Patent Description:
High mortality rates and a reduced quality of life are common in patients with many types of solid tumors, demonstrating an urgent need for new anti-tumor treatments. An important component of successful treatment of advanced or relapsing cancers involves reversing the immunosuppression induced by tumors. Current immunotherapies, including immune checkpoint inhibitors (ICI) antibodies, have thus far attempted to restore anti-tumor T cell responses, either by directly targeting these cells or the antigen presenting cells that activate T cells. Despite the clear clinical benefits in approximately <NUM>% of patients, the response rate remains limited. This is partly because of limited penetration of relatively large biomolecule drugs (e.g. antibodies) into solid tumors and drug-mediated effects on only a fraction of anti-tumor immune cell subsets.

To improve the response rate, other therapies aim to address the immunosuppressive tumor microenvironment (TME) (<NPL>). Immunotherapies that can more readily penetrate solid tumors, such as small molecules (<NPL>), are also promising candidates for use in combination cancer therapies in order to augment co-administered therapies that are only partially effective on their own.

Adenosine is a naturally-occurring purine nucleoside found in mammals, both intracellularly and extracellularly. Adenosine and its phosphorylated derivatives are involved in many biological processes including energy transfer, cell signaling and vasodilation. Extracellular adenosine (ExAdo), and its receptors, are present in healthy tissues but are also overexpressed in numerous types of solid tumors (<NPL>) and murine models of cancer (<NPL>). Signaling via ExAdo has been demonstrated to cause immunosuppression of immune cells found within the tumor microenvironment (TME) (Vigano et. , <NUM> doi: <NUM>/fimmu. ExAdo mediates this immunosuppression by binding to the extracellular domain of adenosine receptors 2A and 2B (A2AR and A2BR). Therefore, high extracellular adenosine concentrations are a validated cause of immunosuppression in solid tumors because they deactivate tumor-targeting immune cells expressing A2AR. Adenosine has a significantly higher affinity for A2AR, and A2AR plays a more important role in T cell immunity compared to A2BR (<NPL>, <NPL>). The remaining two adenosine receptors, A1R and A3R, have different downstream signaling pathways compared to A2AR and A2BR, and their signaling does not normally result in immunosuppression.

A2AR is predominantly found on lymphocyte lineage cells such as T cells and natural killer (NK) cells, as well as on myeloid lineage cells including dendritic cells (DCs), and macrophages (Vigano et al. , <NUM>, supra). Because of the central role of NFκB in many proinflammatory and cytotoxic anti-tumor immune responses, the ExAdo signaling pathway could be targeted by therapies to restore desirable immune responses in cancer patients. These responses include the patient's own cellular immunity (T lymphocytes, natural killer cells, dendritic cells, macrophages) as well as the efficacy of co-administered immunotherapies such as immune checkpoint inhibitors (such as anti-PD-<NUM>, anti-PD-L1, anti-TIGIT, and anti-CTLA-<NUM> monoclonal antibodies), bispecific antibodies, adoptive cell immunotherapy (e.g. CAR-T cell infusion), and anti-cancer vaccines - all of which would be enhanced within a favorable (proinflammatory) TME.

Blockade of immunosuppressive adenosine signaling, especially A2AR, thus represents a therapeutic strategy with broad applicability in cancer therapy, including as a combination treatment with other approved cancer treatments including radiotherapy, targeted therapies for cancers with specific mutations, and conventional chemotherapy.

Small molecule drugs that block A2AR can be classified as either 'orthosteric' or 'allosteric' antagonists. Orthosteric antagonists bind to the same amino acid motif on A2AR that are engaged by the endogenous receptor ligand, adenosine. On the other hand, allosteric antagonists bind to distinct amino acids motifs that are not utilized by the endogenous ligand. To effectively block A2AR signaling, orthosteric inhibitors must outcompete adenosine, which is present at high concentrations in many tumors. Achieving this would require high doses of orthosteric A2AR antagonists, which increases the likelihood of undesirable drug-mediated effects.

Orthosteric A2AR antagonists have been developed (<NPL>; <NPL>) but none have thus far entered phase III clinical trials.

<NPL> discloses the synthesis of pyridine-based compounds without mentioning any pharmaceutical use.

<CIT> discloses compounds as serotonin reuptake inhibitors.

<CIT> discloses <NUM>-amino-<NUM>-cyano-<NUM>-aryl-pyridine derivatives for use in the treatment of cancer.

<CIT> discloses <NUM>,<NUM>-Dicyanopyridine derivatives or their salts said to have a high conductance-type of calcium-activated K channel opening effect and a smooth muscle relaxant effect for bladder based on the K-channel opening effect, which can be used in treating pollakiuria and urinary incontinence.

Currently, there exists an evident medical need for active agents that are able to act effectively in the immunosuppressive tumor microenvironment for providing novel immunotherapeutic options.

The present invention is directed to the unexpected finding of cyanopyridine compounds that are able to inhibit signaling of A2AR as A2AR antagonists which are classified as negative allosteric modulators (NAMs) since they achieve an inhibition of the signaling of the target regardless of the extracellular adenosine concentration, including at high micromolar concentrations present within the TME.

It is an object of the invention to provide new therapeutic agents useful for eliciting or increasing an immune response to immunotherapy, in particular anti-cancer immunotherapy. A first aspect of the invention provides cyanopyridine compounds according to Formula (I), as well pharmaceutically acceptable salts thereof, tautomers, and geometrical isomers.

Another aspect of the invention provides a pharmaceutical composition comprising at least one compound according to the invention, as well pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof.

A first aspect of the invention provides cyanopyridine compounds according to Formula (I), as well pharmaceutically acceptable salts thereof for use in the treatment of a cancer, in particular solid tumor cancers or malignancies presenting or sceptible to presence a resistance to immunotherapy.

Another aspect of the invention relates to a pharmaceutical composition comprising at least one compound according to the invention in combination at least one agent useful in the treatment of cancer.

Another aspect of the invention is a process for the preparation of a compound according to Formula (I) as defined below.

Further objects and advantageous aspects of the invention will be apparent from the claims and/or from the following detailed description of embodiments of the invention with reference to the annexed drawings. Nevertheless, the invention is defined by the claims.

<FIG> represents the concentration-response curves (CRCs) of adenosine (A) and Schild regregression plots (B) obtained with the shift assays of Example <NUM> with compounds of the invention used to confirm allosteric mode of action. A: the shift assay was performed with compounds and data from compound of the invention (Example <NUM>). The largest open symbols: <NUM> of compound, and a half-log dilution was performed until submicromolar concentrations of the compound - represented by the smallest open circle. Closed circles: the adenosine-only control. B: Schild regression plot calculated for the indicated compounds using the shift assay data.

The term "allosteric antagonists" refers to antagonists which block receptor signaling without binding to all or some of the amino acids that the natural ligand (adenosine) uses to bind to the receptor.

The expression "solid tumour cancer" refers to all cancers except cancers of the blood and includes, without being limited to, lung cancer (small cell and non-small cell), breast cancer, ovarian cancer, cervical cancer, uterus cancer, head and neck cancer, melanoma, cancers of the digestive system, hepatocellular carcinoma, colon cancer, rectal cancer, colorectal carcinoma, kidney cancer, prostate cancer, gastric cancer, bronchus cancer, pancreatic cancer, urinary bladder cancer, hepatic cancer and brain cancer.

According to a particular embodiment, a solid tumor cancer with high adenosine signalling, can be characterized by validated RNA transcript signatures in tumor biopsies (<NPL>), pCREB levels in the blood (Seitz https://doi. org/<NUM>/s10637-<NUM>-<NUM>-<NUM>), or could possibly be inferred using A2AR expression levels in tumor biopsies (Allard et al. , <NUM>, supra) or in circulating blood immune cells (DOI: <NUM>/JAD-<NUM>).

A solid cancer condition could be considered to feature 'high adenosine signalling' if more than <NUM>% of patients with this type of cancer have more than a five fold increase of adenosine signature genes compared to healthy tissue controls, see <NPL>. These cancer conditions include cancers of the digestive system such as of the colon, stomach and pancreas and cancers of the lung, cervix, head and neck.

The expression "immunotherapeutic agent" refers to agents which support the immune system to combat a disease such as cancer. There are currently several major categories: adoptive cellular therapies (e.g. CAR-T cells or other tumor infiltrating immune cells), immune checkpoint inhibitor monoclonal antibodies (ICI mAbs), bispecific T cell engagers (BiTEs), novel immunomodulators or molecular adjuvants, and cancer vaccines, all of which could be envisioned to be used in combination with the present molecules. In addition, standard forms of cancer therapy could be used in combination with the present molecules. These include chemotherapy, radiotherapy, and targeted therapy (specific for particular cancer antigens or cancer-associated molecular pathways). In particular, radiotherapy has been described as an appropriate therapeutic combination to the A2AR-targeting approach (Allard et al. , <NUM>, supra).

The term "bispecific T cell engagers" refers to agents such as antibodies that have one binding arm that recognizes a tumor antigen and another binding arm recognizes an antigen on the surface of a T-cell, as reviewed and exemplified in <NPL>.

The term "nanobodies refers to agents that are similar to antibodies but typically much lower in molecular weight, reviewed and exemplified in <NPL>.

As used herein, "treatment" and "treating" and the like generally mean obtaining a desired pharmacological and physiological effect. The effect may be prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof and/or may be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease.

The term "efficacy" of a treatment according to the invention can be measured based on changes in the course of a disease in response to a use or a method according to the invention. The efficacy of a treatment of a cancer according to the invention can be measured by a reduction of tumour volume, and/or an increase of progression-free survival time and/or increased health and well-being of the subject (e.g. repressing a cancer). Inhibition of cancer cell growth may be evidenced, for example, by arrest of cancer cells in a particular phase of the cell cycle, e.g., arrest at the G2/M phase of the cell cycle. Inhibition of cancer cell growth can also be evidenced using well known imaging methods such as magnetic resonance imaging, computerized axial tomography, PET, SPECT, photo-acoustic imaging, X-rays and fluorescence imaging/detection. Cancer cell growth can also be determined macroscopically via measurements with calipers.

In particular, efficacy of a combined treatment according to the invention can be assessed by reduction of tumour size, disappearance of tumour, or modified expression of biomarkers. These biomarkers may be soluble or expressed by cancer or immune system cells. Biomarkers that can be used to demonstrate modifications in A2AR signaling or biological efficacy include intracellular cAMP and pCREB (<NPL>), or downstream effector molecules that are commonly characterized as anti-tumor immune responses including IL-<NUM>, TNF-α or IFN-γ cytokine secretion (<NPL>).

The term "subject" as used herein, refers to a human or a non-human mammal, such as non-human primate (e.g. chimpanzees and other apes and monkey species), a farm animal (e.g. cattle, sheep, pigs, goats and horses), a domestic mammal (e.g. dogs and cats), or a laboratory animal (e.g. rodents, such as mice, rats and guinea pigs).

The term "efficacy" of a treatment according to the invention can be measured based on changes in the course of disease in response to a use or a method according to the invention. For example, the efficacy of a treatment according to the invention can be measured by its impact on signs or symptoms of illness. A response is achieved when the subject experiences partial or total alleviation, or reduction of unwanted symptoms of illness. According to a particular embodiment, the efficacy can be measured through the assessment of toxin target cleavage or viral replication after infection. For example, the efficacy of a toxin or anti-viral treatment according to the invention can be monitored by following the effect on map kinase kinase <NUM> cleavage or by the improvement of cell survival, tissue damage and patient survival. The term "aryl" refers to an unsaturated aromatic carbocyclic group of from <NUM> to <NUM> carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., indenyl, naphthyl). Aryl include phenyl, naphthyl, anthryl, phenanthrenyl and the like.

The term "heteroaryl" refers to a monocyclic or bicyclic unsaturated aromatic moiety of <NUM> to <NUM> ring atoms in which one or more of the ring atoms are selected from N, O or S. Particular examples of heteroaryl groups include optionally substituted pyridyl, pyrrolyl, pyrimidinyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, <NUM>,<NUM>,<NUM>-triazolyl, <NUM>,<NUM>,<NUM>-triazolyl, <NUM>,<NUM>,<NUM>-oxadiazolyl, <NUM>,<NUM>,<NUM>-oxadiazolyl, <NUM>,<NUM>,<NUM>-oxadiazolyl, <NUM>,<NUM>,<NUM>-oxadiazolyl, <NUM>,<NUM>,<NUM>-triazinyl, <NUM>,<NUM>,<NUM>-triazinyl, benzofuryl, [<NUM>,<NUM>-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, <NUM>H-indolyl, benzimidazolyl, imidazo[<NUM>,<NUM>-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl, pyrido[<NUM>,<NUM>-b]pyridyl, pyrido[<NUM>,<NUM>-b]pyridyl, pyrido[<NUM>,<NUM>-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl, <NUM>,<NUM>,<NUM>,<NUM>-tetrahydroquinolyl, <NUM>,<NUM>,<NUM>,<NUM>-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.

The term "heteroalkyl" refers to C<NUM>-C<NUM> -alkyl, preferably C<NUM>-C<NUM> -alkyl, wherein at least one carbon has been replaced by a heteroatom selected from O, N or S, including <NUM>-methoxy ethyl and the like.

The term "heterocycloalkyl" refers to a C<NUM>-C<NUM>-cycloalkyl group according to the definition above, in which up to <NUM> carbon atoms are replaced by heteroatoms chosen from the group consisting of O, S, NR, R being defined as hydrogen or methyl. Heterocycloalkyl include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and the like.

The term "alkoxycarbonyl C<NUM>-C<NUM> alkyl" refers to C<NUM>-C<NUM> alkyl groups having an alkoxycarbonyl substituent, including <NUM>-(benzyloxycarbonyl)ethyl and the like.

Unless otherwise constrained by the definition of the individual substituent, the term "substituted" refers to groups substituted with from <NUM> to <NUM> substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, amino (-NH2, -NH-, -N-), amide (-NHC(O)-), carbonyl (-C(O)-), alkoxycarbonyl (-C(O)O-), carboxylic acid, ether (-O-), thioether (-S-), sulfoxide (-S(O)-) and sulfone (-S(O)<NUM>-), C<NUM>-C<NUM> alkyl, aryl or heteroaryl.

The term "pharmaceutical formulation" refers to preparations which are in such a form as to permit biological activity of the active ingredient(s) to be unequivocally effective and which contain no additional component which would be toxic to subjects to which the said formulation would be administered.

According to one aspect, is provided a cyanopyridine compound according to Formula (I)
<CHM>.

Wherein R<NUM> is selected from aryl optionally substituted by one or more halogen (e.g. fluoro), cyano, hydroxy or C<NUM>-C<NUM> alkyl (e.g. optionally substituted phenyl such as phenyl, halogeno phenyl or phenyl optionally susbsituted by a C<NUM>-C<NUM> alkyl such as methyl) and heteroaryl optionally substituted by one or more halogen, cyano, hydroxy or C<NUM>-C<NUM> alkyl (e.g. optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl, optionally substituted furanyl, optionally substituted indolyl, optionally substituted thiophenyl, optionally substituted pyrazolo, optionally substituted imidazolo, optionally substituted oxazolo, optionally substituted thiazolo, optionally substituted isoxazolo, optionally substituted isothiazolo, optionally substituted triazolo, optionally substituted oxadiazolo, optionally substituted thiodiazolo, optionally substituted tetrazolyl); R<NUM> is selected from H and halogen; R<NUM> is selected from H, CN and optionally substituted C<NUM>-C<NUM> alkyl (e.g. C<NUM>-C<NUM> alkyl optionally substituted by hydroxy, amino, ether, thioether, cyano, halogen or branched C<NUM>-C<NUM> alkyl); R<NUM> is selected from a group XR(R'), an optionally substituted aryl (e.g. optionally substituted phenyl such as phenyl, halogeno phenyl or phenyl optionally substituted by a C<NUM>-C<NUM> alkyl such as methyl) and optionally substituted heteroaryl (e.g. optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl, optionally substituted furanyl, optionally substituted indolyl, optionally substituted thiophenyl, optionally substituted pyrazolo, optionally substituted imidazolo, optionally substituted oxazolo, optionally substituted thiazolo, optionally substituted isoxazolo, optionally substituted isothiazolo, optionally substituted triazolo, optionally substituted oxadiazolo, optionally substituted thiodiazolo, optionally substituted tetrazolyl), wherein X is selected from O, S, N and R and R' are independently an optionally substituted C<NUM>-C<NUM> alkyl (e.g. a C<NUM>-C<NUM> alkyl optionally substituted by hydroxy, amino, ether, thioether, cyano, halogen, aryl, heteroaryl, or a branched C<NUM>-C<NUM> alkyl group), or XRR' form together an optionally substituted heterocyclic alkyl (such as optionally substituted azetidine, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted morpholinyl, optionally substituted piperazine, optionally substituted azepane, optionally substituted azocane); as well as pharmaceutically acceptable salts thereof for use in the treatment of a cancer, in particular in immunotherapy. According to a further aspect, a cyanopyridine compound according to the invention is a compound of Formula (Ia):
<CHM>
wherein R<NUM> and R<NUM> are as defined herein, X is selected from O and S and R<NUM> is an optionally substituted C<NUM>-C<NUM> alkyl (e.g. a C<NUM>-C<NUM> alkyl optionally substituted by hydroxy, amino, ether, thioether, cyano, halogen, aryl, heteroaryl, or a branched C<NUM>-C<NUM> alkyl group); as well as pharmaceutically acceptable salts thereof.

According to a further aspect, a cyanopyridine compound according to the invention is a compound of Formula (Ib):
<CHM>
wherein R<NUM> and R<NUM> are as defined herein and R<NUM> and R<NUM> are independently an optionally substituted C<NUM>-C<NUM> alkyl (e.g. a C<NUM>-C<NUM> alkyl optionally substituted by hydroxy, amino, ether, thioether, cyano, halogen, aryl, heteroaryl, or a branched C<NUM>-C<NUM> alkyl group) or form together an optionally substituted heterocyclic alkyl (e.g. optionally substituted azetidine, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted morpholinyl, optionally substituted piperazine, optionally substituted azepane, optionally substituted azocane); as well as pharmaceutically acceptable salts thereof.

According to a further aspect, a cyanopyridine compound according to the invention is a compound of Formula (I) wherein R<NUM> is selected from H and optionally substituted C<NUM>-C<NUM> alkyl and R<NUM> is selected from an optionally substituted aryl (e.g. optionally substituted phenyl such as phenyl, halogeno phenyl or phenyl optionally substituted by a C<NUM>-C<NUM> alkyl such as methyl) and an optionally substituted heteroaryl (e.g. optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl, optionally substituted furanyl, optionally substituted indolyl, optionally substituted thiophenyl, optionally substituted pyrazolo, optionally substituted imidazolo, optionally substituted oxazolo, optionally substituted thiazolo, optionally substituted isoxazolo, optionally substituted isothiazolo, optionally substituted triazolo, optionally substituted oxadiazolo, optionally substituted thiodiazolo, optionally substituted tetrazolyl).

According to another aspect, is provided a cyanopyridine compound according to Formula (I)
<CHM>
wherein R<NUM> to R<NUM> are as defined herein with the proviso that the compound of Formula (I) is not one of the following compounds :
<NUM>-(<NUM>-(<NUM>H-pyrrol-<NUM>-yl)phenyl)-<NUM>-amino-<NUM>-(benzylthio)pyridine-<NUM>,<NUM>-dicarbonitrile (RN: <NUM>-<NUM>-<NUM>); <NUM>-amino-<NUM>-(benzylthio)-<NUM>-(<NUM>-(<NUM>,<NUM>-dimethyl-<NUM>H-pyrrol-<NUM>-yl)phenyl)pyridine-<NUM>,<NUM>-dicarbonitrile (RN: <NUM>-<NUM>-<NUM>); <NUM>-(<NUM>-(<NUM>H-pyrrol-<NUM>-yl)phenyl)-<NUM>-amino-<NUM>-methoxypyridine-<NUM>,<NUM>-dicarbonitrile (RN: <NUM>-<NUM>-<NUM>); <NUM>-(<NUM>-(<NUM>H-imidazol-<NUM>-yl)phenyl)-<NUM>-amino-<NUM>-methoxypyridine-<NUM>,<NUM>-dicarbonitrile; <NUM>-(<NUM>-(<NUM>H-imidazol-<NUM>-yl)phenyl)-<NUM>-amino-<NUM>-methoxypyridine-<NUM>,<NUM>-dicarbonitrile; <NUM>-amino-<NUM>-(<NUM>'-cyano-<NUM>'-fluoro-[<NUM>,<NUM>'-biphenyl]-<NUM>-yl)-<NUM>-phenylpyridine-<NUM>,<NUM>-dicarbonitrile (RN: <NUM>-<NUM>-<NUM>); <NUM>-amino-<NUM>-(<NUM>'-(hydroxymethyl)-[<NUM>,<NUM>'-biphenyl]-<NUM>-yl)-<NUM>-phenylpyridine-<NUM>,<NUM>-dicarbonitrile (RN: <NUM>-<NUM>-<NUM>); <NUM>-amino-<NUM>-(<NUM>'-chloro-[<NUM>,<NUM>'-biphenyl]-<NUM>-yl)-<NUM>-phenylpyridine-<NUM>,<NUM>-dicarbonitrile (RN: <NUM>-<NUM>-<NUM>); <NUM>-amino-<NUM>-(<NUM>'-chloro-[<NUM>,<NUM>'-biphenyl]-<NUM>-yl)-<NUM>-phenylpyridine-<NUM>,<NUM>-dicarbonitrile (RN: <NUM>-<NUM>-<NUM>); <NUM>-amino-<NUM>-(<NUM>'-chloro-[<NUM>,<NUM>'-biphenyl]-<NUM>-yl)-<NUM>-phenylpyridine-<NUM>,<NUM>-dicarbonitrile (RN: <NUM>-<NUM>-<NUM>); <NUM>-amino-<NUM>-phenyl-<NUM>-(<NUM>'-(trifluoromethyl)-[<NUM>,<NUM>'-biphenyl]-<NUM>-yl)pyridine-<NUM>,<NUM>-dicarbonitrile (RN: <NUM>-<NUM>-<NUM>); <NUM>-amino-<NUM>-phenyl-<NUM>-(<NUM>'-(trifluoromethyl)-[<NUM>,<NUM>'-biphenyl]-<NUM>-yl)pyridine-<NUM>,<NUM>-dicarbonitrile (RN: <NUM>-<NUM>-<NUM>); <NUM>-amino-<NUM>-(<NUM>',<NUM>'-dichloro-[<NUM>,<NUM>'-biphenyl]-<NUM>-yl)-<NUM>-phenylpyridine-<NUM>,<NUM>-dicarbonitrile (RN: <NUM>-<NUM>-<NUM>); <NUM>-amino-<NUM>-(<NUM>'-bromo-[<NUM>,<NUM>'-biphenyl]-<NUM>-yl)-<NUM>-phenylpyridine-<NUM>,<NUM>-dicarbonitrile (RN: <NUM>-<NUM>-<NUM>); or <NUM>-amino-<NUM>-(<NUM>'-methyl-[<NUM>,<NUM>'-biphenyl]-<NUM>-yl)-<NUM>-phenylpyridine-<NUM>,<NUM>-dicarbonitrile (RN: <NUM>-<NUM>-<NUM>).

According to another aspect, is provided a cyanopyridine compound according to Formula (I)
<CHM>
for use as a medicament wherein R<NUM> to R<NUM> are as defined herein with the proviso as defined above.

In a particular embodiment, R<NUM> is an aryl optionally substituted by one or more halogen (e.g. fluoro), cyano, hydroxy or C<NUM>-C<NUM> alkyl (e.g. methyl).

In a further particular embodiment, R<NUM> is a phenyl optionally substituted by one or more halogen (e.g. fluoro), cyano, hydroxy or C<NUM>-C<NUM> alkyl (e.g. methyl).

In a further particular embodiment, R<NUM> is a phenyl optionally substituted by one or more halogen or C<NUM>-C<NUM> alkyl, such as phenyl, halogeno phenyl such as <NUM>-fluorophenyl, <NUM>-fluorophenyl, <NUM>-fluorophenyl or a C<NUM>-C<NUM> alkyl phenyl such as methylphenyl like <NUM>-methylphenyl, <NUM>-methylphenyl, <NUM>-methylphenyl.

In another particular embodiment R<NUM> is an heteroaryl optionally substituted by one or more halogen, cyano, hydroxy or C<NUM>-C<NUM> alkyl.

In a further particular embodiment, R<NUM> is selected from optionally substituted pyridinyl (e.g. pyridin-<NUM>-yl, pyridin-<NUM>-yl, pyridin-<NUM>-yl), optionally substituted thiophenyl (e.g. thiophen-<NUM>-yl, thiophen-<NUM>-yl), optionally substituted pyrazolyl (e.g. pyrazol-<NUM>-yl) and optionally substituted tetrazolyl, wherein optionally substituted refers to an optional substitution by one or more halogen, cyano, hydroxy or C<NUM>-C<NUM> alkyl.

In a further particular embodiment, R<NUM> is an optionally substituted pyridinyl wherein optionally substituted refers to an optional substitution by one or more halogen, cyano, hydroxy or C<NUM>-C<NUM> alkyl such as pyridin-<NUM>-yl, pyridin-<NUM>-yl, pyridin-<NUM>-yl, <NUM>-fluoro-<NUM>-pyridinyl, <NUM>-fluoro-<NUM>-pyridinyl, <NUM>-fluoro-<NUM>-pyridinyl, <NUM>-fluoro-<NUM>-pyridinyl and <NUM>-fluoro-3pyridinyl.

In a further particular embodiment, R<NUM> is an optionally substituted oxazolyl such as <NUM>,<NUM>,<NUM>-oxadiazolyl.

In another particular embodiment R<NUM> is a non-substituted heteroaryl.

In a particular embodiment, R<NUM> is H.

In a particular embodiment, R<NUM> is CN.

In a particular embodiment, R<NUM> is a group XR(R') as defined herein.

In a particular embodiment, R<NUM> is a group OR wherein R is an optionally substituted alkyl such as methyl, ethyl hydroxy ethyl.

In a particular embodiment, R<NUM> is a group SR wherein R is an optionally substituted alkyl such as optionally substituted ethyl phenyl.

In a further particular embodiment, R<NUM> is a group XR(R') wherein XRR' form together an optionally substituted heterocyclic alkyl (such as optionally substituted azetidine, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted morpholinyl, optionally substituted piperazine, optionally substituted azepane, optionally substituted azocane).

In a further particular embodiment, R<NUM> is selected from pyridine, pyrrolidine and azetidine.

In a further particular embodiment, R<NUM> is optionally substituted pyridine.

In a further particular embodiment, R<NUM> is piperidine.

In a further particular embodiment, X is N.

In a further particular embodiment, X is O.

In a further particular embodiment, X is S.

According to a further aspect, the cyanopyridine compound is a compound of Formula (Ib), wherein R<NUM> and R<NUM> form together an optionally substituted heterocyclic alkyl.

According to a further aspect, the cyanopyridine compound is a compound of Formula (Ib), wherein R<NUM> and R<NUM> form together an optionally substituted azetidine or an optionally substituted piperidine.

According to a particular embodiment are provided negative allosteric modulators (NAMs) of A2AR.

Compounds of the present invention include in particular those selected from the following group:.

According to a particular embodiment, the compounds of the invention are selected from the following group:.

The compounds of invention have been named according the IUPAC standards used in the program Chemdraw Professional® (product version <NUM> ).

Pharmaceutical compositions of the invention can contain one or more compounds according to the invention and a pharmaceutically acceptable carrier, diluent or excipient thereof. According to another particular aspect, the A2AR modulation effects can be achieved through the delivery of formulations compounds of the invention by various routes, preferably orally. According to a particular aspect, compositions further comprise a compound useful in a prevention and/or treatment of a cancer, in particular in cancer immunotherapy. Compositions of this invention may also be formulated for parenteral administration including, but not limited to, by injection or continuous infusion. Formulations for injection may be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents including, but not limited to, suspending, stabilizing, and dispersing agents. The composition may also be provided in a powder form for reconstitution with a suitable vehicle including, but not limited to, sterile, pyrogen-free water.

According to a particular embodiment, compositions according to the invention are for oral delivery.

In another particular aspect, compositions according to the invention are adapted for delivery by single or multiple administrations.

According to a particular embodiment, compositions of the invention are veterinary compositions.

Further materials as well as formulation processing techniques and the like are set out in <NPL>,.

According to a particular aspect, is provided a pharmaceutical composition comprising at least one compound according to the invention and a pharmaceutically acceptable carrier, diluent or excipient thereof.

The invention provides compounds of the invention, compositions thereof using the same useful in the prevention and/or treatment of a medical disorder, in particular as A2AR modulators for preventing and/or treating cancers, in particular for use in immunotherapy.

Compounds and compositions of this invention may be administered or delivered in any manner including, but not limited to, orally, parenterally, sublingually, transdermally, transmucosally, topically, via inhalation, intra or peri-tumorally, via buccal or intranasal administration, or combinations thereof. Parenteral administration includes, but is not limited to, intra-venous, intra-arterial, intra-peritoneal, subcutaneous and intra-muscular.

In another particular embodiment, a compound according to the invention is for administration orally.

In another particular embodiment, a compound according to the invention is for administration rectally.

In another particular embodiment, a compound according to the invention is for administration intravenously.

The dosage administered, as single or multiple doses, to an individual will vary depending upon a variety of factors, including pharmacokinetic properties, subject conditions and characteristics (sex, age, body weight, health, and size), extent of symptoms, concurrent treatments, frequency of treatment and the effect desired.

According to one embodiment of the invention, the compounds according to the invention and pharmaceutical formulations thereof can be administered alone or in combination with a co-agent useful in the prevention and/or treatment of a disease.

According to one aspect, compounds of the invention can be administered in combination with at least one therapeutic molecule useful in the treatment of a cancer, in particular in cancer immunotherapy.

According to one aspect, compounds of the invention are to be administered in combination with one or more of treatment selected from radiotherapy, chemotherapy, adoptive cell therapy (e.g. Chimeric Antigen Recaptor T cell; CAR-T, or tumor infiltrating lymphocytes; TILs), anticancer vaccine therapy, targeted biological therapies (e.g. tumor-specific antibodies) or immunomodulating therapy such as immune checkpoint inhibitors, bispecific T cell engagers, or nanobodies that may bind to a single or multiple drug targets.

According to one aspect, compounds of the invention can be administered in combination with an anticancer vaccine or at least one immune check point inhibitor such as at least one PD-<NUM>, PD-L1 or CTLA4 inhibitor or a combination thereof.

According to a further aspect, at least one immune check point inhibitor is selected from a PD-<NUM> inhibitor and a CTLA4 inhibitor.

According to a further aspect, compounds of the invention are to be administered in combination with an anticancer vaccine wherein the said anticancer vaccine elicits cancerspecific immunity and the compounds of the invention are to be administered before and/or after the anti-cancer vaccine administration.

According to a further aspect, compounds of the invention are to be administered in combination with a cellular therapy, such as in combination with Chimeric Antigen Receptor (CAR) T cells (CAR T cell therapy) or tumor infiltrating lymphocytes (TILs) (bulk TIL cellbased cell therapy) that have been expanded ex vivo. Chimeric Antigen Receptor (CAR) T cells are expanded ex vivo according to a standard method, said method comprising:.

TILs are expanded ex vivo according to a standard method, said method comprising:.

According to a further aspect, compounds of the invention are to be administered in combination with said expanded Chimeric Antigen Receptor (CAR) T cells or TILs by the same or different routes.

The invention encompasses a compound of the invention for administration to a subject prior to, simultaneously or sequentially with a therapeutic regimen or at least one co-agent. The compound according to the invention that is administered simultaneously with said at least one co-agent can be administered in the same or different compositions and in the same or different routes of administration.

In an embodiment, subjects according to the invention are suffering from a cancer.

In a further particular embodiment, subjects according to the invention are subjects suffering from a solid tumor cancer selected from, but not limited to, lung cancer (small cell and non-small cell), breast cancer, ovarian cancer, cervical cancer, uterus cancer, head and neck cancer, melanoma, cancers of the digestive system, hepatocellular carcinoma, colon cancer, rectal cancer, colorectal carcinoma, kidney cancer, prostate cancer, gastric cancer, bronchus cancer, pancreatic cancer, urinary bladder cancer and hepatic cancer.

In an embodiment, subjects according to the invention are subjects presenting tumors with elevated: adenosine signaling gene signatures, expression of pCREB, or A2AR as described above.

In a further particular embodiment, subjects according to the invention are subjects suffering from a solid tumor cancer are cancers from the digestive system, in particular pancreatic and colorectal cancer.

In a particular embodiment, the invention provides compounds and compositions useful in the treatment of a cancer, in particular in immunotherapy.

According to a further particular embodiment, compositions of the invention are useful for decreasing the development of tumors and/or to potentiate other cancer treatments including radiotherapy, chemotherapy, adoptive cell therapy (e.g. CAR-T), anti-cancer vaccine therapy, targeted biological therapies (e.g. tumor-specific antibodies) or immunomodulating therapy such as immune checkpoint inhibitors.

In a particular embodiment, the invention provides compounds and compositions which are useful for the treatment of a solid tumor cancer in the form of a combination wherein at least one compound of the invention is to be administered in combination with at least one anti-cancer immunotherapeutic agent.

According to another particular embodiment, compounds and compositions of the invention are useful in combination with a cellular therapy, in particular for improving a immunosuppressive tumor microenvironment, thereby enhancing infiltration of infused cellular therapies into the tumor. According to a further aspect, the combination increases the ability of T cells to kill cancer cells at the disease site.

The invention having been described, the following examples are presented by way of illustration, and not limitation.

The compounds according to Formula (I) can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimisation procedures.

The general synthetic approaches for obtaining compounds of Formula (I) are depicted in Schemes <NUM> to <NUM> below.

Scheme <NUM> represents the preparation of compounds of the invention in a single-step procedure by substitution of cyanopyridines of formula (i) by commercial or synthetic nucleophiles of formula (ii), wherein X, R and R' are as defined herein, in the presence of a base such as trimethylamine in an aprotic solvent such as THF. The synthesis of the cyanopyridines of formula (i) is well documented in the literature and can be prepared following two-step protocols described by <NPL>) or <NPL>) or one-pot protocol such as described by <NPL>).

Scheme <NUM> represents the cross-coupling of the intermediates of formula (iii) and (iv), wherein R<NUM>, R<NUM>, R<NUM> and R<NUM> are as defined above and R<NUM> and R<NUM> are selected from halogeno, boronic acid or boronic pinacol ester group, in presence of a mineral base (such as K<NUM>CO<NUM>) and a source of palladium in catalytic amount (such as palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(<NUM>)). This cross-coupling step can be performed under thermal conditions in apolar solvents like toluene, also called by thermal activation (such as described in <NPL>) or under microwaved irradiation in polar solvents (such as methanol and water ).

Scheme <NUM> presents a specific example of Scheme <NUM> for the synthesis of the intermediate of formula (iiib) by cross-coupling reaction between the bromoaryl of formula (iiia), wherein R<NUM>, R<NUM> and R<NUM> are as defined above, and commercial bis(pinacolato)diboron of formula (v) under thermal activation of microwave irradiation as described in Scheme <NUM>.

Scheme <NUM> illustrates the preparation of compounds (Ib) in a single-step procedure by cyclization of cyanopyridines from commercial or synthesized aldehydes of formula (vi) in the presence of cyclic amine of formula (vii), wherein R<NUM> and R<NUM> are as described above and R<NUM> and R<NUM> form together an optionally substituted heterocyclic alkyl as defined herein, two equivalents of malononitrile (viii), an eventual catalyst (such as <NUM>-(Dimethylamino)pyridine (<NUM>-DMAP)) and an oxidizing agent (such as air) in a polar protic solvent (such as methanol).

Scheme <NUM> illustrates the preparation of an intermediate compound of formula (iiic) in a two-step manner. First, the synthesis of the intermediate of formula (vi) can be achieved from the reaction of commercial bromobenzaldehyde of formula (ix) in the presence of one equivalent of malononitrile (viii), an eventual catalytic amount of a cyclic amine of formula (vii), wherein R<NUM> are as described above and R<NUM> and R<NUM> form together an optionally substituted heterocyclic alkyl as defined herein, and an oxidizing agent (such as air) in a polar protic solvent (such as methanol). The isolated intermediate (vi) can be further reacted in the presence of one equivalent of malononitrile (iii) and one equivalent of amine of formula (vii).

This two-step approach is more adapted to obtain gramme quantities.

Compounds (iiic), as described above, are a specific example of compound (iiia) and can therefore be used in the synthesis of compounds of the invention (I) following the procedure presented Scheme <NUM>.

The following abbreviations refer respectively to the definitions below:
CV (Column dead-volume); cyclo (cyclohexane); DCM (dichloromethane); DHP (<NUM>,<NUM>-dihydropyrane); DMF (dimethylformamide); eq. (Equivalents (mol%)); ESI (Electrospray ionization); HRMS (High-resolution mass spectrum); NMR (Nuclear Magnetic Resonance); PBS (phosphate-buffered saline); r. (room temperature); TFA (Trifluoroacetic acid); TLC (Thin layer chromatography); TOF (Time Of Flight); UPLC (Ultra-high performance liquid chromatography); UV (Ultraviolet).

Compounds of the invention were prepared according to Schemes <NUM> to <NUM> as follows.

General experimental: Unless otherwise noted, all products were obtained from commercial sources and used without further purification. Anhydrous solvents such as methanol, DMF or toluene were purchased over molecular sieve, closed by AcroSeal®.

All preparative columns were performed by flash chromatography on a Buchi Pure C-<NUM> Flash system with a UV detector. The corresponding PureFlash ID cartridges (<NUM>, <NUM>, <NUM>, <NUM> or <NUM>, amorphous silica, <NUM>-<NUM> mesh) were the purchased from Buchi and the flow rates were set according to the preset parameters (<NUM>, <NUM>, <NUM>, <NUM> & <NUM>/min respectively). Samples were loaded as solid deposit prepared with amorphous silica <NUM>-<NUM> mesh.

All described yields are isolated yields unless stated otherwise.

The <NUM>H NMR spectra were recorded on a Bruker <NUM> spectrometer equipped with a cryoprobe and are calibrated on the residual protiated solvent. The <NUM>C NMR spectra were recorded at <NUM> and the solvent resonance is used as internal standard. Both <NUM>H NMR and <NUM>C NMR chemical shifts are reported in parts per million downfield from tetramethylsilane. Low resolution mass spectra were recorded on an Advion PressionL, coupled to an ESI source, operating in positive and negative ion mode simultaneously. HRMS were recorded on a Xevo G2 TOF, coupled to an ESI source, operating either in positive or in negative acquisition mode.

In a small round-bottom flask equipped with a stirrer, an aldehyde of formula (vi) (<NUM> eq. ) and malononitrile (viii) (<NUM> eq. ) were solubilized in methanol (<NUM>) (solution A). The solution A was vigorously stirred right away. In case the aldehyde contains a basic site (e.g., pyridine), no catalyst is needed. Else, in a small vial, a solution of cyclic amine of formula (vii) (<NUM> eq. ) in MeOH (<NUM>) was prepared (solution B). A drop or two of the solution B was added to the solution A. After stirring <NUM> at r. , more malononitrile (viii) (<NUM> eq. ) was added followed by dropwise addition of the rest of solution B. The reaction was stirred at r. , open to air until completion; completion was assessed by TLC (cyclo:EtOAc <NUM>:<NUM>). The medium was diluted with DCM (<NUM> × VMeOH), silica was directly added on top of the mixture and the solvent was removed under reduced pressure. The crude was purified by flash chromatography (<NUM> cartridge for <NUM> to <NUM> mmol of starting aldehyde) with a cyclo:EtOAc gradient (<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>→<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>, <NUM> CV; methanol wash).

In a mortar or the bowl of a mechanical stirring device, an aldehyde of formula (ix) (<NUM> to <NUM> eq. ) and malononitrile (viii) (<NUM> eq. ) were solubilized in MeOH (<NUM> to <NUM>) (solution A). The solution A was vigorously stirred right away. In case the aldehyde contains a basic site (e.g., pyridine), no catalyst is needed. Else, in a small vial, a solution of cyclic amine of formula (vii) in MeOH (<NUM>) was prepared (solution B). While stirring, the solution B was added dropwise to the solution A, up to <NUM> mol% of the amine. In less than <NUM> to <NUM>, a thick white paste must form, stirring was kept for <NUM> to <NUM> before addition of cold water. The precipitate was filtered, rinsed twice with cold water then rinsed three times with a minimum of cold ether. The powder was dried under reduced pressure for <NUM> to <NUM>, yielding intermediate (vi), used without further purification.

In a round-bottom flask, the obtained intermediate of formula (vi) (<NUM> eq. ) was suspended in MeOH (about <NUM>). At <NUM>, the addition of the malononitrile (viii) (<NUM> eq. ) was consecutively followed by dropwise addition of the cyclic amine of formula (vii) (<NUM> eq. The flask was closed by a guard filled with CaCl<NUM> beads (to allow air exchange) and stirred for <NUM> at <NUM> then at r. until completion; completion was assessed by TLC (cyclo:EtOAc <NUM>:<NUM> or DCM:MeOH <NUM>:<NUM>). The crude product was purified by flash chromatography.

The used procedure was adpadted from Pan et al. , <NUM>, supra.

In a <NUM> round-bottom flask equipped with a magnetic stirrer, a commercial or synthetic bromoaryl (<NUM> eq. ), a boronic acid or boronic pinacol ester (<NUM> eq. ), potassium carbonate (<NUM> eq. ) and palladium(II) dichloride (<NUM> eq. ) were consecutively added to toluene (<NUM>). The mixture was stirred at <NUM> for <NUM>, open to air. Completion was assessed by TLC (cyclo:DCM <NUM>:<NUM>). Palladium and salts were removed by filtration on a celite pad, washed with DCM (<NUM> × <NUM>). Finally, the solvents were removed under reduced pressure and the crude product purified by flash chromatography with a cyclo:DCM gradient.

In a <NUM>-<NUM> microwave tube equipped with a magnetic stirrer a commercial or synthetic bromoaryl (<NUM> eq. ), a boronic acid or boronic pinacol ester (<NUM> to <NUM> eq. ) and potassium carbonate (<NUM> eq. ) were solubilized in a THF:H<NUM>O <NUM>:<NUM> mixture (<NUM>). The solution was bubbled with argon for <NUM> before addition of tetrakis(triphenylphosphine)palladium(<NUM>) (<NUM> eq. The tube was sealed and heated at <NUM> or <NUM> for <NUM> to <NUM> under microwave irradiation. The medium was diluted with water and the crude product was extracted by EtOAc × <NUM>. The organic phases were combined, washed with brine, dried over MgSO<NUM> and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (<NUM> cartridge for less than <NUM> mmol of starting bromoaryl) with a cyclo:MixA[toluene:acetone <NUM>:<NUM> mixture] gradient (<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>→<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>, <NUM> CV; methanol wash).

The intermediate was prepared following a two-step protocol described by <NPL>) starting from <NUM>-(trimethoxymethyl)-<NUM>,<NUM>'-biphenyl (<NUM>, <NUM> mmol, <NUM> eq. ) and was isolated as crude powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, (CD<NUM>)<NUM>SO) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, (CD<NUM>)<NUM>SO) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI-) calculated for C<NUM>H<NUM>N<NUM>Cl: [M-H+] m/z = <NUM>, found m/z = <NUM>.

The intermediate was prepared as described above by thermal activation starting from <NUM>-bromobenzaldehyde (<NUM>, <NUM> mmol, <NUM> eq. ) and p-tolylboronic acid (<NUM>, <NUM> eq. ) and was isolated as a translucent oil (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

The intermediate was prepared as described above by thermal activation starting from <NUM>-bromobenzaldehyde (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-fluorophenylboronic acid (<NUM>, <NUM> eq. ) and was isolated as a translucent oil (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (dtd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (dddd, J = <NUM>, <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>).

The intermediate was prepared as described above by thermal activation starting from <NUM>-bromobenzaldehyde (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-fluorophenylboronic acid (<NUM>, <NUM> eq. ) and was isolated as a translucent oil (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>).

The intermediate was prepared as described above by thermal activation starting from <NUM>-bromobenzaldehyde (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-fluorophenylboronic acid (<NUM>, <NUM> eq. ) and was isolated as a translucent oil (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (d, J = <NUM>).

The intermediate <NUM>-(tetrazol-<NUM>-yl)benzaldehyde can be prepared according to the literature (<NPL>). Then, in a dry <NUM> round bottom flask equipped with a magnetic stirrer and a condenser, DHP (<NUM>, <NUM> eq. ) was solubilized in dry toluene (<NUM>) and mixed with a solution of <NUM>-(tetrazol-<NUM>-yl)benzaldehyde (<NUM>, <NUM> mmol, <NUM> eq. ) in dry DMF (<NUM>). The TFA (<NUM>, <NUM> eq. ) was added dropwise. The flask was purged with argon and heated at <NUM> for <NUM>. The completion of the reaction was assessed by TLC (Rf = <NUM> in DCM:MeOH <NUM>:<NUM>) before being stopped by addition of Na<NUM>CO<NUM> <NUM>% in water (<NUM>) and water (<NUM>). The crude product was extracted by EtOAc (<NUM> × <NUM>) and the organic phases were combined, washed with brine (<NUM>), dried over MgSO<NUM> and the solvents were removed under reduced pressure. The purification was done by flash chromatography on a <NUM> silica cartridge with a cyclo:DCM gradient (<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>→<NUM>:<NUM>, <NUM> CV; methanol wash) and isolated as an oil (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>O<NUM>: [M+Cl-] m/z = <NUM>, found m/z = <NUM>.

In a <NUM> round bottom flask equipped with a stirrer and a condenser, DHP (<NUM>, <NUM> eq. ) was solubilized in anhydrous toluene (<NUM>). The flask was flushed with argon before slow addition of TFA (<NUM>, <NUM> eq. ) and pyrazole (<NUM>, <NUM> mmol, <NUM> eq. The solution was heated at <NUM> for <NUM>. Completion was assessed by TLC, revealed with basic KMnO<NUM> (Rf = <NUM> in cyclo:EtOAc <NUM>:<NUM>). The reaction was quenched with aq. NaOH <NUM> (<NUM>) and the crude intermediate was extracted by EtOAc (<NUM> × <NUM>). The organic phases were combined, washed with brine (<NUM>), dried over MgSO<NUM> and the solvents were removed under reduced pressure. The <NUM>-(tetrahydro-<NUM>H-pyran-<NUM>-yl)-<NUM>H-pyrazole intermediate (not drawn) was purified by flash chromatography on a <NUM> silica cartridge with a cyclo:EtOAc gradient (<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>→<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>, <NUM> CV; methanol wash) and isolated as a translucent oil (<NUM>, <NUM> mmol, <NUM>% isolated yield). The <NUM>-bromo-<NUM>-(tetrahydro-<NUM>H-pyran-<NUM>-yl)-<NUM>H-pyrazole intermediate (va) was prepared from the <NUM>-(tetrahydro-<NUM>H-pyran-<NUM>-yl)-<NUM>H-pyrazole intermediate (<NUM>, <NUM> mmol, <NUM> eq. ) following a literature protocol (<NPL>) and isolated as a light-yellow oil (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

In a <NUM> round-bottom flask equipped with a stirrer, <NUM>-bromobenzaldehyde (<NUM>, <NUM> mmol, <NUM> eq. ) and malononitrile (viii) (<NUM>, <NUM> eq. ) were solubilized in methanol (<NUM>) (solution A). The solution A was vigorously stirred right away. A solution of piperidine (<NUM>, <NUM> eq. ) in MeOH (<NUM>) was prepared (solution B) and added dropwise over <NUM> to the solution A. More malononitrile (viii) (<NUM>, <NUM> eq. ) solubilized in MeOH (<NUM>) was added and the reaction was stirred at r. , open to air until completion. Completion was assessed by TLC (Rf = <NUM> cyclo:EtOAc <NUM>:<NUM>). The medium was diluted with DCM (<NUM>), silica was directly added on top of the mixture and the solvent was removed under reduced pressure. The crude was purified by flash chromatography on a <NUM> cartridge with a cyclo:EtOAc gradient (<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>→<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>, <NUM> CV; methanol wash). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>NsBr: [M+H+] m/z = <NUM> & <NUM>, found m/z = <NUM> & <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>Br: [M+H+] m/z = <NUM>, found m/z = <NUM>.

In a small round-bottom flask equipped with a stirrer, <NUM>-bromo-<NUM>-fluorobenzaldehyde (<NUM>, <NUM> mmol, <NUM> eq. ) and malononitrile (viii) (<NUM>, <NUM> eq. ) were solubilized in methanol (<NUM>) (solution A). The solution A was vigorously stirred right away. A solution of piperidine (<NUM>, <NUM> eq. ) in MeOH (<NUM>) was prepared (solution B) and a few drops were added to the solution A. After stirring <NUM> at r. , the rest of solution B was slowly added. The reaction was stirred at r. , open to air until completion. The medium was diluted with water (<NUM>) and brine (<NUM>) and the crude product extracted by AcOEt (<NUM> × <NUM>). The organic phases were combined, dried with MgSO<NUM> and the solvent was removed under reduced pressure. The crude was purified by flash chromatography on a <NUM> silica cartridge with a cyclo:DCM gradient (<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>→<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>, <NUM> CV; methanol wash) and isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>FBr: [M+H+] m/z = <NUM> & <NUM>, found m/z = <NUM> & <NUM>.

In a small round-bottom flask equipped with a stirrer, <NUM>-bromo-<NUM>-fluorobenzaldehyde (<NUM>, <NUM> mmol, <NUM> eq. ) and malononitrile (viii) (<NUM>, <NUM> eq. ) were solubilized in methanol (<NUM>) (solution A). The solution A was vigorously stirred right away. A solution of piperidine (<NUM>, <NUM> eq. ) in MeOH (<NUM>) was prepared (solution B) and a few drops were added to the solution A. After stirring <NUM> at r. , the rest of solution B was slowly added. The reaction was stirred at r. , open to air until completion. The medium was diluted with water (<NUM>) and brine (<NUM>) and the crude product extracted by AcOEt (<NUM> × <NUM>). The organic phases were combined, dried with MgSO<NUM> and the solvent was removed under reduced pressure. The crude was purified by flash chromatography on a <NUM> silica cartridge with a cyclo:DCM gradient (<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>→<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>, <NUM> CV; methanol wash) and isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>FBr: [M+H+] m/z = <NUM> & <NUM>, found m/z = <NUM> & <NUM>.

In a small round-bottom flask equipped with a stirrer, <NUM>-chloro-<NUM>-fluorobenzaldehyde (<NUM>, <NUM> mmol, <NUM> eq. ) and malononitrile (viii) (<NUM>, <NUM> eq. ) were solubilized in methanol (<NUM>). The solution was vigorously stirred right away and cooled to <NUM>. Piperidine (<NUM>, <NUM> eq. ) in MeOH (<NUM>) was slowly added. The reaction was stirred at r. , open to air until completion. The medium was diluted with brine (<NUM>) and the crude product extracted by AcOEt (<NUM> × <NUM>). The organic phases were combined, dried with MgSO<NUM> and the solvent was removed under reduced pressure. The crude was purified by flash chromatography on a <NUM> silica cartridge with a cyclo:EtOAc isocratic gradient (<NUM>:<NUM>, <NUM> CV; methanol wash) and isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>FCl: [M+H+] m/z = <NUM>, found m/z = <NUM>.

In a <NUM> round-bottom flask purged with argon and equipped with a magnetic stirrer, <NUM>-amino-<NUM>-(<NUM>-bromophenyl)-<NUM>-(piperidin-<NUM>-yl)pyridine-<NUM>,<NUM>-dicarbonitrile (iiiaa) (<NUM>, <NUM> mmol, <NUM> eq. ) and bis(pinacolato)diboron (v) (<NUM>, <NUM> eq) were solubilized in degassed toluene (<NUM>). The potassium carbonate (<NUM>, <NUM> eq. ) and tetrakis(triphenylphosphine)palladium(<NUM>) (<NUM>, <NUM> eq. ) were added at the same time and the medium was heated at <NUM> for <NUM>. Completion was assessed by TLC (Rf = <NUM> in cyclo:DCM <NUM>:<NUM>). The palladium and salts were removed by filtration on a celite pad, washed with EtOAc (<NUM> × <NUM>) and the solvents were removed under reduced pressure. The product purified by flash chromatography on a <NUM> cartridge with a cyclo:DCM gradient (<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>→<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>, <NUM> CV; methanol wash) and isolated as an off-white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) C<NUM>H<NUM>N<NUM>O<NUM>B: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared following the general procedure under Scheme <NUM> starting from commercial [<NUM>,<NUM>'-biphenyl]-<NUM>-carbaldehyde (<NUM>, <NUM> mmol, <NUM> eq. ) (intermediate of formula (vi) wherein R<NUM> is phenyl and R<NUM> is a hydrogen) and azetidine (<NUM>, <NUM> eq. ) (cyclo amine of formula (vii)) and was isolated as an off-white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (tdd, J = <NUM>, <NUM>, <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared following the general procedure under Scheme <NUM> starting from commercial [<NUM>,<NUM>'-biphenyl]-<NUM>-carbaldehyde (intermediate of formula (vi) wherein R<NUM> is phenyl and R<NUM> is a hydrogen) (<NUM>, <NUM> mmol, <NUM> eq. ) and pyrrolidine (<NUM>, <NUM> eq. ) (cyclo amine or formula (vii)) and was isolated as an off-white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared following <NPL> starting from commercial [<NUM>,<NUM>'-biphenyl]-<NUM>-carbaldehyde (intermediate of formula (vi) wherein R<NUM> is phenyl and R<NUM> is a hydrogen) (<NUM>, <NUM> mmol, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (tt, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared following Sarkar et al. , <NUM>, supra starting from <NUM>'-fluoro-[<NUM>,<NUM>'-biphenyl]-<NUM>-carbaldehyde (intermediate of formula (vib)) (<NUM>, <NUM> mmol, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+Na+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared following Sarkar et al. , <NUM>, supra starting from <NUM>'-fluoro-[<NUM>,<NUM>'-biphenyl]-<NUM>-carbaldehyde (intermediate of formula (vic)) (<NUM>, <NUM> mmol, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (dq, J = <NUM>, <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+Na+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared following Sarkar et al. , <NUM>, supra starting from <NUM>'-fluoro-[<NUM>,<NUM>'-biphenyl]-<NUM>-carbaldehyde (intermediate of formula (vid)) (<NUM>, <NUM> mmol, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+Na+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared as described above by thermal activation starting from <NUM>-amino-<NUM>-(<NUM>-bromophenyl)-<NUM>-(piperidin-<NUM>-yl)pyridine-<NUM>,<NUM>-dicarbonitrile (intermediate of formula (iiiaa)) (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-methylphenylboronic acid (intermediate of formula (iv) wherein R<NUM> is <NUM>-methylphenyl and R<NUM> is boronic acid) (<NUM>, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (t, J = <NUM>, <NUM>), <NUM> (ddt, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+Na+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared as described above by thermal activation starting from <NUM>-amino-<NUM>-(<NUM>-bromophenyl)-<NUM>-(piperidin-<NUM>-yl)pyridine-<NUM>,<NUM>-dicarbonitrile (intermediate of formula (iiiaa)) (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-methylphenylboronic acid (intermediate of formula (iv) wherein R<NUM> is <NUM>-methylphenyl and R<NUM> is boronic acid) (<NUM>, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+Na+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared following Sarkar et al. , <NUM>, supra starting from <NUM>'-methyl-[<NUM>,<NUM>'-biphenyl]-<NUM>-carbaldehyde (intermediate of formula (via)) (<NUM>, <NUM> mmol, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+Na+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared as described above using microwave-assisted Suzuki cross-coupling at <NUM> for <NUM>, starting from (<NUM>-(<NUM>-amino-<NUM>,<NUM>-dicyano-<NUM>-(piperidin-<NUM>-yl)pyridin-<NUM>-yl)phenyl)boronic acid pinacol ester (intermediate of formula (iiiba)) (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-bromopyridine (intermediate of formula (iv) wherein R<NUM> is <NUM>-pyridinyl and R<NUM> is bromo) (<NUM>, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C23H20N6: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared as described above using microwave-assisted Suzuki cross-coupling at <NUM> for <NUM>, starting from <NUM>-amino-<NUM>-(<NUM>-bromophenyl)-<NUM>-(piperidin-<NUM>-yl)pyridine-<NUM>,<NUM>-dicarbonitrile (intermediate of formula (iiiaa)) (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-pyridineboronic acid (intermediate of formula (iv) wherein R<NUM> is <NUM>-pyridinyl and R<NUM> is boronic acid) (<NUM>, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, quantitative isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared as described above using microwave-assisted Suzuki cross-coupling at <NUM> for <NUM>, starting from <NUM>-amino-<NUM>-(<NUM>-bromophenyl)-<NUM>-(piperidin-<NUM>-yl)pyridine-<NUM>,<NUM>-dicarbonitrile (intermediate of formula (iiiaa)) (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-pyridineboronic acid (intermediate of formula (iv) wherein R<NUM> is <NUM>-pyridinyl and R<NUM> is boronic acid) (<NUM>, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared as described above using microwave-assisted Suzuki cross-coupling at <NUM> for <NUM>, starting from <NUM>-amino-<NUM>-(<NUM>-bromophenyl)-<NUM>-(piperidin-<NUM>-yl)pyridine-<NUM>,<NUM>-dicarbonitrile (intermediate of formula (iiiaa)) (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-thiopheneboronic acid (intermediate of formula (iv) wherein R<NUM> is <NUM>-thiophenyl and R<NUM> is boronic acid) (<NUM>, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, quantitative isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>S: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>S: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared as described above using microwave-assisted Suzuki cross-coupling at <NUM> for <NUM>, starting from <NUM>-amino-<NUM>-(<NUM>-bromophenyl)-<NUM>-(piperidin-<NUM>-yl)pyridine-<NUM>,<NUM>-dicarbonitrile (intermediate of formula (iiiaa)) (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-thiopheneboronic acid (intermediate of formula (iv) wherein R<NUM> is <NUM>-thiophenyl and R<NUM> is boronic acid) (<NUM>, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>S: [M+Na+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>S: [M+H+] m/z = <NUM>, found m/z = <NUM>.

A Suzuki cross-coupling step was performed using microwave-assisted Suzuki cross-coupling starting from (<NUM>-(<NUM>-amino-<NUM>,<NUM>-dicyano-<NUM>-(piperidin-<NUM>-yl)pyridin-<NUM>-yl)phenyl)boronic acid pinacol ester (intermediate of formula (iiiba)) (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-bromo-<NUM>-(tetrahydro-<NUM>H-pyran-<NUM>-yl)-<NUM>H-pyrazole (intermediate of formula (iva)) (<NUM>, <NUM> eq. The deprotection of the pyrazole was done in a dry <NUM> round-bottom flask flushed with argon. The intermediate (<NUM> eq. ) was solubilized in a <NUM>:<NUM> DCM:MeOH mix (<NUM>). TsOH (<NUM>, <NUM> eq. ) was added and the solution was stirred at r. Completion was assessed by TLC (Rf = <NUM> in MixA). Two purifications were performed by flash chromatography on a pre-packed <NUM> silica cartridge with a MixA<NUM>:MeOH isocratic gradient (<NUM>:<NUM>, <NUM> CV) then a cyclo:DCM gradient (<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>→<NUM>:<NUM>, <NUM> CV; methanol wash) (<NUM>, <NUM> mmol, <NUM>% global isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared following the general procedure under Scheme <NUM> starting from <NUM>-(<NUM>-(tetrahydro-<NUM>H-pyran-<NUM>-yl)-<NUM>H-tetrazol-<NUM>-yl)benzaldehyde (intermediate of formula (vie)) (<NUM>, <NUM> mmol, <NUM> eq. ) and purified by flash chromatography on a pre-packed <NUM> silica cartridge with a cyclo:DCM gradient (<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>→<NUM>:<NUM>, <NUM> CV; methanol wash). The deprotection of the tetrazole was performed in the presence of Dowex 50WX8 H+ (<NUM> of resin for <NUM> of compound), in a <NUM>:<NUM> EtOH:H<NUM>O mix (<NUM>) at <NUM> for <NUM>. The resin was filtered off and rinsed with warm EtOH (<NUM> × <NUM>) and the product was isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% global isolated yield). <NUM>H NMR (<NUM>, (CD<NUM>)<NUM>SO) δ <NUM> (s, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS (ESI-) calculated for C<NUM>H<NUM>N<NUM>: [M-H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI-) calculated for C<NUM>H<NUM>N<NUM>: [M-H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared following the general procedure under Scheme <NUM> starting from <NUM>-([<NUM>,<NUM>'-biphenyl]-<NUM>-yl)-<NUM>-amino-<NUM>-chloropyridine-<NUM>,<NUM>-dicarbonitrile (<NUM>, <NUM> mmol) (intermediate of formula (i) wherein R<NUM> is phenyl, R<NUM> is a hydrogen and R<NUM> is a cyano) and diethylamine (<NUM>, <NUM> eq. ) (nucleophile of formula (ii)) and was isolated as a white amorphous powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared following the general procedure under Scheme <NUM> starting from <NUM>-([<NUM>,<NUM>'-biphenyl]-<NUM>-yl)-<NUM>-amino-<NUM>-chloropyridine-<NUM>,<NUM>-dicarbonitrile (<NUM>, <NUM> mmol) (intermediate of formula (i) wherein R<NUM> is phenyl, R<NUM> is a hydrogen and R<NUM> is a cyano) and morpholine (<NUM>, <NUM> eq. ) (nucleophile of formula (ii)) and was isolated as a white amorphous powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM> Hz, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>O: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>O: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared following the general procedure under Scheme <NUM> starting from <NUM>-([<NUM>,<NUM>'-biphenyl]-<NUM>-yl)-<NUM>-amino-<NUM>-chloropyridine-<NUM>,<NUM>-dicarbonitrile (<NUM>, <NUM> mmol) (intermediate of formula (i) wherein R<NUM> is phenyl, R<NUM> is a hydrogen and R<NUM> is a cyano) and N-methylpiperazine (<NUM>, <NUM> eq. ) (nucleophile of formula (ii)) and was isolated as a white amorphous powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CD<NUM>OD) δ <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>). <NUM>C NMR (<NUM>, CD<NUM>OD) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared following the general procedure under Scheme <NUM> starting from <NUM>-([<NUM>,<NUM>'-biphenyl]-<NUM>-yl)-<NUM>-amino-<NUM>-chloropyridine-<NUM>,<NUM>-dicarbonitrile (<NUM>, <NUM> mmol) (intermediate of formula (i) wherein R<NUM> is phenyl, R<NUM> is a hydrogen and R<NUM> is a cyano), benzylmercaptan (<NUM>, <NUM> eq. ) (nucleophile of formula (ii)) and triethylamine (<NUM>, <NUM> eq. ) and was isolated as a white amorphous powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI-) calculated for C<NUM>H<NUM>N<NUM>S: [M-H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>S: [M+Na+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared following the general procedure under Scheme <NUM> starting from <NUM>-([<NUM>,<NUM>'-biphenyl]-<NUM>-yl)-<NUM>-amino-<NUM>-chloropyridine-<NUM>,<NUM>-dicarbonitrile (<NUM>, <NUM> mmol) (intermediate of formula (i) wherein R<NUM> is phenyl, R<NUM> is a hydrogen and R<NUM> is a cyano), methanol (<NUM>) (nucleophile of formula (ii)) and lithium diisopropylamine <NUM> in THF (<NUM>, <NUM> eq. ) was isolated as a white amorphous powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, (CD<NUM>)<NUM>SO) δ <NUM> (broad s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>). <NUM>C NMR (<NUM>, (CD<NUM>)<NUM>SO) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>O: [M+Na+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared following the general procedure under Scheme <NUM> starting from <NUM>-([<NUM>,<NUM>'-biphenyl]-<NUM>-yl)-<NUM>-amino-<NUM>-chloropyridine-<NUM>,<NUM>-dicarbonitrile (<NUM>, <NUM> mmol) (intermediate of formula (i) wherein R<NUM> is phenyl, R<NUM> is a hydrogen and R<NUM> is a cyano), ethanol (<NUM>) (nucleophile of formula (ii)) and lithium diisopropylamine <NUM> in THF (<NUM>, <NUM> eq. ) was isolated as a white amorphous powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, (CD<NUM>)<NUM>SO) δ <NUM> (broad s, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>). <NUM>C NMR (<NUM>, (CD<NUM>)<NUM>SO) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>O: [M+Na+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared following the general procedure under Scheme <NUM> starting from <NUM>-([<NUM>,<NUM>'-biphenyl]-<NUM>-yl)-<NUM>-amino-<NUM>-chloropyridine-<NUM>,<NUM>-dicarbonitrile (<NUM>, <NUM> mmol) (intermediate of formula (i) wherein R<NUM> is phenyl, R<NUM> is a hydrogen and R<NUM> is a cyano), methanol (<NUM>) (nucleophile of formula (ii)) and lithium diisopropylamine <NUM> in THF (<NUM>, <NUM> eq. ) was isolated as a white amorphous powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, (CD<NUM>)<NUM>SO) δ <NUM> (broad s, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>). <NUM>C NMR (<NUM> MHz, (CD<NUM>)<NUM>SO) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>O<NUM>: [M+Na+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared as described above using microwave-assisted Suzuki cross-coupling at <NUM> for <NUM>, starting from (<NUM>-(<NUM>-amino-<NUM>,<NUM>-dicyano-<NUM>-(piperidin-<NUM>-yl)pyridin-<NUM>-yl)phenyl)boronic acid pinacol ester (intermediate of formula (iiiba)) (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-bromo-<NUM>-fluoropyridine (intermediate of formula (iv) wherein R<NUM> is <NUM>-fluoro-<NUM>-pyridinyl and R<NUM> is bromo) (<NUM>, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (p, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared as described above using microwave-assisted Suzuki cross-coupling at <NUM> for <NUM>, starting from (<NUM>-(<NUM>-amino-<NUM>,<NUM>-dicyano-<NUM>-(piperidin-<NUM>-yl)pyridin-<NUM>-yl)phenyl)boronic acid pinacol ester (intermediate of formula (iiiba)) (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-bromo-<NUM>-fluoropyridine (intermediate of formula (iv) wherein R<NUM> is <NUM>-fluoro-<NUM>-pyridinyl and R<NUM> is bromo) (<NUM>, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM><NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared as described above using microwave-assisted Suzuki cross-coupling at <NUM> for <NUM>, starting from (<NUM>-(<NUM>-amino-<NUM>,<NUM>-dicyano-<NUM>-(piperidin-<NUM>-yl)pyridin-<NUM>-yl)phenyl)boronic acid pinacol ester (intermediate of formula (iiiba)) (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-bromo-<NUM>-fluoropyridine (intermediate of formula (iv) wherein R<NUM> is <NUM>-fluoro-<NUM>-pyridinyl and R<NUM> is bromo) (<NUM>, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared as described above using microwave-assisted Suzuki cross-coupling at <NUM> for <NUM>, starting from (<NUM>-(<NUM>-amino-<NUM>,<NUM>-dicyano-<NUM>-(piperidin-<NUM>-yl)pyridin-<NUM>-yl)phenyl)boronic acid pinacol ester (intermediate of formula (iiiba)) (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-bromo-<NUM>-fluoropyridine (intermediate of formula (iv) wherein R<NUM> is <NUM>-fluoro-<NUM>-pyridinyl and R<NUM> is bromo) (<NUM>, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (ddt, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared as described above using microwave-assisted Suzuki cross-coupling at <NUM> for <NUM>, starting from <NUM>-amino-<NUM>-(<NUM>-bromophenyl)-<NUM>-(piperidin-<NUM>-yl)pyridine-<NUM>,<NUM>-dicarbonitrile (intermediate of formula (iiiaa)) (<NUM>, <NUM> mmol, <NUM> eq. ) and and <NUM>-fluoro-<NUM>-pyridineboronic acid (intermediate of formula (iv) wherein R<NUM> is <NUM>-fluoro-<NUM>-pyridinyl and R<NUM> is boronic acid) (<NUM>, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, (CD<NUM>)<NUM>SO) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (dq, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, (CD<NUM>)<NUM>SO) δ <NUM>, <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared as described above using microwave-assisted Suzuki cross-coupling at <NUM> for <NUM>, starting from <NUM>-amino-<NUM>-(<NUM>-bromo-<NUM>-fluorophenyl)-<NUM>-(piperidin-<NUM>-yl)pyridine-<NUM>,<NUM>-dicarbonitrile (intermediate of formula (iiiab)) (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-pyridineboronic acid (intermediate of formula (iv) wherein R<NUM> is <NUM>-pyridinyl and R<NUM> is boronic acid) (<NUM>, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J= <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM> (d, J= <NUM>), <NUM> (d, J= <NUM>), <NUM>, <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared as described above using microwave-assisted Suzuki cross-coupling at <NUM> for <NUM>, starting from <NUM>-amino-<NUM>-(<NUM>-bromo-<NUM>-fluorophenyl)-<NUM>-(piperidin-<NUM>-yl)pyridine-<NUM>,<NUM>-dicarbonitrile (intermediate of formula (iiiac)) (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-pyridineboronic acid (intermediate of formula (iv) wherein R<NUM> is <NUM>-pyridinyl and R<NUM> is boronic acid) (<NUM>, <NUM> eq. ) and was isolated as a paste (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The product was prepared as described above using microwave-assisted Suzuki cross-coupling at <NUM> for <NUM>, starting from <NUM>-amino-<NUM>-(<NUM>-chloro-<NUM>-fluorophenyl)-<NUM>-(piperidin-<NUM>-yl)pyridine-<NUM>,<NUM>-dicarbonitrile (intermediate of formula (iiiad)) (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-pyridineboronic acid (intermediate of formula (iv) wherein R<NUM> is <NUM>-pyridinyl and R<NUM> is boronic acid) (<NUM>, <NUM> eq. ) and was isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>F: [M+H+] m/z = <NUM>, found m/z = <NUM>.

In a <NUM> round-bottom flask equipped with a magnetic stirrer and a condenser, methyl <NUM>-(<NUM>-amino-<NUM>,<NUM>-dicyano-<NUM>-(piperidin-<NUM>-yl)pyridin-<NUM>-yl)benzoate (<NUM>, <NUM> mmol, <NUM> eq. ) was suspended in anhydrous methanol (<NUM>). Hydrazine monohydrate (<NUM>, <NUM> eq. ) was added to the solution then the vessel was purged with argon and sealed. The reaction was heated at <NUM> for <NUM>. Solvents were removed under reduced pressure and the crude product was rinsed with DCM:MeOH <NUM>:<NUM> (<NUM>) and dried under reduced pressure. In a <NUM> round-bottom flask equipped with a magnetic stirrer and a condenser, the intermediate was suspended in an excess of triethyl orthoformate (<NUM>). The vessel was flushed with argon and heated at <NUM> for <NUM>. The reaction was quenched by addition of water (<NUM>) and the crude product was extracted by EtOAc (<NUM> × <NUM>). The organic phases were combined, washed with brine, dried over MgSO<NUM> and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on a silica cartridge on <NUM> silica cartridge, solid deposit, with a cyclo:EtOAc gradient (<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>→<NUM>:<NUM>, <NUM> CV; <NUM>:<NUM>, <NUM> CV) and isolated as a white powder (<NUM>, <NUM> mmol, <NUM>% overall isolated yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. MS (ESI+) calculated for C<NUM>H<NUM>N<NUM>O: [M+H+] m/z = <NUM>, found m/z = <NUM>. HRMS (ESI+) calculated for C<NUM>H<NUM>N<NUM>O: [M+H+] m/z = <NUM>, found m/z = <NUM>.

The potency of the compounds of the invention was tested using adenosine receptor-expressing cells as described below.

Chinese Hamster Ovary (CHO) cells containing an in-house cAMP-based biosensor, described below, and expressing recombinant A2AR were used to characterize the potency of A2AR antagonists according to the invention. The biosensor contains a cAMP binding domain allowing the measurement of Gs and Gi-coupled receptors activation. Cells were treated in a <NUM> well plate with the indicated concentrations of A2AR antagonists, followed by the addition of an A2AR agonist, adenosine. cAMP levels were measured on a luminescent/fluorescent plate reader.

CHO cells expressing A2AR and the biosensor were seeded in a black <NUM>-well plate (Nunc) and grown at <NUM> and <NUM>% CO<NUM> overnight. They were pre-incubated for <NUM> minutes with compounds of the present invention at varied concentrations up to <NUM>, before adding the corresponding EC<NUM> of A2AR agonist, <NUM> of adenosine (Sigma). The cAMP biosensor allowed real-time monitoring of signals using an FDSS/µCELL (Hamamatsu). The assay was conducted in 1X Hanks Balanced Salt Solution (HBSS). The total volume of the reaction was <NUM>µl (<NUM>µl of cells, <NUM>µl of antagonist and <NUM>µl of agonist). Data analysis was performed using GraphPad Prism.

Compounds of the invention were capable of antagonizing the production of cAMP in cell lines that overexpress A2AR, in the absence of other adenosine receptors, as reported in Table <NUM> below where the activity represents the ability of the compound to antagonize the production of cAMP in response to stimulation of A2AR-expressing CHO cells with the A2AR agonist adenosine, as described in the above cAMP assay methods. Therefore, the compounds can be classified as A2AR antagonists.

'Shift assay' using an A2AR-transfected cell line is used to demonstrate the allosteric molecular mode of A2AR inhibition mediated by compounds of the present invention. Those assays use CHO cells containing a BRET-based biosensor and expressing recombinant A2AR, a 'shift assay' was performed in a <NUM>-well plate, with the addition of the indicated concentrations of A2AR antagonists, followed by the addition of a concentration-response curve (CRC) of an A2AR agonist, adenosine. cAMP levels were measured on a luminescent/fluorescent plate reader. Briefly, CHO cells expressing A2AR and the biosensor were seeded in a black <NUM>-well plate and grown at <NUM> and <NUM>% CO<NUM> overnight. They were pre-incubated for <NUM> minutes with compounds of the present invention at various concentrations up to <NUM>, before adding adenosine at increasing concentrations up to <NUM> (CRC). The cAMP biosensor readings and assay volumes were as described in the previous section. Data analysis was performed using GraphPad Prism. A Schild regression plot was calculated for the compounds by using the shift assay data. The Log(DoseRatio-<NUM>) was plot on the y axis against the Log of the antagonist concentration on the x axis.

Negative allosteric modulation of A2AR can be identified using the 'shift assay'. The results are presented under <FIG> where it can be observed that the concentration-response curves (CRCs) of adenosine begin to overlap one another other as the compound concentration is increased (small open circles to larger open circles). Transformation of this data into a Schild regression plot (<FIG>), confirms this classification of compounds of the invention as NAMs because allosteric modulators cause a plateau of the dose-ratios (DR), observed at the top right of the Schild plot. In contrast, orthosteric compounds are characterized by a completely linear DR profile in a Schild regression plot (<NPL>).

Human peripheral blood mononuclear cells (PBMCs) were isolated using density centrifugation from fresh whole blood of healthy human blood donors. Cells were cryopreserved and thawed and rested for several hours in complete cell culture media containing human albumin and antibiotics (penicillin and streptomycin; <NUM> units or mg per ml respectively). Cells were incubated in <NUM>-well microplates with the indicated concentration of A2AR antagonists of the invention, followed by the addition of <NUM> of adenosine-<NUM>'-N-Ethyluronamide (NECA) - an adenosine analog that is a potent A2AR agonist https://doi. org/<NUM>/journal. DMSO was used as the storage diluent for concentrated A2AR antagonists. NECA and DMSO controls (%v/v) were also tested in parallel to the therapeutic candidates. After the indicated incubation time with NECA, cells were either stained to determine their intracellular level of pCREB, or activated with Dynabeads overnight before staining for intracellular cytokines, as described below.

The ability of compounds of the invention to restore normal pCREB levels in human-derived immune cells was tested as follows.

PBMCs that were cultured with A2AR antagonists in the presence of NECA and were subsequently fixed and permeabilized using ice cold paraformaldehyde and methanol-based kit reagents (ThermoFisher and Miltenyi, respectively). Cells were washed with FACS buffer and stained with fluorochrome-conjugated antibodies directed against the following antigens: pCREB (phosphorylated at serine <NUM>), CD4, CD8 - all sourced from Life Technologies, and CD3 (BD Biosciences). Stained cells were acquired using a Fortessa flow cytometer (BD). Gating of the desired cell subsets was performed using FSC-A vs FSC-H to remove doublet cells, FSC vs SSC parameters to identify cells with lymphocyte-like morphology, followed by CD3+ T cell and CD4+ or CD8+ sub-gating. The fold change in mean fluorescence intensity (MFI) of intracellular pCREB in gated CD4 or CD8+ T cells was calculated using NECA-only conditions, and divided by NECA and A2AR antagonist-cultured cells from the same donor. The overall activity of the tested compounds was calculated using the average of at least <NUM> donors.

Compounds of the invention were tested in physiological conditions using healthy human peripheral blood mononuclear cells as well as in the presence of human albumin to increase the physiological relevance of the assay. The compounds of the invention were also compared to control molecules which have been reported previously to antagonize A2AR (orthosteric antagonists) and have been tested in human Phase I or II clinical trials. These include CPI-<NUM>, <NUM>-(<NUM>-methylfuran-<NUM>-yl)-<NUM>-[[<NUM>-[[(<NUM>S)-oxolan-<NUM>-yl]oxymethyl]pyridin-<NUM>-yl]methyl]triazolo[<NUM>,<NUM>-d]pyrimidin-<NUM>-amine (Ciforadenant), PBF-<NUM>, <NUM>-bromo-<NUM>,<NUM>-di(pyrazol-<NUM>-yl)pyrimidin-<NUM>-amine (Taminadenant), MK-<NUM>, <NUM>-(furan-<NUM>-yl)-<NUM>-[<NUM>-[<NUM>-[<NUM>-(<NUM>-methoxyethoxy)phenyl]piperazin-<NUM>-yl]ethyl]-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-hexazatricyclo[<NUM>. <NUM><NUM>,<NUM>]dodeca-<NUM>(<NUM>),<NUM>,<NUM>,<NUM>,<NUM>-pentaen-<NUM>-amine (Preladenant) AZD4635, <NUM>-(<NUM>-chloro-<NUM>-methylpyridin-<NUM>-yl)-<NUM>-(<NUM>-fluorophenyl)-<NUM>,<NUM>,<NUM>-triazin-<NUM>-amine (Imaradenant), and AB928, <NUM>-[<NUM>-Amino-<NUM>-[<NUM>-[[<NUM>-(<NUM>-hydroxypropan-<NUM>-yl)pyridin-<NUM>-yl]methyl]triazol-<NUM>-yl]pyrimidin-<NUM>-yl]-<NUM>-methylbenzonitrile (Etrumadenant), and two other known orthosteric compounds. Table <NUM> below represents the ability of the compounds to restore pCREB to normal physiological levels (immuno-competency) in gated human CD4+ cells and Table <NUM> represents the ability of compounds to restore pCREB to normal physiological levels (immuno-competency) in gated human CD8+ cells as as described above. The activity scale represented is the average for at least <NUM> donors, compared to the NECA-only control.

The activity scale denotes the restoration of a normal anti-tumor response which is assessed by the measure of pCREB level in CD4+ and CD8+ T cells. The minimun of the anti-tumor response is measured in immunocompromised conditions (NECA immunosupression, without A2AR antagonist) and the normal response in immunocompetent conditions (without NECA and A2AR antagonists). '-' denotes no reduction, '+' denotes <NUM> to <NUM>% reduction, '++' denotes <NUM> to <NUM>% reduction, '+++' denotes <NUM> to <NUM>% reduction, and '++++' denotes over <NUM>% reduction. Reduction of pCREB corresponds to restoration of a normal anti-tumor immune response.

As it can be seen on Table <NUM> and <NUM>, compounds of the invention were able to restore the normal physiological levels of pCREB in both CD4 and CD8+ T cells in conditions mimicking high adenosine concentrations. pCREB is a signaling element which is proximal (downstream) to cAMP upon A2AR signaling, and represents a surrogate marker for immunosuppression.

The ability of compounds of the invention to restore anti-tumor cytokine responses in human-derived immune cells was tested as described below.

Additionally, PBMCs that were cultured with A2AR antagonists and NECA were stimulated overnight with <NUM>µl of anti-CD3 and anti-CD28 Dynabeads (Life Technologies) in order to activate T cells, in the presence of GolgiStop (Life Technologies) to prevent secretion of any newly-induced cytokines. Cells were then stained with: a fixable live-dead stain (LD Blue, Life Technologies), the T cell-specific Abs described for the pCREB stain, followed by fixation and permeabilization with commercial kit containing paraformaldehyde and a detergent-based buffer (ThermoFisher). Intracellular staining for cytokines was performed using fluorochrome-conjugated antibodies directed against tumor necrosis factor alpha (TNF-α), interleukin <NUM> (IL-<NUM>), and interferon gamma (IFN-γ) diluted in permeabilization buffer (ThermoFisher). Cells were then washed, acquired, and gated as described for the pCREB assay with the following modifications: dead cells were excluded using the live-dead marker, and gated T cell subsets were then analyzed for the percentage of cytokine positive cells, which was a sub-gate of total CD4+ or CD8+ T cells. The percentage of cytokine positive cells in Dynabead-only control samples was used as the <NUM> % normal (immuno-competent) immune response standard within each donor, whereas the Dynabead plus NECA stimulation condition represents an immunosuppressed control. Restoration of the cytokine response in the presence of A2AR antagonists was calculated as follows, using the average of at least <NUM> donors: <NUM> x (<NUM> - (<NUM> - % cytokine positive cells in presence of A2AR antagonist) / (<NUM> - % cytokine positive cells in immuno-competent control)).

Compounds were tested in a translational assay involving activation of healthy donor human T cells in vitro, in the presence of an immunosuppressive concentration of the A2AR agonist NECA - as described above. The ability of compounds to restore normal cytokine production in activated human blood CD4+ T cells and normal cytokine production in activated human blood CD8+ T cells is represented in Tables <NUM> and <NUM>, respectively. Clinical stage antagonist compounds are described in Table <NUM>.

Claim 1:
A compound according to Formula (I)
<CHM>
wherein R<NUM> is selected from aryl optionally substituted by one or more halogen (e.g. fluoro), cyano, hydroxy or C<NUM>-C<NUM> alkyl and heteroaryl optionally substituted by one or more halogen, cyano, hydroxy or C<NUM>-C<NUM> alkyl; R<NUM> is selected from H and halogen; R<NUM> is selected from H, CN and optionally substituted C<NUM>-C<NUM> alkyl; R<NUM> is selected from a group XR(R'), an optionally substituted aryl and optionally substituted heteroaryl wherein X is selected from O, S, N and R and R' are independently an optionally substituted C<NUM>-C<NUM> alkyl, or XRR' form together an optionally substituted heterocyclic alkyl; as well as pharmaceutically acceptable salts thereof for use in the treatment of a cancer, in particular in immunotherapy.