Indazole derivatives for the treatment of cancer

Abstract

The present invention relates to a compound having the following formula (I): (I) or one of its pharmaceutically acceptable salts, said compound being capable of being used in particular for the treatment of a pathology due to a dysregulation of MKlp2 or a pathology in which the MKlp2 pathway is dysregulated, preferably for the treatment of cancer, bacterial infections or viral infections

Description

DESCRIPTION Title: INDAZOLE DERIVATIVES FOR CANCER TREATMENT Technical field of the invention

[0001] The present invention relates to indazole derivatives, their use as a medicinal product, and in particular, their use for the treatment of cancer, bacterial infections or viral infections. State of the art

[0002] Cancer is one of the leading causes of death in industrialized countries. Various treatments have been developed, such as chemotherapy, radiation therapy, and hormone therapy. Anticancer drugs used in chemotherapy include antimitotic agents, alkylating agents, DNA intercalating agents, topoisomerase I and II inhibitors, and RNA / DNA antimetabolites. However, no treatment is 100% effective for these diseases. Resistance to these treatments, as well as side effects such as peripheral neuropathy, are associated with the use of currently administered drugs. Patients who develop resistance to a particular anticancer drug have tumors that no longer respond to the medication and may continue to grow despite ongoing treatment.

[0003] It is necessary to improve cancer treatment methods. The search for new therapeutic targets for cancer treatment is a priority. The development of new compounds with no or fewer side effects would significantly improve the treatment of these diseases.

[0004] The kinesin MKLP2 plays a crucial role in cytokinesis and is implicated in the development and progression of many human cancers (pancreas, breast, bladder, small cell lung, hepatocellular carcinogenesis, melanoma; numerous references including Groth-Pedersen, L. et al., PLoS One, 2012, 7, e45381). This kinesin is also overexpressed in resistant tumor cells (after radiotherapy or chemotherapy) (Bumstein, KL, Oncogene, 2022, 41, 2824). Its depletion by siRNA decreases the resistance of cancer cells (Taniuchi, K. et al., Cancer Research, 2005, 65, 105). MKLP2 is involved in microtubule organization (Houdusse, A. et al., Biophysical Journal, 2020,120, 289a), chromosome aggregation (Summers, MKJ, Cell. Sci., 2022, 135 (12)) and secretion at the Golgi apparatus (Miserey-Lenkei, S. et al., Nat. Commun., 2017, 8, 1254).High levels of KIF20A expression are correlated with a poor prognosis in cancer patients. MKLP2 is now considered a biomarker for several cancer cells and a new validated target for cancer chemotherapy.

[0005] Currently, only indoles have been described as inhibitors of this protein, notably in patent applications: WO2010 / 150211, WO2014 / 086964 and WO2024 / 121072. Description of the invention

[0006] The aim of the present invention is therefore to provide new effective inhibitors of MKIP2.

[0007] Another objective of the present invention is to provide effective MKIp2 inhibitors to treat pathologies related to MKIp2 dysregulation, and in particular to treat cancer, bacterial infections or viral infections.

[0008] The inhibitors according to the present invention also exhibit higher solubility than the aforementioned indoles.

[0009] The present invention relates first to a compound of formula (I): (I) in which: ° R 1 is chosen from: • a halogen, an (Ci-C6)alkoxy group, -NH2, -CH2-NH-C(=NH)-NH3 + ; TFA', -N3, -SCN, -O-SO2F, a (Ci-Ce)alkyl group substituted by at least one hydroxyl group, a halo(Ci-C6)alkyl group, -CH2-NH-SO2CH3, or -CH2-NH-SO2NH2, • -(CH2)j-NH2, -(CH2)j-NHBoc, where j is an integer from 1 to 5, • -O-SO3X 1 X 1 being chosen from among the alkali metals, • -X 2 -CH2-CH2-SO2F in which X 2 is NH or O, • -NH-C(=O)-OR 4 , R 4 being a (Ci-Ce)alkyl group, • -(CH2)i-NH-C(=O)-OR 5 , R 5being a (Ci-Ce)alkyl group and i being an integer from 1 to 5, • -NH-C(=O)-R 6 , R 6 being a (Ce-Cio)aryl group, said (Ce-Cio)aryl group being optionally substituted by one or more substituent(s) chosen from the group consisting of: halogen, -OH, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(Ci-C6)alkyl, -CN, -NO2, -C(=O)-(Ci-C6)alkyl, halo(Ci-C6)alkoxy, -NH2, and (Ci-C6)alkylamino; ° R 2 is chosen from • -H, -S(=O)2-R 7 , -C(=O)-OR 7 , -C(=O)-O-CH2-R 7 , R 7 being a (C1-Ce)alkyl group, -C(=O)-CH2-O-(CH2-CH2-O)m-CH3, m being between 0 and 10, -P(=O)-(OBn)2, -P(=O)-(OH)2, -P(=O)-(OH)(O-; Na + ),-P(=O)-(OH)(O-; K + ), -P(=O)-(O-; Na + )2, P(=O)-(O-; K + )2, • -C(=O)-R 7 -Y, -C(=O)-R 7 -OY, -C(=O)-OR 7 -Y, -C(=O)-OR 7 -OY, R 7being a (Ci-Ce)alkyl group and Y being chosen from P(=O)-(OBn)2, P(=O)-(OH)2, P(=O)(OH)(O-; Na + ), P(=O)(O-; Na + )2, P(=O)(OH)(O'; K + ), P(=O)(Q-; K + )2 • a group of formula (B) in which L 1 is a cleavable group chosen from among a pH-sensitive group (e.g., hydrazone (-C=N-NH-CO-), ester (-C(=O)-O-), amide (-C(=O)-N-), beta ketoester (-C(=O)-O-CH2-C(=O)-C-), a photo-induction cleavable group (e.g., nitrobenzyl, coumarin), a bioreduction cleavable group (e.g., nitro (-NO2), quinone), and an enzymatically cleavable group (e.g., ester, peptide glycosides), L 2 is a tert-butoxycarbonyl group or a protein-binding connector, and m is an integer equal to 0 or 1 or a pharmaceutically acceptable salt; ° R 3 is chosen from • -H, a halogen, -OH, • a (Ci-Ce)alkoxy radical, a (Cs-Ce)cycloalkoxy radical, a (C3-C6)heterocycloalkoxy radical, a (Ce-Ci6)aryloxy radical, a (C4-Ci4)heteroaryloxy radical, a (Ci-C6)alkyl-heteroaryloxy radical, said radicals being optionally substituted by at least one group selected from a halogen, a thio-(Ci-Ce)alkyl group, a thio-(C4-Cg)heteroaryl group, a thio-(Ci-C6)alkyl-(C6-Cio)aryl group, a thio-(Ci-Ce)-alkyl-(C4-C9)heteroaryl group, said groups being optionally substituted by at least one halogen or by a (Ci-Ce)alkoxy, • -NR 8 R 9 , -O-(Ci-C6)alkyl-NR 8 R 9 , S-(Ci-C6)alkyl-NR 8 R 9 , R 8 and R 9 independently representing H, (Ci-Ce)alkyl or R 8 and R 9 taken together form a cycle of 3 to 7 links, possibly interrupted by one or more heteroatoms, provided that at least one of the R 8 and R 9 not be H, • -NHCOR 10 , R 10 representing a (Ci-Ce)alkyl, (C6-Cio)aryl, (C4-Cg)heteroaryl possibly substituted by at least one halogen, trifluoromethyl, (Ci-C3)alkoxy; ° X is chosen from N, C-CN, C-OMEM, C-OH, C-NO2 and C-NH2; or one of its pharmaceutically acceptable salts.

[0010] Advantageously, R 1 can be chosen from -O-CH3, -halogen, -NH2, -(CH2)2-NHBoc, -(CH2)2-NH2, -CH2-NH-C(=NH)-NH3 + ; TFA-, -(CH2)i-NH-C(=O)-OR 5 , R 5 being a (Ci-Ce)alkyl group and i being an integer from 1 to 5, and -NH-C(=O)-R 6 , R 6 being a (Ce-Cio)aryl group, said (Ce-Cio)aryl group being optionally substituted by one or more substituent(s) selected from the group consisting of: halogen, -OH, (C1-Ce)alkyl, (Ci-Ce)alkoxy, halo(Ci-C6)alkyl, -CN, -NO2, -C(=O)-(Ci-C6)alkyl, halo(Ci-Ce)alkoxy, -NH2, and (Ci-C6)alkylamino. Preferably, R 1may be halogen.

[0011] Advantageously, R 2 can be chosen from H, -S(=O)2-R 7 , - C(=O)-OR 7 , -C(=O)-O-CH2-R 7 , -C(=O)-CH2-O-(CH2-CH2-O)m- CH3, m being between 0 and 10, -P(=O)-(OBn)2, -P(=O)-(OH)2, -P(=O)-(OH)(O-; Na + ), -P(=O)-(OH)(Q-; K + ), -P(=O)-(O-; Na + )2, -P(=O)-(O-; K + )2, -C(=O)-R 7 -Y, -C(=O)-R 7 -OY, -C(=O)-OR 7 -Y, -C(=O)-OR 7 -OY, with, R 7 being a (Ci-Ce)alkyl group and Y being chosen from P(=O)-(OBn)2, P(=O)-(OH)2, P(=O)(OH)(O-; Na + ), P(=O)(OH)(O-; K + ), P(=O)(Q-; Na + )2et P(=O)(O'; K + 2. Preferably, R 2 can be chosen from H, -S(=O)2-CH3, - C(=O)-O-CH3, - C(=O)-O-CH2-CH3, -C(=O)-CH2-O-CH2-CH2-O-CH2-CH2-O-CH3, -P(=O)-(OBn)2, -P(=O)-(OH)2, -P(=O)-(OH)(Q-; Na + ), -P(=O)-(OH)(O-; K + ), -P(=O)-(O-; Na +)2, -P(=O)-(O'; K + )2, -C(=O)-R 7 -Y, -C(=O)-R 7 -OY, -C(=O)-OR 7 -Y, -C(=O)-OR 7 -OY, with, R 7 being a (Ci-Ce)alkyl group and Y being chosen from P(=O)-(OBn)2, P(=O)-(OH)2, P(=O)(OH)(Q-; Na + ), P(=O)(OH)(Q-; K + ), P(=O)(O _ ; N / A + )2 and P(=O)(O _ K + 2. In an even more preferred manner, R 2 can be chosen from H, -P(=O)-(OBn)2, -P(=O)-(OH)2, -P(=O)-(OH)(O-; Na + ), P(=O)(OH)(O'; K + ), P(=O)(O'; K + )2, -C(=O)-R 7 -Y, -C(=O)-R 7 -OY, -C(=O)-OR 7 -Y, -C(=O)-OR 7 -OY, R 7 being an alkyl group in (Ci-Ce), preferably R 7 being a C4 alkyl, and Y being chosen from P(=O)-(OBn)2, P(=O)-(OH)2,, P(=O)(OH)(O-; K + ) and P(=O)(O'; K + )2.

[0012] Advantageously, R 3can be chosen from H, -O-CH3 and a halogen. Preferably, R 3 can be chosen from -O-CH3 and a halogen.

[0013] Advantageously, X can be chosen from N and C-CN.

[0014] The following definitions are intended to illustrate and define the meaning and scope of the various terms used to describe the invention in this text.

[0015] The expression "Ct-Cz" designates a hydrocarbon group that can contain from t to z carbon atoms, for example Ci-C3 designates a linear or branched carbon-based chain that can contain from 1 to 3 carbon atoms.

[0016] The term "alkyl group" refers to: a saturated, linear or branched, aliphatic hydrocarbon group comprising, unless otherwise specified, from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, and pentyl groups.

[0017] The term "aryl group" means a group derived from arenes by removing a hydrogen atom from a carbon atom in the ring. Groups similarly derived from heteroarenes are sometimes included in this definition. When an alkyl radical is substituted by an aryl group, it is called an "arylalkyl" or "aralkyl" radical. "arylalkyl" or "aralkyl" radicals are aryl-alkyl radicals, the aryl and alkyl groups being as defined above. Examples of arylalkyl radicals include benzyl and phenyl radicals.

[0018] The term "heteroaryl group" means: a group derived from heteroarenes by the removal of a hydrogen atom from any atom of the ring; another term is hetaryl.

[0019] The term "halogen" refers to: fluorine, chlorine, bromine or iodine.

[0020] The term "alkoxy group" means: an -O-alkyl radical where the alkyl group is as defined previously. For example, we can mention the -O-(Ci-C4)alkyl groups, and in particular the -O-methyl group, the -O-ethyl group as the -O-Csalkyl group, the -O-propyl group, the -O-isopropyl group, and as the -O-C4alkyl group, the -O-butyl, -O-isobutyl or -O-tert-butyl group.

[0021] The "alkyl", "cycloalkyl", "aryl", "heteroaryl", and "heterocycloalkyl" radicals mentioned above can be substituted by one or more substituents. These substituents include the following groups: amino, hydroxyl, thiol, oxo, halogen, alkyl, alkoxy, alkylthio, alkylamino, aryloxy, arylalkoxy, cyano, trifluoromethyl, carboxy, and carboxyalkyl.

[0022] The term "alkylthio" refers to: an -S-alkyl group, the alkyl group being as defined above.

[0023] The term "alkylamino" means: an -NH-alkyl group, the alkyl group being as defined above.

[0024] The term "aryloxy" means: an -O-aryl group, the aryl group being as defined above.

[0025] The term "arylalkoxy" means: an aryl-alkoxy group, the aryl and alkoxy groups being as defined above.

[0026] The term "carboxyalkyl" means: a HOOC-alkyl- group, the alkyl group being as defined above. Examples of carboxyalkyl groups include carboxymethyl and carboxyethyl.

[0027] The term "haloalkyl group" refers to an alkyl group as defined above, in which one or more hydrogen atoms are replaced by a halogen atom. Examples include fluoroalkyls, notably CF3 and CHF2.

[0028] The term "carboxyl" means: a COOH group.

[0029] The term "oxo" means: "=O".

[0030] The term "OMEM" stands for methoxyethoxy ether.

[0031] In certain embodiments of the invention, the compounds of the invention may contain one or more asymmetric centers and thus exist as racemates and racemic mixtures, simple enantiomers, and individual diastereomeric mixtures. All such isomeric forms of these compounds are included in the present invention, unless expressly stated otherwise.

[0032] In certain embodiments, the compounds of the invention may contain one or more double bonds and thus be in the form of individual Z and / or E isomers or mixtures of Z and / or E isomers. All such isomeric forms of these compounds are included in the present invention, unless expressly stated otherwise.

[0033] In cases where the compounds of the invention can contain several tautomeric forms, the present invention also includes all the tautomeric forms of said compounds, unless expressly stated otherwise.

[0034] Advantageously, the compound of formula (I) can be chosen from 5

[0035] Advantageously, the compound of formula (I) can be chosen from 

[0036] Advantageously, the compound of formula (I) can be chosen from among the compounds represented above, of configuration E.

[0037] The invention also relates to a pharmaceutical composition comprising a compound of formula (I) and at least one pharmaceutically acceptable excipient.

[0038] Advantageously, at least one excipient can be chosen, depending on the desired pharmaceutical form and method of administration, from among the usual excipients known from the state of the art.

[0039] The invention also relates to the compound of formula (I) or the pharmaceutical composition according to the invention, for its use as a medicinal product.

[0040] Advantageously, its use as a drug can be in the treatment of cancer, bacterial infection, or viral infection.

[0041] Advantageously, the cancer can be chosen from among: breast cancer, colon cancer, pancreatic cancer, bladder cancer, thyroid cancer, cervical cancer, pleural mesothelioma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), leukemia, gastric carcinoma, liver cancer such as hepatocellular carcinogenesis, melanoma, glioblastoma, ovarian cancer, prostate cancer, mesothelioma, kidney cancer, sarcoma, medulloblastoma, and chemotherapy-resistant cancer. Preferably, the cancer can be chosen from the group consisting of: breast cancer, colon cancer, glioblastoma, ovarian cancer, prostate cancer, and chemotherapy-resistant cancer.

[0042] Advantageously, the bacterial infection can be chosen from infections due to Eskape bacteria such as Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae (family Enterobacteriaceae), Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.

[0043] Advantageously, the viral infection can be chosen from influenza A virus infection, Covid virus infection, HIV infection, HPV infection, HTLV infection, or respiratory syncytial virus infection.

[0044] The term "infection with influenza A virus" more precisely defines an illness caused by the influenza A virus.

[0045] The term "Covid infection" more precisely defines an illness caused by the SARS-CoV-2 virus.

[0046] The term "HIV infection" more precisely defines a condition caused by the human immunodeficiency virus (HIV), the term "HPV infection" more precisely defines a condition caused by the human papillomavirus (HPV), and the term "HTLV infection" more precisely defines a condition caused by the human T-cell lymphotropic virus (HTLV).

[0047] The term "respiratory syncytial infection" more precisely defines an illness caused by the respiratory syncytial virus (RSV).

[0048] Advantageously, the pharmaceutical composition may also include an anticancer agent.

[0049] Advantageously, the anticancer agent may be an agent suitable for breast cancer, preferably chosen from an agent used for hormone therapy (e.g. tamoxifen, an aromatase inhibitor such as letrozole or anastrozole), an agent used for chemotherapy (e.g. anthracyclines such as doxorubicin or cyclophosphamide, gemcitabine, taxanes such as paclitaxel or docetaxel) and an agent used for targeted therapy (e.g. trastuzumab, pertuzumab, a CDK4 / 6 inhibitor such as palbociclib or ribociclib).

[0050] Advantageously, the anticancer agent may be an agent suitable for non-small cell lung cancer, preferably chosen from an agent used for immunotherapy (e.g., pembrolizumab), an agent used for platinum-based chemotherapy (e.g., cisplatin, carboplatin, pemetrexed, gemcitabine) and an agent used for mutation-targeted therapy (e.g., osimertinib, alectinib, crizotinib).

[0051] Advantageously, the anticancer agent can be an agent suitable for small cell lung cancer, preferably chosen from an agent used for chemotherapy (e.g. cisplatin, etoposide) and an agent used for immunotherapy (e.g. atezolizumab, durvalumab).

[0052] Advantageously, the anticancer agent may be an agent suitable for colorectal cancer, preferably chosen from an agent used for chemotherapy (e.g., 5-FU, leucovorin, oxaliplatin, irinotecan) and an agent used for targeted therapy (e.g., bevacizumab, cetuximab, panitumumab).

[0053] Advantageously, the anticancer agent may be an agent suitable for the treatment of prostate cancer, preferably chosen from an agent used for hormone therapy (e.g. abiraterone acetate, enzalutamide, leuprorelin) and an agent used for chemotherapy (docetaxel).

[0054] Advantageously, the anticancer agent can be an agent suitable for the treatment of ovarian cancer, preferably chosen from an agent used for chemotherapy (e.g., carboplatin, paclitaxel) and an agent used for targeted therapy (bevacizumab, a PARP inhibitor).

[0055] Advantageously, the anticancer agent may be an agent suitable for the treatment of pancreatic cancer, preferably an agent used for chemotherapy (e.g., 5-FU, irinotecan, oxaliplatin, gemcitabine, nab-paclitaxel).

[0056] Advantageously, the anticancer agent may be an agent suitable for the treatment of liver cancer, preferably chosen from an agent used for targeted therapy (e.g. sorafenib, lenvatinib) and an agent used for immunotherapy (e.g. atezolizumab, bevacizumab).

[0057] Advantageously, the anticancer agent may be an agent suitable for the treatment of stomach cancer, preferably chosen from an agent used for chemotherapy (e.g. cisplatin, 5-FU, capecitabine) and an agent used for targeted therapy (e.g. trastuzumab).

[0058] Advantageously, the anticancer agent may be an agent suitable for the treatment of kidney cancer, preferably chosen from an agent used for targeted therapy (e.g., a tyrosine kinase inhibitor such as sunitinib or pazopanib) and an agent used for immunotherapy (e.g., nivolumab, ipilimumab).

[0059] Advantageously, the anticancer agent can be an agent suitable for the treatment of melanoma, preferably chosen from an agent used for immunotherapy (e.g. nivolumab, pembrolizumab) and an agent used for targeted therapy (e.g. a BRAF / MEK inhibitor such as dabrafenib or trametinib).

[0060] Advantageously, the anticancer agent may be an agent suitable for the treatment of chronic myeloid leukemia, preferably a tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, gemcitabine).

[0061] Advantageously, the anticancer agent may be an agent suitable for the treatment of chronic lymphocytic leukemia, preferably chosen from among a BTK inhibitor (e.g. ibrutinib, acalabrutinib) and an agent used for immunochemotherapy (rituximab, bendamustine, fludarabine, cyclophosphamide, rituximab).

[0062] Advantageously, the anticancer agent may be an agent suitable for the treatment of acute myeloid leukemia, preferably chosen from an agent used for intensive chemotherapy (e.g. cytarabine, daunorubicin, gemcitabine) and an agent used for targeted therapy (e.g. midostaurin, enasidenib).

[0063] Advantageously, the anticancer agent can be an agent suitable for the treatment of acute lymphoblastic leukemia, preferably chosen from an agent used for chemotherapy (e.g., an agent used in Hyper-CVAD, BFM protocols) and an agent used for immunotherapy (blinatumomab, inotuzumab ozogamicin).

[0064] Advantageously, the anticancer agent may be an agent suitable for the treatment of Hodgkin lymphoma, preferably an agent used for chemotherapy (e.g., adriamycin, bleomycin, vinblastine, dacarbazine).

[0065] Advantageously, the anticancer agent may be an agent suitable for the treatment of non-Hodgkin lymphoma, preferably an agent used for immunochemotherapy (e.g. rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone).

[0066] Advantageously, the anticancer agent may be an agent suitable for the treatment of multiple myeloma, preferably an agent used for targeted therapy (e.g. bortezomib, lenalidomide, dexamethasone).

[0067] The present invention also relates to a method of treating the pathological conditions indicated above, which includes administering to a patient an effective dose of a compound of formula (I) according to the invention.

[0068] Advantageously, the compound of formula (I) or the pharmaceutical composition of the present invention can be administered orally, sublingually, subcutaneously, intramuscularly, intravenously, topically, locally, intratracheally, intranasally, transdermally or rectally.

[0069] Advantageously, the compound of formula (I) or the pharmaceutical composition of the present invention can be administered to animals and humans for the treatment of the disorders and diseases mentioned above.

[0070] Advantageously, the appropriate unit-dose form can be selected from oral forms such as tablets, soft or hard capsules, powders, granules, and oral solutions or suspensions; sublingual, buccal, intratracheal, intraocular, and intranasal forms; inhalation forms; topical, transdermal, subcutaneous, intramuscular, or intravenous forms; rectal forms; and implants. For topical application, the compound according to the invention can be used in creams, gels, ointments, or lotions.

[0071] Advantageously and according to usual practice, the dosage appropriate for each patient can be determined by the doctor based on the method of administration, the weight and the patient's response.

[0072] Brief description of the figures

[0073] [Fig 1] is a diagram describing the preparation of serial 4-methoxypyridine indazoles

[0074] [Fig 2] is a diagram describing the preparation of serial indazoles in 4-methoxybenzonitrile EXAMPLES

[0075] Other advantages, purposes and particular features of the present invention will become apparent from the following examples, presented for illustrative and non-limiting purposes, in light of the accompanying figures.

[0076] Part 1

[0077] The following examples illustrate the preparation of compounds of formula (I) according to the invention.

[0078] Example 1: Retrosynthetic analysis to access indazoles and their prodrugs

[0079] The retrosynthetic analysis to access the indazoles and their prodrugs is shown in the diagram below. They can be obtained by a Knoevenagel condensation of indazole acetonitrile with 3-formyl-4-methoxybenzonitrile or 4-methoxynicotinaldehyde.

[0080] Indazole acrylonitril is prepared from (1 H-indazol-3-yl)methanol by substituting the alcohol function with KCN.

[0081] The reduction of 1H-indazole-3-carboxaldehydes leads to the corresponding alcohols. 1H-indazole-3-carboxaldehydes are prepared by nitrosation of the corresponding indoles (see diagram below). prodrugs Indazoles functionalized indazoles indazole acetonitrile X » N or X s N or -CN indazole acetonitrile (1H-indazol-3-yl)methanol 1H-indazole-3-carboxaldehyde indoles

[0082] Example 2: Preparation of indazoles acetonitrile 4a-f

[0083] Nitrosation of indoles 1a-f and 1hj with sodium nitrite in the presence of hydrochloric acid leads to 1H-indazole-3-carboxaldehydes 2a-f and 2h-j (38-95%) (RSC Adv., 2018, 8, 13121-13128).

[0084] After reduction of aldehydes 2a-f and 2h-j in the presence of NaBH4, the unisolated intermediate alcohols are substituted in the presence of KCN to form nitriles 4a-f and 4h-j (56-97%) (see diagram below). O.NC. R NaNOs 2; KCN, MFC 35 h MC < DMR'H. O « « i N ' N h ' « 1a R = OMe 4a: RxOMe i6r' ü; 1b. R=B; 4b R=B' 1c R = CH.-NHBoc 4e: R = CH, NhBot.- i72 ! sj WR ^ NHBoc id R- NHBac M<7 4>) 1»: R = I 4e. R = I i56'h'i 1f, R x F 4f R - l;6 7 ".t 1h: R = Cl 4h R X C!87%! 11 R = CH, CH, Boc 4B: R - CH. CH. Bw. 1j R = CF-, 4j R - CF::37” <l

[0085] Two series of indazoles were prepared with a 4-methoxypyridine or 4-methoxybenzonitrile motif.

[0086] Example 2a: Preparation of 4-methoxypyridine serial indazoles

[0087] The Knoevenagel condensation of 4-methoxynicotinaldehyde with the acrylonitrile indazoles 4a-f and 4h-i leads to compounds 5a-f and 5h-i in good yields. Deprotection of the Boc group of compounds 5c-d and 5i leads to amines 5k, 5g, and 5j (Figure 1).

[0088] Example 2b: Preparation of indazoles in the 4-methoxybenzonitrile series

[0089] The Knoevenagel condensation of 3-formyl-4-methoxybenzonitrile with 4a-f and 4h-i leads to compounds 6a-f and 6h-i in good yields. Deprotection of the Boc group of compounds 6c-d and 6i leads to amines 7c-d and 7i (Figure 2).

[0090] The Knoevenagel condensation of 3-formyl-4-halogenobenzonitriles 55-56 with 2-(5-iodo-1 / - / -indazol-3-ol)acetonitrile 4e leads to the compounds 6j-k (see diagram below). H 4e 55 X = Cl (commercial) Gj X = CI (74%) MK114 56: X = I (59%) 6k: X = I (31%) MK115

[0091] Example 3: Preparation of indazoles 9a-b

[0092] To study the effect of substitution on the pyridine ring, we synthesized compounds 9a-b. 9a: R 2 = Cl (14%) MK47 8b: R 2 = I 9b: R 2 = I (31%) MK58

[0093] We designed and synthesized analogs lacking the pyridine ring in which a nitroso group or a MEM replaces the nitrogen atom and the methoxy group has been replaced by a hydrogen atom (11e-11f). Reduction of the NO2 group leads to aniline 12e. Deprotection of the MEM group of 11f yields alcohol 12f (see the scheme below). 11th (72%) MK57 Acetic acid 12th (46%) MK61 MK49

[0094] Example 3a: Preparation of indazoles in the aniline series

[0095] Reduction of indazole 43a-b in the presence of acetic acid and zinc leads to compounds 44a-b (see diagram below).

[0096] Example 3b: Guanidine synthesis

[0097] The reaction of indazole 7c with amino(imino)methanesulfonic acid and then with trifluoroacetic acid leads to salt 29 (see diagram below).

[0098] Example 4: Prodrug Syntheses

[0099] The reaction of 6b and 6e with methanesulfonyl chloride in the presence of NaH leads to methanesulfonyles 13b and 13e (see diagram below). 6b: R = Br MK 27 6e: R = I MK 46 13b: R = Br (82%) MK28 13th: R = I (37%) MK72

[0100] The reaction of 6e with chloroethyl carbamate provides carbamate 15e (see diagram below). 15th (27%) MK80

[0101] Carbamates 14a and 14b were obtained by reaction of 6b with chloroethyl carbamate or with chloromethyl carbamate (see diagram below).

[0102] The reaction of 5e with 2-(2-(2-methoxyethoxy)ethoxy)acetic acid leads to amide 16e (see diagram below). MK 38

[0103] The reaction of bromoesters with dibenzylphosphite yields benzyloxyphosphanoates 17a-b, which were saponified to give the corresponding acids 18a-b (see diagram below). NaOH 1M, MeOH, NaH, DMF, TA, Ar, TA, Ar, HF^-OBn, OBn, O 17a: n = 2 (100%) 18a: n = 2 (82%) 17b: n = 3 (88%) 18b: n = 3 (85%)

[0104] The reaction of 2-(4-bromobutoxy)tetrahydro-2 / - / -pyrane with dibenzylphosphite gives benzyloxyphosphanoate 17c which is then deprotected to give the corresponding alcohol 19a (see diagram below). CPh BFi. MaH. OMRTA Ar OBn DCM, TA. Ar HQ P -OBn p OBn Br OO 17c 19a 036 i

[0105] Alcohols 19a-b were coupled with nitrophenyl chloroform iate to give rise to 20a-b (see diagram below). Pvrdine. THF, O ■ • P OBn DCM, TA s HO - OO 13OBn OO Cl 00-1 19a n - 2 20a. n = 2 i'63 "41 19b: n = 3 20b n = 3.55

[0106] 4-((tert-butyldimethylsilyl)oxy)butan-1-ol reacts with dibenzyl diisopropylphosphoramidate to form 21 which has reacted with nitrophenyl chloroform iate to synthesize 22 (see diagram below).

[0107] Sodium 5-hydroxypentanoate reacts with dibenzyl diisopropylphosphoramidate to form 23 (see diagram below). 1) tetrazole in ACN (0.45 M) 0 °C, Ar, 1 h 2) H2O2, 0 °C, Ar, 1 h 3) NEt3, TA, 20 min 23 (18%)

[0108] The reaction of 6e with 18b, 20b, 22, or 23 leads to the prodrugs 24-27, 44, 46-47, 49, 51, 53, or 57, which have been debenzylated to form 30-34, 45, 48, 50, or 52 (see the scheme below). These prodrugs are then reacted with sodium hydroxide to form the corresponding mono- and di-salts 35-43. TN o "°

[0109] Indazole 6e reacts with tetrabenzyl pyrophosphate to form 28 (see diagram below). NaH, THF, 0 e C, Ar, 3 h 28 (75%) MK88

[0110] Part 2

[0111] The following examples illustrate the preparation of compounds of formula (I) corresponding to the invention.

[0112] The structures of the products obtained were confirmed by NMR 1 H, RMN 13 C, mass spectra, IR and melting point.

[0113] The starting compounds and reagents, unless otherwise specified, are commercially available from Sigma Aldrich, Enamine or Fluorochem, or described in the literature, or can be prepared according to methods described in the literature or known to the state of the art.

[0114] The following abbreviations were used: cale (calculated), DCM (dichloromethane), DIBAL-H (diisobutylaluminium hydride), DMF (N,N-Dimethylformamide), MTBE (methyl tert-butyl ether), PET (petroleum ether), TEA (triethylamine), PyBOP (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate), TFA (trifluoroacetic acid)

[0115] General procedures

[0116] All reactions were carried out under an inert atmosphere (argon) and anhydrous conditions, except for general procedures A and F. Only deionized water was used. All Knoevenagel-type reactions, as well as the synthesis of prodrugs, were performed in the absence of light. After each purification, the compounds were dried overnight under vacuum.

[0117] General Procedure A: Indazole Synthesis

[0118] All protocols were carried out according to the protocol described by Chevalier et al. in RSC Adv., 2018, 8, 13121-13128.

[0119] Dissolve 8 eq of NaNC in 4 M water and 3 M DMF. At 0 °C, slowly add 2.7 eq of 2 M aqueous HCl. Stir the mixture for 10 min, then slowly add 1 eq of indole in 3 M DMF at 0 °C. After complete conversion, quench the reaction with water. Extract the aqueous phase three times with ethyl acetate. Wash the combined organic phases twice with water and once with brine. Dry the organic phase over MgSO4, filter, and evaporate under reduced pressure.

[0120] General Procedure B: Cyanation of Indazoles

[0121] The synthesis was carried out according to the protocol described by Yamada et al. in Heterocycles, 1998, 47 (1), 509-516.

[0122] Dissolve indazole carbaldehyde (1 eq.) in MeOH (0.11 M) and formamide (0.11 M). At 0 °C, add sodium borohydride (1 eq.) in two equal portions, 30 min apart. Leave the solution to stand at 0 °C for 30 min with stirring, then add potassium cyanide (10 eq.). Heat the reaction mixture to 60 °C until the reaction is complete, then quench with water. Extract the aqueous phase three times. Wash the combined organic phases twice with water and once with brine. Dry the organic phase over MgSO4, filter, and evaporate under reduced pressure.

[0123] General Procedure C: Knoevenagel's Response

[0124] Dissolve sodium (3 eq.) in methanol (0.1 M). Add 2-(1 H-indazol-3-yl)acetonitrile (1 eq.). After 10 min of stirring, add aldehyde (1.2 eq.).

[0125] General Procedure D: Deprotection of amines

[0126] Dissolve tert-butyl carbamate (1 eq.) in DCM (0.04 M). Slowly add trifluoroacetic acid (4 mL / mmol) at room temperature to obtain a clear solution.

[0127] General Procedure E: Synthesis of ethyl benzyloxyphosphanoates

[0128] Dissolve sodium hydride (7.5 eq.) in DMF (8 M). At 0 °C, add dibenzyl phosphite solution (7.5 eq.) dropwise to the DMF (8 M). Let the solution stand for 30 min with stirring at room temperature. Then, at 0 °C, add bromoester (1 eq.). Let the reaction mixture stand overnight with stirring at room temperature, then quench the reaction with water. Extract the aqueous phase three times with ethyl acetate. Wash the organic phases with brine, dry over MgSCM, filter, and concentrate under reduced pressure. Purify the crude reaction mixture by flash chromatography on silica gel column (eluent: PET:AcOEt from 1:0 to 3:2) to obtain the corresponding ethyl benzyloxyphosphanoate.

[0129] General Procedure F: Saponification of ethyl benzyloxyphosphanoates

[0130] Dissolve ethyl benzyloxyphosphonate (1 eq.) in MeOH (0.3 M) and then add 0.1 M aqueous sodium hydroxide solution (2 eq.). Leave the solution overnight with stirring at room temperature. After the reaction is complete, quench the reaction with water. Extract the aqueous phase three times with ethyl acetate and then acidify it to pH 2-3 with 1 M HCl. Extract this acidic aqueous phase three times with ethyl acetate. Wash the newly obtained organic phase with brine, dry it over MgSCM, and concentrate it under reduced pressure to obtain the corresponding acid.

[0131] General Procedure G: Reduction of ethyl phosphanoates to corresponding alcohols

[0132] Dilute ethyl phosphanoate (1 eq.) in DCM (0.07 M). At 0 °C, slowly add 1 M DIBAL-H. DCM (4 eq.). Allow the reaction mixture to stand for 4 h with stirring at 0 °C, then concentrate it to dryness under reduced pressure. Purify the crude reaction mixture by flash chromatography on a C18 gel column (eluent: H₂O:MeCN from 1:0 to 0:1) to obtain the desired alcohol.

[0133] General Procedure H Synthesis of (4-nitrophenyl)benzyloxyphosphoryl carbonates

[0134] Dissolve dibenzyl phosphonate (1 eq.) in DCM (0.08 M) and THF (0.15 M). At 0 °C, add 4-nitrophenyl chloroform iate (3 eq.) in three fractions spaced 10 min apart. Add anhydrous pyridine (3 eq.). Allow the reaction mixture to stand for 6 h with stirring at room temperature, then quench the reaction with citric acid (10 wt. in H₂O). Extract the aqueous phase three times with ethyl acetate. Wash the combined organic phases with brine, dry them over MgSCM, filter, and concentrate under reduced pressure. Purify the crude reaction mixture by flash chromatography on silica gel column (eluent: PET:AcOEt from 1:0 to 0:1) to obtain the desired compound.

[0135] General Procedure I: Synthesis of Benzyloxyphosphates

[0136] Dilute dibenzyl diisopropylphosphoramidite (1 eq.) and the desired alcohol (1 eq.) in a tetrazole-acetonitrile solution (0.45 M, 2 eq.). Let the mixture stand for 1 h with stirring at 0 °C. Then, add 30% hydrogen peroxide (0.5 mL / mmol) and let it stand for 1 h with stirring at 0 °C. Add a 0.2 M (1.5 mL / mmol) HCl-MeOH solution. After 30 min with stirring at room temperature, add triethylamine (0.4 mL / mmol). Let the mixture stand for 20 min with stirring, then evaporate under reduced pressure. Solubilize the crude reaction mixture in ethyl acetate and wash three times with 1 M HCl solution. Wash the organic phase with brine, dry over MgSO4, filter, and concentrate under reduced pressure. Purify the crude reaction mixture by flash chromatography on a silica gel column to obtain the desired compound.

[0137] General Procedure J: Debenzylation of benzyloxyphosphanoates and benzyloxyphosphates

[0138] Dissolve benzyloxyphosphanoate or benzyloxyphosphate (1 eq.) in DCM (0.03 M). At -78 °C, add bromotrimethylsilane (10 eq.) to the solution. After stirring for 2 hours at -40 °C, quench the reaction with water and then concentrate the mixture under reduced pressure. Dissolve the residue in MeOH. After overnight storage at -20 °C, filter the solution under reduced pressure, then wash the precipitate three times with MeOH and dry it to obtain the desired compound.

[0139] General Procedure K: Formation of sodium or potassium monosalt

[0140] Suspend the prodrug in water (0.03 M) and then add a 0.1 M aqueous solution of sodium hydroxide or potassium hydroxide (1 eq.). Stir for 2 hours and evaporate to dryness to obtain the desired compound.

[0141] General Procedure L: Formation of sodium or potassium disel

[0142] Suspend the prodrug in water (0.03M) then add Na2CO3 or K2CO3 (2 eq.). Stir for 2 hours and evaporate to dryness to obtain the desired compound.

[0143] General Procedure M Synthesis of benzyloxyphosphoryl carboxylate prodrugs

[0144] Dissolve (4-nitrophenyl)benzyloxyphosphoryl carbonate 20a-b or 22 (1 eq.) and indazole 6b or 6e (1.4 eq.) in THF (0.05 M). Add anhydrous triethylamine (4 eq.). After 5 days of stirring at room temperature, quench the reaction with water. Extract the aqueous phase three times with a large volume of ethyl acetate, then wash the combined organic phases with brine, dry over MgSO4, filter, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (eluent: PET:AcOEt from 1:0 to 0:1) to obtain the desired prodrug.

[0145] Example 5: Indazole synthesis protocols

[0146] Example 5a: 5-methoxyindazole-3-carbaldehyde 2a Chemical formula: C9H8N2O2 Molar mass: 176.1750

[0147] General procedure A is used with 5-methoxyindole (249.6 mg, 1.70 mmol). The reaction mixture is allowed to stand for 3 h under stirring at room temperature. The aqueous phase is extracted with ethyl acetate. After concentration under reduced pressure, 2a is obtained as a brown powder (241.7 mg, yield: 81%). Pf 209 - 211 °C (decomposition)

[0148] HRSM (ESI + , m / z) wedge. for [M+H] + : 177.0658, measured: 177.0658

[0149] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 14.06 (si, 1H); 10.16 (s, 1H); 7.62 (d, J = 9.1 Hz, 1H); 7.50 (d, J = 2.1 Hz, 1H); 7.13 (dd, Ji = 9.1 Hz, J2 = 2.3 Hz, 1H); 3.84 (s, 3H)

[0150] NMR 13C (125 MHz, DMSO-de): 5 (ppm) 187.2; 156.6; 143.1; 136.9; 121.3; 119.3; 112.3; 99.7; 55.4

[0151] IR: v (cm' 1 ) 3197, 3044, 3013, 2947, 2909, 2826, 1871, 1663, 1626, 1593, 1507, 1482, 1452, 1420, 1348, 1323, 1274, 1258, 1216, 1160, 1125, 1077, 1021, 1004, 944, 837, 794, 760, 718

[0152] Example 5b: 5-bromo-1 H-indazole-3-carbaldehyde 2b Chemical formula: C8H5BrN2O Molar mass: 225.0450

[0153] General procedure A was used with 5-bromo-1H-indole (250.0 mg, 1.30 mmol). Allow to stand for 3 h under stirring at room temperature. Extract the medium with AcOEt. Purify the crude by flash chromatography on a silica gel column (eluent: PET:AcOEt 1:0 to 3:2) to obtain compound 2b as a light brown powder (281.6 mg, yield: 95%).

[0154] Pf 218 - 221 °C

[0155] HRSM (ESI-, m / z) calc. for [M81 Br-H] - : 224.9492, measured: 224.9493

[0156] NMR 1 H (300 MHz, acetone-d6): 5 (ppm) 13.24 (si, 1H); 10.20 (s, 1H); 8.36 (d, J = 1.6 Hz, 1 H); 7.73 (d, J = 8.8 Hz, 1 H); 7.62 (dd, J1 = 8.9 Hz, J2 = 1.8 Hz, 1 H)

[0157] NMR 13 C (125 MHz, acetone-d6): 5 (ppm) 187.5; 144.6; 141.3; 131.3; 124.4; 123.2; 117.6; 113.8

[0158] IR: v (cm' 1 ) 3228, 2921, 2888, 1887, 1738, 1656, 1575, 1469, 1442, 1414, 1373, 1361, 1332, 1309, 1261, 1229, 1170, 1134, 1101, 1037, 918, 870, 795, 783, 732, 671

[0159] Example 5c: ((3-formyl-1H-indazol-5-yl)methyl)tert-butyl carbamate 2c Chemical formula: C-14H-17N3O3 Molar mass: 275.3080

[0160] General procedure A is used with tert-butyl((1H-indol-5-yl)methyl)carbamate 1c (399.0 mg, 1.62 mmol). The mixture is left to stand for 24 h under stirring at room temperature and then extracted with ethyl acetate (AcOEt). The crude reaction mixture is purified by flash chromatography on a silica gel column (eluent: heptane:AcOEt from 1:0 to 3:2) to obtain compound 2c as a beige powder (302.0 mg, yield: 68%).

[0161] Pf 164 - 165 °C

[0162] HRSM (ESI-, m / z) calc. for [MH] - : 274.1197, measured: 274.1175

[0163] NMR 1 H (500 MHz, chloroform-d): 5 (ppm) 10.84 (si, 1 H); 10.27 (s, 1 H); 8, 17 (s, 1H); 7.41 (si, 1H); 7.37 (t, J = 9.7 Hz, 1H); 5.01 (if, 1H); 4.45 (d, J = 4.9 Hz, 2H); 1.49 (s, 9H)

[0164] NMR 13 C (125 MHz, chloroform-d): 5 (ppm) 187.5; 156.3; 144.7; 140.8; 135.4; 128.0; 121.3; 119.8; 110.4; 80.1; 44.7; 28.6 (3C)

[0165] IR: v (cm-1 ) 3274, 3136, 3058, 2977, 2929, 2852, 2753, 1676, 1631, 1544, 1509, 1463, 1426, 1389, 1365, 1346, 1293, 1274, 1244, 1173, 1159, 1146, 1132, 1065, 1045, 1031, 955, 936, 888, 859, 794, 763, 749, 713

[0166] Example 5d: (3-formyl-1 H-indazol-5-yl)tert-butyl carbamate 2d Chemical formula: C-13H-15N3O3 Molar mass: 261.2810

[0167] General procedure A is used with tert-butyl(1H-indol-5-yl)carbamate 1d (459.0 mg, 1.98 mmol). Allow the mixture to stand for 17 h under stirring at room temperature. Extract the reaction mixture with ethyl acetate (AcOEt). Purify the crude mixture by flash chromatography on a silica gel column (eluent: heptane:AcOEt from 1:0 to 3:2) to obtain compound 2d as a white powder (413.0 mg, yield: 80%).

[0168] Pf 193-194 °C

[0169] HRSM (ESI-, m / z) calc. for [MH] - : 260.1040, measured: 260.1042

[0170] MRI 1 H (500 MHz, acetone-d6): 5 (ppm) 13.00 (yes, 1H); 10.20 (s, 1H); 8.54 (yes, 1H); 8.53 (s, 1H); 7.66 (dd, J1 = 9.1 Hz, J2= 1.4 Hz, 1H); 7.64 (d, J = 8.9 Hz, 1H); 1.51 (s, 9H)

[0171] MRI 13 C (125 MHz, acetone-d6): 5 (ppm) 187.5; 153.9; 145.2; 139.1; 137.1; 122.2; 121.7; 111.8; 109.7; 80.1; 28.6 (3C)

[0172] IR: v (cm' 1 ) 3334, 2991, 2972, 2935, 2867, 1698, 1663, 1589, 1533, 1503, 1467, 1442, 1425, 1387, 1363, 1348, 1240, 1220, 1166, 1076, 1049, 1029, 965, 946, 908, 876, 852, 814, 796, 770, 723

[0173] Exemple 5e: 5-iodo-1 H-indazole-3-carbaldéhyde 2e H Brute formulas: C8H5IN2O Molaire mass: 272.0455

[0174] General procedure A is used with 5-iodo-1H-indole (500.0 mg, 2.06 mmol). Allow the mixture to stand for 3 h under stirring at room temperature. Extract the reaction mixture with AcOEt. Purify the crude product by flash chromatography on a silica gel column (eluent: PET:AcOEt from 1:0 to 8:2) to obtain compound 2e as a white powder (481.9 mg, yield: 86%).

[0175] Pf 240 - 243 °C (decomposition)

[0176] HRSM (ESI-, m / z) wedge, for [MH]-: 270.9374, measured: 270.9362

[0177] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 14.30 (s, 1 H); 10.17 (s,1H); 8.48 (s, 1H); 7.75 (dd, Ji = 8.7 Hz, J2 = 1.2 Hz, 1H); 7.57 (d, J = 8.7 Hz, 1H)

[0178] NMR 13 C (125 MHz, DMSO-de): 5 (ppm) 187.2; 142.4; 140.2; 135.4; 129.1; 122.7; 113.5; 88.6

[0179] IR: v (cm' 1 ) 3174, 2919, 2843, 1668, 1445, 1329, 1306, 1267, 1099, 914, 871, 763

[0180] Example 5f: 5-fluoro-1 H-indazole-3-carbaldehyde 2f H Chemical formula: C8H5FN2O Molar mass: 164.1394

[0181] General procedure A is used with 5-fluoro-1H-indazole (249.3 mg, 1.85 mmol). Allow the mixture to stand for 5 h under stirring at room temperature. Extract the reaction mixture with AcOEt. Purify the crude product by flash chromatography on a silica gel column (eluent: PET:AcOEt from 1:0 to 3:2) to obtain compound 2f as an orange powder (222.2 mg, yield: 73%).

[0182] Pf 170 - 171 °C

[0183] HRSM (ESI-, m / z) wedge, for [MH]': 163.0314, measured: 163.0313

[0184] NMR 1 H (500 MHz, acetone-d6): 5 (ppm) 13.24 (1H, si); 10.21 (1H, s); 7.84 (dd, Ji = 8.7 Hz, J2 = 2.2 Hz, 1 H); 9.05 (dd, Ji = 9.1 Hz, J2 = 4.2 Hz, 1 H); 7.36 (td or ddd, Ji = 9.1 Hz, J2= 9.1 Hz, J3= 2.2 Hz, 1H)

[0185] NMR13 C (125 MHz, acetone-d6): 5 (ppm) 187.4; 160.5 (d, 1 J C-F = 238 Hz); 145.1; 139.4; 121.9 (d, 3 J C-F = 11 Hz); 117.6 (d, 2 J C-F = 27 Hz); 113.49 (d, 3 J C-F = 9.7 Hz); 105.9 (d, 2 J C-F = 25 Hz)

[0186] IR: v (cm' 1 ) 3312, 3196, 3080, 2937, 1683, 1658, 1592, 1509, 1475, 1438, 1344, 1316, 1249, 1196, 1175, 1062, 952, 854, 790, 718

[0187] Example 5h: 5-chloro-1 H-indazole-3-carbaldéhyde 2h H Brute formulas: C8H5CIN2O Molaire mass: 180.5910

[0188] General procedure A is used with 5-chloro-1H-indole (299.8 mg, 1.98 mmol). Leave the mixture overnight under stirring at room temperature. Extract the reaction mixture with AcOEt. Purify the crude by flash chromatography on a silica gel column (eluent: PET:AcOEt from 1:0 to 4:1) to obtain the compound after 2 hours as a brown powder (311.6 mg, yield: 87%).

[0189] This compound has already been described in “An optimized procedure for direct access to 1 H-indazole-3-carboxaldehyde derivatives by nitrosation of indoles”, A. Chevalier et al., RSC Adv., 2018, 8, 13121-13128.

[0190] NMR 1 H (500 MHz, acetone-d6): 5 (ppm) 13.28 (si, 1 H); 10.20 (s,1H); 8.18 (d, J = 1.8 Hz, 1 H); 7.78 (d, J = 8.9 Hz, 1 H); 7.50 (dd, Ji = 8.9 Hz, J2= 2.0 Hz, 1 H)

[0191] Example 5i: (2-(3-formyl-1H-indazol-5-yl)ethyl)tert-butyl carbamate 2i BocHN N H Chemical formula: C15H 19 N3O3 Molar mass: 289.3350

[0192] General procedure A is used with tert-butyl(2-(1H-indol-5-yl)ethyl)carbamate 1i (261.6 mg, 1.00 mmol). The solution is stirred for 2.5 h at 0 °C and then for 0.5 h at room temperature. The reaction mixture is extracted with ethyl acetate (AcOEt). The crude product is purified by flash chromatography on a silica gel column (eluent: PET:AcOEt from 1:0 to 7:3) to obtain compound 2i as a yellow powder (167.4 mg, yield: 58%).

[0193] Pf 58 - 61 °C

[0194] HRSM (ESI-, m / z) wedge, for [MH]': 288.1354, measured: 288.1354

[0195] NMR 1 H (500 MHz, acetone-d6): 5 (ppm) 13.07 (si, 1H); 10.21 (s, 1H); 8.05 (s, 1H); 7.66 (d, J = 8.6 Hz, 1H); 7.41 (dd, Ji = 8.6 Hz, J2 = 1.3 Hz, 1H); 6.04 (if, 1H); 3.37 (m, 2H); 2.96 (t, J = 7.2 Hz, 2H); 1.37 (s, 9H)

[0196] NMR 13C (125 MHz, acetone-d6): 5 (ppm) 187.8; 156.7; 145.1; 141.7; 136.6; 130.0; 122.1; 121.6; 111.6; 78.6; 43.1; 37.0; 28.7 (3C)

[0197] IR: v (cm' 1 ) 3195, 2977, 1671, 1501, 1455, 1365, 1331, 1250, 1162, 1072, 793

[0198] Example 5j: 5-(trifluoromethyl)-1 H-indazole-3-carbaldehyde 2j F Chemical formula: C9H5F3N2O Molar mass 214.15

[0199] General procedure A is used with 5-(trifluoromethyl)-1H-indole 1j (185.2 mg, 1.00 mmol). Allow the solution to be stirred for 2 h at 0 °C, then quench the reaction with water. Extract the aqueous phase three times with AcOEt. Wash the organic phase with water and then with brine, and dry over Na2SO4. Purify the crude product on a preparative TLC plate (eluent: PET:AcOEt 7:3) to obtain the compound 2j as a brown powder (82 mg, yield: 38%).

[0200] MS (ESI +, m / z): wedge, for [M+H] + : 214.2, measured: 215.2

[0201] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 14.56 (s, 1 H); 10.24 (s, 1 H); 8.44 (s, 1 H); 7.95 (d, J = 8.8 Hz, 1 H); 7.81 (dd, Ji = 8.8 Hz, J2 = 1.5 Hz, 1 H)

[0202] NMR 13 C (125 MHz, DMSO-de): 5 (ppm) 187.5; 144.1; 142.6; 125.6; 124.4 (d, J = 32.2 Hz); 123.7 (d, J = 4.3 Hz); 119.5; 118.5 (d, J = 4.3 Hz); 112.9

[0203] Example 6: Synthesis protocols for nitrile compounds

[0204] Example 6a: 2-(5-methoxy-1H-indazol-3-yl)acetonitrile 4a Chemical formula: C 10 H9N3O Molar mass: 187.2020

[0205] General procedure B is used with 5-methoxyindazole-3-carbaldehyde 2a (226.8 mg, 1.29 mmol). The reaction mixture is allowed to stand for 4 h under stirring and then extracted with EtAc. Purify the crude by flash chromatography on a silica gel column (eluent: heptane:EtAc from 1:0 to 3:2) to obtain compound 4a as a yellow solid (161.8 mg, yield: 67%).

[0206] Pf 127 - 128 °C

[0207] HRSM (ESI-, m / z) calc. for [MH] - : 186.0672, measured: 186.0650

[0208] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 12.95 (si, 1H); 7.44 (d, J = 9.0 Hz, 1H); 7.23 (d, J = 1.9 Hz, 1H); 7.04 (dd, Ji = 9.0 Hz, J2 = 2.2 Hz, 1H); 4.32 (s, 2H); 3.80 (s, 3H)

[0209] NMR 13 C (125 MHz, DMSO-de): 5 (ppm) 154.0; 136.7; 134.2; 121.0; 118.6; 118.1; 111.5; 98.7; 55.4; 15.4

[0210] IR: v (cm -1) 3128, 3048, 2912, 2829, 2247, 1635, 1595, 1514, 1500, 1453, 1441, 1425, 1411, 1334, 1295, 1263, 1225, 1184, 1150, 1070, 1026, 952, 847, 835, 818, 799, 787, 723, 711

[0211] Example 6b: 2-(5-bromo-1 H-indazol-3-yl)acetonitrile 4b NC Chemical formula: C9H6BrN3 Molar mass: 236.0720

[0212] General procedure B is used with 5-bromo-1H-indazole-3-carbaldehyde 2b (362.3 mg, 1.61 mmol). The reaction mixture is allowed to stand for 3 h under stirring and then extracted by DCM. The crude product is purified by flash chromatography on a silica gel column (eluent: PET:AcOEt from 1:0 to 3:2) to obtain compound 4b as a yellow powder (240.0 mg, yield: 71%).

[0213] Pf 137 - 140 °C

[0214] HRSM (ESI ”, m / z) hold, for [M 79 Br-H]“: 233.9672, measured: 233.9690

[0215] NMR 1H (500 MHz, chloroform-d): 5 (ppm) 10.15 (si, 1H); 7.96 (d, J = 1.8 Hz 1H); 7.53 (dd, Ji = 8.1 Hz, J2 = 0.8 Hz, 1H); 7.40 (d, J = 8.9 Hz, 1H); 4.06 (s, 2H)

[0216] NMR 13 C (125 MHz, DMSO-de): 5 (ppm) 139.6; 134.8; 129.3; 122.4; 122.0; 117.8; 112.7; 112.6; 15.4

[0217] IR: v (cm' 1 ) 3439, 3404, 3240, 2937, 2914, 2251, 1896, 1728, 1621, 1574, 1496, 1472, 1446, 1412, 1365, 1330, 1313, 1269, 1236, 1203, 1144, 1086, 1075, 1039, 925, 905, 867, 802, 779, 762, 748, 692, 667

[0218] Example 6c: ((3-(cyanomethyl)-1 H-indazol-5-yl)methyl)tert-butyl carbamate 4c N N Chemical formula: C 15 H 18 N4O2 Molar mass: 286.3350

[0219] General procedure B is used with tert-butyl((3-formyl-1H-indazol-5-yl)methyl)carbamate 2c (506.6 mg, 1.84 mmol). The reaction mixture is allowed to stand for 4 h under stirring and then extracted with ethyl acetate. The crude product is purified by flash chromatography on a silica gel column (eluent: DCM:MeOH from 1:0 to 24:1) to obtain compound 4f as a yellow powder (378.2 mg, yield: 72%).

[0220] Pf 96 - 99 °C

[0221] HRSM (ESI-, m / z) wedge, for [MH] - : 285.1357, measured: 285.1344

[0222] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 13.04 (si, 1H); 7.61 (s, 1H); 7.49 (d, J = 8.6 Hz, 1 H); 7.40 (t, J = 5.4 Hz, 1 H); 7.31 (d, J = 8.6 Hz, 1 H); 4.34 (s, 2H); 4.22 (d, J = 6.0 Hz, 2H); 1.40 (s, 9H)

[0223] NMR 13 C (125 MHz, DMSO-de): 5 (ppm) 155.7; 140.3; 134.7; 132.4; 126.6; 120.6; 117.9; 117.1; 110.4; 77.7; 43.6; 28.2 (3C); 15.5

[0224] IR: v (cm-1 ) 3193, 3164, 3047, 2981, 2908, 2258, 1684, 1633, 1546, 1513, 1475, 1460, 1425, 1409, 1391, 1365, 1292, 1249, 1162, 1147, 1130, 1061, 1046, 1031, 951, 935, 915, 872, 849, 803, 790

[0225] Example 6d: (3-(cyanomethyl)-1 H-indazol-5-yl)tert-butyl carbamate 4d NC H CL. N Chemical formula: C 14 H 16 N4O2 Molar mass: 272.3080

[0226] General procedure B is used with tert-butyl(3-formyl-1H-indazol-5-yl)carbamate 2d (400.0 mg, 1.53 mmol). The reaction mixture is allowed to stand for 3 h under stirring and then extracted with ethyl acetate (EoA). The crude product is purified by flash chromatography on a silica gel column (eluent: heptane:EoA from 1:0 to 3:2) to obtain compound 4d as a yellow solid (395.3 mg, yield: 96%).

[0227] Pf 190 - 193 °C

[0228] HRSM (ESI-, m / z) calc. for [MH] - : 271.1200, measured: 271.1202

[0229] MRI 1 H (500 MHz, acetone-d6): 5 (ppm) 12.12 (yes, 1H); 8.42 (yes, 1H); 8.08 (yes, 1H); 7.50 (s, 2H); 4.25 (s, 2H); 1.50 (s, 9H)

[0230] MRI 13 C (125 MHz, DMSO-de): 5 (ppm) 153.1; 137.5; 134.5; 132.8; 120.7; 120.5; 118.0; 110.5; 106.8; 78.8; 28.2 (3C); 15.5

[0231] IR : v (cm -1 ) 3374, 3339, 3287, 2982, 2933, 2256, 1713, 1686, 1589, 1544, 1509, 1480, 1368, 1329, 1294, 1254, 1157, 1048, 1020, 965, 913, 893, 868, 840, 811, 772, 675

[0232] Exemple 6e: 2-(5-iodo-1 H-indazol-3-yl)acetonitrile 4e H Brute formulas: C9H6IN3 Molaire mass: 283.0725

[0233] General procedure B is used with 5-iodo-1H-indazole-3-carbaldehyde 2e (1.18 g, 4.34 mmol). The reaction mixture is allowed to stand for 4 h under stirring and then extracted with AcOEt. The crude product is purified by flash chromatography on a silica gel column (eluent: PET:AcOEt from 1:0 to 3:2) to obtain compound 4e as a pale yellow powder (688.0 mg; yield: 56%).

[0234] Pf 143 - 146 °C

[0235] HRSM (ESI-, m / z) calc. for [MH] - : 281.9534, measured: 281.9511

[0236] NMR 1 H (500 MHz, acetone-d6): 5 (ppm) 12.41 (si, 1H); 8.27 (s, 1H); 7.65 (dd, Ji = 8.9 Hz, J2 = 1.2 Hz, 1H); 7.46 (d, J = 8.9 Hz, 1H); 4.30 (s, 2H)

[0237] NMR 13 C (125 MHz, acetone-d6): 5 (ppm) 141.6; 135.9; 129.6; 124.7; 117.8; 113.6; 84.3; 16.4

[0238] IR: v (cm' 1 ) 3165, 2912, 2248, 1616, 1474, 1408, 1315, 1234, 1189, 1083, 930, 867, 803, 711

[0239] Example 6f: 2-(5-fluoro-1H-indazol-3-yl)acetonitrile 4f Chemical formula: C9H6FN3 Molar mass: 175.1664

[0240] General procedure B is used with 5-fluoro-1H-indazole-3-carbaldehyde 2f (204.5 mg, 1.24 mmol). The reaction mixture is allowed to stand for 6 h under stirring and then extracted with EtAc. The crude product is purified by flash chromatography on a silica gel column (eluent: DCM:MeOH from 1:0 to 24:1) to obtain compound 4f as an orange lake (146.2 mg, yield: 67%).

[0241] Pf 109 - 110 °C

[0242] HRSM (ESI-, m / z) calc. for [MH] - : 174.0468, measured: 174.0471

[0243] NMR 1 H (500 MHz, acetone-d6): 5 (ppm) 12.38 (s, 1H); 7.63 (dd, Ji = 9.05 Hz, J2 = 4.2 Hz, 1H); 7.57 (dd, Ji = 9.0 Hz, J2 = 2.2 Hz, 1H); 7.25 (td, Ji = 9.1 Hz, J2 = 2.4 Hz, 1H); 4.28 (s, 2H)

[0244] NMR 13C (125 MHz, acetone -d6): 5 (ppm) 158.6 (d, JC-F = 236.7 Hz); 139.5; 136.6 (d, JC-F = 5.7 Hz); 122.1 (d, JC-F = 10.1 Hz); 117.8; 117.0 (d, JC-F = 28.4 Hz); 112.9 (d, JC-F = 9.2 Hz); 104.3 (d, JC-F = 23.8 Hz); 16.4

[0245] IR: v (cm -1 ) 3196, 3074, 2944, 2253, 1886, 1635, 1590, 1504, 1424, 1324, 1291, 1240, 1186, 1106, 1052, 955, 867, 801, 785, 705

[0246] Example 6h: 2-(5-chloro-1 H-indazol-3-yl)acetonitrile 4h Chemical formula: C9H6CIN3 Molar mass: 191.6180

[0247] General procedure B is used with 5-chloroindazole-3-carbaldehyde (606.7 mg, 3.36 mmol) for 2 hours. The reaction mixture is left to stand for 4.5 hours under stirring and then extracted with AcOEt. The crude product is purified by flash chromatography on a silica gel column (eluent: heptane:AcOEt from 1:0 to 3:2) to obtain the compound for 4 hours as a yellow solid (161.8 mg, yield: 67%).

[0248] Pf 129- 132 °C

[0249] HRSM (ESI-, m / z) calc. For [MH] - : 190.0177, measured:

[0250] NMR 1 H (500 MHz, acetone-d6): 5 (ppm) 12.44 (si, 1H); 7.91 (d, J = 1.8 Hz, 1H); 7.62 (dd, Ji = 9.0 Hz, J2= 0.5 Hz, 1H); 7.39 (dd, Ji = 8.9 Hz, J2= 1.9 Hz, 1H); 4.31 (s, 2H)

[0251] NMR 13 C (125 MHz, acetone-d6): 5 (ppm) 140.9; 136.3; 128.0; 126.7; 122.9; 119.5; 117.7; 112.9; 16.3

[0252] IR : v (cm -1 ) 3242, 2938, 2253, 1625, 1475, 1412, 1313, 1235, 1203, 1148, 1044, 931, 868, 805, 783

[0253] Example 6i: (2-(3-(cyanomethyl)-1 H-indazol-5-yl)ethyl)tert-butyl carbamate 4i Crude formula: C 16 H 20 N4O2 Molar mass: 300.3620

[0254] General procedure B is used with tert-butyl(2-(3-formyl-1H-indazol-5-yl)ethyl)carbamate 2i (149.7 mg, 0.52 mmol). The reaction mixture is allowed to stand for 3.5 h under stirring and then extracted with µAcOEt. The crude product is purified by flash chromatography on a silica gel column (eluent: PET:µAcOEt from 1:0 to 11:9) to obtain compound 4i as a yellow solid (114.6 mg, yield: 74%).

[0255] HRSM (ESI-, m / z) wedge, for [M - H]-: 299.1513, measured: 299.1514

[0256] NMR 1 H (500 MHz, acetone-d6): 5 (ppm) 12.19 (si, 1H); 7.66 (s, 1H); 7.51 (d, J = 8.6 Hz, 1H); 7.31 (dd, Ji = 8.6 Hz, J2 = 1.3 Hz, 1H); 6.05 (if, 1H); 4.25 (s, 2H); 3.35 (q, J = 6.8 Hz, 2H); 2.92 (t, J = 6.8 Hz, 2H); 1.39 (s, 9H)

[0257] NMR 13 C (125 MHz, acetone-d6): 5 (ppm) 156.6; 141.4; 136.0; 133.0; 129.2; 122.4; 119.4; 117.9; 111.1; 78.5; 43.1; 36.8; 28.6 (3C); 16.4

[0258] IR: v (cm' 1) 3287, 2932, 2256, 1684, 1506, 1366, 1249, 1164, 1054, 964, 866, 808, 784

[0259] Example 6j: 2-(5-(trifluoromethyl)-1 H-indazol-3-yl)acetonitrile 4j -CM j = N fl Chemical formula: C 10 H6F3N3 Rosary Mass 225.17

[0260] General procedure B is used with 5-(trifluoromethyl)-1H-indazole-3-carbaldehyde 2j (316 mg, 1.48 mmol). The reaction mixture is left to stand for 5 h under stirring at 60 °C and then extracted with EtCl2. The crude product is purified by flash chromatography on a silica gel column (eluent: PET:EtCl2 3:2) to obtain the compound 4j as a brown powder (138 mg, yield: 37%).

[0261] MS (ESI + , m / z) wedge, for [M+H] + : 225.2, measured: 226.2

[0262] NMR 1H (300 MHz, DMSO-de): 5 (ppm) 13.53 (s, 1 H); 8.33-8.32 (m, 1 H); 7.76 (d, J = 8.8 Hz, 1H); 7.67 (dd, Ji = 8.9 Hz, J2 = 1.7 Hz, 1H); 4.49 (s, 2H)

[0263] NMR 13 C (125 MHz, DMSO-de): 5 (ppm) 141.9; 136.9; 123.5; 122.7 (d, J = 3.1 Hz); 121.4 (d, J = 31.4 Hz); 119.9; 118.3 (d, J = 4.5 Hz); 117.8; 111.8; 15.5

[0264] Example 7: Knoevenagel Condensation Protocols

[0265] Example 7a (Z)-2-(5-methoxy-1 H-indazol-3-yl)-3-(4-methoxypyridin-3-yl)acrylonitrile 5a (MK21) Chemical formula: C 17 H 14 N4O2 Molar mass: 306.3250

[0266] General procedure C is used with 2-(5-methoxy-1H-indazol-3-yl)acetonitrile 4a (30.0 mg, 0.16 mmol). Allow the reaction mixture to stand for 3 h under reflux. After cooling to room temperature, quench the reaction with water. Extract the mixture three times with AcOEt. Wash the combined organic phases with brine, dry over MgSO4, filter, and evaporate under reduced pressure. Purify the crude material by preparative plate chromatography (eluent: DCM:MeOH 95:5) to obtain compound 5a as a yellow powder (35.4 mg, yield: 72%).

[0267] Pf 230 - 231 °C (decomposition)

[0268] HRSM (ESI-, m / z) calc, for [MH] - : 305.1044, measured: 305.1006

[0269] NMR 1H (300 MHz, DMSO-de): 5 (ppm) 13,60 (s, 1H); 8,96 (s, 1H); 8,56 (d, J = 5,8 Hz, 1H); 8,10 (s, 1H); 7,57 (d, J = 9,1 Hz, 1H); 7,43 (d, J = 2,1 Hz, 1H); 7,23 (d, J = 5,9 Hz, 1H); 7,13 (dd, Ji = 9,1 Hz, J2= 2,3 Hz, 1H); 3,97 (s, 3H); 3,84 (s, 3H)

[0270] RMN 13 C (75 MHz, DMSO-de): 5 (ppm) 163,0; 155,1; 152,6; 148,6; 137,4; 137,3; 134,1; 119,8; 119,5; 118,7; 116,9; 112,2; 107,3 (2C); 99,3; 56,1; 55,4

[0271] IR: v (cm- 1 ) 3352, 3183, 3055, 2931, 2223, 1675, 1583, 1526, 1499, 1463, 1446, 1368, 1330, 1317, 1278, 1163, 1104, 1020, 973, 919, 851, 817, 770

[0272] Exemple 7b (Z)-2-(5-bromo-1 H-indazol-3-yl)-3-(4-méthoxypyridin-3-yl) acrylonitrile 5b (MK26) Formule brute: C 16 H 11 BrN4O Masse molaire: 355,1950

[0273] General procedure C is used with 2-(5-bromo-1H-indazol-3-yl)acetonitrile (52.4 mg, 0.22 mmol). The reaction mixture is left to ferment for 3.5 h under reflux. After cooling to room temperature, quench the reaction with water and extract the aqueous phase three times with AcOEt. The combined organic phases are dried over MgSCM, filtered, and evaporated under reduced pressure. Compound 5b is obtained after precipitation in an AcOEt:heptane mixture (9:1) as an orange powder (51.9 mg, yield: 66%).

[0274] Pf 248 - 250 °C (decomposition)

[0275] HRSM (ESI-, m / z) holds, for [M 79 Br-H] _ : 353.0043, measured: 353.0042

[0276] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 13.82 (si, 1H); 8.94 (s, 1H); 8.57 (d, J = 5.8 Hz, 1H); 8.30 (d, J = 1.3 Hz, 1H); 8.16 (s, 1H); 7.65 (d, J = 8.9 Hz, 1H); 7.59 (dd, Ji = 8.9 Hz, J2 = 1.5 Hz, 1H); 7.24 (d, J = 5.9 Hz, 1H); 3.98 (s, 3H)

[0277] NMR 13 C (125 MHz, DMSO-de): 5 (ppm) 163.0; 152.9; 148.8; 140.3; 137.5; 135.7; 129.7; 122.1; 120.9; 119.4; 116.8; 114.5; 113.2; 107.3; 106.6; 56.1

[0278] IR: v (cm' 1 ) 3032, 2841, 2715, 2217, 1595, 1497, 1469, 1344, 1307, 1278, 1203, 1183, 1109, 1077, 1018, 909, 849, 794

[0279] Example 7c (Z)-((3-(1-cyano-2-(4-methoxypyridin-3-yl)vinyl)-1 H-indazol-5-yl)methyl) tert-butyl carbamate 5c (MK22) Chemical formula: C 22 H 23 N5O3 Molar mass: 405.4580

[0280] General procedure C is used with tert-butyl((3-(cyanomethyl)-1H-indazol-5-yl)methyl)carbamate (84.5 mg, 0.30 mmol). The mixture is left to react for 4 h under reflux. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure and the residue is dissolved in DCM supplemented with a few drops of MeOH. The crude mixture is purified by preparative plate chromatography (eluent: DCM:MeOH 95:5) to obtain compound 5c as a pale yellow powder (80.9 mg, yield: 68%).

[0281] Pf 198 - 200 °C

[0282] HRSM (ESI-, m / z) wedge, for [MH] - : 404.1728, measured: 404.1703

[0283] NMR 1H (500 MHz, DMSO-de): 5 (ppm) 13,60 (s, 1H); 8,97 (s, 1H); 8,58 (d, J = 5,8 Hz, 1H); 8,12 (s, 1H); 7,92 (s, 1H); 7,61 (d, J = 8,6 Hz, 1H); 7,46 (t, J = 5,8 Hz, 1H); 7.38 (d, J = 8,7 Hz, 1H); 7,25 (d, J = 5,8 Hz, 1H); 4,27 (d, J = 6,0 Hz, 2H); 3,99 (s, 3H); 1.38 (s, 9H)

[0284] RMN 13 C (125 MHz, DMSO-de): 5 (ppm) 163,0; 155,8; 152,8; 148,7; 140,8; 137,9; 134,5; 134,2; 126,9; 119,4 (2C); 117,4; 116,8; 111,0; 107,5; 107,3; 77,8; 56,2; 43,6; 28,2 (3C)

[0285] IR: v (cm’ 1 ) 3352, 3151, 2931, 2223, 1675, 1583, 1523, 1463, 1446, 1368, 1330, 1317, 1278, 1163, 1104, 1047, 1020, 973, 919, 851, 817, 770, 723

[0286] Exemple 7d (Z)-(3-(1-cyano-2-(4-méthoxypyridin-3-yl)vinyl)-1 H-indazol-5-yl)carbamate de tert-butyle 5d (MK25) Formule brute : C 21 H 21 N5O3 Masse molaire: 391,4310

[0287] Dissolve sodium (22.3 mg, 0.97 mmol, 3 eq.) in anhydrous MeOH (3 mL). Add tert-butyl(3-(cyanomethyl)-1H-indazol-5-yl)carbamate 4d (88 mg, 0.323 mmol, 1.0 eq.) to the freshly prepared sodium methoxide solution. After 10 min of refluxing, add 4-methoxynicotinaldehyde (66.5 mg, 0.49 mmol, 1.5 eq.) in MeOH (1 mL) over 3 h using a syringe pump. After complete addition, leave the reaction mixture under refluxing for 0.5 h. Cool the mixture to room temperature and then concentrate it under reduced pressure. Add water and extract three times with ethyl acetate. Dry the combined organic phases over MgSO4, filter and evaporate under reduced pressure. Purify the crude product by preparative plate chromatography (eluent: DCM:MeOH 95:5) to obtain compound 5d as a yellow powder (105.5 mg, yield: 83%).

[0288] Pf 179 - 182 °C

[0289] H. R. S. M. (E. S. I.-, m / z) cale, pour [M-H]": 390,1572, mesurée: 390,1576

[0290] RMN 1 H (500 MHz, DMSO-de): 5 (ppm) 13,52 (s, 1 H); 9,47 (s, 1H); 9,05 (s, 1H); 8,57 (d, J = 5,7 Hz, 1H); 8,37 (s, 1H); 8,08 (s, 1H); 7,56 (d, J = 9,0 Hz, 1H); 7,46 (d, J = 8,9 Hz, 1H); 7,24 (d, J = 5,7 Hz, 1H); 4,02 (s, 3H); 1,50 (s, 9H)

[0291] RMN 13 C (125 MHz, DMSO-de): 5 (ppm) 162,9; 153,0; 152,8; 148,3; 138,0; 137,9; 134,5; 133,3; 120,5; 119,5; 119,2; 116,8; 111,3; 107,3; 107,1; 106,9; 79,0; 56,1; 28,1 (3C)

[0292] IR: v (cm -1 ) 3444, 3192, 2979, 2737, 2222, 1715, 1591, 1561, 1530, 1498, 1457, 1391, 1366, 1331, 1317, 1288, 1239, 1206, 1155, 1077, 1049, 1023, 962, 894, 855, 814, 786, 769, 730

[0293] Exemple 7e: (Z)-2-(5-iodo-1 H-indazol-3-yl)-3-(4-méthoxypyridin-3-yl)acrylonitrile 5e (MK38) Formule brute : C 16 H 11 IN4O Molar mass: 402.1955

[0294] General procedure C is used with 2-(5-iodo-1H-indazol-3-yl)acetonitrile 4e (100 mg, 0.35 mmol). The reaction mixture is allowed to stand for 4 h under stirring at room temperature, then the solvent is evaporated under reduced pressure. The reaction is quenched with water, and the aqueous phase is extracted three times with AcOEt. The combined organic phases are washed three times with water and then once with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Compound 5e is obtained by precipitation in MeOH as a yellow powder (125.8 mg, yield: 89%).

[0295] Pf 267 - 268 °C (decomposition)

[0296] HRSM (ESI + , m / z) wedge, for [M+ H] + : 403.0051, measured: 403.0058

[0297] NMR 1H (500 MHz, DMSO-de): 5 (ppm) 13,78 (si, 1H); 8,94 (s, 1H); 8,57(d, J = 5,8 Hz, 1H); 8,49 (s, 1 H); 8,15 (s, 1H); 7,72 (dd, Ji = 8,8Hz, J2= 1,2 Hz, 1H); 7,52 (d, J = 8. 8Hz, 1H); 7,24 (d, J = 5,8 Hz, 1H); 3,98 (s, 3H)

[0298] RMN 13 C (125 MHz, DMSO-de): 5 (ppm) 163,0; 152,9; 148,9; 140,5; 137,2; 135,8; 134,9; 128,3; 121,9; 119,4; 116,9; 113,3; 107,3; 106,6; 86,2; 56,1

[0299] IR: v (cm- 1 ) 3117, 2705, 2219, 1594, 1496, 1457, 1309, 1275, 1205, 1102, 1015, 906, 845, 785

[0300] Exemple 7f (Z)-2-(5-fluoro-1 H-indazol-3-yl)-3-(4-méthoxypyridin-3-yl)acrylonitrile 5f (MK41) Fo rmule brute : C 16 H 11 FN4O Masse molaire: 294,2894

[0301] General procedure C is used with 2-(5-fluoro-1H-indazol-3-yl)acetonitrile 4f (65.0 mg, 0.37 mmol). The reaction mixture is allowed to stand for 5 h under stirring at room temperature, then quench the reaction with water. The mixture is filtered, and the solid is dried for 10 min. A second fraction is obtained by precipitating the filtrate in MeOH. The two fractions are combined to obtain 5f as a yellow powder (59.0 mg, yield: 54%).

[0302] Pf 247 - 250 °C (decomposition)

[0303] HRSM (ESI + , m / z) wedge, for [M+H] + : 295.0990, measured: 295.0974

[0304] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 13.77 (s, 1H); 8.93 (s, 1H); 8.57 (d, J = 5.2 Hz, 1 H); 8.11 (s, 1 H); 7.86 (d, J = 9.0 Hz, 1 H); 7.71 (d, J = 4.4 Hz, 1 H); 7.39 (t, J = 7.8 Hz, 1H); 7.24 (d, J = 4.8 Hz, 1H); 3.97 (s, 3H)

[0305] NMR 13C (125 MHz, DMSO-de): 5 (ppm) 163,0; 157,8 (d, JC-F = 237,3 Hz); 152,7; 148,8; 139,0; 138,0 (d, JC-F = 6,6 Hz); 134,5; 119,5; 119,3 (d, JC-F = 10,0 Hz); 116,8; 116,1 (d, JC-F = 27,4 Hz); 113,0 (d, JC-F = 10,0 Hz); 107,3; 107, 1; 104, 1 (d, JC-F = 27,8 Hz); 56, 1

[0306] IR: v (cm’ 1 ) 3343, 3245, 3068, 2847, 2228, 1637, 1585, 1484, 1411, 1307, 1278, 1251, 1202, 1098, 1016, 955, 798, 699

[0307] Exemple 7g (Z)-2-(5-amino-1 H-indazol-3-yl)-3-(4-methoxypyridin-3-yl) acrylonitrile 5g (MK36) H2N H Formule brute: C 16 H 13 N5O Masse molaire: 291,3140

[0308] General procedure D is used with tert-butyl(Z)-(3-(1-cyano-2-(4-methoxypyridin-3-yl)vinyl)-1H-indazol-5-yl)carbamate 5d (88.3 mg, 0.23 mmol). Allow the reaction mixture to stand for 3 h under stirring at room temperature, then concentrate under reduced pressure. Solubilize the crude mixture in a 1:1 AcOELMeOH mixture and basify with a saturated aqueous NaHCO3 solution to pH 9. Extract the aqueous phase three times with AcOEt. Dry the combined organic phases over MgSCM, filter, and evaporate under reduced pressure. Solubilize the residue in cold AcOEt and isolate the precipitate by filtration. Concentrate the filtrate to dryness and solubilize it in cold AcOEt. Repeat the procedure until precipitation ceases. Dissolve the combined precipitates in 5 mL of aqueous NaHCO3 solution. Leave the suspension for 1 hour under stirring at room temperature, then filter. Dissolve the precipitate in MeOH.Concentrate the filtrate under reduced pressure to obtain the compound 5g in the form of a reddish-brown powder (40.1 mg, yield: 61%).

[0309] Pf 246 - 248 °C (decomposition)

[0310] HRSM (ESI + , m / z) wedge, for [M+H] + : 292.1193, measured: 292.1193

[0311] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 13.24 (s, 1H); 8.96 (s, 1H); 8.54 (d, J = 5.8 Hz, 1H); 7.92 (s, 1H); 7.39 (d, J = 8.8 Hz, 1H); 7.22 (d, J = 5.8 Hz, 1H); 7.06 (d, J = 1.4 Hz, 1H); 6.85 (dd, Ji = 8.9 Hz, J2 = 1.9 Hz, 1H); 5.08 (s, 2H); 3.99 (s, 3H)

[0312] NMR 13 C (125 MHz, DMSO-de): 5 (ppm) 162.8; 152.4; 148.5; 144.2; 136.5; 135.9; 131.4; 120.9; 119.7; 118.3; 117.1; 112.0; 108.2; 107.2; 99.2; 56.1

[0313] IR: v (cm' 1 ) 3185, 2929, 2531, 2222, 1730, 1631, 1587, 1431, 1371, 1333, 1286, 1240, 1208, 1181, 1102, 1019, 972, 952, 879, 832, 700

[0314] Example 7h (Z)-3-(2-(5-bromo-1 H-indazol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile 6b (MK 27) Chemical formula: C 18 H 11 BrN4O Molar mass: 379.2170

[0315] General procedure C is used with 2-(5-bromo-1H-indazol-3-yl)acetonitrile 4b (62.3 mg, 0.26 mmol). The mixture is left to stand for 3 h under stirring, then quenched with water. The aqueous phase is extracted three times with AcOEt. The combined organic phases are washed twice with water and then once with brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The crude mixture is resuspended in a heptane:AcOEt (9:1) solution at 0 °C, filtered, and dried under reduced pressure to obtain compound 6b as a yellow powder (41.7 mg, yield: 41.7%).

[0316] Pf 280 - 284 °C (decomposition)

[0317] HRSM (ESI + , m / z) wedge, for [M 79 Br + H] +: 379.0116, measured: 379.0181

[0318] NMR 1 H (500 MHz, chloroform-d): 5 (ppm) 13.84 (s, 1H); 8.31 (s, 2H); 8.17(s, 1H); 8.00 (d, J = 8.3 Hz, 1H); 7.65 (d, J = 8.8 Hz, 1H); 7.59 (d, J = 9.0 Hz, 1H); 7.37(d, J = 8.7 Hz, 1H); 3.99 (s, 3H)

[0319] NMR 13 C (125 MHz, DMSO-de): 5 (ppm) 160.6; 140.2; 137.5; 136.6; 136.1; 132.4; 129.7; 123.7; 122.2; 121.0; 118.6; 116.5; 114.5; 113.2; 112.9; 107.4; 102.9; 56.6

[0320] IR: v (cm' 1 ) 3307, 3084, 2948, 2848, 2560, 2226, 2028, 1681, 1662, 1602, 1567, 1493, 1473, 1440, 1351, 1309, 1291, 1265, 1220, 1182, 1169, 1120, 1107, 1053, 1015, 989, 933, 909, 860, 822, 795, 783, 731, 693

[0321] Example 7i: (Z)-((3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-1 H-indazol-5-yl)methyl)carbamate tert-butyl 6c (MK23) Chemical formula: C 24 H 23 N5O3 Molar mass: 429.4800

[0322] General procedure C is used with tert-butyl((3-(cyanomethyl)-1H-indazol-5-yl)methyl)carbamate 4c (84.5 mg, 0.30 mmol). The mixture is allowed to stand for 4 h under stirring and then concentrated to dryness under reduced pressure. The crude material is purified on three successive preparative plates (eluent: DCM:MeOH 95:5, then heptane:AcOEt 1:1, and finally AcOEtheptane 4:1) to obtain compound 6c as a pale yellow powder (45.3 mg, yield: 36%).

[0323] Pf 206 - 208 °C

[0324] HRSM (ESI-, m / z) wedge, for [MH]: 428.1728, measured: 428.1766

[0325] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 13.62 (si, 1H); 8.35 (d, J = 1.7 Hz, 1H); 8.14 (s, 1 H); 8.00 (dd, Ji = 8.7 Hz, J2 = 2.0 Hz, 1 H); 7.92 (s, 1H); 7.62, (d, J = 8.7 Hz, 1 H); 7.45 (t, J = 5.8 Hz, 1H); 7.38 (d, J = 8.8 Hz, 2H); 4.27 (d, J = 5.9 Hz, 2H); 4.01 (s, 3H); 1.38 (s, 9H)

[0326] NMR 13C (125 MHz, DMSO-de): 5 (ppm) 160.6; 155.8; 140.8; 137.8; 136.1; 135.2; 134.3; 132.2; 126.9; 123.7; 119.4; 118.6; 117.4; 116.5; 112.8; 111.1; 108.2; 103.0; 77.8; 56.7; 43.6; 28.2 (3C)

[0327] IR: v (cm- 1 ) 3359, 3183, 3055, 2983, 2931, 2229, 1678, 1611, 1521, 1496, 1465, 1445, 1369, 1325, 1265, 1157, 1100, 1019, 991, 931, 903, 852, 818, 769, 723

[0328] Example 7j (Z)-(3-(1-cyano-2-(4-methoxypyridin-3-yl)vinyl)-1 H-indazol-5-yl)tert-butyl carbamate 6d (MK35) Chemical formula: C 23 H 21 N5O3 Molar mass: 415.4530

[0329] General procedure C is used with tert-butyl((3-(cyanomethyl)-1H-indazol-5-yl)methyl)carbamate 4d (88.0 mg, 0.32 mmol). The mixture is allowed to stand for 3.5 h under stirring and then concentrated under reduced pressure. The residue is dissolved in AcOEt. The precipitate is filtered and then dissolved in an acetone:MeOH (9:1) mixture. The crude material is purified by preparative plate chromatography (eluent: DCM:MeOH 95:5) to form compound 6d as a yellow powder (67.1 mg, yield: 50%).

[0330] Pf 266 - 268 °C

[0331] HRSM (ESI-, m / z) wedge, for [MH]: 414.1572, measured: 414.1549

[0332] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 13.53 (s, 1H); 9.48 (s, 1H); 8.41 (d, J = 1.6 Hz, 1H); 8.40 (if, 1H); 8.11 (s, 1H); 7.99 (dd, Ji = 8.7 Hz, J2 = 1.9 Hz, 1H); 7.56 (d, J = 9.0 Hz, 1H); 7.44 (d, J = 8.8 Hz, 1H); 7.37 (d, J = 8.8 Hz, 1H); 4.05 (s, 3H); 1.50 (s, 9H)

[0333] NMR 13C (125 MHz, DMSO-de): 5 (ppm) 160,5; 153,0; 138,0; 137,9; 136,0; 134,5; 133,8; 131,6; 123,5; 120,5; 119,5; 118,6; 116,5; 112,9; 111,3; 107,9; 106,8; 103,0; 79,0; 56,5; 28,1 (3C)

[0334] IR: v (cm- 1 ) 3319, 2996, 2941, 2224, 1685, 1612, 1595, 1533, 1459, 1443, 1397, 1362, 1316, 1296, 1266, 1249, 1163, 1108, 1066, 1025, 991, 951, 897, 826, 813, 794, 763, 723

[0335] Exemple 7k (Z)-3-(2-cyano-2-(5-iodo-1 H-indazol-3-yl)vinyl)-4-méthoxybenzonitrile 6e (MK46)N H Formule brute: C 18 H 11 IN4O Masse molaire: 426,2175

[0336] General procedure C is used with 2-(5-iodo-1H-indazol-3-yl)acetonitrile 4e (75.0 mg, 0.26 mmol). Allow the mixture to stand for 3 h under stirring at room temperature, then quench the reaction with water. Extract the aqueous phase three times with AcOEt. Wash the combined organic phases three times with water, dry over MgSO4, filter, and evaporate under reduced pressure. Purify the crude material by preparative plate chromatography (eluent: DCM:MeOH 95:5) to obtain compound 6e as a yellow powder (50.7 mg, yield: 46%).

[0337] Pf 267 - 268 °C

[0338] HRSM (ESI-, m / z) wedge, for [MH]': 424.9905, measured: 424.9909

[0339] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 13.81 (s, 1H); 8.47 (s, 1H); 8.32 (d, J = 1.9 Hz, 1 H); 8.14 (s, 1 H); 7.99 (dd, Ji = 8.8 Hz, J2 = 2.2 Hz, 1 H); 7.69 (dd, Ji = 8.9 Hz; J2 = 1.1 Hz, 1H); 7.52 (d, J = 8.9 Hz, 1H); 7.37 (d, J = 9.1 Hz, 1H); 3.99 (s, 3H)

[0340] NMR 13 C (125 MHz, DMSO-de): 5 (ppm) 160.6; 141.1; 136.9; 136.0; 135.8; 134.5; 132.3; 128.2; 123.8; 122.0; 118.6; 116.6; 113.7; 112.8; 107.5; 102.9; 86.1; 56.6

[0341] IR: v (cm' 1 ) 3311, 2922, 2227, 1602, 1493, 1470, 1359, 1266, 1123, 1014, 902, 823, 794, 697, 683

[0342] Example 7I (Z)-3-(2-cyano-2-(5-fluoro-1 H-indazol-3-yl)vinyl)-4-methoxybenzonitrile 6f (MK43)CN H Chemical formula: C 18 H 11 FN4O Molar mass: 318.3114

[0343] General procedure C is used with 2-(5-fluoro-1H-indazol-3-yl)acetonitrile 4f (70.0 mg, 0.37 mmol). The mixture is left to stand for 5 h under stirring at room temperature, then quench the reaction with water. The mixture is filtered, and the filtrate is concentrated to dryness. After precipitation in MeOH, compound 6f is obtained as a yellow powder (31.9 mg, yield: 25%).

[0344] P.f. 283 - 286 °C H. R. S. M. (E S I ", m / z) cale, pour [M-H]’: 317,0839, mesurée: 317,0842

[0345] RMN 1 H (500 MHz, DMSO-de): 5 (ppm) 13,79 (s, 1 H); 8,33 (s, 1 H); 8, 13 (s, 1 H); 8,00 (dd, Ji = 8,9 Hz, J2= 1,7 Hz, 1H); 7,86 (dd, Ji = 9,8 Hz; J2= 0,8 Hz, 1H); 7,72 (dd, Ji = 9,0 Hz; J2= 4,5 Hz, 1H); 7,43-7,34 (m, 2H); 3,99 (s, 3H)

[0346] RMN 13 C (125 MHz, DMSO-de): 5 (ppm) 160,6; 157,9 (d, JC-F = 236,4 Hz); 138,7; 138,1; 136,0; 135,8; 132,4; 123,8; 119,3 (d, JC-F = 10,7 Hz); 118,6; 116,5 (d, JC-F = 11,0 Hz); 116,4; 113,0 (d, JC-F = 10,1 Hz); 112,9; 107,8; 104,2 (d, JC-F = 24,7 Hz); 102,9; 56,6

[0347] IR: v (cm’ 1 ) 3347, 2233, 1708, 1603, 1496, 1472, 1440, 1314, 1250, 1201, 1124, 1098, 1017, 987, 956, 912, 822, 699

[0348] Exemple 7m: (Z)-3-(2-(5-iodo-1-(méthylsulfonyl)-1 H-indazol-3-yl)-2-cyanovinyl)-4-méthoxy benzonitrile 13e (MK72) Chemical formula: C 19 H 13 IN4O3S Molar mass: 504.3025

[0349] Dissolve (Z)-3-(2-(5-iodo-1H-indazol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile 6e (99.0 mg, 0.23 mmol, 1 eq.) in THF (6.5 mL). Add sodium hydride (24.8 mg, 0.62 mmol, 2.7 eq.) at room temperature and let stand for 30 min with stirring, then add methanesulfonyl chloride (23 pL, 0.30 mmol, 1.3 eq.). Let the reaction mixture stand for 4 h with stirring at room temperature, then evaporate under reduced pressure. Purify the crude product by flash chromatography on a silica gel column (eluent: DCM) to obtain compound 13e as a yellow powder (43.4 mg, yield: 37%).

[0350] Pf 232 - 234 °C

[0351] HRSM (ESI + , m / z) wedge, for [M+H] + : 504.9826, measured: 504.9828

[0352] NMR 1H (500 MHz, DMSO-de): 5 (ppm) 8.63 (d, J = 0.9 Hz, 1 H); 8.38 (d, J = 1.8 Hz, 1H); 8.36 (s, 1H); 8.07 (dd, Ji = 8.7 Hz, J2 = 2.1 Hz, 1H); 8.03 (dd, Ji = 8.9 Hz, J2 = 1.5 Hz, 1H); 7.88 (d, J = 8.9 Hz, 1H); 7.42 (d, J = 8.7 Hz, 1H); 4.01 (s, 3H); 3.62 (s, 3H)

[0353] NMR 13 C (125 MHz, DMSO-de): 5 (ppm) 160.9; 143.2; 142.4; 140.3; 138.3; 137.0; 132.9; 129.5; 124.2; 123.1; 118.5; 115.9; 115.1; 113.1; 105.5; 103.0; 90.1; 56.7; 41.2

[0354] IR: v (cm- 1 ) 2225, 1603, 1493, 1377, 1357, 1268, 1177, 1115, 1086, 1039, 1011, 962, 821, 772, 711

[0355] Example 7n (Z)-3-(2-(5-bromo-1-(methylsulfonyl)-1 H-indazol-3-yl)-2-cyanovinyl)-4-methoxy benzonitrile 13b (MK28) Chemical formula: C19H13BrN4O3S Molar mass: 457.3020

[0356] Dissolve (Z)-3-(2-(5-bromo-1H-indazol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile 6b (24.4 mg, 0.04 mmol, 1 eq.) in THF (1.8 mL). Add sodium hydride (2.94 mg, 0.12 mmol, 1.9 eq.). Let stand for 30 min with stirring, then add methanesulfonyl chloride (6 µL, 0.08 mmol, 1.2 eq.). Let the mixture stand for 3 h with stirring at room temperature, then quench the reaction with water. Extract the aqueous phase three times using DCM. Wash the combined organic phases twice with water and once with brine, dry over MgSO4, filter, and concentrate under reduced pressure. Purify the crude material on a silica pad (eluent: DCM: acetone 95:5) to obtain compound 13b as a yellow powder (24.2 mg, yield: 82%).

[0357] Pf 248 - 249 °C

[0358] HRSM (ESI + , m / z) wedge, for [M 79 Br-H] + : 456.9965, measured: 456.9958

[0359] NMR 1H (500 MHz, DMSO-de): 5 (ppm) 8,47 (s, 1 H); 8,38 (d, J = 1,8 Hz, 1H); 8,36 (s, 1H); 8,06 (dd, Ji = 8,9 Hz, J2= 1,7 Hz, 1H); 8,01 (d, J = 9,0 Hz, 1H); 7,90 (dd, Ji = 9,1 Hz, J2= 1,1 Hz, 1H); 7,41 (d, J = 8,8 Hz, 1H); 4,01 (s, 3H); 3,63 (s, 3H) RMN 13 C (125 MHz, DMSO-de): 5 (ppm) 160,8; 143,4; 142,3; 139,9; 136,9; 132,9 (2C); 123,6; 123,5; 123,1; 118,4; 117,6; 115,8; 115,0; 113,1; 105,4; 103,0; 56,7; 41,2

[0360] IR: v (cm’ 1 ) 3120, 3017, 2924, 2853, 2227, 1603, 1586, 1491, 1445, 1414, 1363, 1326, 1291, 1270, 1220, 1171, 1122, 1098, 1064, 1040, 1220, 1171, 1122, 1098, 1040, 1015, 957, 942, 876, 811, 782, 764, 717

[0361] Exemple 7o (Z)-3-(2-(5-(aminométhyl)-1 H-indazol-3-yl)-2-cyanovinyl)-4-méthoxybenzonitrile 7c (MK40) N N H Formule brute: C 19 H 15 N5O Masse molaire: 329,3630

[0362] General procedure D is used with tert-butyl(Z)-((3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-1 H-indazol-5-yl)methyl)carbamate 6c (30.9 mg, 0.07 mmol). Allow the reaction mixture to stand for 3 h under stirring at room temperature, then add MTBE. Once the precipitate has formed, discard the supernatant and then concentrate under reduced pressure to obtain compound 7c as a white solid (14 mg, yield: 61%).

[0363] Pf 243 - 246 °C

[0364] HRSM (ESI" m / z) wedge, for [MH]': 328.1191, measured: 328.1204

[0365] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 13.80 (s, 1H); 8.33 (si, 3H); 8.21 (s, 1H); 8.16 (s, 1H); 8.01 (d, J = 8.0 Hz, 1H); 7.72 (d, J = 7.7 Hz, 1H); 7.57 (d, J = 9.3 Hz, 1H); 7.39 (d, J = 9.0 Hz, 1H); 4.20 (s, 2H); 4.00 (s, 3H)

[0366] NMR 13C (125 MHz, DMSO-de): 5 (ppm) 160.6; 141.3; 138.3; 136.2 (2C); 132.4; 128.1; 127.9; 123.8; 120.8; 119.4; 118.6; 116.4; 112.9; 111.5; 108.3; 103.0; 56.6; 42.6

[0367] IR: v (cm- 1 ) 3042, 2902, 2233, 1683, 1609, 1491, 1334, 1268, 1207, 1174, 1120, 1017, 991, 930, 904, 824, 796, 719

[0368] Example 7p (Z)-3-(2-(5-amino-1 H-indazol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile 7d (MK39) Chemical formula: C 18 H 13 N5O Molar mass: 315.3360

[0369] General procedure D is used with tert-butyl (Z)-(3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-1H-indazol-5-yl)carbamate 6d (45.4 mg, 0.11 mmol). Allow the reaction mixture to stand for 3 h under stirring at room temperature, then evaporate the solvent under reduced pressure. Wash the residue three times with MTBE. Once the precipitate has formed, discard the supernatant and then concentrate under reduced pressure to obtain compound 7d as a brown powder (15 mg, yield: 44%).

[0370] Pf 159-160 °C

[0371] HRS M (ESI + , m / z) wedge, for [M+H] + : 316.1193, measured: 316.1192

[0372] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 14.28 (s, 1 H); 8.80 (s, 1 H); 8.55 (s, 1H); 8.42 (d, J = 8.4 Hz, 1H); 8.33 (s, 1H); 8.15 (d, J = 8.8 Hz, 1H); 7.80 (d, J = 8.6 Hz, 1H); 7.76 (d, J = 8.6 Hz, 1H); 4.42 (s, 3H)

[0373] NMR 13C (500 MHz, DMSO-de): 5 (ppm) 160,6; 139,5; 137,5; 136,1; 135,0; 132,1; 123,4; 121,6; 121,0; 119,5; 118,5; 116,6; 112,8; 112,5; 110,7; 107,3; 102,9; 56,6

[0374] IR: v (cm’ 1 ) 2923, 2629, 2228, 1667, 1604, 1493, 1462, 1435, 1369, 1324, 1270, 1182, 1125, 1019, 948, 821, 798, 720

[0375] Exemple 7q: (Z)-2-(5-bromo-1 H-indazol-3-yl)-3-(4-chloropyridin-3-yl) acrylonitrile 9a (MK47) Cl N N Formule brute: C 15 H8BrCIN4 Masse molaire: 359,6110

[0376] General procedure C is used with 2-(5-bromo-1H-indazol-3-yl)acetonitrile 8a (71.5 mg, 0.30 mmol). Allow the mixture to stand for 6 h under stirring at room temperature, then quench with water. Extract the aqueous phase three times with ethyl acetate (AcOEt). Wash the combined organic phases twice with water and then once with brine, dry over magnesium oxide (MgSO4), filter, and concentrate under reduced pressure. Resuspend the crude mixture in MeOH at 0 °C for 30 min. Filter under reduced pressure and wash three times with MeOH at 0 °C, then dry the precipitate to obtain compound 9a as an orange powder (7.3 mg, yield: 14%).

[0377] Pf 256 °C (decomposition)

[0378] HRS M (ESI + , m / z) wedge, for [M+H] + : 356.9543, measured: 356.9543

[0379] NMR 1H (500 MHz, DMSO-de): 5 (ppm) 13,90 (s, 1H); 9,10 (s, 1H); 8,66 (d, J = 5,3 Hz, 1H); 8,40 (s, 1H); 8,23 (s, 1H); 7,77 (d, J = 5,3 Hz, 1H); 7,67 (d, J = 8,7 Hz, 1H); 7,60 (d, J = 8,9 Hz, 1H)

[0380] RMN 13 C (125 MHz, DMSO-de): 5 (ppm) 151,6; 149,7; 142,7; 140,7; 137,1; 136,2; 129,7; 129,4; 124,6; 122,2; 121,0; 116,0; 114,8; 113,4; 110,1

[0381] IR: v (cm- 1 ) 2901, 2250, 15575, 1472, 1309, 1242, 1026, 908, 820, 758, 688

[0382] Exemple 7r: (Z)-2-(5-bromo-1 H-indazol-3-yl)-3-(4-iodopyridin-3-yl)acrylonitrile 9b (MK58) Formule brute: C 15 H8BrlN4 Masse molaire: 451,0655

[0383] General procedure C is used with 2-(5-bromo-1H-indazol-3-yl)acetonitrile 4b (94.4 mg, 0.40 mmol). The mixture is allowed to stand for 5 h under stirring at room temperature and then evaporated under reduced pressure. The crude material is purified by flash chromatography on a silica gel column (eluent: DCM: MeOH 1:0 to 24:1) to form compound 9b as a pale yellow powder (56.6 mg, yield: 31%).

[0384] Pf 228 - 229 °C (decomposition)

[0385] HRSM (ESI-, m / z) hold, for [M+H] + : 450.9050, measured: 450.9052

[0386] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 13.92 (s, 1 H); 8.91 (s, 1H); 8.44 (s, 1H); 8.30 (d, J = 5.0 Hz 1 H); 8.13 (d, J = 5.3 Hz, 1 H); 8.07 (s, 1H); 7.68 (d, J = 8.8 Hz, 1 H); 7.61 (d, J = 8.7 Hz, 1H)

[0387] NMR 13 C (125 MHz, DMSO-de): 5 (ppm) 150.3; 148.2; 143.1; 140.3; 137.1; 135.0; 133.8; 129.9; 122.3; 120.9; 115.9; 114.8; 113.3; 112.0; 109.3

[0388] IR: v (cm- 1 ) 3246, 3037, 2918, 2226, 1556, 1465, 1400, 1362, 1300, 1259, 1189, 1115, 1062, 966, 908, 852, 829, 788, 718, 694

[0389] Example 7s: (Z)-2-(5-bromo-1 H-indazol-3-yl)-3-(3-nitrophenyl)acrylonitrile 11e Chemical formula: C 16 H9BrN4O2 Molar mass: 369.1780

[0390] General procedure C is used with 2-(5-bromo-1H-indazol-3-yl)acetonitrile 4b (100 mg, 0.42 mmol). The mixture is allowed to stand for 3 h under stirring at room temperature, then the solvent is evaporated under reduced pressure. The crude material is purified by flash chromatography on a silica gel column (eluent: DCM:MeOH 24:1) to obtain compound 11e as a yellow powder (111 mg, yield: 72%).

[0391] Pf 223 - 225 °C

[0392] HRSM (ESI + , m / z) wedge, for [M+H] + : 368.9987, measured: 368.9977

[0393] NMR1 H (300 MHz, acetone-d6): 5 (ppm) 8.96-8.94 (m, 1 H); 8.54 (if, 1H); 8.52 (d, J = 1.5 Hz, 1H); 8.40 (s, 1H); 8.38 (d, J = 2.0 Hz, 1H); 7.90 (t, J = 8.1 Hz, 1H); 7.75-7.71 (m, 1H); 7.63 (dd, Ji = 1.6 Hz, J2 = 7.2 Hz, 1H)

[0394] NMR 13 C (125 MHz, acetone-d6): 5 (ppm) 147.9; 140.3; 140.1; 138.0; 135.3; 135.0; 130.4; 129.9; 124.7; 124.1; 122.8; 120.8; 116.6; 114.8; 113.1; 107.3

[0395] IR: v (cm' 1 ) 3310, 3081, 2922, 2219, 1724, 1694, 1608, 1576, 1526, 1471, 1348, 1316, 1263, 1234, 1181, 1141, 1104, 1055, 1018, 971, 909, 800

[0396] Example 7t: (Z)-2-(5-bromo-1 H-indazol-3-yl)-3-(3-((2-methoxyethoxy)methoxy) phenyl)acrylonitrile 11f (MK 48) Chemical formula: C2oHi8BrN3O3 Molar mass: 428.2860

[0397] Dissolve sodium (23.8 mg, 1.03 mmol, 3.2 eq.) in MeOH (2 mL) and add 2-(5-bromo-1H-indazol-3-yl)acetonitrile 4b (75.8 mg, 0.32 mmol, 1 eq.). After 10 min of stirring, add a solution of 2-((2-methoxyethoxy)methoxy)benzaldehyde (80.9 mg, 0.32 mmol, 1.2 eq.) in MeOH (1.2 mL). Allow the mixture to stand for 5.5 h with stirring at room temperature, then quench with water. Extract the aqueous phase three times with AcOEt. Wash the combined organic phases three times with brine, dry over MgSO4, filter, and concentrate under reduced pressure. Purify the crude by chromatography on a preparative plate (eluent: DCM:MeOH 95:5) to obtain compound 11f as a yellow powder (71.7 mg, yield: 52%).

[0398] Pf 128 - 129 °C

[0399] HRSM (ESI + , m / z) wedge, for [M+H] + : 428.0604, measured: 428.0604

[0400] NMR 1H (500 MHz, DMSO-de): 5 (ppm) 12,80 (s, 1H); 8,42 (d, J = 1,1 Hz, 1H); 8,16 (s, 1H); 7,76 (s, 1H); 7,71 (d, J = 7,6 Hz, 1H); 7,67 (d, J = 8,9 Hz, 1H); 7,58 (dd, Ji = 8,9 Hz, J2= 1,5 Hz, 1H); 7,48 (t, J = 8,2 Hz, 1H); 7,22 (dd, Ji = 8,2 Hz, J2= 1,8 Hz, 1H); 5,36 (s, 2H); 3,83 (t, J = 4,9 Hz); 3,54 (t, J = 4,9 Hz, 2H); 3,29 (s, 3H)

[0401] RMN 13 C (125 MHz, DMSO-de): 5 (ppm) 158,7; 143,6; 141,6; 139,7; 136,1; 130,8 (2C); 123,7; 123,6; 122,4; 119,5; 118,1; 117,9; 115,5; 113,6; 105,7; 94,3; 72,4; 68,7; 58,8

[0402] IR: v (cm’ 1 ) 3290, 2895, 2218, 1600, 1575, 1473, 1306, 1243, 1171, 1109, 1063, 1026, 996, 914, 895, 851, 799, 779, 746, 680

[0403] Exemple 7u: (Z)-3-(3-aminophényl)-2-(5-bromo-1 H-indazol-3-yl)acrylonitrile 12e (MK61) Masse molaire: 339,1960

[0404] In a stand mixer, stir (Z)-2-(5-bromo-1H-indazol-3-yl)-3-(3-nitrophenyl)acrylonitrile 11e (25 mg, 0.07 mmol, 1 eq.), zinc (252 mg, 3.85 mmol, excess), and acetic acid (2 mL) for 20 min at room temperature. Quench the reaction with a saturated aqueous sodium carbonate solution. Extract the aqueous phase three times by DCM. Wash the combined organic phases twice with water and once with brine, dry over MgSO4, filter, and concentrate under reduced pressure. Purify the crude compound by preparative plate chromatography (eluent: DCM:MeOH 24:1) to obtain compound 12e as a yellow powder (11 mg, yield: 46%).

[0405] Pf 190 - 200 °C

[0406] HRSM (ESI + , m / z) wedge, for [M+H] + : 339.0245, measured: 339.0232

[0407] NMR 1H (300 MHz, acétone-d6): 5 (ppm) 12,81 (d, J = 14,7 Hz, 1 H); 8,43 (dd, Ji = 1,5 Hz, J2= 9,9 Hz, 1H); 8,17 (s, 1H); 8,02 (s, 1H); 7,75-7,71 (m, 1H); 7,68 (dd, Ji = 3,5 Hz, J2= 8,7 Hz, 1H); 7,63-7,56 (m, 1H); 7,48 (t, J = 7,7 Hz, 1H); 7,41-7,38 (m, 1H); 7,35-7,28 (m, 1H); 7,23 (t, J = 7,8 Hz, 1H)

[0408] RMN 13 C (125 MHz, acétone-d6): 5 (ppm) 144,1; 143,1; 134,5; 129,9; 129,8; 129,5; 129,4; 124,1; 122,8; 122,7; 121,9; 120,0; 115,0; 118,1; 116,9; 114,5; 112,7

[0409] IR: v (cm’ 1 ) 3210, 2920, 2420, 2218, 1702, 1601, 1579, 1470, 1307, 1263, 1168, 1140, 1111, 1053, 992, 909, 876, 797, 783

[0410] Exemple 7v: (Z)-2-(5-bromo-1 H-indazol-3-yl)-3-(3-hydroxyphényl)acrylonitrile 12f (MK49) H Formule brute: C 16 H 10 BrN3O Masse molaire: 340,1800

[0411] Dissolve (Z)-2-(5-bromo-1H-indazol-3-yl)-3-(3-((2-methoxyethoxy)methoxy)phenyl)acrylonitrile 11f (66.6 mg, 0.16 mmol, 1 eq.) in DCM (0.8 mL). Add trifluoroacetic acid (0.85 mL, 11.10 mmol, excess) and let stand for 2 h with stirring at room temperature. Purify the crude compound by preparative plate chromatography (eluent: DCM:MeOH 95:5 supplemented with 1% triethylamine) to obtain compound 12f as a yellow lake (13.5 mg, yield: 25%).

[0412] Pf 241 - 244 °C

[0413] HRSM (ESI + , m / z) wedge, for [M+H] + : 337.9934, measured: 337.9923

[0414] NMR 1 H (500 MHz, acetone-d6): 5 (ppm) 12.84 (s, 1H); 8.80 (s, 1H); 8.41 (d, J = 1.1 Hz, 1H); 8.10 (s, 1H); 7.68 (d, J = 8.9 Hz, 1H); 7.60 (t, J = 1.5 Hz, 1H); 7.57 (dd, Ji = 8.9 Hz, J2 = 1.5 Hz, 1H); 7.50 (d, J = 7.8 Hz, 1H); 7.38 (t, J = 7.9 Hz, 1H); 7.01 (dd, Ji = 8.2 Hz, J2 = 2.0 Hz, 1H)

[0415] NMR 13 C (125 MHz, acetone-d6): 5 (ppm) 158.8; 144.1; 141.7; 139.8; 136.1; 131.0; 130.8; 123.7; 122.6; 122.3; 119.0; 118.1; 116.4; 115.5; 113.7; 105.1

[0416] IR: v (cm- 1 ) 2331, 2921, 2220, 1579, 1470, 1361, 1331, 1232, 1162, 1112, 992, 942, 910, 780, 679

[0417] Example 7w: (Z)-5-bromo-3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-1 H-indazol-1 methyl carboxylate 14a (MK68)[j V-CN Chemical formula: C 20 H 13 BrN4O3 Molar mass: 437.2530

[0418] Dissolve (Z)-3-(2-(5-bromo-1 H-indazol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile (50 mg, 0.11 mmol, 1 eq.) in THF (2 mL). Add sodium hydride (6.0 mg, 0.26 mmol, 2 eq.) and let stand for 1 h with stirring at room temperature. Add methyl chloroformate (11 µL, 0.14 mmol, 1.1 eq.) and let stand for 3 h with stirring at room temperature. Quench the reaction with a saturated aqueous solution of NH4Cl, filter, wash with MeOH, and dry under reduced pressure to obtain compound 14a as a solid (27 mg, yield: 47%).

[0419] HRSM (ESI + , m / z) wedge, for C 20 H 14 N4O3Br [M+H] + : 437.0249, measured: 437.0232

[0420] NMR 1H (500 MHz, pyrid ine-de): 5 (ppm) 9.75 (d, J = 1.5 Hz, 1 H); 9.67 (d, J = 1.5 Hz, 1 H); 9.62 (s, 1 H); 9.42 (d, J = 8.9 Hz, 1 H); 8.95 (dd, J1 = 1.9 Hz, J2 = 8.7 Hz, 1 H); 8.93 (dd, J1 = 2.0 Hz, J2 = 9.0 Hz, 1H); 8.21 (d, J = 8.7 Hz, 1H); 5.15 (s, 3H); 4.89 (s, 3H)

[0421] NMR 13 C (175 MHz, pyridine): 5 (ppm) 161.3; 150.8; 143.4; 141.1; 140.4; 137.1; 133.0; 132.9; 130.1; 124.9; 118.9; 118.4; 116.9; 116.8; 112.7; 108.2; 105.8; 104.7; 56.4; 54.8

[0422] Example 7x: (Z)-5-bromo-3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-1 H-indazole-1 ethyl carboxylate 14b (MK69) Chemical formula: C 21 H 15 BrN4O3 Molar mass: 451.2800

[0423] Dissolve (Z)-3-(2-(5-bromo-1H-indazol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile 6b (50 mg, 0.11 mmol, 1 eq.) in 2 mL of water. Add sodium hydride (6.0 mg, 0.26 mmol, 2 eq.) and let the reaction mixture stand for 1 h with stirring at room temperature. Add ethyl chloroform iate (14 µl, 0.14 mmol, 1.1 eq.) and let the mixture stand for 3 h with stirring at room temperature. Quench the reaction with a saturated aqueous solution of NH4Cl. Filter the organic phase, wash with MeOH, and dry under reduced pressure to obtain compound 14b as a yellow solid (39 mg, yield: 60%).

[0424] HRSM (ESI + , m / z) wedge, for C 21 H 16 N4O3Br [M+H] + : 451.0406, measured: 451.0396

[0425] NMR 1H (500 MHz, DMSO-de): 5 (ppm) 8,45 (s, 1H); 8,38 (s, 1H); 8,36 (s, 1H); 8,21 (d, J = 8,8 Hz, 1H); 8,07 (dd, J1 = 2,0 Hz, J2 = 8,9 Hz, 1H); 7,90 (dd, J1 = 21,4 Hz, J2= 9,1 Hz, 1H); 7,42 (d, J = 8,7 Hz, 1H); 4,58 (q, J = 7,1 Hz, 2H); 4,02 (s, 3H);1,45 (t, J = 7,3 Hz, 3H)

[0426] RMN 13 C (125 MHz, DMSO-de): 5 (ppm) 160,8; 149,4; 142,7; 141,9; 139,5; 136,7; 132,8 (2C); 123,9; 123,3; 123,1; 118,5; 117,5; 116,5; 115,9; 113,1; 105,7; 102,9; 64,6; 56,7; 14,1

[0427] Exemple 7y (Z)-3-(2-(5-chloro-1 H-indazol-3-yl)-2-cyanovinyl)-4-méthoxybenzonitrile 6h (MK73) Formule brute: C 18 H 11 ClN4O Masse molaire: 334,7630

[0428] General procedure C is used with 2-(5-chloro-1H-indazol-3-yl)acetonitrile 4b (100.6 mg, 0.53 mmol). The reaction mixture is allowed to stand for 4 h under stirring at room temperature and then quenched with water. The aqueous phase is extracted three times with AcOEt. The combined organic phases are washed twice with water and then once with brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The compound is obtained after 6 h by precipitation in MeOH as a yellow powder (132.3 mg, yield: 75%).

[0429] Pf 286 - 289 °C

[0430] HRSM (ESI + , m / z) wedge, for [M+MeOH+H] + : 367.0956, measured: 367.0954

[0431] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 13.85 (si, 1H); 8.33 (d, J = 1.7 Hz, 1H); 8.17 (s, 2H); 8.00 (dd, Ji = 8.7 Hz, J2 = 2.0 Hz, 1H); 7.71 (d, J = 8.9 Hz, 1H); 7.49 (dd, Ji = 8.8 Hz, J2 = 1.7 Hz, 1H); 7.38 (d, J = 8.9 Hz, 1H); 3.99 (s, 3H)

[0432] RMN 13 C (125 MHz, DMSO-de): 5 (ppm) 160,7; 140,1; 137,7; 136,4; 136,1; 132,4; 127,3; 126,6; 123,7; 120,2; 119,1; 118,6; 116,5; 113,0; 112,9; 107,5; 102,9; 56,7

[0433] IR: v (cm’ 1 ) 3308, 2228, 1603, 1493, 1475, 1266, 1121, 1016, 918, 823, 800, 696

[0434] Exemple 7z (Z)-2-(5-chloro-1 H-indazol-3-yl)-3-(4-méthoxypyridin-3-yl) acrylonitrile 5h (MK74) For mule brute: C 16 H 11 ClN4O Masse molaire: 310,7410

[0435] General procedure C is used with 2-(5-chloro-1H-indazol-3-yl)acetonitrile 4b (100.0 mg, 0.52 mmol). The mixture is left to stand for 5 h under stirring at room temperature and then quenched with water. The aqueous phase is extracted three times with AcOEt. The combined organic phases are washed twice with water and then once with brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The compound is obtained, by precipitation in MeOH, as a yellow powder (130.9 mg, yield: 81%).

[0436] Pf 251 - 253 °C

[0437] HRSM (ESI + , m / z) wedge, for [M+H] + : 311.0694, measured: 311.0693

[0438] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 13.84 (si, 1H); 8.94 (s, 1H); 8.58 (d, J = 5.8 Hz, 1H); 8.17 (d, J = 1.5 Hz, 1H); 8.16 (s, 1H); 7.71 (d, J = 8.9 Hz, 1H); 7.49 (dd, Ji = 9.0 Hz, J2 = 1.8 Hz, 1H); 7.25 (d, J = 5.8 Hz, 1H); 3.97 (s, 3H)

[0439] NMR 13C (125 MHz, DMSO-de): 5 (ppm) 163.1; 152.9; 148.9; 140.1; 137.8; 135.7; 127.3; 126.6; 120.2; 119.5; 119.1; 116.8; 113.0; 107.4; 106.8; 56.2

[0440] IR: v (cm- 1 ) 2675, 2214, 1598, 1497, 1471, 1439, 1309, 1279, 1203, 1113, 1014, 917, 849, 808, 787

[0441] Example 7za: (Z)-(2-(3-(1 -cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-1 H-indazol-5-yl)ethyl)tert-butyl carbamate 6i (MK75) BocHN Chemical formula: C25H25N5O3 Molar mass: 443.5070

[0442] General procedure C is used with tert-butyl(2-(3-(cyanomethyl)-1H-indazol-5-yl)ethyl)carbamate 4i (131.5 mg, 0.44 mmol). The mixture is left to stand for 4 h under stirring at room temperature and then quenched with water. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed twice with water and then once with brine, dried over magnesium oxide (MgSO4), filtered, and evaporated under reduced pressure. Compound 6i is obtained by precipitation in MeOH as a yellow powder (117.8 mg, yield: 61%).

[0443] Pf 223 - 224 °C

[0444] HRSM (ESI-, m / z) wedge, for [MH]-: 442.1885, measured: 442.1883

[0445] NMR 1H (500 MHz, DMSO-de): 5 (ppm) 13,58 (si, 1H); 8,33 (d, J = 2,1 Hz, 1H); 8,15 (s, 1H); 8,00 (dd, Ji = 8,7 Hz, J2= 2,0 Hz, 1 H); 7,86 (s, 1H); 7,58 (d, J = 8,7 Hz, 1H); 7,38 (d, J = 8,7 Hz, 1H); 7,32 (d, J = 8,2 Hz, 1H); 6,90 (t, J = 5,4 Hz, 1H); 4,01 (s, 3H); 3,23-3,15 (m, 2H); 2,84 (t, J = 7,3 Hz, 2H); 1,32 (s, 9H)

[0446] RMN 13 C (125 MHz, DMSO-de): 5 (ppm) 160,6; 155,5; 140,6; 137,7; 136,0; 135,4; 133,5; 132,3; 128,5; 123,9; 119,8; 119,0; 118,7; 116,6; 112,9; 111,0; 107,7; 103,0; 77,5; 56,7; 41,8; 35,6; 28,2 (3C)

[0447] IR: v (cm’ 1 ) 3197, 2932, 2223, 1677, 1609, 1513, 1490, 1447, 1366, 1325, 1267, 1159, 1106, 1021, 974, 922, 904, 860, 803

[0448] Exemple 7zb: (Z)-(2-(3-(1-cyano-2-(4-méthoxypyridin-3-yl)vinyl)-1 H-indazol-5-yl)éthyl)carbamate de tert-butyle 5i (MK76) BocHN Formule brute: C23H25N5O3 Masse molaire: 419,4850

[0449] General procedure C is used with tert-butyl(2-(3-(cyanomethyl)-1H-indazol-5-yl)ethyl)carbamate 4i (114.2 mg, 0.38 mmol). The mixture is left to stand for 4 h under stirring at room temperature, then quenched with water. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed twice with water and then once with brine, dried over magnesium oxide (MgSO4), filtered, and evaporated under reduced pressure. Compound 5i is obtained by precipitation in MeOH as a yellow powder (100.5 mg, yield: 63%).

[0450] Pf 197 - 199 °C

[0451] HRSM (ESI-, m / z) wedge, for [MH]': 418.1885, measured: 418.1882

[0452] NMR 1H (500 MHz, DMSO-de): 5 (ppm) 13,55 (si, 1H); 8,95 (s, 1H); 8,57 (d, J = 5,8 Hz, 1H); 8,13 (s, 1H); 7,87 (s, 1H); 7,58 (d, J = 8,7 Hz, 1H); 7,32 (d, J = 8,7 Hz, 1H);7,25 (d, J = 6,0 Hz, 1H); 6,90 (t, J = 5,5 Hz, 1H); 3,99 (s, 3H); 3,23-3,15 (m, 2H); 2,84 (t, J = 7,3 Hz, 2H); 1,32 (s, 9H)

[0453] RMN 13 C (125 MHz, DMSO-de): 5 (ppm) 163,0; 155,5; 152,8; 148,7; 140,5; 137,7; 134,7; 133,4; 128,5; 119,7; 119,5; 119,0; 116,9; 111,0; 107,6; 107,4; 77,5; 56,2; 41,8; 35,6; 28,2 (3C)

[0454] IR: v (cm- 1 ) 3201, 2932, 2225, 1675, 1590, 1532, 1493, 1445, 1363, 1282, 1169, 1102, 1062, 1017, 983, 965, 926, 808, 793, 717

[0455] Exemple 7zc: (Z)-2-(5-(2-aminoéthyl)-1 H-indazol-3-yl)-3-(4-méthoxypyridin-3-yl)acrylonitrile 5j (MK77) N N Formule brute: C 18 H 17 N5O Masse molaire: 319,3680

[0456] General procedure D is used with tert-butyl(Z)-(2-(3-(1-cyano-2-(4-methoxypyridin-3-yl)vinyl)-1H-indazol-5-yl)ethyl)carbamate 5i (96.0 mg, 0.23 mmol). Allow the mixture to stand for 1.5 h under stirring at room temperature. Add MTBE and then concentrate under reduced pressure. Resuspend the crude mixture in MTBE and remove the supernatant to obtain compound 5j as a yellow powder (68.4 mg, yield: 94%).

[0457] HRSM (ESI-, m / z) wedge, for [M-Hp: 320.1506 measured: 320.1507

[0458] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 9.07 (s, 1 H); 8.53 (d, J = 6.0 Hz, 1H); 8.21 (s, 1H); 7.95 (s, 1H); 7.59 (d, J = 8.4 Hz, 1H); 7.36 (d, J = 8.7 Hz, 1H); 7.26 (d, J = 6.0 Hz, 1H); 4.09 (s, 3H); 3.00-2.91 (m, 4H)

[0459] NMR 13 C (75 MHz, MeOH-d4): 5 (ppm) 146.4; 133.8; 130.2; 124.8; 120.1; 115.5; 115.0; 109.9; 102.7; 102.6; 101.0; 99.0; 93.6; 90.0; 89.2; 37.7; 25.3; 21.2

[0460] IR: v (cm' 1 ) 3146, 2922, 2225, 1584, 1487, 1329, 1283, 1204, 1101, 1018, 805

[0461] Example 7zd (Z)-3-(2-(5-(2-aminoethyl)-1 H-indazol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile 7i (MK78)[ / \^-CN H2N Chemical formula: C 20 H 17 N5O Molar mass: 343.3900

[0462] General procedure D is used with tert-butyl(Z)-(2-(3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-1H-indazol-5-yl)ethyl)carbamate 6i (106.5 mg, 0.24 mmol). Allow the mixture to stand for 1.5 h under stirring at room temperature. Add MTBE and then concentrate under reduced pressure. Precipitate the product in MTBE. Remove the supernatant to obtain compound 7i as a yellow powder (13.5 mg, yield: 16%).

[0463] Pf 226 - 227 °C

[0464] HRSM (ESI-, m / z) wedge, for [MH]': 342.1360, measured: 342.1357

[0465] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 8.32 (d, J = 2.1 Hz, 1H); 8.03 (s, 1H); 7.90 (dd, Ji = 8.7 Hz, J2 = 1.9 Hz, 1H); 7.78 (s, 1H); 7.53 (d, J = 8.5 Hz, 1H); 7.34 (d, J = 8.8 Hz, 1H); 7.16 (d, J = 8.2 Hz, 1H); 4.00 (s, 3H); 2.85 (t, J = 6.8 Hz, 2H); 2.78 (t, J = 6.8 Hz, 2H)

[0466] NMR 13 C: A coalescence phenomenon is observed, requiring high-temperature NMR, which degrades the compound. Due to this degradation and low solubility, an NMR spectrum 13 C could not be obtained.

[0467] IR: v (cm' 1 ) 3593, 2924, 2229, 1608, 1456, 1370, 1325, 1267, 1101, 1015, 952, 908, 805

[0468] Example 7ze: (Z)-2-(5-(aminomethyl)-1 H-indazol-3-yl)-3-(4-methoxypyridin-3-yljacrylonitrile 5k (MK79) Chemical formula: C 17 H 15 N5O Molar mass: 305.3410

[0469] General procedure D is used with tert-butyl(Z)-((3-(1-cyano-2-(4-methoxypyridin-3-yl)vinyl)-1 H-indazol-5-yl)methyl)carbamate 5c (98.5 mg, 0.24 mmol). Allow the reaction mixture to stand for 2 h under stirring. Add MTBE and then concentrate under reduced pressure. Precipitate the crude product in MTBE and discard the supernatant. Purify the crude product by preparative plate chromatography (eluent: DCM: MeOH 9:1 + 5% NH3(aq)) to form compound 5k as a yellow powder (33.5 mg, yield: 45%).

[0470] Pf 185 - 188 °C

[0471] HRSM (ESI-, m / z) wedge, for [MH]': 304.1204, measured: 304.1205

[0472] NMR 1 H (500 MHz, MeOH-d4): 5 (ppm) 9.04 (s, 1H); 8.52 (d, J = 5.9 Hz, 1H); 8.23 (s, 1H); 8.05 (s, 1H); 7.58 (dd, Ji = 8.7 Hz, J2 = 0.6 Hz, 1H); 7.49 (dd, Ji = 8.8 Hz, J2 = 1.2 Hz, 1H); 7.24 (d, J = 6.0 Hz, 1H); 4.06 (s, 3H); 3.95 (s, 2H)

[0473] NMR 13C (125 MHz, MeOH-d4): 5 (ppm) 165.7; 153.2; 149.5; 142.7; 139.9; 137.9; 135.6; 128.8; 121.7; 121.3; 119.3; 117.9; 112.1; 109.1; 108.4; 56.9, 46.9

[0474] IR: v (cm' 1 ) 2902, 2224, 1588, 1495, 1458, 1282, 1023, 802

[0475] Example 7zf: (Z)-3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 H-indazole-1 ethyl carboxylate 15e (MK80) Chemical formula: C 21 H 15 IN4O3 Molar mass: 498.2805

[0476] Dissolve (Z)-3-(2-cyano-2-(5-iodo-1H-indazol-3-yl)vinyl)-4-methoxybenzonitrile (50.1 mg, 0.12 mmol, 1 eq.) in DMF (1.3 mL). Add triethylamine (35 pL, 0.25 mmol, 2.1 eq.) and let stand for 10 min with stirring. Add ethyl chloroform iate (15 pL, 0.16 mmol, 1.3 eq.) and stir for 16 h at room temperature. After evaporation under reduced pressure, purify the crude compound by preparative plate chromatography (eluent: DCM) to obtain compound 15e as a pale yellow powder (16.1 mg, yield: 27%).

[0477] Pf 248 - 251 °C

[0478] HRSM (ESI + , m / z) wedge for [M+H] + : 499.0262, measured: 499.0262

[0479] NMR 1H (500 MHz, chloroform-d): 5 (ppm) 8.52 (d, J = 0.9 Hz, 1 H); 8.39 (d, J = 1.8 Hz, 1H); 8.37 (s, 1H); 8.07 (d, J = 9.0 Hz, 1H); 7.88 (dd, Ji = 8.9 Hz, J2 = 1.5 Hz, 1H); 7.77 (dd, Ji = 8.7 Hz, J2 = 1.9 Hz, 1H); 7.07 (d, J = 0.9 Hz, 1H); 4.63 (q, J = 7.1 Hz, 2H); 4.00 (s, 3H); 1.55 (t, J = 7.1 Hz, 3H)

[0480] NMR 13 C (125 MHz, chloroform-d): 5 (ppm) 161.1; 150.2; 143.0; 140.8; 140.6; 138.5; 136.9; 132.8; 129.8; 125.4; 123.5; 118.4; 116.7; 116.2; 114.2; 111.9; 105.0; 89.0; 65.0; 56.5; 14.5

[0481] IR: v (cm- 1 ) 2987, 2226, 1748, 1605, 1501, 1484, 1403, 1380, 1350, 1261, 1249, 1126, 1050, 1013, 927, 846, 810, 757, 675

[0482] Example 7zg: (Z)-2-(5-iodo-1-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)-1H-indazol-3-yl)-3-(4-methoxypyridin-3-yl)acrylonitrile 16e (MK81) Molar mass: 562.3645

[0483] Dissolve (Z)-2-(5-iodo-1H-indazol-3-yl)-3-(4-methoxypyridin-3-yl)acrylonitrile (61.8 mg, 0.15 mmol, 1 eq.) and PyBOP (123.9 mg, 0.24 mmol, 1.6 eq.) in DMF (1.7 mL). Add triethylamine (45.5 pL, 0.32 mmol, 2.1 eq.) and 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (32 pL, 0.21 mmol, 1.4 eq.) successively. Stir the reaction mixture for 17 h at room temperature. Quench the reaction with water and then filter. Wash the precipitate three times with methanol to obtain compound 16e in the form of a white powder (16.4 mg, yield: 19%).

[0484] Pf 189 - 191 °C

[0485] HRSM (ESI + , m / z) wedge for [M+H] + : 563.0786, measured: 563.0784

[0486] NMR 1H (700 MHz, DMSO-de): 5 (ppm) 8,97 (s, 1 H); 8,63 (s, 1H); 8,62 (d, J = 5,7 Hz, 1H); 8,38 (s, 1H); 8,23 (d, J = 8,9 Hz, 1H); 8,05 (dd, Ji = 8,7 Hz, J2= 1,0 Hz, 1H); 7,29 (d, J = 5,8 Hz, 1 H); 5,05 (s, 2H); 3,99 (s, 3H); 3,78 (t, J = 4,6 Hz, 2H); 3,62 (t, J = 4,5 Hz, 2H); 3,54 (t, J = 4,7 Hz, 2H); 3,40 (t, J = 4,8 Hz, 2H); 3,20 (s, 3H)

[0487] RMN 13 C (175 MHz, DMSO-de): 5 (ppm) 169,8; 163,3; 153,7; 149,3; 142,6; 141,6; 139,2; 138,7; 129,5; 124,5; 119,0; 116,7; 116,0; 107,5; 104,9; 90,5; 71,2; 70,3; 70,0; 69,6; 69,2; 58,0; 56,3

[0488] IR: v (cm- 1 ) 2902, 2226, 1728, 1586, 1478, 1417, 1396, 1322, 1274, 1204, 1156, 1092, 1011, 964, 917, 849, 808

[0489] Exemple 7zh (Z)-3-(5-amino-2-chlorophényl)-2-(5-bromo-1 H-indazol-3-yl)acrylonitrile 44a (MK59)NH2 Formule brute: C 16 H 10 BrCIN4 Masse molaire: 373,6380

[0490] Solubilize (Z)-2-(5-bromo-1H-indazol-3-yl)-3-(2-chloro-5-nitrophenyl)acrylonitrile 43a (101.4 mg, 0.25 mmol, 1 eq.) and zinc (1 g, excess) in glacial acetic acid (4 mL). Allow the mixture to stand for 1 h with stirring, then filter through Celite. Extract three times by DCM. Wash the combined organic phases twice with water and once with brine, dry over MgSO4, filter, and evaporate under reduced pressure. Purify the crude product by flash chromatography on silica gel column (eluent: DCM:MeOH, 1:0 to 96:4) to obtain 44a as a yellow powder (13.4 mg, yield: 14%).

[0491] Pf: 253-254 °C (decomposition)

[0492] HRSM (ESI + , m / z) wedge for [M 35 CI+H] + 372.9850, measured 372.9857 [M 35 CI+H] + ,

[0493] NMR 1H (500 MHz, acétone-d6): 5 (ppm) 12,90 (s, 1H); 8,38 (dd, Ji = 1,8 Hz, J2= 0,5 Hz, 1H); 8,27 (s, 1H); 7,70 (dd, Ji = 8,9 Hz, J2= 0,5 Hz,1H); 7,60 (dd, Ji = 8,9 Hz, J2= 1,7 Hz,1H); 7,47 (d, J = 2,7 Hz, 1H); 7,25 (d, J = 8,9 Hz, 1H); 6,84 (dd, Ji = 8,8 Hz, J2= 2,6 Hz,1H); 5.14 (brs, 2H).

[0494] RMN 13 C (125 MHz, acétone-d6): 5 (ppm) 148,9; 141,7; 141,0; 139,5; 132,0; 131,0; 130,8; 123,4; 122,5; 121,9; 118,6; 117,2; 115,7; 115; 113,8; 107,6

[0495] IR: v (cm’ 1 ) 3225, 2920, 2225, 1702, 1596, 1568, 1469, 1401, 1361, 1312, 1250, 1167, 1109, 1047, 910, 799, 691.

[0496] Exemple 7zi (Z)-3-(5-amino-2-bromophényl)-2-(5-bromo-1 H-indazol-3-yl)acrylonitrile 44b (MK60) H Formule brute: C 16 H 10 Br2N4 Masse molaire: 418,0920

[0497] Solubilize (Z)-2-(5-bromo-1H-indazol-3-yl)-3-(2-bromo-5-nitrophenyl)acrylonitrile 43b (101.4 mg, 0.25 mmol, 1 eq.) and zinc (1 g, in excess) in glacial acetic acid (4 mL). Allow the mixture to stand for 1 h with stirring, then filter through Celite. Extract three times by DCM. Wash the combined organic phases twice with water and once with brine, dry over MgSO4, filter, and evaporate under reduced pressure. Purify the crude product by flash chromatography on silica gel column (eluent: DCM:MeOH, 1:0 to 96:4) to obtain 44b as a yellow powder (11.3 mg, yield: 12%).

[0498] Pf: 262 - 264 °C (decomposition)

[0499] HRSM (ESI-, m / z) wedge for [M 79 Br-H]- 416.9345, measured: 416.9343,

[0500] NMR 1H (500 MHz, acetone-d6): 5 (ppm) 12.90 (s, 1H); 8.41 (dd, Ji = 1.7 Hz, J2 = 0.5 Hz, 1 H); 8.20 (s, 1H); 7.70 (dd, Ji = 8.9 Hz, J2 = 0.6 Hz, 1 H); 7.60 (dd, Ji = 8.9 Hz, J2 = 1.7 Hz, 1 H); 7.45 (d, J = 2.7 Hz, 1 H); 7.42 (d, J = 8.6 Hz, 1 H); 6.78 (dd, Ji = 8.6 Hz, J2 = 2.7 Hz, 1H); 5.17 (if, 2H).

[0501] NMR 13 C (125 MHz, acetone-d6): 5 (ppm) 149.5; 143.5; 141.7; 139.5; 134.7; 134.2; 130.9; 123.5; 122.5; 118.8; 117.1; 116.3; 115.7; 115.5; 113.8; 107.8

[0502] IR: v (cm' 1 ) 3219, 2921, 2222, 1703, 1593, 1469, 1310, 1247, 1169, 1110, 944, 911, 877, 800, 686.

[0503] Example 7zj (Z)-4-chloro-3-(2-cyano-2-(5-iodo-1 / - / -indazol-3-yl)vinyl) benzonitrile 6j (MK114)Crude formula: C 17 H8ClIN4 Molar mass: 430.63

[0504] General procedure C is used with 3-formyl-4-chlorobenzonitrile (121 mg, 0.73 mmol) to obtain 6j in the form of a yellow powder (211 mg, yield: 74%).

[0505] RMN 1 H (400 MHz, DMSO-de): 5 (ppm) 9,28 (s, 1H); 8,58 (s, 1H); 8,49 (s, 1H); 8,30 (s, 1 H); 8,25 (s, 1 H); 7,75 (d, J = 9,4 MHz, 1 H); 7,56-7,54 (m, 2H)

[0506] RMN 13 C (100 MHz, DMSO-de): 5 (ppm) 164,3; 160,3; 139,8; 138,3; 135,6; 135,2; 134,0; 131,6; 130,4; 130,2; 128,9; 128,7; 122,4; 113,9; 110,5; 87,3; 53,7

[0507] Exemple 7zk: 3-formyl-4-iodobenzonitrile 56 O Formule brute : C8H4INO Masse molaire 257,03

[0508] Dissolve 3-formyl-4-chlorobenzonitrile (100 mg, 0.60 mmol, 1 eq.) and sodium iodide (181 mg, 1.21 mmol, 2 eq.) in acetonitrile (0.3 M). After 3 days of stirring at room temperature, quench the reaction with water. Extract the aqueous phase three times using DCM. Wash the combined organic phases with brine, dry over MgSO4, filter, and concentrate under reduced pressure to obtain a white powder (92 mg, yield: 59%).

[0509] NMR 1 H (400 MHz, chloroform-d): 5 (ppm) 10.44 (s, 1H); 8.19 (s, 1H); 7.79 (d, J = 8.3 Hz, 1 H); 7.61 (d, J = 8.3 Hz, 1 H)

[0510] NMR 13 C (100 MHz, chloroform-d): 5 (ppm) 187.6; 142.2; 137.4; 133.3; 133.2; 132.0; 116.9; 112.2

[0511] Example 7zl: (Z)-4-iodo-3-(2-cyano-2-(5-iodo-1 / - / -indazol-3-yl)vinyl)benzonitrile 6k (MK115) CN i NC H N Chemical formula: Molar mass 522.09

[0512] General procedure C is used with 3-formyl-4-iodobenzonitrile 56 (71 mg, 0.28 mmol) to obtain 6k in the form of a yellow powder (40 mg, yield: 31%).

[0513] NMR 1 H (400 MHz, DMSO-de): 5 (ppm) 13.88 (s, 1H); 9.28 (s, 1H); 8.58 (d, J = 2.8 Hz, 1 H); 8.49 (s, 1 H); 8.30 (s, 1 H); 8.25 (s, 1H); 7.92 (d, J = 8.4 Hz, 1 H); 7.78-7.73 (m, 1H); 7.55 (d, J = 8.8 Hz, 1H)

[0514] NMR 13 C (100 MHz, DMSO-de): 5 (ppm) 141.2; 139.8; 137.5; 136.1; 135.6; 135.2; 134.3; 131.6; 130.4; 128.9; 122.5; 121.0; 113.9; 111.2; 87.4

[0515] Example 7zm (Z)-3-(2-cyano-2-(5-(trifluoromethyl)-1 H-indazol-3-yl)vinyl)-4- methoxybenzonitrile 6I O CN NC (Z F ; , C H 'N N H Chemical formula: C 19 H 11 F3N4O Molar mass: 368.32

[0516] General procedure C is used with 2-(5-(trifluoromethyl)-1 H-indazol-3-yl)acetonitrile 4j (152 mg, 0.68 mmol) and 3-formyl-4-methoxybenzonitrile (119 mg, 0.74 mmol) to obtain 6I as a yellow solid (160 mg, yield: 63%).

[0517] MS (ESI + , m / z) wedge, for [M+H] + : 369.2, measured: 369.2

[0518] NMR 1 H (400 MHz, DMSO-de): 5 (ppm) 14.06 (s, 1 H); 8.49 (s, 1 H); 8.36 (s, 1H); 8.36 (d, J = 2.1 Hz, 1H); 8.26 (s 1H); 8.02 (dd, Ji = 8.7 Hz, J2 = 2.2 Hz, 1H); 7.88 (d, J = 8.6 Hz, 1H); 7.76 (d, J = 9.1 Hz, 1H); 3.99 (s, 3H)

[0519] NMR 13 C (100 MHz, DMSO-de): 5 (ppm) 160.7; 142.5; 139.2; 137.1; 132.2; 132.3; 126.0; 123.5; 123.3; 123.2 (d, J = 2.6 Hz); 122.7 (d, J = 31.8 Hz); 118.6 (d, J = 4.7 Hz); 118.1 (d, J = 4.2 Hz); 116.5; 112.9; 112.6; 106.8; 103.0; 56.7

[0520] Example 8: Synthesis protocol for phosphonates and phosphates

[0521] Example 8a: 17a ethyl 5-(bis(benzyloxy)phosphoryl)pentanoate U 0Bn > p -OBn H O Chemical formula: C 21 H 27 O5P Molar mass: 390.4158

[0522] General procedure E is used with ethyl 5-bromovalerate (100 pL, 0.63 mmol) to obtain compound 17a as a colorless oil (245 mg, quantitative yield).

[0523] NMR 1 H (500 MHz, chloroform-d): 5 (ppm) 7.40-7.31 (m, 10H); 5.06-5.03 (m, 2H); 4.97-4.93 (t, J = 8.6 Hz, 2H); 4.10 (q, J = 7.0 Hz, 2H); 2.24 (t, J = 7.3 Hz, 2H); 1.78-1.58 (m, 6H); 1.23 (t, J = 6.8 Hz, 3H) ppm

[0524] NMR 13 C (125 MHz, chloroform-d): 5 (ppm) 173.2; 136.4 (2C); 128.6 (4C); 128.4 (2C); 127.9 (4C); 67.1; 67.0; 60.4; 33.7; 25.8; 25.6; 21.9; 14.2

[0525] Example 8b: ethyl 4-(bis(benzyloxy)phosphoryl)butanoate 17b OO He 11 F ^ 0Bn OBn Chemical formula: C 20 H 25 O5P Molar mass: 376.3888

[0526] General procedure E is used with ethyl 4-bromobutyrate (200 pL, 1.34 mmol) to obtain compound 17b as a colorless oil (517 mg, yield: 98%).

[0527] NMR 1 H (500 MHz, chloroform-d): 5 (ppm) 7.29-7.25 (m, 10H); 5.01-4.95 (m, 2H); 4.89-4.85 (m, 2H), 4.05 (q, J = 7.6 Hz, 2H); 2.28 (t, J = 7.3 Hz, 2H); 1.87-1.68 (m, 4H); 1.18-1.12 (m, 3H)

[0528] NMR 13 C (125 MHz, chloroform-d): 5 (ppm) 172.5; 136.5; 136.4; 128.6 (4C); 128.3 (2C); 127.9 (4C); 67.2; 67.1; 60.3; 34.5; 24.4; 18.0; 14.2

[0529] Example 8c: Dibenzyl (4-((tetrahydro-2 / - / -pyran-2-yl)oxy)butyl)phosphonate 17cP OBn O Chemical formula: C 23 H 31 O5P Molar mass: 418.47

[0530] General procedure E is used with 2-(4-bromobutoxy)tetrahydro-2 / - / -pyrane (200 mg, 0.84 mmol) to obtain 17c in the form of a yellow oil (303 mg, yield: 86%).

[0531] NMR 1 H (400 MHz, chloroform-d): 5 (ppm) 7.37-7.30 (m, 10H); 5.08-5.02 (m, 2H); 4.98-4.93 (m, 2H); 4.52 (t, J = 3.8 Hz, 1H); 3.84-3.78 (m, 1H); 3.72-3.66 (m, 2H); 3.50-3.44 (m, 1 H); 3.37-3.30 (m, 1 H); 1.83-1.47 (m, 11 H)

[0532] Example 8d: 5-(bis(benzyloxy)phosphoryl)pentanoic acid 18a U OBn P' II 0Bn O Chemical formula: C 19 H 23 O5P Molar mass: 362.3618

[0533] General procedure F is used with ethyl 5-(bis(benzyloxy)phosphoryl)pentanoate 17a (100 mg, 0.26 mmol) to obtain compound 18a as a pale yellow oil (78 mg, yield: 82%).

[0534] NMR 1 H (300 MHz, MeOH-d4): 5 (ppm) 7.40-7.34 (m, 10H); 5.07-5.03 (m, 2H); 5.00-4.97 (m, 2H); 2.26 (t, J = 7.2 Hz, 2H); 1.83 (quint, J = 8.4 Hz, 2H); 1.68-1.56 (m, 4H)

[0535] NMR 13 C (75 MHz, MeOH-d4): 5 (ppm) 177.0; 137.8; 137.7; 129.7 (4C); 129.6 (2C); 129.2 (4C); 68.7; 68.6; 34.3; 27.3; 26.6; 22.9

[0536] Example 8e: 4-(bis(benzyloxy)phosphoryl)butanoic acid 18b . OBn HO x f x ^^P'OBn II OO Chemical formula: C 18 H 21 O5P Molar mass: 348.3348

[0537] General procedure F is used with ethyl 4-(bis(benzyloxy)phosphoryl)butanoate 17b (229 mg, 0.61 mmol) to obtain compound 18b as a pale yellow oil (181 mg, yield: 85%).

[0538] NMR 1 H (500 MHz, chloroform-d): 5 (ppm) 8.87 (s, 1H); 7.42-7.32 (m, 10H); 5.10-5.05 (m, 2H); 5.01-4.97 (m, 2H); 2.46-2.39 (m, 4H); 1.95-1.90 (m, 2H)

[0539] Example 8f: dibenzyl (4-hydroxybutyl)phosphanoate 19a . OBn II O Chemical formula: C 18 H 23 O4P Molar mass: 334.3518

[0540] Dissolve dibenzyl(4-((tetrahydro-2 / - / -pyran-2-yl)oxy)butyl)phosphonate 17c (160 mg, 0.38 mmol, 1 eq.) in DCM (0.1 M). Add tritylium tetrafluoroborate (189 mg, 0.57 mmol, 1.5 eq.). After 2 h of stirring at room temperature, concentrate the solution under reduced pressure. Purify the crude product by silica gel column chromatography (eluent: PET:AcOEt from 1:0 to 0:1 then AcOEt:MeOH from 1:0 to 9:1) to obtain 19a as a brown oil (123 mg, yield: 96%).

[0541] HRSM (ES I + ,m / z) wedge for [M+H] + : 335.1407, measured: 335.1409

[0542] NMR 1 H (500 MHz, chloroform-d): 5 (ppm) 7.37-7.31 (m, 10H); 5.07-5.03 (m, 2H); 4.98-4.94 (m, 2H); 3.59 (t, J = 6.2 Hz, 2H); 1.81-1.75 (m, 2H); 1.65-1.56 (m, 4H + H2O)

[0543] NMR 13 C (75 MHz, chloroform-d): 5 (ppm) 136.5; 136.4; 128.6 (4C); 128.4 (2C); 127.9 (4C); 67.2; 37.1; 61.7; 33.2; 26.5; 19.0

[0544] Example 8g: dibenzyl (5-hydroxypentyl)phosphanoate 19b OBn HO / X ' / X / ^ x p 'OBn II O Chemical formula: C 19 H 25 O4P Molar mass: 348.3788

[0545] General procedure G is used with ethyl 5-(bis(benzyloxy)phosphoryl)pentanoate 17b (125 mg, 0.32 mmol) to obtain compound 19b as a colorless oil (81 mg, yield: 73%).

[0546] HRSM (ES I + ,m / z) wedge for [M+H] + : 349.1563, measured: 349.1563

[0547] NMR 1 H (500 MHz, chloroform-d): 5 (ppm) 7.38-7.30 (m, 10H); 5.08-5.03 (m, 2H); 4.98-4.94 (m, 2H); 3.59 (t, J = 6.8 Hz, 2H); 1.78-1.72 (m, 2H); 1.64-1.55 (m, 2H + H2O); 1.51 (quint, J = 7.0 Hz, 2H); 1.39 (quint, J = 7.3 Hz, 2H)

[0548] Example 8h: 4-(bis(benzyloxy)phosphoryl)butyl (4-nitrophenyl)carbonate 20a OBn CL p-OBn F oo Chemical formula: C 25 H 26 NO8P Molar mass: 499.4558

[0549] General procedure H is used with dibenzyl (4-hydroxybutyl)phosphanoate 19a (97 mg, 0.29 mmol) to obtain compound 20a as a colorless oil (91 mg, yield: 63%).

[0550] HRSM (ES I+, m / z) calculated for [M+H]+: 500.1469, measured: 500.1469

[0551] NMR 1 H (500 MHz, chloroform-d): 5 (ppm) 8.25 (d, J = 8.8 Hz, 2H); 7.37-7.30 (m, 12H); 5.09-5.04 (m, 2H); 4.99-4.95 (m, 2H); 4.22 (t, J = 6.0 Hz, 2H); 1.83-1.68 (m, 6H)

[0552] NMR 13 C (125 MHz, chloroform-d): 5 (ppm) 155.5; 152.5; 145.4; 136.4; 136.3; 128.7 (4C); 128.5 (2C); 128.0 (4C); 125.3 (2C); 121.8 (2C); 68.7; 67.3; 67.2; 29.0; 26.2; 18.9

[0553] Example 8i: 5-(bis(benzyloxy)phosphoryl)pentyl (4-nitrophenyl)carbonate 20b o Chemical formula: C 26 H 28 NO8P Molar mass: 513.4828

[0554] General procedure H is used with dibenzyl (5-hydroxypentyl)phosphanoate 19b (81 mg, 0.23 mmol) to obtain compound 20b as a colorless oil (66 mg, yield: 55%).

[0555] HRSM (ES L, m / z) wedge for [M+H] + : 514.1625, measured: 514.1621

[0556] NMR 1 H (500 MHz, chloroform-d): 5 (ppm) 8.26 (d, J = 8.9 Hz, 2H); 7.37-7.30 (m, 10H); 5.08-5.04 (m, 2H); 4.98-4.94 (m, 2H); 4.22 (t, J = 6.5 Hz, 2H); 1.80-1.58 (m, 6H); 1.48-1.42 (m, 2H)

[0557] NMR 13C (125 MHz, chloroform-d): 5 (ppm) 155.5; 152.5; 145.4; 136.4; 136.3; 128.6 (4C); 128.5 (2C); 128.0 (4C); 125.3 (2C); 121.8 (2C); 69.1; 67.2; 67.1; 28.0; 26.6; 26.5; 25.3; 22.1; 22.0

[0558] Example 8j: 21a dibenzyl (4-hydroxybutyl)phosphate HO Chemical formula: C 18 H 23 O5P Molar mass: 350.3508

[0559] General procedure I is used with 4-((tert-butyldimethylsilyl)oxy)butan-1-ol (60 pL, 0.26 mmol). Purify the crude by silica gel column chromatography (eluent: PET:AcOEt from 1:0 to 0:1) to obtain compound 21a as a colorless oil (91.4 mg, yield: 100%).

[0560] HRSM (ES I + ,m / z) wedge for [M+H] + : 351.1356, measured: 351.1355

[0561] NMR 1H (500 MHz, chloroform-d): 5 (ppm) 7.40-7.30 (m, 10H); 5.08-4.98 (m, 4H); 4.02 (q, J = 6.7 Hz, 2H); 3.60 (t, J = 6.3 Hz, 2H); 1.84 (si, 1 H); 1.70 (quint, J = 6.9 Hz, 2H); 1.57 (quint, J = 6.9 Hz, 2H)

[0562] NMR 13 C (125 MHz, chloroform-d): 5 (ppm) 135.9 (d, J = 6.4 Hz, 2C); 128.7 (d, J = 4.6 Hz, 8C); 128.1 (2C); 69.4 (d, J = 5.5 Hz, 2C); 67.9 (d, J = 5.5 Hz); 62.2; 28.6; 26.8 (d, J = 6.4 Hz)

[0563] Example 8k: dibenzyl (4-hydroxypropyl)phosphate 21b HCL, CL 9 BnO' 0Bn Chemical formula: C 17 H 21 O5P Molar mass: 336.3238

[0564] General procedure I is used with 4-((tert-butylphenylyloxyl)propan-1-ol (165.5 mg, 0.53 mmol) and HCl in MeOH (1.4 mL of 0.9 M). Purify the crude by silica gel column chromatography (eluent: PET:AcOEt from 1:0 to 0:1) to obtain compound 21b as a colorless oil (89.0 mg, yield: 50%).

[0565] LCMS (ESI + , m / z, HSS T3) wedge, for [M+H] + : 337.2, measured: 337.3

[0566] NMR 1 H (400 MHz, chloroform-d): 5 (ppm) 7.40 - 7.30 (m, 10H); 5.09-4.99 (m, 4H); 4.18 - 4.09 (m, 2H); 3.69 (t, J = 5.9 Hz, 2H); 1.82 (quint., J = 5.6 Hz, 2H)

[0567] NMR 13 C (100 MHz, chloroform-d): 5 (ppm) 135.9 (d, Jc-p = 6.6 Hz, 2C); 128.8 (8C); 128.1 (2C); 69.6 (d, Jc-p = 5.8 Hz, 2C); 64.8 (d, Jc-p = 6.0 Hz); 58.3; 32.9 (d, Jc-p = 5.8 Hz)

[0568] Example 81: Dibenzyl (4-hydroxypentyl)phosphate 21c Bond 0Bn Chemical formula: C 19 H 25 O5P Molar mass: 364.3778

[0569] General procedure I is used with 4-((te / i-butyldiphenylsilyl)oxy)pentan-1-ol (165.5 mg, 0.53 mmol) and HCl in MeOH (2.5 mL of 0.9 M). Purify the crude by silica gel column chromatography (eluent: PET:AcOEt from 1:0 to 0:1) to obtain compound 21c as a colorless oil (268.4 mg, yield: 74%).

[0570] LCMS (ESI + , m / z, HSS T3) wedge, for [M+H] + : 365.2, measured: 365.4

[0571] NMR 1 H (400 MHz, chloroform-d): 5 (ppm) 7.40-7.29 (m, 10H); 5.10-4.95 (m, 4H); 4.00 (q, J = 6.5 Hz, 2H); 3.60 (t, J = 6.4 Hz, 2H); 1.69-1.58 (m, 2H); 1.58-1.49 (m, 2H); 1.45-1.33 (m, 2H)

[0572] NMR 13C (100 MHz, chloroform-d): 5 (ppm) 136.0 (d, Jc-p = 6.8 Hz, 2C); 128.7 (8C); 128.1 (2C); 69.4 (d, Jc-p = 5.6 Hz, 2C); 67.9 (d, Jc-p = 6.2 Hz); 62.7; 32.2; 30.0 (d, Jc-p = 5.6 Hz); 21.7

[0573] Example 8m: 4-((bis(benzyloxy)phosphoryl)oxy)butyl (4-nitrophenyl)carbonate 22a Chemical formula: C 25 H 26 NO9P Molar mass: 515.4548

[0574] General procedure H is used with dibenzyl(4-hydroxybutyl)phosphate 21a (660.0 mg, 1.88 mmol, 1 eq.) to obtain compound 22a as a colorless oil (909.2 mg, yield: 94%).

[0575] HRSM (ES I + ,m / z) wedge for [M+H] + : 516.1418, measured: 516.1415

[0576] NMR 1 H (500 MHz, chloroform-d): 5 (ppm) 8.27 (d, J = 9.3 Hz, 2H); 7.38-7.31 (m, 12H); 5.10 - 4.99 (m, 4H); 4.25 (t, J = 6.1 Hz, 2H); 4.03 (q, J = 6.3 Hz, 2H); 1.82-1.69 (m, 4H)

[0577] NMR 13 C (125 MHz, chloroform-d): 5 (ppm) 155.6; 152.6; 145.6; 135.9 (2C); 128.7 (8C); 128.1 (2C); 125.5 (2C); 121.9 (2C); 69.5 (d, J = 5.5 Hz, 2C); 68.9; 67.1 (d, J = 5.5 Hz); 26.7 (d, J = 7.3 Hz); 24.9

[0578] Example 8n: 4-((bis(benzyloxy)phosphoryl)oxy)propyl (4-nitrophenyl)carbonate 22b • 1 1 O 03r ' Q P W OB LJ'ni I Chemical formula: C 24 H 24 NO9P Molar mass: 501.43

[0579] General procedure H is used with dibenzyl(4-hydroxypropyl)phosphate 21b (89 mg, 0.26 mmol) to obtain compound 22b as a colorless oil (113.7 mg, yield: 87%).

[0580] NMR 1 H (500 MHz, chloroform-d): 5 (ppm) 8.25 (d, J = 9.2 Hz, 2H); 7.40 - 7.30 (m, 12H); 5.12-4.99 (m, 4H); 4.32 (t, J = 6.2 Hz, 2H); 4.13 (q, J=5.9 Hz, 2H); 2.03 (quint, J = 6.0 Hz; 2H)

[0581] NMR 13 C (125 MHz, chloroform-d): 5 (ppm) 155.5; 152.4; 145.5; 135.8 (d, Jc-p = 6.4 Hz, 2C); 128.7 (8C); 128.1 (2C); 125.4 (2C); 121.9 (2C); 69.5 (d, Jc-p = 5.5 Hz, 2C); 65.4; 63.9 (d, Jc-p = 6.4 Hz); 29.3 (d, Jc-p = 7.3 Hz)

[0582] Example 8o: 4-((bis(benzyloxy)phosphoryl)oxy)pentyl 22c (4-nitrophenyl)carbonate ® O O. / NOP OBn 0OBn Chemical formula C 26 H 28 NO9P i ' ' * OO

[0583] General procedure I is used with dibenzyl(4-hydroxypentyl)phosphate 21c (168.7 mg, 0.46 mmol). Purify the crude to obtain compound 22c as a colorless oil (216 mg, yield: 88%).

[0584] NMR 1H (500 MHz, chloroforme-d): 5 (ppm) 8.27 (d, J = 9.0 Hz, 2H); 7.43 - 7.28 (m, 12H); 5.10 - 4.98 (m, 4H); 4.24 (t, J = 6.5 Hz, 2H); 4.00 (q, J = 6.6 Hz, 2H); 1.78 - 1.59 (m, 4H); 1.50 - 1.40 (m, 2H)

[0585] MRI 13 C (125 MHz, chloroform-d): 5 (ppm) 155.6; 152.6; 145.5; 136.0 (d, Jc-p = 7.2 Hz, 2C); 128.7 (8C); 128.1 (2C); 125.4 (2C); 121.9 (2C); 69.4 (d, Jc-p = 5.5 Hz, 2C); 69.3; 67.6 (d, Jc-p = 6.4 Hz); 29.8 (d, JC-P = 7.3 Hz); 28.1; 21.9

[0586] Example 8p: acidic 5-((bis(benzyloxy)phosphoryl)oxy)pentanoic 23 OO The 11 JL HCT O ' OBn OBn Brute formulas: C 19 H23O6P Molaire mass: 378.3608

[0587] General procedure I is used with sodium 5-hydroxypentanoate (400.9 mg, 2.86 mmol). Purify the crude by C18 column chromatography (eluent: H2O:MeCN from 1:0 to 0:1) to obtain compound 23 as a colorless oil (350.1 mg, yield: 32%).

[0588] NMR 1 H (500 MHz, chloroform-d): 5 (ppm) 7.22 (s, 10H); 4.94 (d, J = 7.7 Hz, 4H); 3.89 (si, 2H); 2.19 (if, 2H); 1.53 (if, 4H)

[0589] NMR 13 C (125 MHz, chloroform-d): 5 (ppm) 207.2; 135.9 (d, J = 7.3 Hz, 2C); 128.6 (8C); 128.1 (2C); 69.6 (d, J = 4.9 Hz, 2C); 68.3 (d, J = 4.2 Hz); 36.4; 29.9; 21.4

[0590] Example 8q: (Z)-(5-(3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 H-indazol-1-yl)-5-oxopentyl) dibenzyl phosphanoate 24 (MK86) Chemical formula: C37H32IN4O5P Molar mass: 770.5642

[0591] Dissolve (Z)-3-(2-cyano-2-(5-iodo-1H-indazol-3-yl)vinyl)-4-methoxybenzonitrile 6e (64 mg, 0.14 mmol, 1.4 eq.), 5-(bis(benzyloxy)phosphoyl)pentanoic acid 18a (36 mg, 0.10 mmol, 1.0 eq.), and Mukaiyama salt (38 mg, 0.15 mmol, 1.5 eq.) in DMF (1.4 mL). Add triethylamine (49 pL, 0.35 mmol, 3.5 eq.). Shake the solution for 5 days at room temperature. Quench the reaction with water. Extract the aqueous phase three times with ethyl acetate and wash the combined organic phases with brine, dry over MgSO4, filter, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (eluent: DCM:MeOH from 1:0 to 9:1). Concentrate the pure fraction under reduced pressure and precipitate the impurity in DCM to obtain compound 24 as a yellow powder (23 mg, yield: 65%).

[0592] NMR 1H (500 MHz, chloroforme-d): 5 (ppm) 8,44 (s, 1H); 8,39 (d, 1 H); 8,28 (s, 1H); 8,24 (d, J = 9,0 Hz, 1H); 7,86 (d, J = 8,7 Hz, 1H); 7,77 (d, J = 8,7 Hz, 1H); 7,33-7,28 (m, 10H); 7,07 (d, J = 9,1 Hz, 1H); 5,07-5,03 (m, 2H); 4,98-4,94 (m, 2H); 4,01 (s, 3H); 3,19 (t, J = 7,1 Hz, 2H); 1,90-1,81 (m, 6H)

[0593] RMN 13 C (125 MHz, chloroforme-d): 5 (ppm) 172,8; 161,0; 142,6; 139,9; 139,8; 138,6; 136,8; 136,4; 136,3; 132,6; 129,5; 128,6 (4C); 128,4 (2C); 128,0 (4C); 125,7; 123,2; 118,2; 117,5; 115,7; 111,8; 105,1; 89,6; 67,2; 67,1; 56,6; 53,5; 34,4; 26,5; 25,4; 22,1

[0594] Exemple 8r: (Z)-3-(1-cyano-2-(5-cyano-2-méthoxyphényl)vinyl)-5-iodo-1 H-indazole-1 -carboxylate de 4-(bis (benzyloxy)phosphoryl)butyle 26 (MK90) Formule brute: C 37 H 32 IN4O6P Masse molaire: 786,5632

[0595] General procedure M is used with dibenzyl (4-hydroxybutyl)phosphanoate 20a (45 mg, 0.09 mmol) and (Z)-3-(2-cyano-2-(5-iodo-1 H-indazol-3-yl)vinyl)-4-methoxybenzonitrile 6e (54 mg, 0.13 mmol, 1.4 eq.) to obtain product 26 in the form of a yellow oil (33 mg, yield: 33%).

[0596] NMR 1 H (500 MHz, chloroform-d): 5 (ppm) 8.51 (s, 1H); 8.35 (s, 2H); 8.01 (d, J = 8.8 Hz, 1H); 7.85 (dd, Ji = 1.42 Hz, J2 = 8.9 Hz, 1H); 7.76 (dd, Ji = 1.3 Hz, J2 = 8.7 Hz, 1H); 7.33-7.29 (m, 10H); 7.05 (d, J = 8.7 Hz, 1H); 5.07-5.03 (m, 2H); 4.97-4.93 (m, 2H); 4.48 (t, J = 6.5 Hz, 2H); 3.98 (s, 3H); 1.93 (quint, J = 6.8 Hz, 2H); 1.88-1.72 (m, 4H)

[0597] NMR 13 C (125 MHz, chloroform-d): 5 (ppm) 161.1; 150.2; 143.0; 140.8; 140.5; 138.5; 136.8; 136.3; 132.3; 129.8; 128.7 (4C); 128.6 (2C); 128.0 (4C); 125.4; 123.4; 118.3; 116.6; 116.1; 111.9; 104.9; 104.7; 89.0; 68.0; 67.4; 67.3; 56.4; 29.4; 26.2; 25.1; 19.1

[0598] Example 8s: (Z)-(5-(3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 H-indazol-1-yl)-5-oxopentyl)phosphate dibenzyl 25 (MK89) OBn Chemical formula: C 37 H 32 IN4O8P Molar mass: 786.5632

[0599] Dissolve (Z)-3-(2-cyano-2-(5-iodo-1H-indazol-3-yl)vinyl)-4-methoxybenzonitrile 6e (380.1 mg, 0.89 mmol, 1.4 eq.), 5-((bis(benzyloxy)phosphoyl)oxy)pentanoic acid 18a (240.6 mg, 0.64 mmol, 1.0 eq.), and Mukaiyama salt (325.4 mg, 1.27 mmol, 2 eq.) in DMF (6.5 mL). Add triethylamine (315 pL, 2.26 mmol, 3.5 eq.). Shake the reaction mixture for 5 days at room temperature, then quench the reaction with water. Extract the aqueous phase three times with a large volume of ethyl acetate, then wash the combined organic phases with brine, dry over MgSO4, filter, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (eluent: PET:AcOEt from 1:0 to 0:1) to obtain product 25 as a yellow resin (139.1 mg, yield: 28%).

[0600] NMR 1H (500 MHz, chloroforme-d): 5 (ppm) 8,46 (si, 1H); 8,40 (d, J = 1,7 Hz, 1H); 8,29 (s, 1H); 8,28 (d, J = 8,9 Hz, 1H); 7,89 (dd, Ji = 1,3 Hz, J2= 8,9 Hz, 1H); 7,79(dd, Ji = 2,0 Hz, J2= 8,7 Hz, 1H); 7,36-7,26 (m, 10H); 7,08 (d, J = 8,7 Hz, 1H); 5,08-4,98 (m, 4H); 4,07 (q, J = 6,5 Hz, 2H); 4,02 (s, 3H); 3,24 (t, J = 7,4 Hz, 2H); 1,93-1,73 (m, 4H)

[0601] RMN 13 C (125 MHz, chloroforme-d): 5 (ppm) 173,1; 161,0; 142,7; 140,1; 139,9; 138,8; 136,9; 136,0 (2C); 132,7; 129,6; 128,7 (8C); 128,1 (2C); 125,6; 123,4; 118,3; 117,6; 115,9; 111,9; 105,7; 105,1; 89,6; 69,4 (d, J = 5,5 Hz, 2C); 67,5 (d, J = 5,5 Hz); 56,6; 34,4; 29,7(d, J = 7,3 Hz); 20,5

[0602] Exemple 8t: (Z)-3-(1-cyano-2-(5-cyano-2-méthoxyphényl)vinyl)-5-iodo-1 H-indazole-1 -carboxylate de 4-((bis(benzyloxy)phosphoryl)oxy)butyle 27 (MK91) BnO 0Bn Formule brute: C37H32IN4O7P Masse molaire: 802,5622

[0603] General procedure M is used with 4-(bis(benzyloxy)phosphoryl)oxy)butyl (4-nitrophenyl)carbonate 22a (207.3 mg, 0.40 mmol, 1 eq.) and (Z)-3-(2-cyano-2-(5-iodo-1 H-indazol-3-yl)vinyl)-4-methoxybenzonitrile 6e (240 mg, 0.56 mmol, 1.4 eq.) to obtain product 27 in the form of a yellow resin (241.7 mg, yield: 75%).

[0604] NMR 1 H (500 MHz, chloroform-d): 5 (ppm) 8.48 (si, 1H); 8.36-8.32 (s, 2H); 8.00 (d, J = 8.9 Hz, 1H); 7.84 (dd, J1 = 0.8 Hz, J2 = 9.1 Hz, 1H); 7.74 (dd, J1 = 1.5 Hz, J2 = 8.7 Hz, 1H); 7.35-7.28 (m, 10H); 7.04 (d, J = 8.7 Hz, 1H); 5.08-4.97 (m, 4H); 4.51 (t, J = 6.5 Hz, 2H); 4.07 (q, J = 6.4 Hz, 2H); 3.97 (s, 3H); 1.95-1.74 (m, 4H)

[0605] NMR 13C (125 MHz, chloroform-d): 5 (ppm) 161.0; 150.1; 142.9; 140.7; 140.5; 138.5; 136.8; 135.8 (d, J = 6.4 Hz, 2C); 132.6; 129.7; 128.7 (8C); 128.0 (2C); 125.2; 123.3; 118.3; 116.5; 116.1; 111.9; 104.8; 104.6; 89.0; 69.4 (d, J = 5.5 Hz, 2C); 68.0; 67.1 (d, J = 5.5 Hz); 56.4; 26.7; 24.9

[0606] Example 8u: (Z)-(3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 H-indazol-1-yl) dibenzyl phosphanoate 28 (MK88) Chemical formula: C 32 H24lN4O4P Molar mass: 686.4462

[0607] Dissolve (Z)-3-(2-cyano-2-(5-iodo-1H-indazol-3-yl)vinyl)-4-methoxybenzonitrile 6e (25 mg, 0.06 mmol, 1.0 eq.) and sodium hydride (6 mg, 0.15 mmol, 2.5 eq.) in THF (1 mL). After 30 min of stirring at room temperature, add a tetrabenzylpyrophosphate solution (126 mg, 0.23 mmol, 4.0 eq.) in 200 µL of THF dropwise at 0 °C. After 2 h of stirring at 0 °C, quench the reaction mixture with ice-cold water. Extract the aqueous phase three times with ethyl acetate, then wash the combined organic phases with brine, dry over MgSO4, filter, and concentrate under reduced pressure. Purify the crude by silica gel column chromatography (eluent: PET:AcOEt from 1:0 to 3:2) to obtain product 28 in the form of a yellow powder (30 mg, yield: 75%).

[0608] NMR 1H (500 MHz, chloroforme-d): 5 (ppm) 8,32 (s, 1H); 8,29 (s, 1H); 8,10 (s, 1H); 7,84 (d, J = 9,0 Hz, 1H); 7,70 (t, J = 9,7 Hz, 2H); 7,23-7,18 (m, 10H); 7,01 (d, J = 8,6 Hz, 1H); 5,25-5,21 (m, 2H); 5,14-5,10 (m, 2H); 3,94 (s, 3H)

[0609] RMN 13 C (125 MHz, chloroforme-d): 5 (ppm) 160,9; 144,2; 139,4; 137,3; 136,6; 134,4; 134,3; 132,6; 129,3; 128,9 (2C); 128,5 (4C); 128,3 (4C); 124,5; 124,5; 123,7; 118,3; 116,0; 115,8; 111,7; 105,0; 87,9; 71,1; 71,0; 56,4

[0610] Exemple 8v: Acide (Z)-(5-(3-(1-cyano-2-(5-cyano-2-méthoxyphényl)vinyl)-5-iodo-1 H-indazol-1-yl)-5-oxopentyl) phosphonique 30 (MK93)Fomule brute: C23H 20 IN4O5P Masse molaire: 590,3142

[0611] General procedure J is used with dibenzyl (Z)-(5-(3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 H-indaol-1-yl)-5-oxopentyl)phosphonate 24 (108 mg, 0.76 mmol) to obtain compound 30 as a light brown solid (26 mg, yield: 92%).

[0612] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 8.60 (s, 1 H); 8.37 (s, 2H); 8.25 (d, J = 9.3 Hz, 1H); 8.07-8.02 (m, 2H); 7.41 (d, J = 8.8 Hz, 1H); 4.01 (s, 3H); 3.23 (t, J = 6.6 Hz, 2H); 1.82 (t, J = 6.3 Hz, 2H); 1.63-1.57 (m, 4H)

[0613] Example 8w: (Z)-5-(3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 H-indazol-1-yl)-5-oxopentyldihydrogen phosphate 31 (MK94) OH Chemical formula: C 23 H 20 IN4O6P Molar mass: 606.3132

[0614] General procedure J is used with (Z)-(5-(3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 H-indazol-1-yl)-5-oxopentyl) dibenzyl phosphate 25 (105.8 mg, 0.13 mmol) to obtain compound 31 as a light brown solid (36.4 mg, yield: 45%).

[0615] Pf: 228 - 231 °C

[0616] LCMS (ESI+, m / z, BEH) calc for [M-CsHioOsP+Hf: 427.0, measured: 42.2

[0617] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 8.59 (s, 1H); 8.38 (s, 1H); 8.34 (s, 1H); 8.06 (d, J = 9.0 Hz, 1H); 8.03 (s, 2H); 7.41 (d, J = 8.4 Hz, 1H); 4.54 (t, J = 6.2 Hz, 2H); 4.02 (s, 3H); 3.90 (q, J = 6.5 Hz, 2H); 1.94-1.67 (m, 4H)

[0618] NMR 13 C (175 MHz, DMSO-de): 5 (ppm) 173.0; 160.8; 141.8; 141.5; 138.9; 138.4; 136.9; 132.7; 129.1; 124.6; 123.0; 118.4; 116.9; 115.8; 113.1; 105.5; 103.0; 90.3; 56.8; 33.9; 30.7; 29.5 (d, Jc-p = 7.3 Hz); 20.1

[0619] NMR 31P (192 MHz, chloroform-d): 5 (ppm) -1.1 (brs)

[0620] Example 8x: (Z)-3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 H-indazol-1 -carboxylate of (4-(phosphonooxy)butyl 34 (M K95) Chemical formula: C23H20IN4O7P Molar mass: 622.3122

[0621] General procedure J is used with (Z)-3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 H-indazol-1 -carboxylate of 4-((bis(benzyloxy)phosphoryl) oxy)butyl 27 (40.4 mg, 0.05 mmol) to obtain compound 30 as a pale yellow solid (30.1 mg, yield: 96%).

[0622] Pf 189-191 °C

[0623] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 11.01 (si, 2H); 8.58 (s, 1H); 8.38 (s, 1H); 8.34 (s, 1H); 8.06 (dd, J1 = 8.6 Hz, J2 = 1.9 Hz, 1 H); 8.03 (s, 2H); 7.41 (d, J = 9.1 Hz, 1 H); 4.54 (t, J = 6.7 Hz, 2H); 4.01 (s, 3H); 3.90 (q, J = 6.7 Hz, 2H); 1.97-1.67 (m, 4 H)

[0624] NMR13 C (100 MHz, DMSO-de): 5 (ppm) 160.8; 149.5; 142.5; 141.9; 139.9; 138.3; 136.9; 132.8; 129.3; 124.6; 123.2; 118.5; 116.6; 115.9; 113.1; 105.7; 103.0; 89.9; 67.9; 64.7 (J = 4.1 Hz); 56.7; 26.3 (J = 7.2 Hz); 24.6

[0625] NMR 31 P (192 MHz, chloroform-d): 5 (ppm) -1.0 (brs)

[0626] IR: v (cm' 1 ) 2229, 1733, 1603, 1496, 1404, 1352, 1271, 1112, 1011, 677

[0627] Example 8y: (Z)-hydrogen (5-(3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1H-indazol-1-yl)-5-oxopentyl)phosphonate potassium 35 (MK99) Chemical formula: C 23 H 18 IN4O5P - K + Molar mass: 628.4046

[0628] General procedure K is used with (Z)-(5-(3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 H-indazol-1-yl)-5-oxopentyl)phosphonic acid 30 (20 mg, 0.03 mmol) in the presence of KOH to obtain compound 35 as a yellow powder (14 mg, yield: 66%).

[0629] Example 8z: (Z)-(5-(3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 H-indazol-1-yl)-5-oxopentyl)phosphonate potassium 37 (MK100) Chemical formula: C 23 H 18 IN4O5P 2- K 2+ Molar mass: 666.4949

[0630] The general procedure L is used with (Z)-(5-(3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 H-indazol-1-yl)-5-oxopentyl) phosphonic acid 30 (20 mg, 0.03 mmol) in the presence of K2CO3 to obtain compound 37 as a yellow powder (23 mg, quantitative yield).

[0631] Example 8za: (Z)-hydrogen 4-((3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 / - / -indazole-1 -carbonyl)oxy)sodium butylphosphate 40 (MK 96) Chemical formula: C 23 H 19 IN4NaO7P Molar mass: 644.2940

[0632] General procedure K is used with (Z)-3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 / - / -indazole-1-carboxylate of 4-(phosphonooxy)butyl 34 (20.3 mg, 0.03 mmol) in the presence of NaOH to obtain compound 40 as a pale yellow powder (18.0 mg, yield: 86%)

[0633] Pf 291-293 °C

[0634] NMR 1 H (400 MHz, DMSO-de): 5 (ppm) 8.58 (s, 1H); 8.38 (d, J = 2.1 Hz, 1H); 8.34 (s, 1H); 8.10-8.00 (m, 3H); 7.41 (d, J = 9.0 Hz, 1H); 4.53 (t, J = 6.8 Hz, 2H); 4.01 (s, 3H); 3.63 (q, J = 6.4 Hz, 2H); 1.93-1.56 (m, 4H)

[0635] NMR 13C (175 MHz, DMSO-de): 5 (ppm) 160.9; 149.5; 142.3; 141.7; 139.9; 138.3; 136.8; 132.8; 129.2; 124.5; 123.2; 118.5; 116.7; 116.0; 113.1; 105.6; 103.0; 89.8; 68.4; 62.4 (d, Jc-p = 5.2 Hz); 56.7; 26.9 (d, Jc-p = 7.2 Hz); 25.1

[0636] Example 8zb: (Z)-hydrogen 4-((3-(1-cyano-2-(5-cyano-2-methoxyphenyl) vinyl)-5-iodo-1 / - / -indazole-1 -carbonyl)oxy)potassium butylphosphate 41 (MK 97) Molecular formula: C 23 HI9IKN4O7P Molar mass: 660.4025

[0637] General procedure K is used with (Z)-3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 / - / -indazole-1 -carboxylate of 4-(phosphonooxy)butyl 34 (19.0 mg, 0.03 mmol) in the presence of KOH to obtain compound 41 as a pale yellow powder (18.8 mg, yield: 93%).

[0638] NMR 1H (400 MHz, DMSO-de): 5 (ppm) 8,58 (s, 1H); 8,39 (d, J = 1,9 Hz, 1H); 8,34 (s, 1 H); 8,07-8,02 (m, 3H); 7,41 (d, J = 8,8 Hz, 1 H); 4,52 (t, J = 6,7 Hz, 2H); 4,01 (s, 3H); 3,63 (q, J = 6,6 Hz, 2H); 1,93-1,56 (m, 4H)

[0639] RMN 13 C (175 MHz, DMSO-de): 5 (ppm) 160,9; 149,4; 142,3; 141,6; 139,8; 138,3; 136,8; 132,8; 129,2; 124,5; 123,1; 118,5; 116,6; 116,0; 113,1; 105,6; 103,0; 89,8; 68,4; 62,4; 56,7; 26,9 (d, Jc-p = 6,7 Hz); 25,0

[0640] Exemple 8zc: (Z)-4-((3-(1-cyano-2-(5-cyano-2-méthoxyphényl)vinyl)-5-iodo-1 / - / -indazole-1-carbonyl)oxy)butyl phosphate de potassium 43 (MK 98) Formule brute: C23H 18 IK2N4O7P Masse molaire: 698,4928

[0641] General procedure L is used with (Z)-3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 / - / -indazole-1 -carboxylate of 4-(phosphonooxy)butyl 34 (19.6 mg, 0.03 mmol) in the presence of K2CO3 to obtain compound 43 as a pale yellow powder (19.0 mg, yield: 86%).

[0642] NMR 1 H (400 MHz, DMSO-de): 5 (ppm) 8.50 (s, 1H); 8.36 (s, 1H); 8.30 (s, 1H); 8.03 (d, J = 9.0 Hz, 1H); 7.97 (s, 2H); 7.39 (d, J = 8.9 Hz, 1H); 4.51 (t, J = 6.7 Hz, 2H); 4.01 (s, 3H); 3.77 (si, 2H); 1.94-1.62 (m, 4H)

[0643] NMR 13 C (175 MHz, DMSO-de): 5 (ppm) 160.8; 149.4; 142.2; 141.4; 139.7; 138.2; 136.9; 132.7; 129.1; 124.4; 123.0; 118.5; 116.5; 115.9; 113.1; 105.4; 103.0; 89.8; 68.1; 58.1; 56.8; 26.6 (d, J C -p = 5.7 Hz); 24.8

[0644] Example 8zd: (Z)-(4-(3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 / - / - indazol-1-yl)-4-oxobutyl)phosphonate dibenzyl 44 (MK102) CN M.O.O NC > I'm i : N N 0 .1 OBn 0Bn bro, C,?! JNLO-^ Ma»i' "-wairu 7SÜ.54

[0645] Dissolve (Z)-3-(2-cyano-2-(5-iodo-1 / - / -indazol-3-yl)vinyl)-4-methoxybenzonitrile 6e (195 mg, 0.46 mmol, 1.4 eq.), 4-(b / s(benzyloxy)phosphoyl)butanoic acid 18b (114 mg, 0.33 mmol, 1 eq.), and Mukaiyama salt (167 mg, 0.65 mmol, 2 eq.) in DMF (3 mL). Add triethylamine (136 pL, 0.98 mmol, 3 eq.). After 7 days of stirring at room temperature, quench the reaction with water. Extract the aqueous phase three times with ethyl acetate. Wash the combined organic phases with brine, dry over MgSO4, filter, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (eluent: DCM:MeOH from 1:0 to 9:1). Concentrate the fractions of interest under reduced pressure. After overnight storage in MeOH at -20 °C, filter the precipitate and then dissolve it in DCM to obtain 44 as a yellow powder (87 mg, yield: 28%).

[0646] NMR 1H (400 MHz, chloroform-d): 5 (ppm) 8.49-8.43 (m, 2H); 8.38-8.37 (m, 2H); 7.91 (d, J = 8.2 Hz, 1H); 7.82 (d, J = 8.0 Hz, 1H); 7.35-7.29 (m, 10H + CDCh); 7.11 (d, J = 8.4 Hz, 1H); 5.12-5.07 (m, 2H); 5.03-4.98 (m, 2H); 4.05 (s, 3H); 3.36 (t, J = 6.9 Hz, 2H); 2.20-2.11 (m, 2H); 2.04-1.96 (m, 2H)

[0647] Example 8ze: (Z)-(4-(3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 / - / -indazol-1-yl)-4-oxobutyl)phosphonic acid 45 (MK103) CM MeO NC I ' H NNOX OH O ► orrjie ch-^iqje, C H.„IN.ÎO. Mass «are b / t>

[0648] General procedure J is used with dibenzyl (Z)-(5-(3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 / - / -indazol-1-yl)-5-oxobutyl)phosphonate 44 (40 mg, 0.05 mmol) to obtain 45 in the form of a yellow powder (14 mg, yield: 46%).

[0649] NMR 1H (400 MHz, DMSO-de): 5 (ppm) 8,58 (s, 1H); 8,37-8,36 (m, 2H); 8,23 (d, J = 8,8 Hz, 1H); 8,07-7,99 (m, 2H); 7,41 (d, J = 8,8 Hz, 1H); 4,01 (s, 3H); 2,01-1,90 (m, 2H); 1,73-1,65 (m, 2H); 1,17 (t, J = 7,1 Hz, 2H)

[0650] RMN 13 C (100 MHz, DMSO-de): 5 (ppm) 173,4; 161,3; 142,6; 139,0; 137,4; 133,4; 129,8; 125,3; 123,7; 119,0; 117,6; 116,3; 113,6; 106,4; 103,5; 90,8; 57,2; 31,2; 26,5

[0651] Exemple 8zf: (Z)-3-(1-cyano-2-(5-cyano-2-méthoxyphényl)vinyl)-5-iodo-1 / - / - indazol-1 -carboxylate de 5-((b / s(benzyloxy)phosphoryl)oxy)pentyle 46 (MK105) X ' - CN O NC ( I i N N O O* OBn Fermait brute C Jlt H JN. O -P Masse r'o'd ’c 816 69

[0652] General procedure M is used with 4-((b / s(benzyloxy)phosphoryl) oxy)pentyl (4-nitrophenyl)carbonate 22 (307.4 mg, 0.58 mmol) and (Z)-3-(2-cyano-2-(5-iodo-1 / - / -indazol-3-yl)vinyl)-4-methoxybenzonitrile 6e (335.4 mg, 0.79 mmol) to obtain 46 in the form of a yellow resin (138.7 mg, yield: 29%).

[0653] NMR 1 H (400 MHz, chloroform-d): 5 (ppm) 8.49 (d, J = 1.1 Hz, 1 H); 8.36 (d, J = 1.7 Hz, 1 H); 8.35 (s, 1 H); 8.02 (d, J = 8.8 Hz, 1 H); 7.85 (dd, Ji = 8.9 Hz, J2 = 1.5 Hz, 1 H); 7.75 (dd, Ji = 8.7 Hz, J2 = 2.0 Hz, 1H); 7.37-7.27 (m, 10H); 7.05 (d, J = 8.8 Hz, 1H); 5.10-4.94 (m, 4H); 4.50 (t, J = 6.9 Hz, 2H); 4.02 (q, J = 6.6 Hz, 2H); 3.98 (s, 3H); 1.87 (quint, J = 7.1 Hz, 2H); 1.70 (quint, J = 6.9 Hz, 2H); 1.57-1.44 (m, 2H)

[0654] NMR 13C (125 MHz, chloroforme-d): 5 (ppm) 161,1; 150,2; 142,9; 140,7; 140,5; 138,5; 136,8; 135,9 (d, Jc-p = 6,6 Hz, 2C); 132,6; 129,8; 128,7 (4C); 128,6 (4C); 128,0 (2C); 125,3; 123,4; 118,3; 116,6; 116,1; 111,9; 104,9; 104,7; 88,7; 69,3 (d, Jc-p = 5,7 Hz, 2C); 68,5; 67,5 (d, Jc-p = 6,0 Hz); 56,5; 29,8 (d, Jc-p = 7,0 Hz); 28,2

[0655] Exemple 8zg: (Z)-3-(1-cyano-2-(5-cyano-2-méthoxyphényl)vinyl)-5-bromo-1 / - / - indazol-1 -carboxylate de 4-((b / s(benzyloxy)phosphoryl)oxy)butyle 47 (MK106) CM O NC Z B' ' » N F u»m JIC trJe C • 4“ l? BrN4O P Mdwe '"ularo 755,56

[0656] General procedure M is used with (Z)-3-(2-(5-bromo-1 / - / -indazol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile 6b (150 mg, 0.40 mmol) and (4-nitrophenyl) 4-((bis(benzyloxy)phosphoryl)oxy)butyl carbonate 22 (150 mg, 0.29 mmol) to obtain 47 as a yellow powder (219 mg, yield: 34%).

[0657] NMR 1 H (400 MHz, chloroform-d): 5 (ppm) 8.38-8.33 (m, 2H); 8.30 (d, J = 1.6 Hz, 1H); 8.12 (d, J = 8.9 Hz, 1H); 7.74 (dd, Ji = 8.8 Hz, J2 = 2.1 Hz, 1H); 7.68 (dd, Ji = 9.0 Hz, J2 = 1.7 Hz, 1H); 7.28-7.27 (m, 10H); 7.04 (d, J = 8.8 Hz, 1H); 5.10-4.97 (m, 4H); 4.51 (t, J = 6.5 Hz, 2H); 4.07 (q, J = 6.1 Hz, 2H); 3.97 (s, 3H); 1.98-1.86 (m, 2H); 1.86-1.73 (m, 2H)

[0658] NMR 13C (100 MHz, chloroform-d): 5 (ppm) 161.1; 150.1; 143.2; 140.6; 140.0; 136.8; 135.8 (d, Jc-p = 7.2 Hz); 133.1; 132.6; 128.7; 128.0; 124.7; 123.5; 123.3; 118.4; 118.3; 116.3; 116.1; 111.9; 104.8; 104.6; 69.4 (d, Jc-p = 5.7 Hz); 68.0; 67.2 (d, Jc-p = 6.0 Hz); 56.4; 26.7 (d, Jc-p = 7.1 Hz); 25.0

[0659] Example 8zh: (Z)-3-(1-cyano-2-(5-cyano-2-methoxyphenyl) vinyl)-5-iodo-1 H- indazol-1 -carboxylate of 5-(phosphonooxy)pentyl 48 (MK107) CN O NC I. H N K , R-OH O OH rough drill -P Milk mass 636 34

[0660] General procedure J is used with (Z)-3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 / - / -indazol-1-carboxylate of 4-((b / s(benzyloxy)phosphoyl)oxy)pentyl 46 (163.9 mg, 0.20 mmol) to obtain 48 in the form of a yellow powder (14 mg, yield: 11%).

[0661] Pf 187 - 190 °C

[0662] NMR 1 H (400 MHz, DMSO): 5 (ppm) 10.92 (si, 2H); 8.60 (s, 1H); 8.38 (d, J = 1.7 Hz, 1 H); 8.34 (s, 1 H); 8.08–8.04 (m, 2H); 7.42 (d, J = 8.8 Hz, 1 H); 4.52 (t, J = 6.7 Hz, 2H); 4.02 (s, 3H); 3.85 (q, J = 6.5 Hz, 2H); 1.89–1.82 (m, 2H); 1.71–1.64 (m, 2H); 1.54– 1.47 (m, 2H)

[0663] NMR 13 C (125 MHz, DMSO): 5 (ppm) 160.9; 149.5; 142.5; 141.9; 139.9; 138.3; 136.9; 132.9; 129.3; 124.6; 123.2; 118.5; 116.6; 116.0; 113.1; 105.8; 103.0; 89.9; 68.3; 64.9 (d, Jc-p = 5.2 Hz, 2C); 56.8; 29.5 (d, Jc-p = 6.8 Hz); 27.6; 21.6

[0664] IR: v (cm− 1 ) 2948, 2228, 1736, 1603, 1496, 1404, 1351, 1270, 1240, 1112, 1007, 676

[0665] Example 8zi: (Z)-(5-(5-bromo-3-(1-cyano-2-(5-cyano-2-methoxyphenyl) vinyl)- 1 / - / -indazol-1 -yl)-5-oxopentyl)phosphonate of dibenzyle 49 (MK108)CM MuO' NC Br ' H ; N N BnO OS-' f 5r< M>tt bwiu C H Ü-N ; Q. P hte.-ts rx)'di>'C 723,56

[0666] Dissolve (Z)-3-(2-cyano-2-(5-bromo-1 / - / -indazol-3-yl)vinyl)-4-methoxybenzonitrile 6b (315 mg, 0.83 mmol, 1.4 eq.), 5-(b / s(benzyloxy)phosphoyl)pentanoic acid 18a (215 mg, 0.59 mmol, 1 eq.), and Mukaiyama salt (303 mg, 1.19 mmol, 2 eq.) in DMF (4 mL). Add triethylamine (247 pL, 1.78 mmol, 3 eq.). After 6 days of stirring at room temperature, quench the reaction with water. Extract the aqueous phase three times with ethyl acetate. Wash the combined organic phases with brine, dry over MgSCM, filter, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (eluent: DCM:MeOH from 1:0 to 9:1). Concentrate the fractions of interest under reduced pressure. After overnight storage in MeOH at -20 °C, filter the precipitate under vacuum and then dissolve it in DCM to obtain 49 as a yellow powder (85 mg, yield: 20%).

[0667] NMR 1H (400 MHz, chloroform): 5 (ppm) 8.44-8.41 (m, 2H); 8.33 (s, 1 H); 8.29 (d, J = 1.4 Hz, 1 H); 7.82 (dd, Ji = 8.7 Hz, J2 = 2.0 Hz, 1 H); 7.75 (dd, Ji = 8.9 Hz, J2 = 1.8 Hz, 1H); 7.37-7.31 (m, 10H); 7.10 (d, J = 8.7 Hz, 1H); 5.11-5.06 (m, 2H); 5.01-4.96 (m, 2H); 4.04 (s, 3H); 3.23 (t, J = 7.3 Hz, 2H); 1.95-1.73 (m, 6H)

[0668] Example 8zj: (Z)-(5-(3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-bromo-1 / - / -indazol-1-yl)-5-oxopentyl)phosphonic acid 50 (MK109) CN MoO NC B- H j N N f-ü'rrjle truki C. P Masw molaro 543.31

[0669] General procedure J is used with dibenzyl (Z)-(5-(3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-bromo-1 H-indazol-1 -yl)-5-oxopentyl)phosphonate 44 (82 mg, 0.11 mmol) to obtain 50 in the form of a yellow powder (70 mg, quantitative yield).

[0670] NMR 1H (400 MHz, DMSO-de): 5 (ppm) 8,46 (s, 1H); 8,39-8,37 (m, 3H); 8,07 (d, J = 8,5 Hz, 1 H); 7,90 (d, J = 8,8 Hz, 1 H); 7,42 (d, J = 8,8 Hz, 1 H); 4,01 (s, 3H); 2,51 (s, 2H + DMSO-de); 1,87-1,80 (m, 2H); 1,66-1,54 (m, 4H)

[0671] Exemple 8zk: (Z)-(6-(3-(1-cyano-2-(5-cyano-2-méthoxyphényl)vinyl)-5-iodo-1 / - / - indazol-1-yl)-6-oxohexyl)phosphonate de dibenzyle 51 (MK110) CN MeO ' NC U ; K H N oT \ f or- b’uto C i ( iH ( ,vN|O P r-a dire 794,59

[0672] Dissolve (Z)-3-(2-cyano-2-(5-iodo-1 / - / -indazol-3-yl)vinyl)-4-methoxybenzonitrile 6e (117 mg, 0.28 mmol, 1.4 eq.), 6-(b / s(benzyloxy)phosphoyl)hexanoic acid 18c (74 mg, 0.20 mmol, 1 eq.), and Mukaiyama salt (100 mg, 0.39 mmol, 2 eq.) in DMF (2 mL). Add triethylamine (82 pL, 0.59 mmol, 3 eq.). After 7 days of stirring at 30 °C, quench the reaction with water. Extract the aqueous phase three times with ethyl acetate. Wash the combined organic phases with brine, dry over MgSO4, filter, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (eluent: DCM:MeOH from 1:0 to 9:1). Concentrate the fractions of interest under reduced pressure. After overnight storage in MeOH at -20 °C, filter the precipitate under vacuum and then dissolve it in DCM to obtain a yellow powder (96 mg, yield: 62%).

[0673] NMR 1H (400 MHz, chloroforme-d): 5 (ppm) 8,45 (s, 1 H); 8,40 (d, J = 1,7 Hz, 1 H); 8,29-8,27 (m, 2H); 7,87 (dd, Ji = 8,2 Hz, J2= 1,2 Hz, 1 H); 7,78 (dd, Ji = 7,7 Hz, J2= 1,9 Hz, 1H); 7,38-7,27 (m, 10H); 7,08 (d, J = 8,7 Hz, 1H); 5,08-5,02 (m, 2H); 4,98-4,93 (m,2H); 4,02 (s, 3H); 3,20 (t, J = 7,4 Hz, 2H); 1,85-1,74 (m, 4H); 1,71-1,60 (m, 2H); 1,53-1,45 (m, 2H)

[0674] RMN 13 C (100 MHz, DMSO-de): 5 (ppm) 173,4; 160,9; 142,4; 139,9; 138,6; 136,7; 136,5; 136,4; 132,6; 129,5; 128,6 (4C); 128,4 (2C); 127,9 (4C); 125,4; 123,3; 118,2; 117,5; 115,8; 111,8; 105,6; 105,0; 89,4; 67,1; 67,0; 56,5; 34,7; 30,0; 26,6; 25,2; 23,8; 22,2

[0675] Exemple 8zl: acide (Z)-(6-(3-(1-cyano-2-(5-cyano-2-méthoxyphényl)vinyl)-5- iodo-1H-indazol-1-yl)-6-oxohexyl)phosphonique 52 (MK111) GN Weo NC ' I h N O .. f> UH U üM ' c'tt< Uc Drue C.. M l\. CP Masse wane ÔQ-» 34

[0676] General procedure J is used with dibenzyl (Z)-(6-(3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 / - / -indazol-1-yl)-6-oxohexyl) phosphonate 51 (92 mg, 0.12 mmol) to obtain 52 in the form of a yellow powder (62 mg, yield: 87%).

[0677] NMR 1 H (400 MHz, DMSO-de): 5 (ppm) 8.61 (s, 1 H); 8.37 (s, 2H); 8.25 (d, J = 8.8 Hz, 1H); 8.08-8.02 (m, 2H); 7.42 (d, J = 8.8 Hz, 1H); 4.02 (s, 3H); 3.24-3.18 (m, 2H); 1.79-1.70 (m, 2H); 1.58-1.46 (m, 6H)

[0678] Example 8zm: (Z)-(5-(5-chloro-3-(1-cyano-2-(5-cyano-2-methoxyphenyl) vinyl)- 1H-indazol-1-yl)-5-oxopentyl) dibenzyl phosphonate 53 (MK112) CK MeO NC -Z.. CI H NN BnO OQr- FôBBWfc» all»: CjïHæCMiOBP Mass "ne a M 670. H

[0679] Dissolve (Z)-3-(2-cyano-2-(5-chloro-1 / - / -indazol-3-yl)vinyl)-4-methoxybenzonitrile 6h (108 mg, 0.32 mmol, 1.4 eq.), 5-(b / s(benzyloxy)phosphoyl)pentanoic acid 18a (84 mg, 0.23 mmol, 1 eq.), and Mukaiyama salt (118 mg, 0.46 mmol, 2 eq.) in DMF (2.3 mL). Add triethylamine (96 pL, 0.69 mmol, 3 eq.). After 7 days of stirring at 30 °C, quench the reaction with water. Extract the aqueous phase three times with DCM. Wash the combined organic phases with brine, dry over MgSO4, filter, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (eluent: DCM:MeOH from 1:0 to 9:1). Concentrate the fractions of interest under reduced pressure. After overnight storage in MeOH at -20 °C, filter the precipitate and then dissolve it in DCM to obtain a yellow powder (45 mg, yield: 29%).

[0680] NMR 1H (400 MHz, chloroforme-d): 5 (ppm) 8,43-8,40 (m, 2H); 8,30 (s, 1H); 8,08 (s, 1H); 7,77 (dd, Ji = 8,7 Hz, J2= 1,6 Hz, 1H); 7,57 (dd, Ji = 9,0 Hz, J2= 1,4 Hz, 1H); 7,35-7,28 (m, 10H); 7,07 (d, J = 8,7 Hz, 1H); 5,09-5,06 (m, 2H); 4,99-4,94 (m, 2H); 4,01 (s, 3H); 3,20 (t, J = 7,3 Hz, 2H); 1,92-1,73 (m, 6H)

[0681] RMN 13 C (100 MHz, chloroforme-d): 5 (ppm) 168,2; 156,2; 138,0; 135,0; 134,2; 132,0; 131,6; 131,5; 127,8; 126,4; 125,9; 123,9 (4C); 126,7 (2C); 123,2 (4C); 119,5; 118,5; 115,3; 113,4; 112,2; 111,1; 107,1; 100,2; 62,5; 62,4; 51,7; 29,5; 21,8; 20,4; 20,3; 17,3

[0682] Exemple 8zn: acide (Z)-(4-((3-(1-cyano-2-(5-cyano-2-méthoxyphényl)vinyl)-5- iodo-1 / - / -indazole-1 -carbonyl)oxy)butyl) phosphonique 32 (MK113) CN O r NC ' z ': s H I. N M O -x O* ' ° OH f c'rr-Je tfutc Mass «o'aife 606 3 •>

[0683] General procedure J is used with dibenzyl (4-(b / s(benzyloxy)phosphoyl)butyl (Z)-3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 H-indazole-1-carboxylate 26 (80 mg, 0.10 mmol) to obtain 32 in the form of a brown powder (50 mg, yield: 81%).

[0684] NMR 1 H (500 MHz, DMSO-de): 5 (ppm) 8.59 (s, 1 H); 8.38-8.33 (m, 2H); 8.07-7.98 (m, 1 H); 8.07-8.02 (m, 1 H); 7.41 (dd, Ji = 1.6 Hz, J2 = 8.0 Hz, 1 H); 7.37-7.29 (m, 1 H); 4.54-4.50 (m, 2H); 4.00 (s, 3H); 1.92-1.87 (m, 2H); 1.81-1.56 (m, 4H)

[0685] NMR 13 C (125 MHz, DMSO-de): 5 (ppm) 161.3; 149.5; 143.0; 142.4; 138.7; 137.4; 133.3; 129.8; 128.8; 128.2; 127.9; 125.1; 123.9; 119.0; 113.6; 106.4; 103.5; 90.3; 68.3; 65.8; 57.2; 29.1; 19.6

[0686] Example 8zo: (Z)-3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-5-iodo-1 H-indazole-1 -carboxylate of 4-((bis(benzyloxy)phosphoryl)oxy)propyl 57 (MK118) O \ BnO PO Z ÔBn I ormult; bïiiln C 3t; H iC IN O7P Molar mass: 788.6352

[0687] General procedure M was used with 4-((bis(benzyloxy)phosphoyl)oxy)propyl(4-nitrophenyl)carbonate 22b (126.8 mg, 0.25 mmol) and (Z)-3-(2-cyano-2-(5-iodo-1 H-indazol-3-yl)vinyl)-4-methoxybenzonitrile 6e (145.7 mg, 0.34 mmol) to obtain compound 57 as a yellow resin (40.0 mg, yield: 20%).

[0688] NMR 1H (400 MHz, chloroform-d): 5 (ppm) 8.50 (d, J = 1.1 Hz, 1 H); 8.35 (d, J = 2.0 Hz, 1 H); 8.33 (s, 1 H); 8.01 (d, J = 8.9 Hz, 1 H); 7.85 (dd, Ji = 8.9 Hz, J2 = 1.4 Hz, 1 H); 7.76 (dd, Ji = 8.8 Hz, J2 = 2.1 Hz, 1H); 7.37-7.27 (m, 10H); 7.05 (d, J = 8.7 Hz, 1H); 5.10-4.95 (m, 4H); 4.58 (t, J = 6.2 Hz, 2H); 4.20 (q, J = 6.1 Hz, 2H); 3.98 (s, 3H); 2.17 (quint, J = 5.9 Hz, 2H)

[0689] NMR 13 C (125 MHz, chloroform-d): 5 (ppm) 161.1; 150.1; 143.1; 140.8; 140.6; 138.6; 136.8; 135.8 (d, Jc-p = 6.7 Hz, 2C), 132.7; 129.8; 128.7 (8C); 128.0 (2C); 125.4; 123.4; 118.3; 116.6; 116.1; 111.9; 105.0; 104.7; 89.1; 69.6 (d, Jc-p = 5.8 Hz, 2C); 64.8; 64.1 (d, Jc-p = 5.8 Hz); 56.5; 29.5 (d, Jc-p = 7.4 Hz)

[0690] Example 9: Synthesis protocol for the trifluoroacetate salt of guanidine

[0691] Example 9a: Trifluoroacetate of (Z)-1-((3-(1-cyano-2-(5-cyano-2-methoxyphenyl)vinyl)-1 H-indazol-5-yl) methyl)guanidinium 29 (MK87) o NC NH HN N Chemical formula: C 22 H 18 F3N7O3 Molar mass: 372.4115

[0692] Dissolve (Z)-3-(2-(5-(aminomethyl)-1H-indazol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile 7c (40.6 mg, 0.12 mmol, 1 eq.) and amino(imino)methanesulfinic acid (14.8 mg, 0.14 mmol, 1.2 eq.) in MeOH (1.2 mL) and water (1.2 mL). Then, add triethylamine (240 pL, 1.72 mmol, 14.3 eq.). Stir the reaction mixture for 24 h at room temperature. After complete conversion, evaporate the mixture under reduced pressure. Add TFA (1 mL) and stir for 1 h. Add acetone and filter the precipitate to obtain a white powder (13.6 mg, yield: 23%).

[0693] NMR 1H (500 MHz, chloroform-d): 5 (ppm) 13.72 (si, 1H); 9.50 (if, 1H); 9.08 (si; 1H); 8.82 (si, 1H); 8.35 (if, 1H); 8.14 (s, 1H); 8.13 (s, 1H); 8.02 (d, J = 8.3 Hz, 1H); 7.68 (d, J = 8.5 Hz, 1 H); 7.48 (d, J = 8.4 Hz, 1 H); 7.39 (d, J = 8.6 Hz, 1 H); 4.59 (s, 2H); 4.01 (s, 3H)

[0694] NMR 13 C (125 MHz, chloroform-d): 5 (ppm) 178.1; 160.6; 141.1; 138.3; 136.2; 135.7; 132.5; 130.1; 127.4; 123.8; 119.3 (2C); 118.7; 116.4; 112.9; 111.6; 108.6; 103.0; 56.8; 44.9

[0695] Example 10: Biological Tests

[0696] Some compounds from the previous examples have undergone biological testing which has demonstrated their relevance as MKLP-2 inhibitors.

[0697] MATERIALS AND METHODS

[0698] Test 1: Expression and purification of MKLP-2 constructs

[0699] For protein expression, the MKLP-2 expression plasmid was transformed in competent E. coli BL21(DE3) host cells (New England Biolabs, Evry, France). A colony of transformed bacteria was transferred to 250 mL of LB medium with appropriate antibiotics and pre-cultured overnight at 37°C. The bacterial culture was transferred to 1 L of 2xYT medium (supplemented with appropriate antibiotics) and cultured at 37°C until an OD of 0.6–1.0 was obtained. The cells were induced with 1 mM IPTG and cultured at 37°C for 4 h. The bacteria were harvested by centrifugation, frozen in liquid nitrogen, and stored at -20°C.The cells were resuspended in 20 mL of resuspension buffer (50 mM Hepes, pH 7.5, 500 mM NaCl, 5 mM MgCl2, 2 mM TCEP, 40 mM imidazole, 5% glycerol and the complete antiprotease cocktail without EDTA (Roche, Boulogne-Billancourt, France)), disrupted twice by sonication for 5 min at 40% and centrifuged for 30 min at 60,000 g (Beckmann JA-25.50 rotor, at 4 °C). The supernatant was loaded onto a 5 mL Ni-loaded His-trap FF column (GE Life Sciences, Velizy-Villacoublay, France) pre-equilibrated in buffer A (20 mM Hepes, pH 7.5, 300 mM NaCl, 5 mM MgCl2, 40 mM imidazole). The protein was eluted with 20 column volumes of buffer C (20 mM Hepes, pH 7.5, 300 mM NaCl, 5 mM MgCl2, 500 mM imidazole) and collected in 5 mL fractions.The MKLP-2-containing fractions were concentrated to approximately 5 mL using a Vivaspin 20 centrifugal concentrator and loaded onto a Superdex 5200 16 / 600 column (GE Life Sciences, Velizy-Villacoublay, France) equilibrated with buffer D (20 mM Hepes, pH 7.5, 150 mM NaCl, 5 mM MgCl2, 1 mM TCEP). The purified protein was collected in 1 mL fractions, analyzed by SDS-PAGE, concentrated to 6–10 mg / mL as described above, aliquoted, frozen in liquid nitrogen, and stored at -80 °C.

[0700] Test 2: Measurement of ATPase levels

[0701] All experiments were carried out at room temperature (25 °C) in a 96-well plate using a CLARIOstar Plus (BMG Labtech) at a final volume of 20 pL per well.

[0702] Steady-state ATPase levels were measured using the pyruvate kinase / lactate dehydrogenase linked assay as previously published (Günther et al., 1997). Basal ATPase activity was measured using 1.5 pM of MKLP-21-565 for each assay.

[0703] For optimal inhibitor solubility, the tests (as well as the control tests in the absence of inhibitor) were performed in the presence of no more than 10% DMSO. The data were analyzed using BMG Labtech's MARS data analysis software to obtain the kinetic variables.

[0704] Test 3: Determination of ICs 50

[0705] The values ​​of the CI 50 for the inhibition of basal and MT-stimulated ATPase activity of MKLP-2 1-565 were determined by measuring ATPase activity in the presence of increasing concentrations of inhibitor ranging from 0 to 16 pM.

[0706] When necessary, inhibitor concentrations were adjusted according to the initial ICso value. Each experiment was performed in three replicates, and the averaged data points are presented as mean ± standard deviation.

[0707] The values ​​of the CI 50 were determined by fitting the experimental data to the "normalized inhibitor vs variable slope" equation in the Prism software (GraphPad, San Diego, USA).

[0708] Test 4: Cell culture and proliferation assays

[0709] Cancer cell lines were obtained from the American Type Culture Collection (Rockville, MD) and cultured according to the supplier's instructions. K562R (doxorubicin-resistant) leukemia cells were obtained through a generous donation from JP Marie (France). Briefly, MDA-MB-231 breast carcinoma cells, K562 and K562R leukemia cells, A2780 cells, and cis A2780 cells were cultured in RPMI 1640 supplemented with 10% fetal bovine serum and 1% glutamine. U87-MG glioblastoma cells were cultured in Dulbecco's Minimal Essential Medium (DMEM) containing 4.5 g / L glucose supplemented with 10% fetal bovine serum (FCS) and 1% glutamine.

[0710] Lung carcinoma cells A549 and gastric carcinoma cells NCI-N87 were cultured in RPM1 1640 supplemented with 10% fetal calf serum and 1% glutamine.

[0711] The MRC-5 human cell line derived from healthy lung tissue was cultured in DMEM containing 4.5 g / L of glucose supplemented with 10% FCS and 1% glutamine.

[0712] Primary human umbilical vein endothelial cells (HUVECs) isolated from the umbilical cord vein were obtained from Promocell (Germany). The HUVECs were cultured in endothelial cell growth medium 2 (EGM-2), a low-serum (2% v / v) medium optimized for the culture of endothelial cells from large blood vessels.

[0713] Human HTERT-RPE1 cells and C4-2 prostate carcinoma cells were cultured in DMEM / F12 medium containing 10% fetal bovine serum and 1% glutamine. SK-OV-3 ovarian carcinoma cells were cultured in Gibco McCoy's 5A supplemented with 10% FCS and 1% glutamine.

[0714] Mia-Paca2 pancreatic carcinoma cells were cultured in Gibco DMEM medium supplemented with 10% FCS and 1% glutamine.

[0715] All cell lines were maintained at 37°C in a humid atmosphere containing 5% CO2.

[0716] Cell viability was determined by a luminescent assay according to the manufacturer's instructions (Promega, Madison, Wl, USA). For the determination of the IC 50 The cells were seeded in 96-well plates (3 x 10 3 cells / wells) containing 90 pL of growth medium. After 24 h of culture, the cells were treated with the test compounds at 10 different concentrations. Each concentration was obtained by serial dilutions in the culture medium from the stock solution. Control cells were treated with the vehicle. Each experiment was performed in triplicate.

[0717] After 72 h of incubation, 100 pL of CellTiter Glo reagent was added for 15 min before recording the luminescence with a PolarStar Omega spectrophotometric plate reader (BMG LabTech). Dose-response curves were plotted using Graph Prism software and IC50 values ​​were recorded. 50 were calculated using Graph Prism software from polynomial curves (logistic equations with four or five parameters).

[0718] Table 1 below includes the cell viability results of the MRC5 and RPE1 cell lines after 72 hours of incubation in the presence of 10⁻¹⁰ 5 or 10' 6 M of drugs. [Table 1] CYTOTOXICITY Cell viability (%) Code ID Product Patent MRC5 RPE1 10 -5 M 10 -6 M 10 -5 M 10 -6 M MK27 6b 45.5 45.1 4.2 23.8 MK46 6th 25.3 43.2 1.5 25.3 MK68 13b 89.8 91.7 77.7 97.8 MK69 14b 4.6 41.0 1.9 25.8 MK72 14th 39.2 43.6 7.9 26.3 MK73 6h 46.5 56.4 22.9 34.5 MK74 5h 99.1 110.3 103.7 104.2 MRC5: human fetal lung; RPE1: human retinal pigment epithelium

[0719] Table 2 below includes the results of determining the Clso of drugs that kill more than 50% of the cells of the MRC5 and RPE1 cell lines at 10 minutes. 5 Mr. [Table 2] CYTOTOXICITY CI Code ID 50 (nM) Patented product MRC5 RPE1 HUVEC MK27 6b 378.0 ± 23.4 MK46 6e 252.2 ± 5.7 429.2 ± 28.0 20 ± 2.2 MK69 14b 746.4 ± 55.0 201.6 ± 44.4 MK72 14e 1621.3 ± 205.1 310 ± 12.8 MK73 6h 797.9 ± 35.9 31.3 ± 4.7 MK86 24 27.8 ± 5.5 MRC5: human fetal lung; RPE1: human retinal pigment epithelium; HUVEC: human umbilical vein endothelial cells

[0720] Table 3 below includes the cell viability results of the K562, K562R, A2780, A2780 cis and C4-2 cell lines after 72 h incubation in the presence of 10' 5 or 10' 6 M of drugs. [Table 3] CYTOTOXICITY Activity Cell Viability Code ID (%) ATPasiqu Breve product K562 K562R A2780 A2780 cis C4-2 e tt CI 50 (µM) 10 -5 10 -6 10 -5 10 -6 10 -5 10 -6 10 -5 10 -6 10 -5 10 -6 MMMMMMMMMM 103, MK21 5a 4.6 98.0 62.2 95.7 6 MK22 5c 8.4 54.4 93.5 33.5 97.2 MK23 6c 23.8 69.1 92.3 40.6 98.0 MK25 5d 16.1 94.7 28.8 94.1 MK26 5b 1.2 100 75.6 94.4 18, MK27 6b 5.3 8.5 2.5 9.5 2.1 11.0 2.9 16.5 6.8 6 MK28 13e 41.6 15.8 11.2 16.8 MK35 6d > 50 99.8 88.7 76.5 97.9 MK36 5g > 50 78.6 97.9 27, 46, 55, MK38 5e 18.4 17.8 34.6 66.3 35.0 92.0 86.2 78.6 9 4 4 MK39 7d > 50 15.2 21.5 MK40 7c 2.3 9.5 30.3 MK41 5f > 50 88.6 100 MK43 6f 42.3 100 97.3 MK46 6e 2.1 4.9 13.1 1.4 11.0 10.3 17.4 4.9 18.0 8.9 7.1 MK47 9a 21.0 61.8 92.8 MK48 11f > 50 30.3 90.2 MK49 12f > 50 89.3 92.9 101, 54, 105, 76, MK57 11e 2.5 13.6 44.7 96.5 97.9 0 3 4 3 103, 87, 94, 101, MK58 9b 1.5 87.5 66.1 88.0 99.5 0 4 8 8 MK59 44a > 50 MK60 44b > 50 MK61 12e > 50 32, 50, 36, MK68 13b > 50 18.4 23.2 38.2 62.8 83.1 69.3 34.5 3 8 0 MK69 14b > 50 5,3 10,6 4,0 14,2 8,3 28,5 1,9 18,2 0,7 12,0 21, MK72 14e > 50 7,3 8,7 7,1 10,8 8,7 25,9 3,5 12,8 15,9 7 13, 16, 19, MK73 6h 0.3 13.2 13.5 15.7 27.6 30.4 18.7 18.3 4 2 2 71, 102, 100, 96, 103, 84, MK74 5h 0.7 56.0 80.6 91.9 99.5 0 7 2 0 8 1 MK75 6i > 50 48,4 88,7 MK76 5i 15.7 49.0 99.9 MK77 5j 8.5 95.1 98.6 MK78 7i > 50 95.5 96.4 MK79 5k > 50 85.7 98.4 MK80 15e > 50 7,3 9,2 9,1 22,7 3,3 15,0 55, MK81 16e > 50 17,6 69,7 69,1 93 96,4 8 MK86 24 2,2 8,0 9,0 10,3 12,2 100, 103, 106 MK87 29 > 50 92.2 3 3 1 10, MK88 28 > 50 5,7 12,9 11,1 18,3 9,6 3 10, MK89 25 > 50 4.3 6.5 10.0 15.2 13.6 7 10, MK90 26 > 50 3,9 5,2 8,3 11,6 10,6 3 12, MK91 27 > 50 5,6 4,9 12,8 14,3 16,7 2 14, MK93 30 > 50 3,9 9,3 5,0 6,5 5,6 10,6 6,2 8,4 14,2 3 MK94 31 > 50 2,2 6,7 1,5 6,5 0,4 11,4 MK95 34 > 50 3,2 9,2 4,1 4,7 3,1 9,3 4,9 5,2 11,0 13,0 MK96 40 > 50 5,5 11,0 5,0 8,8 11,6 11,9 MK97 41 > 50 4,1 9,6 3,1 8,8 9,5 11,1 MK98 43 > 50 2,2 8,0 5,6 7,0 0,9 7,3 6,0 8,0 4,6 9,7 MK10 37 > 50 3,0 3,3 1,9 6,1 3,0 7,3 0 MK10 44 > 50 2,1 6,4 2,5 6,4 3,7 11,7 2 MK10 45 > 50 3,1 6,6 4,3 8,0 2,3 3,5 4,3 9,3 2,4 6,2 3 MK10 54 > 50 6,1 7,2 1,6 5,0 5,6 7,8 4 MK10 46 > 50 9,4 7,7 9,3 11,0 6,0 5,8 5 MK10 47 > 50 7,9 9,4 7,9 9,7 7,7 6,5 6 MK10 48 > 50 2,9 6,0 5,2 8,3 3,7 4,8 4,2 4,8 5,9 7,1 7 MK10 49 > 50 4,2 5,6 6,6 8,5 4,6 5,8 8 MK10 50 > 50 6,3 6,4 5,7 6,0 3,9 5,2 3,6 3,5 2,3 5,6 9 MK11 51 > 50 6.4 7.4 5.9 6.4 6.8 5.9 0 MK111 52 > 50 7.6 7.6 4.4 11.0 2.5 4.7 4.5 4.2 5.0 6.1 MK11 6d 2.0 4.6 3.3 53.0 4.6 21.8 4 MK11 6k 2.9 11.1 1.1 12.4 2.8 10.5 5 MK11 102, 41, 100, 6I 17.3 67.8 88.7 6 9 4 1 K562: Caucasian human chronic myeloid leukemia cell line; K562R: doxorubicin-resistant K562 cell line; A2780: human ovarian carcinoma cell line; A2780 cis: cisplatin-resistant human ovarian carcinoma cell line; C4-2: human prostate carcinoma cell line.

[0721] Table 4 below includes the results of the IC determinations 50 drugs that kill more than 50% of cells of the K562, K562R, A2780, A2780 cis and C4-2 cell lines at 10 -5 Mr. [Table 4] CYTOTOXICITY Code ID CI 50 (nM) Patented product K562 K562R A2780 A2780 cis C4-2 11263,3± MK25 5d 1928,5 8132.3 ± MK26 5b 204.5 MK27 6b 71.0 ± 1.9 89.0 ± 2.8 108.0 ± 10.5 137.0 ± 32.9 71.3 ± 2.3 MK28 13e 260.0 ± 60.0 917.7 ± 33.0 MK38 5e 860.5 ± 8.2 MK39 7d 406.0 ± 24.0 MK40 7c 608.0 ± 38.0 MK46 6e 64.0 ± 4.4 51.1 ± 5.5 98.4 ± 2.3 131.2 ± 13.4 58.7 ± 1.7 MK68 13b 46.4 ± 1.2 MK69 14b 36.7 ± 1.2 54.3 ± 3.2 193.0 ± 19.5 31.9 ± 4.2 63.3 ± 2.3 MK72 14e 41.7 ± 2.8 87.0 ± 2.2 63.6 ± 9.7 107.7 ± 12.0 53.9 ± MK86 24 ± 29.4 1.4 58.8 ± 4.01 MK88 28 39.8 ± 4.1 321.0 ± 38.0 62.6 ± 1.3 MK89 25 33.0 ± 0.2 67.3 ± 0.8 33.3 ± 10.5 MK90 26 9.3 ± 0.48 30 ± 1.7 6 ± 0.4 MK91 27 29.4 ± 0.9 84.6 ± 9.5 17.0 ± 5.0 MK93 30 8.8 ± 0.9 39.9 ± 3.7 23.8 ± 0.9 70.8 ± 1.6 9.9 ± 0.3 MK94 31 14.1 ± 1.7 48.8 ± 1.4 34 ± 1.8 20.9 ± 1.5 MK95 34 3.8 ± 0.2 59.3 ± 2.7 23.9 ± 3.3 85.1 ± 0.9 5 ± 0.12 MK96 40 26.6 ± 1.7 71.6 ± 0.4 70.4 ± 3.2 MK97 41 417 ± 21 600 ± 49 490 ± 7.7 MK98 43 22.2 ± 2.7 31 ± 1.2 26 ± 2.7 MK99 35 338 ± 28 356 ± 12.3 316 ± 38 MK100 37 26.3 ± 0.7 60 ± 7.9 59.4 ± 1.3 MK102 44 8.7 ± 0.2 30.9 ± 2.0 31.8 ± 8 MK103 45 140 ± 0.6 266 ± 13.9 51.2 ± 7.5 115 ± 14.5 72.2 ± 5 MK104 54 5.2 ± 0.3 74.8 ± 9.6 38.7 ± 4 49.6 ± 2.2 40.4 ± 4.4 MK105 46 19.6 ± 0.2 29 ± 1.8 37.3 ± 1.3 MK106 47 58.8 ± 4.7 99 ± 0.8 77.3 ± 5 MK107 48 42.6 ± 4.6 54.9 ± 0.9 88.8 ± 17.6 43.7 ± 8.9 24 ± 4.7 MK108 49 7.6 ± 0.9 39 ± 1.9 23.7 ± 2.9 97.1 ± 3.5 25.4 ± 3.1 MK109 50 18,2 ± 4,4 40,9 ± 2,6 59,3 ± 8,0 58,4 ± 10,7 50,4 ± 0,7 MK110 51 31,6 ± 7,5 97,6 ± 9,8 54,1 ± 0,7 MK111 52 16.6 ± 2.5 27.9 ± 1.2 43.6 ± 6.5 94.2 ± 10.5 33.8 ± 0.7 MK113 32 69.3 ± 1.6 50.3 ± 2.9 31.8 ± 0.7 MK114 6d 897 ± 29 2600 ± 374 399 ± 43 MK115 6k 412 ± 16 1200 ± 114 244 ± 49, Methoxypaprotrain 4000 ± 300 K562: Caucasian human chronic myeloid leukemia cell line; K562R: doxorubicin-resistant K562 cell line; A2780: human ovarian carcinoma cell line; A2780 cis: cisplatin-resistant human ovarian carcinoma cell line; C4-2: human prostate carcinoma cell line.

[0722] Table 5 below includes the cell viability results of the U87-MG, MDA-MB-231, HCT 116, MiaPaCa-2, A549, SK-OV-3 and NCI-N87 cell lines after 72 h incubation in the presence of 10' 5 or 10' 6 M of drugs. [Table 5] CYTOTOXICITY Cod Cell Viability (%) ID du e MDA-MB- MiaPaCa- prod U87-MG HCT 116 A549 SK-OV-3 NCI-N87 Brev 231 2 uit et 10- 5 10- 6 10- 5 10- 6 10- 10- 6 10- 10- 6 10- 10- 10- 5 10- 6 10- 10- M M M M 5 M M 5 M M 5 M 6 M M M 5 M 6 M MK2 113, 110, 102, 79, 101, 5a 86,6 1 6 8 4 4 7 MK2 82, 100, 67, 5c 94,4 74,6 92,9 2 5 9 2 MK2 83, 104, 106, 66, 101, 6c 76,3 3 4 3 2 6 2 MK2 72, 5d 91,5 84,1 97,9 5 7 MK2 75, 5b 79,9 84,6 95,0 6 1 MK2 24, 18, 41, 18, 40, 6b 27,7 12,8 39,2 3,2 32,5 5,9 37,5 22,9 41,0 7 1 6 0 9 3 MK2 21, 13e 41,6 31,7 45,4 8 4 MK3 62, 103, 105, 6d 49,4 5 6 9 0 MK3 73, 66, 56, 63, 96, 105, 72, 87, 5e 77.3 65.9 96.4 83.4 73.2 38.5 8 9 1 7 5 8 0 0 8 MK4 17, 36, 20, 51, 6e 6.3 49.2 2.6 38.0 9.5 33.1 5.9 53.6 6 7 4 5 9 MK5 102, 107, 75, 73, 79, 89, 11e 92.8 99.7 7 4 3 4 3 2 8 MK5 103, 74, 69, 89, 93, 9b 90.3 90.3 92.2 8 1 1 5 6 9 MK6 56, 33, 89, 98, 57, 62, 13b 84.1 58.4 82.8 87.1 8 9 2 6 2 3 6 MK6 11, 41, 28, 56, 14b 46.8 5.6 28.9 7.2 16.1 57.1 9 4 1 8 7 MK7 24, 20, 24, 38, 50, 60, 14e 41.1 27.5 42.4 51.8 2 6 9 6 6 9 0 MK7 33, 24, 41, 48, 46, 51, 6h 31.2 26.4 33.6 51.0 3 4 6 8 9 6 6 MK7 89, 89, 101, 97, 97, 100, 104, 83, 99, 5h 91,2 4 3 7 4 3 4 0 1 7 2 U87-MG: Human glioblastoma astrocytoma cell line; MDA-MB-231: Caucasian human breast adenocarcinoma cell line; HCT116: Human colon carcinoma cell line; MiaPaCa-2: Human pancreatic carcinoma cell line; A549: Human lung carcinoma cell line; SK-OV-3: Human ovarian adenocarcinoma cell line; NCI-N87: Human gastric carcinoma cell line.

[0723] Table 6 below includes the IC50 determination results for drugs that kill more than 50% of cells from the U87-MG, MDA-MB-231, HCT 116, MiaPaCa-2, A549, SK-OV-3 and NCI-N87 cell lines at 10 -5 Mr. [Table 6] CYTOTOXICITY Code ID IC50 (nM) MDA-MiaPa patented product U87-MG HCT 116 A549 SK-OV-3 NCI-N87 MB-231 Ca-2 371.6 ± 236.4 ± 371.6 ± 247.0 498.4 ± 383.1 ± 473.8 ± MK27 6b 18.7 23.6 8.9 ± 26.5 13.2 61.8 160.0 731.0 ± 815.1 ± MK28 13th 9.5 12.1 583.0 ± 441.2 ± 170.7 389.4 ± 162.6 ± 124.0 ± MK46 6th 97.0 53.9 ± 37.2 34.1 38.2 2.8 349.4 ± 53.2 ± 392.6 ± MK69 14b 16.2 2.6 22.2 291.8 ± 177.8 295.4 ± MK72 14th 11.6 ± 25.3 8.0 96.9 ± 137.4 388.0 ± 84.5 ± MK73 6h 2.6 ± 10.4 6.0 1.8 U87-MG: Human glioblastoma astrocytoma cell line; MDA-MB-231: Caucasian human breast adenocarcinoma cell line; HCT116: Human colon carcinoma cell line; MiaPaCa-2: Human pancreatic carcinoma cell line; A549: Human lung carcinoma cell line; SK-OV-3: Human ovarian adenocarcinoma cell line; NCI-N87: Human gastric carcinoma cell line.

[0724] Table 7 below includes the results of IC50 determinations of drugs on cells of the PC3, CAOV3, OV90, OVCAR4 and OVCAR8 lines after 72 hours of incubation. [Table 7] CYTOTOXICITY Code ID CI50 (nM) Patented product PC3 CAOV3 OV90 OVCAR4 OVCAR8 MK46 6e 127 ± 4.8 87 ± 9.2 82 ± 10.4 48.8 ± 5.3 45 ± 4.8 MK93 30 153 ± 18 51.3 ± 1.8 3810 ± 955 119 ± 17.6 199 ± 2.1 MK95 34 65.1 ± 3 83.8 ± 2.9 619 ± 153 116 ± 9.9 135 ± 26.4 PC3 human prostate adenocarcinoma cell line; CAOV3: human high-grade ovarian adenocarcinoma cell line; OV90: Human epithelial ovarian carcinoma cell line; OVCAR4: Human ovarian carcinoma cell line refractory to cisplatin; OVCAR8: Human advanced ovarian carcinoma cell line heavily treated with cisplatin and carboplatin.

[0725] Table 8 below includes the results of determining the IC50 of the drugs on the PBMC cell line after 72 hours of incubation. [Table 8] CYTOTOXICITY Product ID Patent Code CI50 (nM) PBMC MK46 6th 911 ± 118 MK93 30 > 10,000 MK95 34 > 10,000 PBMC: peripheral blood mononuclear cells.

[0726] Table 9 below includes the results of determining the thermodynamic solubility of drugs in PBS at pH = 7.4 and at 20 °C. [Table 9] Product ID Patent Code Solubility (µM) MK46 6th 1 MK86 24 < 1 MK90 26 < 1 MK93 30 38 ± 12 MK95 34 5 ± 1 MK96 40 11 ± 2 MK97 41 13 ± 1 MK98 43 16 ± 7 MK99 35 4 ± 2 MK100 37 < 1 MK102 44 < 1 MK104 54 < 1 MK107 48 75 ± 24 MK109 50 1.8 ± 0.1 MK113 32 16 ± 4

[0727] Table 10 below includes the results of determining the chemical, metabolic and plasma stabilities of the drugs in PBS at a concentration of 1 µM. [Table 10] Stability Half-life time (t 1 / 2 ) Product ID Patent Code Plasma Chemical Metabolic (mouse) (human) MK46 6th > 24 h 7 ± 1 > 2h > 2h MK93 30 > 24 h 32 ± 3 48 ± 9 51 ± 2 Chemical: chemical stability in PBS at pH = 7.4; Metabolic: metabolic stability at 37 °C in the presence of 0.5 mg / mL of mouse liver microsomes and NADPH as a co-factor; Plasma: stability in mouse or human plasma at 37 °C.

Claims

DEMANDS 1. Compound of formula (I): i< ; ' (I) in which: ° R 1 is chosen from: • a halogen, (Ci-Ce)alkoxy, -NH2, -CH2-NH-C(=NH)-NH3 + ; TFA-, -N3, -SCN, -O-SO2F, a (Ci-Ce)alkyl group substituted by at least one hydroxyl group, a halo(Ci-C6)alkyl group, -CH2-NH-SO2CH3, or -CH2-NH-SO2NH2, • -(CH2)j-NH2, -(CH2)j-NHBoc, where j is an integer from 1 to 5, • -O-SO3X 1 X 1 being chosen from among the alkali metals, • -X 2 -CH2-CH2-SO2F in which X 2 is NH or O, •-NH-C(=O)-OR 4 , R 4 being a (Ci-Ce)alkyl group, • -(CH2)i-NH-C(=O)-OR 5 , R 5 being a (Ci-Ce)alkyl group and i being an integer from 1 to 5, • -NH-C(=O)-R 6 , R 6being a (Ce-Cio)aryl group, said (Ce-Cw)aryl group being optionally substituted by one or more substituent(s) chosen from the group consisting of: halogen, -OH, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkyl, -CN, -NO2, -C(=O)-(Ci-C6)alkyl, halo(Ci-Ce)alkoxy, -NH2, and (Ci-C6)alkylamino; ° R 2 is chosen from • -H, -S(=O)2-R 7 , -C(=O)-OR 7 , -C(=O)-O-CH2-R 7 , R 7 being a (Ci-Ce)alkyl group, -C(=O)-CH2-O-(CH2-CH2-O)m-CH3, m being between 0 and 10, -P(=O)-(OBn)2, -P(=O)-(OH)2, -P(=O)-(OH)(O-; Na + ),-P(=O)-(OH)(O-; K + ), -P(=O)-(O-; Na + )2, P(=O)-(O-; K + )2, • -C(=O)-R 7 -Y, -C(=O)-R 7 -OY, -C(=O)-OR 7 -Y, -C(=O)-OR 7 -OY, R 7 being a (Ci-Ce)alkyl group and Y being chosen from P(=O)-(OBn)2, P(=O)-(OH)2, P(=O)(OH)(O-; Na + ), P(=O)(O-; Na +)2, P(=O)(OH)(O-; K + ), P(=O)(O-; K + )2, • a group of formula (B) i. ||; in which L 1 is a cleavable group chosen from among a pH-sensitive group, a photo-induction cleavable group, a bioreduction cleavable group, and an enzymatically cleavable group, L 2 is a tert-butoxycarbonyl group or a protein-binding connector, and m is an integer equal to 0 or 1 or a pharmaceutically acceptable salt; ° R 3 is chosen from • -H, a halogen, -OH, • a (Ci-Ce)alkoxy radical, a (Cs-Ce)cycloalkoxy radical, a (C3-C6)heterocycloalkoxy radical, a (Ce-Ci6)aryloxy radical, a (C4-Ci4)heteroaryloxy radical, a (Ci-C6)alkyl-heteroaryloxy radical, said radicals being optionally substituted by at least one group selected from a halogen, a thio-(Ci-Ce)alkyl group, a thio-(C4-Cg)heteroaryl group, a thio-(Ci-C6)alkyl-(C6-Cio)aryl group, a thio-(Ci-Ce)-alkyl-(C4-C9)heteroaryl group, said groups being optionally substituted by at least one halogen or by a (Ci-Ce)alkoxy, • -NR 8 R 9 , -O-(Ci-C6)alkyl-NR 8 R 9 , S-(Ci-C6)alkyl-NR 8 R 9 , R 8 and R 9 independently representing H, (Ci-Ce)alkyl or R 8 and R 9 taken together form a cycle of 3 to 7 links, possibly interrupted by one or more heteroatoms, provided that at least one of the R 8 and R 9 not be H, • -NHCOR 10 , R 10 representing a (Ci-Ce)alkyl, (C6-C)aryl, (C4-Cg)heteroaryl possibly substituted by at least one halogen, trifluoromethyl, (C1-C3)alkoxy; ° X is chosen from N, C-CN, C-OMEM, C-OH, C-NO2 and C-NH2; or one of its pharmaceutically acceptable salts.

2. Compound according to claim 1, wherein R 1 is chosen from -0-CH3, -halogen, -NH2, -(CH2)2-NHBoc, -(CH2)2-NH2, -CH2-NH-C(=NH)-NH3 + ; TFA-, -(CH2)i-NH-C(=O)-OR 5 , R 5 being a (Ci-Ce)alkyl group and i being an integer from 1 to 5, and -NH-C(=O)-R 6 , R 6 being a (C6-Cio)aryl group, said (Ce-Cio)aryl group being optionally substituted by one or more substituent(s) chosen from the group consisting of: halogen, -OH, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkyl, -CN, -NO2, -C(=O)-(Ci-C6)alkyl, halo(Ci-Ce)alkoxy, -NH2, and (Ci-C6)alkylamino.

3. Composed according to any one of claims 1 to 2, wherein R 2 is chosen from H, -S(=0)2- R 7 , - C(=0)-0- R 7 , - C(=O)-O-CH2- R 7 , -C(=O)-CH2-O-(CH2-CH2-O)m- CH3, m being between 0 and 10, -P(=O)-(OBn)2, -P(=O)-(OH)2, -P(=O)-(OH)(O-; Na + ), -P(=O)-(OH)(O-; K + ), -P(=O)-(O-; Na + )2, -P(=O)-(O-; K + )2, -C(=O)-R 7 -Y, -C(=O)-R 7 -OY, -C(=O)-OR 7 -Y, -C(=O)-OR 7 -OY, with, R 7 being a (Ci-Ce)alkyl group and Y being chosen from P(=O)-(OBn)2, P(=O)-(OH)2, P(=O)(OH)(Q-; Na + ), P(=O)(OH)(O-; K + ), P(=O)(O-; Na + )2, and P(=O)(O-; K + )2.

4. Composed according to any one of claims 1 to 3, wherein R 3 is chosen from - H, -O-CH3 and a halogen.

5. Composed according to any one of claims 1 to 4, wherein X is selected from N and C-CN.

6. Composed according to any one of claims 1 to 5 selected from in which said compound may be of Z or E configuration.

7. Pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and at least one pharmaceutically acceptable excipient.

8. Pharmaceutical composition according to claim 7, further comprising an anticancer agent.

9. Compounded according to any one of claims 1 to 5 or pharmaceutical composition according to any one of claims 7 to 8 for its use as a medicinal product.

10. Compound according to any one of claims 1 to 6 or pharmaceutical composition according to any one of claims 7 to 8 for its use according to claim 9, in the treatment of cancer, bacterial infections or viral infections. 11.A compound according to any one of claims 1 to 6 or a pharmaceutical composition according to any one of claims 7 to 8 for its use according to any one of claims 7 to 8, wherein the cancer is selected from breast cancer, colon cancer, pancreatic cancer, bladder cancer, thyroid cancer, cervical cancer, pleural mesothelioma, non-small cell lung cancer, small cell lung cancer, leukemia, gastric carcinoma, liver cancer such as hepatocellular carcinogenesis, melanoma, glioblastoma, ovarian cancer, prostate cancer, mesothelioma, kidney cancer, sarcoma, medulloblastoma and chemotherapy-resistant cancer.

12. Compound according to any one of claims 1 to 6 or pharmaceutical composition according to any one of claims 7 to 8 for its use according to any one of claims 9 to 10, wherein the bacterial infection can be selected from infections due to Eskape bacteria such as Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae (family Enterobacteriaceae), Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.

13. Compound according to any one of claims 1 to 6 or pharmaceutical composition according to any one of claims 7 to 8 for its use according to any one of claims 9 to 10, wherein the viral infection can be selected from influenza A virus infection, Covid virus infection, HIV infection, HPV infection, HTLV infection or respiratory syncytial virus infection.

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