Guanfacine derivatives and their uses

Abstract

The present invention relates to guanfacine derivatives of formula (I), and the isomers, stereoisomers, tautomers, and pharmaceutical acceptable salts thereof. The invention further relates to pharmaceutical compositions comprising such compounds of formula (I) and their use for treating a cancer.

Description

[0001] GUANFACINE DERIVATIVES AND THEIR USES FIELD OF THE INVENTION The present invention relates to the field of medicine, in particular guanfacine derivatives and their uses for treating diseases. More particularly, the invention provides alpha2-adrenergic receptor (α2-AR) agonists for the treatment of cancer. BACKGROUND OF THE INVENTION Cancer is the second leading cause of death worldwide. Indeed, nearly 1 in 6 deaths is due to cancer. The prevalence of cancer is also extremely high as more than 15 million new cases are diagnosed each year, and the number of new cases is expected to rise by about 70% over the next 2 decades. Among the most common cancers, lung cancers account for 1.69 million deaths per year, colorectal cancer for 774000 deaths per year, and breast cancer for 571000 deaths per year. Many treatment options exist nowadays for cancer, including for example surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy, immunotherapy and palliative care. The choice of the best treatments depends on the type, location and grade of the cancer as well as the patient's health and preferences. The α2-AR are a family of G-protein–coupled receptors with 3 pharmacological subtypes, α2A, α2B, and α2C. They have been used for decades to treat common medical conditions such as hypertension; attention-deficit / hyperactivity disorder; various pain and panic disorders; symptoms of opioid, and alcohol withdrawal; and for sedation and to reduce anesthetic requirements. Centrally acting alpha2-adrenergic receptors agonists stimulate α2-AR in the central nervous system (brain and spinal cord). When α2-AR are stimulated, sympathetic nervous system activity decreases. This decreased sympathetic activity leads to a drop in blood pressure and heart rate. WO 2021 / 214129 and J. Zhu, et al. (Nature, 618, 607–615 (2023)) have currently shown that agonists of α2-AR, such as Guanabenz, Clonidine or Guanfacine, have surprisingly strong anti- tumor activity when used as monotherapies in multiple immunocompetent murine tumor models, including ICB-resistant models, but not in immunodeficient models. It was also observed striking effects in human tumor xenografts implanted in mice reconstituted with human peripheral blood mononuclear cells. The anti-tumor effects of α2-AR agonists were reverted by α2-AR antagonists, and were absent in α2-AR knockout mice, demonstrating on- target action exerted on host cells, not tumor cells. Tumors from treated mice contained increased infiltrating CD8+ T lymphocytes and reduced infiltrating myeloid-derived suppressor cells (MDSC), which were more apoptotic. Single-cell RNA sequencing revealed upregulation of innate and adaptive immune response pathways in macrophages and T cells. Consequently, the discovery and the synthesis of new α2-AR agonists are relevant and promising approaches for anti-cancer therapies. More particularly, it could significantly improve clinical efficacy of cancer immunotherapy. However, many of the effects of centrally active α2-AR agonists are mediated by decreasing sympathetic activity and lead to side hypotensive and sedative effects that could be harmful to patients and / or limit the dose of α2- AR agonists that could be safely administered to patients, thereby potentially limiting the therapeutic anti-cancer benefit. Therefore, there remains a need to identify further α2-AR agonists having an efficient effect on α2-AR while limited CNS penetrance. The development of new peripherally restricted α2-AR agonists could be of interest as anti-cancer therapies and, more specifically anti-cancer immunotherapies. The present invention seeks to meet these and other needs. SUMMARY OF THE INVENTION In this context, the inventors have provided new guanfacine derivatives as efficient α2-AR agonists while being not efficient in penetrating the BBB, demonstrating thereby the therapeutic interest of such derivatives in medicine, more particularly in anti-cancer therapies. The present invention thus provides new compounds of formula (I): R9wherein: ^ --- is a single or a double bound; ^ X is C=O, C-R1, or N-R1with R1is absent or represents a radical selected in a group consisting of a hydrogen, a halogen, a cyano, a (C1-C6)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1- C6)alkyloxy, a 3-6 membered cycloalkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a hydroxy, and a NRaRbwith Raand Rbrepresent independently a hydrogen or a (C1- C6)alkyl; ^ Y is C=O, C-R2, or N-R2with R2is absent or represents a radical selected in a group consisting of a hydrogen, a halogen, a cyano, a (C1-C6)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1- C6)alkyloxy, a 3-6 membered cycloalkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a hydroxy, and a NRa’Rb’with Ra’and Rb’represent independently a hydrogen or a (C1- C6)alkyl; ^ Z is C=O, C-R3, or N-R3with R3is absent or represents a radical selected in a group consisting of a hydrogen, a halogen, a cyano, a (C1-C6)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1- C6)alkyloxy, a 3-6 membered cycloalkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a hydroxy, and a NRa’’Rb’’with Ra’’and Rb’’represent independently a hydrogen or a (C1- C6)alkyl; ^ R4represents a radical selected in a group consisting of a hydrogen, a halogen, and a (C1-C6)alkyl; ^ R5represents a radical selected in a group consisting of a hydrogen, a halogen, and a (C1-C6)alkyl; ^ R6represents a radical selected in a group consisting of a hydrogen, a halogen, a cyano, a (C1-C6)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a 3-6 membered cycloalkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, and a 3-12 membered heteroaryl; ^ R7represents a hydrogen, or a (C1-C6)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (C1-C6)alkyloxy, a -NH(C1-C6)alkyl, and a -N((C1- C6)alkyl)2; ^ R8represents a hydrogen, or a (C1-C6)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (C1-C6)alkyloxy, a -NH(C1-C6)alkyl, and a -N((C1- C6)alkyl)2; and ^ R9represents a hydrogen, or a (C1-C6)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (C1-C6)alkyloxy, a -NH(C1-C6)alkyl, and a -N((C1- C6)alkyl)2; or R8 and R9 may form together a 5-7 membered ring, partially unsaturated or saturated, N,N’-heterocycloalkyl optionally substituted by at least one radical selected in a group consisting of a (C1-C6)alkyl, a hydroxy, a (C1-C6)alkyloxy, a -NH(C1-C6)alkyl, a - N((C1-C6)alkyl)2, and a ketone; and the isomers, stereoisomers, tautomers, and pharmaceutical acceptable salts thereof. In an embodiment, the compound of formula (I) is such that R4, R5, R7, R8, and R9represent H. In a further embodiment, the compound of formula (I) is such that R6represents a radical selected in a group consisting of a hydrogen, a halogen, preferably a chlorine, a cyano, and a (C1-C6)alkyl, preferably a methyl. In a further embodiment, the compound of formula (I) is such that R1is absent or represents a radical selected in a group consisting of a hydrogen, a halogen, preferably a bromine or a chlorine, a cyano, a (C1-C6)alkyl, preferably a methyl, an ethyl, or an isopropyl, a 3-6 membered cycloalkyl, preferably a cyclopropyl, and a NRaRbwith Raand Rbrepresent independently a hydrogen or a (C1-C6)alkyl, preferably a hydrogen. In a further embodiment, the compound of formula (I) is such that R2is absent or represents a radical selected in a group consisting of a hydrogen, and a (C1-C6)alkyl, preferably a methyl, an ethyl, or an isopropyl. In a further embodiment, the compound of formula (I) is such that wherein R3 is absent or represents a radical selected in a group consisting of a hydrogen, a halogen, preferably a chlorine or a bromine, and a (C1-C6)alkyl, preferably a methyl. In a particular embodiment, the compound of formula (I) has a formula selected in a group consisting of: R9R9 Particularly, said compound has the following formula (IA) or (IF): In a particular embodiment, a compound of the invention is selected in a group consisting of: - Example 1: N-carbamimidoyl-2-(5-chloro-1H-indazol-4-yl)acetamide, HCl; - Example 2: N-carbamimidoyl-2-(3,5-dichloro-1H-indazol-4-yl)acetamide, HCl; - Example 3: 2-(3-bromo-5-chloro-1H-indazol-4-yl)-N-carbamimidoylacetamide, HCl; - Example 4: N-carbamimidoyl-2-(5-chloro-3-cyano-1H-indazol-4-yl)acetamide, HCl; - Example 5: N-carbamimidoyl-2-(6-chloro-1-methyl-1H-indazol-7-yl)acetamide, HCl; - Example 6: N-carbamimidoyl-2-(3,6-dichloro-1-methyl-1H-indazol-7-yl)acetamide; - Example 7: N-carbamimidoyl-2-(5-chloro-1-methyl-1H-indazol-4-yl)acetamide, HCl; - Example 8: 2-(3-bromo-5-chloro-1-methyl-1H-indazol-4-yl)-N-carbamimidoylacetamide, HCl; - Example 9: N-carbamimidoyl-2-(5-chloro-2-methyl-2H-indazol-4-yl)acetamide, HCl; - Example 10: N-carbamimidoyl-2-(1-methyl-1H-indazol-7-yl)acetamide, HCl; - Example 11: N-carbamimidoyl-2-(1,6-dimethyl-1H-indazol-7-yl)acetamide, HCl; - Example 12: N-carbamimidoyl-2-(2,6-dimethyl-2H-indazol-7-yl)acetamide, HCl; - Example 13: N-carbamimidoyl-2-(6-chloro-1-ethyl-1H-indazol-7-yl)acetamide, HCl; - Example 14: N-carbamimidoyl-2-(6-chloro-2-ethyl-2H-indazol-7-yl)acetamide, HCl; - Example 15: N-carbamimidoyl-2-(6-chloro-1-isopropyl-1H-indazol-7-yl)acetamide, HCl; - Example 16: N-carbamimidoyl-2-(6-chloro-2-isopropyl-2H-indazol-7-yl)acetamide, HCl; - Example 17: N-carbamimidoyl-2-(5-chloro-3-cyano-1-methyl-1H-indazol-4-yl)acetamide, HCl; - Example 18: N-carbamimidoyl-2-(1H-indol-7-yl)acetamide, HCO2H; - Example 19: N-Carbamimidoyl-2-(1H-indol-4-yl)acetamide, HCO2H; - Example 20: N-carbamimidoyl-2-(3-chloro-1H-indol-4-yl)acetamide, HCl; - Example 21: N-carbamimidoyl-2-(5-chloro-3-cyclopropyl-1H-indazol-4-yl)acetamide, HCO2H; - Example 22: 2-(3-amino-5-chloro-1H-indazol-4-yl)-N-carbamimidoylacetamide, HCl; - Example 23: N-carbamimidoyl-2-(6-chloro-1H-indazol-7-yl)acetamide, HCl; and - Example 24: 2-(3-bromo-6-chloro-1H-indazol-7-yl)-N-carbamimidoylacetamide, HCl. A further object of the invention is a compound of formula (I) as defined herein for use as a drug or a medicine. A further object of the invention is a pharmaceutical composition comprising a compound of formula (I) as defined herein and a pharmaceutically acceptable excipient. A further object of the invention is a pharmaceutical composition as defined herein for use for treating a cancer. Preferably, the cancer is selected in a group consisting of myelofibrosis, acute lymphoblastic leukemia, acute myeloblastic leukemia adrenal gland carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, glioblastoma, head and neck cancer, hepatocellular carcinoma, Hodgkin’s lymphoma, kidney cancer, lung cancer, melanoma, Merkel cell skin cancer, mesothelioma, multiple myeloma, myeloproliferative disorders, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, salivary gland cancer, sarcoma, squamous cell carcinoma, testicular cancer, thyroid cancer, urothelial carcinoma, and uveal melanoma. In a particular embodiment, the pharmaceutical composition comprising a compound of formula (I) as defined herein is administered at a dose ranging from 0.001 mg / kg body weight to 30 mg / kg body weight. In a further particular embodiment, the pharmaceutical composition is administered in combination with another antitumoral drug, especially chemotherapy, immunotherapy, hormonotherapy and / or radiotherapy, preferably immunotherapy. LEGEND OF FIGURES Figure 1: Anti-tumor efficacy of Example 3 of the invention in a murine syngeneic subcutaneous colorectal tumor model (MC38). Figure 2: Anti-tumor efficacy of Example 3 of the invention was assessed in a murine syngeneic subcutaneous liver tumor model (HEPA 1-6). Figure 3: Anti-tumor efficacy of Example 3 of the invention was assessed in a syngeneic murine subcutaneous lung tumor model (TC-1). Figure 4: Anti-tumor efficacy of Example 3 of the invention was assessed in a murine syngeneic subcutaneous lung tumor model (LLC1). DETAILED DESCRIPTION OF THE INVENTION Definitions According to the present invention, the terms below have the following meanings: The terms mentioned herein with prefixes such as for example C1-C6,can also be used with lower numbers of carbon atoms such as C1-C2. If, for example, the term C1-C6is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 6 carbon atoms, especially 1, 2, 3, 4, 5, or 6 carbon atoms. If, for example, the term C1-C3is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 3 carbon atoms, especially 1, 2, or 3 carbon atoms. As used herein “---” represents a single or a double bound. A skilled person will be easily able to determine the nature of “---”, i.e. a single or a double bound according to the valency rules. The term “alkyl” refers to a saturated, linear or branched aliphatic group. The term “(C1- C6)alkyl” more specifically means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, or hexyl. The term “alkenyl” refers to an unsaturated, linear or branched aliphatic group comprising at least one carbon-carbon double bound. The term “(C2-C6)alkenyl” more specifically means ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, or hexenyl. The term “alkynyl” refers to an unsaturated, linear or branched aliphatic group comprising at least one carbon-carbon triple bound. The term “(C2-C6)alkynyl” more specifically means ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, or hexynyl The term “alkoxy” or “alkyloxy” corresponds to the alkyl group as above defined bonded to the molecule by an -O- (ether) bond. (C1-C6)alkoxy or (C1-C6)alkyloxy includes methoxy or methyloxy, ethoxy or ethyloxy, propoxy or propyloxy, isopropoxy or isopropyloxy, butoxy or butyloxy, isobutoxy or isobutyloxy, pentoxy or pentyloxy, isopentoxy or isopentyloxy, and hexoxy or hexyloxy. The term “3-14 membered ring” corresponds to a ring having between 3 and 14 atoms. Such a term includes, for instance, the term “5-14 membered ring” having between 5 and 14 atoms, and the term “5-7 membered ring” having between 5 and 7 atoms. The term “ring” corresponds to a mono-, bi, or tricycle, which can be saturated, partially unsaturated or unsaturated, and optionally comprises at least one heteroatom. Particularly, the term “ring” includes a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl. The term “cycloalkyl” corresponds to a saturated, partially unsaturated or unsaturated mono-, bi- or tri-cyclic alkyl group comprising between 3 and 14, preferably between 3 and 10 atoms of carbons. It also includes fused, bridged, or spiro-connected cycloalkyl groups. The term “cycloalkyl” includes for instance cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, preferably cyclopropyl. The term “heterocycloalkyl” corresponds to a saturated, partially unsaturated or unsaturated cycloalkyl group as above defined further comprising at least one heteroatom such as nitrogen (N-heterocycloalkyl), oxygen (O-heterocycloalkyl), or sulphur atom (S-heterocycloalkyl). It also includes fused, bridged, or spiro-connected heterocycloalkyl groups. Representative heterocycloalkyl groups include, but are not limited to dioxolanyl, benzo [1,3] dioxolyl, azetidinyl, oxetanyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1,4-dioxanyl, pyrrolinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl, 1,4-dithianyl, pyrrolidinyl, oxozolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and tetrahydrothiophenyl. "Cycloalkyl" and "heterocycloalkyl" also include cycloalkenyl and heterocycloalkenyl which correspond respectively to a partially unsaturated cycloalkyl and a partially unsaturated heterocycloalkyl such as cyclohexenyl, imidazolinyl, dihydropyranyl, for instance 3,6-dihydro- 2H-pyranyl and 3,4-dihydro-2H-pyranyl, pyrazolinyl, azetinyl, pyranyl, and tetrahydropyridinyl, for instance 1,2,3-6-tetrahydropyridinyl. The term “aryl” corresponds to a mono- or bi-cyclic aromatic hydrocarbons having from 6 to 12 carbon atoms. For instance, the term “aryl” includes phenyl, biphenyl, naphthyl and anthracenyl. In a particular embodiment, the aryl is a phenyl. The term “heteroaryl” as used herein corresponds to an aromatic, mono- or poly-cyclic group comprising between 3 and 20 atoms and comprising at least one heteroatom such as nitrogen, oxygen or sulphur atom. As used herein, the term “heteroaryl” further includes the “fused arylheterocycloalkyl” and “fused heteroarylcycloalkyl”. The terms “fused arylheterocycloalkyl” and “fused heteroarylcycloalkyl” correspond to a bicyclic group in which an aryl as above defined or a heteroaryl is respectively bounded to the heterocycloalkyl or the cycloalkyl as above defined by at least two carbons. In other terms, the aryl or the heteroaryl shares a carbon bond with the heterocycloalkyl or the cycloalkyl. Examples of such mono- and poly-cyclic heteroaryl group, fused arylheterocycloalkyl and fused arylcycloalkyl may be: pyridinyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, furazanyl, thiadiazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolinyl, indanyl, quinolinyl, isoquinolinyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, triazinyl, thianthrenyl, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, chromenyl, xanthenyl, phenoxanthinyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, indazolyl, purinyl, quinolizinyl, phtalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, oxazolidinyl, benzotriazolyl, benzoisoxazolyl, oxindolyl, benzoxazolyl, benzoxazolinyl, benzoxazinyl, benzothienyl, benzothiazolyl, benzodiazepinyl, benzazepinyl, benzoxazepinyl, isatinyl, dihydrobenzodioxepinyl, dihydropyridyl, pyrimidinyl, s-triazinyl, oxazolyl, or thiofuranyl. A fused arylheterocycloalkyl is for instance an indolinyl (phenyl fused to a pyrrolidinyl) and a dihydrobenzofuranyl (phenyl fused to a dihydrofuranyl). The term “halogen” corresponds to a fluorine, chlorine, bromine, or iodine atom, preferably a fluorine, chlorine or bromine. The expression “substituted by at least” means that the radical is substituted by one or several groups of the list. For instance, the expression “a (C1-C6)alkyl substituted by at least one halogen, preferably a fluorine” may include a fluoromethyl (-CH2F), a difluoromethyl (-CHF2), or a trifluoromethyl (-CF3). The expression “optionally substituted” means that the radical is not substituted or substituted by one or several groups of the list. The isomers are molecules or polyatomic ions with identical molecular formula, i.e., the same number of atoms of each element with distinct arrangements of atoms in space. The “stereoisomers” are isomeric compounds that have the same molecular formula and sequence of bonded atoms, but differ in the 3D-dimensional orientations of their atoms in space. The stereoisomers include enantiomers, diastereoisomers, cis-trans and E-Z isomers, conformers, and anomers. In a particular embodiment of the invention, the stereoisomers include diastereoisomers and enantiomers. The “tautomers” are isomeric compounds that differ only in the position of the protons and the electrons. The “hydrates” are compounds further comprising at least one molecule of water. For instance, if the compound comprises one molecule of water, it corresponds to a monohydrate form. If the compound comprises two molecules of water, it corresponds to a dihydrate form. The “pharmaceutically salts” include inorganic as well as organic acids salts. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, maleic, methanesulfonic and the like. Further examples of pharmaceutically inorganic or organic acid addition salts include the pharmaceutically salts listed in J. Pharm. Sci. 1977, 66, 2, and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use edited by P. Heinrich Stahl and Camille G. Wermuth 2002. In a particular embodiment, the salt is selected from the group consisting of chlorhydrate, and formate. The “pharmaceutically salts” also include inorganic as well as organic base salts. Representative examples of suitable inorganic bases include sodium or potassium salt, an alkaline earth metal salt, such as a calcium or magnesium salt, or an ammonium salt. As used herein, the terms “treatment”, “treat” or “treating” refer to any act intended to ameliorate the health status of patients such as therapy, prevention, prophylaxis and retardation of a disease, in particular a cancer. In certain embodiments, such terms refer to the amelioration or eradication of the disease, or symptoms associated with it. In other embodiments, this term refers to minimizing the spread or worsening of the disease, resulting from the administration of one or more therapeutic agents to a subject with such a disease. In particular, such terms refer to decreased development of tumors, decreased tumor burden, tumor regression, and / or prevention or delay of metastasis occurrence and cancer relapse. As used herein, the terms “subject”, “individual” or “patient” are interchangeable and refer to a mammal, even more preferably to a human, including adult, child, newborn and human at the prenatal stage. However, the term "subject" can also refer to non-human animals, in particular mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others. In a particular embodiment, the subject is resistant to any other anticancer treatment. Optionally, the subject is a chemoresistant subject. In a particular aspect, the subject is resistant to immunotherapy. In other words, the cancer is immune-resistant. The terms “quantity,” “amount,” and “dose” are used interchangeably herein and may refer to an absolute quantification of a molecule. As used herein, the terms "active principle", "active ingredient", "active pharmaceutical ingredient", “medicine”, and “drug” are equivalent and refers to a component of a pharmaceutical composition having a therapeutic effect. As used herein, the term “therapeutic effect” refers to an effect induced by an active ingredient, or a pharmaceutical composition according to the invention, capable to prevent or to delay the appearance or development of a cancer, or to cure or to attenuate the effects of a cancer. As used herein, the term “effective amount” refers to a quantity of an active ingredient or of a pharmaceutical composition which prevents, removes or reduces the deleterious effects of a cancer. It is obvious that the quantity to be administered can be adapted by the man skilled in the art according to the subject to be treated, to the nature of the cancer, etc. In particular, doses and regimen of administration may be function of the nature, of the stage and of the severity of the cancer to be treated, as well as of the weight, the age and the global health of the subject to be treated, as well as of the judgment of the doctor. As used herein, the term "pharmaceutically acceptable excipient" refers to any ingredient except active ingredients which are present in a pharmaceutical composition. Its addition may be aimed to confer a particular consistency or other physical or gustative properties to the final product. A pharmaceutically acceptable excipient must be devoid of any interaction, in particular chemical, with the active ingredients. As used herein, the term “immunotherapy”, “immunotherapeutic agent” or “immunotherapy treatment” refers to a cancer therapeutic treatment using the immune system to reject cancer. The therapeutic treatment stimulates the patient's immune system to attack the malignant tumor cells. It includes immunization of the patient with tumor antigens (e.g., by administering a cancer vaccine), in which case the patient's own immune system is trained to recognize tumor cells as targets to be destroyed, or administration of molecules stimulating the immune system such as cytokines, or administration of therapeutic antibodies as drugs, in which case the patient's immune system is recruited by the therapeutic antibodies to destroy tumor cells. In particular, antibodies are directed against specific antigens such as the unusual antigens that are presented on the surfaces of tumors. The terms “kit”, “product” or "combined preparation", as used herein, defines especially a "kit of parts" in the sense that the combination partners (a) and (b), as defined in the present application can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners (a) and (b), i.e., simultaneously or at different time points. The parts of the kit of parts can then be administered simultaneously or chronologically staggered, that is at different time points for any part of the kit of parts. The ratio of the total amounts of the combination partner (a) to the combination partner (b) to be administered in the combined preparation can be varied. The combination partners (a) and (b) can be administered by the same route or by different routes. As used herein, the term “simultaneous” refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered simultaneously, i.e., at the same time. As used herein, the term “sequential” refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered sequentially, i.e., one after the other. Preferably, when the administration is sequential, all the active ingredients are administered in less than about an hour, preferably less than about 10 minutes, even more preferably in less than about a minute. As used herein, the term “separate” refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered at distinct time of the day. Preferably, when the administration is separate, the active ingredients are administered with an interval of about 1 hour to about 24 hours, preferably with an interval of about 1 hour and 15 hours, more preferably with an interval of about 1 hour and 8 hours, even more preferably with an interval of about 1 hour and 4 hours. Compounds The present invention provides new compounds of the following formula (I), including isomers, stereoisomers, tautomers, and pharmaceutical acceptable salts thereof, of therapeutic interest. According to the invention, a compound has the following formula (I): R9wherein: ^ --- is a single or a double bound; ^ X is C=O, C-R1, or N-R1with R1is absent or represents a radical selected in a group consisting of a hydrogen, a halogen, a cyano, a (C1-C6)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1- C6)alkyloxy, a 3-6 membered cycloalkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a hydroxy, and a NRaRbwith Raand Rbrepresent independently a hydrogen or a (C1- C6)alkyl; ^ Y is C=O, C-R2, or N-R2with R2is absent or represents a radical selected in a group consisting of a hydrogen, a halogen, a cyano, a (C1-C6)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1- C6)alkyloxy, a 3-6 membered cycloalkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a hydroxy, and a NRa’Rb’with Ra’and Rb’represent independently a hydrogen or a (C1- C6)alkyl; ^ Z is C=O, C-R3, or N-R3 with R3 is absent or represents a radical selected in a group consisting of a hydrogen, a halogen, a cyano, a (C1-C6)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1- C6)alkyloxy, a 3-6 membered cycloalkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a hydroxy, and a NRa’’Rb’’with Ra’’and Rb’’represent independently a hydrogen or a (C1- C6)alkyl; ^ R4represents a radical selected in a group consisting of a hydrogen, a halogen, and a (C1-C6)alkyl; ^ R5represents a radical selected in a group consisting of a hydrogen, a halogen, and a (C1-C6)alkyl; ^ R6represents a radical selected in a group consisting of a hydrogen, a halogen, a cyano, a (C1-C6)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a 3-6 membered cycloalkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, and a 3-12 membered heteroaryl; ^ R7represents a hydrogen, or a (C1-C6)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (C1-C6)alkyloxy, a -NH(C1-C6)alkyl, and a -N((C1- C6)alkyl)2; ^ R8represents a hydrogen, or a (C1-C6)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (C1-C6)alkyloxy, a -NH(C1-C6)alkyl, and a -N((C1- C6)alkyl)2; and ^ R9represents a hydrogen, or a (C1-C6)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (C1-C6)alkyloxy, a -NH(C1-C6)alkyl, and a -N((C1- C6)alkyl)2; or R8and R9may form together a 5-7 membered ring, partially unsaturated or saturated, N,N’-heterocycloalkyl optionally substituted by at least one radical selected in a group consisting of a (C1-C6)alkyl, a hydroxy, a (C1-C6)alkyloxy, a -NH(C1-C6)alkyl, a - N((C1-C6)alkyl)2, and a ketone. According to the nature of X, Y, and Z, a skilled person will easily determine the nature of “-- -”, i.e. a single or a double bound. For instance, without limitation, a compound of formula (I) may have the following formulae: R9R9 R9R9 According to the invention, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) is such that R7represents a hydrogen, or a (C1-C6)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (C1-C6)alkyloxy, a -NH(C1-C6)alkyl, and a -N((C1- C6)alkyl)2. In a particular embodiment, R7is a hydrogen. According to the invention, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) is such that R8and R9represent independently a hydrogen, or a (C1-C6)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (C1-C6)alkyloxy, a -NH(C1-C6)alkyl, and a -N((C1-C6)alkyl)2, or R8and R9may form together a 5-7 membered ring, partially unsaturated or saturated, at particular a N,N’-heterocycloalkyl optionally substituted by at least one radical selected in a group consisting of a (C1-C6)alkyl, a hydroxy, a (C1-C6)alkyloxy, a - NH(C1-C6)alkyl, a -N((C1-C6)alkyl)2, and a ketone. Optionally, R8and / or R9are a hydrogen. In a particular embodiment, R8and R9are a hydrogen. In a particular embodiment, R8and R9form together an imidazolinyl optionally substituted by at least one radical selected in a group consisting of a (C1-C6)alkyl, a hydroxy, a (C1- C6)alkyloxy, a -NH(C1-C6)alkyl, a -N((C1-C6)alkyl)2, and a ketone. In a specific embodiment, R8and R9form together an imidazolinyl substituted by a methyl and a ketone. According to the invention, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) is such that R4and R5represents independently a radical selected in a group consisting of a hydrogen, a halogen, and a (C1-C6)alkyl. In a particular embodiment, R4and R5are a hydrogen. In a particular embodiment, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) is such that R4, R5, R7, R8, and R9represent H. According to the invention, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) is such that R6represents a radical selected in a group consisting of a hydrogen, a halogen, a cyano, a (C1-C6)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a 3-6 membered cycloalkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, and a 3-12 membered heteroaryl. In a particular embodiment, R6represents a radical selected in a group consisting of a hydrogen, a halogen, preferably a chlorine, a cyano, and a (C1-C6)alkyl, preferably a methyl. In a more particular embodiment, R6represents a radical selected in a group consisting of a hydrogen, a chlorine, and a methyl. According to the invention, a compound of formula (I) is such that X is C=O, C-R1, or N-R1with R1is absent or represents a radical selected in a group consisting of a hydrogen, a halogen, a cyano, a (C1-C6)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a 3-6 membered cycloalkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a hydroxy, and a NRaRbwith Raand Rbrepresent independently a hydrogen or a (C1-C6)alkyl. In an embodiment, X is C-R1or N-R1with R1is such as defined herein. In a particular embodiment, R1is absent or represents a radical selected in a group consisting of a hydrogen, a halogen, preferably a bromine or a chlorine, a cyano, a (C1-C6)alkyl, preferably a methyl, an ethyl, or an isopropyl, a 3-6 membered cycloalkyl, preferably a cyclopropyl, and a NRaRbwith Raand Rbrepresent independently a hydrogen or a (C1-C6)alkyl, preferably a hydrogen. In a further embodiment, X is C-R1with R1is a radical selected in a group consisting of a hydrogen, a halogen, preferably a bromine or a chlorine, a cyano, a 3-6 membered cycloalkyl, preferably a cyclopropyl, and a NRaRbwith Raand Rbrepresent independently a hydrogen or a (C1-C6)alkyl, preferably a hydrogen. In a further embodiment, X is N-R1with R1is absent or represents a radical selected in a group consisting of a hydrogen, and a (C1-C6)alkyl, preferably a methyl, an ethyl, or an isopropyl. According to the invention, a compound of formula (I) is such that Y is C=O, C-R2, or N-R2with R2is absent or represents a radical selected in a group consisting of a hydrogen, a halogen, a cyano, a (C1-C6)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a 3-6 membered cycloalkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a hydroxy, and a NRa’Rb’with Ra’and Rb’represent independently a hydrogen or a (C1-C6)alkyl. In an embodiment, Y is C-R2or N-R2with R2is such as defined herein. In a particular embodiment, R2 is absent or represents a radical selected in a group consisting of a hydrogen, and a (C1-C6)alkyl, preferably a methyl, an ethyl, or an isopropyl. In a further embodiment, Y is C-R2with R2is a hydrogen. In a further embodiment, Y is N-R2with R2is absent or represents a radical selected in a group consisting of a hydrogen, and a (C1-C6)alkyl, preferably a methyl, an ethyl, or an isopropyl. According to the invention, a compound of formula (I) is such that Z is C=O, C-R3, or N-R3with R3is absent or represents a radical selected in a group consisting of a hydrogen, a halogen, a cyano, a (C1-C6)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a 3-6 membered cycloalkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a hydroxy, and a NRa’’Rb’’with Ra’’and Rb’’represent independently a hydrogen or a (C1-C6)alkyl. In an embodiment, Z is C-R3or N-R3with R3is such as defined herein. In a particular embodiment, R3is absent or represents a radical selected in a group consisting of a hydrogen, a halogen, preferably a chlorine or a bromine, and a (C1-C6)alkyl, preferably a methyl. In a further embodiment, Z is C-R3with R3is a hydrogen, or a halogen, preferably a chlorine or a bromine. In a further embodiment, Z is N-R3with R3is absent or represents a radical selected in a group consisting of a hydrogen, and a (C1-C6)alkyl, preferably a methyl. In a further aspect, a compound of the invention has a formula selected in a group consisting of: R9R9 particular and preferred embodiments. In a further aspect, a compound of the invention has a formula selected in a group consisting of:

[0002] R9R9 A preferred compound of the invention having th formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) is selected in a group consisting of: - Example 1: N-carbamimidoyl-2-(5-chloro-1H-indazol-4-yl)acetamide, HCl; - Example 2: N-carbamimidoyl-2-(3,5-dichloro-1H-indazol-4-yl)acetamide, HCl; - Example 3: 2-(3-bromo-5-chloro-1H-indazol-4-yl)-N-carbamimidoylacetamide, HCl; - Example 4: N-carbamimidoyl-2-(5-chloro-3-cyano-1H-indazol-4-yl)acetamide, HCl; - Example 5: N-carbamimidoyl-2-(6-chloro-1-methyl-1H-indazol-7-yl)acetamide, HCl; - Example 6: N-carbamimidoyl-2-(3,6-dichloro-1-methyl-1H-indazol-7-yl)acetamide; - Example 7: N-carbamimidoyl-2-(5-chloro-1-methyl-1H-indazol-4-yl)acetamide, HCl; - Example 8: 2-(3-bromo-5-chloro-1-methyl-1H-indazol-4-yl)-N-carbamimidoylacetamide, HCl; - Example 9: N-carbamimidoyl-2-(5-chloro-2-methyl-2H-indazol-4-yl)acetamide, HCl; - Example 10: N-carbamimidoyl-2-(1-methyl-1H-indazol-7-yl)acetamide, HCl; - Example 11: N-carbamimidoyl-2-(1,6-dimethyl-1H-indazol-7-yl)acetamide, HCl; - Example 12: N-carbamimidoyl-2-(2,6-dimethyl-2H-indazol-7-yl)acetamide, HCl; - Example 13: N-carbamimidoyl-2-(6-chloro-1-ethyl-1H-indazol-7-yl)acetamide, HCl; - Example 14: N-carbamimidoyl-2-(6-chloro-2-ethyl-2H-indazol-7-yl)acetamide, HCl; - Example 15: N-carbamimidoyl-2-(6-chloro-1-isopropyl-1H-indazol-7-yl)acetamide, HCl; - Example 16: N-carbamimidoyl-2-(6-chloro-2-isopropyl-2H-indazol-7-yl)acetamide, HCl; - Example 17: N-carbamimidoyl-2-(5-chloro-3-cyano-1-methyl-1H-indazol-4-yl)acetamide, HCl; - Example 18: N-carbamimidoyl-2-(1H-indol-7-yl)acetamide, HCO2H; - Example 19: N-Carbamimidoyl-2-(1H-indol-4-yl)acetamide, HCO2H; - Example 20: N-carbamimidoyl-2-(3-chloro-1H-indol-4-yl)acetamide, HCl; - Example 21: N-carbamimidoyl-2-(5-chloro-3-cyclopropyl-1H-indazol-4-yl)acetamide, HCO2H; - Example 22: 2-(3-amino-5-chloro-1H-indazol-4-yl)-N-carbamimidoylacetamide, HCl; - Example 23: N-carbamimidoyl-2-(6-chloro-1H-indazol-7-yl)acetamide, HCl; and - Example 24: 2-(3-bromo-6-chloro-1H-indazol-7-yl)-N-carbamimidoylacetamide, HCl. In a particular embodiment, a compound of formula (I) is such that X is C-R1with R1is such as defined herein, Y is N-R2with R2is absent (e.g. Y is N), and Z is N-R3with R3is such as defined herein. According to this embodiment, a compound of the invention has the formula R9are such as Typically, a compound of formula (IA) is selected compound is selected in a group consisting of: - Example 1: N-carbamimidoyl-2-(5-chloro-1H-indazol-4-yl)acetamide, HCl; - Example 2: N-carbamimidoyl-2-(3,5-dichloro-1H-indazol-4-yl)acetamide, HCl; - Example 3: 2-(3-bromo-5-chloro-1H-indazol-4-yl)-N-carbamimidoylacetamide, HCl; - Example 4: N-carbamimidoyl-2-(5-chloro-3-cyano-1H-indazol-4-yl)acetamide, HCl; - Example 7: N-carbamimidoyl-2-(5-chloro-1-methyl-1H-indazol-4-yl)acetamide, HCl; - Example 8: 2-(3-bromo-5-chloro-1-methyl-1H-indazol-4-yl)-N-carbamimidoylacetamide, HCl; - Example 17: N-carbamimidoyl-2-(5-chloro-3-cyano-1-methyl-1H-indazol-4-yl)acetamide, HCl; - Example 21: N-carbamimidoyl-2-(5-chloro-3-cyclopropyl-1H-indazol-4-yl)acetamide, HCO2H; and - Example 22: 2-(3-amino-5-chloro-1H-indazol-4-yl)-N-carbamimidoylacetamide, HCl. In a particular embodiment, a compound of formula (I) is such that X is N-R1with R1is such as defined herein, Y is N-R2with R2is absent (e.g. Y is N), and Z is C-R3with R3is such as defined herein. According to this embodiment, a compound of the invention has the formula R9are such as Typically, a compound of formula (IB) is selected compound is selected in a group consisting of: - Example 5: N-carbamimidoyl-2-(6-chloro-1-methyl-1H-indazol-7-yl)acetamide, HCl; - Example 6: N-carbamimidoyl-2-(3,6-dichloro-1-methyl-1H-indazol-7-yl)acetamide; - Example 10: N-carbamimidoyl-2-(1-methyl-1H-indazol-7-yl)acetamide, HCl; - Example 11: N-carbamimidoyl-2-(1,6-dimethyl-1H-indazol-7-yl)acetamide, HCl; - Example 13: N-carbamimidoyl-2-(6-chloro-1-ethyl-1H-indazol-7-yl)acetamide, HCl; - Example 15: N-carbamimidoyl-2-(6-chloro-1-isopropyl-1H-indazol-7-yl)acetamide, HCl; - Example 23: N-carbamimidoyl-2-(6-chloro-1H-indazol-7-yl)acetamide, HCl; and - Example 24: 2-(3-bromo-6-chloro-1H-indazol-7-yl)-N-carbamimidoylacetamide, HCl. In a particular embodiment, a compound of formula (I) is such that X is C-R1with R1is such as defined herein, Y is N-R2with R2is such as defined herein, and Z is N-R3with R3is absent (e.g. Z is N). According to this embodiment, a compound of the invention has the formula (IC): R9are such as defined Typically, a compound of formula (IC) is: - Example 9: N-carbamimidoyl-2-(5-chloro-2-methyl-2H-indazol-4-yl)acetamide, HCl. In a particular embodiment, a compound of formula (I) is such that X is N-R1with R1is absent (e.g. X is N), Y is N-R2with R2is such as defined herein, and Z is C-R3with R3is such as defined herein. According to this embodiment, a compound of the invention has the formula R9,with R2, R3, R4, R5, R6, R7, R8, and R9 are such as preferred embodiments. Typically, a compound of formula (ID) is selected compound is selected in a group consisting of: - Example 12: N-carbamimidoyl-2-(2,6-dimethyl-2H-indazol-7-yl)acetamide, HCl; - Example 14: N-carbamimidoyl-2-(6-chloro-2-ethyl-2H-indazol-7-yl)acetamide, HCl; and - Example 16: N-carbamimidoyl-2-(6-chloro-2-isopropyl-2H-indazol-7-yl)acetamide, HCl. In a particular embodiment, a compound of formula (I) is such that X is N-R1with R1is such as defined herein, Y is C-R2with R2is such as defined herein, and Z is C-R3with R3with R3is such as defined herein. According to this embodiment, a compound of the invention has the R9formula are such Typically, a compound of formula (IE) is: - Example 18: N-carbamimidoyl-2-(1H-indol-7-yl)acetamide, HCO2H. In a particular embodiment, a compound of formula (I) is such that X is C-R1with R1is such as defined herein, Y is C-R2with R2is such as defined herein, and Z is N-R3with R3with R3is such as defined herein. According to this embodiment, a compound of the invention has the R9 Typically, a compound of formula (IF) is selected compound is selected in a group consisting of: - Example 19: N-Carbamimidoyl-2-(1H-indol-4-yl)acetamide, HCO2H; - Example 20: N-carbamimidoyl-2-(3-chloro-1H-indol-4-yl)acetamide, HCl; Therapeutic applications As illustrated by examples, the inventors have demonstrated the therapeutic interest of the new compounds of the invention. Accordingly, the present invention relates to a pharmaceutical or veterinary composition comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) according to the invention or any particular compound as disclosed herein. Preferably, the pharmaceutical composition further comprises a pharmaceutically or veterinary acceptable carrier or excipient. The present invention relates to the use of a compound of (I), (IA), (IB), (IC), (ID), (IE), or (IF) according to the invention or any particular compound as disclosed herein as a drug or a medicine. The invention further relates to a method for treating a disease in a subject, wherein a therapeutically effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) according to the invention or any particular compound as disclosed herein, is administered to said subject in need thereof. The invention also relates to the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) according to the invention or any particular compound as disclosed herein, for the manufacture of a medicine. The invention also relates to a pharmaceutical composition comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) according to the invention or any particular compound as disclosed herein for use as a drug. The present invention also concerns: - a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound for preventing and / or treating or for use for preventing and / or treating a cancer; and / or - a pharmaceutical composition comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, and an antitumor drug, in particular for the prevention and / or the treatment of cancer or for use in the prevention and / or the treatment of cancer; and / or - a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound, for preventing and / or treating a cancer or for use for preventing and / or treating a cancer in combination with an antitumor drug such as chemotherapy, immunotherapy, and / or hormonotherapy, and / or with radiotherapy, optionally before, simultaneously and / or after surgery (e.g., tumor resection); and / or - a kit comprising (a) a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein; and (b) an antitumor drug as a combined preparation for simultaneous, separate or sequential use, for preventing and / or treating cancer or for use for preventing and / or treating a cancer; and / or - the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound, for the manufacture of a medicament, a medicine or a drug for the prevention and / or the treatment of a cancer; and / or - the use of a pharmaceutical composition comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, and an additional antitumor drug, for the manufacture of a medicament, a medicine or a drug for the prevention and / or the treatment of a cancer; and / or - the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound, for the manufacture of a medicament, a medicine or a drug for the prevention and / or the treatment of a cancer in combination with a treatment with an antitumor drug such as chemotherapy, immunotherapy, and / or hormonotherapy, and / or with radiotherapy, optionally before, simultaneously and / or after surgery (e.g., tumor resection); and / or - a method for treating a cancer, in a subject in need thereof, comprising administering an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) as defined herein including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound; - a method for treating a cancer, in a subject in need thereof, comprising administering an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) as defined herein including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound, and an additional antitumor drug, optionally with radiotherapy; - a method for treating a cancer, in a subject in need thereof, comprising administering an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), or (IF) as defined herein including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound; the method further comprises chemotherapy, immunotherapy, hormonotherapy and / or radiotherapy, optionally before, simultaneously and / or after surgery (e.g., tumor resection). The term “cancer”, as used herein, refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. The cancer may be solid tumor or hematopoietic tumor. Examples of cancer include, but are not limited to, solid tumors and hematological cancers, including carcinoma, lymphoma, blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors (including carcinoid tumors, gastrinoma, and islet cell cancer), mesothelioma, schwannoma (including acoustic neuroma), meningioma, adenocarcinoma, melanoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include chronic myeloid leukemia, acute lymphoblastic leukemia, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), squamous cell carcinoma, lung cancer, small-cell lung cancer, non-small cell lung cancer, glioma, gastrointestinal cancer, renal cancer, ovarian cancer, bile duct cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, melanoma, skin cancer, thyroid cancer, neuroblastoma, osteosarcoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, oesophagal cancer, colon cancer, head and neck cancer, brain cancer, gastric cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer, multiple myeloma, acute myelogenous leukemia (AML), chronic lymphocytic leukemia, mastocytosis and any symptom associated with mastocytosis. In a particular aspect, the cancer is chosen among of myelofibrosis, acute lymphoblastic leukemia, acute myeloblastic leukemia adrenal gland carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, glioblastoma, head and neck cancer, hepatocellular carcinoma, Hodgkin’s lymphoma, kidney cancer, lung cancer, melanoma, Merkel cell skin cancer, mesothelioma, multiple myeloma, myeloproliferative disorders, non- Hodgkin lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, salivary gland cancer, sarcoma, squamous cell carcinoma, testicular cancer, thyroid cancer, urothelial carcinoma, and uveal melanoma. In a particular aspect, the cancer is resistant or has a low response to immunotherapy. More specifically, the cancer can be resistant to a treatment with a checkpoint inhibitor such as an antibody against PD-1, PD-L1, CTLA-4 and the like. The administration route can be topical, transdermal, oral, rectal, sublingual, intranasal, intrathecal, intratumor or parenteral (including subcutaneous, intramuscular, intravenous and / or intradermal). Preferably, the administration route is parental, oral or topical. The pharmaceutical composition is adapted for one or several of the above-mentioned routes. The pharmaceutical composition, kit, product or combined preparation is preferably administered by injection or by intravenous infusion or suitable sterile solutions, or in the form of liquid or solid doses via the alimentary canal. The pharmaceutical composition can be formulated as solutions in pharmaceutically compatible solvents or as emulsions, suspensions or dispersions in suitable pharmaceutical solvents or vehicles, or as pills, tablets or capsules that contain solid vehicles in a way known in the art. Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and carrier such as cocoa butter, or in the form of an enema. Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient. Every such formulation can also contain other pharmaceutically compatible and nontoxic auxiliary agents, such as, e.g. stabilizers, antioxidants, binders, dyes, emulsifiers or flavoring substances. The formulations of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof. The pharmaceutical compositions are advantageously applied by injection or intravenous infusion of suitable sterile solutions or as oral dosage by the digestive tract. Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. Pharmaceutical compositions according to the invention may be formulated to release the active drug substantially immediately upon administration or at any predetermined time or time period after administration. Preferably, the treatment with the compound according to the invention or the pharmaceutical composition according to the invention starts no longer than a month, preferably no longer than a week, after the diagnosis of the disease. In a particular embodiment, the treatment starts the day of the diagnosis. The compound according to the invention or the pharmaceutical composition according to the invention may be administered as a single dose or in multiple doses. Preferably, the treatment is administered regularly, preferably between every day and every month, more preferably between every day and every two weeks, more preferably between every day and every week, even more preferably the treatment is administered every day. In a particular embodiment, the treatment is administered several times a day, preferably 2 or 3 times a day, even more preferably 3 times a day. The duration of treatment with the compound according to the invention or the pharmaceutical composition according to the invention is preferably comprised between 1 day and 50 weeks, more preferably between 1 day and 30 weeks, still more preferably between 1 day and 15 weeks, even more preferably between 1 day and 10 weeks. In a particular embodiment, the duration of the treatment is of about 1 week. Alternatively, the treatment may last as long as the disease persists. The amount of compound according to the invention or of pharmaceutical composition according to the invention to be administered has to be determined by standard procedure well known by those of ordinary skills in the art. Physiological data of the patient (e.g. age, size, and weight) and the routes of administration have to be taken into account to determine the appropriate dosage, so as a therapeutically effective amount will be administered to the patient. In a particular embodiment, is administered at a dose ranging from 0.001 mg / kg body weight to 30 mg / kg body weight. In one embodiment, the compound of the invention can be used in combination with another antitumor drug or antineoplastic agent. The additional antitumor drug can be selected in the non-exhaustive list of antitumor agents consisting of an inhibitor of topoisomerases I or II, an anti-mitotic agent, a DNA alkylating agent, an agent causing crosslinking of DNA, an anti-metabolic agent, a targeted agent such as a kinase inhibitor, a histone deacetylase inhibitor and an anti-EGFR agent and / or a therapeutical antibody designed to mediate cytotoxicity against the cancer cells or to modulate one of their key biological functions. Antimitotic agents include, but are not limited to, paclitaxel, docetaxel and analogs such as larotaxel (also called XRP9881; Sanofi-Aventis), XRP6258 (Sanofi-Aventis), BMS-184476 (Bristol-Meyer-Squibb), BMS-188797 (Bristol-Meyer-Squibb), BMS-275183 (Bristol-Meyer- Squibb), ortataxel (also called IDN 5109, BAY 59-8862 or SB-T-101131; Bristol-Meyer- Squibb), RPR 109881A (Bristol-Meyer-Squibb), RPR 116258 (Bristol-Meyer-Squibb), NBT- 287 (TAPESTRY), PG-paclitaxel (also called CT-2103, PPX, paclitaxel poliglumex, paclitaxel polyglutamate or XyotaxTM), ABRAXANE®(also called Nab-paclitaxel; ABRAXIS BIOSCIENCE), tesetaxel (also called DJ-927), IDN 5390 (INDENA), taxoprexin (also called docosahexanoic acid-paclitaxel; PROTARGA), DHA-paclitaxel (also called Taxoprexin®), and MAC-321 (WYETH). Preferably, antimitotic agents are docetaxel, paclitaxel, and is more preferably docetaxel. Inhibitors of topoisomerases I and / or II include, but are not limited to etoposide, topotecan, camptothecin, irinotecan, amsacrine, intoplicin, anthracyclines such as doxorubicin, epirubicin, daunorubicin, idarubicin and mitoxantrone. Inhibitors of topoisomerase I and II include, but are not limited to intoplicin. The additional antitumor agent can be alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, metal salts and triazenes. Non-exhaustive examples thereof include uracil mustard, chlormethine, cyclophosphamide (CYTOXAN®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, cisplatin, carboplatin, fotemustine, oxaliplatin, thiotepa, streptozocin, dacarbazine, and temozolomide. In a particular embodiment, the DNA alkylating agent is preferably cisplatin, carboplatin, temozolomide, fotemustine or dacarbazine. Anti-metabolic agents block the enzymes responsible for nucleic acid synthesis or become incorporated into DNA, which produces an incorrect genetic code and leads to apoptosis. Non- exhaustive examples thereof include, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors, and more particularly methotrexate, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, 5-fluorouracil, gemcitabine and capecitabine. In a particular embodiment, such an agent is gemcitabine. The additional anti-tumor agent can also be a targeted agent, in particular a kinase inhibitor. The kinase may be selected from the group consisting of intracellular tyrosine or serine / threonine kinases, receptors tyrosine or serine / threonine kinase. The kinase could be selected among EGFR family, ALK, B-Raf, MEK, and mTOR. For instance, the agents may have ability to inhibit angiogenesis based on the inhibitory activities on VEGFR and PDGFR kinases. In particular, the targeted agent can be selected among the multiple kinase inhibitor drugs which are already approved: Gleevec®, which inhibits Bcr-Abl and c-Kit, and Iressa®and Tarceva®, which both inhibit EGFR, sorafenib (Nexavar®, BAY 43-9006) which inhibits Raf, dasatinib (BMS-354825) and nilotinib (AMN-107, Tasigna®) which also inhibits Bcr-Abl, lapatinib which also inhibits EGFR, temsirolimus (Torisel®, CCI-779) which targets the mTOR pathway, sunitinib (Student®, SU11248) which inhibits several targets including VEGFR as well as specific antibodies inactivating kinase receptors: Herceptin®and Avastin®. The anti- EGFR agent can be selected among gefitinib, erlotinib, lapatinib, vandetanib, afatinib, osimertinib, neratinib, dacomitinib, brigatinib, canertinib, naquotinib, nazartinib, pelitinib, rociletinib, icotinib, AZD3759, AZ5104 (CAS № 1421373-98-9), poziotinib, WZ4002, preferably is erlotinib or cetuximab. The ALK can be selected among crizotinib, entrectinib, ceritinib, alectinib, brigatinib, lorlatinib, TSR-011, CEP-37440, and ensartinib. The B-Raf inhibitor can be selected among vemurafenib, dabrafenib, regorafenib, and PLX4720. The MEK inhibitor can be selected among cobimetinib, trametinib, binimetinib, selumetinib, PD-325901, CI-1040, PD035901, U0126, TAK-733. The antitumor agent can be IDO1 inhibitors such as epacadostat. The term “therapy”, as used herein, refers to any type of treatment of cancer (i.e., antitumor therapy), including an adjuvant therapy and a neoadjuvant therapy. Therapy comprises radiotherapy and therapies, preferably systemic therapies such as hormone therapy, chemotherapy, immunotherapy and monoclonal antibody therapy. The term “adjuvant therapy”, as used herein, refers to any type of treatment of cancer given as additional treatment, usually after surgical resection of the primary tumor, in a patient affected with a cancer that is at risk of metastasizing and / or likely to recur. The aim of such an adjuvant treatment is to improve the prognosis. Adjuvant therapies comprise radiotherapy and therapy, preferably systemic therapy, such as hormone therapy, chemotherapy, immunotherapy and monoclonal antibody therapy. The term “hormone therapy” or “hormonal therapy” or “hormonotherapy” refers to a cancer treatment having for purpose to block, add or remove hormones. For instance, in breast cancer, the female hormones estrogen and progesterone can promote the growth of some breast cancer cells. So, in these patients, hormone therapy is given to block estrogen and a non-exhaustive list commonly used drugs includes: tamoxifen, toremifene, anastrozole, exemestane, letrozole, goserelin, leuprolide, megestrol acetate, and fluoxymesterone. As used herein, the term “chemotherapeutic treatment” or “chemotherapy” refers to a cancer therapeutic treatment using chemical or biological substances, in particular using one or several antineoplastic agents. The term “radiotherapeutic treatment” or “radiotherapy” is a term commonly used in the art to refer to multiple types of radiation therapy including internal and external radiation therapies or radioimmunotherapy, and the use of various types of radiations including X-rays, gamma rays, alpha particles, beta particles, photons, electrons, neutrons, radioisotopes, and other forms of ionizing radiations. The term “therapeutical antibody” refers to any antibody having an anti-tumoral effect. Preferably, the therapeutical antibody is a monoclonal antibody. Therapeutic antibodies are generally specific for surface antigens, e.g., membrane antigens. Most preferred therapeutic antibodies are specific for tumor antigens (e.g., molecules specifically expressed by tumor cells), such as CD20, CD52, ErbB2 (or HER2 / Neu), CD33, CD22, CD25, MUC-1, CEA, KDR, aVb3, and the like. The therapeutical antibody includes, but is not limited to, antibodies such as trastuzumab (anti-HER2 antibody), rituximab (anti-CD20 antibody), alemtuzumab, gemtuzamab, cetuximab, pertuzumab, epratuzumab, basiliximab, daclizumab, labetuzumab, sevirumab, tuvurimab, palivizumab, infliximab, omalizumab, efalizumab, natalizumab, clenoliximab, and bevacizumab. In a particular aspect, the antitumor agent can be an immunomodulator. The immunomodulator can be a cancer vaccine, molecules stimulating the immune system such as cytokines, therapeutic antibodies, preferably monoclonal antibodies, in particular antibodies directed against antigens specifically presented or overexpressed at the membrane of tumor cells or directed against cell receptors which blockade prevent tumor growth, adoptive T-cell therapy, immune checkpoint inhibitor treatment, and any combination thereof. For instance, the immunomodulator can be: - an immune checkpoint inhibitor (ICI), preferably an inhibitor of of PD-1 (programmed cell death protein 1), PD-L1 (programmed cell death ligand), PD-L2, CTLA-4 (cytotoxic T lymphocyte associated protein 4), TIM-3 (T-cell immunoglobulin and mucin-domain containing-3), LAG-3 (Lymphocyte-activation gene 3), NKG2D, NKG2L, KIR, VISTA, BTLA (B- and T-lymphocyte attenuator), or TIGIT (T cell immunoreceptor with Ig and ITIM domains), , especially an antibody directed against an anti-CTLA-4 such as ipilimumab, an antibody directed against PD-1 such as nivolumab, pembrolizumab, or BGB-A317, an antibody directed against PDL1 such as atezolizumab, avelumab, or durvalumab, an antibody directed against LAG-3 such as BMS-986016, an antibody directed against TIM-3, an antibody directed against TIGIT, an antibody directed against BLTA, or a combination thereof; or - an activator of a costimulatory molecule, in particular an agonist of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1 BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand; In some embodiments, the PD-1 inhibitor is selected from PDR001 (Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck & Co), Pidilizumab (CureTech), MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB- A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune). Several anti-PD-1 antibodies are already clinically approved and others are still in clinical developments. For instance, the anti-PD1 antibody can be selected from the group consisting of Pembrolizumab (also known as Keytruda lambrolizumab, MK-3475), Nivolumab (Opdivo, MDX-1106, BMS-936558, ONO-4538), Pidilizumab (CT-011), Cemiplimab (Libtayo), Camrelizumab, AUNP12, AMP-224, AGEN-2034, BGB-A317 (Tisleizumab), PDR001 (spartalizumab), MK-3477, SCH-900475, PF-06801591, JNJ-63723283, genolimzumab (CBT- 501), LZM-009, BCD-100, SHR-1201, BAT-1306, AK-103 (HX-008), MEDI-0680 (also known as AMP-514) MEDI0608, JS001 (see Si-Yang Liu et al., J. Hematol. Oncol.10:136 (2017)), BI-754091, CBT-501, INCSHR1210 (also known as SHR-1210), TSR-042 (also known as ANB011), GLS-010 (also known as WBP3055), AM-0001 (Armo), STI-1110 (see WO 2014 / 194302), AGEN2034 (see WO 2017 / 040790), MGA012 (see WO 2017 / 19846), or IBI308 (see WO 2017 / 024465, WO 2017 / 025016, WO 2017 / 132825, and WO 2017 / 133540), monoclonal antibodies 5C4, 17D8, 2D3, 4H1, 4A11, 7D3, and 5F4, described in WO 2006 / 121168. Bifunctional or bispecific molecules targeting PD-1 are also known such as RG7769 (Roche), XmAb20717 (Xencor), MEDI5752 (AstraZeneca), FS118 (F-star), SL- 279252 (Takeda) and XmAb23104 (Xencor). Antibodies directed against CTLA-4 and bifunctional or bispecific molecules targeting CTLA- 4 are also known such as ipilimumab, tremelimumab, MK-1308, AGEN-1884, XmAb20717 (Xencor), MEDI5752 (AstraZeneca). Antibodies directed against TIGIT are also known in the art, such as BMS-986207 or AB154, BMS-986207 CPA.9.086, CHA.9.547.18, CPA.9.018, CPA.9.027, CPA.9.049, CPA.9.057, CPA.9.059, CPA.9.083, CPA.9.089, CPA.9.093, CPA.9.101, CPA.9.103, CHA.9.536.1, CHA.9.536.3, CHA.9.536.4, CHA.9.536.5, CHA.9.536.6, CHA.9.536.7, CHA.9.536.8, CHA.9.560.1, CHA.9.560.3, CHA.9.560.4, CHA.9.560.5, CHA.9.560.6, CHA.9.560.7, CHA.9.560.8, CHA.9.546.1, CHA.9.547.1, CHA.9.547.2, CHA.9.547.3, CHA.9.547.4, CHA.9.547.6, CHA.9.547.7, CHA.9.547.8, CHA.9.547.9, CHA.9.547.13, CHA.9.541.1, CHA.9.541.3, CHA.9.541.4, CHA.9.541.5, CHA.9.541.6, CHA.9.541.7, and CHA.9.541.8 as disclosed in WO19232484. Anti-TIGIT antibodies are also disclosed in WO16028656, WO16106302, WO16191643, WO17030823, WO17037707, WO17053748, WO17152088, WO18033798, WO18102536, WO18102746, WO18160704, WO18200430, WO18204363, WO19023504, WO19062832, WO19129221, WO19129261, WO19137548, WO19152574, WO19154415, WO19168382 and WO19215728. The LAG-3 inhibitor can be selected from LAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb), or TSR-033 (Tesaro). Further known anti-LAG-3 antibodies include those described, e.g., in WO 2008 / 132601, WO 2010 / 019570, WO 2014 / 140180, WO 2015 / 116539, WO 2015 / 200119, WO 2016 / 028672, US 9,244,059, US 9,505,839, which are incorporated herein by reference in their entirety. The TIM-3 inhibitor can be MGB453 (Novartis) or TSR-022 (Tesaro). Further known anti- TIM-3 antibodies include those described, e.g., in WO 2016 / 111947, WO 2016 / 071448, WO 2016 / 144803, US 8,552,156, US 8,841,418, and US 9,163,087, which are incorporated herein by reference in their entirety. Preferably, the immunotherapy is selected from the group consisting of ipilimumab, nivolumab, BGB-A317, pembrolizumab, atezolizumab, avelumab, or durvalumab, BMS-986016, and epacadostat, or any combination thereof. Further aspects and advantages of the invention will be disclosed in the following experimental section, which should be regarded as illustrative and not limiting. EXAMPLES I. CHEMISTRY EXAMPLES The purity data provided in the examples described below were obtained using the following methods: Method 1 – UPLC Acidic Method Apparatus: Waters HClass; Binary Solvent Pump, SM-FTN, CMA, PDA, QDa; Column: Waters ACQUITY UPLC®CSH C18, 1.7 µm, 2.1 x 30 mm at 40 °C; Detection: UV at 210- 400 nm unless otherwise indicated, MS by electrospray ionisation; Solvents and Gradient: 0.1% Formic in water / MeCN 98 / 2 to 0 / 100 over 2.5 minutes. Flow rate 0.77 mL / Min. Method 2 – UPLC Basic Method Apparatus: Waters HClass; Binary Solvent Pump, SM-FTN, CMA, PDA, QDa; Column: Waters ACQUITY UPLC®BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C; Detection: UV at 210-400 nm unless otherwise indicated, MS by electrospray ionisation; Solvents and Gradient: 0.1% Ammonia in water / MeCN 98 / 2 to 0 / 100 over 2.5 minutes. Flow rate 0.77 mL / Min. Method 3 – LCMS Acidic Method Apparatus: Agilent 1260; Binary Pump, HiP Sampler, Column Compartment, DAD:, G6150 MSD; Column: Waters Cortecs C18, 30 x 2.1 mm, 2.7μm, at 40 °C; Detection: UV at 260nm + / - 90nm unless otherwise indicated, MS by electrospray ionisation; Solvents and Gradient: 0.1% Formic in water / MeCN 98 / 2 to 0 / 100 over 2.5 minutes. Flow rate 1.35 mL / Min. Method 4 – LCMS Basic Method Apparatus: Agilent 1260; Binary Pump, HiP Sampler, Column Compartment, DAD:, G6150 MSD; Column: Phenomenex Evo C18, 30 x 2.1 mm, 2.6μm, at 40 °C; Detection: UV at 260nm + / - 90nm unless otherwise indicated, MS by electrospray ionisation; 0.1% Ammonia in water / MeCN 98 / 2 to 0 / 100 over 2.5 minutes. Flow rate 1.35 mL / Min. The NMR data provided in the examples described below were obtained as followed: NMR spectra were recorded using a Bruker 400MHz Avance Neo spectrometer fitted with a Bruker 5mm iProbe, or a Bruker 500MHz Avance III HD spectrometer equipped with a Bruker 5mm SmartProbeTM. Spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance. The chemical shifts are reported in parts per million. Data were acquired using Bruker TopSpin software and processed using MestreNova software. Abbreviations for multiplicities observed in NMR spectra are as follows: s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet), br (broad). Solvents, reagents and starting materials were purchased and used as received from commercial vendors unless otherwise specified. The intermediates and compounds described below were named using ChemDraw®version 21.0.0 (PerkinElmer). I.1. GENERAL PROTOCOL FOR THE SYNTHESIS OF FINAL COMPOUNDS Protocol 1 YX a p- (0.05- 0.10 eq) in DCM (10-40 vol) at RT was added 3,4-dihydro-2H-pyran (1.10-1.25 eq). After 2- 24 h, the reaction mixture was quenched with sat. aq. NaHCO3, and extracted with DCM. The combined organic phases were dried over MgSO4, then filtered through over a silica plug eluting with DCM. The solvents were evaporated, and the residue purified by crystallisation or silica gel chromatography to afford the product P1-2. Protocol 2 a was . The reaction mixture was heated to 40 °C and stirred under nitrogen for 5 min. To the reaction mixture was added dropwise ethyl 2-bromoacetate (3 eq) and the reaction mixture was stirred at 40 °C for 20 min to afford an organozinc solution. Separately, was prepared a stirring mixture of P2-1 (1 eq) and Pd(tBu3P)2(0.1 eq) in THF (20 vol). This solution was de-gassed and then the organozinc solution was transferred into the reaction mixture. The reaction mixture was again degassed and then heated to 60 °C and stirred under nitrogen for 1-72 h. The reaction mixture was cooled to RT, quenched with sat. aq. NH4Cl and extracted with DCM. The combined organic phases were dried (MgSO4, Na2SO4or phase separator) and solvents evaporated. The residue was purified by silica gel chromatography to afford the product P2-2. Protocol 3-A(THP) YX (THP)YX P3-1 P3-2To a stirred solution of P3-1 (1 eq) and N-Boc guanidine (3 eq) in dry DMF (10-30 vol) at RT was added potassium tert-butoxide (2 eq). The reaction mixture was stirred at RT for 1-24 h. Water was added and either the precipitated product directly collected by filtration, or the mixture was extracted with EtOAc and solvents evaporated and the residue purified by silica chromatography to afford P3-2. Protocol 3-B (THP)YX(THP)YX To a stirred mixture of P3-3 (1 eq) and guanidine.HCl (10 eq) was added sodium methoxide in MeOH (10 eq of a 30 wt% solution in MeOH). The reaction mixture was stirred at RT for 1-4 h then diluted with water (20 mL). Either the product was isolated directly by filtration, or the mixture was extracted with EtOAc and purified by silica gel chromatography to afford P3-4. Protocol 4 – Boc and / or THP deprotection(THP) Y XH HYX P4-1 P4-2The protected intermediate P4-1 was taken up in 4 M HCl in dioxane (10-50 eq) or 6 M HCl in IPA (10-50 eq) and stirred for 1-24 h at either RT or 60 °C before concentrating under reduced pressure to afford the product P4-2.HCl. I.2. EXAMPLES Example 1: N-carbamimidoyl-2-(5-chloro-1H-indazol-4-yl)acetamide, HCl N The title compound was prepared Protocol 4, isolated as HCl salt. m / z 252 M+H @ 0.67 min, Method 21H NMR (400 MHz, DMSO) δ 12.44 (s, 1H), 8.53 (br s, 2H), 8.30 (br s, 2H), 8.29 (d, J = 1.1 Hz, 1H), 7.56 – 7.47 (m, 1H), 7.39 (d, J = 8.8 Hz, 1H), 4.29 (s, 2H). 1H exchangeable not observed. Boc- N-carbamimidoyl-2-(5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4- yl)acetamide Intermediate 1 N The title compound was 3-A. m / z 436 M+H @ 1.36 min, Method 31H NMR (400 MHz, DMSO) δ 11.16 (br s, 1H), 8.71 (br s, 2H), 8.27 (s, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.44 (d, J = 8.9 Hz, 1H), 5.85 (dd, J = 9.6, 2.6 Hz, 1H), 4.16 (s, 2H), 3.91 – 3.84 (m, 1H), 3.79 – 3.69 (m, 1H), 2.45 – 2.32 (m, 1H), 2.09 – 1.91 (m, 2H), 1.81 – 1.67 (m, 1H), 1.60 – 1.56 (m, 2H), 1.41 (s, 9H). ethyl 2-(5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)acetate Intermediate 2 N The title compound was 2. m / z 323 M+H @ 1.62 min, Method 31H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.51 – 7.43 (m, 1H), 7.38 (d, J = 8.9 Hz, 1H), 5.69 (dd, J = 9.2, 2.8 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 4.06 (s, 2H), 4.05 – 3.96 (m, 1H), 3.79 – 3.68 (m, 1H), 2.60 – 2.46 (m, 1H), 2.19 – 2.11 (m, 1H), 2.11 – 2.02 (m, 1H), 1.84 – 1.62 (m, 3H), 1.23 (t, J = 7.1 Hz, 3H). 4-bromo-5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole Intermediate 3 N The title compound was 1H-indazole (Ambeed) using protocol 1. m / z 315 M+H @ 1.81 min, Method 31H NMR (400 MHz, DMSO) δ 8.11 (d, J = 0.9 Hz, 1H), 7.83 (dd, J = 8.9, 0.9 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 5.89 (dd, J = 9.5, 2.4 Hz, 1H), 3.92 – 3.82 (m, 1H), 3.82 – 3.68 (m, 1H), 2.43 – 2.29 (m, 1H), 2.08 – 1.93 (m, 2H), 1.82 – 1.66 (m, 1H), 1.63 – 1.51 (m, 2H). Example 2: N-carbamimidoyl-2-(3,5-dichloro-1H-indazol-4-yl)acetamide, HCl Cl The title compound was prepared Protocol 4, isolated as HCl salt. m / z 286 M+H @ 0.53 min, Method 21H NMR (500 MHz, DMSO) δ 13.62 (s, 1H), 12.10 (s, 1H), 8.46 – 8.05 (m, 4H), 7.58 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 9.0 Hz, 1H), 4.45 (s, 2H). N-carbamimidoyl-2-(3,5-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4- yl)acetamide Intermediate 4 Cl The title compound was 3-B. m / z 370 M+H @ 0.89 min, Method 31H NMR (500 MHz, DMSO) δ 7.68 (d, J = 9.0 Hz, 1H), 7.63 (v br. s, 2H), 7.50 (d, J = 9.0 Hz, 1H), 6.52 (s, v br.2H), 5.84 (dd, J = 9.7, 2.6 Hz, 1H), 4.14 (s, 2H), 3.90 – 3.84 (m, 1H), 3.74 (ddd, J = 11.5, 8.3, 6.2 Hz, 1H), 2.35 – 2.24 (m, 1H), 2.05 – 1.92 (m, 2H), 1.77 – 1.67 (m, 1H), 1.61 – 1.53 (m, 2H). ethyl 2-(3,5-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)acetate Intermediate 5 Cl To a stirred solution of DMF (8 mL) was added NCS (268 mg, 2.0 mmol) and the mixture warmed to 45 °C for 18 h. The reaction mixture was allowed to cool to RT and then diluted with MTBE (50 mL) and washed successively with water (25 mL), 1:1 brine:water (2 x 20 mL) and brine (20 mL). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (MTBE / iso-hexane) to afford the title compound as a colourless solid (504 mg, 67 %). m / z 357 M+H @ 1.82 min, Method 31H NMR (400 MHz, DMSO) δ 7.80 (d, J = 9.1 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 5.88 (dd, J = 9.6, 2.4 Hz, 1H), 4.29 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.91 – 3.82 (m, 1H), 3.80 – 3.69 (m, 1H), 2.37 – 2.22 (m, 1H), 2.05 – 1.93 (m, 2H), 1.77 – 1.65 (m, 1H), 1.61 – 1.51 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H). Example 3: 2-(3-bromo-5-chloro-1H-indazol-4-yl)-N-carbamimidoylacetamide.HCl Br The title compound was prepared Protocol 4, isolated as HCl salt. m / z 330 M+H @ 0.54 min, Method 11H NMR (500 MHz, DMSO) δ 13.75 (s, 1H), 12.07 (s, 1H), 8.23 (s, 4H), 7.60 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 4.50 (s, 2H). 2-(3-bromo-5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-N- carbamimidoylacetamide Intermediate 6 Br The title compound was 3-B. m / z 414 M+H @ 0.85 min, Method 11H NMR (400 MHz, DMSO) δ 7.69 (d, J = 9.0 Hz, 1H), 7.59 (br. s, 1H), 7.49 (d, J = 9.0 Hz, 1H), 6.53 (br. s, 2H), 5.85 (dd, J = 9.7, 2.4 Hz, 1H), 4.20 (s, 2H), 3.91 – 3.83 (m, 1H), 3.79 – 3.69 (m, 1H), 3.17 (d, J = 5.2 Hz, 1H), 2.38 – 2.24 (m, 1H), 2.05 – 1.91 (m, 2H), 1.78 – 1.66 (m, 1H), 1.61 – 1.53 (m, 2H). ethyl 2-(3-bromo-5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)acetate Intermediate 7 Br To a stirred solution of in DMF (30 mL) was added portionwise NBS (851 mg, 4.78 mmol) and the mixture warmed to 45 °C. After 16 h, the mixture was allowed to cool, quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with 1 M aq LiCl solution (2 x 30 mL), dried over MgSO4, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (MTBE / iso-hexanes) to afford the title compound as a colourless solid (1.10 g, 55 %). m / z 401 M+H @ 1.90 min, Method 11H NMR (500 MHz, DMSO) δ 7.81 (d, J = 9.1 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 5.89 (dd, J = 9.6, 2.4 Hz, 1H), 4.34 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.90 – 3.84 (m, 1H), 3.79 – 3.70 (m, 1H), 2.36 – 2.25 (m, 1H), 2.05 – 1.94 (m, 2H), 1.77 – 1.67 (m, 1H), 1.61 – 1.54 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H). Example 4: N-carbamimidoyl-2-(5-chloro-3-cyano-1H-indazol-4-yl)acetamide, HCl N The title compound was prepared Protocol 4, isolated as HCl salt. m / z 277 M+H @ 0.49 min, Method 1,1H NMR (500 MHz, DMSO) δ 14.67 (s, 1H), 11.98 (s, 1H), 8.22 (s, 4H), 7.78 (d, J = 8.9 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 4.44 (s, 2H). N-carbamimidoyl-2-(5-chloro-3-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4- yl)acetamide Intermediate 8 N The title compound was 3-B. m / z 361 M+H @ 0.92 min, Method 1, 1H NMR (500 MHz, DMSO) δ 7.85 (d, J = 9.0 Hz, 1H), 7.70 (br. s, 2H), 7.61 (d, J = 9.0 Hz, 1H), 6.54 (br. s, 2H), 6.04 (dd, J = 9.3, 2.2 Hz, 1H), 4.09 (s, 2H), 3.92 – 3.84 (m, 1H), 3.79 (dt, J = 11.5, 6.5 Hz, 1H), 2.39 – 2.25 (m, 1H), 2.06 – 2.00 (m, 2H), 1.80 – 1.70 (m, 1H), 1.63 – 1.58 (m, 2H). ethyl 2-(5-chloro-3-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)acetate Intermediate 9 N To a degassed stirring suspension 0.24 mmol) and tBuXPhos Pd G3 (19 mg, 24 μmol) in NMP (0.50 mL) was added zinc cyanide (36 mg, 0.31 mmol) and the mixture heated to 100 °C. After 9 h, the mixture was allowed to cool, diluted with water (5 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layers were dried over Na2SO4and concentrated in vacuo. The crude product was purified by chromatography on silica gel (MTBE / iso-hexanes) to afford the title compound as a colourless oil (51 mg, 49 %). m / z 348 M+H @ 1.78 min, Method 1. Example 5: N-carbamimidoyl-2-(6-chloro-1-methyl-1H-indazol-7-yl)acetamide, HCl NNThe title compound was prepared Protocol 4, isolated as HCl salt. m / z 266 M+H @ 0.61 min, Method 11H NMR (400 MHz, DMSO) δ 12.13 (s, 1H), 8.32 (s, 4H), 8.08 (s, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 4.49 (s, 2H), 4.19 (s, 3H). N-Boc-N-carbamimidoyl-2-(6-chloro-1-methyl-1H-indazol-7-yl)acetamide Intermediate 10 NNThe title compound was 3-A. m / z 366 M+H @ 1.23 min, Method 31H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 8.70 (s, 2H), 8.04 (s, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 8.6 Hz, 1H), 4.36 (s, 2H), 4.17 (s, 3H), 1.41 (s, 9H). ethyl 2-(6-chloro-1-methyl-1H-indazol-7-yl)acetate Intermediate 11 NNThe title compound was prepared Protocol 2. m / z 253 M+H @ 1.42 min, Method 31H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 4.29 (s, 2H), 4.26 (s, 3H), 4.22 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). 7-bromo-6-chloro-1-methyl-1H-indazole Intermediate 12 NNA stirred mixture of 3-bromo-4-chloro- (500 mg, 2.11 mmol), K2CO3(1.75 g, 12.6 mmol) and methylhydrazine (554 μL, 10.5 mmol) in NMP (5 mL) was sealed under nitrogen and heated at 200 °C for 1 h under microwave irradiation. The reaction mixture was diluted with water (2 mL) and extracted with EtOAc (2 x 5 mL). The combined organic extracts were dried over MgSO4and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc / iso-hexanes) to afford the title compound as a colourless solid (195 mg, 37 %). m / z 245 M+H @1.62 min, Method 31H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 4.44 (s, 3H). Example 6: N-carbamimidoyl-2-(3,6-dichloro-1-methyl-1H-indazol-7-yl)acetamide NNThe title compound was Protocol 4 to obtain free base after preparative HPLC. m / z 300 M+H @ 0.80 min, Method 11H NMR (500 MHz, DMSO) δ 7.86 (br. s, 4H), 7.55 (d, J = 8.6 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 4.22 (s, 2H), 4.17 (s, 3H). N-Boc-N-carbamimidoyl-2-(3,6-dichloro-1-methyl-1H-indazol-7-yl)acetamide Intermediate 13 NNTo a stirred mixture of (1 mL) was added NCS (23 mg, 170 μmol). After 18 h, the mixture was diluted with water (2 mL) and extracted with DCM (2 x 5 mL). The combined organic layers were dried over Na2SO4and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc / iso-hexanes) to afford the title compound as a white solid (27. mg, 28 %, 59%). m / z 300 M-Boc+H @ 1.51, Method 3 Example 7: N-carbamimidoyl-2-(5-chloro-1-methyl-1H-indazol-4-yl)acetamide, HCl N The title compound was Protocol 4 to obtain HCl salt. m / z 266 M+H @ 0.57 min Method 11H NMR (500 MHz, DMSO) δ 12.12 (d, J = 7.4 Hz, 1H), 8.50 – 8.11 (m, 5H), 7.66 (d, J = 8.9 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 4.28 (s, 2H), 4.05 (s, 3H). N-Boc-N-carbamimidoyl-2-(5-chloro-1-methyl-1H-indazol-4-yl)acetamide Intermediate 14 N The title compound was 3-A. m / z 366 M+H @ 0.61 min, Method 3, gradient over 1 min1H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 1.0 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 4.25 (s, 2H), 4.08 (s, 3H), 1.49 (s, 9H). (3 exchangeable NH signals not observed). ethyl 2-(5-chloro-1-methyl-1H-indazol-4-yl)acetate Intermediate 15 N The title compound was prepared Protocol 2. m / z 253 M+H @ 1.38 min, Method 3,1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 1.0 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.06 (s, 2H), 4.05 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). 4-bromo-5-chloro-1-methyl-1H-indazole and 4-bromo-5-chloro-2-methyl-2H-indazole Intermediate 16 N To a stirred mixture of 4-bromo-5- (650 mg, 2.81 mmol) and Cs2CO3(1.83 g, 5.62 mmol) in DMF (5 mL) was added iodomethane (190 μL, 3.09 mmol). After 1.5 h, the mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over MgSO4and concentrated in vacuo. The crude product was purified by chromatography on silica gel (MTBE / iso-hexanes) to afford the title compound as a pale yellow solid. m / z 245 M+H @ 1.56 Method 11H NMR (500 MHz, CDCl3) δ 7.96 (s, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 4.07 (s, 3H). Intermediate 17 same procedure, was also isolated the title compound as a pale yellow oil (350 mg, ~30% (60% purity)) m / z 245 M+H @ 1.45 Method 1 Example 8: 2-(3-bromo-5-chloro-1-methyl-1H-indazol-4-yl)-N-carbamimidoylacetamide, HCl Br The title compound was prepared Protocol 4. m / z 344 @ 0.64 min, Method 11H NMR (400 MHz, DMSO) δ 11.97 (s, 1H), 8.23 (s, 4H), 7.76 (d, J = 9.1 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 4.49 (s, 2H), 4.05 (s, 3H). N-Boc-2-(3-bromo-5-chloro-1-methyl-1H-indazol-4-yl)-N-carbamimidoylacetamide Intermediate 18 Br The title compound was 3-A. m / z 444 @ 1.33 min, Method 1 ethyl 2-(3-bromo-5-chloro-1-methyl-1H-indazol-4-yl)acetate Intermediate 19 Br To a stirred solution of Intermediate 15 (50 mg, 0.2 mmol) in DMF (1 mL) was added NBS (39 mg, 0.22 mmol). After 18 h, the mixture was diluted with water (2 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layers were dried over Na2SO4and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc / iso-hexanes) to afford the title compound as a colourless solid (50 mg, 75 %). m / z 331 @ 1.61 min, Method 11H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 8.9 Hz, 1H), 7.28 – 7.23 (m, 1H), 4.41 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 4.02 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H). Example 9: N-carbamimidoyl-2-(5-chloro-2-methyl-2H-indazol-4-yl)acetamide, HCl The title compound was prepared Protocol 4 to obtain HCl salt. m / z 266 M+H @ 0.52 min, Method 11H NMR (500 MHz, DMSO) δ 12.13 (s, 1H), 8.53 (s, 1H), 8.42 (br. s, 2H), 8.25 (br. s, 2H), 7.59 (dd, J = 9.1, 0.9 Hz, 1H), 7.26 (d, J = 9.1 Hz, 1H), 4.20 (s, 2H), 4.17 (s, 3H). N-Boc-N-carbamimidoyl-2-(5-chloro-2-methyl-2H-indazol-4-yl)acetamide Intermediate 20 The title compound was 3-A. m / z 366 M+H @ 1.08 min, Method 1,1H NMR (500 MHz, CDCl3) δ 7.92 (s, 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.27 (s, 1H), 4.21 (s, 3H), 4.03 (s, 2H), 1.45 (s, 9H). (3 exchangeable NH signals not observed). Ethyl 2-(5-chloro-2-methyl-2H-indazol-4-yl)acetate Intermediate 21 The title compound was prepared Protocol 2. m / z 253 M+H @ 1.29 min, Method 11H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.73 (s, 1H), 7.30 (d, J = 9.2 Hz, 1H), 4.38 (s, 3H), 4.16 (q, J = 7.1 Hz, 2H), 4.00 (s, 2H), 1.25 (t, J = 7.2 Hz, 3H). Example 10: N-carbamimidoyl-2-(1-methyl-1H-indazol-7-yl)acetamide, HCl NNThe title compound was prepared using Protocol 3-B followed by treatment with HCl in IPA to afford the HCl salt. m / z 232 M+H @ 0.37 min, Method 11H NMR (500 MHz, DMSO): δ 12.12 (s, 1H), 8.39 (v. br. s, 2H), 8.26 (v. br. s, 2H), 8.03 (s, 1H), 7.70 (dd, J = 8.1, 1.1 Hz, 1H), 7.28 (d, J = 7.0 Hz, 1H), 7.08 (dd, J = 8.0, 7.0 Hz, 1H), 4.34 (s, 2H), 4.19 (s, 3H). Ethyl 2-(1-methyl-1H-indazol-7-yl)acetate Intermediate 22 NNThe title compound was prepared 1H-indazole (BLD Pharmatech GmbH) using Protocol 2. m / z 219 M+H @ 1.23 min, Method 1,1H-NMR (500 MHz, DMSO): δ 8.01 (s, 1H), 7.71 – 7.63 (m, 1H), 7.24 – 7.16 (m, 1H), 7.05 (dd, J = 8.2, 6.9 Hz, 1H), 4.20 (s, 2H), 4.17 (s, 3H), 4.13 (q, J = 7.1 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H). Example 11: N-carbamimidoyl-2-(1,6-dimethyl-1H-indazol-7-yl)acetamide, HClN NThe title compound was prepared Protocol 4 to afford the HCl salt. m / z 246 M+H @ 0.80 min, Method 2,1H NMR (400 MHz, DMSO) δ 12.14 (s, 1H), 8.46 – 8.16 (m, 4H), 7.94 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 4.34 (s, 2H), 4.17 (s, 3H), 2.37 (s, 3H). N-carbamimidoyl-2-(1,6-dimethyl-1H-indazol-7-yl)acetamide Intermediate 23 NNThe title compound was 3-A.1H NMR (500 MHz, MeOD) δ 7.87 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 4.24 (s, 3H), 4.22 (s, 2H), 2.43 (s, 3H), 1.48 (s, 9H). (3 exchangeable protons not observed) Ethyl 2-(1,6-dimethyl-1H-indazol-7-yl)acetate Intermediate 24 NNThe title compound was prepared 1H-indazole (Pharmablock) using Protocol 2. m / z 233 M+H @ 1.34 min, Method 3,1H NMR (500 MHz, DMSO) δ 7.93 (d, J = 1.0 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 4.20 (s, 3H), 4.16 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 2.38 (s, 3H), 1.22 – 1.14 (m, 3H). Example 12: N-carbamimidoyl-2-(2,6-dimethyl-2H-indazol-7-yl)acetamide, HCl The title compound was prepared from Intermediate 25 using Protocol 4 to afford HCl salt. m / z 246 M+H @ 0.75 min, Method 2,1H NMR (400 MHz, DMSO) δ 11.72 (s, 1H), 8.27 (s, 1H), 8.24 (bs, 4H), 7.52 (d, J = 8.5 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 4.14 (s, 2H), 4.13 (s, 3H), 2.32 (s, 3H). Boc-N-carbamimidoyl-2-(2,6-dimethyl-2H-indazol-7-yl)acetamide Intermediate 25 The title compound was 3-A.1H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 8.84 – 8.63 (m, 2H), 8.24 (s, 1H), 7.48 (d, J = 8.5 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 4.12 (s, 3H), 4.05 (s, 2H), 2.28 (s, 3H), 1.39 (s, 9H). ethyl 2-(2,6-dimethyl-2H-indazol-7-yl)acetate Intermediate 26 The title compound was prepared 2H-indazole (Pharmablock) using Protocol 2. m / z 233 M+H @ 1.21 min, Method 3,1H NMR (500 MHz, DMSO) δ 8.24 (d, J = 1.4 Hz, 1H), 7.48 (dd, J = 8.5, 1.4 Hz, 1H), 6.88 (dd, J = 8.6, 1.4 Hz, 1H), 4.12 (s, 3H), 4.07 (q, J = 1.3 Hz, 2H), 3.98 (s, 2H), 2.28 (d, J = 1.3 Hz, 3H), 1.18 (t, J = 1.6 Hz, 3H). Example 13: N-carbamimidoyl-2-(6-chloro-1-ethyl-1H-indazol-7-yl)acetamide, HCl The title compound was prepared Protocol 3-B then treatment with HCl in IPA to afford the HCl salt. m / z 280 M+H @ 0.66 min, Method 1,1H NMR (500 MHz, DMSO) δ 12.39 (s, 1H), 8.48 (br. s, 2H), 8.26 (br. s, 2H), 8.13 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 4.52 (q, J = 7.2 Hz, 2H), 4.43 (s, 2H), 1.36 (t, J = 7.2 Hz, 3H). Ethyl 2-(6-chloro-1-ethyl-1H-indazol-7-yl)acetate Intermediate 27 The title compound was prepared Protocol 2, separating using silica gel chromatography (MTBE / iso-hexanes). m / z 267 M+H @ 1.55 min, Method 11H NMR (500 MHz, CDCl3) δ 7.97 (s, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 4.58 (q, J = 7.3 Hz, 2H), 4.24 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H). Ethyl 2-(6-chloro-2-ethyl-2H-indazol-7-yl)acetate Intermediate 29 The title compound was prepared Protocol 2, separating using silica gel chromatography (MTBE / iso-hexanes). m / z 267 M+H @ 1.55 min, Method 1,1H NMR (500 MHz, CDCl3) δ 7.90 (s, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 4.54 – 4.42 (m, 2H), 4.30 – 4.08 (m, 4H), 1.61 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 6.9 Hz, 3H). 7-bromo-6-chloro-1-ethyl-1H-indazole and 7-bromo-6-chloro-2-ethyl-2H-indazole Intermediate 28 To a stirred mixture of 7- 0.65 mmol) and Cs2CO3(633 mg, 1.94 mmol) in DMF (2 mL) was added iodoethane (67 μL, 0.97 mmol). After 1 h, the mixture was quenched with sat. aq. NH4Cl (10 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over MgSO4and concentrated in vacuo to afford a ~5:4 mixture of the title compounds as a yellow oil (144 mg). 7-bromo-6-chloro-1-ethyl-1H-indazole, m / z 259 M+H @ 1.77 min Method 1 7-bromo-6-chloro-2-ethyl-2H-indazole, m / z 259 M+H @ 1.44 min Method 1 Example 14: N-carbamimidoyl-2-(6-chloro-2-ethyl-2H-indazol-7-yl)acetamide, HCl The title compound was prepared Protocol 3-B then treatment with HCl in IPA to afford the HCl salt. m / z 280 M+H @ 0.66 min, Method 1,1H NMR (500 MHz, DMSO) δ 11.90 (s, 1H), 8.48 (s, 1H), 8.38 – 8.10 (m, 4H), 7.70 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 4.45 (q, J = 7.3 Hz, 2H), 4.23 (s, 2H), 1.49 (t, J = 7.3 Hz, 3H). Example 15: N-carbamimidoyl-2-(6-chloro-1-isopropyl-1H-indazol-7-yl)acetamide, HCl The title compound was prepared Protocol 3-B then treatment with HCl in IPA to afford the HCl salt. m / z 294 M+H @ 0.73 min, Method 1,1H NMR (500 MHz, DMSO) δ 12.19 (s, 1H), 8.39 (br. s, 2H), 8.24 (br. s, 2H), 8.16 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 5.00 (hept, J = 6.5 Hz, 1H), 4.47 (s, 2H), 1.46 (d, J = 6.3 Hz, 6H). Ethyl 2-(6-chloro-1-isopropyl-1H-indazol-7-yl)acetate Intermediate 30 The title compound was prepared Protocol 2, separating using silica chromatography (MTBE / iso-hexanes). m / z 281 M+H @ 1.68 min, Method 1,1H NMR (500 MHz, CDCl3) δ 8.00 (s, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 4.98 (hept, J = 6.5 Hz, 1H), 4.27 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 1.56 (d, J = 6.5 Hz, 6H), 1.27 – 1.24 (m, 3H). Ethyl 2-(6-chloro-2-isopropyl-2H-indazol-7-yl)acetate Intermediate 32 The title compound was prepared Protocol 2, separating using silica chromatography (MTBE / iso-hexanes). m / z 281 M+H @ 1.60 min, Method 1,1H NMR (500 MHz, CDCl3) δ 7.92 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 4.78 (hept, J = 6.7 Hz, 1H), 4.26 – 4.13 (m, 4H), 1.62 (d, J = 6.7 Hz, 6H), 1.25 (t, J = 7.1 Hz, 3H). 7-bromo-6-chloro-1-isopropyl-1H-indazole and 7-bromo-6-chloro-2-isopropyl-2H- indazole Intermediate 31 To a stirred mixture of 7- 0.65 mmol) and Cs2CO3 (633 mg, 1.94 mmol) in DMF (2 mL) was added 2-iodopropane (97 μL, 0.97 mmol) and the mixture heated to 50 °C for 1 h. The mixture was allowed to cool then poured into sat. aq. NH4Cl (10 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over MgSO4and concentrated in vacuo to afford the title compounds as a ~3:2 mixture as yellow oil (135 mg). 7-bromo-6-chloro-1-isopropyl-1H-indazole m / z 273 M+H @ 1.58 min, Method 1 7-bromo-6-chloro-2-isopropyl-2H-indazole m / z 273 M+H @ 1.91 min, Method 1 Example 16: N-carbamimidoyl-2-(6-chloro-2-isopropyl-2H-indazol-7-yl)acetamide, HCl The title compound was Protocol 3-B then treatment with HCl in IPA to afford the HCl salt. m / z 294 M+H @ 0.74 min, Method 1,1H NMR (500 MHz, DMSO) δ 11.91 (s, 1H), 8.51 (s, 1H), 8.35 (br. s, 2H), 8.22 (br. s, 2H), 7.69 (d, J = 8.9 Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H), 4.82 (hept, J = 6.7 Hz, 1H), 4.23 (s, 2H), 1.54 (d, J = 6.6 Hz, 6H). Example 17: N-carbamimidoyl-2-(5-chloro-3-cyano-1-methyl-1H-indazol-4-yl)acetamide, HCl N The title compound was prepared from Intermediate 33 using Protocol 3-B then treatment with HCl in IPA to afford the HCl salt. m / z 291 M+H @ 0.57 min, Method 1,1H NMR (500 MHz, DMSO) δ 12.26 (s, 1H), 8.41 (br. s, 2H), 8.21 (br. s, 2H), 7.94 (d, J = 9.0 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 4.43 (s, 2H), 4.21 (s, 3H). Ethyl 2-(5-chloro-3-cyano-1-methyl-1H-indazol-4-yl)acetate Intermediate 33 N To a stirred mixture of Intermediate and Pd-170 (Johnson and Matthey, 16 mg, 23 μmol) in DMF (1 mL) was added zinc cyanide (36 mg, 0.30 mmol) and the mixture heated to 100 °C for 2.5 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layers were dried over Na2SO4and concentrated in vacuo. The crude product was purified by chromatography on silica gel (MTBE / iso-hexanes) to afford the title compound as a white solid (56 mg, 0.20 mmol, 86 %). m / z 278 M+H @ 1.50 min, Method 1,1H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 8.9 Hz, 1H), 7.38 (d, J = 8.9 Hz, 1H), 4.32 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 4.15 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). Example 18: N-carbamimidoyl-2-(1H-indol-7-yl)acetamide, HCO2H NH HTo a stirred solution of and guanidine.HCl (145 mg, 1.52 mmol) in DMF (2.5 mL) was added potassium tert-butoxide (133 mg, 1.19 mmol). After 22 h, the mixture was concentrated in vacuo and the residue triturated with DCM (5 mL) and filtered. The solid residue was further washed with DCM (3 mL) then triturated with water (5 mL) and again filtered. The solid was further washed with water (2 x 3 mL), then DCM (1 mL). The aqueous washings were combined then extracted with DCM (5 mL) then all the DCM extracts were combined then concentrated in vacuo to leave a yellow-orange solid which was purified by preparative HPLC to obtain the title compound as a pale brown solid (36 mg, 27%, 95%) m / z 217.1 M+H @ 0.43 min, Method 1,1H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.63 (br s, 2H), 8.31 (s, 1H), 7.58 (br s, 2H), 7.42 (dd, J = 7.1, 1.9 Hz, 1H), 7.31 (t, J = 2.8 Hz, 1H), 6.97 – 6.89 (m, 2H), 6.42 (dd, J = 3.1, 1.8 Hz, 1H), 3.84 (s, 2H).1 exchangeable NH not observed. Methyl 2-(1H-indol-7-yl)acetate Intermediate 34 NH To a stirred suspension of 1H-Indol- 1.43 mmol) in a mixture of MeOH (1 mL) and toluene (4 mL) was added trimethylsilyl)diazomethane solution (2.1 mL of a 2 M solution in hexanes, 4.2 mmol). The reaction was stirred for 1.25 h then quenched with acetic acid (245 μL, 4.28 mmol). After a further 20 min, sat. aq. NaHCO3(10 mL) was added. After a further 30 min, the mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4and concentrated in vacuo to afford the title compound as a waxy brown solid (263 mg, 88 %). m / z 190 M+H @ 1.20 min, Method 1,1H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 7.47 – 7.42 (m, 1H), 7.33 (app. t, J = 2.8 Hz, 1H), 6.94 (dd, J = 4.5, 0.8 Hz, 2H), 6.44 (dd, J = 3.1, 1.9 Hz, 1H), 3.94 (s, 2H), 3.62 (s, 3H). Example 19: N-Carbamimidoyl-2-(1H-indol-4-yl)acetamide, HCO2H H The title compound was using the same protocol as N- carbamimidoyl-2-(1H-indol-7-yl)acetamide then purified by reverse phase preparative chromatography to afford the formic acid adduct m / z 217 M+H @ 0.58 min, Method 1,1H NMR (500 MHz, DMSO) δ 11.04 (s, 1H), 8.56 (br s, 2H), 8.30 (s, 1H), 7.49 (br s, 2H), 7.30 – 7.23 (m, 2H), 7.00 (app. t, J = 7.6 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 6.51 (s, 1H), 3.78 (s, 2H), 1 x NH not observed. Methyl 2-(1H-indol-4-yl)acetate Intermediate 35 The title compound was prepared acid using the same protocol as Intermediate 34 m / z 190 M+H @ 1.08 min, Method 1,1H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 7.36 – 7.27 (m, 2H), 7.03 (dd, J = 8.2, 7.1 Hz, 1H), 6.90 – 6.84 (m, 1H), 6.43 (ddd, J = 3.1, 2.0, 1.0 Hz, 1H), 3.86 (s, 2H), 3.59 (s, 3H). Example 20: N-carbamimidoyl-2-(3-chloro-1H-indol-4-yl)acetamide, HCl Cl The title compound was prepared Protocol 4 to afford the HCl salt m / z 251 M+H @ 0.70 min, Method 2,1H NMR (400 MHz, DMSO) δ 11.79 (s, 1H), 11.47 (s, 1H), 8.26 (s, 4H), 7.48 (d, J = 2.7 Hz, 1H), 7.37 (dd, J = 8.3, 1.0 Hz, 1H), 7.11 (dd, J = 8.3, 7.1 Hz, 1H), 6.92 (dd, J = 7.2, 0.9 Hz, 1H), 4.26 (s, 2H). Boc-N-carbamimidoyl-2-(3-chloro-1H-indol-4-yl)acetamide Intermediate 36 Cl The title compound was 3-A. m / z 351 M+H @ 1.38 min, Method 1. Methyl 2-(3-chloro-1H-indol-4-yl)acetate Intermediate 37 Cl To a stirred solution of Intermediate 35 (235 mg, 1.18 mmol) in DMF (2 mL) at 0 ºC was added NCS (189 mg, 1.42 mmol). After 2 h, the mixture was allowed to warm to RT. After a further 1 h, the mixture was treated with water:brine (3:1, 10 mL) and extracted with EtOAc (10 mL). The organic phase was washed successively with water:brine (1:1, 2 x 10 mL) and brine (10 mL), dried over MgSO4, and concentrated to afford the title compound as a purple solid (300 mg, 94 %).1H NMR (500 MHz, DMSO) δ 11.40 (s, 1H), 7.46 (d, J = 2.7 Hz, 1H), 7.33 (dd, J = 8.2, 1.0 Hz, 1H), 7.08 (dd, J = 8.3, 7.1 Hz, 1H), 6.88 (dd, J = 7.1, 0.9 Hz, 1H), 4.12 (s, 2H), 3.61 (s, 3H). Example 21: N-carbamimidoyl-2-(5-chloro-3-cyclopropyl-1H-indazol-4-yl)acetamide, HCO2H The title compound was using Protocol 4 , purifying by preparative reverse phase chromatography to afford the formic acid adduct m / z 292 M+H @ 0.63 min, Method 3,1H NMR (400 MHz, DMSO) δ 12.62 (s, 1H), 8.20 (s, 1H), 7.75 (v. br. s, 2H), 7.31 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 6.68 (v. br. s, 2H), 4.21 (s, 2H), 2.27 – 2.16 (m, 1H), 0.90 – 0.80 (m, 4H), (1 exchangeable signal not observed). N-Boc-N-carbamimidoyl-2-(5-chloro-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-4-yl)acetamide Intermediate 38 The title compound was 3-A. m / z 476 M+H @ 1.65 min, Method 3,1H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 8.73 (s, 2H), 7.62 (d, J = 8.9 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H), 5.74 (dd, J = 9.7, 2.5 Hz, 1H), 4.39 (s, 2H), 3.91 – 3.80 (m, 1H), 3.79 – 3.64 (m, 1H), 2.40 – 2.26 (m, 1H), 2.19 – 2.10 (m, 1H), 2.06 – 1.83 (m, 2H), 1.79 – 1.65 (m, 1H), 1.60 – 1.50 (m, 2H), 1.40 (s, 9H), 0.95 – 0.79 (m, 4H). Ethyl 2-(5-chloro-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)acetate Intermediate 39 A stirred mixture of , intermediate 3872-318 (150 mg, 0.35 mmol) and Cs2CO3(229 mg, 0.70 mmol) in a mixture of 1,4-dioxane (4 mL) and water (0.40 mL) was degassed under a flow of N2for 5 min whereupon sodium 2'- (dicyclohexylphosphino)-2,6-dimethoxy-[1,1'-biphenyl]-3-sulfonate hydrate (40 mg, 75 μmol) and Pd(OAc)2(8 mg, 0.04 mmol) were added and the reaction mixture heated at 80 °C for 18 h. The mixture was allowed to cool to RT then diluted with water (5 mL) and extracted with EtOAc (10 mL). The organic phase was washed with brine (5 mL), dried over MgSO4and concentrated. The crude product was purified by chromatography on silica gel (MTBE / iso- hexanes) to afford the title compound as a yellow gum, still containing significant unreacted bromide starting material (75 mg, ~32 %, (55% purity)). m / z 363 M+H @ 1.87 min, Method 3,1H NMR (400 MHz, DMSO) δ 7.63 (d, J = 8.9 Hz, 1H), 7.44 (d, J = 8.9 Hz, 1H), 5.75 (dd, J = 9.7, 2.6 Hz, 1H), 4.35 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.91 – 3.81 (m, 1H), 3.80 – 3.65 (m, 1H), 2.40 – 2.24 (m, 1H), 2.18 (tt, J = 8.2, 5.1 Hz, 1H), 2.07 – 1.93 (m, 1H), 1.93 – 1.87 (m, 1H), 1.81 – 1.62 (m, 1H), 1.62 – 1.45 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H), 0.95 – 0.76 (m, 4H). Example 22: 2-(3-amino-5-chloro-1H-indazol-4-yl)-N-carbamimidoylacetamide, HCl NH2The title compound was prepared Protocol 4, isolated as HCl salt. m / z 267 M+H @ 0.43 min, Method 1, 1H NMR (400 MHz, DMSO) δ 12.40 (br. s, 1H), 8.36 (br. s, 2H), 8.28 (br. s, 2H), 7.37 – 7.32 (m, 2H), 4.33 (s, 2H), 3 x NH exchanges with water. N-Boc-2-(3-amino-5-chloro-1H-indazol-4-yl)-N-carbamimidoylacetamide Intermediate 40 The title compound was 3-A. m / z 615 M+H @ 1.98 min, Method 1. ethyl 2-(5-chloro-3-((diphenylmethylene)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-4-yl)acetate Intermediate 41 A stirred mixture of , Cs2CO3(554 mg, 1.7 mmol), XantPhos Pd G3 (54 mg, 56 μmol), benzophenone imine (143 μL, 0.85 mmol) and 1,4-dioxane (4 mL) was degassed for 5 min (N2stream) before heating at 90 °C for 18 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over MgSO4and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-20% MTBE / iso-hexanes) to afford the title compound as a sticky yellow gum (260 mg, 87 %). m / z 502 M+H @ 2.31 min, Method 1 1H NMR (500 MHz, DMSO) δ 7.78 – 7.71 (m, 2H), 7.62 – 7.57 (m, 1H), 7.57 – 7.48 (m, 3H), 7.43 (d, J = 8.9 Hz, 1H), 7.37 – 7.29 (m, 3H), 7.20 – 7.13 (m, 2H), 5.70 (dd, J = 6.7, 3.6 Hz, 1H), 4.31 (s, 2H), 3.87 (q, J = 7.1 Hz, 2H), 3.51 – 3.43 (m, 1H), 3.30 – 3.26 (m, 1H), 1.87 – 1.82 (m, 1H), 1.74 – 1.64 (m, 1H), 1.59 – 1.54 (m, 1H), 1.52 – 1.44 (m, 2H), 1.34 – 1.24 (m, 1H), 0.88 (t, J = 7.1 Hz, 3H). Example 23: N-carbamimidoyl-2-(6-chloro-1H-indazol-7-yl)acetamide, HCl NNHThe title compound was prepared Protocol 4, isolated as HCl salt. m / z 252 M+H @ 0.61 min, Method 3, 1H NMR (400 MHz, DMSO) δ 12.19 (s, 1H), 8.48 – 8.16 (m, 4H), 8.14 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 4.31 (s, 2H), 1 x NH not observed. Boc N-carbamimidoyl-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7- yl)acetamide Intermediate 42 The title compound was 3-A. m / z 436 M+H @ 1.37 min, Method 3. ethyl 2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-yl)acetate Intermediate 43 The title compound was prepared Protocol 2, separating using silica chromatography (MTBE / iso-hexanes). m / z 323 M+H @ 1.61 min, Method 3, 1H NMR (500 MHz, CDCl3) δ 8.14 (s, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 5.68 (dd, J = 9.3, 2.9 Hz, 1H), 4.24 – 4.07 (m, 5H), 3.81 – 3.73 (m, 1H), 2.26 – 2.19 (m, 1H), 2.18 – 1.99 (m, 2H), 1.79 – 1.56 (m, 3H), 1.24 (t, J = 7.1 Hz, 3H). ~3:1 product mix of 6-chloro-7-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole and 6- chloro-7-iodo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole Intermediate 44 To a suspension of and p-toluenesulfonic acid monohydrate (20 mg, 0.11 mmol) in DCM (4 mL) was added 3,4-dihydro-2H-pyran (211 μL, 2.3 mmol). The reaction mixture was stirred for 2 h before diluting with DCM (10 mL) and washing with sat. aq. NaHCO3(20 mL), drying over MgSO4, and concentrating in vacuo. The crude product was purified by silica gel chromatography (MTBE / iso-hexanes) to afford the title compounds as a ~3:1 product mix as a yellow gum (630 mg, ~80%). m / z 385 M+Na @ 1.69 min, Method 3. 6-chloro-7-iodo-1H-indazole Intermediate 45 NNHI ClTo a stirred suspension of 4-chloro-2-fluoro-3-iodobenzaldehyde (750 mg, 2.6 mmol) in 1,4- dioxane (5 mL) was added hydrazine monohydrate (265 μL, 5.3 mmol). The reaction mixture was heated to 100 °C and stirred for 5 days. After completion (LCMS) the solvent was evaporated. The residue was was purified by silica gel chromatography (EtOAc / iso-hexanes) to afford the title compound as a colourless solid (599 mg, 77 %). m / z 279 M+H @ 1.32 min, Method 31H NMR (400 MHz, DMSO) δ 13.33 (s, 1H), 8.30 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H). Example 24: 2-(3-bromo-6-chloro-1H-indazol-7-yl)-N-carbamimidoylacetamide, HCl NNHThe title compound was Protocol 4, isolated as HCl salt. m / z 330 M+H @ 0.82 min, Method 3, 1H NMR (400 MHz, DMSO) δ 13.81 (s, 1H), 12.35 (s, 1H), 8.44 (br. s, 2H), 8.26 (br. s, 2H), 7.56 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 4.32 (s, 2H). Boc-2-(3-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-yl)-N- carbamimidoylacetamide Intermediate 46 The title compound was 3-A. m / z 514 M+H @ 1.83 min, Method 3. ethyl 2-(3-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-yl)acetate Intermediate 47 To a stirred solution of 0.41 mmol) in DMF (2 mL) was added NBS (90 mg, 0.51 mmol). After 18 h, the mixture was diluted with MTBE (40 mL) and washed successively with 1:1 brine:water (2 x 40 mL) and brine (50 mL), dried over MgSO4, and concentrated on to silica (~3 g). The crude product was purified by silica gel chromatography (MTBE / iso-hexanes) to afford unprotected material as a grey solid (~50 mg). This material was taken up in DCM (3 mL) and treated with p-toluenesulfonic acid monohydrate (5 mg, 0.03 mmol) and dihydropyran (80 μL, 0.88 mmol) and stirred at RT for 72 h. Sat. aq. NaHCO3(10 mL) was added and the phases were separated through a hydrophobic frit, washing with DCM (5 mL). The combined organic phases were concentrated on to silica (~500 mg) and the crude product purified by silica gel chromatography (MTBE / iso-hexanes) to afford the title compound as a colourless solid (44 mg, ~16 %, ~60% Purity). m / z 423 M+Na @ 1.97 min, Method 3,1H NMR (500 MHz, DMSO) δ 7.59 (d, J = 8.6 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 5.72 (dd, J = 8.8, 2.4 Hz, 1H), 4.37 – 4.09 (m, 4H),* 3.84 – 3.78 (m, 1H), 3.64 (ddd, J = 11.6, 10.0, 3.4 Hz, 1H), 2.45 – 2.33 (m, 1H), 2.11 – 2.02 (m, 2H), 1.78 – 1.38 (m, 5H), 1.20 (t, J = 7.1 Hz, 3H). II. BIOLOGY EXAMPLES II.1. ASSAYS FOR ADRENERGIC a2 FUNCTIONAL ACTIVITIES II.1.A. Stimulation of GTP binding in CHO cells Materials CHO-K1 cells stably transfected with plasmid containing the human sequence for adrenergic receptors: α2A, α2Band α2Cwere purchased from Perkin Elmer (EC-030-C, ES-31-C and ES- 032-C, respectively). Cells were maintained in Ham’s F12 (11765054, Gibco) with addition of 10 % (v / v) FBS and 0.4 mg / ml Geneticin (10131027, Gibco) at 37 °C, 5 % CO2and passaged twice weekly. HTRF GTP binding kit was purchased from Perkin Elmer (62GTPPEC). Methods Membrane preparations Cells were detached in Versene for up to 15 minutes with agitation. All collected cells were centrifuged at 300 xg for 5 minutes (RT) and supernatants were discarded. Cell pellets were resuspended in ice-cold HE buffer: 20 mM HEPES (H0887, Merck), 10 mM EDTA (E7889, Merck), pH 7.4. The cell suspension was then homogenised using a Dounce homogeniser with 20x strokes of pestle A, followed by 20x strokes with pestle B. Homogenates were centrifuged for 600 xg for 10 minutes at 4 °C. The supernatants were then transferred to high-speed centrifuge tubes (NC654, Appleton Woods). Pellets were again resuspended in ice-cold HE buffer: 20 mM HEPES (H0887, Merck), 10 mM EDTA (E7889, Merck), pH 7.4and homogenised using a Dounce homogeniser with 20x strokes of pestle A, followed by 20x strokes with pestle B, then centrifuged for 600 xg for 10 minutes at 4 °C. Supernatants were pooled and centrifuged at 40,000xg for 1 h at 4 °C. Each pellet was resuspended in 400 µl of 20 mM HEPES with 10 % (w / v) glycerol (332031000, ThermoScientific). All steps were performed on ice. Membrane suspensions were passed 10x through the insulin syringe (324892, BD Microfine), aliquoted and stored at -80 °C until further use. Protein content was established using the BCA kit (23225, ThermoFisher) with bovine serum albumin standards. HTRF GTP binding assay To evaluate the potential agonists of α2 adrenergic receptors (α2A, α2Band α2C) HTRF GTP binding kit was used with some modification to the manufacturer’s protocol. Tested compounds were dispensed into 384 white ProxiPlates Plus (6008280, Perkin Elmer) using an ECHO acoustic dispenser with automatic DMSO backfill. Guanfacine (HU-17416, Medchemtronica AB) was used as a reference compound. All compounds were run in duplicates on each plate. For plate controls, 30 µM norepinephrine (N5785, Merck) and vehicle control (DMSO) were used. Then, the assay mix was prepared by mixing stimulation buffer #3, MgCl2, 1x GTP Eu Cryptate reagent, 1x GTP d2 antibody and membrane preparation. MgCl2 concentration per well was 50 mM for α2Aand α2C, 8 mM for α2B. The amount of membrane proteins was established for each membrane preparation in a validation experiment (range 0.5-2 µg of protein per well). 10 µl of assay mix was added per well and assay plates were briefly centrifuged. Then plates were sealed with the optically clear plate seals (4311971, Applied Biosystems) and incubated for 6 h at room temperature. Plates were read on Pherastar FSX (BMG Labtech) using the Pherastar HTRF module. Fluorescence was read at two channels: 665 nm and 620 nm and the ratio between channels was calculated. Data was expressed as the percentage activation versus 30 µM norepinephrine. Results. As evidenced in Table 1 below, the compounds of the present invention stimulate GTP binding on a2-overexpressing CHO cells. Table 1: a2A a2A a2B a2B Compound pEC50 Emax pEC50 Emax (nM) (%) (nM) (%) Example 1 5.8 78 5.5 98 Example 2 6.8 87 6.4 62 Example 3 6.8 99 6.4 70 Example 4 5.8 115 5.6 78 Example 5 6.1 95 5.5 63 Example 6 5.5 80 5.1 50 Example 7 5.9 84 5.4 37 Example 8 6.2 114 5.4 71 Example 9 5.1 16 5.1 28 Example 10 5.6 62 5.2 63 Example 11 5.8 73 5.5 29 Example 12 5.4 14 5.9 4 Example 13 6.2 80 5.6 51 Example 14 6.2 5 5.7 5 Example 15 6.1 67 5.7 33 Example 16 6.1 5 6.4 3 Example 17 5.9 69 5.5 19 Example 18 5.5 23 6.4 2 Example 19 6.2 31 5.7 21 Example 20 7.1 44 5.9 50 Example 21 6.4 93 5.5 81 Example 22 6.2 30 6.0 17 Example 23 5.6 77 5.3 52 Example 24 5.3 47 5.0 25 II.2. ANTITUMORAL ACTIVITY IN VIVO II.2.A Summary of the results Example 3 of the invention at 30 mg / kg i.p, QD, significantly delayed growth of MC38 tumors compared to vehicle control in syngeneic host with tumour growth inhibition (% TGI) is ± 40% 13 days (D13) post treatment (Figure 1). Example 3 of the invention at 30 mg / kg i.p, QD, significantly delayed growth of Hepa 1-6 tumors compared to vehicle control in syngeneic host with tumour growth inhibition (% TGI) is ± 39% 19 days (D19) post treatment (Figure 2). Example 3 of the invention at 30 mg / kg i.p, QD, significantly delayed growth of TC-1 tumors compared to vehicle control in syngeneic host with tumour growth inhibition (% TGI) is ± 30% 14 days (D14) post treatment (Figure 3). Example 3 of the invention at 30 mg / kg i.p, QD, significantly delayed growth of LLC1 tumors compared to vehicle control in syngeneic host with tumour growth inhibition (% TGI) is ± 43% 7 days (D7) post treatment (Figure 4). II.2.B Murine syngeneic MC38 Colorectal tumor model In this study the anti-tumor efficacy of Example 3 of the invention was assessed in a murine syngeneic subcutaneous colorectal tumor model (MC38). C57BL / 6 female mice (6-8 weeks old) were inoculated with 106MC38 mouse tumor cells, subcutaneously in the right upper flank region (Day -7). When tumors reached a size of about 100-130mm³ (Day 0), mice (n=9 per group) were allocated randomly into groups and treatment was initiated. Mice were administered vehicle intraperitoneal (i.p). (1:1 ratio of 0.25% Tween80 / 0.5% Hydroxy propyl methyl cellulose (HPMC) E4M in water with 2% DMSO and 0.25% Tween80 / 0.5% Hydroxy propyl methyl cellulose (HPMC) E4M in saline with 2% DMSO) as control or Example 3 of the invention at 30mg / kg prepared in vehicle i.p., QD as single agent until the end of the experiment. Intraperitoneal administration of Example 3 of the invention at a dose of 30 mg / kg on D13 post- treatment resulted in a significant reduction in tumor growth compared to the vehicle-treated group (p = 0.0025, Day 13; Figure 1). The TGI at this time point was ± 40%, indicating the anti-tumor efficacy of Example 3 of the invention at the administered dose. II.2.C Murine syngeneic Hepa 1-6 liver tumor model In this study the anti-tumor efficacy of Example 3 of the invention was assessed in a murine syngeneic subcutaneous liver tumor model (HEPA 1-6). C57BL / 6 female mice (6-8 weeks old) were inoculated with 5.106Hepa 1-6 mouse tumor cells, subcutaneously in the right flank region (Day -5). When tumors reached a size of about 70- 100mm³ (Day 0), mice (n=10 per group) were allocated randomly into groups and treatment was initiated. Mice were administered vehicle intraperitoneal (i.p). (1:1 ratio of 0.25% Tween80 / 0.5% Hydroxy propyl methyl cellulose (HPMC) E4M in water with 2% DMSO and 0.25% Tween80 / 0.5% Hydroxy propyl methyl cellulose (HPMC) E4M in saline with 2% DMSO) as control or Example 3 of the invention at 30mg / kg prepared in vehicle i.p., QD as single agent until the end of the experiment. Intraperitoneal administration of Example 3 of the invention at a dose of 30 mg / kg on D28 post- treatment significantly inhibited tumor growth compared to the vehicle-treated group (p = 0.0050, Day 28; Figure 2). The TGI at D19 post-treatment was ± 39%, demonstrating the anti- tumor efficacy of Example 3 of the invention at this dosage. II.2.C Murine syngeneic TC-1 lung tumor model In this study the anti-tumor efficacy of Example 3 of the invention was assessed in a syngeneic murine subcutaneous lung tumor model (TC-1). C57BL / 6 female mice (6-8 weeks old) were inoculated with TC-1 mouse tumor cells, subcutaneously in the right flank region (Day -9). When tumors reached a size of about 70- 100mm³ (Day 0), mice (n=10 per group) were allocated randomly into groups and treatment was initiated. Mice were administered vehicle intraperitoneal (i.p). (1:1 ratio of 0.25% Tween80 / 0.5% Hydroxy propyl methyl cellulose (HPMC) E4M in water with 2% DMSO and 0.25% Tween80 / 0.5% Hydroxy propyl methyl cellulose (HPMC) E4M in saline with 2% DMSO) as control or Example 3 of the invention at 30mg / kg prepared in vehicle i.p., QD as single agent until the end of the experiment. Intraperitoneal administration of Example 3 of the invention at a dose of 30 mg / kg on D14 post- treatment significantly inhibited tumor growth compared to the vehicle-treated group (p = 0.0034 at Day 14. Figure 3). The TGI at D14 post-treatment was ± 30%, demonstrating the anti- tumor efficacy of Example 3 of the invention at this dosage. II.2.D Murine syngeneic LLC1 lung tumor model In this study the anti-tumor efficacy of Example 3 of the invention was assessed in a murine syngeneic subcutaneous lung tumor model (LLC1). C57BL / 6 female mice (6-8 weeks old) were inoculated with 106LLC1 mouse tumor cells, subcutaneously in the right flank region (Day -5). When tumors reached a size of about 30- 90mm³ (Day 0), mice (n=10 per group) were allocated randomly into groups and treatment was initiated. Mice were administered vehicle intraperitoneal (i.p). (1:1 ratio of 0.25% Tween80 / 0.5% Hydroxy propyl methyl cellulose (HPMC) E4M in water with 2% DMSO and 0.25% Tween80 / 0.5% Hydroxy propyl methyl cellulose (HPMC) E4M in saline with 2% DMSO) as control or Example 3 of the invention at 30mg / kg prepared in vehicle i.p., QD as single agent until the end of the experiment. Intraperitoneal administration of Example 3 of the invention at a dose of 30 mg / kg on D11 post- treatment significantly inhibited tumor growth compared to the vehicle-treated group (p=0.0002 at Day 11. Figure 4). The TGI at D7 post-treatment was ± 43%, demonstrating the anti-tumor efficacy of Example 3 of the invention at this dosage. II.2.D Statistical analysis Sidak’s multiple comparison statistical analysis (two-way ANOVA) was performed using the graphpad prism software. III. PHARMACOKINETIC EXAMPLES III.1. DETERMINATION OF PERMEABILITY AND EFFLUX IN CACO-2 CELLS As mentioned in the introduction, the compounds of the invention have to exhibit a limited, if any, CNS penetrance, in order to avoid deleterious side effects that can occur if these compounds penetrate significantly into the brain. The present assay aims at showing that the compounds of the invention do not have any significant CNS penetrance by showing that they are substrates of transporters that efflux them from brain. Indeed, it is well known in the art that xenobiotics that are substrates of transporters such as P- Glycoprotein are not efficient in penetrating the Blood-Brain Barrier, and are thus less effective in the Central Nervous System (Alfred H. Schinkel, “P-Glycoprotein, a gatekeeper in the blood–brain barrier”, Advanced Drug Delivery Reviews 36 (1999) 179–194). The present assay thus aims at showing that the compounds of the present invention are substrates to such transporters present in the Caco-2 cell line and thus do not cross the Blood- Brain Barrier. Protocol Summary The permeability of test compounds across confluent Caco-2 monolayers were assessed using 96-well Transwell plates by adding compound into the apical and basolateral compartments (bidirectional) and determining test compound levels in the opposing compartment after 2 hours at 37°C in a CO2 incubator. Following sampling at T=0 and 2hrs from both compartments, the samples are analysed by UPLC-MS. Experimental Procedure The Caco-2 Permeability assay used cells purchased from ECACC (86010202) and cultured inhouse. Caco-2 cells are plated on a 96-transwell permeable system as a single monolayer and allowed to differentiate for 21 days to phenotypically mimic intestinal epithelial cells. Dilutions of a 10 mM test compound DMSO stock solution were prepared in buffer (supplemented HBSS, pH6 or 7.4 for apical; supplemented HBSS, pH7.4 for basolateral)) so that the final DMSO concentration was 0.1% and the final test compound concentration tested was 10 uM. Following addition of test compound (in duplicate) into either the apical or basolateral compartment, the samples were incubated for 2 hours at 37 °C in a CO2 incubator. Aliquots were sampled at T=0 and 2hrs and mixed with acetonitrile (containing internal standard). All the samples were mixed, centrifuged and the supernatants analysed by UPLC-MS with quantification against a calibration line prepared in matched HBSS buffer. Lucifer Yellow permeability was performed during the incubation period to assess monolayer integrity. Data Analysis Test Compound was quantified in each compartment and concentrations determined and against a calibration curve prepared in matched HBSS buffer. The apparent permeability coefficient (Papp) was calculated using the following equation: Papp=VR / (Area*Time)*(CR / C0) wherein VR is the solution volume in the receiver chamber; Area is the surface area for the transport; Time is incubation time, expressed in seconds; C0 is the initial concentration in the donor chamber; CR is the final concentrations in receiver chamber. The efflux ratio was calculated using the following equation: Efflux ratio = Papp (A-B) / Papp(B-A) where Papp (A-B) and Papp (B-A) are the Papp values of compound in Apical to Basolateral and Basolateral to Apical directional transport, respectively. Results. Compounds are considered to be P-Glycoprotein substrates when the value of efflux ratio is > 3. Compounds of the present invention typically have efflux ratios > 3 whereas guanfacine has an efflux ratio < 3 (1.5), as evidenced in Table 2 below. Table 2: Compound Efflux ratio Guanfacine 1.5 Example 2 29 Example 3 30 III.2. DETERMINATION OF THE CONCENTRATION A2A ANTAGONISTS IN BRAIN AND CEREBROSPINAL FLUID COMPARED TO PLASMA The present assay aims at showing that the compounds of the invention do not have any significant CNS penetrance by determining the concentration of these compounds in brain and cerebrospinal fluid (CSF) compared to plasma. Method.7-9 weeks old female Balb-c mice (obtained from SLAC Laboratory Animal Co. Ltd., Shanghai, China or SIPPR-B&K Laboratory Animal Co. Ltd., Shanghai, China) were dosed orally at a dose of 10 mg / kg, as a 1.00 mg / mL suspension in 10%DMSO+10%solutol+80% water, adjusted to pH 3-4 (homogenous opaque suspension). Animals were fasted at least 12 hours prior to the administration. All animals had access to Certified Rodent Diet (Catalog # M01-F, SLAC Laboratory Animal Cl. Ltd., Shanghai, China) ad libitum 4 hours post dosing. Serial bleeding (about 30 μL blood per time point) were performed from submandibular or saphenous vein. Those samples were transferred into prechilled microcentrifuge tubes containing 2 μL of K2EDTA (0.5M) as anti-coagulant and placed on wet ice for further treatment. Immediately after blood collection, the whole brain was harvested immediately at the designed time points. At selected timepoints post-dose, CSF was collected from cisterna magna. Blood samples were processed for plasma by centrifugation at approximately 4 °C, 3000g 15 min within half an hour of collection. Plasma samples were stored in polypropylene tubes, quick frozen over dry ice and kept at -70 °C until LC / MS / MS analysis. Brain samples were weighed, rinsed in cold distilled water to remove blood, and homogenized using pre-cooled water at the ratio of 1:4 (1 g brain used 4mL water). And the brain homogenization was kept at -70 °C until LC / MSMS analysis. CSF was quick frozen over dry ice and kept at -70 °C until LC / MS / MS analysis. Results. Example 3 of the invention was dosed at 5 mg / kg by oral route and concentrations in brain or CSF of mice were found to be significantly lower compared to the concentrations present in plasma (brain / plasma ratio <0.1). Individual and Mean Concentration of Example 3 after PO Administration (5 mg / kg) are provided in Table 3 below. Table 3: Plasma Concentration (ng / mL) Time (h) Mouse 1 Mouse 2 Mouse 3 Mean 1.0 854 877 1058 930 Brain Concentration (ng / g) Time (h) Mouse 1 Mouse 2 Mouse 3 Mean 1.0 68.3 61.8 61.9 64.0 CSF Concentration (ng / mL) Time (h) Mouse 1 Mouse 2 Mouse 3 Mean 1.0 3.90 2.83 2.66 3.13 Brain / Plasma Ratio Time (h) Mouse 1 Mouse 2 Mouse 3 Mean 1.0 0.0800 0.0705 0.0585 0.0688 CSF / Plasma Ratio Time (h) Mouse 1 Mouse 2 Mouse 3 Mean 1.0 0.00457 0.00323 0.00251 0.00337

Claims

CLAIMS 1. A compound of formula (I): wherein:^ --- is a single or a double bound; ^ X is C=O, C-R1, or N-R1with R1is absent or represents a radical selected in a group consisting of a hydrogen, a halogen, a cyano, a (C1-C6)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1- C6)alkyloxy, a 3-6 membered cycloalkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a hydroxy, and a NRaRbwith Raand Rbrepresent independently a hydrogen or a (C1- C6)alkyl; ^ Y is C=O, C-R2, or N-R2with R2is absent or represents a radical selected in a group consisting of a hydrogen, a halogen, a cyano, a (C1-C6)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1- C6)alkyloxy, a 3-6 membered cycloalkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a hydroxy, and a NRa’Rb’with Ra’and Rb’represent independently a hydrogen or a (C1- C6)alkyl; ^ Z is C=O, C-R3, or N-R3with R3is absent or represents a radical selected in a group consisting of a hydrogen, a halogen, a cyano, a (C1-C6)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1- C6)alkyloxy, a 3-6 membered cycloalkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a hydroxy, and a NRa’’Rb’’with Ra’’and Rb’’represent independently a hydrogen or a (C1- C6)alkyl;^ R4represents a radical selected in a group consisting of a hydrogen, a halogen, and a (C1-C6)alkyl; ^ R5represents a radical selected in a group consisting of a hydrogen, a halogen, and a (C1-C6)alkyl; ^ R6 represents a radical selected in a group consisting of a hydrogen, a halogen, a cyano, a (C1-C6)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, a 3-6 membered cycloalkyl optionally substituted by at least one radical selected in a group consisting of a halogen, a hydroxy, and a (C1-C6)alkyloxy, and a 3-12 membered heteroaryl; ^ R7represents a hydrogen, or a (C1-C6)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (C1-C6)alkyloxy, a -NH(C1-C6)alkyl, and a -N((C1- C6)alkyl)2; ^ R8represents a hydrogen, or a (C1-C6)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (C1-C6)alkyloxy, a -NH(C1-C6)alkyl, and a -N((C1- C6)alkyl)2; and ^ R9represents a hydrogen, or a (C1-C6)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (C1-C6)alkyloxy, a -NH(C1-C6)alkyl, and a -N((C1- C6)alkyl)2; or R8and R9may form together a 5-7 membered ring, partially unsaturated or saturated, N,N’-heterocycloalkyl optionally substituted by at least one radical selected in a group consisting of a (C1-C6)alkyl, a hydroxy, a (C1-C6)alkyloxy, a -NH(C1-C6)alkyl, a - N((C1-C6)alkyl)2, and a ketone; and the isomers, stereoisomers, tautomers, and pharmaceutical acceptable salts thereof.

2. The compound according to claim 1, wherein R4, R5, R7, R8, and R9represent H.

3. The compound according to claim 1 or 2, wherein R6represents a radical selected in a group consisting of a hydrogen, a halogen, preferably a chlorine, a cyano, and a (C1-C6)alkyl, preferably a methyl.

4. The compound according to any one of claims 1 to 3, wherein R1is absent or represents a radical selected in a group consisting of a hydrogen, a halogen, preferably a bromine or a chlorine, a cyano, a (C1-C6)alkyl, preferably a methyl, an ethyl, or an isopropyl, a 3-6 memberedcycloalkyl, preferably a cyclopropyl, and a NRaRbwith Raand Rbrepresent independently a hydrogen or a (C1-C6)alkyl, preferably a hydrogen.

5. The compound according to any one of claims 1 to 4, wherein R2is absent or represents a radical selected in a group consisting of a hydrogen, and a (C1-C6)alkyl, preferably a methyl, an ethyl, or an isopropyl.

6. The compound according to any one of claims 1 to 5, wherein R3is absent or represents a radical selected in a group consisting of a hydrogen, a halogen, preferably a chlorine or a bromine, and a (C1-C6)alkyl, preferably a methyl.

7. The compound according to any one of claims 1 to 6, wherein said compound has a formula selected in a group consisting of: R9R9R9R97.

8. The compound according to any one of claims 1 to 7, wherein said compound has a formula selected in a group consisting of: R9R91 to 7.

9. The compound according to claim 1, wherein said compound is selected in a group consisting of: - Example 1: N-carbamimidoyl-2-(5-chloro-1H-indazol-4-yl)acetamide, HCl; - Example 2: N-carbamimidoyl-2-(3,5-dichloro-1H-indazol-4-yl)acetamide, HCl; - Example 3: 2-(3-bromo-5-chloro-1H-indazol-4-yl)-N-carbamimidoylacetamide, HCl; - Example 4: N-carbamimidoyl-2-(5-chloro-3-cyano-1H-indazol-4-yl)acetamide, HCl; - Example 5: N-carbamimidoyl-2-(6-chloro-1-methyl-1H-indazol-7-yl)acetamide, HCl; - Example 6: N-carbamimidoyl-2-(3,6-dichloro-1-methyl-1H-indazol-7-yl)acetamide; - Example 7: N-carbamimidoyl-2-(5-chloro-1-methyl-1H-indazol-4-yl)acetamide, HCl; - Example 8: 2-(3-bromo-5-chloro-1-methyl-1H-indazol-4-yl)-N-carbamimidoylacetamide, HCl; - Example 9: N-carbamimidoyl-2-(5-chloro-2-methyl-2H-indazol-4-yl)acetamide, HCl; - Example 10: N-carbamimidoyl-2-(1-methyl-1H-indazol-7-yl)acetamide, HCl; - Example 11: N-carbamimidoyl-2-(1,6-dimethyl-1H-indazol-7-yl)acetamide, HCl;- Example 12: N-carbamimidoyl-2-(2,6-dimethyl-2H-indazol-7-yl)acetamide, HCl; - Example 13: N-carbamimidoyl-2-(6-chloro-1-ethyl-1H-indazol-7-yl)acetamide, HCl; - Example 14: N-carbamimidoyl-2-(6-chloro-2-ethyl-2H-indazol-7-yl)acetamide, HCl; - Example 15: N-carbamimidoyl-2-(6-chloro-1-isopropyl-1H-indazol-7-yl)acetamide, HCl; - Example 16: N-carbamimidoyl-2-(6-chloro-2-isopropyl-2H-indazol-7-yl)acetamide, HCl; - Example 17: N-carbamimidoyl-2-(5-chloro-3-cyano-1-methyl-1H-indazol-4-yl)acetamide, HCl; - Example 18: N-carbamimidoyl-2-(1H-indol-7-yl)acetamide, HCO2H; - Example 19: N-Carbamimidoyl-2-(1H-indol-4-yl)acetamide, HCO2H; - Example 20: N-carbamimidoyl-2-(3-chloro-1H-indol-4-yl)acetamide, HCl; - Example 21: N-carbamimidoyl-2-(5-chloro-3-cyclopropyl-1H-indazol-4-yl)acetamide, HCO2H; - Example 22: 2-(3-amino-5-chloro-1H-indazol-4-yl)-N-carbamimidoylacetamide, HCl; - Example 23: N-carbamimidoyl-2-(6-chloro-1H-indazol-7-yl)acetamide, HCl; and - Example 24: 2-(3-bromo-6-chloro-1H-indazol-7-yl)-N-carbamimidoylacetamide, HCl.

10. The compound according to any one of claims 1 to 9, for use as a drug or a medicine.

11. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 9, and a pharmaceutically acceptable excipient.

12. The pharmaceutical composition according to claim 14, for use for treating a cancer.

13. The pharmaceutical composition for use according to claim 12, wherein the cancer is selected in a group consisting of myelofibrosis, acute lymphoblastic leukemia, acute myeloblastic leukemia adrenal gland carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, glioblastoma, head and neck cancer, hepatocellular carcinoma, Hodgkin’s lymphoma, kidney cancer, lung cancer, melanoma, Merkel cell skin cancer, mesothelioma, multiple myeloma, myeloproliferative disorders, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, salivary gland cancer, sarcoma, squamous cell carcinoma, testicular cancer, thyroid cancer, urothelial carcinoma, and uveal melanoma.

14. The pharmaceutical composition for use according to claim 12 or 13, wherein the compound is administered at a dose ranging from 0.001 mg / kg body weight to 30 mg / kg body weight.

15. The pharmaceutical composition for use according to any one of claims 12 and 14, wherein said pharmaceutical composition is administered in combination with another antitumoral drug, especially chemotherapy, immunotherapy, hormonotherapy and / or radiotherapy, preferably immunotherapy.

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