of the pharmaceutical or veterinary formulation will depend upon the nature of the active compound and its route of administration. Any route of administration may be used, for example oral, parenteral and topical administration.

For example, the pharmaceutical or veterinary composition may be formulated for oral administration and may contain one or more physiologically compatible carriers or excipients, in solid or liquid form. These preparations may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents.

The pharmaceutical or veterinary composition may be formulated for parenteral administration in combination with conventional injectable liquid carriers, such as water or suitable alcohols. Conventional pharmaceutical or veterinary excipients for injection, such as stabilizing agents, solubilizing agents, and buffers, may be included in such compositions. These pharmaceutical or veterinary compositions may be injected intramuscularly, intraperitoneally, or intravenously.

The pharmaceutical composition may be formulated for topical administration. Formulations include creams, lotions, gels, powders, solutions and patches wherein the compound is dispersed or dissolved in suitable excipients.

The pharmaceutical compositions may be in any form, including, among others, tablets, pellets, capsules, aqueous or oily solutions, suspensions, emulsions, or dry powdered forms suitable for reconstitution with water or other suitable liquid medium before use, for immediate or retarded release.

The appropriate excipients and/or carriers, and their amounts, can readily be determined by those skilled in the art according to the type of formulation being prepared.

Anticancer treatment

It forms part of the invention the combination comprising A) a compound selected from the group consisting of a compound of formula (I), (III), (IV), and (V) as defined above, or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I), (III), (IV), or (V), respectively, or of its pharmaceutically or veterinary acceptable salt, together with one or more pharmaceutically or veterinary acceptable excipients or carriers; and B) a drug selected from the group consisting of: i) an immune checkpoint inhibitor, ii) an inhibitor of an anti-apoptotic protein, and iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor; the single pharmaceutical or veterinary composition as defined in embodiment 117, or the package or kit of parts as defined in embodiment 118, for use in the treatment and/or prevention of cancer.

For the purposes of the invention, the term“treatment” or variants of the word means to reduce, stabilize, or inhibit the progression of cancer in patients already suffering from the disease. The term“prevention” is used herein to refer to include both preventing the onset of clinically evident cancer altogether and delaying its onset.

This aspect may also be formulated as a method of treatment and/or prevention of cancer, which comprises administering to a mammal subject in need thereof, including a human subject, either

a) a therapeutically effective amount of the combination comprising A) a compound selected from the group consisting of a compound selected from the group consisting of a compound of formula (I), (III), (IV), and (V) as defined above, or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I), (III), (IV), or (V), respectively, or of its

pharmaceutically or veterinary acceptable salt; and B) a drug selected from the group consisting of: i) an immune checkpoint inhibitor, ii) an inhibitor of an anti-apoptotic protein, and iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor, together with one or more pharmaceutically or veterinary acceptable excipients or carriers; or alternatively

b) the single pharmaceutical or veterinary composition as defined in embodiment 117; or alternatively c) the package or kit of parts as defined in embodiment 118. It also forms part of the invention the use of a combination comprising: A) a compound selected from the group consisting of a compound selected from the group consisting of a compound of formula (I), (III), (IV), and (V) as defined above, or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I), (III), (IV), or (V), respectively, or of its pharmaceutically or veterinary acceptable salt; and B) a drug selected from the group consisting of: i) an immune checkpoint inhibitor, ii) an inhibitor of an anti-apoptotic protein, and iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor, as defined above; for the preparation of a medicament for the treatment and/or prevention of cancer.

In embodiment 119, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the medicament comprises a single pharmaceutical or veterinary composition as defined in embodiment 117 or a package or kit of parts as defined in embodiment 118.

In embodiment 120, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the treatment comprises the simultaneous, concurrent, separate or sequential administration of the compound selected from the group consisting of a compound of formula (I), (III), (IV), and (V) as defined above, and the drug selected from the group consisting of i) an immune checkpoint inhibitor, ii) an inhibitor of an anti-apoptotic protein, and iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor.

It also forms part of the invention a compound selected from the group consisting of a compound of formula (I), (III), (IV), and (V), or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I), (III), (IV), or (V), respectively, or of its pharmaceutically or veterinary acceptable salt, together with one or more pharmaceutically or veterinary acceptable excipients or carriers, for administration in combination with a drug selected from the group consisting of: i) an immune checkpoint inhibitor, ii) an inhibitor of an anti-apoptotic protein, and iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor; together with one or more pharmaceutically or veterinary acceptable excipients or carriers, for simultaneous, concurrent, separate or sequential use in the treatment and/or prevention of cancer, wherein the compound A) and the drug B) are as previously defined.

It also forms part of the invention a compound a drug selected from the group consisting of i) an immune checkpoint inhibitor, ii) an inhibitor of an anti-apoptotic protein, and iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor; together with one or more pharmaceutically or veterinary acceptable excipients or carriers, for administration in combination with a compound selected from the group consisting of a compound of formula (I), (III), (IV), and (V), or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I), (III), (IV), or (V), respectively, or of its pharmaceutically or veterinary acceptable salt, together with one or more pharmaceutically or veterinary acceptable excipients or carriers, for simultaneous, concurrent, separate or sequential use in the treatment and/or prevention of cancer, wherein the compound A) and the drug B) are as previously defined.

In embodiment 121 , optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the cancer is selected from the group consisting of hematological tumors, such as lymphomas, myelomas, and leukemias; and solid tumors.

In embodiment 122, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the cancer is selected from the group consisting of Non-Hodgkin’s Lymphoma, Hodgkin’s disease, hepatopancreatic tumor, biliar tumor, gastrointestinal tumor, bladder cancer, breast cancer, cervical cancer, colorectal cancer, CNS tumor, melanoma, prostate cancer, renal cancer, small-cell lung cancer, non small-cell lung cancer, acute myeloid leukemia (AML), B-cell chronic lymphocytic leukemia (CLL), T-cell acute lymphoblastic leukemia (T-ALL), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL) (including germinal center B-cell-like (GCB) and activated B-cell-like (ABC) types), and acute lymphoblastic leukemia.

Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word“comprise” encompasses the case of“consisting of. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Reference signs related to drawings and placed in parentheses in a claim, are solely for attempting to increase the intelligibility of the claim, and shall not be construed as limiting the scope of the claim. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.

Examples

HPLC Methods (purification methods):

HPLC Method 7: Purified by prep-HPLC Reversed phase HPLC was carried out on luna (100 x 30 mm; 5um). Solvent A: water with 0.1% TFA; Solvent B: acetonitrile. Gradient: At 25 °C, 1% of B to 40% of B within 12 min; then 100% B over 2 min, Flow rate: 20ml/min. UV.

Preparation of intermediate l-04j: 2,4-dichloro-7-[3-(3-fluoropyrrolidin-1-yl)propoxy1-6-methoxy-guinoline A mixture of 2,4-dichloro-6-methoxy-quinolin-7-ol (compound 1-17a of WO2015192981) (829 mg, 3.40 mmol) and commercially available 3-(3-fluoropyrrolidin-1-yl)propan-1-ol (CAS RN 920003-05-0) (500 mg, 3.40 mmol), PPfi3 (1.16 g, 4.42 mmol) in THF (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was added DEAD (769 mg, 4.42 mmol) at 0 °C under N2. Then the mixture was stirred at 20 °C for 16 hours under N2 atmosphere. LC-MS showed the reaction was completed. The mixture was quenched by water 20 mL and concentrated in reduced pressure at 40 °C to give a residue. The residue was extracted with ethyl acetate (50 mL><3). The combined organic phase was washed with brine (50 mLx2), dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum to give the crude product. The crude product was purified by column chromatography (S1O₂, Petroleum ether/Ethyl acetate=100:1 to 0:1, DCM: Methanol=1/0 to 10:1) to give intermediate l-04j (700 mg, 55.16% yield) as a yellow solid. ESI-MS (M+1): 373.1 found for

C17H19CI2FN2O2 (calc. 372.08).

Preparation of intermediate l-09z1 : 4-chloro-7-[3-(3-fluoropyrrolidin-1-yl)propoxy1-6-methoxy-2-(5-methyl-2- furvDquinoline

Intermediate l-09z1 was obtained in an analogous manner to intermediate l-09a as described in WO2015192981 starting from l-04j and 4,4,5,5-tetramethyl-2-(5-methyl-2-furyl)-1 ,3,2-dioxaborolane (reactant R-04b of WO2015192981). 44.7% yield. ESI-MS (M+1): 419.1 calc, for C₂₂H₂₄CIFN₂O₃.

Preparation of compound 1-5-08: 7-[3-(3-fluoropvrrolidin-1-vl)propoxv1-6-methoxv-2-(5-methvl-2-furyl)-N-[(1- methyl-4-piperidyl)methyl]quinolin-4-amine

Compound 1-5-08 was prepared as described in the PCT application WO2015192981 following the same synthetic route as for compound 5-01 (synthetic route 3b) and using the same reagents unless otherwise indicated.

G9a and DNMT1 enzyme activity assay

When assayed against G9a and DNMT1 (following the protocol described in WO2015192981), the achieved inhibitory activity of compound 1-5-08 (where 1 mM < IC₅₀ £ 10mM (+), 500 nM < IC₅₀ < 1 pM (++), 100 nM < IC50 < 500 nM (+++) and IC50 <100 nM (++++)) was:

1-5-08: G9a (+) and DNMT1 (+++)

Cell lines, culture mediums and treatments

Cells were cultured with standard RPMI-1640 Medium with L-glutamine and sodium bicarbonate, liquid, sterile-filtered, as described in Fresquet et al.,“Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma”, Blood 2014; vol.123, pp. 4111-4119.

Cell lines used are available at ATCC or DSMZ repositories; otherwise, reference/s indicating their original derivation are indicated, as shown in Tables 5-10, 10a and 10b:

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

TablelOa

TablelOb

Compounds used for cell treatment were purchased from the following suppliers: ABT199 (Selleckchem, S8048), S63845 (Selleckchem, S8383), A1331852 (Selleckchem, S7801), doxorubicin (Selleckchem, S1208), rituximab (Selleckchem, A2009), P505-15 (Selleckchem, S8032) and Alvespimycin (Selleckchem, S1142). aRT-PCR

Total messenger RNA was isolated using TRIzol Reagent (Invitrogen, Carlsbad, CA). Genomic DNA was removed by DNAsel treatment (Invitrogenn, ref. 18068015) and cDNA was synthesized with the M-MLV RT enzyme (Invitrogen, ref. 28025013) following manufacturer’s instructions. Quantitative real-time polymerase chain reaction (PCR) was performed in triplicate by SYBR Green Master Mix (Applied Biosystems) and analyzed on an ABI Prism 7500 System (Applied Biosystems) following manufacturer’s protocol. Results were normalized to PGK1, and 2-ACt values were used for expression analysis as described in Fresquet et al, Blood 2014. Primers used in Quantitative real-time PCR are listed in Table 11.

Table 11

Western blotting

Expression of apoptotis, necroptosis and autophagy-related proteins was performed using standard Western blotting techniques. To identify MAVS protein oligomerization, SDS-AGE electrophoresis was performed as previously described (Roulois et at.,“DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts", Cell 2015, vol. 1625, pp. 974-986). Western blots were performed as previously described (Richter-Larrea et al.,“Reversion of epigenetically mediated BIM silencing overcomes chemoresistance in Burkitt lymphoma”, Blood 2010, vol. 116, pp. 2531-2542). Antibodies used were:

Caspase 8 (1C12), Caspase 3 (9662), and Caspase 9 (C9), P-RIP1 (D1L35), RPI-1 (D94C12), RIP-3 (E1210), Beclin-1 (D40C5), LC3B (2775) and PARP (9542) from Cell Signaling Technology; Bcl2 (sc-783) from Santa Cruz; Actin (ab-1) from Calbiochem, Bim (AAP-330) from Stressgen; P62 (P0067) from Sigma and BclXL (ab2568), P-RIP-3 (EPR9627) and McM (ab32087) from Abeam.

Anexin cell assay

Lymphoma cells were seeded in triplicate in 96-well plates in the presence of the different drugs. After 48 hours, apoptosis was measured using the Annexin V-FITC Apoptosis Detection Kit (BD Biosciences) or the Cell Death Detection ELISA KIT (Roche), as indicated in the corresponding figure, following the

manufacturer’s instructions. Synergy in vitro assay

To determine the in vitro anti-tumor effect of the different drugs alone and in combination, cancer patient- derived cell lines were cultured in culture media using the standard conditions described above. In particular, cells were plated at a density of 30.000 cells per well, and drugs were then added at the different concentrations indicated. After 24 to 48 hours, cell proliferation and survival were determined for each treatment condition using the MTS Assay Kit (ab197010) following manufacturer’s instructions. This assay uses a colorimetric method for the sensitive quantification of viable cells, allowing assessment of cell proliferation, cell viability and cytotoxicity.

The synergy between compounds was determined by the Chou-Talalay method for drug combination (Chou, T.C.,“Drug combination studies and their synergy quantification using the Chou-Talalay method”, Cancer research 2010, vol. 70, pp. 440-446). Briefly, the Chou-Talalay method is based on the median-effect equation, derived from the mass-action law principle, which is the unified theory that provides the common link between single entity and multiple entities, and first order and higher order dynamics. This general equation encompasses the Michaelis-Menten, Hill, Henderson-Hasselbalch, and Scatchard equations in biochemistry and biophysics. The resulting combination index (Cl) theorem of Chou-Talalay offers quantitative definition for additive effect (Cl = 1), synergism (Cl < 1), and antagonism (Cl > 1) in drug combinations. Transgenic mouse model

The Rb1 F/F; Trp53F/F; PtenF/F; Rbl1-/-mice were generated by breeding Rb1 F/F; Rbl1-/-37and Trp53F/F; PtenF/F mice (Moral M, et al.,“ Akt activation synergizes with Trp53 loss in oral epithelium to produce a novel mouse model for head and neck squamous cell carcinoma. Cancer Res. 2009 Feb 1 ;69(3):1099-108;

Martinez-Cruz AB, et. al.,“ Spontaneous squamous cell carcinoma induced by the somatic inactivation of retinoblastoma and Trp53 tumor suppressors. Cancer Res. 2008 Feb 1 ;68(3):683-92; Santos M, et al.,“In vivo disruption of an Rb-E2F-Ezh2 signaling loop causes bladder cancer”, Cancer Research 2014, vol. 74(22), pp. 6565-6577J. Adenovirus expressing Cre recombinase under keratin K5 promoter (Ramirez A, et al, “Sequences 5' of the bovine keratin 5 gene direct tissue- and cell-type-specific expression of a lacZ gene in the adult and during development”, Differentiation; research in biological diversity 1994, vol. 58(1), pp. 53-64); was obtained from the Viral Vector Production Unit of the Autonoma University of Barcelona and surgically delivered to the bladder lumen. Tumor development was routinely followed by computerized tomography and inspection by palpation. Tissues were collected and processed as reported below at the time of euthanasia. The treatments of these transgenic mice started at the time of tumor detection using 1-3-04 at doses of 5 mg/kg intraperitoneally five days per week, CDDP once per week at a dose of 3 mg/kg, anti-PD-L1 once per week for a total of three injections of 200mg per injection, and the different combinations of these agents as described below.

Results

Epigenetic inhibitors trigger ERV-mediated IFN response and RIP1 kinase-mediated necroptosis The epigenetic inhibitor compound 1-3-04 was tested in 24 cell lines derived from patients with diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype that is molecularly sub-classified into germinal center B-cell-like (GCB) and activated B-cell-like (ABC) types. Compound 1-3-04 induced dose- dependent cell death, as shown by increased number of annexin positive cells and poly ADP ribose polymerase (PARP) cleavage (Fig. 1a-b). However, cleavage of caspases 3, 8 and 9, which is the hallmark of apoptosis, or expression changes in other protein and gene components of intrinsic and extrinsic apoptosis pathways, were not observed (Fig. 1b).

Alternative non-apoptotic models of cell death including autophagy and necroptosis were then investigated. While expression of autophagic-related proteins Beclin, LC3B and p62 was not modified, compound 1-3-04 increased phosphorylation of Receptor-interacting protein (RIP) kinases 1 and 3 (Fig. 1b), which is the biochemical hallmark of activated necroptosis.

To investigate the mechanistic basis of RIP1-mediated necroptosis, analysis of Endogenous retroviral genes (ERV) was performed. Expression of ERVs highly increased in DLBCL cells after treatment with compound 1- 3-04 (Fig. 2a). Accordingly, increased expression of downstream ERV-recognition RIG-I and MDA5 genes, IMAVS protein oligomerization and IFN-stimulated genes (ISGs) weres observed after treatment with compound 1-3-04 (Fig. 2b-c y Fig. 3).

These data demonstrate that compound 1-3-04 induces the expression of ERVs in DLBCL cells, which in turn triggers RIP-1 -mediated necroptosis and activates IFN responses. In vitro synergistic effects in hematological malignancies

To test synthetically lethal drug combinations in GCB- and ABC-DLBCL cells lines, compound 1-3-04 was combined with the BCL-2 inhibitor venetoclax (ABT199). This combination synergistically increased the cell death induced by compound 1-3-04 (Table 12). The synthetic lethal phenotype was more evident when using a constant dose of the epigenetic inhibitor with increasing doses of ABT199, reducing compound 1-3-04 treatment IC_50S over 50 fold.

Table 12: Data of venetoclax (ABT199) synergistic effects with 1-3-04 in GCB-DLBCL and ABC-DLBCL cell lines

In cells resistant to BCL-2-mediated apoptosis, compound 1-3-04 was combined with inhibitors of MCL-1

(S63845) or BCL-XL (A1331852). In this case, a synergistic induction of cell death was also observed (Table

13 and 14).

Table 13: Combination of 1-3-04 with inhibitors of BCL-XL (A1331852) in DLBCL cells resistant to BCL-2 inhibition.

Table 14: Combination of 1-3-04 with inhibitors of MCL-1 (S63845) in DLBCL cells resistant to BCL-2 inhibition.

Next it was tested whether the epigenetic drug 1-3-04 targeting G9a/DNMT could also exhibit synergistic anti- tumor effects in combination with apoptotic inhibitors in other B-cell lymphoid malignancies beyond DLBCL To this end, compound 1-3-04 was tested alone and in combination with ABT199 in peripheral blood samples from patients with newly diagnosed B-cell chronic lymphocytic leukemia (CLL), which is considered a BCL-2- dependent tumor (Table 15). Eleven of 12 cases treated with ABT199 exhibited an ICso<1 mM and thus were considered sensitive to BCL-2 inhibition, being this effect synergistic in combination with compound 1-3-04 (Table 15). Remarkably, the only CLL resistant case P12 exhibited a major synergistic response to the combination of compound 1-3-04 with ABT199, as shown by the decrease in the IC50S from 1.000nM to 60nM.

Table 15: Synergistic effect of 1-3-04 with apoptosis inducers in chronic lymphocytic leukemia (CLL) cell lines

Similar synergistic anti-tumor effects were observed when cell lines from B-cell leukemias and lymphomas other than DLBCL where treated with a combination of 1-3-04 and ABT199 (Table 16). Table 16: Synergistic effect of 1-3-04 with apoptosis inducers in B-cell leukemias and lymphomas other than DLBCL

It was also evaluated whether such drug combinations could be similarly effective in other hematological malignancies such as acute myeloid leukemia (AML), which also represents a BCL-2-dependent tumor. Six of the seven cell lines derived from patients with AML carrying different genetic abnormalities were sensitive to BCL-2 inhibition, all of which exhibited synergistic effects with the combination of compound 1-3-04 and ABT199 (Table 17). The resistant cell line HEL showed reduced levels of BCL-2 expression and high expression of BCL-XL, being accordingly sensitive to BCL-XL inhibition, and displaying synergistic effect to the combination of compound 1-3-04 and A1331852 (Table 17).

Table 17: Synergistic effect of 1-3-04 with apoptosis inducers in acute myeloid leukemia (AML) cell lines

It was then tested the effects of the dual epigenetic drugs in combination with apoptotic inhibitors in other hematological malignancies that do not principally depend on BCL-2 for cell survival, such as multiple myeloma (MM). In combination with compound 1-3-04, six of the six MM cell lines testes showed a potent synergistic effect in combination with MCL-1 inhibition (Table 18). Finally, six cell lines derived from patients with T-cell acute lymphoblastic leukemia (T-ALL), which is considered to rely in most of the cases on MCL-1 and BCL-XL for survival, were treated. Accordingly, the six cell lines responded to MCL-1 and/or BCL-XL inhibition, and these responses were synergistically increased in combination with compound 1-3-04 (Table

19).

Table 18: Synergistic effect of 1-3-04 with apoptosis inducers in multiple myeloma (MM) cell lines

Table 19: Synergistic effect of 1-3-04 with apoptosis inducers in T-cell acute lymphoblastic leukemia (T-ALL) cell lines

Importantly, the synthetically lethality was also achieved when using epigenetic inhibitors different from compound 1-3-04 (Table 20).

Table 20: Data of 1-3-35, 4-2-02, and 4-3-03, synergistic effects with ABT199 in DLBCL cell lines

Overall, these data indicate that the combination of the tested epigenetic inhibitors with anti-apoptotic protein inhibitors synergistically induces cell death in primary samples and cell lines from different hematological malignancies (CLL, AML, MM and T-ALL). Finally, it was investigated whether G9a/DNMT inhibitors could also act in synergy with commonly used chemotherapeutic agents. All the chemotherapeutic agents tested showed synergy when used in combination with compound 1-3-04 in different BLBCL cell lines (Table 21).

Table 21 : Data of doxorubicin, rituximab (anti-CD20), P505-15 (Syk inhibitor), alvespimycin (HSP90 inh.) synergistic effects with 1-3-04 in DLBCL cell lines

These data demonstrate that tested epigenetic inhibitors synergistically induce cell death in hematological malignancies when used in combination with common chemotherapeutic agents.

In vitro synergistic effects in solid malignancies

Next, the effects of the combination of dual epigenetic drugs with apoptotic inhibitors were tested in other malignancies, in particular solid malignancies. For that, breast cancer, hepatocarcinoma, colon cancer, and lung cancer cell lines were treated with different concentrations of compound 1-3-04 along with MCL-1 or BCL-XL inhibitors. All cell lines tested showed a synergistic cell-death effect of the inhibitors (Table 22, 23, 24, and 25).

Table 22: Synergistic effect of 1-3-04 with apoptosis inducers in breast cancer cell lines

Table 23: Synergistic effect of 1-3-04 with apoptosis inducers in hepatocarcinoma cell lines

Table 24: Synergistic effect of 1-3-04 with apoptosis inducers in cell lines from colon cancer

Table 25: Synergistic effect of 1-3-04 with apoptosis inducers in cell lines from lung cancer

These results demonstrate that the synergistic cell-death action of dual epigenetic drugs with apoptotic inhibitors is useful in the treatment of diverse malignant conditions.

In vivo synergistic effects in hematological malignancies

Next, two different in vivo therapeutic experiments were carried out in two cell lines derived from patients with GCB-DLBCL (Karpas422) and ABC-DLBCL (HBL1). On each case, 2,5x10⁶ cells were injected

subcutaneously in immunodeficient Rag2-/-IL2gammacr-/- mice (Traggiai et al.,“Development of a human adaptive immune system in cord blood cell-transplanted mice”, Science 2004, vol. 304(5667), pp. 104-7). For each cell line, between 8 and 10 mice were used for each treatment condition, which consisted in ABT 199, compound 1-3-04, ABT199 plus compound 1-3-04, and no therapy (DMSO as vehicle). Drug schedules and doses were as follows: compound 1-3-04 at 2.5 mg/kg administered intraperitoneally (ip) 5 days per week (Monday untill Friday), ABT 199 at 25 mg/kg administered ip. 2 days per week (Monday and Thursday), during 18 days for karpas422, and 24 days for HBL1. Treatment was started when tumors reached a volume of 150 mm³. Monitoring of tumor responses was performed by measuring tumor volumes with an external caliper every 3 to 5 days using the formula: (4TT/3) X (width/2)2 x (length/2). As shown in Fig. 4a-b, therapeutic combination of compound 1-3-04 and ABT199 reduced the median tumor volume to half at days 18 and 25 (end of treatment) in comparison to individual treatments, demonstrating the synergistic effect of the drug combination in mice in vivo.

In vivo synergistic effects in solid tumors

Two different in vivo therapeutic experiments were performed in which 5 x10⁶ cells in a volume of 100 pi suspension were subcutaneously implanted in both flanks of each mice (n = 20). Tumor growth was measured twice a week by digital caliper and tumor volume (mm3) was calculated using the following formula: 4p x (length/2 x (width/2)2)/3. When tumor volume reached between 150-250 mm3, mice were randomized in 4 groups (n = 5) to receive the different treatments: vehicle (10% DMSO dissolved in PBS, Sigma), compound 1-3-04, cisplatin (CDDP) or both combined. Compound 1-3-04 was dissolved in PBS and 5 mg/kg was administrated intraperitoneally (i.p.) five days per week. Cisplatin was injected intraperitoneally once per week with a dose of 6mg/kg. After fifteen days of treatment, mice were euthanized when the humane endpoint was reached in compliance with FELASA and OEBA-CIEMAT Guidelines, and engrafted tumors were collected and preserved in formalin. Statiscal results were determined by the Mann-Whitney t-test: ^*p-value < 0.05, ^**p-value < 0.01 ^**** value < 0.0001. As shown shown in Fig. 5a, the combination of 1-3-04 and CDDP acted synergistically on tumours, thereby completely preventing tumour growht.

In a second in vivo model, a novel transgenic quadruple knockout

mouse model of metastatic bladder cancer was generated by inoculation of an adenoviruses coding for the Cre recombinase regulated by the regulatory elements of keratin K5 (AdK5Cre) (Ramirez A, et al,“Sequences 5' of the bovine keratin 5 gene direct tissue- and cell-type-specific expression of a lacZ gene in the adult and during development”, Differentiation; research in biological diversity 1994, vol. 58(1), pp. 53-64.; Santos M, et al.,“In vivo disruption of an Rb-E2F-Ezh2 signaling loop causes bladder cancer”, Cancer Research 2014, vol. 74(22), pp. 6565-6577.J. After 90-120 days of the intravesical AdK5Cre inoculation, the presence of tumor lesions was detected in all mice. Kaplan-Meier curve of tumor free after treatment with the compound 1-3-04 (5mg/kg; i.p.), cisplatin (3mg/kg; i.p.), or both was obtained using the log-rank text (1-3-04+CDDP n=14; 1-3- 04 n=20; CDDP n=15) and compared to vehicle-treated mice (n=23, vehicle = PBS). As shown in Fig. 5b-c, treatment of QKO mice with 1-3-04, produced a significant reduction in tumor and metastatic burden in comparison with the control group or the group treated only with CDDP. This reduction was further increased when 1-3-04 was combined with CDDP, which indicates a synergistic therapeutic effect. In most cases, animals with 1-3-04+CDDP combination only showed tumor remnants with reduced cell proliferation, increased apoptosis and autophagy and decreased FI3K9me2 and FI3K27me3, with no changes in G9a and Ezh2 expression. It was also observed that tumors from animals treated with 1-3-04+CDDP showed reduced enrichment of E2f and Myc target genes and genes involved in the epithelial to mesenchymal transition, clustering with normal bladder samples. Moreover, GSEA revealed that the treatment counteracted the gene repression mediated by overexpression of Ezh2, and reduced the expression of genes induced by Egfr without effect on S6, Akt, Erk and Stat3 activity.

In vivo combination effect in with immune checkpoint inhibitors

Finally, it was tested whether ERV-mediated IFN responses induced by compound 1-3-04 could sensitize tumor cells to immunotherapeutic agents. To this end, AML was selected as a model disease, and generated an immunocompetent model of human-like AML by selective expression of MLL-AF9 genes in mouse hematopoietic stem cells. This model recapitulated the principal features of human disease in vivo, including the development of aggressive AML within 1 month, and could be re-transplanted into immunocompetent mouse hosts. Flow cytometry analysis showed PDL1 expression in leukemia initiating cells (LICs), which responded to therapy with compound 1-3-04 in vitro. Remarkably, AML-bearing mice responded to therapy with compound 1-3-04 in combination with anti-PD1 antibodies (Fig. 6). These proof-of-principle data indicate that compound 1-3-04 could sensitize tumor cells to checkpoint blockade inhibitors.

Next, this effect of the 1-3-04 was further tested in a second mouse model. QKO mice were treated with anti- PD-L1 alone or in combination with 1-3-04, or 1-3-04 +CDDP, based on the observation that PD-L1 was upregulated after in vitro treatment with 1-3-04. Mice sacrificed at mid-treatment (Fig. 7a) displayed similar incidences of tumors and metastases. However, those groups treated with 1-3-04 + anti-PD-L1 showed massive immune infiltrations composed of CD3+, CD8+ and NK cells with a very limited amount of CD4+ and CD163+ cells. At day +28, 75% of animals in the group treated with anti-PD-L1 alone showed evidence of tumor and metastases, while only 28% or 17% of the animals treated with the 1-3-04 +anti-PD-L1 , with or without CDDP respectively, showed evidence of the primary tumor or metastatic disease (Fig. 7b), thereby demonstrating a synergistic effect. When mice treated with 1-3-04 +anti-PD-L1 (or 1-3-04 +CDDP+anti-PD- L1) were maintained for an additional 28 days without treatment, no significant re-growth of tumors or metastases was observed (Fig. 7c). These data demonstrate that 1-3-04 not only increased the host immune reactivation against the tumors and metastases, but also promoted a significant sustained response when combined with immune checkpoint blockade, providing a rationale for exploring this strategy in patients with BC.

For reasons of completeness, various aspects of the invention are set out in the following numbered clauses: Clause 1. A combination comprising:

A) a compound selected from the group consisting of a compound of formula (I) as defined in the first aspect of the invention, a compound of formula (III) as defined in the seventh aspect of the invention, a compound of formula (IV) as defined in the eighth aspect of the invention, and a compound of formula (V) as defined in the ninth aspect of the invention; and

Clause 2. The combination according to clause 1 , wherein the compound A) is a compound of formula (I). Clause 3. The combination according to clause 2, wherein in the compound of formula (I), X is as defined in embodiment 1 or in embodiment 1a.

Clause 4. The combination according to clause 2, wherein in the compound of formula (I), X is as defined in embodiment 2.

Clause 5. The combination according to clause 2, wherein in the compound of formula (I), X is as defined in embodiment 3.

Clause 6. The combination according to clause 2, wherein in the compound of formula (I), X is as defined in embodiment 4.

Clause 7. The combination according to any of the clauses 2-6, wherein in the compound of formula (I), L is as defined in embodiment 5.

Clause 8. The combination according to any of the clauses 2-6, wherein in the compound of formula (I), L is a moiety of formula (XXI) as defined in embodiment 6.

Clause 9. The combination according to any of the clauses 2-6, wherein in the compound of formula (I), the moiety -L-R4 is as defined in embodiment 7.

Clause 10. The combination according to any of the clauses 2-9, wherein in the compound of formula (I), R1 is as defined in embodiment 8.

Clause 11. The combination according to any of the clauses 2-9, wherein in the compound of formula (I), R1 is as defined in embodiment 9.

Clause 12. The combination according to any of the clauses 2-9, wherein in the compound of formula (I), R1 is Cy⁷as defined in embodiment 10.

Clause 13. The combination according to any of the clauses 2-9, wherein in the compound of formula (I), R1 is as defined in embodiment 11.

Clause 14. The combination according to any of the clauses 2-9, wherein in the compound of formula (I), R1 is as defined in embodiment 12. Clause 15. The combination according to any of the clauses 2-14, wherein in the compound of formula (I), is as defined in embodiment 13.

Clause 16. The combination according to any of the clauses 2-14, wherein in the compound of formula (I), is as defined in embodiment 14.

Clause 17. The combination according to any of the clauses 2-16, wherein in the compound of formula (I), R₃ is as defined in embodiment 15.

Clause 18. The combination according to any of the clauses 2-16, wherein in the compound of formula (I), R₃ is as defined in embodiment 16.

Clause 19. The combination according to any of the clauses 2-16, wherein in the compound of formula (I), R₃ is as defined in embodiment 17.

Clause 20. The combination according to any of the clauses 2-16, wherein in the compound of formula (I), in R₃, R^f is as defined in embodiment 18.

Clause 21. The combination according to any of the clauses 2-16, wherein in the compound of formula (I), R₃ is a moiety of formula (XX) as defined in embodiment 19.

Clause 22. The combination according to any of the clauses 2-16, wherein in the compound of formula (I), R₃ is as defined in embodiment 20.

Clause 23. The combination according to any of the clauses 2-22, wherein in the compound of formula (I), R₄ is as defined in embodiment 21.

Clause 24. The combination according to any of the clauses 2-22, wherein in the compound of formula (I), R₄ is as defined in embodiment 22.

Clause 25. The combination according to clause 2, wherein the compound of formula (I) is selected from the group consisting of: 1-1-01, 1-1-02, 1-2-01 , 1-3-01, 1-3-02, 1-3-03, 1-3-04, 1-3-05, 1-3-06, 1-3-07, 1-3-08, 1-3-09, 1-3-10, 1-3-11, 1-3-12, 1-3-13, 1-3-14, 1-3-15, 1-3-16, 1-3-17, 1-3-18, 1-3-19, 1-3-20, 1-3-21, 1-3-22, 1-3-23, 1-3-24, 1-3-25, 1-3-26, 1-3-27, 1-3-28, 1-3-29, 1-3-30, 1-3-31, 1-3-32, 1-3-33, 1-3-34, 1-3-35, 1-3-36, 1-3-37, 1-3-38, 1-3-39, 1-3-40, 1-3-41, 1-3-42, 1-3-43, 1-3-44, 1-3-45, 1-3-46, 1-3-47, 1-3-48, 1-3-49, 1-3-50, 1-3-51, 1-3-52, 1-3-53, 1-3-54, 1-3-55, 1-3-56, 1-4-01, 1-4-02, 1-4-03, 1-5-01, 1-5-02, 1-5-03, 1-5-04, 1-5-05, 1-5-06, 1-5-07, 1-5-08, 1-6-01, 1-6-02, 1-7-01, 1-7-02, 1-7-04, 1-7-05, 1-8-01, 1-8-02, 1-9-01, 1-10-01 , 1-11-01, 1-11-02, 1-11-03, 1-11-04, 1-11-05, 1-11-06, 1-11-07, 1-11-08, 1-11-09, 1-11-10, 1-11-11, 1-11-12, 1-11-13, 1-12-01, 1-12-02, 1-12-03, 1-12-04, 1-12-05, 1-12-06, 1-13-01, 1-14-01, 1-15-01, 1-16-01, 1-16-02, 1-17-01, 1-17-02, 1-18-01, 1-18-02, 1-19-01, 1-19-02, 1-19-03, 4-1-01, 4-1-02, 4-1-03, 4-1-04, 4-1-05, 4-1-06, 4-1-07, 4-1-08, 4-1-09, 4-1-10, 4-1-11, 4-1-12, 4-1-13, 4-1-14, 4-2-01, 4-2-02, 4-2-03, 4-2-04, 4-2-05, 4-2-06,

4-2-07, 4-2-08, 4-2-09, 4-2-10, 4-2-11, 4-2-12, 4-2-13, 4-2-14, 4-2-15, 4-2-16, 4-2-17, 4-2-18, 4-2-19, 4-2-20,

4-2-21, 4-2-22, 4-3-01, 4-3-02, 4-3-03, 4-3-04, 4-3-05, 4-3-06, 4-3-07, 4-3-08, 4-3-09, 4-3-10, 4-3-11, 4-3-12,

4-3-13, 4-3-14, 4-3-15, 4-3-16, 4-3-17, 4-3-18, 4-3-19, 4-3-20, 4-3-21, 4-3-22, 4-3-23, 4-3-24, 4-3-25, 4-4-01 ,

4-5-01, 4-6-01, 4-7-01, 4-8-01, 4-9-01, 4-10-01 , 4-10-02, 3-1-01, 3-1-02, 3-1-03, 3-1-04, 3-1-05, 3-1-06, 3-1- 07, 3-1-08, 3-1-09, 3-1-10, 3-1-11, 3-1-12, 3-1-13, 3-1-14, 3-1-15, 3-1-16, 3-1-17, 3-1-18, 3-1-19, 3-1-20, 3-1- 21, 3-1-22, 3-1-23, 3-2-01, 3-2-02, 3-2-03, 3-2-04, 3-2-05, 3-2-06, 3-2-07, 3-2-08, 3-2-09, 3-3-01, 3-3-02, 3-3- 03, 3-3-04, 3-3-05, 3-3-06, 3-3-07, 3-4-01, 3-4-02, 3-4-03, and 3-4-04.

Clause 26. The combination according to clause 2, wherein the compound of formula (I) is 1-3-04. Clause 27. The combination according to clause 2, wherein the compound of formula (I) is 1-3-35.

Clause 28. The combination according to clause 2, wherein the compound of formula (I) is 1-5-08.

Clause 29. The combination according to clause 2, wherein the compound of formula (I) is 3-1-03.

Clause 30. The combination according to clause 2, wherein the compound of formula (I) is 4-2-02.

Clause 31. The combination according to clause 2, wherein the compound of formula (I) is 4-2-12.

Clause 32. The combination according to clause 2, wherein the compound of formula (I) is 4-3-03.

Clause 33. The combination according to clause 1 , wherein the compound A) is a compound of formula (III). Clause 34. The combination according to clause 33, wherein the compound of formula (III) is a compound of formula (Ilia).

Clause 35. The combination according to clause 33, wherein the compound of formula (III) is a compound of formula (lllb).

Clause 36. The combination according to clause 33, wherein the compound of formula (III) is a compound of formula (lllc).

Clause 37. The combination according to clause 33, wherein the compound of formula (III) is a compound of formula (Hid).

Clause 38. The combination according to any of the clauses 33-37, wherein in the compound of formula (III), RAI is as defined in embodiment 28.

Clause 39. The combination according to any of the clauses 33-37, wherein in the compound of formula (III), RAI is as defined in embodiment 29.

Clause 40. The combination according to any of the clauses 33-37, wherein in the compound of formula (III), RAI is as defined in embodiment 30.

Clause 41. The combination according to any of the clauses 33-37, wherein in the compound of formula (III), RAI is as defined in embodiment 31.

Clause 42. The combination according to any of the clauses 33-37, wherein in the compound of formula (III), RAI is as defined in embodiment 32.

Clause 43. The combination according to any of the clauses 33-42, wherein in the compound of formula (III), R_A2 is as defined in embodiment 33.

Clause 44. The combination according to any of the clauses 33-43, wherein in the compound of formula (III), R_A3 is as defined in embodiment 34.

Clause 45. The combination according to any of the clauses 33-43, wherein in the compound of formula (III), R_A ^d in R_A3 is as defined in embodiment 35.

Clause 46. The combination according to any of the clauses 33-43, wherein in the compound of formula (III), R_A3 is a moiety of formula (XIV) as defined in embodiment 36.

Clause 47. The combination according to any of the clauses 33-43, wherein in the compound of formula (III), R_A3 is as defined in embodiment 37.

Clause 48. The combination according to any of the clauses 33-47, wherein in the compound of formula (III), RA5, RA8, RAID, RAM, RAIS are as defined in embodiment 38.

Clause 49. The combination according to any of the clauses 33-47, wherein in the compound of formula (III), RA8, and RA-IO are as defined in embodiment 39. Clause 50. The combination according to any of the clauses 33-47, wherein in the compound of formula (III), R_AM, and R_AI_S are as defined in embodiment 40.

Clause 51. The combination according to any of the clauses 33-47, wherein in the compound of formula (III), RA6, RA9, RAH, RAI2, RAI3, and RAI6 are as defined in embodiment 41.

Clause 52. The combination according to any of the clauses 33-47, wherein in the compound of formula (III), R_A4 and R_A7are as defined in embodiment 42.

Clause 53. The combination according to any of the clauses 33-47, wherein in the compound of formula (III), R_AI7 and R_AI₈ are as defined in embodiment 43.

Clause 54. The combination according to any of the clauses 33-47, wherein in the compound of formula (III), R_A4-R_AI8 are as defined in embodiment 44.

Clause 55. The combination according to any of the clauses 33-47, wherein in the compound of formula (III), R_A4-R_AI8 are as defined in embodiment 45.

Clause 56. The combination according to any of the clauses 33-47, wherein in the compound of formula (III), RA4-RAI8 are as defined in embodiment 46.

Clause 57. The combination according to any of the clauses 55-56, wherein in the compound of formula (III), R_A4-R_AI8 that are other than H are as defined in embodiment 47.

Clause 58. The combination according to clause 33, the compound of formula (III) is selected from the group consisting of: 2-1-01, 2-1-02, 2-1-03, 2-1-04, 2-1-05, 2-1-06, 2-2-01, 2-2-02, 2-2-03, 2-2-04,2-2-05,2-2-06, 2-2-07, 2-2-08, 2-2-09, 2-2-10, 2-2-11, 2-2-12, 2-2-13, 2-3-01 , 2-3-02, 2-3-03, 2-3-04, 2-4-01, 2-4-02, 2-4-03, 2-4-04, and 2-4-05.

Clause 59. The combination according to clause 33, wherein the compound of formula (III) is 2-2-06.

Clause 60. The combination according to clause 1 , wherein the compound A) is a compound of formula (IV). Clause 61. The combination according to clause 60, wherein the compound of formula (IV) is a compound of formula (IVa).

Clause 62. The combination according to clause 60, wherein the compound of formula (IV) is a compound of formula (IVb).

Clause 63. The combination according to any of the clauses 60-62, wherein in the compound of formula (IV), R_AI9 is as defined in embodiment 51.

Clause 64. The combination according to any of the clauses 60-62, wherein in the compound of formula (IV), R_AI9 is as defined in embodiment 52.

Clause 65. The combination according to any of the clauses 60-62, wherein in the compound of formula (IV), R_AI9 is as defined in embodiment 53.

Clause 66. The combination according to any of the clauses 60-62, wherein in the compound of formula (IV), R_AI9 is as defined in embodiment 54.

Clause 67. The combination according to any of the clauses 60-66, wherein in the compound of formula (IV), R_A2_O is as defined in embodiment 55.

Clause 68. The combination according to any of the clauses 60-67, wherein in the compound of formula (IV), R_A2I is as defined in embodiment 56.

Clause 69. The combination according to any of the clauses 60-67, wherein in the compound of formula (IV), R_A ^k in R_A2I is as defined in embodiment 57.

Clause 70. The combination according to any of the clauses 60-67, wherein in the compound of formula (IV), R_A2I is a moiety of formula (XV) as defined in embodiment 58.

Clause 71. The combination according to any of the clauses 60-67, wherein in the compound of formula (IV), R_A2I is as defined in embodiment 59.

Clause 72. The combination according to any of the clauses 60-71 , wherein in the compound of formula (IV), R_A22 and R_A24 are as defined in embodiment 60.

Clause 73. The combination according to any of the clauses 60-72, wherein in the compound of formula (IV), R_A23 and R_A25 are as defined in embodiment 61.

Clause 74. The combination according to any of the clauses 60-71 , wherein in the compound of formula (IV), R_A22-R_A25 are as defined in embodiment 62.

Clause 75. The combination according to any of the clauses 60-71 , wherein in the compound of formula (IV), R_A22-R_A25 are as defined in embodiment 63.

Clause 76. The combination according to clause 75, wherein in the compound of formula (IV), R_A22-R_A25 that are other than H are as defined in embodiment 64.

Clause 77. The combination according to any of the clauses 60-71 , wherein in the compound of formula (IV), R_A22-R_A25 are as defined in embodiment 65.

Clause 78. The combination according to clause 1 , wherein the compound A) is a compound of formula (V). Clause 79. The combination according to clause 78, wherein in the compound of formula (V), RB⁰ is a moiety comprising at least 5 carbon atoms.

Clause 80. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), RB is a radical selected from the group consisting of formula (a) (i.e. a compound (Va)) and formula (b) (i.e. a compound (Vb)) as defined in embodiment 67.

Clause 81. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), R_B is a radical of formula (a) (i.e. a compound (Va)) as defined in embodiment 68.

Clause 82. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), R_B is a radical of formula (a) (i.e. a compound (Va)) as defined in embodiment 69.

Clause 83. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), R_B is a radical of formula (a) (i.e. a compound (Va)) as defined in embodiment 70.

Clause 84. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), R_B is a radical of formula (a) (i.e. a compound (Va)) as defined in embodiment 71.

Clause 85. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), R_B is a radical of formula (a) (i.e. a compound (Va)) as defined in embodiment 72.

Clause 86. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), RB is a radical of formula (b) (i.e. a compound (Vb)) as defined in embodiment 73.

Clause 87. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), R_B is a radical of formula (b) (i.e. a compound (Vb)) as defined in embodiment 74.

Clause 88. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), R_B is a radical of formula (c) (i.e. a compound (Vc)) as defined in embodiment 75. Clause 89. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), R_B is a radical of formula (c) (i.e. a compound (Vc)) as defined in embodiment 76.

Clause 90. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), R_B is a radical of formula (c) (i.e. a compound (Vc)) as defined in embodiment 77.

Clause 91. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), R_B is a radical of formula (d) (i.e. a compound (Vd)) as defined in embodiment 78.

Clause 92. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), R_B is a radical of formula (d) (i.e. a compound (Vd)) as defined in embodiment 79.

Clause 93. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), R_B is a radical of formula (d) (i.e. a compound (Vd)) as defined in embodiment 80.

Clause 94. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), R_B is a radical of formula (d) (i.e. a compound (Vd)) as defined in embodiment 81.

Clause 95. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), R_B is a radical of formula (d) (i.e. a compound (Vd)) as defined in embodiment 82.

Clause 96. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), R_B is a radical of formula (d) (i.e. a compound (Vd)) as defined in embodiment 83.

Clause 97. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), R_B is a radical of formula (d) (i.e. a compound (Vd)) as defined in embodiment 84.

Clause 98. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), R_B is a radical of formula (e) (i.e. a compound (Ve)) as defined in embodiment 85.

Clause 99. The combination according to any of the clauses 78-79, wherein in the compound of formula (V), RB is a radical of formula (e) (i.e. a compound (Ve)) as defined in embodiment 86.

Clause 100. The combination according to any of the clauses 78-99, wherein in the compound of formula (V), RBI is as defined in embodiment 87.

Clause 101. The combination according to any of the clauses 78-99, wherein in the compound of formula (V), RBI is as defined in embodiment 88.

Clause 102. The combination according to any of the clauses 78-99, wherein in the compound of formula (V), RBI is as defined in embodiment 89.

Clause 103. The combination according to any of the clauses 78-99, wherein in the compound of formula (V), RBI is as defined in embodiment 90.

Clause 104. The combination according to any of the clauses 78-99, wherein in the compound of formula (V), RBI is as defined in embodiment 91.

Clause 105. The combination according to any of the clauses 78-99, wherein in the compound of formula (V), RBI is as defined in embodiment 92.

Clause 106. The combination according to any of the clauses 78-105, wherein in the compound of formula (V), RB2 is as defined in embodiment 93.

Clause 107. The combination according to any of the clauses 78-106, wherein in the compound of formula (V), RB3 is as defined in embodiment 94. Clause 108. The combination according to any of the clauses 78-106, wherein in the compound of formula (V), RB3 is as defined in embodiment 95.

Clause 109. The combination according to any of the clauses 78-106, wherein in the compound of formula (V), RB3 is as defined in embodiment 96.

Clause 110. The combination according to any of the clauses 78-106, wherein in the compound of formula (V), RB3 is as defined in embodiment 97.

Clause 111. The combination according to any of the clauses 78-106, wherein in the compound of formula (V), RB3 is as defined in embodiment 98.

Clause 112. The combination according to any of the clauses 78-106, wherein in the compound of formula (V), RB3 is a moiety of formula (XXVI) as defined in embodiment 99.

Clause 113. The combination according to any of the clauses 78-106, wherein in the compound of formula (V), RB3 is as defined in embodiment 100.

Clause 114. The combination according to clause 78, wherein the compound of formula (V) is selected from the group consisting of 3-5-01 , and 3-5-02.

Clause 115. The combination according to any of the clauses 1-114, wherein the drug B) is an inhibitor of an anti-apoptotic protein.

Clause 116. The combination according to clause 115, wherein the inhibitor of an anti-apoptotic protein is as defined in embodiment 102.

Clause 117. The combination according to any of the clauses 115-116, wherein the inhibitor of an anti- apoptotic protein is as defined in embodiment 103.

Clause 118. The combination according to any of the clauses 115-117, which is as defined in embodiment

104.

Clause 119. The combination according to any of the clauses 115-118, which is as defined in embodiment

105.

Clause 120. The combination according to any of the clauses 1-114, wherein the drug B) is an immune checkpoint inhibitor.

Clause 121. The combination according to clause 120, wherein the immune checkpoint inhibitor is as defined in embodiment 106.

Clause 122. The combination according to any of the clauses 120-121 , wherein the immune checkpoint inhibitor is as defined in embodiment 107.

Clause 123. The combination according to any of the clauses 120-122, which is as defined in embodiment 108.

Clause 124. The combination according to any of the clauses 120-123, which is as defined in embodiment 109.

Clause 125. The combination according to any of the clauses 1-114, wherein the drug B) is a

chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor.

Clause 126. The combination according to clause 125, wherein the chemotherapeutic agent is as defined in embodiment 110. Clause 127. The combination according to any of the clauses 125-126, wherein the chemotherapeutic agent is as defined in embodiment 111.

Clause 128. The combination according to any of the clauses 125-127, which is as defined in embodiment 112

Clause 129. The combination according to any of the clauses 125-128, which is as defined in embodiment 113.

Clause 130. The combination according to any of the clauses 125-129, further comprising an immune checkpoint inhibitor as defined in any of the embodiments 106-107.

Clause 131. The combination according to clause 130, which is as defined in embodiment 115.

Clause 132. The combination according to any of the clauses 130-131 , which is as defined in embodiment 116.

Clause 133. A single pharmaceutical or veterinary composition as defined in embodiment 117.

Clause 134. A package or kit of parts composition as defined in embodiment 118.

Clause 135. A combination as defined in any of clauses 1-132, or a single pharmaceutical or veterinary composition as defined in clause 133, or a package or kit of parts as defined in clause 134, for use in the treatment and/or prevention of cancer.

Clause 136. The combination, the single pharmaceutical or veterinary composition, or the package or kit of parts for use according to clause 135, as defined in embodiment 120.

Clause 137. The combination, the single pharmaceutical or veterinary composition, or the package or kit of parts for use according to any of the clauses 135-136, as defined in embodiment 121.

Clause 138. The combination, the single pharmaceutical or veterinary composition, or the package or kit of parts for use according to any of the clauses 135-137, as defined in embodiment 122.

Clause 139. A compound selected from the group consisting of a compound of formula (I), (III), (IV), and (V), or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I), (III), (IV), or (V), respectively, or of its pharmaceutically or veterinary acceptable salt, together with one or more pharmaceutically or veterinary acceptable excipients or carriers, for administration in combination with a drug selected from the group consisting of: i) an immune checkpoint inhibitor, ii) an inhibitor of an anti-apoptotic protein, and iii) a chemotherapeutic agent, together with one or more pharmaceutically or veterinary acceptable excipients or carriers, for simultaneous, concurrent, separate or sequential use in the treatment and/or prevention of cancer, wherein the compound and the drug are as defined in any of the clauses 1-132.

Clause 140. A a drug selected from the group consisting of: i) an immune checkpoint inhibitor, ii) an inhibitor of an anti-apoptotic protein, and iii) a chemotherapeutic agent, together with one or more pharmaceutically or veterinary acceptable excipients or carriers, for administration in combination with a compound selected from the group consisting of a compound of formula (I), (III), (IV), and (V), or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I), (III), (IV), or (V), respectively, or of its pharmaceutically or veterinary acceptable salt, together with one or more pharmaceutically or veterinary acceptable excipients or carriers, for simultaneous, concurrent, separate or sequential use in the treatment and/or prevention of cancer, wherein the compound and the drug are as defined in any of the clauses 1-132.

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Claims

1. A combination comprising:

A) a compound of formula (I), or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of any of its pharmaceutically or veterinary acceptable salts; and

B) a drug selected from the group consisting of:

i) an immune checkpoint inhibitor;

ii) an inhibitor of an anti-apoptotic protein; and

wherein:

X is a biradical selected from -NR^a’-, -0-, -CR^bR^c- and

b) one or more substituents R^d, and/or

a) one Cy⁵; and/or b) one or more substituents R^d, and/or

wherein L is attached to X through Cy³ or Z³; and L is attached to -R₄ through either Cy³ or Z³, or alternatively, through any of the substituents of Cy³ or Z³;

R3 is selected from the group consisting of R^f, -OR^f, -NR^a’R^f, and -NR^a’COR^f; R₄ is independently selected from H, halogen, -N0₂, -CN, -OR^a’, -OC(Y)R^a’, -OC(Y)OR^a’, -OC(Y)NR^a’R^a’,

each R^a’ is independently H or R^a; each R^a is independently selected from the group consisting of (Ci-Ce)al kyl, (C₂-C₆)al kenyl, (C₂-C₆)alkynyl, (C₂-C₆)hydrocarbon chain having one or more double bonds and one or more triple bonds, and Cy⁸, wherein each R^a is optionally substituted with one or more halogen atoms,

R^b and R^c are independently selected from the group consisting of H, halogen, (Ci-Cejalkyl, (C₂-Ce)al kenyl, (C₂-C₆)alkynyl, (C₂-C₆)hydrocarbon chain having one or more double bonds and one or more triple bonds, and a Cy⁹; wherein (Ci-Cejalkyl, (C₂-C₆)al kenyl, (C₂-C₆)alkynyl, (C₂-C₆)hydrocarbon chain and Cy⁹ are independently optionally substituted with one or more halogen atoms; or alternatively

b) one or more substituents R^d, and/or

c) one or more substituents Z⁶ optionally substituted with one or more substituents R^d and/or one Cy¹¹; wherein Cy¹⁰ and Cy¹¹ are optionally substituted with one or more substituents independently selected from R^d, and Z⁷ optionally substituted with one or more substituents R^d; each R^d is independently selected from halogen, -NO2, -CN, -OR^3’, -OC(Y)R^a’, -OC(Y)OR^a’, -OC(Y)NR^a’R^a’, -NR^aR^a’, -NR^aC(Y)R^a’, -NR^aC(Y)OR^a’, -NR^aC(Y)NR^aR^a’, -NR^aS(0)₂R^a’, -NR^SCWR^3’, -SR^a’, -S(0)R^a’, -S(0)0R^a’, -S0₂R^a’, -S0₂(0R^a), -S0₂NR^a R^a’, -SC(Y)NR^aR^a’, -C(Y)R^a’, -C(Y)OR^a’, -C(Y)NR^aR^a’,

a) one Cy¹³, and/or

b) one or more substituents R^d, and/or

c) one or more substituents Z⁸ optionally substituted with one or more substituents R^d and/or one Cy¹³; wherein Cy¹³ is optionally substituted with one or more substituents independently selected from R^d, and Z¹³ optionally substituted with one or more substituents R^d; each R^f is independently Cy¹⁴, or Z⁹ optionally substituted with one or more substituents R^d and/or one Cy¹⁵; wherein Cy¹⁴ or Cy¹⁵ are independently optionally substituted with:

a) one Cy¹⁶; and/or

b) one or more substituents R^d, and/or

Cy⁷ is a known ring system selected from the group consisting of:

(i) phenyl;

(ii) 5- or 6-membered heteroaromatic ring;

unsaturated; (iv) 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring;

wherein Cy⁷ is optionally substituted with:

a) one Cy¹⁸, and/or

b) one or more substituents R^d, and/or

c) one or more substituents Z¹¹ optionally substituted with one or more substituents R^d and/or one Cy¹⁹; wherein Cy¹⁸or Cy¹⁹are optionally substituted with one or more substituents independently selected from R^d, and Z¹² optionally substituted with one or more substituents R^d;

Z¹-Z¹³ are independently selected from the group consisting of (Ci-Ci2)alkyl, (C2-Ci2)al kenyl, (C2-Ci2)alkynyl, and (C2-Ci2)hydrocarbon chain having one or more double bonds and one or more triple bonds, wherein any carbon atom of Z¹-Z¹³ is optionally a spiro atom substituted with R^hand R', and R^h and R', together with the spiro carbon atom, form a known ring system comprising a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring;

Cy¹-Cy⁴, Cy¹²-Cy¹⁵, and Cy¹⁸are independently a known ring system selected from the group consisting of phenyl; 5- or 6-membered heteroaromatic ring; 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7- membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring;

Cy⁵-Cy⁶, Cy⁸-Cy¹¹, Cy¹⁶-Cy¹⁷, and Cy¹⁹are independently a known ring system selected from the group consisting of phenyl; 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 5- or 6-membered heteroaromatic ring; wherein in the carbocyclic rings all ring members are carbon atoms; and in the heterocyclic and

2. The combination according to claim 1 , wherein in the compound of formula (I), X is a biradical -NR^a- (i.e. a compound (la)).

3. The combination according to any of the claims 1-2, wherein in the compound of formula (I), L is a moiety of formula (XXI):

wherein: m and n are independently a value selected from 0 to 2; p is a value selected from 0 to 1 ; Ri and R^kare independently selected from the group consisting of H, halogen, and (Ci-C3)alkyl optionally substituted with one or more halogen atoms; or alternatively

Ri and R^k, together with the spiro carbon atom to which they are attached, form a known ring system comprising a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring;

Cy²⁰ is a known ring system selected from the group consisting of phenyl; 5- or 6-membered heteroaromatic ring; 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring; and Cy²⁰ is optionally substituted with one or more substituents selected from halogen and

(Ci-C3)alkyl optionally substituted with one or more halogen atoms,

Cy²¹ is a known ring system selected from the group consisting of phenyl; 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 5- or 6-membered heteroaromatic ring; and Cy²¹ is optionally substituted with one or more substituents selected from halogen and (Ci-C₃)alkyl optionally substituted with one or more halogen atoms.

4. The combination according to any of the claims 1-3, wherein in the compound of formula (I), Ri is Cy⁷ optionally substituted as defined in claim 1.

5. The combination according to any of the claims 1-4, wherein in the compound of formula (I), R₂ is selected from halogen, -CN and -OR^3’.

6. The combination according to any of the claims 1-5, wherein in the compound of formula (I), R₃ is selected from the group consisting of -OR^f, and -NR^a’R^f.

7. The combination according to any of the claims 1-6, wherein in the compound of formula (I), R₃ is methoxy.

8. The combination according to any of the claims 1-6, wherein in the compound of formula (I), R₃ is a moiety of formula (XX):

wherein

Cy²² is a known ring system selected from the group consisting of phenyl; 5- or 6-membered heteroaromatic ring; 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic ring; and 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring, which is fused, bridged-fused or spiro-fused to a 3- to 7-membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic monocyclic ring; and Cy²² is optionally substituted with one or more substituents selected from halogen and (Ci-C₃)alkyl optionally substituted with one or more halogen atoms,

X¹ and X²are independently H or halogen, and

r is a value selected from 0 to 6.

9. The combination according to any of the claims 1-8, wherein in the compound of formula (I), R₄ is independently selected from H, and -C(Y)NR^aOR^a’.

10. The combination according to any of the claims 1-9, wherein the inhibitor of an anti-apoptotic protein of the combination of the invention is selected from the group consisting of: Venetoclax (ABT199); Navitoclax (A855071.0); (R)-Gossypol acetic acid (AT101); Obatoclax (GX15-070); (R)-Gossypol; S55746; (aR)-a-[[(5S)- 5-[3-Chloro-2-methyl-4-[2-(4-methyl-1-piperazinyl)ethoxy]phenyl]-6-(5-fluoro-2-furanyl)thieno[2,3-d]pyrimidin- 4-yl]oxy]-2-[[1-(2,2,2-trifluoroethyl)-1 H-pyrazol-5-yl]methoxy]benzenepropanoic acid (S63845); 7-[5-[[4-[4- [(Dimethylamino)sulfonyl]-1-piperazi-nyl]phenoxy]methyl]-1 ,3-dimethyl-1 H-pyrazol-4-yl]-1-[2-(4-morpholinyl)- ethyl]-3-[3-(1 -naphthalenyloxy)propyl]-1 H-indole-2-carboxylic acid (A1210477); 2-[[4-[[(4-Bromophenyl)- sulfonyl]amino]-1-hydroxy-2-naphthalenyl]thio]acetic acid; 2-((4-(4-Bromophenylsulfonamido)-1- hydroxynaphthalen-2-yl)thio)acetic acid (UMI77); Gossypol (BL193); APG1252; 5-[3-[4-(Aminomethyl)- phenoxy]propyl]-2-[8-[2-(2-benzothiazolyl)hydrazinylidene]-5,6,7,8-tetrahydro-2-naphthalenyl]-4-thiazole- carboxylic acid (WEHI539); 6-[8-[(2-Benzothiazolylamino)carbonyl]-3,4-dihydro-2(1 H)-isoquinolinyl]-3-[5- methyl-1 -(tricyclo[3.3.1.13,7]dec-1 -ylmethyl)-1 H-pyrazol-4-yl]-2-pyridinecarboxylic acid (A1331852); N-[4-[4- [3-[2-(4-Chlorophenyl)-5-methyl-1-(1-methylethyl)-4-(methylsulfonyl)-1 H-pyrrol-3-yl]-5-fluorophenyl]-1- piperazinyl]phenyl]-4-[[(1 R)-3-(4-hydroxy-1-piperidinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoro- methyl)sulfonyl]-benzenesulfonamide (BM1197); 2-[8-[(2-Benzothiazolylamino)carbonyl]-3,4-dihydro-2(1 H)- isoqui-nolinyl]-5-[3-[4-[3-(dimethylamino)-1-propyn-1-yl]-2-fluorophenoxy]propyl]-4-thiazolecarboxylic acid (A1155463); Beclanorsen; Apogossy-polone; N-[4-[[2-(1 ,1-Dimethylethyl)phenyl]-sulfonyl]phenyl]-2, 3,4- trihydroxy- 5-[[2-(1-methylethyl)phenyl]methyl]benzamide (TW37); 4-[4-[(4'-Chloro[1 ,1'-biphenyl]-2-yl)methyl]- 1-piperazinyl]-N-[[4-[[(1 R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl]amino]-3-nitrophenyl]sulfonyl]- benzamide (ABT737); Augmerosen; Cheleritrine.

11. The combination according to any of the claims 1-9, wherein the immune checkpoint inhibitors of the combination of the invention is selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, ipilimumab, tremelimumab, spartalizumab, pidilizumab, dostarlimab, cemiplimab, SHR-1210, LY3300054, CK-301 , BMS-936559, 3D-2-02-0015, STI-1014, Indoximod, epacadostat, BMS-986205, navoximod free base, navoximod phosphate, 3-(5-fluoro-1 H-indol-3-yl)pyrrolidine- 2,5-dione, LY3321367, TSR-022, OREG-103, MEDI-570, GSK3359609, JTX-2011 , lirilumab, LAG525, relatlimab, TSR-033, IMP321 , REGN3767, GSK2831781 , KD033, RG6058, and OMP-313M32.

12. The combination according to any of the claims 1-9, wherein the chemotherapeutic agent is selected from the group consisting of platin compounds, alkylating agents other than platin compounds, topoisomerase inhibitors, histone deacetylase inhibitors, anti-CD33 antibodies, protein cereblon binders, proteasome inhibitors, kinase inhibitors, DNA intercalating agents, and antimetabolites.

13. A single pharmaceutical or veterinary composition which comprises a therapeutically effective amount of: a) a compound of formula (I), or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically or veterinary acceptable salt; and

b) a drug selected from the group consisting of:

i) an immune checkpoint inhibitor;

ii) an inhibitor of an anti-apoptotic protein; and

iii) a chemotherapeutic agent other than an inhibitor of an anti-apoptotic protein and an immune checkpoint inhibitor; together with one or more pharmaceutically or veterinary acceptable excipients or carriers; wherein the compound of formula (I) and the drug are as defined in any of the claims 1-12.

14. A package or kit of parts comprising:

a) a first pharmaceutical or veterinary composition which comprises a therapeutically effective amount of a compound of formula (I) as defined in any of the claims 1-9, or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically or veterinary acceptable salt, together with one or more pharmaceutically or veterinary acceptable excipients or carriers; and

i) an immune checkpoint inhibitor;

ii) an inhibitor of an anti-apoptotic protein; and

as defined in any of the claims 1 , or 10-12, together with one or more pharmaceutically or veterinary acceptable excipients or carriers;

wherein compositions a) and b) are separate compositions.

15. A combination as defined in any of claims 1-12, a single pharmaceutical or veterinary composition as defined in claim 12, or a package or kit of parts as defined in claim 14, for use in the treatment and/or prevention of cancer.

16. The combination, the single pharmaceutical or veterinary composition, or the package or kit of parts for use according to claim 15, wherein the cancer is selected from the group consisting of Non-Hodgkin’s

Lymphoma, Hodgkin’s disease, hepatopancreatic tumor, biliar tumor, gastrointestinal tumor, bladder cancer, breast cancer, cervical cancer, colorectal cancer, CNS tumor, melanoma, prostate cancer, renal cancer, small-cell lung cancer, non small-cell lung cancer non small-cell lung cancer, acute myeloid leukemia (AML), B-cell chronic lymphocytic leukemia (CLL), T-cell acute lymphoblastic leukemia (T-ALL), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL) (including germinal center B-cell-like (GCB) and activated B- cell-like (ABC) types), and acute lymphoblastic leukemia.

17. A compound of formula (I), or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically or veterinary acceptable salt, together with one or more pharmaceutically or veterinary acceptable excipients or carriers, for administration in combination with a drug selected from the group consisting of:

i) an immune checkpoint inhibitor;

ii) an inhibitor of an anti-apoptotic protein; and

together with one or more pharmaceutically or veterinary acceptable excipients or carriers, for simultaneous, concurrent, separate or sequential use in the treatment and/or prevention of cancer, wherein the compound of formula (I) and the drug are as defined in any of the claims 1-12.

18. A drug selected from the group consisting of:

i) an immune checkpoint inhibitor;

ii) an inhibitor of an anti-apoptotic protein; and

together with one or more pharmaceutically or veterinary acceptable excipients or carriers, for administration in combination with a compound of formula (I), or a pharmaceutically or veterinary acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically or veterinary acceptable salt, together with one or more pharmaceutically or veterinary acceptable excipients or carriers, for simultaneous, concurrent, separate or sequential use in the treatment and/or prevention of cancer, wherein the compound of formula (I) and the drug are as defined in any of the claims 1-12.