SHP2 PYRAZINE-TYPE PHOSPHATASE INHIBITORS

Abstract

The invention provides novel pyrazine derivatives of formula (I): (see Formula) or a pharmaceutically acceptable tautomer, solvate, or salt thereof, wherein the substituents are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment of diseases, for example, cancer.

Description

PYRAZOLE[3,4-B]PYRAZINE-TYPE SHP2 PHOSPHATASE INHIBITORS FIELD OF THE INVENTION The invention relates to new pyrazine derivatives, to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, for example, cancer. RELATED REQUESTS This application relates to UK patent application number 1911928.8, filed on 20 August 2019, the contents of which are incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) is a ubiquitously expressed protein tyrosine phosphatase encoded by the PTPN11 gene. SHP2 contains two N-terminal tandem SH2 domains (N-SH2, C-SH2), a catalytic phosphatase (PTP) domain, and a C-terminal end with 2 tyrosine phosphorylation sites. SHP2 switches between active “open” and inactive “closed” forms due to autoinhibitory interactions between the N-SH2 domain and the PTP domain. This naturally occurring autoinhibition is released when bis-tyrosylphorrylated peptides bind to the N-SH2 domains and SHP2 adopts an “open” conformation, resulting in activation of the enzyme and exposure of the PTP domain for recognition of the substrate and catalysis. PTPN11 mutations have been linked to several human diseases, including cancer. Germline PTPN11 mutations are associated with developmental disorders, such as Noonan syndrome and Leopard syndrome, while somatic mutations occur in several types of hematological malignancies, such as JMML and more unusually in solid tumors. SHP2 is required for signaling downstream of receptor tyrosine kinases (e.g., EGFR, ALK, PDGFR) and plays a positive role in the regulation of many cellular processes, such as proliferation in response to growth factor and cytokine stimulation. Previous studies have shown that SHP2 acts upstream of Ras and is required for complete, sustained activation of the MAPK pathway. RTK deregulation often leads to a wide range of cancers, making SHP2 a valuable target in RTK-activated cancers. SHP2 is also reported to play a role in regulating immune responses by mediating immune control pathways (e.g., PD-1) as immunoreceptor tyrosine-based inhibitory motifs (ITIMs) bind to SH2 domains of SHP2 to mediate a negative signal. It has been reported that some SHP2 inhibitor compounds show an inhibitory effect on the proliferation of cancer cells in vitro and on the increase in tumor volume in a mouse xenograft model (Nature ( 2016) 535:148-152). The present invention describes a novel series of compounds which selectively inhibit SHP2 and which have anticancer activity. SUMMARY OF THE INVENTION In one aspect, the invention provides a compound of formula (I): on«i ηη / ζζηζ / Ε / γ or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen or hydroxyl; R2 and R3 are independently selected from hydrogen, halogen, 0-4 alkyl, Ci-4 haloalkyl, Ci-4 hydroxyalkyl and -CN; X is O or CR4R5; R4 and R5 are independently selected from hydrogen, halogen, hydroxyl, Ci-4 alkyl, Ci-4 alkoxy and C1-4 haloalkyl; R6 and R7 are hydrogen, C1-4 alkoxy or halogen (for example, chlorine or fluorine), or R6 and R7 join to form a ring A which is optionally substituted by one or more (for example, 1, 2, or 3) groups R10; Ring A is: (i) a nitrogen-containing five-membered heterocyclic ring (for example, an aromatic ring or a non-aromatic ring) wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O, and S, or (ii) a nitrogen-containing six-membered aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O, and S; or (iii) a nitrogen-containing six-membered non-aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S; R8 is selected from Ci-4 haloalkyl (e.g. -CF3), -CH3 and halogen (e.g. chlorine or fluorine); R9 is selected from hydrogen, C1-4 alkyl (e.g. -CH3), Ci-4 haloalkyl (e.g. -CF3) and halogen (e.g. chlorine); R10 is independently selected from halogen, cyano, cyanoC1-4alkyl (eg -CH2CN), hydroxy, =0 (oxo), C1-4alkyl (eg -CH3, -CH(CH3)2 or -CH2CH3), haloC1-4alkyl (eg -CHF2), C1-4alkoxy (eg -OCHs, -OCH2CH3 and -OCH / CHsjz), hydroxylC1-4alkyl (eg -CH2C(CH3)2OH, -CH( CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH or -CH2OH), C1-4 alkoxy C1-4 alkylene (e.g. -CH2-O-CH3 or -CH2-CH2-O-CH3), C1- alkylsulfone 4 (eg -SO2CH3), amino, monoC1-4alkylamino, diC1-4alkylamino (eg -N(CH3)2), aminoC1-4alkylene (eg CH2NH2), -Ci-4-Calkylene (=O)NH(2-q)(Ci-e)q alkyl), -Co4-NHC(=0)C1-6 alkylene, C0-4 alkylene sulfonamide (e.g. -SO2NRX2 or -CH2SO2NRX2), in where Rx is independently selected from H and O-e alkyl), 3- to 6-membered cycloalkyl, optionally substituted five- or six-membered unsaturated heterocyclic group containing 1, 2, 3, or 4 heteroatoms selected from O, N, or S, where the substituent optionally selected from C1-4 alkyl, C1-4 alkyl substituted with 3 to 6 membered cycloalkyl, Cm alkyl substituted with an optionally substituted five or six membered unsaturated heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from O , N, or S where the optional substituent is selected from C1-4 alkyl, C1-4 alkyl substituted with an optionally substituted four to six membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O, N, or S, where the optional substituent is selected from C1-4 alkyl and an optionally substituted four- to six-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4 alkyl; and q is selected from 0, 1, or 2. In further aspects of the invention, a compound of formula (I) is provided for use in the prophylaxis or treatment of a disease or condition as described herein, wherein the methods for the prophylaxis or treatment of a disease or condition as described herein comprise administering to a patient a compound of formula (I), pharmaceutical compositions comprising a compound of formula (I) and processes for the synthesis of a compound of formula (I). DEFINITIONS Unless the context indicates otherwise, references to formula (I) in all sections of this document (including uses, methods and other aspects of the invention) include references to all other subformulas, subgroups, embodiments and examples as defined in this description. “Potency” is a measure of drug activity that is expressed in terms of the amount required to produce an effect of a given intensity. A highly potent drug evokes a greater response at low concentrations. Power is proportional to affinity and effectiveness. Affinity is the ability of the drug to bind to a receptor. Efficacy is the relationship between οη«ι ηη / ζζηζ / Ε / γ receptor occupancy and the ability to initiate a response at the molecular, cellular, tissue or system level. The term “inhibitor” refers to an enzyme inhibitor which is a type of ligand or drug that blocks or dampens biological responses mediated by SHP2. Inhibitors mediate their effects by binding to the active site or allosteric sites on enzymes, or they may interact at unique binding sites that are not normally involved in the biological regulation of enzyme activity. Inhibition can arise directly or indirectly, and can be mediated by any mechanism and at any physiological level. As a result, inhibition by ligands or drugs can manifest under different circumstances in functionally different ways. The inhibitory activity may be reversible or irreversible depending on the longevity of the inhibitor-enzyme complex, which, in turn, depends on the nature of the inhibitor-enzyme binding. As used herein, the term “mediated” as used, for example, in conjunction with SHP2 as described herein (and applies, for example, to various physiological processes, diseases, states, conditions, therapies , treatments or interventions) is intended to operate in a limiting manner so that the various processes, diseases, states, conditions, treatments and interventions to which the term is applied are those in which the protein plays a biological role. In cases where the term is applied to a disease, condition, or condition, the biological role played by the protein may be direct or indirect and may be necessary and / or sufficient for the manifestation of the symptoms of the disease, condition, or condition ( or its etiology or progression). Therefore, the function of the protein (and in particular aberrant levels of function, for example, overexpression or underexpression) do not necessarily have to be the proximal cause of the disease, state or condition: instead, mediated diseases, states or conditions are contemplated to include those having multifactorial etiologies and complex progressions in which the protein in question is only partially involved. In cases where the term is applied to treatment, prophylaxis or intervention, the role played by the protein may be direct or indirect and may be necessary and / or sufficient for the operation of the treatment, prophylaxis or the outcome of the intervention. . Thus, a protein-mediated disease state or condition includes the development of resistance to any particular cancer drug or treatment. The term treatment, as used herein in the context of treating a condition, i.e., condition, disorder or disease, generally refers to treatment and therapy, whether for a human or an animal (eg, in veterinary applications), in which some desired therapeutic effect is achieved, for example, inhibition of the progress of the condition, and includes a reduction in the rate of progress, an interruption in the rate of progress, amelioration of the condition, the decrease or relief of at least one symptom associated with or caused by the condition being treated and the cure of the condition. For example, treatment may be the reduction of one or more symptoms of a disorder or the complete eradication of a disorder. οη«ι ηη / ζζηζ / Ε / γ The term "prophylaxis" (i.e., the use of a compound as a prophylactic measure), as used herein in the context of treating a condition, i.e., condition, disorder, or disease, generally refers to prophylaxis. or prevention, whether for a human or an animal (for example, in veterinary applications), in which some desired preventive effect is achieved, for example, in preventing the occurrence of a disease or protecting against a disease. Prophylaxis includes the complete and total blocking of all symptoms of a disorder for an indefinite period of time, the mere slowing down of the onset of one or more symptoms of the disease, or the reduced possibility of the disease occurring. References to the prophylaxis or treatment of a disease state or condition, such as cancer, include, within their scope, alleviating or reducing the incidence, for example, of cancer. The combinations of the invention can produce a therapeutically effective effect relative to the therapeutic effect of the individual compounds / agents when administered separately. The term “effective” includes advantageous effects such as additivity, synergy, reduction of side effects, reduction of toxicity, longer time to disease progression, longer survival time, sensitization or resensitization of one agent to another, or better index of answer. Advantageously, an effective effect may allow lower doses of each of the components to be administered to a patient, thereby decreasing the toxicity of the chemotherapy, while producing and / or maintaining the same therapeutic effect. . A "synergistic" effect, in the present context, refers to a therapeutic effect produced by the combination that is greater than the sum of the therapeutic effects of the agents in the combination when presented individually. An "additive" effect, in the present context, refers to a therapeutic effect produced by the combination that is greater than the therapeutic effect of any of the agents in the combination when presented individually. The term "response rate", as used herein, refers, in the case of a solid tumor, to the degree of reduction in tumor size at a given time point, for example 12 weeks. So, for example, a 50% response rate means a 50% reduction in tumor size. References herein to a “clinical response” refer to response rates of 50% or greater. A “partial response” is defined herein as a response rate of less than 50%. As used herein, the term “combination,” as applied to two or more compounds and / or agents, is intended to define the material in which the two or more agents are associated. The terms “combined” and “combining” in this context should be interpreted accordingly. The association of the two or more compounds / agents in a combination may be physical or non-physical. Examples of combined and physically associated compounds / agents include: • compositions (eg, unit formulations) comprising the two or more compounds / agents in the mixture (eg, within the same unit dose); οη«ι ηη / 77Π7 / Ε / γ • compositions comprising material in which the two or more compounds / agents are chemically / physicochemically linked (for example, by cross-linking, molecular agglomeration or attachment to a common carrier moiety) ; • compositions comprising material in which the two or more compounds / agents are chemically / physicochemically packaged together (for example, arranged on or within lipid vesicles, particles (for example, micro or nanoparticles) or emulsion droplets); • pharmaceutical cases, pharmaceutical packages or patient packages in which the two or more compounds / agents are packaged or presented together (for example, as part of a unit dose set); Examples of non-physically associated and combined compounds / agents include: • material (eg, a non-unitary formulation) comprising at least one of the two or more compounds / agents together with instructions for the extemporaneous association of at least one compound to form a physical association of the two or more compounds / agents; • material (eg, a non-unitary formulation) comprising at least one of the two or more compounds / agents together with instructions for combination therapy with the two or more compounds / agents; • material comprising at least one of the two or more compounds / agents together with instructions for administration to a patient population in which the other of the two or more compounds / agents have been administered (or are being administered); • material comprising at least one of the two or more compounds / agents in an amount or in a form that is specifically adapted for use in combination with the other of the two or more compounds / agents. As used herein, the term "combination therapy" is intended to define therapies which comprise the use of a combination of two or more compounds / agents (as defined above). Therefore, references to "combination therapy", "combinations" and the use of compounds / agents "in combination" in this application may refer to compounds / agents that are administered as part of the same general treatment regimen. As such, the dosage of each of the two or more compounds / agents may differ: each may be administered at the same time or at different times. It will therefore be appreciated that the compounds / agents in the combination may be administered sequentially (eg, before or after) or simultaneously, either in the same pharmaceutical formulation (i.e., together), or in different pharmaceutical formulations ( that is, separately). Simultaneously in the same formulation it is like a unitary formulation, while simultaneously in different pharmaceutical formulations it is non-unitary. The dosages of each of the two or more compounds / agents in a combination therapy may also differ with respect to the route of administration. οη«ι ηη / ζζηζ / Ε / γ As used herein, the term “pharmaceutical kit” defines a set of one or more unit doses of a pharmaceutical composition together with dosing means (e.g., measuring device) and / or delivery means (e.g., inhaler or syringe), all optionally contained within a common outer packaging. In pharmaceutical kits comprising a combination of two or more compounds / agents, the individual compounds / agents may have unitary or non-unitary formulations. Unit doses can be found contained within a blister. Optionally, the pharmaceutical kit may additionally comprise instructions for its use. As used herein, the term “pharmaceutical package” defines a set of one or more unit doses of a pharmaceutical composition, optionally contained within a common outer packaging. In pharmaceutical packages comprising a combination of two or more compounds / agents, the individual compounds / agents may have unitary or non-unitary formulations. Unit doses can be found contained within a blister. Optionally, the pharmaceutical package may further comprise instructions for use. The term “optionally substituted,” as used herein, refers to a group that may be found unsubstituted or substituted by a substituent as defined herein. The prefix “Cx-y” (where x and y are integers), as used herein, refers to the number of carbon atoms in a given group. Therefore, a C1-6 alkyl group contains 1 to 6 carbon atoms, a C3-6 cycloalkyl group contains 3 to 6 carbon atoms, a C1-4 alkoxy group contains 1 to 4 carbon atoms, and so on. successively. The term "amino", as used herein, refers to the -NH2 group. The term "halo" or "halogen" as used herein refers to fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine. Each and every hydrogen in the compound (such as in an alkyl group or where they are referred to as hydrogen) includes all isotopes of hydrogen, in particular 1H and 2H (deuterium). The term "oxo", as used herein, refers to the =O group. The term "C1-4 alkyl", as used herein as a group or part of a group, refers to a linear or branched saturated hydrocarbon group containing 1 to 4 carbon atoms, respectively. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, nbutyl, isobutyl, sec-butyl, tere-butyl and the like. The term "C2-4 alkenyl" or "C2-6 alkenyl", as used herein as a group or part of a group, refers to a linear or branched hydrocarbon group containing 2 to 4 or 2 to 6 carbon atoms, respectively, and containing a carbon-carbon double bond. Examples of such groups include C3-4 alkenyl or C3-6 alkenyl groups, such as ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, butenyl, buta-1,4-dienyl, pentenyl, and hexenyl. The term “C2-4 alkynyl” or “C2-6 alkynyl,” as used herein as a group or part of a group, refers to a linear or branched hydrocarbon group having 2 a4ode2 to 6 on« l 00177071^1^1 carbon atoms, respectively, and containing a carbon-carbon triple bond. Examples of such groups include C3-4 alkynyl or C3-6 alkynyl groups such as ethynyl and 2-propynyl (propargyl) groups. The term “C1-4 alkoxy”, as used herein as a group or part of a group, refers to a -O-C1-4 alkyl group wherein C1-4 alkyl is as defined in the present description. Examples of such groups include methoxy, ethoxy, propoxy, butoxy and the like. The term “C3-6 cycloalkyl,” as used herein, refers to a saturated monocyclic hydrocarbon ring of 3 to 6 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like. The term “C3-6 cycloalkenyl,” as used herein, refers to a partially saturated monocyclic hydrocarbon ring of 3 to 6 carbon atoms having one or more (commonly one) carbon-carbon double bonds. Examples of such groups include cyclopentenyl, cyclohexenyl, and cyclohexadienyl. The term "Cm hydroxyalkyl", as used herein as a group or part of a group, refers to a C1-4 alkyl group as defined herein wherein one or more (e.g., 1, 2 or 3) of a hydrogen atom is replaced with a hydroxyl group. The term “C1-4 hydroxyalkyl” therefore includes C1-4 monohydroxyalkyl, and also C1-4 polyhydroxyalkyl. There may be one, two, three, or more hydrogen atoms that are replaced with a hydroxyl group, so Ci-4 hydroxyalkyl may have one, two, three, or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and the like. The term “C1-4 haloalkyl”, as used herein as a group or part of a group, refers to a C1-4 alkyl group as defined herein wherein one or more (e.g. 1,2 or 3) of a hydrogen atom is replaced with a halogen. The term “Ci-4haloalkyl” therefore includes monohaloCi-4alkyl and also polyhaloCi-4alkyl. There can be one, two, three, or more hydrogen atoms that are replaced with a halogen, so Ci-4haloalkyl can have one, two, three, or more halogens. Examples of such groups include fluoroethyl, fluoromethyl, difluoromethyl, trifluoromethyl or trifluoroethyl and the like. The term "haloC1-4alkoxy", as used herein as a group or part of a group, refers to a group -O-Ci-4alkylas defined herein wherein one or more (for For example, 1, 2 or 3) of a hydrogen atom is replaced with a halogen. The term “Ci-4 haloalkoxy” therefore includes Ci-4 monohaloalkoxy and also Ci-4 polyhaloalkoxy. There can be one, two, three or more hydrogen atoms that are replaced with a halogen, so Ci-4haloalkoxy can have one, two, three or more halogens. Examples of such groups include fluoroethyloxy, difluoromethoxy or trifluoromethoxy and the like. The term "heterocyclyl group" as used herein should include, unless the context indicates otherwise, both aromatic and non-aromatic ring systems. Therefore, for example, the term "heterocyclyl group" includes within its scope aromatic, non-aromatic, unsaturated, partially saturated and saturated heterocyclyl ring systems. In general, unless the οη«ι ηη / ζζηζ / Ε / γ context indicates otherwise, such groups may be monocyclic or bicyclic (including fused, spiro, and bridged bicyclic groups) and may contain, for example, of 3 to 12 ring members, most commonly 5 to 10 ring members. Reference to 4 to 7 ring members includes 4, 5, 6, or 7 ring atoms and reference to 4 to 6 ring members includes 4, 5, or 6 ring atoms. Examples of monocyclic groups are groups containing 3, 4, 5, 6, 7 and 8 ring members, more commonly 3 to 7, or 4 to 7 and preferably 5, 6 or 7 ring members, more preferably 5 or 6 members of the ring. Examples of bicyclic groups are those containing 8, 9, 10, 11, and 12 ring members, and more commonly 9 or 10 ring members. Heterocyclyl groups may be heteroaryl groups having 5 to 12 ring members, most commonly 5 to 10 ring members. Where reference is made herein to a heterocyclyl group, the heterocyclyl ring can be, unless the context otherwise indicates, optionally substituted, i.e., unsubstituted or substituted, by one or more (for example, 1, 2, 3 or 4, in particular one or two) substituents as defined in the present description. The heterocyclyl group can be, for example, a five- or six-membered monocyclic ring or a bicyclic structure that is formed from five- and six-membered fused rings or two six-membered fused rings, or two five-membered fused rings. Each ring may contain up to five particularly selected nitrogen, sulfur, and oxygen heteroatoms and oxidized forms of nitrogen or sulfur. In particular, the heterocyclyl ring will contain up to 4 heteroatoms, more particularly up to 3 heteroatoms, more commonly up to 2, for example a single heteroatom. In one embodiment, the heterocyclyl ring will contain one or two heteroatoms selected from N, O, S, and oxidized forms of N or S. In one embodiment, the heterocyclyl ring contains at least one ring nitrogen atom. Nitrogen atoms in heterocyclyl rings may be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heterocyclyl group, including any ring amino group substituents, will be less than five. Heterocyclyl groups can be attached via a carbon atom or a heteroatom (e.g., nitrogen). Likewise, heterocyclyl groups can be found substituted on a carbon atom or on a heteroatom (for example, nitrogen). Examples of five-membered aromatic heterocyclyl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups. Examples of six-membered aromatic heterocyclic groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl. The term "heteroaryl" is used herein to denote a heterocyclyl group having aromatic character. The term "heteroaryl" encompasses polycyclic (eg, bicyclic) ring systems in which one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the group can be found attached by the aromatic ring or by a non-aromatic ring. οη«ι ηη / 77Π7 / Ε / γ Examples of heteroaryl groups are monocyclic and bicyclic groups containing five to twelve ring members, and more commonly five to ten ring members. Examples of five-membered heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole and tetrazole groups. Examples of six-membered heteroaryl groups include, but are not limited to, pyridine, pyrazine, pyridazine, pyrimidine and triazine. A bicyclic heteroaryl group may be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ring containing 0, 1, 2, or 3 ring heteroatoms; c) a pyrimidine ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; d) a pyrrole ring fused to a 5- or 6-membered ring containing 0, 1, 2 or 3 ring heteroatoms; e) a pyrazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms; f) an imidazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 heteroatoms in the ring; g) an oxazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms; h) an isoxazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms; i) a thiazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 heteroatoms in the ring; j) an isothiazole ring fused to a 5- or 6-membered ring containing 0, 1, or 2 ring heteroatoms; k) a thiophene ring fused to a 5- or 6-membered ring containing 0, 1, 2, or 3 heteroatoms in the ring; I) a furan ring fused to a 5- or 6-membered ring containing 0, 1, 2, or 3 ring heteroatoms; m) a cyclohexyl ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; and n) a cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms. οη«ι ηη / 77Π7 / Ε / γ Particular examples of bicyclic heteroaryl groups containing a five-membered ring fused to another five-membered ring include, but are not limited to, imidazothiazole (e.g., imidazo[2,1-b]thiazole) and imidazoimidazole (e.g., imidazo[1,2-a]imidazole). Particular examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, bencisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g., pyrazolo[1,5-a]pyrimidine), triazolopyrimidine (e.g., [1,2,4]triazolo[ 1,5-a]pyrimidine), benzodioxole, imidazopyridine and pyrazolopyridine (for example, pyrazolo[1,5a]pyridine). Particular examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinoline, isoquinoline, chromane, thiochromane, isochromane, chromene, isochromene, benzodioxane, quinolizine, benzoxazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine, and pteridine. Examples of polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran, 2,3-dihydro-benzo[1,4]dioxin, benzo[1,3]dioxol, 4, 5,6,7-tetrahydrobenzofuran, tetrahydrotriazolopyrazine (e.g., 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine), chromane, thiochromane, isochromane, chromene, isochromene , benzodioxane, benzoxazine, benzodiazepine and indoline. A nitrogen-containing heteroaryl ring must contain at least one ring nitrogen atom. The nitrogen-containing heteroaryl ring may be found N-bonded or C-bonded. Each ring may further contain up to about four other heteroatoms particularly selected from nitrogen, sulfur and oxygen. In particular, the heteroaryl ring will contain up to 3 heteroatoms, for example 1, 2 or 3, more commonly up to 2 nitrogens, for example a single nitrogen. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, which includes any substituents on the ring amino group, will be less than five. Examples of nitrogen-containing heteroaryl groups include, but are not limited to, monocyclic groups such as pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl (e.g. 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl and bicyclic groups such as quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazolyl and benzisothiazole, indolyl, 3H-indolyl, isoindolyl , indolizinyl, isoindolinyl, purinyl (e.g., adenine [6-aminopurine], guanine [2-amino-6hydroxypurine]), indazolyl, quinolizinyl, benzoxazinyl, benzodiazepinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthypyridinyl and pteridinyl . οη«ι ηη / 77Π7 / Ε / γ Examples of nitrogen-containing polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydroisoquinolinyl, tetrahydroquinolinyl, and indolinyl groups. The term "non-aromatic" encompasses, unless the context indicates otherwise, unsaturated ring systems without aromatic character, partially saturated and saturated heterocyclyl ring systems. The terms “unsaturated” and “partially saturated” refer to rings where the ring structure(s) contains atoms that share more than one valence bond, that is, the ring contains at least one bond. multiple, for example, a C=C, C=C or N=C bond. The term “saturated” refers to rings where there are no multiple bonds between the ring atoms. Saturated heterocyclyl groups include piperidinyl, morpholinyl, and thiomorpholinyl. Partially saturated heterocyclyl groups include pyrazolinyl, for example pyrazolin-2-yl and pyrazolin-3-yl. Examples of non-aromatic heterocyclyl groups are groups having 3 to 12 ring members, most commonly 5 to 10 ring members. Such groups may be monocyclic or bicyclic, for example having 3 to 7 ring members, in particular 4 to 6 ring members. Such groups have, in particular, 1 to 5 or 1 to 4 ring member heteroatoms (most commonly 1,2 or 3 ring member heteroatoms), generally selected from nitrogen, oxygen and sulfur and oxidized forms thereof. Heterocyclyl groups may contain, for example, cyclic ether moieties (e.g. as in tetrahydrofuran and dioxane), cyclic thioether moieties (e.g. as in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g. as in pyrrolidine ), cyclic amide residues (e.g., as in pyrrolidone), cyclic thioamides, cyclic thioesters, cyclic ureas (e.g., as in imidazolidin-2-one), cyclic ester residues (e.g., as in butyrolactone), sulfones cyclic (for example, as in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides and combinations thereof (for example, thiomorpholine). Particular examples include morpholinyl, piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), piperidinonyl, pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2 -yl and pyrrolidin-3-yl), pyrrolidonyl, azetidinyl, pyranyl (2H-pyran or 4H-pyran), dihydrothienyl, dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, tetrahydrofuranyl, tetrahydrothienyl, dioxanyl, oxanyl (also known as tetrahydropyranyl) (e.g. oxan-4-yl), imidazolinyl, imidazolidinonyl, oxazolinyl, thiazolinyl, pyrazolin-2-yl, pyrazolidinyl, piperazinonyl, piperazinyl and N-alkylpiperazines such as N-methylpiperazinyl. In general, typical non-aromatic heterocyclyl groups include saturated groups such as piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl and N-alkylpiperazines such as Nmethylpiperazinyl. In a non-aromatic nitrogen-containing heterocyclyl ring, the ring must contain at least one ring nitrogen atom. The nitrogen-containing heterocyclyl ring can be found N-linked or C-linked. Heterocyclic groups can contain, for example, cyclic amine moieties (e.g. in pyrrolidinyl), cyclic amides (such as a pyrrolidinonyl, piperidinonyl or caprolactamyl) , cyclic sulfonamides (such as an isothiazolidinyl 1,1-dioxide, [1,2]thiazinanyl 1,1-dioxide or [1,2]thiazepanyl 1,1-dioxide) and combinations thereof. οη«ι ηη / 77Π7 / Ε / γ Particular examples of non-aromatic nitrogen-containing heterocyclyl groups include aziridinyl, morpholinyl, thiomorpholinyl, piperidinyl (for example, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl), pyrrolidinyl; (e.g. pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl), pyrrolidonyl, dihydrotothiazolyl, imidazolinyl, imidazolidinonyl, oxazolinyl, thiazolinyl, 6H-1,2,5-thiadiazinyl, pyrazolin-2yl, pyrazolin -3-yl, pyrazolidinyl, piperazinyl, and N-alkylpiperazines such as N-methylpiperazinyl. Heterocyclyl groups may be polycyclic fused ring systems or bridged ring systems such as the oxa- and aza-analogs of bicycloalkanes, tricycloalkanes (eg, adamantane and oxa-adamantane). For an explanation of the distinction between fused and bridged ring systems, see Advanced Organic Chemistry, by Jerry March, 4th edition, Wiley Interscience, pages 131-133, 1992. Where, in a definition of a cyclic group or ring, it is indicated that the cyclic group contains a certain number of ring members heteroatoms, for example, as in the expression "a 5- or 6-membered ring containing 0, 1, or 2 "nitrogen ring members", this should be understood to mean that, apart from the certain number of ring members heteroatoms that are specified, the remaining ring members are carbon atoms. The compound of formula (I) may contain saturated cyclic groups that can be attached to the rest of the molecule through one or more bonds. When the cyclic group is attached to the rest of the molecule by two or more bonds, these bonds (or two of these bonds) can form on the same atom (usually a carbon atom) of the ring or different atoms of the ring. When bonds form on the same ring atom, this results in a cyclic group with a single atom (commonly a quaternary carbon) attached to two groups. In other words, when the compound of formula (I) includes a cyclic group, that group may be found attached to the rest of the molecule by a bond or the cyclic group and the rest of the molecule may have an atom in common, e.g. , a spiro compound. The heterocyclyl group can each be unsubstituted or substituted by one or more (for example, 1, 2 or 3) substituent groups. For example, heterocyclyl or carbocyclyl groups may be unsubstituted or substituted by 1,2, 3 or 4 substituents and, in particular, are unsubstituted or have 1, 2 or 3 substituents as defined herein. Where the cyclic group is saturated, there may be 2 substituents attached to the same carbon (where the substituents are the same which are called geminal disubstitution or “gem”). A combination of substituents is permitted only if such combination results in a stable or chemically feasible compound (i.e., one that is not substantially altered when held at 40°C or lower for at least one week). The various functional groups and substituents that form the compounds of the invention are particularly chosen so that the molecular weight of the compound of the invention does not exceed 1000. More commonly, the molecular weight of the compound will be less than 750, for example, less than 700, or less than 650, or less than 600, or less than 550. More particularly, the molecular weight is less than 525 and, for example, is 500 or less. οη«ι ηη / 77Π7 / Ε / γ DETAILED DESCRIPTION OF THE INVENTION The invention provides a compound of formula (I): οη«ι ηη / ζζηζ / Ε / γ or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein X, R1, R2, R3, R6, R7, R8 and R9 are as defined herein. x X is O or CR4R5. When In one embodiment, R4 and R5 are independently selected from hydrogen, halogen, Ci4 alkyl and Ci-4 haloalkyl (e.g., Ci haloalkyl). In one embodiment, X is O and the compound of formula (I) is a compound of formula (la): In one embodiment, X is CR4R5 and the compound of formula (I) is a compound of formula (Ib): where R1, R2, R3, R4, R5, R6, R7, R8, and R9 are as defined in the present description. In particular, X is O and the compound of formula (I) is a compound of formula (la). In one embodiment, select from fluorine, chlorine, bromine or iodine). In one embodiment, X is CR4R5 and R4 and R5 are independently selected from hydrogen, fluorine, and trifluoromethyl. In one embodiment, X is CR4R5 and R4 and R5 are hydrogen. In one embodiment, X is CR4R5 and R4 and R5 are halogens (e.g., fluorine). In one embodiment, chlorine, bromine or iodine). In one embodiment, X is CR4R5 and R4 is hydrogen and R5 is fluorine or trifluoromethyl. In one embodiment, X is CR4R5 and R4 is hydrogen and R5 is fluorine. In one embodiment, X is CR4R5 and R4 is hydrogen and R5 is trifluoromethyl. In one embodiment, chlorine, bromine or iodine), and the compound of formula (Ib) is a compound of formula (Ibj: οη«ι ηη / 77Π7 / Ε / γ (Ibj. where R1, R2, R3, R5, R6, R7, R8, and R9 are as defined in the present description. In one embodiment of the compound of formula (Ibj, R5 is fluorine or trifluoromethyl, in particular fluorine. In one embodiment, chlorine, bromine or iodine), and the compound of formula (Ib) is a compound of formula (Ib'j: on«i ηη / ζζηζ / Ε / γ (Ib”). where R1, R2, R3, R5, R6, R7, R8, and R9 are as defined in the present description. In one embodiment of the compound of formula (Ib”), R5 is fluorine or trifluoromethyl, in particular trifluoromethyl. R1 R1 is hydrogen or hydroxyl. In one embodiment, R1 is hydrogen, and the compound of formula (I) is a compound of formula (II): where X, R2, R3, R6, R7, R8, and R9 are as defined in the present description. In one embodiment, R1 is hydroxyl, and the compound of formula (I) is a compound of formula (III): where X, R2, R3, R6, R7, R8, and R9 are as defined in the present description. In particular, R1 is hydroxyl, and the compound of formula (I) is a compound of formula (III). In particular, R1 is hydroxyl and X is O, and the compound of formula (III) is a compound of formula (III'): οη«ι ηη / ζζηζ / Ε / γ where R2, R3, R6, R7, R8 and R9 are as defined in the present description. R2and R3 R2 and R3 are independently selected from hydrogen, halogen, Ci-4 alkyl, C1-4 haloalkyl, Ci-4 hydroxyalkyl and -CN. In one embodiment, R2 and R3 are independently selected from hydrogen, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 hydroxyalkyl and -CN. In one embodiment, R2 and R3 are hydrogen. In one embodiment, R2 is hydrogen and R3 is selected from Cm alkyl, Ci-4 haloalkyl, Ci-4 hydroxyalkyl and -CN. In one embodiment, R2 is hydrogen and R3 is selected from Ci-4 alkyl, C 1-4 haloalkyl, and Ci-4 hydroxyalkyl. In one embodiment, R2 is hydrogen and R3 is Ci-4 alkyl, for example, -CH3. In one embodiment, R2 is hydrogen and R3 is halogen, for example, -F. In one embodiment, R2 is halogen, for example, -F and R3 is hydrogen. In one embodiment, R2 and R3 are halogen, for example, -F. In one embodiment, R2 is hydrogen and R3 is selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl and -CN, and the compound of formula (I) is a compound of formula (IV): where X, R1, R3, R6, R7, R8, and R9 are as defined in the present description. In one embodiment, the compound of formula (IV) is a compound of formula (IVj: on«l 0017707IRIM (IV') where X, R1, R3, R6, R7, R8, and R9 are as defined in the present description. In one embodiment, the compound of formula (IV) is a compound of formula (IV"): (IV”) where X, R1, R3, R6, R7, R8, and R9 are as defined in this description. In one embodiment of the compound of formulas (IV), (IV) and (IV”), R3 is selected from Ci-4 alkyl, Ci-4 haloalkyl, and Ci-4 hydroxyalkyl. In one embodiment of the compound of formulas (IV), (IV') and (IV"), R3 is selected from C1-4 alkyl, for example, -CH 3. In particular, the compound of formula (IV) is a compound of formula (IV”), R3 is selected from C1-4 alkyl, for example, -CH3. In one embodiment of the compound of formulas (IV), (IV') and (IV"), R3 is selected from C1-4 alkyl, for example, -CH 3 and X is O. In particular, the compound of formula (IV) is a compound of formula (IV"), R3 is selected from C1-4 alkyl, for example, -CH3 and X is O. R8 R8 is selected from C1-4 haloalkyl (e.g. -CF3), -CH3 and halogen (e.g. chlorine or fluorine). In one embodiment, R8 is selected from C1-4 alkyl (e.g., -CH3), C1-4 haloalkyl (e.g., -CF3) and chloro. In one embodiment, R8 is selected from -CH3, chlorine and fluorine. In one embodiment, R8 is halogen, (for example, fluorine, chlorine, bromine or iodine, for example, fluorine or chlorine), and the compound of formula (I) is a compound of formula (V) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: οη«ι ηη / 77Π7 / Ε / γ where X, R1, R2, R3, R6, R7 and R9 are as defined in the present description, where R8 is halogen, in particular where R8 is chlorine. In one embodiment, R8 is selected from methyl, chlorine and fluorine. In one embodiment, R8 is selected from chlorine and fluorine. In one embodiment, R8 is methyl. In particular, R8 is fluorine. In particular, R8 is chlorine. In one embodiment of the compound of formula (V), X is CR4R5. In particular, in one embodiment of the compound of formula (V), X is O. In one embodiment of the compound of formula (V), R1 is hydrogen. In particular, in one embodiment of the compound of formula (V), R1 is hydroxyl. In particular, in one embodiment of the compound of formula (V), X is O and R1 is hydroxyl. R9 R9 is selected from hydrogen, C1-4 alkyl (e.g. -CH3), Ci-4 haloalkyl (e.g. -CF3) and halogen (e.g. chlorine). In one embodiment, R9 is selected from hydrogen, -CH3, -CF3, chlorine and fluorine. In one embodiment, R9 is selected from hydrogen, -CH3, -CFs, and chlorine. In particular, R9 is hydrogen and the compound of formula (I) is a compound of formula (VI) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (VI) where X, R1, R2, R3, R6, R7 and R8 are as defined in the present description. In one embodiment of the compound of formula (VI), X is CR4R5. In particular, in one embodiment of the compound of formula (VI), X is O. In one embodiment of the compound of formula (VI), R1 is hydrogen. In particular, in one embodiment of the compound of formula (VI), R1 is hydroxyl. In particular, in one embodiment of the compound of formula (VI), R8 is halogen, for example, chlorine. In particular, in one embodiment of the compound of formula (VI), X is O, R1 is hydroxyl, and R8 is chloro. R6yR7 R6 and R7 are hydrogen, C1-4 alkoxy or halogen (for example, chlorine or fluorine), or R6 and R7 join to form a ring A which is optionally substituted by one or more (for example, 1, 2, or 3) groups R10. In one embodiment, R6 and R7 are hydrogen or halogen (e.g., chlorine or fluorine), or R6 and R7 join to form a ring A which is optionally substituted by one or more (e.g., 1,2, or 3) R10 groups. ; Ring A is: (i) a nitrogen-containing five-membered heterocyclic ring (e.g., an aromatic ring or a non-aromatic ring) wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S, or (i) a nitrogen-containing six-membered aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or (i¡) a nitrogen-containing six-membered non-aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S; and R10 is independently selected from halogen, cyano, C1-4 cyanoalkyl (e.g. -CH2CN), hydroxyl, =0 (oxo), C1-4 alkyl (e.g. -CH3, -CH(CH3)2 or -CH2CH3), Ci-4 haloalkyl(e.g. -CHF2), C1-4 alkoxy (e.g. -OCH3, -OCH2CH3 and -OCH(CH3)2), Ci-4 hydroxylalkyl(e.g. -CH2C(CH3)2OH, - CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH or -CH2OH), alkoxy Ci-4alkylene Ci-4(e.g. -CH2-O-CH3o -CH2-CH2-O-CH3), alkylsulfone Ci- 4(e.g. -SO2CH3), amino, Ci-4 monoalkylamino, Cu dialkylamino (e.g. -N(CH3)2), Ci-4 aminoalkylene(e.g. CH2NH2), -Ci-4-alkylene(= O)NH(2-q)(Ci-6alkyl)q), -Co-4-alkylene-NHC(=0)C1-6alkyl, Co-4alkylenesulfonamide (e.g. -SO2NRX2 or -CH2SO2NRX2), wherein Rx is independently selected from H and Ci-β alkyl), 3- to 6-membered cycloalkyl, optionally substituted five- or six-membered unsaturated heterocyclic group containing 1, 2, 3, or 4 heteroatoms selected from O, N, or S, wherein the optional substituent is selected from Ci-4 alkyl, Ci-4 alkyl substituted with 3 to 6 membered cycloalkyl, Ci-4 alkyl substituted with an optionally substituted five or six membered unsaturated heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from O, N, or S where the optional substituent is selected from Ci-4 alkyl, substituted Ci-4 alkyl with an optionally substituted four- to six-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O, N, or S , where the optional substituent is selected from Ci-4 alkyl and an optionally substituted four- to six-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O, N, or S where the optional substituent is selected from Ci-4 alkyl; and q is selected from 0, 1 or 2. In one embodiment, R6 and R7 are hydrogen, Ci-4 alkoxy or fluorine, or R6 and R7 join to form a ring A which is optionally substituted by one or more (e.g., 1,2, or 3) R10 groups. In one embodiment, R6 and R7 are hydrogen or fluorine, or R6 and R7 join together to form a ring A which is optionally substituted by one or more (for example, 1,2 or 3) R10 groups; Ring A is: (i) a nitrogen-containing five-membered heterocyclic ring (for example, an aromatic ring or a non-aromatic ring) wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O, and S, or (ii) a nitrogen-containing six-membered aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O, and S; or (i¡) a nitrogen-containing six-membered non-aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S; and R10 is independently selected from halogen, cyano, Ci-4 cyanoalkyl (e.g. -CH2CN), hydroxyl, =0 (oxo), Ci-4 alkyl (e.g. -CH3, -CH(CH3)2 or -CH2CH3), Ci-4 haloalkyl (e.g. -CHF2), Ci-4 alkoxy (e.g. -OCHs, -OCH2CH3 and -OCH(CH3)2), Ci-4 hydroxyalkyl (e.g. -CH2C(CH3)2OH, - CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH or -CH2OH), Ci-4 alkoxy Ci-4 alkylene (e.g. -CH2-O-CH3 or -CH2-CH2-O-CH3), alkylsulfone Ci-4 (e.g. -SO2CH3), amino, monoalkylamino Ci-4, dialkylamino Cm (e.g. -N(CH3)2), aminoalkylene Ci-4 (e.g. CH2NH2), -alkylene Ci-4-C (=O)NH(2-q)(Ci-e)q alkyl), -Co-4-alkylene-NHC(=0)C1-6 alkylene, Co-4 alkylene sulfonamide (e.g. -SO2NRX2 or - CH2SO2NRX2), where Rx is selected independently of οη«ι ηη / 77Π7 / Ε / γ H and Ci-β alkyl), 3- to 6-membered cycloalkyl, optionally substituted five- or six-membered unsaturated heterocyclic group containing 1, 2, 3, or 4 heteroatoms selected from O, N, or S, where the optional substituent is selected Ci-4 alkyl, Ci-4 alkyl substituted with 3 to 6 membered cycloalkyl, Cu alkyl substituted with an optionally substituted five or six membered unsaturated heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from O, N, or S where the optional substituent is selected from Ci-4 alkyl, C1-4 alkyl substituted with an optionally substituted four- to six-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O, N, or S, where the optional substituent is selected from C1-4 alkyl and an optionally substituted four- to six-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4 alkyl; and q is selected from 0, 1, or 2. In one embodiment, R6 and R7 are hydrogen or halogen (for example, chlorine or fluorine). In one embodiment, R6 and R7 are hydrogen, C1-4O alkoxy fluorine. In one embodiment, R6 and R7 are hydrogen or Cm alkoxy. In one embodiment, R6 and R7 are hydrogen. In particular, R7 is hydrogen and R6 is halogen (for example, chlorine or fluorine), and the compound of formula (I) is a compound of formula (Vil) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: οη«ι ηη / ζζηζ / Ε / γ R9 In particular, in one embodiment of the compound of formula (Vil), R8 is fluorine. In particular, in one embodiment of the compound of formula (Vil), R8 is chlorine. In one embodiment of the compound of formula (Vil), X is CR4R5. In particular, in one embodiment of the compound of formula (Vil), X is O. In one embodiment of the compound of formula (Vil), R 1 is hydrogen. In particular, in one embodiment of the compound of formula (Vil), R 1 is hydroxyl. In particular, in one embodiment of the compound of formula (Vil), R8 is halogen, for example chlorine or fluorine. In particular, in one embodiment of the compound of formula (Vil), R 9 is hydrogen. In particular, in one embodiment of the compound of formula (Vil), X is O, R1 is hydroxyl, R9 is hydrogen and R8 is chlorine or fluorine. In one embodiment, R6 and R7 join together to form a ring A which is optionally substituted by one or more (for example, 1,2 or 3) R10 groups; where ring A is: (i) a nitrogen-containing five-membered heterocyclic ring (for example, an aromatic ring or a non-aromatic ring) wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O, and S, or (ii) a nitrogen-containing six-membered aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O, and S; or (i¡) a nitrogen-containing six-membered non-aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from NyS. In one embodiment, ring A is a nitrogen-containing five-membered heterocyclic ring (e.g., an aromatic ring or a non-aromatic ring), or a nitrogen-containing six-membered aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S. In one embodiment, ring A is pyrazolyl, thiazolyl, pyrazinyl, and pyridyl. So this, with the fused benzo moiety forms indazolyl, benzothiazolyl, quinoxalinyl or quinolinyl, respectively. In one embodiment, ring A is a nitrogen-containing five-membered heterocyclic ring (e.g., an aromatic ring or a non-aromatic ring), wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S. . In one embodiment, ring A is a nitrogen-containing five-membered heterocyclic ring (e.g., an aromatic ring or a non-aromatic ring), or a nitrogen-containing six-membered aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S. In one embodiment, ring A is a nitrogen-containing five-membered heterocyclic ring wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S. In one embodiment, ring A is a nitrogen-containing five-membered heterocyclic ring wherein the heterocyclic ring optionally contains an additional heteroatom selected from N, O and S. In one embodiment, ring A is a nitrogen-containing five-membered heterocyclic ring wherein the heterocyclic ring optionally contains an additional heteroatom which is N or S. In one embodiment, ring A is a nitrogen-containing five-membered aromatic heterocyclic ring wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S. In one embodiment, ring A is a five-membered nitrogen-containing heterocyclic ring wherein the heterocyclic ring contains an additional heteroatom which is N. on«l 00177071^1^1 In one embodiment, ring A is a five-membered heterocyclic ring containing aromatic nitrogen wherein the heterocyclic ring contains an additional heteroatom which is N. In one embodiment, ring A is a five-membered nitrogen-containing heterocyclic ring wherein the heterocyclic ring contains an additional heteroatom which is S. In one embodiment, ring A is a nitrogen-containing five-membered aromatic heterocyclic ring wherein the heterocyclic ring contains an additional heteroatom which is S. In one embodiment, ring A is pyrroliium, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl and triazolyl, for example, where ring A is thiazolyl or pyrazolyl. In one embodiment, ring A is a nitrogen-containing five-membered heterocyclic ring (e.g., an aromatic ring or a non-aromatic ring), wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S. , and the compound of formula (I) is a compound of formula (VIII) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: οη«ι ηη / 77Π7 / Ε / γ wherein wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S. In one modality, the rest is selected from the following options in Table I, where c is 0, 1.2 or 3: Table I ΜΛ / a / zuzz / uu ι»υο For example, the remainder on«i ηη / ζζηζ / Ε / γ οη«ι ηη / 77Π7 / Ε / γ is selected from options A, B, C, D, E, F, G, Η, I, O, P and Q in Table I. In particular, the rest is selected from options C, D, E, F, G, Η, I, O, P and Q in Table I. In particular, the rest is selected from the options D, Η, P and Q in Table I. In one embodiment, the remainder is selected from D and H. In particular, the rest is selected from: where c is 0, 1,2 or 3, for example οη«ι ηη / 77Π7 / Ε / γ In one embodiment, the compound of formula (VIII) is a compound of formula (Villa) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: wherein X, R1, R2, R3, R8, R9 and R10 are as defined herein, for example, where R10 is Ci-4 alkyl. In particular, the compound of formula (Villa) is a compound of formula (Vlllb) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: οη«ι ηη / ζζηζ / Ε / γ (Vlllb) where X, R1, R2, R3, R8 and R9 are as defined in the present description. In particular, the compound of formula (Villa) is a compound of formula (Vlllc) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (Vlllc) where X, R1, R2, R3, R8 and R9 are as defined in the present description. In particular, the compound of formula (VIII) is a compound of formula (IX) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (IX) where X, R1, R2, R3, R8, R9 and R10 are as defined in the present description. In particular, the compound of formula (VIII) is a compound of formula (IXa) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: οη«ι ηη / 77Π7 / Ε / γ wherein X, R1, R2, R3, R8, and R9 are as defined herein, and R10 is independently selected from Ci-4 alkyl (eg, -CH3) and halogen (eg, -CH3). example, chlorine). In particular, R10 is independently selected from C1-4alkyl (eg -CHs), when on the nitrogen or carbon atom, and halogen (eg, chlorine), when on the carbon atom. In particular, the compound of formula (VIII) is a compound of formula (IXb) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (IXb) where X, R1, R2 and R3 are as defined in this description. In particular, the compound of formula (VIII) is a compound of formula (X) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: on«i ηη / ζζηζ / Ε / γ where X, R1, R2, R8, R9 and R10 are as defined in the present description. In particular, in one embodiment of the compound of formula (VIII), (Villa), (VilIb), (VIHe), (IX), (IXa) and (X), R8 is halogen, for example chlorine or fluorine. In particular, in one embodiment of the compound of formula (VIII), (Villa), (Vlllb), (Ville), (IX), (IXa) and (X), R8 is fluorine. In particular, in one embodiment of the compound of formula (VIII), (Villa), (Vlllb), (Ville), (IX), (IXa) and (X), R8 is chlorine. In one embodiment of the compound of formula (VIII), (Villa), (Vlllb), (Vlllc), (IX), (IXa) and (X), X is CR4R5. In particular, in one embodiment of the compound of formula (VIII), (Villa), (Vlllb), (Vlllc), (IX), (IXa) and (X),XesO. In one embodiment of the compound of formula (VIII), (Villa), (Vlllb), (Vlllc), (IX), (IXa) and (X), R1 is hydrogen. In particular, in one embodiment of the compound of formula (VIII), (Villa), (Vlllb), (Vlllc), (IX), (IXa) and (X), R1 is hydroxyl. In particular, in one embodiment of the compound of formula (VIII), (Villa), (Vlllb), (Vlllc), (IX), (IXa) and (X), R9 is hydrogen. In particular, in one embodiment of the compound of formula (VIII), (Villa), (Vlllb), (Vlllc), (IX), (IXa) and (X), X is O, R1 is hydroxyl, R9 is hydrogen and R8 is chloro or fluoride. In one embodiment, ring A is: (i) a nitrogen-containing six-membered aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or (i) a nitrogen-containing six-membered non-aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S. In one embodiment, ring A is a nitrogen-containing six-membered aromatic heterocyclic ring, and the compound of formula (I) is a compound of formula (XI) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: οη«ι ηη / ζζηζ / Ε / γ where X, R1, R2, R3, R8, R9 and R10 are as defined herein, and 6-Het is: (i) a nitrogen-containing six-membered aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or (ii) a nitrogen-containing six-membered non-aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S. When ring A is a six-membered ring containing nitrogen, if the ring is aromatic, then the ring may optionally contain one or two additional heteroatoms selected from N, O and S. However, if the six-membered ring containing Nitrogen is not aromatic, so the ring may optionally contain one or two additional heteroatoms selected from N and S, that is, the ring may not include an additional heteroatom which is O. In one embodiment, 6-Het is a six-membered nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S. In particular, 6-Het is a six-membered nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N. In particular, 6-Het is a six-membered nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains an additional heteroatom selected from N. In particular, 6-Het is a six-membered nitrogen-containing heterocyclic ring, wherein the heterocyclic ring contains an additional heteroatom which is N. In one embodiment, the remainder is selected from the following options in Table II, where c is 0, 1.2 or 3: b C. d F Table II ΟΠΕΙ nn / 77A7 / E / Y is selected from options D, E, G and H in Table II, more particularly is selected from D, E and H, for example D. In particular, the rest is selected from: where c is 0, 1,2 or 3. In particular, the rest is: where c is 0, 1,2 or 3. In particular, the rest on«l 0017707IRIM is selected from options E and G in Table II, in particular option G. In particular, the rest where c is 0, 1,2 or 3. In particular the rest οη«ι ηη / ζζηζ / Ε / γ where c is 0, 1,2 or 3. In one embodiment, the compound of formula (I) is a compound of formula (XII) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XII) where X, R1, R2, R3, R8, R9 and R10 are as defined in the present description. In one embodiment, the compound of formula (XII) is a compound of formula (Xlla) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (Xlla) where X, R1, R2, R3, R8 and R9 are as defined in the present description. In one embodiment, the compound of formula (XII) is a compound of formula (Xllb) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: οη«ι ηη / 77Π7 / Ε / γ (XI Ib) where X, R1, R2, R3, R8, R9 and R10 are as defined in the present description. In one embodiment, the compound of formula (XII) is a compound of formula (Xllc) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (Xllc) where X, R1, R2, R3, R8, R9 and R10 are as defined in the present description. In one embodiment of the compound of formula (Xllc), R10 is halogen, cyano, C1-4 alkyl (eg -CH3, -CH(CH3)2, or -CH2-CH3), C1-4 haloalkyl (eg -CHF2 ), C1-4 alkoxy (e.g., OCH3, -OCH2CH3 and -OCH(CH3)2), C1-4 hydroxylalkyl (e.g., -CH2C(CH3)2OH, -ΟΗ(ΟΗ3)ΟΗ2ΟΗ, ​​CH(CH3)OH , -CH2CH2OH or -CH2OH), amino, monoC1-4alkylamino, diC1-4alkylamino (eg, -N(CHs)2), aminoC1-4alkylene (eg, -CH2NH2), and a saturated heterocyclic group of four a six membered optionally substituted containing 1 or 2 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4alkyl. In one embodiment of the compound of formula (Xllc), R10 is dialkylaminoCi-4(for example N(CH3)2), alkoxyC1-4 (for example -OCH3, -OCH2CH3 and -OCH(CH3)2), haloalkylCi- 4(eg, -CF3) and optionally substituted four to six membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4alkyl. In one embodiment, ring A includes a nitrogen atom adjacent to (i.e., directly attached to) the benzene ring and the compound of formula (I) is a compound of formula (Xllla) or (XIIIb) or a tautomer or a solvate or a pharmaceutical salt thereof, that is: (Xllla) or οη«ι ηη / ζζηζ / Ε / γ (Xlllb) where X, Q, R1, R2, R3, RB, R9 and R10 are as defined in the present description. R10 is independently selected from halogen, cyano, C1-4 cyanoalkyl (eg -CH2CN), hydroxy, =0 (oxo), C1-4alkyl (eg -CH3, -CH(CH3)2 or -CH2CH3), C1-4 haloalkyl (e.g. -CHF2), C1-4 alkoxy (e.g. -OCH3, -OCH2CH3 and -OCH(CH3)2), C1-4 hydroxylalkyl (e.g. -CH2C(CH3)2OH, - CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH or -CH2OH), C1-4 alkoxy C1-4 alkylene (e.g. -CH2-O-CH3 or -CH2-CH2-O-CH3), alkylsulfone C1-4 (e.g. -SO2CH3), amino, C1-4 monoalkylamino, C1-4 dialkylamino (e.g. -N(CH3)2), C1-4 aminoalkylene (e.g. CH2NH2), -Ci-4 alkylene -C(=O)NH(2-q)(Ci-e)q alkylene, -Ci-4 alkylene-NHC(=O)C1-6 alkylene, C0-4 alkylene sulfonamide (e.g. -SChNRv or - CFESCENRv), wherein Rx is independently selected from H and Ci-s alkyl), 3- to 6-membered cycloalkyl, optionally substituted five- or six-membered unsaturated heterocyclic group containing 1, 2, 3, or 4 heteroatoms selected from O, N, or S, where the optional substituent is selected from C1-4 alkyl, C1-4 alkyl substituted with 3- to 6-membered cycloalkyl, C1-4 alkyl substituted with an optionally substituted five- or six-membered unsaturated heterocyclic group containing 1, 2 , 3 or 4 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4 alkyl, C1-4 alkyl substituted with an optionally substituted four to six membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4 alkyl, and an optionally substituted four- to six-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4 alkyl; and q is selected from 0, 1, or 2. In one embodiment, R10 is independently selected from halogen, cyano, Ci-4 cyanoalkyl (e.g., -CH2-CN), hydroxyl, =0 (oxo), Ci-4 alkyl (e.g., -CH30 -CH2CH3), C1 haloalkyl. -4, C1-4 alkoxy (e.g. -OCH3), C1-4 hydroxylalkyl (e.g. -CH2C(CH3)2OH, -CH(CH3)CH2OH, CH(CH3)OH, -CH2CH2OH or -CH2OH), Ci-4 alkoxy Ci-4 alkylene (e.g. -CH2-O-CH3 or -CH2-CH2-OCH3), Ci-4 alkylsulfone (e.g. -SO2CH3), amino, Ci-4 monoalkylamino, Ci-4 dialkylamino (e.g. -N(CHs)2), C1-4 aminoalkylene (e.g. -CH2NH2), -Ci-4-alkylene(=O)NH(2-q)(C1e alkyl)q), -alkylene Ci-4-NHC(=O)C1-6 alkyl, C0-4 alkylene sulfonamide (e.g., -SO2NRX2 or CH2SO2NRx2, where Rx is independently selected from H and Ci-θ alkyl), and a saturated heterocyclic group of four to optionally substituted six-membered containing 1 or 2 heteroatoms selected from O, N, or S where the optional substituent is selected from C14 alkyl; and q is selected from 0, 1 or 2. In one embodiment, R10 is independently selected from halogen, cyano, Ci-4 cyanoalkyl (e.g. -CH2-CN), hydroxyl, =0 (oxo), Ci-4 alkyl (e.g. -CH30 -CH2CH3), Ci-haloalkyl -4, C1-4 alkoxy (e.g. -OCH3), C1-4 hydroxylalkyl (e.g. -CH2C(CH3)2OH, -CH(CH3)CH2OH, CH(CH3)OH, -CH2CH2OH or -CH2OH), Ci-4 alkylene Ci-4 alkoxy (e.g. -CH2-O-CH3 or -CH2-CH2-OCH3), Ci-4 alkylsulfone (e.g. -SO2CH3), amino, Ci-4 monoalkylamino, Ci-4 dialkylamino (e.g. -N(CHs)2), -Ci-4-alkyleneamino (e.g. -CH2NH2), -Ci-4-alkylene(=O)NH(2-q)(C1e alkyl)q), - Ci-4 alkylene-NHC(=O)C1-6 alkylene, -Co-4 alkylenesulfonamide (e.g., -SO2NRX2 or CH2SO2NRx2, where Rx is independently selected from H and Ci-e alkyl), and a saturated heterocyclic group of four an optionally substituted six-membered containing 1 or 2 heteroatoms selected from O, N, or S where the optional substituent is selected from Ci-4 alkyl. In one embodiment, two R10 substituents are present; an R10 is =0 (oxo) and an R10 is independently selected from halogen, cyano, Ci-4 cyanoalkyl (e.g. -CH2-CN), hydroxyl, Ci-4 alkyl (e.g. -CH3 or -CH2CH3), Ci haloalkyl -4, Ci-4 alkoxy (e.g. -OCH3), Cm hydroxylalkyl (e.g. -CH2C(CH3)2OH, -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH or CH2OH), Ci alkoxy -4Ci-4alkylene(e.g. -CH2-O-CH3 or -CH2-CH2-O-CH3), Ci-4alkylsulfone(e.g. -SO2CH3), amino, monoalkylaminoCi-4, dialkylaminoCi-4( e.g. -N(CHs)2), C1-4 aminoalkylene (e.g. -CH2NH2), -Ci-4-alkylene(=O)NH(2-q)(Ci-e alkyl)q) , -C1-4alkyleneNHC(=O)C1-6alkyl, Co-4alkylenesulfonamide (e.g., -SChNRú or -CHpSOpNRú, where Rxis independently selected from H and Ci-β alkyl), and a saturated heterocyclic group of four an optionally substituted six-membered containing 1 or 2 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4 alkyl. In one embodiment, q is 0 or 1. In particular, q is 1. In particular, q is 2. In one embodiment, no substituent is present or an R10 substituent is present. In particular, an R10 substituent is present. In particular, two R10 substituents are present. In particular, no R10 substituent is present. οη«ι ηη / 77Π7 / Ε / γ In one embodiment, R10 is independently selected from halogen, cyano, Ci-4 cyanoalkyl (e.g. -CH2-CN), hydroxyl, =0 (oxo), C1-4 alkyl (e.g. -CH30 -CH2CH3), Ci haloalkyl -4, C1-4 alkoxy (e.g. -OCH3), C1-4 hydroxylalkyl (e.g. -CH(CH3)CH2OH, -CH(CH3)OH, CH2CH2OH or -CH2OH), C1-4 dialkylamino (e.g. , -N(CH3)2), and C1-4 alkoxy C1-4 alkylene (e.g. -CH2-O-CH3), for example where R10 is independently selected from halogen, cyano, hydroxyl, =0 (oxo), and C1-4 alkyl (e.g. -CH3 or -CH2CH3). In one embodiment, R10 is independently selected from halogen, cyano, C1-4 cyanoalkyl (e.g., -CH2-CN), hydroxyl, =0 (oxo), C1-4 alkyl (e.g., -CH3 or -CH2CH3), haloalkyl. Ci-4, C1-4 alkoxy (e.g. -OCHs), C1-4 hydroxylalkyl (e.g. -CH(CH3)CH2OH, -CH(CH3)OH, CH2CH2OH or -CH2OH) and Ci-4 alkoxyCi-alkylene 4 (e.g. -CH2-O-CH3), for example where R10 is independently selected from halogen, cyano, hydroxyl, =0 (oxo) and C1-4 alkyl (e.g. CH30-CH2CH3). In one embodiment, R10 is independently selected from halogen, cyano, Ci-4 cyanoalkyl (e.g., -CH2-CN), hydroxyl, =0 (oxo), C1-4 alkyl (e.g., -CH3 or -CH2CH3), haloalkyl. Ci-4, C1-4 alkoxy (e.g. -OCH3), hydroxyl C1-4 alkyl (e.g. -CH(CH3)CH2OH, -CH(CH3)OH, CH2CH2OH or -CH2OH) and C1-4 alkoxy C1 alkylene -4 (e.g. -CH2-O-CH3), for example where R10 is independently selected from halogen, cyano, hydroxyl, =0 (oxo) and C1-4 alkyl (e.g. CH3 or -CH2CH3). In one embodiment, R10 is independently selected from halogen, cyano, hydroxyl, =0 (oxo), and C1-4 alkyl (e.g., -CH3 or -CH2CH3), for example where R10 is independently selected from hydroxyl, =0 (oxo). ) and Ci-4 alkyl (e.g. -CH3). In one embodiment, R10 is independently selected from halogen (e.g., chlorine or fluorine), =0 (oxo), C1-4 alkyl (e.g., -CH3, -CH2CH3, -CH(CH3)2), C1-4 alkoxy (e.g. -OCH3), and Ci-4 dialkylamino (e.g. -N(CH3)2), e.g. where R10 is independently selected from halogen, =0 (oxo), and C1-4 alkyl (e.g. -CH3 or -CH2CH3). In one embodiment, R10 is independently selected from halogen (e.g., chlorine), cyano, Ci-4 cyanoalkyl (e.g., -CH2-CN), Ci-4 alkoxy (e.g., -OCH3, -OCH2CH3 and -OCH(CH3 )2), =0 (oxo), Ci-4 alkyl (e.g. -CH3, -CH2CH3 and -CH(CHs)2), Ci-4 hydroxyalkyl (e.g. -CH2OH, CH2CH2OH or -CH2C(CH3) 2OH), C1-4 haloalkyl (e.g. -CHF2), C1-4 dialkylamino (e.g. N(CHs)2), C1-4 alkoxy C1-4 alkylene (e.g. -CH2-O-CH3 or - CH2-CH2-O-CH3), -alkylene Co-4C(=O)NH(2.q)(Cy-6 alkyl)q) (e.g. -CO-N(CH3)2, -CH2- CH2-CO-N(CH3)2, -CH2-CO-N(CH3)2, -CH2CO-NH(C(CH3)3) or -CH2-CO-NH(CH3), four to six saturated heterocyclic group O- or N-containing members (for example, tetrahydrofuranyl, morpholino, azetidinyl or oxetanyl), and C1-4 alkyl (for example, C1 alkyl) substituted with an optionally substituted five- or six-membered unsaturated heterocyclic group (for example, heterocyclic group unsaturated five-membered) containing 1, 2, 3, or 4 heteroatoms selected from O, N, and S (e.g., N or O) where the optional substituent is selected from C1-4 alkyl (e.g., -CH3). οη«ι ηη / 77Π7 / Ε / γ In one embodiment, R10 is halogen (e.g., chloro), cyano, Ci-4 alkyl (e.g., -CH3, CH(CH3)2 or -CH2CH3), C1-4 haloalkyl (e.g., -CHF2), C1-alkoxy. 4 (e.g. -OCH3, -OCH2CH3 or -OCH(CH3)2), C1-4 alkoxy Cu alkene (e.g. -CH2OCH3), C1-4 dialkylamino (e.g. N(CH3)2) or a group optionally substituted (e.g., unsubstituted) four- to six-membered saturated heterocyclic containing 1 or 2 heteroatoms selected from O or N where the optional substituent is selected from C1-4 alkyl (e.g., morpholinyl or azetidinyl). In one embodiment, R10 is -Co-4-C alkylene(=0)NH(2-q;(Ci-e)q alkylene which is selected from Ci-4-C alkylene(=O)NH(2-q) (Ci-e)q alkyl) (e.g. -CH2-CH2-CO-N(CH3)2, -CH2-CO-N(CH3)2, -CH2CO-NH(C(CH3)3) or -CH2 -CO-NH(CH3) and -CO-N(CH3)2). In one embodiment, R10 is independently selected from halogen, cyano, hydroxyl, =0 (oxo), and C14 alkyl (e.g., -CH3 or -CH2CH3), for example where R10 is independently selected from C1-4 alkyl (e.g., -CH3), halogen or oxo. In one embodiment, R10 is independently selected from =0 (oxo), hydroxyl and C1-4 alkyl (e.g., -CH3 or -CH2CH3). In particular, R10 is independently selected from =0 (oxo), hydroxyl and CH3. In particular, a substituent R10 is present and R10 is selected from =O(oxo), hydroxyl and -CH3. In particular, a substituent R10y R10es -CH3 is present. In one embodiment, two R10 substituents are present, one R10 is =0 (oxo) and one R10 is C1-4 alkyl (e.g., -CH3o -CH2CH3). In one embodiment, two R10 substituents are present and one is halogen, eg chloro and one R10 is C1-4 alkyl (eg -CH3 or -CH2CH3). In one embodiment, R10 is C1-4 alkyl (e.g., -CH3, -CH2CH3, or -CH(CH3)2). In one embodiment, R10 is halogen, for example, chlorine. In one embodiment, R10 is an optionally substituted four to six membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4alkyl. In one embodiment, R10 is an optionally substituted four to six membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O and N, where the optional substituent is selected from C1-4alkyl. In one embodiment, R10 is a four to six membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O and N (eg, morpholinyl or azetidinyl). In one embodiment, R10 is independently selected from halogen (eg, chlorine), C1-4 alkoxy (eg, -OCH3), =0 (oxo), C1-4 alkyl (eg, -CH3 or -CH2CH3), hydroxylC1alkyl -4 (e.g. -CH2CH2OH or -CH2OH), C1-4 dialkylamino (e.g. -N(CH3)2), Cu alkoxy C1-4 alkylene (e.g. -CH2-O-CH3O -CH2-CH2- O-CH3), and a four- to six-membered saturated heterocyclic group containing O (e.g., tetrahydrofuran). οη«ι ηη / 77Π7 / Ε / γ It is to be understood that the above definitions of heterocycles and R10 substituents encompass all possible tautomeric forms of the rings. Thus, for example, the following compound can exist in the following tautomeric forms, both of which are included within the scope of formula (I): on«l 00177071^1^1 Tautomer B Also, for example, the following compound can exist in the following tautomeric forms, both of which are included within the scope of formula (I): Tautomer B In one modality, the rest is selected from: οη«ι ηη / 77Π7 / Ε / γ In one embodiment, the remainder οη«ι ηη / ζζηζ / Ε / γ is selected from: In one modality, the rest is selected from: In one modality, the rest is selected from: In particular, in one embodiment, the remainder οη«ι ηη / 77Π7 / Ε / γ is: on«l 0017707IRIM Combinations of substituents In one embodiment, the compound of formula (I) is a compound of formula (XIV') or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XIV') where X, R2, R3, R6, R7, R8 and R9 are as defined in this description. In one embodiment, the compound of formula (XIV') is a compound of formula (XV) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XV) where R2, R3, R6, R7, R8 and R9 are as defined in the present description. In one embodiment, the compound of formula (XV) is a compound of formula (XVI) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: οη«ι ηη / 77Π7 / Ε / γ (XVI) where R3, R6, R7, R8 and R9 are as defined in the present description. In one embodiment, the compound of formula (XVI) is a compound of formula (XVIa) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: where R3, R6, R7, R8 and R9 are as defined in the present description. In one embodiment, the compound of formula (XVIa) is a compound of formula (XVIb) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XVIb) where R®, R7, R8 and R9 are as defined in the present description. In one embodiment, the compound of formula (XVIb) is a compound of formula (XVII) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: οη«ι ηη / ζζηζ / Ε / γ where Rs, R7, and R8 are as defined herein. In one embodiment, R8 is halogen. In one embodiment, the compound of formula (XVII) is a compound of formula (XVIII) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XVIII) where R1, R2, R3, R8, R9, A and R10 are as defined in the present description. In one embodiment, of the compound of formula (XVIII), the rest is selected from the following, where R8 is halogen: In particular, in one embodiment, of the compound of formula (XVIII), the rest is selected from the following, where R8 is halogen: For example, A particular group of compounds In one aspect, the invention provides a compound of formula (Γ): οη«ι ηη / 77Π7 / Ε / γ or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen or hydroxyl; R2 is hydrogen; R3 is hydrogen or Ci-4 alkyl, (eg -CH3); X is O or CR4R5; wherein, when R6 and R7 are independently selected from hydrogen and halogen (for example, chlorine or fluorine); or R6 and R7 join together to form a Ring A which is optionally substituted by one or more (for example, 1,2, or 3) R10 groups; wherein ring A is a five- or six-membered aromatic heterocyclic ring comprising one or two nitrogen atoms (e.g., two nitrogen atoms); R8 is halogen (for example, chlorine or fluorine); R9 is hydrogen; R10 are independently selected from halogen (e.g. chloro), C1-4 alkyl (e.g. -CH3o -CHpCHs), C1-4 alkoxy (e.g. -OCH3), C1-4 dialkylamino (e.g. -N(CH3) 2), C1-4 haloalkyl (e.g., -CF3), and an optionally substituted four- to six-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-alkyl -4 (for example, morpholinyl or azetidinyl). In one embodiment of the compound of formula Γ, the remainder οη«ι ηη / ζζηζ / Ε / γ In particular, in one embodiment of the compound of formula Γ, the remainder is selected from: οη«ι ηη / 77Π7 / Ε / γ for example, Particular compounds In one embodiment, the invention provides a compound of formula (I) which is one of Examples 1-27 or is a pharmaceutically acceptable tautomer, ΛΖ-oxide, salt or solvate thereof. In one embodiment, the invention provides a compound of formula (I) which is selected from one of the following compounds, or a pharmaceutically acceptable tautomer, / V-oxide, salt or solvate thereof: {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(3,4-dichloro- 2-methyl-2H-indazol-5-¡l)1 H-pyrazolo[3,4-b]pyrazín-5-¡l}methanol; (3S,4S)-8-{3-[5-chloro-3-(dimethylamino)quinoxalin-6-yl]-5-methyl-1 H-pyrazolo[3,4-b]pyrazin-6-yl}- 3-methyl2-oxa-8-azaspiro[4.5]decane-4-amine; {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-¡l]-3-(2-chlorophen¡l)- 1H-prázolo[3,4b]pyrazin-5-íl}methanol; {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-íl]-3-(3-chloro-2-fluoropheníl )-1Hpyrazolo[3,4-b]pyraz¡n-5-¡l}methanol; and {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-¡l]-3-(5-chloro-3- methoxyqu¡noxal¡n-6-¡l)1 H-pyrazolo[3,4-b]pyraz¡n-5-¡l}methanol. In one embodiment, the invention provides a compound of formula (I) which is the following compound, or a pharmaceutically acceptable tautomer, ΛΖ-oxide, salt or solvate thereof: {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(3,4-dichloro-2-methyl-2H- indazol-5-yl)1 H-pyrazolo[3,4-b]pyrazin-5-íl}methanol. In one embodiment, the invention provides a compound of formula (I) which is the following compound, or a pharmaceutically acceptable tautomer, Λ / oxide, salt or solvate thereof: (3S,4S)-8-{3-[5-chloro-3-(dimethylamino)quinoxalan-6-yl]-5-methyl-1 H-pyrazolo[3,4 -b]pyrazín-6-íl}-3-methyl2-oxa-8-azaspiro[4.5]decane-4-amine. In one embodiment, the invention provides a compound of formula (I) which is the following compound, or a pharmaceutically acceptable tautomer, / V-oxide, salt or solvate thereof: {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-¡l]-3-(2-chlorophen¡l)- 1H-prázolo[3,4b]pyrazin-5-íl}methanol. In one embodiment, the invention provides a compound of formula (I) which is the following compound, or a tautomer, ΛΖ-oxide, salt or pharmaceutically acceptable solvate thereof: {6-[(3S,4S)-4-amino -3-methyl-2-oxa-8-azaspyro[4.5]decan-8-¡l]-3-(3-chloro-2-fluorophen¡l)-1 Hpyrazolo[3,4-b]pyraz¡ n-5-¡l}methanol. In one embodiment, the invention provides a compound of formula (I) which is the following compound, or a pharmaceutically acceptable tautomer, A / -oxide, salt or solvate thereof: {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-íl]-3-(5-chloro-3-methoxyqu ¡noxal¡n-6-¡l)1 H-pyrazolo[3,4-b]p¡razin-5-¡l}methanol. For the avoidance of doubt, it should be understood that each general and specific embodiment and example for a substituent may be combined with each general and specific embodiment and example for one or more, in particular all, other substituents as defined herein and that All these modalities are covered by this application. In one embodiment, the invention provides a compound of formula (I) as defined herein or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein X, R1, R2, R3, R6, R7, R8y R9 are as defined in the present description, and wherein the compound of formula (I) is not: οη«ι ηη / 77Π7 / Ε / γ that is, it is not 6-((3S,4S)-4-amino-3-met¡l-2-oxa-8-azaspiro[4.5]decan-8-¡l)-3-(2 ,3-d¡c!orophenyl)-1Hpyrazolo[3,4-b]pyrazin-5-yl)methanei. In one embodiment, the invention provides a compound of formula (I) as defined herein or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein X, R1, R2, R3, R6, R7, R8y R9 are as defined in the present description, and wherein the compound of formula (I) is not: or a salt or tautomer thereof i.e., it is not 6-((3S,4S)-4-amyrium-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-¡l)-3 -(2,3-diciorophenyl)-1Hpyrazolo[3,4-b]pyrazin-5-yl)methanol or a salt or tautomer thereof. In one embodiment, the invention provides a compound of formula (I) as defined herein or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein X, R1, R2, R3, R6, R7, R8 , and R9 are as defined in the present description, and wherein the compound of formula (I) is not Example 16 in WO2019213318. In one embodiment, the invention provides a compound of formula (I) as defined herein or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein X, R1, R2, R3, R6, R7, R8y R9 are as defined in the present description, and wherein the compound of formula (I) is not: on«l 0017707IRIM that is, it is not (6-((3S>4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(2-flouro -3chlorophenyl)-1 H-pyrazoium[3,4-b]pyrazín-5-íl)methaneL In one embodiment, the invention provides a compound of formula (I) as defined herein or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein X, R1, R2, R3, R6, R7, R8y R9 are as defined in the present description, and wherein the compound of formula (I) is not: or a salt or tautomer thereof i.e. it is not (6-((3S!4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-( 2-flouro-3chlorophenyl)-1 H-pyrazolo[3,4-b]pyrazin-5-íl)methanol or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment, the invention provides a compound of formula (I) as defined herein or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein X, R1, R2, R3, R6, R7, R8y R9 are as defined herein, and wherein the compound of formula (I) is not Example 19C in WO2019183364. SALTS, SOLVATES, TAUTOMERS, ISOMERS, N-OXIDES, ESTERS, PRODRUGS AND ISOTOPES A reference to a compound of formula (I), subgroups thereof (for example, formulas (I), (la), (Ib), (Ib'), (Ib”), (II), (III ), (III'), (IV), (IV'), (IV”), (V), (VI), (Vil), (VIII), (Villa), (Vlllb), (Vlllc), ( IX), (IXa), (X), (XI), (XII), (Xlla), (Xllb), (Xllb), (Xllc), (Xllla), (Xlllb), (XIV), (XIV' ), (XV), (XVI), (XVIa), (XVIb), (XVII), (XVIII) and (Γ)) and any example also includes ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers unless specified), tautomers, Noxides, asters, prodrugs, isotopes and protected forms thereof, for example, as described below; in particular, the salts or tautomers or isomers or N-oxides or solvates thereof; and more particularly the salts or tautomers or N-oxides or solvates thereof. In one embodiment, reference to a compound of formula (I), sub-groups thereof (e.g. formulae (I), (la), (Ib), (Ibj, (Ib”), (II), (III), (lllj, (IV), (IVj, (IV”), (V), (VI), (Vil), (VIII), (Villa), (Vlllb), (Vlllc), (IX), (IXa) , (X), (XI), (XII), (Xlla), (Xllb), (Xllb), (Xllc), (Xllla), (Xlllb), (XIV), (XIV'), (XV), (XVI), (XVIa), (XVIb), (XVII), (XVIII) and (I*)) and any example also includes the salts or tautomers or solvates thereof. You go out Many compounds of formula (I) may exist in the form of salts, for example acid addition salts or, in certain cases salts of organic and inorganic bases such as carboxylate, sulfonate and phosphate salts. All of these salts are within the scope of this invention, and references to compounds of formula (I) include the salt forms of the compounds. The salts of the present invention can be synthesized from the parent compound containing an acidic or basic moiety by conventional chemical methods such as the methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor) , Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are used. Acid addition salts (mono- or disalts) can be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include mono- or disalts that are formed with an acid selected from acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g., L-ascorbic), L-aspartic, benzenesulfonic, benzoic acids. , 4-acetamidobenzoic, butanoic, (+) camphoric, camphorsulfonic, (+)-(1 S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic , ethanesulfonic, 2hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g., D-glucuronic), glutamic (e.g., L-glutamic), α-oxoglutaric, glycolic, hippuric, hydrohalic acids ( e.g., hydrobromic, hydrochloric, hydroiodic), isethionic, lactic (e.g., (+)L-lactic, (±)-DL-lactic), lactobionic, maleic, malic, (-)-L-malic, malonic, ( ±)-DL-mandelic, methanesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic, 1-hydroxy-2-naphtho¡ic, nicotinic, nitric, oleic, oratic, oxalic, palmitic, pamoic, phosphoric, propionic , pyruvic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L-tartaric, thiocyanic, ptoluenesulfonic, undecylenic, and valeric amino acids, as well as adium amino acids and cation exchange resins. on«l 00177077B / Y A particular group of salts consists of salts that are formed from acetic, hydrochloric, hydroiodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, melic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic. A particular salt is the hydrochloride salt. In one embodiment the compound is the sodium salt or mesylate. If the compound is anionic, or has a functional group which can be anionic (for example, COOH can be -COOj), then a salt can be formed with an organic or inorganic base, generating a suitable cation. Examples of suitable inorganic cations Examples of suitable organic cations include, but are not limited to, alkali metal ions such as L+, Na+ and K+, alkaline earth metal cations such as Ca2+ and Mg2+, and other cations such as Al3+ or Zn+. Examples of some suitable substituted ammonium ions are those derived from from: methylamine, ethylamine, diethylamine, propylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and tromethamine, as well as amino acids, such as Usine and arginine. An example of a common quaternary ammonium ion is N(CH3)4+. When the compounds of formula (I) contain an amine function, they can form quaternary ammonium salts, for example, by reaction with an alkylating agent according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of formula (I). The compounds of the invention can exist as mono- or disalts depending on the pKa of the acid from which the salt is formed. Salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are set forth in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pages 1-19. However, salts that are not pharmaceutically acceptable can also be prepared as intermediate forms which can then be converted to pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention. In one embodiment of the invention, there is provided a pharmaceutical composition comprising a solution (e.g., an aqueous solution) containing a compound of formula (I) and subgroups and examples thereof as described herein in the form of a salt in a concentration greater than 10 mg / mL, typically greater than 15 mg / mL and typically greater than 20 mg / mL. N-oxides Compounds of formula (I) containing an amine function can also form Noxides. A reference herein to a compound of formula (I) containing an amine function also includes the N-oxide. οη«ι ηη / ζζηζ / Ε / γ When a compound contains several amine functions, one or more nitrogen atoms can be oxidized to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocyclyl group. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g., a peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4th edition, Wiley Interscience, pages. More particularly, N-oxides can be formed by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example , in an inert solvent such as dichloromethane. In one embodiment of the invention, the compound is an N-oxide, for example, of a nitrogen atom in the group R6 or R7, for example a pyridine N-oxide. Tautomers and geometric isomers Compounds of formula (I) can exist in a number of different geometric isomeric forms, and tautomeric forms and references to compounds of formula (I) include all of these forms. For the avoidance of doubt, where a compound may exist in one of several isomeric or tautomeric geometric forms and only one is specifically described or shown, all others are, however, encompassed by formula (I). For example, certain heteroaryl rings can exist in the two tautomeric forms such as A and B shown below. For simplicity, a formula may illustrate one form, but the formula must be interpreted as encompassing both tautomeric forms. οη«ι ηη / ζζηζ / Ε / γ Other examples of tautomeric forms include, for example, the keto, enol and enolate forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / alcohol imino, amidine / enediamines, nitroso / oxime, thioketone / enethiol, and nitro / acinitro. 5 \ ,OH H* C—c - c=c I H / \ keto enol enolate Stereoisomers Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms. Stereocenters are illustrated in the usual way, by using “hatched” or “solid” wedge lines, for example, οη«ι ηη / ζζηζ / Ε / γ Where a compound is described as a mixture of two diastereoisomers / epimers, the configuration of the stereocenter is not specified and is represented by straight lines. Where compounds of formula (I) contain one or more chiral centers and may exist in the form of two or more optical isomers, references to compounds of formula (I) include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers or as mixtures (e.g. racemic or non-racemic mixtures) or two or more optical isomers, unless the context requires otherwise. Optical isomers can be characterized and identified by their optical activity (i.e., as + and - isomers, or d and I isomers) or can be characterized in terms of their absolute stereochemistry by using the “R and S” nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4th edition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew. Int Chem. English Ed., 1966, 5, 385-415. Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to those skilled in the art. As an alternative to chiral chromatography, optical isomers can be separated by forming diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluoyl-L-acid. tartaric, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid, by separating the diastereoisomers by preferential crystallization, and then dissociating the salts to give the individual enantiomer of the free base. Furthermore, enantiomeric separation can be achieved by covalently attaching an enantiomerically pure chiral auxiliary to the compound and then performing separation of diastereisomers by using conventional methods such as chromatography. This is then followed by the cleavage of the covalent bond mentioned above to generate the appropriate enantiomerically pure product. Where the compounds of formula (I) exist as two or more optical isomeric forms, one enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Therefore, in certain circumstances, it may be desirable to use as a therapeutic agent only one of a pair of enantiomers, or only one of a plurality of diastereoisomers. Accordingly, the invention provides compositions containing a compound of formula (I) having one or more chiral centers, wherein at least 55% (e.g., at least 60%, 65%, 70%, 75%, 80% %, 85%, 90% or 95%) of the compound of formula (I) is present as a single optical isomer (e.g., enantiomer or diastereoisomer). In a general embodiment, 99% or more (e.g., substantially all) of the total amount of the compound of formula (I) may be present as the sole optical isomer (e.g., enantiomer or diastereoisomer). Compounds spanning double bonds may have an E (entgegen) or Z (zusammen) stereochemistry at said double bond. Substituents on divalent or (partially) saturated cyclic radicals can have the cis or trans configuration. The terms cis and trans, when used in the present description, are in accordance with the nomenclature of Chemical Abstracts (J. Org. Chem. 1970, 35 (9), 2849-2867), and refer to the position of substituents on a ring residue. Those compounds of formula (I) that are stereochemically pure are of special interest. When a compound of formula (I) is specified, for example, as R, this means that the compound is substantially free of the S isomer. If a compound of formula (I) is specified, for example, as E, this means that the compound is substantially free of the Z isomer. The terms cis, trans, R, S, E and Z are well known to those skilled in the art. Isotopic variations The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the invention, that is, compounds of formula (I), wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or number of mass different from the atomic mass or mass number commonly found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H(D) and 3H(T), carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as such as 123L, 125L and 1311, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P and sulfur, such as 35S. Certain isotopically labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. Compounds of formula (I) may also have valuable diagnostic properties, as they can be used to detect or identify the formation of a complex between a compound being labeled and other molecules, peptides, proteins, enzymes or receptors. Detection or identification methods may use compounds that are labeled with labels such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase), etc. The radioactive isotopes tritium, i.e. 3H(T) and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and rapid means of detection. on«i ηη / ζζηζ / Ε / γ Substitution with heavier isotopes such as deuterium, i.e. 2H(D), may provide certain therapeutic advantages resulting from superior metabolic stability, for example, an increase in in vivo half-life or reduction in dosage requirements, and therefore it can be used in some circumstances. In particular, each reference to hydrogen in the application should be interpreted to encompass ’Hy2H, whether hydrogen is explicitly defined or hydrogen is implicitly present to satisfy the valence of the relevant atom (in particular that of carbon). Substitution with positron-emitting isotopes, such as 11C, 18F, 15O, and 13N, may be useful in positron emission topography (PET) studies to examine target occupancy. The isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations by using appropriate isotopically labeled reagents in place of the unlabeled reagents used previously. Esters Asters such as carboxylic acid esters, acyloxy esters and phosphate esters of compounds of formula (I) containing a carboxylic acid group or a hydroxyl group are also covered by formula (I). Examples of esters are compounds containing the group -C(=O)OR, where R is an aster substituent, for example, a C1-7 alkyl group, a C3-12 heterocyclyl group, or a C5-12 aryl group. , typically a C1-6 alkyl group. Particular examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(=O)OCH2CH3, C(=O)OC(CH3)3, and -C(=O)OPh. Examples of acyloxy groups (reverse ester) are represented by -OC(=O)R, where R is an acyloxy substituent, for example, a C1-6 alkyl group, a C3-12 heterocyclyl group, or an aryl group. C5-12, typically a C1-6 alkyl group. Particular examples of acyloxy groups include, but are not limited to, -OC(=O)CH3 (acetoxy), -OC(=O)CH2CH3, OC(=O)C(CH3)3, -OC(=O) Ph, and -OC(=O)CH2Ph. Examples of phosphate esters are those that are derived from phosphoric acid. In one embodiment of the invention, formula (I) includes within its scope asters of compounds of formula (I) containing a carboxylic acid group or a hydroxyl group. In another embodiment of the invention, formula (I) does not include within its scope esters of compounds of formula (I) containing a carboxylic acid group or a hydroxyl group. Solvates and crystal forms Also encompassed by formula (I) are any polymorphic forms of the compounds, and solvates such as hydrates, alcoholates and the like. The compounds of the invention can form solvates, for example, with water (ie hydrates) or common organic solvents. As used herein, the term “solvate” means a physical association of the compounds of the present invention with one or more solvent molecules. This physical association involves various degrees of ionic and covalent bonding, including οη«ι ηη / 77Π7 / Ε / γ hydrogen bonding. In certain cases, the solvate will be able to be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The term "solvate" is intended to encompass both the solution phase and isolable solvates. Non-limiting examples of suitable solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine and the like. The compounds of the invention can exert their biological effects while in solution. Solvates are well known in pharmaceutical chemistry. They may be important to the processes of preparation of a substance (e.g. in relation to its purification), the storage of the substance (e.g. its stability) and the ease of handling of the substance and are often formed as part of the isolation or purification steps of a chemical synthesis. One skilled in the art can determine by standard and long-used techniques whether a hydrate or other solvate has been formed by the isolation conditions or the purification conditions used to prepare a given compound. Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g., single-crystal X-ray crystallography or X-ray powder diffraction), and nuclear magnetic resonance ( NMR) in solid state (SS-NMR, also known as magic angle rotation NMR or MAS-NMR). Such techniques are part of the standard analytical toolkit of the skilled chemist such as NMR, IR, HPLC and MS. Alternatively, those skilled in the art may deliberately form a solvate by using crystallization conditions that include an amount of the solvent that is required for the particular solvate. The standard methods described herein can then be used to establish whether solvates formed. Additionally, the compounds of the present invention may have one or more polymorphic or amorphous crystalline forms and, as such, are intended to be included within the scope of the invention. Complexes Formula (I) also includes within its scope complexes (eg inclusion complexes or clathrates with compounds such as cyclodextrins or metal complexes) of the compounds. Inclusion complexes, clathrates and metal complexes can be formed by methods well known to those skilled in the art. Prodrugs Also encompassed by formula (I) are any prodrugs of the compounds of formula (I). By "prodrugs" is meant, for example, any compound that is converted in vivo to a biologically active compound of formula (I). For example, some prodrugs are esters of the active compound (eg, a metabolically labile and physiologically acceptable ester). During metabolism, the ester group (-C(=O)OR) is cleaved to produce the active drug. Such esters can be formed by esterification, for example, of any of the carboxylic acid groups (-C(=O)OH) in the parent compound, with, οη«ι ηη / ζζηζ / Ε / γ where appropriate, protection prior to any other reactive groups present in the parent compound, followed by deprotection if required. Examples of such metabolically labile esters include those of the formula -C(=O)OR, where R is: C1-7 alkyl (e.g. -Me, -Et, -nPr, -ÍPr, -nBu, -sBu, -¡Bu, -tBu); C1-7 aminoalkyl (for example, aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-C1-7alkyl (eg, acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1-(1-methoxy-1-methyl)ethyl-carbonxyloxyethyl; 1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1-Isopropoxy-carbonyloxyethyl, cyclohexyl-carbonyloxymethyl, 1-cyclohexyl-carbonyloxyethyl, cyclohexyloxy-carbonyloxymethyl, 1-cyclohexyloxy-carbonyloxyethyl, (4-oxanyloxy)carbonyloxymethyl, 1-(4-oxanyloxy)carbonyloxyethyl, (4-oxanyl)carbonyloxymethyl ; and 1-(4-tetrahydropyranyl)carbonyloxyethyl). Also, some prodrugs are activated enzymatically to produce the active compound, or a compound which, upon further chemical reaction, produces the active compound (for example, as in antigen-directed enzyme prodrug therapy (ADEPT), of gene-directed enzyme prodrug therapy (GDEPT), and ligand-directed enzyme prodrug therapy (LIDEPT), etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or it may be an amino acid ester derivative. In one embodiment, formula (I) does not include prodrugs of the compounds of formula (I) within its scope. METHODS FOR THE PREPARATION OF COMPOUNDS OF FORMULA (I) In this section, as in all other sections of this application, unless the context otherwise indicates, references to formula (I) also include all other sub-formulas (for example, formulas (I), (la), (Ib), (Ib'), (Ib”), (II), (III), (III'), (IV), (IV'), (IV”), (V), (VI), ( Vil), (VIII), (Villa), (Vlllb), (Vlllc), (IX), (IXa), (X), (XI), (XII), (Xlla), (Xllb), (Xllb) , (Xllc), (Xllla), (Xlllb), (XIV), (XIV'), (XV), (XVI), (XVIa), (XVIb), (XVII), (XVIII) and (I*) ) and examples thereof as defined herein, unless the context indicates otherwise. The compounds of formula (I) can be prepared according to synthetic methods well known to those skilled in the art. According to a further aspect of the invention, there is provided a process for preparing a compound of formula (I), or a pharmaceutically acceptable tautomer, stereoisomer, / V-oxide, salt, or solvate thereof, comprising: (a) coupling a compound of formula (A) or a protected derivative thereof: οη«ι ηη / ζζηζ / Ε / γ wherein ethoxymethyl; SEM) or is hydrogen, and Z is a metal residue (such as zinc halide, for example, zinc chloride) or a leaving group (such as a halogen, for example, iodine or bromine) with a compound of formula (B) or a protected version thereof R7 οη«ι ηη / ζζηζ / Ε / γ (B) where Rs, R7, R8 and R9 are as defined above in the present description for the compounds of formula (I) and V represents a metallic or metalloid residue (such as boronic acid , pinacol boronate, magnesium halide or zinc halide, for example, boronic acid, pinacol boronate) or a leaving group such as halogen, followed by a suitable deprotection reaction to remove the protecting groups; and / or (b) coupling a compound of formula (C) or a protected derivative thereof: wherein R1, R6, R7, R8 and R9 are as defined above in the present description for the compounds of formula (I), P represents a protecting group (such as 2-tetrahydropyran; THP or 2(trimethylsilyljetoxymethyl; SEM) or is hydrogen , L is a leaving group (such as chloride), with a compound of formula (D) or a protected derivative thereof, wherein X, R2 and R3 are as defined above in the present description for compounds of formula (I). and / or, (c) reacting a compound of formula (K) or a protected derivative thereof, οη«ι ηη / 77Π7 / Ε / γ wherein 2-tetrahydropyran; THP or 2-(trimethylsilyl)ethoxymethyl; SEM), Ν,Ν-dimethylsulfamoyl or hydrogen, L3 is a leaving group (such as halogen, for example, bromine): (i) with an organometallic species of the formula CH3M, where M is a metal (for example CHs-ZnHal, where Hal is halogen, for example, chloride, bromide or iodide) in the presence of a metal catalyst (such as dichloride ( 1,3-di¡soprop¡limidazole-2-yl¡dene)(3chloropyrid¡l)palladium(ll)) to give a compound of formula (I) where R1 is H; or (i) with an alkyl boronate (such as potassium (2-trimethylsilyl)-ethoxymethyl trifluoroborate) in the presence of a photoredox catalyst (such as [lr{dFCF3ppy}2(bpy)]PF6), a metal catalyst (such as the complex of nickel(II) and ethylene glycol dimethyl ether chloride), a ligand (such as 4,4'-ditert-butyl-2,2'-dipyridyl), a base (such as dipotassium phosphate), and a light source (such as a blue LED), to give a compound of formula (I) wherein R1 is OH; and / or (d) cyclization of a compound of formula (R), or a protected derivative thereof; wherein a protected hydrazine derivative; and / or in each case optionally followed by a deprotection step; or (e) deprotection of a protected derivative of a compound of formula (I); and / or (f) interconversion of a compound of formula (I) or a protected derivative thereof into a further compound of formula (I) or a protected derivative thereof; and / or (g) optionally the formation of a pharmaceutically acceptable salt of a compound of formula (I). In one embodiment, the process for preparing a compound of formula (I), or a tautomer, stereoisomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, comprises (a) coupling a compound of formula (A) or a protected derivative of the same: wherein and Zes a leaving group (such as a halogen, for example, iodine or bromine) with a compound of formula (B) or a protected version thereof R7 Rs / il / ReV (B) where Rs, R7, R8 and R9 are as defined hereinabove for compounds of formula (I) and V represents a metal or metalloid residue (such as boronic acid, pinacol boronate, magnesium halide or zinc halide, eg boronic acid, pinacol boronate) or a leaving group such as halogen, and / or (b) deprotection of a protected derivative of a compound of formula (I); and / or (c) interconversion of a compound of formula (I) or a protected derivative thereof into a further compound of formula (I) or a protected derivative thereof; and / or (d) optionally formation of a pharmaceutically acceptable salt of a compound of formula (I). Preparative methods (a), (b), (c) and (d) Compounds of formula (B) are commercially available, or are prepared using methods analogous to those described in the examples. Process (a) typically comprises, reacting a compound of formula (A) with a compound of formula (B) in a suitable solvent, a suitable base and a suitable catalyst at a suitable temperature. Examples of suitable bases are potassium carbonate or potassium phosphate. Examples of suitable catalysts are [1,1'bis(diphenylphosphino)ferrocene]palladium(ll) dichloride. Examples of suitable solvents are 1,2-dimethoxyethane or tetrahydrofuran. Where Z is a metal residue such as zinc halide, the process typically comprises reacting a compound of formula (A) with a compound of formula (B) where V is a leaving group such as halogen. Typically, compounds of formula (A) where Z is a leaving group such as a halogen that is dissolved in a suitable solvent such as tetrahydrofuran are treated with a reagent such as lithium chloride-isopropyl magnesium chloride complex solution, for an adequate time such as 35 minutes to completely effect metalation. The newly formed organomagnesium species is treated with a suitable metal salt, such as zinc chloride, to effect transmetalation and optionally stirred for a suitable time, such as 10 minutes, then allowed to warm to a suitable temperature, such as room temperature, for a period of time such as 40 min. The resulting zinc heteroaryl reagent is used directly in the cross-coupling reaction with formula (B) through the use of a suitable catalyst such as methanesulfonate(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1' -biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(ll) (paladacyclo SPhos G4) at a suitable temperature such as room temperature for a suitable time such as 18 h. Compounds of formula (D), or protected derivatives thereof, are obtained from commercially available starting materials, which are prepared from literature procedures or by using methods indicated in the examples described in this application or methods analogous to these. Compounds of formula (C), or a protected derivative thereof, in particular where R1 is hydrogen, can be obtained by reacting a compound of formula (E): οη«ι ηη / ζζηζ / Ε / γ p(E) where P represents a suitable amine protecting group (such as 2-(trimethylsilyl)ethoxymethyl; SEM) or is hydrogen, and L1 and L2 independently represent leaving groups (such as a halide, eg chloro, bromo or iodo ) with a compound of formula (B) or protected derivative thereof, by using a method analogous to process (a). Compounds of formula (E) are obtained from commercially available starting materials, which are prepared from literature procedures or by using methods set forth in the examples described in this patent or methods analogous thereto. Compounds of formula (A) or protected derivatives thereof can be obtained by reacting the compound of formula (E), where R1 is H, with a compound of formula (D) or a protected derivative thereof, through the use of a suitable base such as diisopropylethylamine, in a suitable solvent such as dimethylsulfoxide or A / -methyl-2-pyrrolidinone, at a suitable temperature such as 80°C to 150°C. Compounds of formula (A) or protected derivatives thereof can be obtained from compounds of formula (F) or protected derivatives thereof οη«ι ηη / 77Π7 / Ε / γ (F) wherein or is hydrogen, by introducing a suitable leaving group Z such as a halogen, for example by using a suitable halogenating reagent (such as A / -iodosuccinamida) followed by an optional protection step to introduce the amine protecting group P (such as 2-tetrahydropyran; THP or 2(trimethyls¡l¡l)ethoxymethyl; SEM). Compounds of formula (A), or protected derivatives thereof, in particular where R1 is H or -OH, can be obtained by reacting a compound of formula (X') or a protected derivative thereof: p(X') where R1 is hydrogen or hydroxyl, P represents a protecting group (such as 2tetrahydropyran; THP or 2-(trimethylsil¡l)ethoxymethyl; SEM) or is hydrogen, and L1 and L2 independently represent leaving groups (such as a halide, for example, chlorine, bromine or iodine), with a compound of formula (D) or protected derivative thereof. Compounds of formula (Xj, in particular where R1 is OH or protected derivatives thereof, can be obtained by reacting a compound of formula (Y) or a protected derivative thereof: (Y) οη«ι ηη / ζζηζ / Ε / γ where P represents a protecting group (such as 2-tetrahydropyran; THP or 2(trimethylsilyl)ethoxymethyl; SEM) or is hydrogen, and L1 and L2 independently represent leaving groups (such as a halide, for example, chlorine, bromine or iodine), with methanol in the presence of a photoredox catalyst (such as 2,4,5,6-tetra(9H-carbazole-9-yl)isophthalonítrilo), a peroxide reagent such as solution of tere-butyl peracetate, an acid (such as TFA), and a light source (such as a blue LED), in a solvent such as DMSO. Alternatively, the reaction can be carried out with an excess of an alcohol, such as methanol in the presence of a metal salt such as silver(II) nitrate, an oxidant such as ammonium persulfate, an acid (such as TFA), in a solvent such as DMSO or water and a heat source (30-150°C). Alternatively, compounds of formula (X'), or protected derivatives thereof, can be obtained by reacting a compound of formula (W) or a protected derivative thereof: R1 Y»P(W) where P represents a protecting group (such as 2-tetrahydropyran; THP or 2(trimethylsilyl)ethoxymethyl; SEM) or is hydrogen, and L1 is a leaving group (such as a halogen, for example example, iodine or bromine), with a suitable halogenating agent (such as / V-bromosuccinimide or Nyodosuccinimide) to introduce a leaving group such as a halogen (for example, bromine or iodine). Compounds of formula (W), or protected derivatives thereof, in particular where R1 is hydrogen, can be obtained by reacting a compound of formula (Yj or a protected derivative thereof: (Y') wherein P represents a protecting group (such as 2-tetrahydropyran; THP or 2(trimethylsilyljetoxymethyl; SEM) or is hydrogen, and L1 is a leaving group (such as a halogen, for example, iodine or bromine), with an organometallic residue (such as an organomagnesium species, for example, magnesium methyl chloride). Compounds of formula (Yj, or protected derivatives thereof, can be obtained by reacting a compound of formula (Zj or a protected derivative thereof: <£ c a (Z) where P represents a protecting group (such as 2-tetrahydropyran; THP or 2(trimethylsil¡l)ethoxymethyl; SEM) or is hydrogen, and L1 is a leaving group (such as a halogen, for example for example, iodine or bromine), with an oxidizing agent (such as a peroxide reagent, for example, trifluoroperacetic acid). Compounds of formula (F), or protected derivatives thereof, can be obtained by reacting a compound of formula (G) or (Gj, or mixtures of (G) and (Gj, and protected derivatives thereof). ^alkyl wherein Under such conditions, one or more protecting groups may also be removed and therefore the cyclization step may optionally be followed by a reprotective step, for example, with di-tere-butyl dicarbonate to give a derivative of / V-Boc. The compounds of formula (G) and (Gj or protected derivatives thereof can be obtained by reacting a compound of formula (H) or a protected derivative thereof, wherein X, R1, R2 and R3 are as defined above in the present description for compounds of formula (I), where Z is a leaving group (such as a halogen) with a vinyl alkoxy derivative such as pinacol ester of (E)-1-ethoxyethene-2-boronic acid by metal catalysis (e.g., by using palladium acetate and a suitable ligand such as 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, i.e. Sphos and a base such as palladium phosphate potassium).The reaction may take place in a suitable solvent or combination of solvents, such as κ c N K acetonitrile and water, and at a suitable temperature such as 70 °C. Compounds of formula (H) or protected derivatives thereof can be obtained by reacting a compound of formula (J): V N NH2(J) with a compound of formula (D) or protected derivative thereof, wherein, Z is a leaving group (such as a halogen) and V is a leaving group (such as a halogen), with a suitable base (such as / V, / V-diisopropylethilamine), in a suitable solvent (such as A / -methyl-2-pyrrolidone) at a suitable temperature (such as 120 ° C). Compounds of formula (K), or protected derivatives thereof, can be obtained by reacting a compound of formula (L) or a protected derivative thereof: wherein ), Ν,Ν-dimethylsulfamoyl or is hydrogen, L2 is a leaving group (such as halogen, for example, iodide), L3 is a leaving group (such as halogen, for example, bromide), with a compound of formula (B), by using procedures such as those described for (a). Compounds of formula (L), or a protected derivative thereof, can be obtained by reacting a compound of formula (M): (M) wherein P represents a suitable protecting group such as 2-(trimethylsill)ethoxymethyl (SEM) or Ν,Ν-dimethylsuIfamoyl, L1 is a leaving group such as chloride, L2 is a leaving group such as iodide and L3 is a leaving group such as bromide, with a compound of formula (D) by using procedures such as those described for (b). The compounds of formula (M), or protected derivatives thereof, can be obtained from commercially available starting materials, which are prepared from literature procedures or by using methods indicated in the examples described. in this patent or analogous methods. Alternatively, compounds of formula (L), or protected derivatives thereof, can be obtained by reacting a compound of formula (N) or a protected derivative thereof: οη«ι ηη / 77Π7 / Ε / γ wherein R2 and R3, are as defined above in the present description for the compounds of formula (I), P represents an amine protecting group (such as 2-(trimethylsilyl)ethoxymethyl; SEM) or is hydrogen, with a suitable halogenating agent (such as / V-bromosuccinimide or Nyodosuccinimide) to introduce a leaving group such as a halogen (for example, bromine or iodine). Compounds of formula (N), or protected derivatives thereof, can be obtained by reacting a compound of formula (O) or protected derivatives thereof: where R2 and R3, are as defined above in the present description for the compounds of formula (I), with a suitable halogenating agent such as A / -iodosuccinímide to introduce a leaving group such as a halogen and suitable conditions to introduce the protecting group. Compounds of formula (O), or protected derivatives thereof, where X is a nitrogen, can be obtained by reacting a compound of formula (P): (Ρ) on«l 0017707IRIM where R2 and R3, are as defined above in the present description for the compounds of formula (I), L2 is a leaving group such as chloride, with a suitable hydrazine derivative such as hydrazine hydrate. Compounds of formula (P), or protected derivatives thereof, can be obtained by reacting a compound of formula (Q): (Q) with a compound of formula (D) or a protected derivative thereof, where L1 and L2 are leaving groups such as chloride. The compounds of formula (Q), or protected derivatives thereof, are obtained from commercially available starting materials, or are prepared from literature procedures or by using methods indicated in the examples described in this patent or analogous methods. Compounds of formula (R), or protected derivatives thereof, can be obtained by reacting a compound of formula (S) or a protected derivative thereof: (S) wherein R1, R6, R7, R8 and R9 are as defined above in the present description for compounds of formula (I) and both L1 and L2 represent a suitable leaving group, such as a halogen, with a compound of formula (D ). Compounds of formula (S), or protected derivatives thereof, can be obtained by reacting a compound of formula (T) or a protected derivative thereof: οη«ι ηη / ζζηζ / Ε / γ (Τ) wherein R1, R6, R7, R8 and R9 are as defined above in the present description for the compounds of formula (I) and both L1 and L2 represent a suitable leaving group, such as a halogen, with a suitable oxidizing reagent such as manganese (IV) oxide. Compounds of formula (T), or protected derivatives thereof, can be obtained by reacting a compound of formula (U) or a protected derivative thereof: R1 where R' is as defined above in the present description for compounds of formula (I) and both L1 and L2 represent suitable leaving groups, such as a halogen, with compound of formula (B), where V is a metallic residue or metalloid (such as a magnesium halide). The compounds of formula (U), or protected derivatives thereof, can be obtained by reacting a compound of formula (Vj or a protected derivative thereof: (V') where R1, is as defined above in the present description for the compounds of formula (I) and both L1 and L2 represent suitable leaving groups, such as a halogen, with a suitable oxidizing agent such as Dess-Martin periodinane. Compounds of formula (V), or protected derivatives thereof, can be obtained by reacting a compound of formula (W) or a protected derivative thereof: (W) wherein R1 is as defined above in the present description for the compounds of formula (I) and both L1 and L2 represent a suitable leaving group, such as a halogen, with an alcohol, such as methanol in the presence of a photoredox catalyst ( such as 2,4,5,6-tetra(9H-carbazole-9yl)isophthalonitrile), an oxidant reagent such as tere-butyl peracetate solution, an acid (such as TFA), and a light source (such as a blue LED), in a solvent such as DMSO. The compounds of formula (W), or protected derivatives thereof, are obtained from commercially available starting materials, or are prepared from literature procedures or by using methods indicated in the examples described in this patent or analogous methods. Compounds of formula (T), or protected derivatives thereof, can also be obtained by reacting a compound of formula (Z') or a protected derivative thereof: R7 CHO on«i ηη / ζζηζ / Ε / γ where Rs, R7, R8 and R9 are as defined above in the present description for compounds of formula (I) with a compound of formula (W). The process typically comprises reacting a compound of formula (W) with a reagent such as lithium chloride-2,2,6,6-tetramethylpiperidine magnesium chloride complex solution, for a suitable time such as 2.5 minutes to completely effect metalation. The newly formed organomagnesium species is treated with a compound of formula (Z') and allowed to warm, for example, to room temperature and stirred for a suitable time, such as 18 h. The compounds of formula (Z'), or protected derivatives thereof, are prepared by using methods indicated in the examples described in this patent or analogous methods. Deprotection of a protected derivative of a compound of formula (I) Process (e) typically comprises any suitable deprotection reaction, the conditions of which will depend on the nature of the protecting group. When the protecting group P represents SEM, such a deprotection reaction will typically comprise the use of a suitable acid in a suitable solvent, followed by the removal of the hydroxymethyl adduct that forms during acid deprotection of the SEM protecting group with ethylenediamine. For example, the acid may suitably comprise trifluoroacetic acid or hydrogen chloride and the solvent may suitably comprise dichloromethane, DMF or methanol. Optionally, a mixture of solvents can be used, for example, water and methanol. The second stage involves concentration in vacuo, followed by dissolving the crude material in a suitable solvent such as methanol and treatment with a suitable stripping reagent such as ethylenediamine in a suitable solvent such as methanol. Where the protecting group is an A / ,A / -dimethylsulfamoyl (SO2NMe2) group, a stronger acid such as trifluoromethanesulfonic acid can be used at a suitable temperature. When R1= OH and the protecting group P represents SEM, such a deprotection reaction will typically make use of a suitable acid (e.g., methanesulfonic acid or TFA) in a suitable solvent (e.g., DCM, with or without water), followed by of the elimination of the hydroxymethyl adduct that forms during the acid deprotection of the SEM protecting group, with ethylenediamine or ammonia in a suitable solvent (for example, DCM, CHCI3, IPA, MeOH, water, or mixtures thereof). For example, the deprotection reaction involves the use of methanesulfonic acid in a mixture of DCM / water at RT and the second step involves treating the crude product with ethylenediamine and / or ammonia in a mixture of DCM and water. When R1=H and the protecting group P represents THP, such a deprotection reaction will typically comprise the use of a suitable acid (e.g., HCl) in a suitable solvent (e.g., dioxane, MeOH) at a temperature between room temperature and 40 °C. In other cases, when R1 = H and the compound is only protected with Boc, such a deprotection reaction will typically comprise the use of a suitable acid (for example, TFA or HCl) in a suitable solvent (DCM, MeOH, dioxane). Deprotection can be carried out according to the procedures described herein as the general procedures for the preparation of compounds of formula (I), Methods 1-5. Formation of a pharmaceutically acceptable salt of a compound of formula (I) Salt formation can be carried out by treating a compound of formula (I) in the free base form, which is dissolved in a suitable solvent, with a stoichiometric amount or excess of a pharmaceutically acceptable organic or inorganic acid. , then isolating the resulting salt by methods well known in the art, for example, solvent evaporation or crystallization. General If appropriate, the reactions previously described in processes (a), (b) and (c) are followed or preceded by one or more reactions known to those skilled in the art and are carried out in an order appropriate to achieve the Required substitutions defined above to provide other compounds of formula (I). Non-limiting examples of such reactions whose conditions can be found in the literature include: protection of reactive functions, deprotection of reactive functions, halogenation, dehalogenation, dealkylation, alkylation and arylation of amine, aniline, alcohol and phenol, Mitsunobu reaction on hydroxyl groups, οη«ι ηη / 77Π7 / Ε / γ cycloaddition reactions on groups appropriate, reduction of nitro, esters, cyano, aldehydes, coupling reactions that are catalyzed by transition metals, acylation, sulfonylation / introduction of sulfonyl groups, saponification / hydrolysis of ester groups, amidification or transesterification of ester groups, esterification or amidification of carboxylic groups, halogen exchange, nucleophilic substitution with amine, thiol or alcohol, reductive amination, oxime formation on carbonyl and hydroxylamine groups, S-oxidation, N-oxidation, and salification. A wide range of well-known functional group interconversions to convert a precursor compound to a compound of formula I is known to those skilled in the art and is described in Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, 1992. For example , possible functionalizations that are catalyzed by metals, such as the use of organotin reagents (the Stille reaction), Grignard reagents and reactions with nitrogen nucleophiles are described in “Palladium Reagents and Catalysts” [Jiro Tsuji, Wiley , ISBN 0-470-85032-9] and “Handbook of OrganoPalladium Chemistry for Organic Synthesis” [Volume 1, edited by Ei-ichi Negishi, Wiley, ISBN 0-471-31506-0], Protective groups In many of the reactions described above, it may be necessary to protect one or more groups to prevent the reaction from taking place at an undesirable location in the molecule. Examples of protective groups and methods of protection and deprotection of functional groups can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999). A hydroxy group can be protected, for example, as an ether (-OR) or an ester (-OC(=O)R), for example, as: a t-butyl ether; a tetrahydropyranyl ester (THP); a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (OC(=O)CH3). An aldehyde or ketone group can be protected, for example, as an acetal (R-CH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=O) is treated with, for example, a primary alcohol. The aldehyde or ketone group is easily regenerated by hydrolysis using a large excess of water in the presence of acid. οη«ι ηη / 77Π7 / Ε / γ An amine group can be protected, for example, as an amide (-NRCO-R) or a carbamate (NRCO-OR), for example, as: a methyl methylamide (-NHCO-CH3); a benzyl carbamate (-NHCO-OCH2C6H5, -NH-Cbz or NH-Z); as a t-butyl carbamate (-NHCO-OC(CH3)3, -NH-Boc); a 2-biphenyl-2-propyl carbamate (-NHCOOCfCHs^CeFLCeHs, -NH-Bpoc), such as a 9fluorenylmethyl carbamate (-NH-Fmoc), such as a 6-nitroveratrile carbamate (-NH-Nvoc), such as a 2-trimethylsilylethyl carbamate (-NH-Teoc), as a 2,2,2-trichloroethyl carbamate (-NH-Troc), as an allyl carbamate (-NH-Alloc), or as a 2(-phenylsulfonyl) carbamate etílo (-NH-Psec). For example, in compounds of formula I containing an amino group, the amino group can be protected by a protecting group as defined above in the present description, where a preferred group is the tert-butyloxycarbonyl (Boc) group while Additional functionalization is introduced. Where further modification of the amino group is not required, the protecting group can be carried through the reaction sequence to give an N-protected form of a compound of formula (I) which can then be deprotected by standard methods ( for example, acid treatment in the case of the Boc group) to give the compound of formula (I). Other protecting groups for amines, such as cyclic amines and heterocyclic N-H groups, include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl) groups, benzyl groups such as a paramethoxybenzyl (PMB) group, and tetrahydropyranyl (THP) groups. A carboxylic acid group can be protected as an ester, for example, as: a C1-7 alkyl ester (for example, a methyl ester; a t-butyl ester); a C1-7 haloalkyl ester (for example, a C1-7 trihaloalkyl ester); a trialkylsilyl Ci-7-C1-7 alkyl ester; or an aryl Cs-2o-C1-7 alkyl ester (for example, a benzyl ester; a nitrobenzyl ester; para-methoxybenzyl ester. A thiol group can be protected, for example, as a thioether (-SR) , for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=O)CH3). Isolation and purification of the compounds of the invention The compounds of the invention can be isolated and purified according to standard techniques well known to those skilled in the art and examples of such methods include chromatographic techniques such as column chromatography (e.g., flash chromatography) and HPLC. A particularly useful technique in the purification of compounds is preparative liquid chromatography which uses mass spectrometry as a means of detecting purified compounds emerging from the chromatography column. Preparative LC-MS is a standard and effective method used for the purification of small organic molecules such as the compounds described herein. Methods for liquid chromatography (LC) and mass spectrometry (MS) can be varied to provide better separation of raw materials and better detection of samples by MS. Optimization of the preparative gradient LC method will involve variable columns, volatile eluents and modifiers, and gradients. Methods are well known in the art to optimize preparative LC-MS methods and then use them to purify compounds. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC / MS; J οη«ι ηη / ζζηζ / Ε / γ Comb Chem.·, 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquid chromatography / mass spectrometer platform for the preparative purification and analytical analysis of compound librarles; J Comb Chem.; 2003; 5(3); 322-9. An example of such a system for purifying compounds by preparative LC-MS is described below in the Examples section of this application (under the heading “Mass Directed Purification LC-MS System”). The recrystallization methods of the compounds of formula (I) and the salt thereof can be carried out by methods well known to those skilled in the art: see, for example, (P. Heinrich Stahl (Editor), Camille G. Wermuth ( Editor), ISBN: 3-90639-026-8, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Chapter 8, Wiley-VCH Publishing). The products obtained from an organic reaction are rarely pure when isolated directly from the reaction mixture. If the compound (or a salt thereof) is solid, it can be purified and / or crystallized by recrystallization from a suitable solvent. A good recrystallization solvent should dissolve a moderate amount of the substance to be purified at elevated temperatures, but only a small amount of the substance at a lower temperature. This should dissolve impurities easily at low temperatures or not at all. Finally, the solvent must be easily removed from the product being purified. This commonly means that it has a relatively low boiling point and one skilled in the art will know the recrystallization solvents for a particular substance or, if that information is not available, will try various solvents. To get a good yield of the material being purified, the minimum amount of hot solvent is used to dissolve all impure material. In practice, 3-5% more solvent than necessary is used so that the solution is not saturated. If the impure compound contains an impurity that is insoluble in the solvent, then it can be filtered off and the solution allowed to crystallize. Also, if the impure compound contains trace amounts of colored material that is not native to the compound, this can be removed by adding a small amount of decolorizing agent, for example, by activating charcoal in the hot solution, filtering it, and then allowing it to cool down. it crystallizes. Commonly, crystallization occurs spontaneously upon cooling of the solution. If not, crystallization can be induced by cooling the solution below room temperature or by adding a single crystal of pure material (a seed crystal). Recrystallization can also be carried out and / or performance optimized by using an antisolvent or cosolvent. In this case, the compound is dissolved in a suitable solvent at elevated temperature, filtered, and then an additional solvent in which the required compound has low solubility is added to aid crystallization. The crystals are then typically isolated by use of vacuum filtration, washed and then dried, for example, in an oven or by desiccation. Other examples of methods for purification include sublimation, which includes a heating step under vacuum, for example, using a cold finger, and crystallization from the melt (Crystallization Technology Handbook, 2nd Edition, edited by A Mersmann, 2001). BIOLOGICAL EFFECTS οη«ι ηη / 77Π7 / Ε / γ The compound of the invention is anticipated to be useful in medicine or therapy. Compounds of the invention, subgroups and examples thereof have been shown to inhibit SHP2. Such inhibition leads to inhibition of tumor cell proliferation and activation of T cell immune responses toward cancer cells, which may be useful for preventing or treating the disease states or conditions described herein, e.g. the diseases and conditions discussed below and the diseases and conditions described in the “Background of the Invention” section above in which SHP2 plays a role. Therefore, for example, it is anticipated that the compounds of the invention will be useful in alleviating or reducing the incidence of cancer, preventing or treating diseases or conditions mediated by SHP2, for example, diseases or conditions such as cancers in which there are mutations activators within upstream components (such as RAS, KRAS and NRAS) of the MAPK pathway or cancers activated by the receptor tyrosine kinase (RTK). The compounds of the present invention may be useful for the treatment of the adult population. The compounds of the present invention may be useful for the treatment of the pediatric population. The compounds of the present invention have been shown to be good inhibitors of SHP2. Compounds of formula (I) are capable of binding to SHP2 and exhibiting potency for SHP2. The efficacies of the compounds of the present invention against SHP2 have been determined by using the assay protocol described herein and other methods known in the art. More particularly, compounds of formula (I) and subgroups thereof have potency for SHP2. Certain compounds of the invention are those that have ICso values ​​less than 0.1 μΜ, in particular less than 0.01 or 0.001 μΜ. The function of SHP2 has been implicated in many diseases due to its role in cell survival and proliferation, primarily through activation of the RAS-ERK signaling pathway, as well as oncogenesis. As a consequence of their affinity for SHP2 it is anticipated that the compounds may be useful in treating or preventing a variety of diseases or conditions, including disorders associated with cell accumulation (e.g., cancer, autoimmune disorders, inflammation and restenosis), disorders where excessive apoptosis results in cell loss (e.g. stroke, heart failure, neurodegeneration such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, AIDS, ischemia (stroke, myocardial infarction) and osteoporosis ) or the treatment of autoimmune diseases such as multiple sclerosis (MS). Therefore, it is also anticipated that the compounds of the invention as defined herein may be useful in the treatment of other conditions such as inflammation, hepatitis, ulcerative colitis, gastritis, autoimmunity, inflammation, restenosis, stroke, heart failure. cardiac, neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, myotonic dystrophy, and amyotrophic lateral sclerosis, AIDS, ischemias such as traumatic brain injury, spinal cord injury, cerebral ischemia, οη«ι ηη / 77Π7 / Ε / γ cerebral ischemia / reperfusion (I / R) injury, acute and chronic CNS ischemia, stroke or myocardial infarction, degenerative diseases of the musculoskeletal system such as osteoporosis, autoimmune diseases such as multiple sclerosis ( MS) and type I diabetes, and eye diseases such as retinal degeneration that result from loss of control of programmed cell death. As a consequence of their activity against SHP2, it is anticipated that the compounds may be useful in the treatment or prevention of proliterative disorders such as cancer. Examples of cancers (and their benign counterparts) which can be treated (or inhibited) include, but are not limited to, tumors of epithelial origin (adenomas and carcinomas of various types, including adenocarcinomas, squamous cell carcinomas, cell carcinomas, transitional and other carcinomas) such as carcinomas of the bladder and urinary tract, breast, gastrointestinal tract (including esophagus, stomach (gastric), small intestine, colon, intestine, colorectal, rectum and anus), liver (hepatocellular carcinoma), gallbladder biliary and biliary system, exocrine pancreas, kidney (e.g., renal cell carcinoma), lung (e.g., adenocarcinomas, small cell lung carcinomas, non-small cell lung carcinomas, bronchioalveolar carcinomas, and mesotheliomas), head and neck (e.g., cancers of the tongue, oral cavity, larynx, pharynx, nasopharynx, tonsils, salivary glands, nasal cavity and paranasal sinuses), ovary, fallopian tubes, peritoneum, vagina, vulva, penis, testicles, cervix, myometrium, endometrium, thyroid ( for example, follicular thyroid carcinoma), brain, adrenal, prostate, skin and adnexa (for example, melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, dysplastic nevus); hematologic malignancies (i.e., leukemias, lymphomas) and premalignant hematologic disorders and borderline malignancy disorders, including hematologic malignancies and conditions that are associated with the lymphoid lineage (e.g., acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL ], B cell lymphomas such as diffuse large B cell lymphoma [DLBCL], follicular lymphoma, Burkitt lymphoma, mantle cell lymphoma, T cell lymphomas and leukemias, natural killer [NK] cell lymphomas, Hodgkin lymphomas , hairy cell leukemia, monoclonal gammopathy of undetermined significance, plasmacytoma, multiple myeloma, and posttransplant lymphoproliferative disorders), and hematologic malignancies and conditions that are associated with the myeloid lineage (e.g., acute myelogenous leukemia [AML], chronic myelogenous leukemia [CML], chronic myelomonocytic leukemia [CMML], hypereosinophilic syndrome, myeloproliferative disorders such as polycythemia vera, essential thrombocythemia and primary myelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome and promyelocytic leukemia); tumors of mesenchymal origin, for example, sarcomas of soft tissues, bones or cartilage such as osteosarcomas, fibrosarcomas, chondrosarcomas, rhabdomyosarcomas, leiomyosarcomas, liposarcomas, angiosarcomas, Kaposi's sarcoma, Ewing's sarcoma, synovial sarcomas, epithelioid sarcomas, gastrointestinal stromal tumors, benign and malignant histiocytomas, and dermatofibrosarcoma protuberans; tumors of the central or peripheral nervous system (for example, astrocytomas (for example, gliomas), neuromas and glioblastomas, meningiomas, ependymomas, pineal tumors and schwannomas); endocrine tumors (for example, pituitary tumors, adrenal οη«ι ηη / 77Π7 / Ε / γ tumors, islet cell tumors, parathyroid tumors, carcinoid tumors, and medullary thyroid carcinoma); ocular and adnexal tumors (for example, retinoblastoma); germ cell and trophoblastic tumors (e.g., teratomas, seminomas, dysgerminomas, hydatidiform moles, and choriocarcinomas); and pediatric and embryonal tumors (e.g., medulloblastoma, neuroblastoma, Wilms tumor, and primitive neuroectodermal tumors); or syndromes, congenital or otherwise, that leave the patient susceptible to neoplasia (e.g., xeroderma pigmentosum). Cell growth is a tightly controlled function. Cancer, a condition of abnormal cell growth, occurs when cells replicate uncontrollably (increase in number), grow uncontrollably (become larger), and / or experience a reduction in cell death through apoptosis (cell death). programmed), necrosis or anoikis. In one embodiment, abnormal cell growth is selected from uncontrolled cell proliferation, excessive cell growth, or reduction in programmed cell death. In particular, the condition or disease of abnormal cell growth is a cancer. Thus, in the pharmaceutical compositions, uses or methods of this invention for treating a disease or condition comprising abnormal cell growth (i.e., uncontrolled and / or rapid cell growth), the disease or condition comprising abnormal cell growth abnormal, in one embodiment, is a cancer. The compounds of the invention may be useful in the treatment of metastasis and metastatic cancers. Metastasis or metastatic disease is the spread of disease from one organ or part to another non-adjacent organ or part. Cancers that can be treated with the compounds of the invention include primary tumors (i.e., cancer cells at the site of origin), local invasion (cancer cells penetrating and infiltrating surrounding normal tissues in the local area), and metastatic tumors ( or secondary), that is, tumors that have formed from malignant cells which have circulated through the bloodstream (hematogenous spread) or through lymphatics or through body cavities (transcoelomic) to other sites and tissues in the body . In particular, the compounds of the invention may be useful in the treatment of metastasis and metastatic cancers. In one embodiment, the hematological malignancies are a leukemia. In another embodiment, the hematological malignancies are a lymphoma. In one embodiment, the cancer is AML. In another embodiment, the cancer is CLL. In one embodiment, the compound of the invention is for use in the prophylaxis or treatment of leukemia, such as acute or chronic leukemia, in particular acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), leukemia chronic lymphocytic leukemia (CLL), or chronic myeloid leukemia (CML). In one embodiment, the compound of the invention is for use in the prophylaxis or treatment of lymphoma, such as acute or chronic lymphoma, in particular Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or diffuse lymphoma. of large B lymphocytes. In one embodiment, the compound of the invention is for use in the prophylaxis or treatment of acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL). οη«ι ηη / 77Π7 / Ε / γ The cancers may be cancers which are sensitive to treatment with SHP2 inhibitors. The cancers may be cancers which overexpress SHP2. The cancers may be cancers which are SHP2 wild type. The cancers may be cancers which are SHP2 mutant. In one embodiment, the cancer has activating mutations in SHP2. Particular cancers include hepatocellular carcinoma, melanoma, esophageal, renal, colon, colorectal, lung, for example, NSCLC, mesothelioma or lung adenocarcinoma, breast, bladder, gastrointestinal, ovarian and prostate cancers. Particular cancers include those with activated SHP2 (activating mutations, amplified and / or with overexpression of wild type SHP2), for example, hepatocellular carcinoma, breast, lung, colorectal and neuroblastoma. Particular cancers include those with oncogenic alterations in the RAS-RAFMEK-ERK pathway, including mutant forms of KRAS. Particular cancers include those where RTK activity drives disease or resistance to cancer therapies. The compounds of the invention will be particularly useful in the treatment or prevention of cancers of a type associated with or characterized by the presence of elevated Ras, BRAF and / or MEK signaling. Elevated levels of Ras, BRAF, or MEK signaling are found in many cancer types and are associated with poor prognosis. In addition, cancers with Ras activating mutations may also be sensitive to an SHP2 inhibitor. Elevated levels of Ras signaling and mutations in Ras can be identified using the techniques described herein. A further subset of cancers consists of melanoma NRas and AML NRas. Another subset of cancers consists of KRas lung cancer, KRas pancreatic cancer, and KRas colorectal cancer (CRC). In one embodiment, the cancer is colorectal, breast, lung, and brain. In one embodiment, the cancer is a pediatric cancer. In one embodiment, the cancer is breast cancer, leukemia, lung cancer, liver cancer, gastric cancer, laryngeal cancer, or oral cancer. Whether a particular cancer is one which is sensitive to SHP2 inhibitors can be determined by a method as set forth in the section entitled "Diagnostic Methods". A further aspect provides the use of a compound for the manufacture of a medicament for the treatment of a disease or condition as described herein, in particular cancer. Certain cancers are resistant to treatment with particular drugs. This may be due to tumor type (most common epithelial malignancies are inherently chemoresistant and the prostate is relatively resistant to currently available chemotherapy or radiotherapy regimens) or resistance may arise spontaneously as the disease οη«ι ηη / ζζηζ progresses. / Ε / γ progresses or as a result of treatment. In this regard, references to the prostate include prostate resistant to antiandrogen therapy, particularly abiraterone or enzalutamide, or castration resistant prostate. Similarly, references to multiple myeloma include bortezomib-insensitive or refractory multiple myeloma and references to chronic myelogenous leukemia include imitanib-insensitive chronic myelogenous leukemia and refractory chronic myelogenous leukemia. In this regard, references to mesothelioma include mesothelioma resistant to topoisomerase poisons, alkylating agents, antitubulins, antifolates, platinum compounds, and radiation therapy, particularly cisplatin-resistant mesothelioma. References to melanoma include melanomas that are resistant to treatment with BRAF and / or MEK inhibitors. The compounds may also be useful in the treatment of tumor growth, pathogenesis, resistance to chemotherapy and radiotherapy by sensitizing cells to chemotherapy and as an antimetastatic agent. Therapeutic interventions against cancer of all types necessarily increase the stress placed on target tumor cells. SHP2 inhibitors represent a class of chemotherapeutics with the potential to: (i) sensitize malignant cells to anticancer drugs and / or treatments; (ii) alleviate or reduce the incidence of resistance to drugs and / or anticancer treatments; (iii) reverse resistance to drugs and / or cancer treatments; (iv) potentiate the activity of drugs and / or treatments against cancer; (v) delay or prevent the onset of resistance to cancer drugs and / or treatments. In one embodiment, the invention provides a compound for use in treating a disease or condition which is mediated by SHP2. In a further embodiment, the disease or condition that is mediated by SHP2 is a cancer that is characterized by overexpression and / or increased activity of SHP2. A further aspect provides the use of a compound for the manufacture of a medicament for the treatment of a disease or condition as described herein, in particular cancer. In one embodiment, a compound is provided for use in the prophylaxis or treatment of a disease or condition mediated by SHP2. In one embodiment, a pharmaceutical composition is provided that comprises an effective amount of at least one compound as defined. In a further aspect of the present invention, there is provided a compound as defined herein. In one embodiment, a method for the prophylaxis or treatment of cancer is provided comprising the steps of administering to a mammal a medicament comprising at least one compound as defined. DIAGNOSTIC METHODS Prior to administration of a compound of formula (I), a patient can be examined to determine whether a disease or condition from which the patient suffers or may be suffering is on«l 0017707IRIM amenable to treatment with a compound that inhibits SHP2. The term "patient" includes human and veterinary subjects such as primates, in particular human patients. For example, a biological sample taken from a patient can be analyzed to determine whether a condition or disease, such as cancer, that the patient suffers from or may be suffering from is characterized by a genetic abnormality or abnormal expression of proteins that leads to the upregulation of SHP2 levels or upregulation of a biochemical pathway downstream of SHP2. Examples of such abnormalities resulting in activation or sensitization of SHP2, loss or inhibition of regulatory pathways affecting SHP2 expression, upregulation of receptors or their ligands, cytogenetic aberrations, or the presence of mutant variants of receptors or ligands. Tumors with upregulation of SHP2, particularly overexpression or activating mutants of SHP2, or that include activating mutations in a Ras isoform such as KRAS, may be particularly sensitive to SHP2 inhibitors. Ras mutations have been detected in cell lines and primary tumors including, but not limited to, melanoma, colorectal cancer, non-small cell lung cancer, and cancers of the pancreas, prostate, thyroid, urinary tract, and upper respiratory tract (Cancer Res . 2012; 72:2457-2467). The term positive regulation includes elevated expression or overexpression, which includes gene amplification (i.e., multiple gene copies), cytogenetic aberration, and increased expression by a transcriptional or post-translational effect. Therefore, the patient can undergo a diagnostic test to detect a characteristic marker of SHP2 upregulation. The term diagnosis includes screening. Marker includes genetic markers including, for example, measurement of DNA composition to identify SHP2 amplification or the presence of SHP2 mutations, or to identify the presence of Ras mutations (e.g., KRAS). The term marker also includes markers that are characteristic of SHP2 upregulation, including protein levels, protein status, and mRNA levels of the proteins mentioned above. Gene amplification includes more than 7 copies, as well as gains of between 2 and 7 copies. Diagnostic assays to detect KRAS mutations are described in de Castro et al. Br. J. Cancer. July 10, 2012; 107(2):345-51. doi: 10.1038 / bjc.2012.259. Epub June 19, 2012, “A comparison of three methods for detecting KRAS mutations in formalin-fixed colorectal cancer specimens” and the references cited therein. Diagnostic tests and examinations are typically performed on a biological sample (i.e., body tissue or body fluids) selected from tumor biopsy samples, blood samples (isolation and enrichment of removed tumor cells), cerebrospinal fluid, plasma, serum , saliva, stool biopsies, sputum, chromosome analysis, pleural fluid, peritoneal fluid, buccal swabs, skin or urine biopsy. Methods of identification and analysis of cytogenetic aberration, genetic amplification, mutations and protein upregulation are known to those skilled in the art. Detection methods could οη«ι ηη / 77Π7 / Ε / γ include, but are not limited to, standard methods such as DNA sequence analysis by conventional Sanger or next generation sequencing methods, chain reaction reverse transcriptase polymerase (RT-PCR), RNA sequencing (RNAseq), nanostrand hybridization proximity RNA nCounter assays such as fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) allele specific. Newer next-generation sequencing (NGS) technologies, such as massively parallel sequencing, allow for whole-exorna sequencing or whole-genome sequencing. In RT-PCR screening, the level of mRNA in the tumor is assessed by creating a cDNA copy of the mRNA followed by amplification of the cDNA by PCR. PCR amplification methods, primer selection, and conditions for amplification are known to those skilled in the art. Nucleic acid manipulations and PCR are carried out by standard methods, as described, for example, in Ausubel, F.M. and others, eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc., or Innis, M.A. and others, eds. (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are also described in Sambrook et al., (2001), 3aEd, Molecular Cloning: A Laboratory Manual, Coid Spring Harbor Laboratory Press. Alternatively, a commercially available kit for RT-PCR (e.g., Roche Molecular Biochemicals) may be used, or the methodology set forth in US Patents 4,666,828; 4,683,202; 4,801,531; 5,192,659, 5,272,057, 5,882,864, and 6,218,529 and are incorporated herein by reference. An example of an in situ hybridization technique for assessing mRNA expression would be fluorescence in situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152:649). In general, in situ hybridization comprises the following main steps: (1) fixation of the tissue to be tested; (2) prehybridization treatment of the sample to increase the accessibility of the target nucleic acid and reduce non-specific binding; (3) hybridization of the nucleic acid mixture to the nucleic acid in the biological tissue or scaffold; (4) post-hybridization washes to remove nucleic acid fragments that do not bind upon hybridization, and (5) detection of hybridized nucleic acid fragments. Probes used in such applications are typically labeled, for example, with radioisotopes or fluorescent indicators. Certain probes are sufficiently long, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, to allow specific hybridization with the target nucleic acid(s) under stringent conditions. Standard methods for carrying out FISH are described in Ausubel, F.M. and others, eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical OverView by John M. S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pages 077-088; Series: Methods in Molecular Medicine. Methods for determining gene expression are described in (DePrimo et al (2003), BMC Cancer, 3:3). Briefly, the protocol is as follows: double-stranded cDNA is synthesized from total RNA by using a (dT)24 oligomer to prime the synthesis of first-strand cDNA οη«ι ηη / 77Π7 / Ε / γ polyadenylated mRNA, followed by second-strand cDNA synthesis with random hexamer primers. Double-stranded cDNA is used as a template for in vitro transcription of cDNA using biotinylated ribonucleotides. The cRNA is chemically fragmented according to protocols described by Affymetrix (Santa Clara, CA, United States), and then hybridized overnight with gene-specific oligonucleotide probes on human genome arrays. Alternatively, single nucleotide polymorphism (SNP) arrays, a type of DNA microarray, can be used to detect polymorphisms within a population. Alternatively, protein products expressed from mRNAs can be analyzed by immunohistochemistry of tumor samples, solid-phase immunoassay with microtiter plates, immunoelectroblotting, two-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry, and other methods. known in the art for the detection of specific proteins for example, capillary electrophoresis. Detection methods would include the use of site-specific antibodies. Those skilled in the art will recognize that all of these well-known techniques can be used for the detection of upregulation of SHP2, detection of SHP2 or SHP2 variants or mutants, or loss of negative regulators of SHP2 in the present case. Abnormal levels of proteins such as SHP2 can be measured by using standard protein assays, for example, the assays described herein. Elevated levels or overexpression could also be detected in a tissue sample, for example, tumor tissue, by measuring protein levels with an assay such as that from Chemicon International. The protein of interest would be immunoprecipitated from the sample and its levels would be measured. Testing methods also include the use of markers. In other words, overexpression of SHP2 or mutant SHP2 can be measured by tumor biopsy. Methods for assessing gene copy changes include techniques commonly used in cytogenetics laboratories such as MLPA (multiplex ligand-gated probe amplification), a multiplex PCR method that detects abnormal copy numbers, or other detection techniques. PCRs that can detect gene amplification, gain and deletion. Exfunctional assays could also be used where appropriate, for example measuring circulating leukemia cells in a cancer patient, to assess response to challenge with an SHP2 inhibitor. Therefore, all of these techniques could also be used to identify tumors particularly suitable for treatment with the compounds of the invention. Therefore, in a further aspect of the invention, the use of a compound according to the invention for the manufacture of a medicament for the treatment or prophylaxis of a condition or disease state in a patient who has been examined is included. and have been determined to have or be at risk for a disease or condition which would be susceptible to treatment with an SHP2 inhibitor. οη«ι ηη / ζζηζ / Ε / γ Another aspect of the invention includes a compound of the invention for use in the prophylaxis or treatment of cancer in a patient selected from a subpopulation possessing SHP2 amplification. Another aspect of the invention includes a compound of the invention for use in the prophylaxis or treatment of cancer in a patient possessing loss of a negative regulator of SHP2. Another aspect of the invention includes a compound of the invention for use in the prophylaxis or treatment of cancer in a patient selected from a subpopulation possessing RTK-driven activation of the MAPK signaling pathway. MRI determination of vessel normalization (e.g., using MRI gradient echo, rotation echo, and contrast enhancement to measure blood volume, relative vessel size, and vascular permeability) in combination with circulating biomarkers can also be used to identify patients suitable for treatment with a compound of the invention. Therefore, a further aspect of the invention is a method for the diagnosis and treatment of a condition or disease state mediated by SHP2, which method comprises (i) examining a patient to determine whether a disease or condition from which the patient suffers or may be suffering from is one which would be susceptible to treatment with an SHP2 inhibitor; and (i) where the disease or condition to which the patient is therefore susceptible is indicated, the patient is then administered a compound of formula (I) and subgroups or examples thereof as defined in the present description. Advantages of the compounds of the invention The compounds of formula (I) have a number of advantages over prior art compounds. The compounds of the invention may have a particular advantage in one or more of the following aspects: (i) Higher power; (i) Superior in vivo efficacy (II) Superior PK; (iv) Superior metabolic stability; (v) Superior oral bioavailability; (vi) Superior physicochemical properties; and / or (vii) Superior safety profile or therapeutic index (TI). Superior in vivo potency and efficacy Compounds of formula (I) have an increase in affinity for SHP2 and, in particular, an increase in cellular potency against cell lines known to be sensitive to SHP2 antagonists. The enhancement of target binding is a highly desirable property in a pharmaceutical compound since it allows a reduction in the drug dose and a good separation (“therapeutic window”) between the activity and the toxic effects of SHP2. on«l 00177077B / Y Compounds of formula (I) have better cellular potency and / or better selectivity for SHP2 cell lines. As a result of an increase in potency against SHP2, the compounds of the invention may have an increase in in vivo efficacy in cell lines and in vivo models of cancer. PK and superior metabolic stability Compounds of formula (I) may have advantageous ADMET properties, for example, improved metabolic stability (e.g., as determined with mouse liver microsomes), improved P450 profile, short half-life and / or beneficial clearance ( for example, low or high clearance). Many compounds of formula (I) have also been found to have a better PK profile. These characteristics could confer the advantage of having more drugs available in the systemic circulation to reach the appropriate site of action to exert their therapeutic effect. Increasing drug concentrations to exert pharmacological action on tumors potentially leads to improved efficacy which thus allows for a reduction in dosage administration. Therefore, compounds of formula (I) should exhibit a reduction in dosage requirements and should be more easily formulated and administered. This results in a good separation (“therapeutic window”) between SHP2 activity and toxic effects. Many compounds of formula (I) have a reduction in Cmax that is required for efficacy (due to improved SHP2 and / or PK potency). Superior oral bioavailability Potentially, compounds of the invention have physicochemical properties suitable for oral exposure (oral exposure or AUC). In particular, compounds of formula (I) may exhibit better oral bioavailability or better reproducibility of oral absorption. Oral bioavailability can be defined as the ratio (F) of the plasma exposure of a compound when dosed orally to the plasma exposure of the compound when dosed intravenously (i.v.), expressed as a percentage. Compounds having an oral bioavailability (F value) of greater than 10%, 20% or 30%, more particularly greater than 40%, are particularly advantageous because they can be administered orally instead of, or as well as, by administration parenteral. Superior physicochemical properties Compounds of formula (I) may have advantageous physicochemical properties, in particular chemical stability under acidic conditions and a reduction in lipophilicity. Lipophilicity can be measured by using a partition coefficient (logP) or a distribution coefficient (logD). The partition coefficient is a ratio of concentrations of non-ionized compound between two immiscible phases (n-octanol and water) in equilibrium, while the distribution coefficient is the ratio of the sum of the concentrations of all forms of the compound ( ionized plus non-ionized) in each of the two phases. High lipophilicity is associated with poor drug properties, such as low aqueous solubility, poor pharmacokinetic properties (low oral bioavailability), unwanted drug metabolism, and high promiscuity. οη«ι ηη / ζζηζ / Ε / γ compounds with optimal lipophilicity might have higher chances of success in drug development. However, reduction of logP (or calculated logP, clogP) may be difficult to achieve while maintaining an acceptable level of potency for inhibition of protein-protein interactions (PPI) due to the lipophilic nature of the targets being targeted. they imply. Safety profile or superior therapeutic index (TI) In the late 1990s, a number of drugs, which were approved by the US FDA, had to be withdrawn from sale in the United States when they were found to be involved in deaths caused by poor heart function. . Later it was discovered that a side effect of these drugs was the development of arrhythmias caused by the blockage of hERG channels in heart cells. The hERG channel is one of a family of potassium ion channels whose first member was identified in the late 1980s in a mutant Drosophila melanogaster fruit fly (see Jan, L.Y. and Jan, Y.N. (1990). A Superfamily of Ion Channels. Nature, 345(6277):672). The biophysical properties of the hERG potassium ion channel are described in Sanguinetti, M.C., Jiang, C., Curran, M.E., and Keating, M.T. (nineteen ninety five). A Mechanistic Link Between an Inherited and an Acquired Cardiac Arrhythmia: HERG encodes the Ikr potassium channel. Cell, 81:299307, and Trudeau, M.C., Warmke, J.W., Ganetzky, B., and Robertson, G.A. (nineteen ninety five). HERG, a Human Inward Rectifier in the Voltage-Gated Potassium Channel Family. Science, 269:92-95. Therefore, elimination of hERG blocking activity remains an important consideration in the development of any new drug. Compounds that have a reduction in hERG activity and / or have a good separation between hERG activity and activity have a higher "therapeutic window" or "therapeutic index". One method to measure hERG activity is the membrane attachment electrophysiology method. Alternative methods for measuring hERG functional activity include hERG binding assays, which can use commercially available membranes that are isolated from cells stably expressing the hERG channel or commercially available cell lines expressing the hERG channel. Compounds may also have a better cardiac safety index (CSI) [CSI = IC50 of hERG / Cmax (unbound)] (Shultz et al., J. Med. Chem., 2011; Redfern et al., Cardiovasc. Res., 2003). This may be due to an increase in the hERG IC50 or a decrease in the Cmax that is required for efficacy (due to better power and / or PK). Particular compounds may show a CV advantage in vivo. Some particular compounds have a reduction in hERG ion channel blocking activity. Compounds may have mean ICso values ​​against hERG that are greater than 30-fold, or greater than 40-fold, or greater than 50-fold the ICso values ​​of the compounds in cell proliferation assays. PHARMACEUTICAL FORMULATIONS While it is possible for the active compound to be administered alone, it is generally presented as a pharmaceutical composition (e.g., formulation). οη«ι ηη / ζζηζ / Ε / γ Therefore, the present invention further provides pharmaceutical compositions, as defined above, and methods of preparing a pharmaceutical composition comprising (e.g., mixing) at least one compound of formula (I) (and subgroups thereof as defined in the present description), together with one or more pharmaceutically acceptable excipients and, optionally, other therapeutic or prophylactic agents as described in the present description. The pharmaceutically acceptable excipient(s) may be selected from, for example, carriers (e.g., a solid, liquid or semi-solid carrier), adjuvants, diluents, filling or bulking agents, granulating agents. , coating agents, release control agents, binding agents, disintegrants, lubricating agents, preservatives, antioxidants, buffering agents, suspending agents, thickening agents, flavoring agents, sweeteners, flavor masking agents, stabilizers or any other excipient that It is conventionally used in pharmaceutical compositions. Examples of excipients for various types of pharmaceutical compositions are set out in more detail below. The term “pharmaceutically acceptable,” as used herein, refers to compounds, materials, compositions and / or dosage forms that are, within the scope of good medical judgment, suitable for use in contact with tissue. a subject (e.g., a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, in proportion to a reasonable risk / benefit ratio. Each excipient must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation. Pharmaceutical compositions containing compounds of formula (I) can be formulated according to known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, United States. The pharmaceutical compositions can be found in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intravaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they may be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery to a target organ or tissue by injection, infusion or other means of delivery. Delivery may be by bolus injection, short-term infusion or long-term infusion and may be by passive delivery or by use of a suitable infusion pump or syringe driver. Pharmaceutical formulations adapted for parenteral administration include sterile aqueous and non-aqueous injection solutions that may contain antioxidants, buffers, bacteriostats, cosolvents, surfactants, organic solvent mixtures, cyclodextrin complexing agents, emulsifying agents (to form and stabilize formulations emulsion), liposome components to form liposomes, gelling polymers to form polymeric gels, lyophilization protectants and combinations of agents to, among others, stabilize the active ingredient in a soluble form and make the formulation isotonic with the blood of the intended recipient. Pharmaceutical formulations for parenteral administration may also take the form of sterile aqueous and non-aqueous suspensions which may include suspending agents and thickening agents (R. G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21(2) 2004, pages 201-230). Formulations may be presented in unit or multiple dose containers, e.g. sealed ampoules, vials and pre-filled syringes, and may be stored in a cryo-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, e.g. , water for injectable preparations, immediately prior to use. In one embodiment, the formulation is provided as an active pharmaceutical ingredient in a bottle for subsequent reconstitution by use of an appropriate diluent. The pharmaceutical formulation can be prepared by lyophilization of a compound of formula (I), or subgroups thereof. Freeze-drying refers to the cryo-drying procedure of a composition. Therefore, in the present description, freeze-drying and cryo-drying are used synonymously. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets. The pharmaceutical compositions of the present invention for parenteral injection may also comprise sterile pharmaceutically acceptable aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (such as sunflower oil , safflower oil, corn oil or olive oil), and injectable organic asters such as ethyl oleate. Adequate fluidity can be maintained, for example, by the use of thickening materials such as lecithin, by maintaining the particle size required in the case of dispersions, and by the use of surfactants. The compositions of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include tonicity-adjusting agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable dosage form can be produced by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin. In a typical embodiment of the invention, the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion. For intravenous administration, the solution may be dosed as is or may be injected into an infusion bag (containing a pharmaceutically acceptable excipient, such as 0.9% saline or dextrose). at 5%), before administration. In another typical embodiment, the pharmaceutical composition is in a form suitable for subcutaneous (s.c.) administration. Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), tablets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as mouth patches. Thus, tablet compositions may contain a unit dose of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, for example; lactose, sucrose, sorbitol or mannitol; and / or a non-sugar-derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and starches such as starch of corn. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (for example, swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (for example, stearates), preservatives (for example, parabens), antioxidants (eg, BHT), buffering agents (eg, phosphate or citrate buffers), and effervescent agents such as citrate / bicarbonate mixtures. Such excipients are well known and need not be discussed in detail herein. Tablets can be designed to release the drug either upon contact with stomach fluids (immediate-release tablets) or to release in a controlled manner (controlled-release tablets) over a prolonged period of time or with a specific region of the Gl tract. . Capsule formulations can be hard gelatin or soft gelatin and can contain the active component in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or synthetic or plant-derived equivalents thereof. Solid dosage forms (eg, tablets, capsules, etc.) may be coated or uncoated. Coatings can act as a protective film (eg, a polymer, wax, or varnish) or as a mechanism to control drug release or for aesthetic or identification purposes. The coating (eg, a Eudragit™ type polymer) can be designed to release the active component at a desired location within the gastrointestinal tract. Thus, the coating can be selected to degrade under certain pH conditions within the gastrointestinal tract, thereby releasing the compound selectively in the stomach or ileum, duodenum, jejunum, or colon. . Instead of, or in addition to, a coating, the drug can be presented in a solid matrix comprising a release-controlling agent, for example, a release-delaying agent, which can be tailored to release the compound in a controlled manner in the gastrointestinal tract. Alternatively, the drug can be presented in a polymer coating, for example, a ΟΠΕΙ nn / 77A7 / E / Y Polymethacrylate polymer coating, which can be tailored to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or release delay coating may take the form of an erodible polymer (for example, a maleic anhydride polymer) which erodes substantially continuously as the dosage form passes through the tract. gastrointestinal. In another alternative, the coating can be designed to disintegrate under microbial action in the intestine. As a further alternative, the active compound can be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed release or sustained release formulations (eg, ion exchange resin based formulations) can be prepared according to methods well known to those skilled in the art. The compound of formula (I) can be formulated with a carrier and administered in the form of nanoparticles, where the increase in the surface area of ​​the nanoparticles helps its absorption. Furthermore, nanoparticles offer the possibility of direct penetration into the cell. Nanoparticle drug delivery systems are described in "Nanoparticle Technology for Drug Delivery", edited by Ram B Gupta and Uday B. Kompella, Informa Healthcare, ISBN 9781574448573, published March 13, 2006. Nanoparticles for drug delivery Drugs are also described in J. Control. Release, 2003, 91 (1-2), 167-172, and in Sinha et al. Mol. Cancer Ther. August 1, (2006) 5, 1909. Pharmaceutical compositions typically comprise from about 1% (w / w) to about 95% active ingredient and from 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient or combination of excipients. Typically, the compositions comprise from about 20% (w / w) to about 90% (w / w) of active ingredient and from 80% (w / w) to 10% (w / w) of an excipient or a combination of pharmaceutically acceptable excipients. The pharmaceutical compositions comprise from about 1% to about 95%, typically from about 20% to about 90% active ingredient. The pharmaceutical compositions according to the invention can be found, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre-filled syringes, dragees, tablets or capsules. The pharmaceutically acceptable excipient(s) may be selected according to the desired physical form of the formulation and, for example, may be selected from diluents (e.g., solid diluents such as fillers or volumetric; and liquid diluents such as solvents and cosolvents), disintegrants, buffering agents, lubricants, flow aids, release control agents (e.g., release retarding polymers or waxes), binders, granulating agents, pigments , plasticizers, antioxidants, preservatives, flavoring agents, flavor masking agents, tonicity adjusting agents and coating agents. on«i ηη / ζζηζ / Ε / γ Experts will have the experience to select the appropriate amounts of ingredients for use in formulations. For example, tablets and capsules typically contain 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids, and / or 0-99% (w / w) filling or bulking agents ( depending on the dose of the drug). They may also contain 0-10% (w / w) polymer binders, 0-5% (w / w) antioxidants, 0-5% (w / w) pigments. Slow release tablets would also contain 0-99% (w / w) polymers (depending on dosage). Tablet or capsule film coatings typically contain 0-10% (w / w) release control polymers (e.g., retardants), 0-3% (w / w) pigments and / or 0-2 % (w / w) of plasticizers. Parenteral formulations generally contain 0-20% (w / w) buffers, 0-50% (w / w) cosolvents, and / or 0-99% (w / w) water for injection (WFI) (depending on of the dose and whether they have been lyophilized). Formulations for intramuscular depots may also contain 0-99% (w / w) oils. Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, by granulating a resulting mixture, if desired, and by processing the mixture, if desired or necessary, after the addition of excipients. appropriate, in tablets, dragee cores or capsules. They may also be incorporated into a polymer or waxy matrix that allows the active ingredients to diffuse or be released in measured amounts. The compounds of the invention can also be formulated as solid dispersions. Solid dispersions are extremely fine homogeneous dispersed phases of two or more solids. Solid solutions (molecular dispersion systems), a type of solid dispersion, are well known for their use in pharmaceutical technology (see (Chiou and Riegelman, J. Pharm. Sci., 60, 1281-1300 (1971)) and They are useful for increasing dissolution rates and increasing the bioavailability of poorly water soluble drugs. This invention also provides solid dosage forms comprising the solid solution described herein. Solid dosage forms include tablets, capsules, chewable tablets, and dispersible or effervescent tablets. Known excipients can be mixed with the solid solution to provide the desired dosage form. For example, a capsule may contain the solid solution that is mixed with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant and a surfactant. Additionally, a capsule may contain a bulking agent, such as lactose or microcrystalline cellulose. A tablet may contain the solid solution that is mixed with at least one disintegrant, a lubricant, a surfactant, a bulking agent and a glidant. A chewable tablet may contain the solid solution which is mixed with a bulking agent, a lubricant and, if desired, an additional sweetening agent (such as an artificial sweetener), and suitable flavorings. Solid solutions can also be formed by spraying solutions of drug and a suitable polymer onto the surface of inert carriers such as οη«ι ηη / 77Π7 / Ε / γ such as sugar microspheres (“peas”). These microspheres can be subsequently filled into capsules or compressed into tablets. Pharmaceutical formulations may be presented to a patient in “patient packages” that contain a complete course of treatment in a single package, commonly a blister pack. Patient packs have an advantage over traditional prescriptions, where a pharmacist divides the patient's supply of a pharmaceutical product from a bulk supply, in that the patient always has access to the leaflet contained in the patient pack, which is normally absent from patient prescriptions. The inclusion of a package insert has been shown to improve patient compliance with physician instructions. Compositions for topical use and nasal delivery include ointments, creams, sprays, patches, gels, liquid drops and inserts (e.g., intraocular inserts). Such compositions can be formulated according to known methods. Examples of formulations for rectal or intravaginal administration include weights and suppositories which may be found formed, for example, from a molded or waxy material containing the active compound. Solutions of the active compound can also be used for rectal administration. Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and may be administered in a standard manner through the use of powder inhaler devices or aerosol dispensing devices. Such devices are well known. For administration by inhalation, powder formulations typically comprise the active compound together with an inert solid powder diluent such as lactose. Compounds of formula (I) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, for example, from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, the particular subranges of the compound are 0.1 milligrams to 2 grams of active ingredient (most commonly 10 milligrams to 1 gram, e.g., 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (e.g., 1 microgram to 10 milligrams, for example, 0.1 milligrams to 2 milligrams of active ingredient). For oral compositions, a unit dosage form may contain 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, for example, 100 milligrams to 1 gram of active compound. The active compound will be administered to a patient in need thereof (for example, a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect. TREATMENT METHODS Compounds of formula (I) and subgroups as defined herein may be useful in the prophylaxis or treatment of a range of SHP2-mediated οη«ι ηη / 77Π7 / Ε / γ conditions or disease states. Examples of such conditions or disease states are set out above. The compounds are generally administered to a subject in need of such administration, for example a human or animal patient, typically a human. The compounds will typically be administered in amounts that are therapeutically or prophylactically useful and which are generally non-toxic. However, in certain situations (for example, in the case of life-threatening diseases), the benefits of administering a compound of formula (I) may outweigh the disadvantages of any toxic effects or side effects, in which case It may be considered desirable to administer compounds in amounts associated with a degree of toxicity. The compounds may be administered for a prolonged period to maintain beneficial therapeutic effects or may be administered only for a short period. Alternatively, they may be administered continuously or in a manner that provides intermittent dosing (e.g., pulsatile manner). A typical daily dose of the compound of formula (I) can be found in the range of 100 picograms to 100 milligrams per kilogram of body weight. The compounds of the invention can also be administered by bolus or continuous infusion. The amount of compound that is administered and the type of composition that is used will be proportional to the nature of the disease or physiological condition being treated and will be at the discretion of the physician. It may be beneficial to use a compound of the invention as a single agent or to combine the compound of the invention with another agent which acts by a different mechanism to regulate cell growth, thus addressing two of the developmental features of the cancer. Combinations of experiments can be carried out, for example, as described in Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regulat 1984;22:27-55. Compounds as defined herein may be administered as the sole therapeutic agent or may be administered in combination therapy with one or more other compounds (or therapies) for the treatment of a particular disease state, e.g., a neoplastic disease such as cancer as defined above in the present description. In one embodiment, the combination therapy comprises a compound of formula I and one or more other anticancer compounds (or therapies) for the treatment of cancer. For the treatment of the above conditions, the compounds of the invention may be advantageously employed in combination with one or more medicinal agents, more particularly, with other anticancer agents or adjuvants (support agents in therapy) in anticancer therapy. cancer. Examples of other therapeutic agents or treatments that can be administered together (either at the same time or at different time intervals) with the compounds of formula (I) include, but are not limited to: οη«ι ηη / 77Π7 / Ε / γ 1. Topoisomerase I inhibitors; 2. Antimetabolites and nucleoside derivatives; 3. Tubulin-targeting agents, including vinca alkaloids, epothilones, tubulin-binding agents, and taxanes; 4. DNA binders such as platinum and anthracycline agents and topoisomerase II inhibitors; 5. Alkylating agents; 6. Monoclonal antibodies; 7. Antihormones such as GnRA, estrogen receptor antagonists, selective estrogen receptor modulators (SERMs), aromatase inhibitors, antiandrogens; 8. Signal transduction inhibitors; 9. Proteasome inhibitors; 10. DNA methyl transferase inhibitors; 11. Recombinant interferons and retinoids; 12. Therapies that target chromatin; 13. Radiotherapy; I 14. Other therapeutic or prophylactic agents. Examples of other therapeutic agents or treatments that can be administered together (either at the same time or at different time intervals) with the compounds of formula (I) include, but are not limited to: I. Platinum compounds; II. Taxane compounds; III. Topoisomerase I inhibitors; IV. Topoisomerase II inhibitors; V. Vinca alkaloids; SAW. Nucleoside derivatives; Vile. Antimetabolites; VIII. Alkylating agents; IX. Other cytotoxics; X. Anthracyclines, anthracenediones and related drugs; XI. Epothilones; XII. DNA methyl transferase inhibitors; XIII. Histone methyl transferase inhibitors; XIV. Antifolates; XV. Cytotoxic antibiotics; XVI. Tubulin binding agents; XVII. Signal transduction inhibitors; XVIII. Mitotic kinase inhibitors; οη«ι ηη / 77Π7 / Ε / γ XIX. CDK inhibitors; XX. PI3K / AKT pathway inhibitors; XXI. ERK inhibitors; XXII. Hsp90 inhibitors; 5 XXIII. Monoclonal antibodies, antibody derivatives, bispecific antibodies and antibody-like therapeutic proteins or other therapeutic proteins and related agents; XXIV. Estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or estrogen synthesis inhibitors; 10 XXV. Aromatase inhibitors and related drugs; XXVI. Antiandrogens (i.e., androgen receptor antagonists) and related agents; XXVII. Hormones and analogues thereof; XXVIII. Steroids; 15 XXIX. Steroid cytochrome P450 17 alpha-hydroxylase-17,20-lyase (CYP17) inhibitor; XXX. Gonadotropin-releasing hormone agonists or antagonists (GnRA); XXXI. Glucocorticoids; XXXII. Differentiating agents; XXXIII. Hedgehog pathway inhibitors; 20 XXXIV. Dehydrogenase inhibitors; XXXV. Exportin 1 inhibitors; XXXVI. Polymerase inhibitors; XXXVII. Farnesyltransferase inhibitors; XXXVIII. Therapies that target chromatin; 25 XXXIX. Drugs that target the ubiquitin-proteasome pathway, including proteasome inhibitors; XL. Photodynamic drugs; XLI. Anticancer agents derived from marine organisms; XLII. Radiolabeled drugs for radioimmunotherapy; 30 XLIII. Telomerase inhibitors; XLIV. Matrix metalloproteinase inhibitors; XLV. Recombinant interferons and interleukins; XLVI. Selective immune response modulators; XLVII. Therapeutic vaccines; 35 XLVIII. Cytokine activating agents; XLIX. Cytokine conjugates; L. Arsenic trioxide; LI. G protein-coupled receptor (GPCR) inhibitors; οη«ι ηη / ζζηζ / Ε / γ 100 LIL Enzymes; LUI. DNA repair inhibitors; LIV. Death agonist receptor; LV. Other immunotherapies; LVL Regulators of cell death (apoptosis); LVIL Modifiers or gene editors; LVIII. Bromodomain inhibitors; LIX. Radiotherapy for radical, palliative or prophylactic purposes (or, for adjuvant or neoadjuvant purposes); I LX. Prophylactic agents (adjuvants); that is, agents that reduce or alleviate some of the side effects associated with chemotherapy agents. In one embodiment, the combination therapy comprises a compound of formula I and one or more other anticancer compounds (or therapies) for the treatment of cancer, optionally in combination with radiotherapy and / or prophylactic agents. In one embodiment, the combination therapy comprises a compound of formula I in combination with radiotherapy and / or prophylactic agents. Particular examples of anticancer agents or adjuvants (or salts thereof) include, but are not limited to, any of the agents selected from groups (I) - (LIX) and optionally group (LX), below : I. Platinum compounds, for example cisplatin (optionally combined with amifostine), carboplatin, oxaliplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, satraplatin or triplatin tetranitrate, in particular cisplatin, carboplatin, or oxaliplatin; II. Taxane compounds, for example paclitaxel, paclitaxel protein binding particles (Abraxane™), docetaxel, cabazitaxel, larotaxel; ortataxel, tesetaxel or simotaxel, in particular paclitaxel, paclitaxel protein binding particles (Abraxane™), or docetaxel; III. Topoisomerase I inhibitors, for example camptothecin compounds, for example camptothecin, irinotecan (CPT11), SN-38, topotecan, bryostatin, kallistatin, nogitecan, belotecan, exatecan, rubitecan or lurtotecan, in particular camptotecan, irinotecan or topotecan; IV. Topoisomerase II inhibitors, for example antitumor epipodophyllotoxins or podophyllotoxin derivatives, for example etoposide, teniposide, sobuzoxane, edotecarin, amonafide, amrubicin or pixantrone, in particular etoposide or teniposide; V. Vinca alkaloids, for example vinblastine, vincristine, liposomal vincristine (OncoTCS), vinorelbine, vindesine, vinflunine, vinvesir, eribulin or taliblastine; in particular vinblastine, vincristine or vinorelbine; SAW. Nucleoside derivatives, e.g. 5-fluorouracil (5-FU, optionally in combination with leucovorin, e.g. LV5FU2), gemcitabine, capecitabine, tegafur (optionally in combination with uracil known as UFT, or in combination with οη«ι ηη / 77Π7 / Ε / γ 101 gimeracil and oteracil potassium known as TS- 1 or S1), cladribine, cytarabine (Ara-C, cytosine arabinoside), fludarabine, clofarabine, nelarabine; forodesine, doxifluridine, galocitabine, sapacitabine, emitefur, or troxacitabine; Vile. Antimetabolites, for example clofarabine, aminopterin or methotrexate, azacytidine, cytarabine, floxuridine, pentostatin, thioguanine, thiopurine, 6-mercaptopurine, hydroxyurea (hydroxycarbamide) or trifluridine (optionally in combination with tipiracil); VIII. Alkylating agents, such as nitrogen mustards or nitrosourea, for example cyclophosphamide, chlorambucil, carmustine (BCNU), ambamustine, bendamustine, thiotepa, melphalan, treosulfan, lomustine (CCNU), busulfan, dacarbazine, estramustine, fotemustine, ifosfamide (optionally in combination with mesna), pipobromane, procarbazine, streptozocin, temozolomide, uracil, mechlorethamine, mechlorethamine oxide hydrochloride, methylcyclohexylchloroethylnitrosurea, nimustine (ACNU), prednimustine, mechlorethamine, etoglucide; streptozotocin, irofulven, mitolactol, glufosfamide, evofosfamide, ethyleneimines or methylamelamines including altretamine, triethylenemelamine, trimethylololmelamine, triethylenephosphoramide, triethylenethiophosphoramide, or trimemylololamine; IX. Other cytotoxics, such as dolastatin, eleutherobin, pancratistatin, sarcodictyin A, or spongistatin; X. Antraciclinas, antracenodionas y fármacos relacionados, por ejemplo, daunorrubicina, doxorrubicina (opcionalmente en combinación con dexrazoxano), formulaciones liposomales de doxorrubicina (por ejemplo, Caelyx™, Myocet™, Doxil™), idarrubicina, mitoxantrona, epirrubicina o amsacrina, o valrubicin; XI. Epothilones, for example ixabepilone, patupilone, BMS-310705, epothilone A, epothilone B, deoxypothilone B (also known as epothilone D or KOS-862), aza-epothilone B (also known as BMS-247550), aulimalide, isolaulimalide, or lueterobin; XII. DNA methyl transferase inhibitors, for example temozolomide, azacitidine, decitabine (alone or in combination with a cytidine deaminase inhibitor, such as cedazurdine) or guadecitabine (SGI-110); XIII. Histone methyl transferase inhibitors, for example EZH2 inhibitors such as tazemetostat, PF-06821497, CPI-1205 or CPI-0209; XIV. Antifolates, for example methotrexate, disodium pemetrexed, raltitrexed, pralatrexate, edatrexate or trimetrexate; XV. Cytotoxic antibiotics, for example, antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin, mithramycin, aclarubicin, pirarubicin, anthramycin, azaserine, cactinomycin, calicheamicin, carabinomycin, scintorubicin, spectricin, carabinomycin, carminomycin, marcelomycin, olivomycins, peplomycin, puromycin, chelamycin, rebecamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, dynemycin including dynemycin A, centanamycin (CC-1065), including its synthetic analogue adozelesin, carzelesin, and on«l 0017707IRIM 102 bizelesin, duocarmycin, including the synthetic analogue pibrozelesin (KW-2189), or zinostatin; XVI. Tubulin binding agents, for example combrestatin, colchicines, demecolcine, noscapine or nocodazole; XVII. Signal transduction inhibitors such as kinase inhibitors, for example receptor tyrosine kinase inhibitors (e.g. EGFR (epidermal growth factor receptor (Erbbl) inhibitors), VEGFR (growth factor receptor) inhibitors vascular endothelial), PDGFR (platelet-derived growth factor receptor) inhibitors, FGFR (fibroblast growth factor receptor inhibitors), Axl inhibitors, MTKI (multi-target kinase inhibitors), c-Kit inhibitors , other Erbb inhibitors, e.g. Errb2 (HER2), Errb3 (HER3) or Errb4 (HER4), Trk inhibitors, Flt3 inhibitors, JAK inhibitors, RET inhibitors, MET inhibitors, Btk inhibitors, ALK inhibitors , ROS1 inhibitors, FYN inhibitors, Src inhibitors, Bcr-Abl inhibitors, hexokinase inhibitors, Raf inhibitors, ROCK inhibitors, MEK inhibitors or PI3K inhibitors, for example, imatinib, erlotinib, gefitinib, afatinib ( dual EGFR / HER2), brigatinib (ALK / EGFR), osimertinib (EGFR), almonertinib (EGFR), olmutinib (EGFR), icotinib (EGFR), alflutinib (EGFR), lazertinib (EGFR), zorifertinib (EGFR), mefatinib ( EGFR), sutetinib (EGFR), dasatinib, lapatinib (EGFR) dovitinib (CHIR 258), axitinib (AG-13736), nilotinib, vandetanib, vatalinib, saracatinib (AZD-0530), bosutinib, bafetinib (NS-187), abivertinib (EGFR, Btk), mobocertinib (EGFR, Erbb2), anlotinib (multiple kinase), avapritinib (KIT, PDGF), lenvatinib (E-7080) (multiple kinase), pyrotinib (multiple kinase), lonidamine (hexokinase), BMS- 690514, nintedanib (tyrosine kinase), ponatinib (multiple kinase), tivozanib (KRN-951) (multiple kinase), R-1530 (multiple kinase), vatalanib (PDGF, VEGF), PF-337210 (VEGF), AEE-788 (multiple kinase), tesevatinib (XL-647) (multiple kinase), K-0706, ripretinib (KIT, PDGF), dacomitinib (EGFR, Erbb2 / Erbb4), neratinib (EGFR, Erbb2 / Erbb4), varlitinib (EGFR, Erbb2 / Erbb4), tucatinib (Erbb2), larotrectinib (Trk), erdafitinib (FGFR), infigratinib (FGFR), pemigatinib (FGFR), rogaratinib (FGFR), derazantinib (FGFR), E-7090 (FGFR), HMPL-453 ( FGFR), zoligratinib (FGFR), futibatinib (FGFR), brivanib (FGFR, VEGFR), Ki 23057 (FGFR), surufatinib (FGFR, VEGFR), pazopanib (GW 786034), cediranib (KIT, VEGFR, PDGFR), orantinib ( FGF, PDGF, VEGF), H3B-6527, MAX-40279, ICP-105, telatinib (BAY-57-9352) (KIT, PDGFR, VEGFR), pegaptanib (VEGFR), semaxanib (MAPK, VEGFR), quizartinib (AC -220) (Flt3, KIT, PDGFR), crenolanib (CP 868596) (Flt3, PDGFR), lestaurtinib (multiple kinase), Cabozantinib (XL-184) (VEGFR2, Axl, MET, RET), selpercatinib (RET), capmatinib (MET), MK-2461 (MET), SU-11274 (MET), PHA-665752 (MET), ibrutinib (Btk), acalabrutinib (Btk), asciminib (Bcr-Abl), flumatinib (Abl), zanubrutinib (Btk ), ruxolitinib (JAK), itacitinib (JAK), pacritinib (JAK), momelotinib (JAK), INCB-52793 (JAK), gusacitinib (JAK / SYK), ilginatinib οη«ι ηη / ζζηζ / Ε / γ 103 (JAK), cerdulatinib (Syk, JAK), fedratinib (TG-101348) (Flt3, Jak2, RET), tandutinib (Flt3, KIT, PDGF), pexidartinib (KIT, Flt3), midostaurinib (Flt3, KIT, PKC) , zotiraciclib (FLT3), alectinib (ALK), crizotinib (ALK), ceritinib (ALK), lorlatinib (ALK, Ros1), entrectinib (ALK, Ros1, TRK), masitinib (multiple kinase), sorafenib, sunitinib, vemurafenib (PLX4032 or RG7204), dabrafenib, encorafenib, regorafenib (BAY-73-4506) (FGFR3, KIT), selumetinib (AZD6244), trametinib (GSK121120212), binimetinib (BRAF, MEK), cobimetinib (MEK), mirdametinib (PD325901) (MEK ), refametinib (MEK), uprosertib (AKT, MEK), pimasertib (MEK), dactolisib (BEZ235), buparlisib (BKM-120; NVP-BKM-120), alpelisib (BYL719) (PI3), copanlisib (BAY-80 -6946), paxalisib (PI3K / mTOR / AKT pathway), S-49076 (multiple kinase), rigosertib (multiple kinase), rebastinib (multiple kinase), ZSTK-474, fimepinostat (CUDC907) (PI3K and HDAC), apitolisib ( GDC-0980; RG-7422), pictilisib (GDC-0941, RG-7321, GNE-477), delalisib (formerly CAL-101, GS 1101, GS-1101, IC87114), serabelisib (MLN1117, INK1117) (PI3K ), sapanisertib (MLN0128 (INK128)), duvelisib (IPI-145, INK1197) (PI3K), ipatasertib (GDC-0068), afuresertib, MK-2206, MK-8156, SKLB-1028, LY294002, SF1126 or PI-103 , sonolisib (PX -866), GSK1059615 (PI3K), pilaralisib (XL147) (PI3K); SF-1126 (multiple kinase) or AT13148 or pan-Raf inhibitors such as PLX8394, RAF-265 or other signal transduction inhibitors such as mTOR inhibitors, including temsirolimus, everolimus (RAD 001), and RAS inhibitors such as AMG-510, LY-3499446, MRTX-849, or ARS-3248, or isoprenyltransferase inhibitors such as antroquinonol; XVIII. Mitotic kinase inhibitors such as Aurora kinase inhibitors, for example AT9283, barasertib (AZD1152), danusertib (PHA-739358), alisertib (MLN-8237), or CYC-116, or PLK (mitotic kinase inhibitors). polo), such as PLK-1 or PLK-4, including rigosertib, onvansertib, CYC-140, GSK-461364, CFI-400945, or volasertib; XIX. CDK inhibitors, for example AT7519, roscovitine, seliciclib, alvocidib (flavopiridol), abemaciclib, dinaciclib (SCH-727965), 7-hydroxy-staurosporine (UCN-01), JNJ-7706621, PHA533533, ZK-304709, zotiraciclib or AZD -5438 and including CDK4 inhibitors such as palbociclib (PD332991), abemaciclib, dinaciclib, lerociclib, trilaciclib or ribociclib (LEE011); XX. PI3K / AKT pathway inhibitors including PKA / B and / or PKB (akt) inhibitors, PI3K inhibitors, mTOR inhibitors and / or calmodulin inhibitors (hairpin translocation inhibitors) e.g. PI3K inhibitors such as apitolisib, buparlisib, copanlisib, pictilisib, dactolisib, delalisib, serabelisib, duvelisib, ipatasertib, alpelisib, afuresertib, paxalisib, sonolisib, pilaralisib, fimepinostat (CUDC-907), SKLB-1028, GSK1059615 (PI3K), ZSTK-474, GSK -2636771, samotolisib (LY-3023414), LY294002, SF1126 and PI-103, mTOR inhibitors such as sirolimus (originally known as rapamycin), and rapamycin analogs such as RAD 001 (everolimus), COI 779 (temsirolemus), AP23573 and ridaforolimus, or sapanisertib (MLN0128 (INK128)), an on«l 00177071^1^1 inhibitor 104 dual mTOR complex I (mTORCI) and mTORC2, PKA / B (or C) inhibitors, e.g. perifosine, ipatasertib, uprosertib, afuresertib, MK-2206, MK-8156, AT13148, capivasertib (AZD5363), triciribine, enzastaurin , XL-418, GSK-690693, or RX-0201; XXI. ERK inhibitors, including ulixertinib, ASTX029, LY3214996, LTT462, MK-8353, SCH772984, AZD-0364, ASN-007, or KO-947; XXII. Hsp90 inhibitors, e.g. onalespib (AT13387), herbimycin, geldanamycin (GA), 17-allylamino-17-desmethoxygeldanam¡cin (17-AAG), e.g. NSC-330507, Kos-953 and CNF-1010, 17-dimethoxygeldanamycin hydrochloride (17DMAG), e.g. NSC-707545 and Kos-1022, NVP-AUY922 (VER-52296), NVP-BEP800, CNF-2024 (BIIB-021 an oral purine), alvespimycin, Ganetespib (STA-9090), SNX-5422 (SC-102112), or IPI-504 or pimitespib; XXIII. Monoclonal antibodies (unconjugated or conjugated to radioisotopes, toxins or other agents, for example, anticancer cytotoxic agents, such as antibody-drug conjugates), antibody derivatives, bispecific antibodies and antibody-like therapeutic proteins (such as DARTs®, Duobodies ®, Bifes®, XmAbs®, TandAbs® or Fab derivatives), or other therapeutic proteins and related agents, such as anti-CD, anti-VEGFR, anti-HER2 or anti-EGFR antibodies, for example, rituximab (CD20) , ofatumumab (CD20), ibritumomab tiuxetan (CD20), GA101 (CD20), tositumomab (CD20), veltuzumab (CD20), epratuzumab (CD22), lintuzumab (CD33), gemtuzumab ozogamicin (CD33), alemtuzumab (CD52), galiximab ( CD80), trastuzumab (HER2 antibody), pertuzumab (HER2), trastuzumab-DM1 (HER2), ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, ertumaxomab (HER2 and CD3), cetuximab (EGFR), matuzumab (EGFR), panitumumab ( EGFR), necitumumab (EGFR), nimotuzumab (EGFR), zalutumumab (EGFR), bevacizumab (VEGF), ramucirumab (VEGFR), catumaxumab (EpCAM and CD3), abagovomab (CA125), farletuzumab (folate receptor), elotuzumab (CS1 ). CD4), SGN40 (CD40), ficlatuzumab, (anti-HGF), blinatumomab (CD3 modulator; B cell antigen modulator CD19), tafasitamab-cxix (CD19), brentuximab vedotin (CD30), daratumumab (IgGlkappa Antibody), moxetumomab, ranibizumab (anti-VEGF), enfortumab vedotin, sacítuzumab govitecan, obinutuzumab (CD20), inotuzumab ozogamicin (CD22), belantamab mafodotin, brentuximab vedotin (CD30), obinutuzumab (CD20), mogamulizumab (CCR4), polatuzumab vedotin (CD79b), isatuximab (CD38), dinutuximab (GD2), olaratumab (BMI 3G3, PDGF mAb), margetuximab , anti-FGFR mAb (IMC-D11), anti-PDGF-beta receptor mAb (1B3), aflibercept (AVE-0005) (VEGF trap), or immunomodulatory antibodies, including checkpoint inhibitors or agents such as antibodies CTLA-4 blockers and / or antibodies against PD-1 and PD-L1 and / or PD-L2, by οη«ι ηη / 77Π7 / Ε / γ 105 example ipilimumab (CTLA4), MK-3475 (pembrolizumab, formerly lambrolizumab, anti-PD-1), nivolumab (anti-PD-1), BMS-936559 (anti-PD-L1), MPDL320A, AMP-514 or MEDI4736 (anti-PD-L1), or tremelimumab (formerly ticilimumab, CP-675.206, antiCTLA-4); atezolizumab (anti-PDL1), durvalumab (anti-PDL1), avelumab (anti-PDL1), cemiplimab (anti-PD-1), pidilizumab (anti-PD-1); PDR-001 (anti-PD-1), espartalizumab (anti-PD-1), ipilumumab (anti-CTLA-4), abatacept (antibody fragment and conjugated to CTLA-4), anti-LAG3, such as relatlimab, LAG-525, TSR-033, IBI-110 or FS-118, and anti-OX40 (CD134) agents, e.g., MOXR0916, MEDI6469, PF-04518600, MEDI0562, BMS 986178, ISB-830, KY-1005, or INCAGN-1949; XXIV. Estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or inhibitors of estrogen synthesis, for example tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene or keoxifene; XXV. Aromatase inhibitors and related drugs, such as exemestane, anastrozole, letrozole, testolactone aminoglutethimide, mitotane or vorozole; fadrozole, liarozole, atamestane, formestane, dexaminoglutethimide or trilostane; XXVI. Antiandrogens (i.e. androgen receptor antagonists) and related agents, for example bicalutamide, nilutamide, flutamide, cyproterone, ketoconazole, apalutamide, darolutamide or enzalutamide; XXVII. Hormones and analogues thereof such as medroxyprogesterone, diethylstilbestrol (also known as diethylstilbestrol) or octreotide; finasteride, fludrocortisone, fluoxymesterone, arzoxifene, pasireotide or vapreotide; XXVIII. Spheroids, for example dromostanolone propionate, megestrol acetate, nandrolone (decanoate, fenpropionate), fluoxymestrone, gossypol, calusterone, epithiostanol or mepitiostane; XXIX. Steroid cytochrome P450 17alpha-hydroxylase-17,20-lyase (CYP17) inhibitor, e.g. abiraterone; or fadrozole; XXX. Gonadotropin-releasing hormone agonists or antagonists (GnRA), for example, abarelix, goserelin acetate, histrelin acetate, leuprolide acetate, triptorelin, buserelin, deslorelin; leuprorelin or nafarelin; XXXI. Glucocorticoids, for example prednisone, prednisolone or dexamethasone; XXXII. Differentiating agents, such as retinoids, rexinoids, vitamin D or retinoic acid and retinoic acid metabolism blocking agents (RAMBA) for example accutane, alitretinoin, bexarotene, or tretinoin; fenretinide, isotretinoin or retinamide Rll; XXXIII. Hedgehog pathway inhibitors, such as glasdegib, vismodegib or sonidegib; XXXIV. D es hydrogenase inhibitors such as isocitrate dehydrogenase inhibitors, including enasidenib, ivosidenib, vorasidenib, IDH-305, olutasidenib, DS-1001b, enfludenib, dihydroorotate dehydrogenase inhibitors that οη«ι ηη / 77Π7 / Ε / γ 106 include laflunimus, brequinar, ASLAN-003, AG-636, BAY-2402234, or PTC-299; or pyruvate dehydrogenase inhibitors such as devimistat or KULA-18; XXXV. Exportin 1 inhibitors such as selinexor, eltanexor, verdinexor, or felezonexor; polymerase inhibitors, such as DNA or RNA polymerase inhibitors, including lurbinectedin; XXXVI. Farnesyltransferase inhibitors, for example tipifarnib; XXXVII. Therapies that target chromatin, such as histone deacetylase (HDAC) inhibitors, e.g., sodium butyrate, suberoylanilide hydroxamide acid (SAHA), depsipeptide (FR 901228), dacinostat (NVP-LAQ824), R306465 / JNJ-16241199 , JNJ26481585, trichostatin A, vorinostat, chlamidocin, A-173, JNJ-MGCD-0103, PXD-101, apicidin; belinostat, panobinostat, romidepsin, resminostat, abexinostat, entinostat, quisinostat, pracinostat, tefinostat, mocetinostat, givinostat or fimepinostat; XXXVIII. Drugs that target the ubiquitin-proteasome pathway including proteasome inhibitors, for example, bortezomib, carfilzomib, ixazomib, marizomib (salinosporamide a), oprozomib, ubenimex CEP-18770, MLN-9708, or ONX-0912; NEDD8 inhibitors; HDM2 antagonist, idasanutlin (RG7388), HDM-201, KRT-232 (AMG-232), nutlin 3a, RG7112, CGM-097, ALRN-6924, Debio-0123, LY-3143921, MI-773 (SAR405838), milademetan (DS-3032b), APG-115, or BI-907828, or ASTX295 or UBX0101; deubiquitinase inhibitors (DUB); or ubiquitin-specific protease inhibitors such as HBX-41108; XXXIX. Photodynamic drugs, for example porfimer sodium or temoporfin; XL. Anticancer agents derived from marine organisms such as trabectidine; XLL Radiolabeled medicinal products for radioimmunotherapy, for example with a beta-emitting isotope (for example, Iodine-131, tritium-90) or an alpha-emitting isotope (for example, Bismuth-213 or Actinium-225) for example ibritumomab , tositumomab iodine, alpha radium 223; iobenguane, or lutetium Lu 177-dotatate; XLII. Telomerase inhibitors, for example telomestatin; XLIII. Matrix metalloproteinase inhibitors, for example batimastat, marimastat, prinostat or metastat; XLIV. Recombinant interferons (such as interferon-γ and interferon a) and interleukins (for example, interleukin 2), for example, aldesleukin, denileukin diftitox, interferon alfa 2a, interferon alfa 2b, or peginterferon alfa 2b; XLV. Selective immune response modulators, for example, thalidomide, or thalidomide derivatives such as lenalidomide; or pomalidomide (ENMD 0995, CC-4047); XLVI. Therapeutic vaccines such as sipuleucel-T (Proveng) OncoVex, live intravesical BCG, mDC3 vaccine, PEPIDH1M vaccine, vaccine targeting T-VEC or IDH1; XLVII. Cytokine-activating agents include picibanil, romurtide, sizofiran, virulizine, or thymosin; οη«ι ηη / ζζηζ / Ε / γ 107 XLVIIL Cytokine conjugates, such as cytokine-toxin conjugates, including tagraxofusp; XLIX. Arsenic trioxide: L. G protein-coupled receptor (GPCR) inhibitors, for example atrasentan; Lll. Enzymes such as L-asparaginase, pegaspargase, rasburicase, or pegademase; Lll. DNA repair inhibitors such as PARP inhibitors, for example, olaparib, rucaparib, veliparib, iniparib, INO-1001, AG-014699, ONO-2231; or talazoparib; LUI. Receptor death agonists (for example, TNF-related receptor apoptosis-inducing ligand (TRAIL)), such as mapatumumab (formerly HGS-ETR1), conatumumab (formerly AMG 655), PRO95780, lexatumumab, dulanermin, CS1008 , apomab or recombinant TRAIL ligands such as recombinant human TRAIL ligand / Apo2; LIV. Other immunotherapies such as oncolytic viruses, such as talimogene laherparepvec (TVEC); CAR-T cell therapy, such as anti-CD-19 CAR T cell therapy eg, tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene, idecabtagene, brexucabtagene autoleucel (KTE-X19); engineered T cell receptor therapy (TCRT); TLR agonists such as motolimod, imiquimod, rintatolimod or resiquimod or immune checkpoint inhibitors such as PD-1 / PD-L1 inhibitors, eg Lazertinib, CA-170, CCX-4503, PCC0208025 (BMS202), GS -4224, INCB-086550, or RRx-001; LV. Regulators of cell death (apoptosis) including Bcl-2 antagonists (B cell lymphoma 2) such as venetoclax (ABT-199 or GDC-0199), ABT-737, ABT-263, TW37, sabutoclax, obatoclax, and MIM1 and IAP antagonists, including LCL-161 (Novartis), Debio-1143 (Debiopharma / Ascenta), AZD5582, Birinapant / TL-32711 (TetraLogic), CUDC427 / GDC-0917 / RG-7459 (Genentech), JP1201 ( Joyant), T-3256336 (Takeda), GDC-0152 (Genentech), ASTX660 or HGS-1029 / AEG-40826 (HGS / Aegera); and inhibitors of myeloid cell leukemia-1 (MCL-1, a member of the BCL2 family) including AMG-176, MIK665, and S63845; LVI. Gene editors or modifiers, such as CRISPR / Cas9, zinc finger nucleases or synthetic nucleases, or TALEN; LVII. Bromodomain inhibitors, including BET inhibitors such as GSK525762, GSK2820151, OTX-015 / MK-8628, BMS-986158, CPI-0610, RO6870810 / TEN-010, RVX000222, FT-1101, ABBV-075, BAY1238097, INCB05 4329, INCB057643, PLX51107 or ZEN003694; LVIII. Radiation therapy for radical, palliative or prophylactic purposes (or, for adjuvant or neoadjuvant purposes); I LIX. Prophylactic agents (adjuvants); that is, agents that reduce or alleviate some of the side effects associated with chemotherapy agents, for example οη«ι ηη / ζζηζ / Ε / γ 108 a) antiemetic agents, b) agents that prevent or decrease the duration of neutropenia associated with chemotherapy and prevent complications arising from reduced levels of platelets, red blood cells or white blood cells, for example, interleukin-11 (for example, oprelvekin), erythropoietin (ROS) (e.g., epoetin alfa, epoetin beta) or analogues thereof (e.g., darbepoetin alfa), colony-stimulating factor analogues such as granulocyte-macrophage colony-stimulating factor (GMCSF) (e.g. sargramostim), or granulocyte colony-stimulating factor (GCSF) or analogues thereof (for example, filgrastim, pegfilgrastim, lenograstim, leridistim, mirimostim, molgramostim, nartograstim), c) agents that inhibit bone resorption, such as denosumab or bisphosphonates, for example, zoledronate, zoledronic acid, pamidronate or ibadronate, d) agents that suppress inflammatory responses such as dexamethasone, prednisone, or prednisolone, e) agents used to reduce blood levels of growth hormone and IGF-I (and other hormones) in patients with acromegaly or other rare hormone-producing tumors, such as synthetic forms of the hormone somatostatin, e.g. acetate lanreotide octreotide, f) antidote for medications that decrease folic acid levels, such as leucovorin, or folinic acid, g) pain relievers, for example opioids such as morphine, diamorphine or fentanyl, h) non-steroidal anti-inflammatory drugs (ΑΙΝΕ) such as COX2 inhibitors, for example celecoxib, etoricoxib or lumiracoxib, i) agents for mucositis, e.g. palifermin, j) agents that modulate the metabolism of anticancer drugs, i.e. a PK enhancer, eg a P450 (eg a 3A4 inhibitor) such as cobicistat or a cytidine deaminase inhibitor (eg zebularine, tetrahydrouridine or cedazuridine) or thymidine phosphorylase inhibitor (for example, tipiracil); I k) agents for the treatment of side effects including anorexia, cachexia, edema or thromoembolic episodes, such as megestrol acetate. In one embodiment, the compound of formula I is combined with a RAS-MAPK pathway inhibitor such as a BRAF inhibitor, a RAF inhibitor, a MEK inhibitor or an ERK inhibitor as described herein. Each of the compounds present in the combinations of the invention can be given in individually varying dosage schedules and by different routes. In this way, the dosage of each of the two or more compounds / agents may differ: each may be administered at the same time or at different times. A person skilled in the art would know through his or her common general knowledge the dosage regimens and combination therapies to be used. For example, the οη«ι ηη / ζζηζ / Ε / γ 109 compound of the invention can be used in combination with one or more other agents that are administered according to its existing combination regimen. Examples of standard combination regimens are provided below. When the compound of formula (I) is administered in combination therapy with one, two, three, four or more other therapeutic agents (typically one or two, more typically one), the compounds may be administered simultaneously or sequentially. In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. In one embodiment, the compound of formula (I) is administered to a patient undergoing treatment with one or more therapeutic compounds. It will be appreciated that the typical method and order of administration and the respective amounts and dosage regimens for each component of the combination will depend on the particular other agent and medicinal compound of the present invention being administered, its route of administration, the particular tumor that is being treated and the particular guest being treated. Those skilled in the art can determine the weight ratio of the compound according to the present invention and the anticancer agent(s) when administered as a combination. Said ratio and the exact dosage and frequency of administration depend on the particular compound according to the invention and the other anticancer agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, diet, time of administration and general physical condition of the particular patient, the mode of administration, as well as other medications that the individual may be taking, as is well known to those skilled in the art. in technique. Additionally, it is evident that the effective daily amount can be reduced or increased depending on the response of the subject being treated and / or depending on the evaluation of the physician prescribing the compounds of the present invention. The compounds of the invention may also be administered in conjunction with suitable standard chemotherapy regimens, which may be determined by those skilled in the art (for example as described in JCO Clin Cancer Inform 4:60-70), including, for example, For example, PC (paclitaxel and carboplatin), FR (fludarabine and rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM (fludarabine, cyclophosphamide and mitoxideantrone) FCR (fludarabine, cyclophosphamide and rituximab), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate and cytarabine), ICE (ifosfamide, carboplatin and etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab plus CHOP), RCVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE), ICE-V (ICE plus vincristine), R-MCP (rituximab-MCP), or FOLFOX or FLOX (folinic acid, fluorouracil and oxaliplatin). The compounds of the invention can also be administered together with non-chemotherapeutic treatments such as radiotherapy, photodynamic therapy, gene therapy; surgery and controlled diets. Radiotherapy can be for radical, palliative, adjuvant, neoadjuvant or prophylactic purposes. ΟΠΕΙ nn / 77A7 / E / Y 110 The compounds of the present invention also have therapeutic applications in the sensitization of tumor cells for radiotherapy and chemotherapy. Therefore, the compounds of the present invention can be used as a radiosensitizer and / or chemosensitizer or can be given in combination with another radiosensitizer and / or chemosensitizer. In one embodiment, the compound of the invention is used as a chemosensitizer. The term radiosensitizer is defined as a molecule that is administered to patients in therapeutically effective amounts to increase the sensitivity of cells to ionizing radiation and / or promote the treatment of diseases that can be treated with ionizing radiation. The term chemosensitizer is defined as a molecule that is administered to patients in therapeutically effective amounts to increase the sensitivity of cells to chemotherapy and / or promote the treatment of diseases that can be treated with chemotherapy. Currently, many cancer treatment protocols employ radiosensitizers in conjunction with , RSU 1069, SR 4233, EO9, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (lUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically effective analogues and derivatives thereof. Photodynamic therapy (PDT) of cancers uses visible light as a radiation activator of the sensitizing agent. Examples of photodynamic radiosensitizers include, but are not limited to, the following: hematoporphyrin derivatives, photophrin, benzoporphyrin derivatives, tin etioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective derivatives of the same. Radiosensitizers may be administered together with a therapeutically effective amount of one or more other compounds, including, but not limited to: compounds that promote the incorporation of radiosensitizers into target cells; compounds that control the flow of therapeutic agents, nutrients and / or oxygen to target cells; chemotherapeutic agents that act on the tumor with or without additional radiation; or other therapeutically effective compounds to treat cancer or other diseases. Chemosensitizers may be administered together with a therapeutically effective amount of one or more other compounds, including, but not limited to: compounds that promote the incorporation of chemosensitizers into target cells; compounds that control the flow of therapeutic agents, nutrients and / or oxygen to target cells; chemotherapeutic agents that act on the tumor or other therapeutically effective compounds to treat cancer or other diseases. Calcium antagonists, for example verapamil, are found useful in combination with antineoplastic agents to establish chemosensitivity in tumor cells resistant to accepted chemotherapeutic agents and to enhance the efficacy of such compounds in drug-sensitive neoplasms. οη«ι ηη / 77Π7 / Ε / γ 111 For use in combination therapy with another chemotherapeutic agent, the compound of formula (I) and one, two, three, four or more additional therapeutic agents may be formulated, for example, together in a dosage form containing two , three, four or more therapeutic agents, that is, in a unitary pharmaceutical composition containing all components. In an alternative, the individual therapeutic agents can be formulated separately and presented together in the form of a kit, optionally with instructions for use. In one embodiment, the present invention further provides a combination drug wherein the compound of formula (I) and at least one or more therapeutic agents are physically associated. In one embodiment, the compound of formula (I) and at least one or more therapeutic agents are: (a) in the mixture; (b) chemically / physicochemically linked; (c) chemically / physicochemically packaged; or (d) not mixed but copacked or copresented. In another embodiment, the compound of formula (I) and at least one or more therapeutic agents are not physically associated. In a further embodiment, this further optionally includes (a) instructions for the extemporaneous association of the compound of formula (I) and at least one or more therapeutic agents to form a physical association of the two or more compounds; or (b) instructions for combination therapy with the compound of formula (I) and at least one or more therapeutic agents; or (c) instructions for administration to a patient population. When the individual agents are presented in the form of a kit, the kit may comprise two or more separate pharmaceutical compositions: a compound of Formula (I), and one or more additional pharmaceutical compounds. The case may comprise a container for containing the separate compositions, such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit comprises instructions for the use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosage intervals, or when the prescribing healthcare professional desires titration of the individual components of the combination. In a further embodiment, the invention provides a combination of a compound as defined herein and another therapeutic agent, for example another therapeutic agent as defined above. In another embodiment, the invention provides a pharmaceutical composition comprising a compound as defined herein together with a pharmaceutically acceptable carrier and one or more therapeutic agents as defined above. In one embodiment, the pharmaceutical composition comprises a compound of formula I together with a pharmaceutically acceptable carrier and optionally one or more therapeutic agents. In another embodiment, the invention relates to the use of a combination according to the invention in the manufacture of a pharmaceutical composition for inhibiting the growth of tumor cells. on«i ηη / ζζηζ / Ε / γ 112 In a further embodiment, the invention relates to a product containing a compound of formula I and one or more anticancer agents, as a combination of the preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer. In a further embodiment, the invention relates to a compound of formula (I) for use in the treatment of a disease or condition defined in the present description, wherein the patient undergoes treatment with one or more of others therapeutic compounds. EXAMPLES The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples. Compounds are named, for example, by using an automated naming package such as AutoNom (MDL), by using IUPAC rules, or as named by the chemical supplier. In the examples, the following abbreviations are used. οη«ι ηη / 77Π7 / Ε / γ 113 AcOH acetic acid Ac. Aqueous B2pin2 Bis(pinacolato)diboron Boc tert-butyloxycarbonyl 5 BuLi butyllithium Cbz Carboxybenzyl DCE 1,2-dichloroethane DCM dichloromethane DIPEA Λ / , / V-diisopropylethylamine 10 DMF A / ,A / -dimethylformamide DMP Dess-Martin periodinane DMSO dimethylsulfoxide Et3N triethylamine EtOAc ethyl acetate 15 EtOH ethanol Et2O diethyl ether Et3S¡H Triethylsilane HOAt 1 -hydroxyazabenzotriazole HPLC high-pressure liquid chromatography 20 IPA isopropyl alcohol KO'Bu Potassium tert-butoxide LED Light-emitting diode MeCN acetonitrile MeOH methanol 25 Min minutes MS mass spectrometry NaBH(OAc)3 sodium triacetoxyborohydride NaOEt Sodium ethoxide NaO'Bu Sodium tert-butoxide 30 NBS / V-bromosuccinimide NMP / V-methyl-2-pyrrolydinene NMR nuclear magnetic resonance spectroscopy Pd / C Palladium on carbon Pd2(dba)s tr¡s(dibenzyl¡deneacetone)d¡palladium(0) 35 Pd(OAc)2 palladium(lI) acetate Pd(PPh3 )4 tetrakis(triphenylphosphine)palladium(0) 114 Gasoline petroleum ether fraction with boiling point range 40-60 °C RT Ambient temperature Sat Saturated SEM 2-(trimethylsilyl)ethoxymethyl SIO2 silica TBAF tetrabutylammonium fluoride TFA trifluoroacetic acid THF tetrah id rof urane TMBE tert-butyl methyl ether TLC Thin layer chromatography TMSOTf Trimethylsilyl trifluoromethanesulfonate οη«ι ηη / ζζηζ / Ε / γ Synthetic methods All starting materials and solvents were obtained from commercial sources or prepared according to literature citations. Unless otherwise stated, all reactions were shaken. Organic solutions were routinely dried over anhydrous magnesium sulfate. Hydrogenations were performed in a Parr hydrogenator, a Thales H-cube flow reactor under the conditions indicated, or under a hydrogen balloon. Microwave reactions were performed in a CEM Discover and Smithcreator microwave reactor, which is heated to a constant temperature by using variable power microwave irradiation. Normal phase column chromatography was routinely carried out on an automated flash chromatography system such as the CombiFlash Companion or CombiFlash RF system using pre-packaged silica cartridges (230-400 mesh, 40-63 pm). . SCX was purchased from Supelco and treated with 1 M hydrochloric acid prior to use. Unless otherwise indicated, the reaction mixture to be purified was first diluted with MeOH and acidified with a few drops of AcOH. This solution was loaded directly into the SCX and washed with MeOH. The desired material was then eluted by washing with a solvent such as 1% NHsalt in MeOH. NH2 ion exchange silica gel purification was performed with Strata NH2 (55 pm, 70 Á) columns, which were loaded directly onto the NH2 column and eluted with a solvent such as methanol. Biotage® SNAP KP-NH silica gel columns were purchased from Biotage®. Reverse phase purification was performed using Biotage® Ultra C18 SNAP silica gel columns and were purchased from Biotage®. MRI data 1H NMR spectra were acquired on a Bruker Avance III spectrometer at 400 MHz, an AL400 (400 MHz; produced by JEOL), a Mercury 400 (400 MHz; produced by Agilent Technologies, Inc.), a Bruker Avance III HD NMR spectrometer of 500 MHz, or a Bruker Avance NEO NMR spectrometer (400 MHz). Any of the central peaks of chloroform-d, dimethylsulfoxide-cfe, or an internal standard of tetramethylsilane were used as references. For NMR data, where the number of 115 assigned protons is less than the theoretical number of protons in the molecule, it is assumed that the apparently missing signal(s) are hidden by the solvent and / or water peaks . Furthermore, where NMR spectra of protic solvents were obtained, NH and / or OH proton exchange with solvent occurs and, therefore, such signals are not typically observed. Analytical and Preparative LC-MS Systems Analytical LC-MS system and method description In the following examples, compounds were characterized by mass spectroscopy using the systems and operating conditions set forth below. Where atoms with different isotopes are present and a single mass is quoted, the mass quoted for the compound is the monoisotopic mass (i.e. 35CI;79Br, etc.). Shimadzu Nexera οη«ι ηη / 77Π7 / Ε / γ HPLC system: Shimadzu SIL-30AC autosampler / 2x Shimadzu LC-30AD pumps Mass spectrometer detector: Shimadzu LCMS-2020 single quadrupole mass spectrometer Second detector: Shimadzu SPD-M20A diode array detector MS operating conditions Qarray DC Voltage: 20V on ES Pos (-20V on ES Neg) Drying Gas Flow: 20.0 L / min DL Temperature: 300°C Heat Lock Temperature: 350°C Nebulizer Gas Flow: 1.5 L / min Scan interval: 100-750 amu Ionization mode: Electrospray Positive-Negative Switching Aqilent 1290 Infinitv II LC-MS System - 6130 HPLC system: Agilent 1290 Infinity II Mass spectrometer detector: Agilent 6130 single quadrupole Second detector: Agilent 1290 Infinity II diode array detector MS operating conditions Capillary Voltage: 3000 V Fragmenter / Gain: 70 Gain: 1 Drying Gas Flow: 13.0 L / min Gas Temperature: 350°C Nebulizer Pressure: 40 psig 116 Scan range: 150-1000 amu Sheath gas temperature: 360°C Sheath gas flow: 10.0 L / min Nozzle voltage: 300 (+ve mode) / 1750 (-ve mode) Ionization mode : Agilent Jet Stream Electrospray Positive-Negative Switching οη«ι ηη / ζζηζ / Ε / γ The LCMS spectra were alternatively measured with a mass spectrometry detector (SQD) manufactured by Waters Corporation under the following two conditions, and the [M+H]+ values ​​were displayed. MS detection: ESI positive UV detection: 254nm Column flow rate: 0.5 mL / min Mobile phase: water / acetonitrile (0.1% formic acid) Injection volume: 1 μί Method Column: Acguity BEH, 2.1 x50 mm, 1.7 μm Gradient: Time (min) 0 0.1 2.1 3.0 water / acetonitrile (0.1% formic acid) 95 / 5 95 / 5 5 / 95 ARREST Preparative LC-MS system and method description Preparative LC-MS is a standard and effective method used for the purification of small organic molecules such as the compounds described herein. Methods for liquid chromatography (LC) and mass spectrometry (MS) can be varied to provide better separation of raw materials and better detection of samples by MS. Optimization of the preparative gradient LC method will involve variable columns, volatile eluents and modifiers, and gradients. Methods are well known in the art to optimize preparative LC-MS methods and then use them to purify compounds. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC-MS; J Comb Chem.; 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquid chromatography / mass spectrometer platform for the preparative purification and analytical analysis of compound librarles; J Comb Chem.; 2003; 5(3); 322-9. Various systems for purifying compounds by preparative LC-MS are described below, although one skilled in the art will appreciate that alternative systems and methods to those described could be used. From the information provided in this description, or using 117 alternative chromatographic systems, one skilled in the art could purify the compounds described herein by preparative LC-MS. Mass Directed Purification LC-MS System Preparative LC-MS is a standard and effective method used for the purification of small organic molecules such as the compounds described herein. Methods for liquid chromatography (LC) and mass spectrometry (MS) can be varied to provide better separation of raw materials and better detection of samples by MS. Optimization of the preparative gradient LC method will involve variable columns, volatile eluents and modifiers, and gradients. Methods are well known in the art to optimize preparative LC-MS methods and then use them to purify compounds. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC / MS; J Comb Chem.; 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquid chromatography / mass spectrometer platform for the preparative purification and analytical analysis of compound librarles; J Comb Chem.; 2003; 5(3); 322-9. Such a system for purifying compounds by preparative LC-MS is described below, although one skilled in the art will appreciate that alternative systems and methods to those described could be used. In particular, normal-phase preparative LC-based methods could be used instead of the reversed-phase methods described herein. Most preparative LC-MS systems use reversed-phase LC and volatile acid modifiers, because the approach is very effective for the purification of small molecules and because the eluents are compatible with ion electrospray mass spectrometry. positive. Alternatively, other chromatographic solutions, for example, normal phase LC, alternatively buffered mobile phase, basic modifiers, etc., as described in the analytical methods described above, could be used to purify the compounds. Agilent 1260 Preparative LC-MS System Hardware: Autosampler: G2260A Prep ALS Pumps: 2x G1361A preparation pumps for preparative flow gradient, G1311C VL quaternary pump for pumping modifier in preparative flow and G1310B ¡Socratic pump for auxiliary pump flow UV Detector: G1365C 1260 MWD MS Detector: G6120B quadrupole LC-MS Fraction collector: 2x G1364B 1260 FC-PS G1968D active separator Software: Agilent OpenLab C01.06 MS Agilent Operating Conditions: Capillary voltage: 3000 V ΟΠΑΙ nn / 77A7 / E / Y 118 Shredder / Gain: Drying gas flow: 70 / 1 12.0L / min Drying gas temperature: Nebulizer pressure: 275°C Vaporizer temperature: Scan interval: psig 200°C 125-800 amu οη«ι ηη / 77Π7 / Ε / γ Ionization mode: Positive by electrospray Columns: 1. Waters XBridge Prep C18 5m OBD 100 x 19 mm Which is typically used for ammonium bicarbonate-based methods 2. Waters SunFire Prep C18 OBD 5m 100 x 19 mm Which is typically used for TFA-based methods 3. Waters XBridge Prep Fenil 5m OBD 100 x 19 mm Which is typically used for ammonium acetate-based methods with neutral pH 4. Supelco Ascentis RP-Amida 5m 100 x 21.2 mm Which is typically used for formic acid based methods 5. Phenomenex Synergi Fusion-RP 4m 100 x 21.2 mm Which is typically used for formic acid based methods Flowing: Solvent A: water Solvent B: acetonitrile Solvent C: choice of available modifiers: 2.5% trifluoroacetic acid in water 2.5% formic acid in water 250 mM ammonium bicarbonate in water pH 9.4 250 mM ammonium acetate Auxiliary solvent: 90:10 methanol:water + 0.2% formic acid (for all types of chromatography) Methods: According to the analytical trace, the most appropriate type of preparative chromatography was chosen. A typical routine was to run an analytical LC-MS using the type of chromatography (low or high pH) most appropriate for the compound structure. Once the analytical trace showed good chromatography, a suitable preparative method of the same type was chosen. Typical operating conditions for the low and high pH chromatography methods were: Flow rate: 25 mL / min Gradient: In general, all gradients had an initial stage of 0.4 minutes with 95% A + 5% B (with additional modifier C). Then, according to the analytical trace, a gradient of 6.6 minutes was chosen in order to achieve a good separation (for example, from 5% to 50% B 119 for early retention compounds; from 35% to 80% B for medium retention compounds, and so on). Wash: a 1.6 minute wash step was performed at the end of the gradient Auxiliary flow rate: 0.8 mL / min Solvent: All compounds were commonly dissolved in 100% MeOH or 100% DMSO. From the information provided, one skilled in the art could purify the compounds described herein by preparative LC-MS. Waters Fractionlynx System Hardware: 2767 Double Loop Autosampler / Fraction Collector Prep pump 2525 CFO (column fluid organizer) for column selection RMA (Waters Reagent Manager) as auxiliary pump ZQ Waters mass spectrometer Waters 2996 Photodiode Array Detector ZQ Waters mass spectrometer Software: Masslynx 4.1 Waters MS Operating Conditions: οη«ι ηη / 77Π7 / Ε / γ Capillary voltage: 3.5 kV (3.2 kV in negative ES) Cone voltage: Source temperature: 25 V 120 °C Multiplier: 500 V Scan interval: 125-800 amu Ionization mode: positive by Electrospray or negative by electrospray Alternatively, reverse phase preparative HPLC column chromatography was performed under the following conditions. Column: CAPCELL PAK C18 AQ manufactured by SHISEIDO, 30 x 50 mm, 5 pm UV detection: 254 nm Column flow rate: 40 mL / min Mobile phase: water / acetonitrile (0.1% formic acid) Injection volume: 1.0 mL Basic Gradient Method: Water / acetonitrile 0%-50% (8 minutes) Aqilent Infinite Lab LC / MSD 120 LCMS analysis was carried out by using a Waters X-Select CSH C18 (2.5 gm, 4.6x30 mm) or Waters °C and eluted with an acetonitrile gradient appropriate for the lipophilicity of the compound for 4 or 15 minutes at a constant flow rate of 2.5 mL / min. The aqueous portion of the mobile phase was 0.1% formic acid (CSH C18 column) or 10 mM ammonium bicarbonate (BEH C18 column). LC-UV chromatograms were recorded by using an Agilent VWD or DAD detector at 254 nm. Mass spectra were recorded by using an Agilent MSD detector with electrospray ionization switching between positive and negative ion mode. The sample concentration was adjusted to give an adequate UV response. Waters Acquitv QDa UPLC / MS analysis was carried out using a Waters Acquity CSH C18 or BEH C18 column (2.1 x 30 mm) maintained at a temperature of 40 °C and eluted with a linear gradient of acetonitrile appropriate for the lipophilicity of the compound for 3 or 10 minutes at a constant flow rate of 0.77 mL / min. The aqueous portion of the mobile phase was 0.1% formic acid (CSH C18 column) or 10 mM ammonium bicarbonate (BEH C18 column). LC-UV chromatograms were recorded using a Waters Acquity PDA detector between 210 and 400 nm. Mass spectra were recorded using a Waters Acquity QDa detector with electrospray ionization switching between positive and negative ion mode. The sample concentration was adjusted to give an adequate UV response. Achiral preparative chromatography The examples of compounds described have been subjected to HPLC purification, where indicated, using methods developed following the recommendations described in Snyder L. R., Dolan J. W., High-Performance Gradient Elution The Practical Application of the LinearSolvent- Strength Model, Wiley, Hoboken, 2007. Chiral preparative chromatography Preparative separations using chiral stationary phases (CSP) are the natural technique to apply to the resolution of enantiomeric mixtures. Likewise, this can be applied to the separation of diastereomers and achiral molecules. Methods are well known in the art to optimize preparative chiral separations in CSP and then use them to purify compounds. Such methods are described in Beesley T. E., Scott R.P.W.; Chiral Chromatography; Wiley, Chichester, 1998. οη«ι ηη / ζζηζ / Ε / γ 121 Preparation 1: 6-chloro-3-iodo-5-methyl-1-(oxan-2-yl)-1 H-pyrazolo[3,4-6]pyrazine Stage 1 EITHER Stage 2 Stage3 ...................* 0 ií Cr''0 r-o / X οη«ι ηη / 77Π7 / Ε / γ fI Stage 4 Stage 5 Χ / .Νχχ / Stage 6 >10^ / ]' ίγ N--*Γ MlM 00 V ~Ή;Ό-O \ J\ ) Step 1: 6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-6]pyrazine A solution of 6-chloro-1 / 7-pyrazolo[3,4-b]pyrazine (17.85 g, 113.7 mmol) and TSOH.H2O (0.1 eq) in THF (150 mL) was cooled on ice ( internal temperature ~ 10 °C). Dihydropyran (20.6 mL, 227.4 mmol) was added slowly over 5 minutes. The cooling bath was removed and the reaction mixture was stirred for 90 minutes. EtOAc (250 mL) was added and the organic phase was washed with saturated NaHCOs (150 mL), brine and then dried (MgSO4). This was repeated with an additional 17.8 g. The organic layers from both experiments were evaporated to give ~55 g of an orange solid. TBME (40 mL) and heptane (400 mL) were added and the mixture was heated to 90 °C and then allowed to cool. A very small amount of brown precipitate appeared, which was removed by filtration. The filtrate was stirred until the product crystallized. The product was collected by filtration to give batch 1 (20 g) as a white crystalline solid. The filtrate was concentrated to ~30 mL and then diluted with heptane (100 mL) to induce crystallization. Batch 2 (15.8 g, white crystalline solid) was collected by filtration. MS: [M+H]+= 239. Ή NMR (500 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.61 (s, 1H), 5.95 (dd, J = 10.2, 2.6 Hz, 1H) , 3.94 (qd, J = 13.2, 4.1, 1.9 Hz, 1H), 3.77-3.69 (m, 1H), 2.49-2.41 (m, 1H), 2.08-2.01 (m, 1H), 1.95 (dq, J = 13.0, 3.5 Hz, 1H), 1.86-1.72 (m, 1H), 1.62-1.55 (m, 2H). Step 2: 6-chloro-1-(oxan-2-yl)-1H-4A5-pyrazolo[3,4-b]pyrazin-4-one 6-Chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (18 g, 75.41 mmol) was dissolved in MeCN (150 mL) and chilled on ice. Urea-hydrogen peroxide complex (14.9 g, 158.4 mmol) was added batchwise. Trifluoroacetic anhydride (20.9 mL, 150.8 mmol) was added dropwise as a solution in 30 mL (MeCN) over 15 minutes, maintaining the internal temperature < 10 °C. The reaction mixture was stirred at 0-5 Ό for 30 minutes, and then allowed to warm to RT over 1 hour. A thick precipitate formed and an additional 50 mL of MeCN was added to it to mobilize it. The mixture was poured into a stirred mixture of 4M sodium thiosulfate (100 mL), NaHCOs (50 g solid) and ice water (300 mL). The mixture was stirred for 10 minutes and then DCM (300 mL) was added. The DCM layers were isolated and the aqueous layer was extracted with additional DCM (2 x 100 mL). The DCM layers were combined and washed with water (200 mL), dried (MgSO4) and evaporated to dryness. The process was repeated with 18 g 122 additional 6-chloro-T(oxan-2-yl)-1 H-pyrazolo[3,4-b]pyrazine. The crude products from both experiments were combined and recrystallized from EtOAc (300 mL). The crystalline material was collected by filtration, dissolved in PhMe and evaporated to give 6-chloro-1-(oxan-2-yl)-1 / - / -4A5-p¡razolo[3.4t>]pyrazin-4 -one (11 g, 28%, crop 1) as a white crystalline solid. The filtrate was concentrated and dissolved in hot EtOAc (40 mL). Heptane (400 mL) was added and the mixture was heated until all material was dissolved. The solution was allowed to cool and the product crystallized. The product was collected by filtration, dissolved in PhMe and evaporated to give 6-chloro-1-(oxan-2-yl)-1 / 7-4A5-p¡razolo[3,4-£>]p¡raz ¡n-4one (18.46 g, 48%, crop 2), MS: [M+H]+= 255.1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.55 (s, 1H) , 5.91 (dd, J = 10.1,2.6 Hz, 1H), 4.01-3.91 (m, 1H), 3.79-3.68 (m, 1H), 2.45-2.34 (m, 1H), 2.08-1.97 (m, 1H) , 1.93 (dq, J = 13.1,3.6 Hz, 1H), 1.86-1.73 (m, 1H), 1.61-1.55 (m, 2H). Step 3: 6-chloro-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine Methylmagnesium chloride (3.0 M in diethyl ether) (163 mL, 489 mmol) was added dropwise in 1 h 15 minutes to a solution of 6-chloro-1-(oxan-2-yl)-1 / 7-4A5 -pyrazolo[3,4-b]pyrazín-4-one (41.5 g, 163 mmol) in toluene (833 mL) which is cooled in a dry ice / acetone bath to -60SC (internal temperature). The mixture was stirred at this temperature for 6 h, then quenched with saturated NH4CI (400 mL) and diluted with water (300 mL) and EtOAc (300 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (2 x 300 mL). The organics were combined and washed with brine (300 mL), dried (MgSO4), and concentrated to give the crude product as a red solid (38.6 g). The crude residue was dissolved in acetonitrile (50 mL) at reflux. The solution was cooled to RT. The precipitate was isolated by filtration, washed with / -hexane (50 mL) to give a beige solid (-17 g). The solid (harvest 1) was heated once more in acetonitrile (25 mL) at reflux. The solution was cooled to RT, the pink-brown solid was filtered, washed with hexane (10 mL) and dried overnight in the vacuum oven at 40SC to provide the title compound (11.92 g) as a pink-brown solid. , MS: [M+H]+= 253, 255.1H NMR (500 MHz, DMSO-d6) δ 8.47 (s, 1 H), 5.91 (dd, J = 10.2, 2.6 Hz, 1H), 3.97-3.88 (m, 1H), 3.77-3.66 (m, 1H), 2.70 (s, 3H), 2.49-2.42 (m, 1H), 2.06-2.00 (m, 1H), 1.94 (dq, J = 13.1,3.5 Hz , 1H), 1.83-1.72 (m, 1H), 1.61-1.55 (m, 2H). Step 4: 6-chloro-5-methyl-1 H-pyrazolo[3,4-d]pyrazine A solution of hydrogen chloride (4.0 M in 1,4-dioxane) (128 mL, 513 mmol) was added dropwise to a suspension of 6-chloro-5-methyl-1-(oxan-2-yl)- 1 H-pyrazolo[3,4-b]pyrazine (33.21 g, 131 mmol) in methanol (633 mL). The brown mixture was stirred at room temperature overnight. After concentration, the residue was dissolved in MeOH-CHCls (1 / 1 mixture; 400 mL) and then basified with an aqueous solution of NaHCOs (55 g in 400 mL). The separated aqueous layer was extracted with MeOH-CHCls (1 / 1 mixture; 4 x 400 mL). The organics were combined, washed with brine (300 mL), dried over Na2SO4, filtered and then concentrated in vacuo to give a crude beige solid (28.5 g). The material was suspended in / -hexane (3 x 200 mL), collected by filtration and dried under vacuum under 40 °C overnight to give 6-chloro-5-methyl-1 / 7-pyrazolo[3,4 -t>]pyrazine (20.73 g, 121 mmol, 92% yield) as a beige solid, MS: [M+H]+= 169.1H NMR (500 MHz, DMSO-d6) δ 14.13 (s, 1H), 8.41 (s, 1H), 2.68 (s, 3H). Step 5: 6-chloro-3-iodo-5-methyl-1H-pyrazolo[3,4-í)]pyrazine ΟΠΕΙ nn / 77A7 / E / Y 123 1-iodopyrrolidine-2,5-dione (55.3 g, 246 mmol) was added to a solution of 6-chloro-5-methyl-1Hpyrazolo[3,4-t>]pyrazine (20.73 g , 123 mmol) in A / ,A / -dimethylformamide (409 mL). The mixture was stirred at 50 °C for 6 h. The reaction mixture was slowly added to a rapidly stirred mixture of a saturated aqueous solution of sodium thiosulfate (400 mL) and water (400 mL). The precipitate was collected by filtration and washed with water (3 x 200 mL) and / -hexane (100 mL). The solid was dissolved in THF (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 6-chloro-3-iodo-5-methyl-1 / 7-pyrazolo[3.4t>]pyrazine ( 19.42 g, 64.6 mmol, 52.6% yield) as a cream solid (dried in the vacuum oven at 40 °C). The aqueous layer was extracted with EtOAc (3 x 400 mL). The organic extracts were combined, dried over Na2SO4 and concentrated in vacuo to give a red-brown oil. Water (200 mL) was added. A beige solid formed which was filtered and washed with water (2 x 200 mL). The solid was dried in the vacuum oven at 40 °C. 6-Chloro-3-iodo-5-methyl-1 / 7-pyrazolo[3,4-b]pyrazine (12.86 g, 41.5 mmol, 33.7% yield) was isolated as a beige solid, MS: [M +H]+= 295.1H NMR (500 MHz, DMSOd6) δ 14.49 (s, 1H), 2.70 (s, 3H). Step 6: 6-chloro-3-iodo-5-methyl-1-(oxan-2-yl)-1H-pyrazoIo[3,4-b]pyrazine 3.4-Dihydro-2 / 7-pyrane (50 mL, 547 mmol) and p-toluenesulfonic acid monohydrate (2.085 g, 10.96 mmol) were added to a solution of 6-chloro-3-iodo-5-methyl-1 / 7-pyrazolo[3,4-b]pyrazine (32.28 g, 110 mmol) in THF (647 mL). The mixture was stirred at RT overnight. After concentrating the mixture in vacuo at 30SC to half the volume, the mixture was poured into a solution of NaHCOs (36.8 g, 438 mmol) in water (300 mL). The aqueous layer was extracted with EtOAc (200 mL). The organics were combined and washed with brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo to give an orange-pink solid which was dry loaded onto silica gel and purified by silica gel chromatography. (330 g column; gradient elution, 0-100%, DCM / hexane) to give a white solid (33.98 g). The solid was suspended in / -hexane (100 mL) and stirred for 1 h, then filtered, washed with / -hexane (50 mL) and dried in the vacuum oven at 40SC. 6-chloro3-iodo-5-methyl-1-(oxan-2-yl)-1 / 7-pyrazolo[3,4-b]pyrazine (31.29 g, 81 mmol, 73.9% yield) was isolated as a white solid, MS: [M+H]+= 379.1H NMR (500 MHz, DMSO-d6) δ 5.88 (dd, J = 10.3, 2.5 Hz, 1H), 3.97-3.88 (m, 1H), 3.77-3.66 (m, 1H), 2.72 (s, 3H), 2.47-2.37 (m, 1H), 2.06-1.98 (m, 1H), 1.94 (dq, J = 13.0, 3.4 Hz, 1H), 1.83- 1.71 (m, 1H), 1.64-1.52 (m, 2H). Preparation 2: 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-ó]pyrazine on«i ηη / ζζηζ / Ε / γ (2-(Chloromethoxy)ethyl)trimethyls¡lane (56.8 mL, 321 mmol) was added over 30 min to a solution of 6-chloro-3-iodo-1 / 7-pyrazolo[3,4-b ]pyrazine (75 g, 267 mmol) and DIPEA (93 mL, 535 mmol) in THF 124 (1118 mL) at 0 °C. After 18 h of stirring, the reaction mixture was concentrated in vacuo to a yellow solution, which was treated with saturated ammonium chloride (500 mL), then water (300 mL) and extracted with EtOAc (2 x 400 mL). ). The combined organic phases were concentrated and then purified by silica gel chromatography (1 kg cartridge, 0-10% EtOAc / isohexane) to provide 6-chloro-3-iodo-1-((2-(trimethylsilyl) ethoxy)methyl)-1 / - / -pyrazolo[3,4-t>]pyrazine as a light yellow solid (which is dried in the vacuum oven at 40 °C), MS: [M+H]+= 411 ,1H NMR (500 MHz, chloroform-d) δ 8.58 (s, 1H), 5.79 (s, 2H), 3.74-3.63 (m, 2H), 1.00-0.89 (m, 2H), -0.03 (s, 9H ). Preparation 3: (6-chloro-3-iodo-1-{[2-(tnmethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-ó]pyrazin-5yl)methanol οη«ι ηη / 77Π7 / Ε / γ OH CiAt N Yes / x To a solution of 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1 / 7-pyrazolo[3,4-& / pyrazine (68.5 g, 165 mmol) in methanol (700 mL) silver nitrate (14 g, 82 mmol) was added. The mixture was heated to 40SC and then a solution of sodium persulfate (110 g, 462 mmol) in water (210 mL) was added for 30 minutes. The mixture was stirred at 40 °C for 1 h, then cooled. The mixture was carefully diluted with a solution of sodium carbonate (49.0 g, 462 mmol) in water (2 L) and the precipitate was collected by filtration. The filter cake was extracted with dichloromethane:methanol (9:1, 1 L) and then concentrated on loose silica gel (150 g). The silicate was purified by silica gel chromatography (1 kg, 0-10% EtOAc / isohexane) to provide (6-chloro-3-iodo-1 -((2(trimethyls¡l¡l)ethoxy) )methyl)-1 / 7-pyrazolo[3,4-b]pyrazín-5-íl)methanol (27.9 g, 60.8 mmol, 36.8% yield) as a white solid. MS: [M+H]+= 441.1H NMR (500 MHz, DMSO-d6) δ 5.73 (s, 2H), 5.59 (t, J = 6.0 Hz, 1H), 4.80 (d, J = 6.1 Hz, 2H ), 3.68- 3.53 (m, 2H), 0.91-0.79 (m, 2H), -0.09 (s, 9H). Preparation 4: 5-bromo-4-chloro-2-methyl-2H-indazole A solution of sodium nitrite (58.6 g, 0.85 mol) in water (98 mL) was added to an ice-bath cooling solution of 4-bromo-3-chloro-2-methylaniline (150 g, 0.68 mol) in acetic acid (3 L) with mechanical stirring and the mixture was allowed to stand for 1 h at room temperature. Most of the solvent evaporated and the residue was suspended in water (500 mL) and filtered, washed with water (250 mL x 125 4), gasoline (250 mL x 4) and dried under vacuum at 40 °C, to give 5-bromo-4-chloro-1 / 7-indazole (130 g), 1H NMR (400 MHz, DMSO-d6) : 13.61 (1H, s), 8.16 (1H, s), 7.62 (1H, d), 7.53 (1H, dd). Solid trimethyloxonium tetrafluoroborate (258 g, 1.74 mol) was charged to an ice bath cooling solution of 5-bromo-4chloro-1 / 7-indazole (367 g, 1.59 mol) in EtOAc (1.9 L) and the The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with gasoline (1.9 L) and allowed to stand for 10 minutes before filtration, washing with gasoline (400 mL x 2). The filter cake was combined with saturated sodium bicarbonate (1.5 L), EtOAc (2 L) and the phases were separated. The organic phase was washed with saturated sodium bicarbonate, dried (MgSO^ and concentrated in vacuo to give the title compound (236 g),1H NMR (400 MHz, DMSO-afe): 8.53 (1H, s), 7.56 (1H, dd), 7.48 (1H, d), 4.20 (3H, s). Preparation 5: 5-bromo-4-chloro-2-ethyl-2H-indazole ΟΠΑΙ ηη / 77Π7 / Ε / Υ Triethyloxonium hexafluorophosphate (20 g, 80.6 mmol) was added to 5-bromo-4-chloro-1 / 7-indazole (12.4 g, 53.7 mmol) in EtOAc (186 ml) and the resulting mixture was stirred at room temperature for evening. The reaction mixture was quenched with saturated sodium bicarbonate (125 mL), and the phases were separated. The aqueous was extracted with EtOAc (70 mL) and the combined organics were washed with brine (70 mL), dried (MgSO4), and concentrated in vacuo. The red / brown residue was treated with activated carbon (12.5 g) in ethanol (125 mL) and EtOAc (125 mL). After stirring at room temperature, the mixture was filtered and concentrated in vacuo to give the title compound (9.88 g). 1H NMR (400 MHz, DMSO-cfe): 8.58 (1H, s), 7.58 (1H, s), dd), 7.48 (1H, d), 4.49 (2H, q), 1.52 (3H, t). Preparation 6: 5-bromo-3,4-dichloro-2-methyl-2H-indazole To a solution of 5-bromo-4-chloro-2-methyl-2 / 7-índazol (5 g, 20.3 mmol) in DMF (50 mL) was added NCS (2.99 g, 22.4 mmol) at 0SC. The mixture was stirred at RT overnight. Water (150 mL) was added at RT. The mixture was stirred at RT for 1 h. The precipitate was collected, washed with water, and dried at 60 °C for 3 h under reduced pressure to give the title compound (5.63 g). MS: [M+H]+= 279, 281. Preparation 7: 5-bromo-4-chloro-2,3-dimethyl-2H-indazole 126 / V-butyllithium (2.5 M in hexanes, 4 mL, 10.0 mmol) was added to a cooling (-10 °C) solution of diisopropylamine (1.5 mL, 10.5 mmol) in THF (10 mL). The mixture was stirred for 10 minutes before cooling to −78 °C. To this solution was added a solution of 5-bromo-4-chloro-2-methyl-2 / 7-indazole (2.0 g, 8.15 mmol) in THF (10 mL). The mixture was heated to 0 °C for 10 minutes, then cooled again to −78 °C. Iodomethane (0.66 mL, 10.6 mmol) was added and the mixture was stirred at −78 °C for 1 h. The οη«ι ηη / ζζηζ / Ε / γ mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried (NazSCh), filtered and concentrated. The crude product was purified by silica gel column chromatography (gradient elution, EtOAc / 15% isohexane). %), to give the title compound (1.7 g), MS: [M+H]+= 259, 261,263. Preparation 8: 7-bromo-2,8-dichloroquinoxaline Boc,. ।ri ,NH?Stage 1 Stage 2 Stage 3 if í ñ η Bocf 80c Π ---------* Y ► i; I> NO;. SA γ NO28r γ' NO2SU γ 'NO2 Ci OI CiCí Oo Stage 4 Stage 5Λγ Stage 6 < 'Y' '800 Ύ' Brx'U'^NOa CíCI In a 2 L three-necked flask, a solution of 3-chloro-2-nitroaniline (60 g, 348 mmol) in AcOH (600 mL) was treated in portions with NBS (61.9 g, 348 mmol). The resulting orange solution was heated at 806C for 1.5 h. The reaction mixture was cooled to RT and poured into stirred ice water (800 mL). The resulting orange precipitate was collected by filtration and washed with water (200 mL). The orange residue was collected and dissolved in EtOAc (500 mL). The solution was dried with MgSO4, filtered and the solvent was concentrated in vacuo to give an orange solid (86.5 g). The residue was recrystallized from 10% EtOAc / iso-hexane (500 mL). The resulting solid was filtered, rinsed with iso-hexane (100 mL), and dried in vacuo to give a light orange solid (39.88 g, 158.6 mmol, 46%). The filtrate was concentrated in vacuo to give an orange solid. The residue was recrystallized from 10% Ac / isohexane (250 mL). The resulting solid was filtered, rinsed with iso-hexane (50 mL), and dried in vacuo to give a light orange solid (20 g, 79.53 mmol, 23%). d), 6.84 (1H, d), 6.40 (2H, s). Step 2: Tere-butyl N-(4-bromo-3-chloro-2-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate 127 In a 2 L three-necked flask, a solution of 4-bromo-3-chloro-2nitroaniline (59.88 g, 226 mmol) in THF (400 mL) was treated in portions at <10 °C (internal temperature, water bath). ice) with a solution of di-tert-butyl dicarbonate (99 g, 452 mmol) in THF (200 mL). N,Ndimethylpyridin-4-amine (2.76 g, 22.62 mmol) was added portionwise and the resulting orange solution was stirred at RT for 18 h. The reaction mixture was concentrated in vacuo to give a pale brown solid. The residue was triturated with isohexane (300 mL). The resulting solid was filtered, rinsed with iso-hexane (50 mL) and dried under vacuum to provide the desired product (97.5 g, 214 mmol, 94% yield) as a sticky colorless solid.1H NMR in CDCI3: 7.81 (1H, d), 7.16 (1H, d), 1.45 (18H, s). Step 3: N-(4-bromo-3-chloro-2-r>itrophenyl)tere-butyl carbamate In a 2 L 3-neck flask, a solution of tere-butyl N-(4-bromo-3-chloro-2-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate (97.5 g, 214 mmol) in DCM (600 mL) with a solution of trifluoroacetic acid (32.9 ml, 427 mmol) in DCM (250 mL). The resulting orange solution was stirred at RT for 0.5 h. The reaction mixture was quenched at neutral pH with saturated aqueous NaHCO3 (300 mL). The phases were separated and the aqueous layer was extracted with DCM (2 x 100 mL). The organic extracts were combined and dried over MgSO4, filtered and concentrated in vacuo to give tere-butyl N-(4-bromo-3-chloro2-nitrophenyl)carbamate (75 g, 212 mmol, 99% yield). as a light orange solid, 1H NMR in CDCI3: 8.06 (1H, d), 7.72 (1H, d), 7.12 (1H, s), 1.53 (9H, s). Step 4: Ethyl 2-[(4-bromo-3-chloro-2-nitrophenyl)[(tert-butoxy)carbonyl]amino]acetate In a 1 L three-necked flask, a suspension of N-(4-bromo-3-chloro-2nitrophenyl)tere-butyl carbamate (75 g, 211 mmol) and cesium carbonate (138 g, 422 mmol) in DMF (300 mL) at <10aC (internal temperature, ice bath) with a solution of ethyl 2-bromoacetate (24.59 mL, 222 mmol) in DMF (125 mL). The resulting orange suspension was stirred at <10SC for 0.5 h. The reaction mixture was partitioned between EtOAc (300 mL) and water (300 mL). The aqueous layer was extracted with EtOAc (2 x 200 mL). The organic extracts were combined and washed with saturated brine (2 x 100 mL) and then dried over MgSO4, filtered and concentrated in vacuo to give a dark orange oil (—100 mL). The dark orange oil was added to the stirred water (200 mL). The resulting orange precipitate was collected by filtration, washed with water (50 mL), and dried under vacuum to give an orange solid (107 g, 196 mmol, 93% yield). 1H NMR in DMSO-d6: 8.14 ( 1H, d), 7.57 (1H, t), 4.40-3.98 (4H, m), 1.41 - 1.15 (12H, m). Step 5: Ethyl 2-[(4-bromo-3-chloro-2-nitrophenyl)amino]acetate In a 2 L 3-neck flask, a solution of ethyl 2-[(4-bromo-3-chloro-2nitrophenyl)[(tert-butox¡)carbon¡l]amino]acetate ( 107 g, 196 mmol) in DCM (600 mL) with a solution of trifluoroacetic acid (75 mL, 978 mmol) in DCM (200 mL). The resulting orange solution was stirred at RT for 18 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (700 mL) followed by slow addition in portions of solid NaHCO3 (40 g, 476 mmol) to neutral pH. The phases were separated and the aqueous layer was extracted with DCM (2 x 250 mL). The organic extracts were combined and washed with saturated brine (1 x 150 mL) and then dried over MgSO4, filtered and concentrated in vacuo to provide 2-[(4-bromo-3-chloro-2-nitrophenyl)am! no]ethyl acetate (77.47 g, οη«ι ηη / ζζηζ / Ε / γ 128 184 mmol, 94% yield) as a light orange solid.1H NMR in DMSO-d6: 7.68 (1H, d), 6.78 (1H, d), 6.70 (1 H, t), 4.12 (2H, q), 4.04 (2H, d), 1.20 (3H, t). Step 6: 7-bromo-8-chloro-1,2,3.4-tetrahydroquinoxalin-2-one In a 2 L three-necked flask, a solution of ethyl 2[((4bromo-3-chloro-2-nitrophenyl)amino] acetate (35.93 g, 96 mmol) in THF (200 mL) was portioned and MeOH (200 mL) at 0aC (internal temperature, ice bath) with a solution of sodium dithionite (71.2 g, 409 mmol) in water (200 mL). The resulting orange suspension was stirred at RT for 2 h. The mixture The reaction mixture was diluted with water (50 mL) and solid sodium carbonate (65 g, 613 mmol) was slowly added portionwise until pH 9. The MeOH and THF were removed in vacuo and the aqueous solution was extracted with Me- THF (2 4dihydroquinoxalin-2(1 H)-one (26.4 g, 96 mmol, 94% yield) as a thick green solid. 1H NMR in DMSO-d6: 9.93 (1H, s), 7.14 (1H, d ), 6.63 (1H, d), 6.40 (1H, br s), 3.75 (2H, s). Step 7: 7-Bromo-8-chloroquinoxalin-2-ol In a 2 L three-necked flask, a solution of 7-bromo-8-chloro-1,2,3,4tetrahydroquinoxalin-2-one (60 g, 174 mmol) in THF (425 mL) was treated in portions. MeOH (425 mL) at <10aC (internal temperature, ice bath) with potassium tert-butoxide (39.1 g, 349 mmol). The resulting orange suspension was stirred at RT for 18 h under a stream of air. Water (200 mL) was added followed by the slow addition of AcOH (50 mL). The resulting orange precipitate was collected by filtration; washed with water (100 mL) followed by TBME (50 mL) and dried under vacuum to provide 7-bromo-8-chloroquinoxalin-2-ol (41.81 g, 155 mmol, 89% yield) as a pale orange solid. ,1H NMR in DMSO-d6: 8.17(1 H, s), 7.697.55 (2H, br s). Step 8: 7-Bromo-2,8-dichloroquinoxaline In a 1 L three-necked flask, a suspension of 7-bromo-8chloroquinoxalin-2-ol (35 g, 129 mmol) in MeCN (300 mL) was treated dropwise at 50 °C under N2 with a trichloride solution. phosphoryl (36.2 mL, 388 mmol) in MeCN (50 mL). The resulting brown suspension was heated at 80 °C for 3 h and then cooled to RT. The dark brown reaction mixture was concentrated in vacuo and the POCI3 was removed by azeotroping with PhMe (250 mL). The brown residue was dissolved in MeCN (500 mL) and the mixture quenched by slow addition of water (~306C). EtOAc (500 mL) was added and the mixture filtered, yielding a dark brown solid. The crude solid was dissolved in EtOAc (200 mL) and combined with the filtrate. The phases separated. The aqueous layer was extracted with EtOAc (3 x 200 mL). The organic extracts were combined and washed with saturated brine (1 x 200 mL) and then dried over MgSO4, filtered and concentrated in vacuo to give a dark orange solid (34.52 g, 96%, crude). The crude product was purified by silica gel chromatography (330 g cartridge, 0-30% DCM / iso-hexane) to provide 7-bromo-2,8-dichloroquinoxaline (27.69 g, 99 mmol, 76%). yield) as an off-white solid, 1H NMR in DMSO-d6: 9.13 (1H, s), 8.23 ​​(1H, d), 8.08 (1H, d). οη«ι ηη / 77Π7 / Ε / γ 129 Preparation 9: 7-bromo-8-chloro-2-methoxyquinoxaline οη«ι ηη / ζζηζ / Ε / γ 7-Bromo-2,8-dichloroquinoxaline (2 g, 7.12 mmol) and potassium carbonate (3.94 g, 28.5 mmol) were combined in a 100 mL three-necked flask in MeOH (40 mL). The resulting colorless suspension was heated at 65 °C (internal temperature) for 18 h. The reaction mixture was cooled to RT. Water (150 mL) was added and the precipitate was filtered to give 7-bromo-8-chloro-2-methoxyquinoxaline (1.79 g, 6.48 mmol, 91% yield) as a colorless solid, MS: [M+H ]+=275.1H NMR in DMSO-d6: 8.69 (1H, s), 8.00-7.89 (2H, m), 4.10 (3H, s). Preparation 10: 7-bromo-8-chloro- / V,A / -dimethylquinoxalin-2-amine In a 100 mL three-necked flask, 2 M dimethylamine in THF solution (22 mL, 44.0 mmol) was treated with 7-bromo-2,8-dlchloroquinoxaline (2.01 g, 7.16 mmol) at 0 °C ( internal temperature, ice bath). The resulting yellow solution was warmed to RT and stirred for 3 h. The reaction mixture was concentrated in vacuo and partitioned between EtOAc (50 mL) and saturated aqueous NaHCOs (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2 x 50 mL). The organic extracts were combined and washed with saturated brine (1 x 50 mL) and then dried over MgSO4, filtered, and concentrated in vacuo to provide 7-bromo-8-chloro-A / , / V-dimethylquinoxalin-2- amine (1.98 g, 6.77 mmol, 95% yield) as a light yellow solid, MS: [M+H]+=288.1H NMR (500 MHz, DMSO-cfe) δ 8.76 (s, 1H), 7.72 ( d, J = 8.8 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 3.29 (s, 6H). Preparation 11: 2-(Azetidin-1-yl)-7-bromo-8-chloroquinoxaline Azetidine (0.49 mL, 7.20 mmol) was added to a solution of 7-bromo-2,8-dichloroquinoxaline (1.00 g, 3.60 mmol) and triethylamine (1.00 mL, 7.20 mmol) in THF (5 mL) and the mixture It turned yellow immediately. It was stirred at RT for 80 h and then partitioned between EtOAc and saturated aqueous NaHCO. The phases were separated, the aqueous phase extracted with EtOAc and the combined organic phases washed with brine, dried (MgSO4 + hydrophobic frit) and concentrated to give the title compound (1.05 g), 1H NMR (400 MHz , DMSO-óe): 8.36 (1H, s), 7.71 (1H, d), 7.64 (1H, d), 4.28 (4H, t), 2.49-2.41 (2H, m). 130 Preparation 12: 7-Bromo-8-chloro-2-(morpholin-4-yl)quinoxaline οη«ι ηη / ζζηζ / Ε / γ 7-Bromo-8-chloro-2-(morpholin-4-¡l)quinoxalína was prepared from 7-bromo-2,8-dichloroquinoxaline and morpholine by using a procedure similar to that of Preparation eleven. Preparation 13: 4-chloro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole Method A A mixture of 5-bromo-4-chloro-2-methyl-2 / 7-indazole (12.14 g, 49.45 mmol), bis(pinacolato)diboron (18.83 g, 74.18 mmol), the [1,1'-bis complex (diphenylphosphino)ferrocene]dichloropalladium (II) with dichloromethane (4.038 g, 4.945 mmol) and potassium acetate (9.706 g, 98.90 mmol) in 1,4-dioxane (120 mL) was degassed, purged with nitrogen and stirred at 120 °C for 5 h. The reaction was cooled to RT, filtered through a pad of Celite and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by NH silica gel column chromatography (gradient elution, 0-70% EtOAc / hexane), to give the title compound (14.36 mg), MS: [M+H]+= 293, 295. Method B 'PrMgCI.LiCI (1.3 M in THF, 63 mL, 82.0 mmol) was added to a solution of 5-bromo-4-chloro-2methyl-2 / 7-indazole (10.00 g, 40.73 mmol) in THF (100 mL) which is cooled in ice to <5aC internal temperature under nitrogen. The mixture was maintained below 10SC internal temperature throughout the addition and then stirred at <5SC for 5 h. The mixture was cooled to -10aC internal temperature and isopropoxy pinacolborane (25.00 mL, 122.6 mmol) was added. The mixture was stirred at this temperature for 1 hour and then quenched with water. Saturated aqueous NH4CI was added and the aqueous mixture was then extracted with EtOAc. The combined organic phases were washed with water, brine and then dried (MgSÜ4) and concentrated. The residue was dissolved in IPA and then water was added to cause precipitation. The solid was collected by filtration. The solid was further crushed with gasoline and then collected by filtration to provide a pale yellow solid (10.18 g, 34.79 mmol, 85%). Preparation 14: 4-chloro-2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole 131 Prepared as preparation 10 above by using 5-bromo-4-chloro-2-ethyl-2 / 7-indazole. MS: [M+H]+= 307. Preparation 15: (3,4-dichloro-2-methyl-2H-indazol-5-yl)boronic acid οη«ι ηη / 77Π7 / Ε / γ A stirred solution of 5-bromo-3,4-dichloro-2-methyl-2 / 7-indazole (36.4 g, 130 mmol) in THF (364 mL) was cooled to 5SC (internal temperature) under nitrogen. Isopropylmagnesium chloride-lithium chloride complex in THF (1.3 M) (200 mL, 260 mmol) was added dropwise via cannula over 25 minutes. The temperature remained at 5 °C for the duration of the addition. The mixture was allowed to warm to room temperature over the course of 1 h. The mixture was cooled again to 5SC and then triisopropyl borate (100 mL, 431 mmol) was added via cannula over 10 minutes. The mixture was stirred for 1 h at room temperature, then cooled to 5SC and quenched with AcOH (145 mL, 2533 mmol). The mixture was added dropwise to stirred water (6 L) and the precipitate was collected by filtration to yield the crude product. The product was dissolved in a solution of NaOH (10.5 g, 263 mmol) in water (350 mL) and then washed with TBME (350 mL). The aqueous layer was treated with 1 M HCl (300 mL, 300 mmol) and the precipitate was collected by filtration to produce (3,4dichloro-2-methyl-2 / 7-indazol-5-¡l)boron acid. co (23.9 g, 88 mmol, 67.6% yield) as a beige solid, MS: [M+H]+= 245.1H NMR (500 MHz, DMSO-d6) δ 8.33 (s, 2H), 7.51 (d , J = 8.7 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 4.12 (s, 3H). Preparation 16: 8-chloro-A / ,A / -dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2amine A suspension of bis-pinacolatodiboron (2.58 g, 10.16 mmol), 7-bromo-8-chloro- / V,A / dimethylquinoxalin-2-amine (1.98 g, 6.77 mmol), and potassium acetate (1.994 g, 20.31 mmol) was degassed. mmol) in 1,4-dioxane (20 mL) by using three nitrogen fill / evacuation cycles. The reaction mixture was then treated with Pd(dppf)Cl2 (0.495 g, 0.677 mmol) and the degassing cycle repeated. The resulting red suspension was heated to 100SC (internal temperature) for 1.5 h. The reaction mixture was cooled to room temperature, then concentrated in vacuo. The crude product was purified by silica gel chromatography (24 g cartridge, 0-100% DCM / iso-hexane) to provide the title compound as a light yellow solid (790 mg), MS: [M +H]+= 334.1H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 1H), 7.75 (d, 1H), 7.46 (d, 1H), 3.32 (s, 6H), 1.35 (s, 12H). The following boronates were manufactured in a similar way 132 Name MS and NMR (DMSO-cfe, 500 MHz) O-CD O— z z / / cf 8-chloro-2-methoxy¡-7- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan -2¡l)quinoxaline MS: [M+H]+ = 321 8.70 (s, 1H), 7.96 (d, 1H), 7.76 (d, 1H), 4.10 (s, 3H), 1.37 (s, 12H) . Γ [ n— yv-ó Cl 4-chloro-2,3-dimethyl-5(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2yl)-2 / 7-indazole MS: [M +H]+ = 307 7.42 (d, 1H), 7.35 (d, 1H), 4.06 (d, 3H), 2.83 (s, 3H), 1.32 (s, 12H). O-CD O— z z \\ / / 2-(azetidin-1 -i l)-8-chloro7-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2yl)qu¡noxaline MS: [M +H]+ = 346 8.37 (s, 1H), 7.76 (d, 1H), 7.48 (d, 1H), 4.27 (t, 4H), 2.44 (p, 2H), 1.35 (s, 12H). — O-aí O— z z \\ / / 0 4-(8-chloro-7-(4,4,5,5tetramethyl-1,3,2dioxaborolan-2yl)quinoxalin-2yl)morpholine MS: [M+H] + = 376 8.90 (s, 1H), 7.78 (d, 1H), 7.52 (d, 1H), 3.86-3.74 (m, 8H), 1.36 (s, 12H) οη«ι ηη / 77Π7 / Ε / γ Preparation 17: 3,4-dichloro-2-methyl-2H-indazole-5-carbaldehyde To a solution of 5-bromo-3,4-dichloro-2-methyl-indazole (10.0 g, 35.7 mmol) in THF (100 mL), isopropylmagnesium chloride-lithium chloride complex (1.3 mol / L in THF, 55 mL, 71.4 mmol) at 0 °C, and then the mixture was stirred at 0 °C for 1 h. Then, DMF (11.0 mL, 143 mmol) was added at the same temperature and the mixture was stirred at 0SC for 30 minutes, quenched with saturated aqueous NH4CI, and diluted with water. The mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and then concentrated to give a pale yellow solid. The crude product was suspended with EtOAc / heptane (1:1, 10 mL), and stirred at room temperature for 1 h. The precipitate was collected, washed with hexane, and dried at 50 °C for 3 h under reduced pressure, to give the title compound (5.50 g), MS: [M+H]+= 229, 231 Preparation 18: 4-chloro-2-methyl-2H-indazole-5-carbaldehyde 133 CL Cl οη«ι ηη / 77Π7 / Ε / γ 4-Chloro-2-methyl-2 / 7-indazole-5-carbaldehyde was prepared from 5-bromo-4-chloro-2-methyl-2 / 7indazole by using a procedure similar to that of preparation 17 above. , MS: [M+H]+= 195. Preparation 19: (3,4-dichloro-2-methyl-2H-indazol-5-yl)(3,5-dichloro-6-methylpyrazin-2-yl)methanol To a solution of 3,5-dichloro-2-methyl-pyrazine (391 mg, 2.40 mmol) in THF (5 mL), lithium chloride-2,2,6 chloride complex was added. 6-tetramethylpiperidinylmagnesium (1 mol / L in THF, 2.88 mL, 2.88 mmol) at -60SC. After stirring for 45 minutes, 3,4-dichloro-2-methyl-ndazol-5carbaldehyde (500 mg, 2.18 mmol) was added to the mixture at the same temperature and then stirred at -60 °C for 10 minutes. , then the mixture was stirred at RT for 30 minutes. After quenching with saturated aqueous NH4CI, the mixture was diluted with water, and extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and then concentrated to give a brown residue, which was purified by hot water chromatography. silica gel column (EtOAc / hexane) to give the title compound (510 mg) as a pale yellow amorphous. MS: [M+H]+ = 391,393. Preparation 20: (4-chloro-2-methyl-2H-indazol-5-yl)(3,5-dichloro-6-methylpyrazin-2-yl)methanol The title compound was prepared from 4-chloro-2-methyl-indazol-5-carbaldehyde and 3,5-dichloro-2methyl-pyrazine by using a procedure similar to that of preparation 19 above, MS: [M +H]+ = 357. Preparation 21:3,4-dichloro-5-(3,5-dichloro-6-methylpyrazine-2-carbonyl)-2-methyl-2H-indazole 134 οη«ι ηη / 77Π7 / Ε / γ Manganese (IV) oxide (1.93 g, 19.5 mmol) was added to a solution of (3,4-dichloro-2-methylindazol-5-íl)-(3,5-dichloro-6-methyl-pyrazin -2-¡l)methanol (510 mg, 1,301 mmol) in chloroform (10.2 mL) at RT. The mixture was stirred at RT for 6 h. Additional manganese(IV) oxide (1.93 g, 19.5 mmol) was added to the reaction mixture. The mixture was stirred at RT for 18 h. After filtration, the filtrate was concentrated to give a pale yellow solid, which was suspended in hexane, collected by filtration, and dried under vacuum at 50SC to give the title compound (490 mg), MS: [M+ H]+ = 389, 391. Preparation 22: 4-chloro-5-(3,5-dichloro-6-methylpyrazine-2-carbonyl)-2-methyl-2H-indazole To a stirred solution of (4-chloro-2-methyl-2 / - / -ndazol-5-l)(3,5-dichloro-6-methylpyrazin-2-l)methanol (0.32 g, 0.895 mmol) in DCM (8.95 mL) manganese (IV) oxide (1.56 g, 17.9 mmol) was added at RT. The suspension was stirred overnight before it was filtered, washed with DCM (3x) and concentrated to give the title compound (0.231 g) which was used without further purification, MS: [M+H]+ = 355. Preparation 23: (S)-2-oxa-8-azaspiro[4.5J decan-4-amine To a solution of tere-butyl (4S)-4-('('tert-butylsulfinyl)amino)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.10 g, 0.28 mmol) is prepared By the method as described in document WO2016203405 in MeOH (1 mL) 4 M HCl in 1,4-dioxane (0.70 mL, 2.8 mmol) was added at RT. The 135 mixture was stirred at 50 °C for 30 minutes, cooled to RT. Volatiles were removed under reduced pressure, the residue was azeotroped with toluene and the resulting crude fS)-2-oxa-8-azaspiro[4.5]decane-4-amine salt was used without further purification, MS: [M+ H]+= 157. Preparation 24: (1 / ?>8-azaspiro[4.5]decan-1-amine οη«ι ηη / ζζηζ / Ε / γ Prepared tere-butyl (1 / =?)-1-('('tert-butylsulfin¡l>)amino)-8-azaspiro[4.5]decane-8-carboxylate by the method as described in WO2016203405 was deprotected by using a similar procedure as in Preparation 23. The resulting bis(1ñ,)-8-azaspiro[4.5]decan1-amine hydrochloride salt was used without additional purification. Preparation 25: (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride BocN,OEt EtO' Stage 1 q A ..OTBS Stage 2 ,OTSS H' Stage 3 ... λ BocN bocN ) Stage 4 ¡ OH Stage 5 HO' OTBS HO'OTBS .. OH BocN’^x· ] Stage 7 mouth Stage 8 HO OH Stage 9 EITHER Step 1: Ethyl (2S)-2-[(tert-butyldimethylsilyl)oxy]propanoate The reaction mixture of ethyl (2S)-2-hydroxypropanoate (95.0 g, 0.8 mol) in DCM (1 L) was cooled to 0 °C, then imidazole (81.6 g, 1.2 mol) and TBSCI (133.3 g, 0.88 mol), were stirred at room temperature for approximately 1.5 h. The reaction mixture was poured into water (1.0 L), extracted with DCM (2 x 500 mL), then washed with brine, dried over Na2SO4, concentrated in vacuo, purified using a silica column (ether petroleum / EtOAc=50 / 1 to 20 / 1) to give the product (180.0 g, 97%) as a colorless oil.1H NMR (500 MHz, CDCL) δ: 4.33 (s, 1H), 4.22 (s, 2H ), 1.44 (d, J= 6.7 Hz, 3H), 1.32 (t, J= 7.1 Hz, 3H), 0.97 (s, 9H), 0.15 (s, 6H). 136 Stage 2: (2S)-2-[(tert-butyld¡methylsil¡l)ox¡]propanal A solution of ethyl (2S)-2-[(tert-butyldimethylsilyl)oxy]propanoate (131.0 g, 0.56 mol) in toluene (800 mL) was cooled to -60 °C, added DIBAL-H (1.5 M, 560 mL, 0.85 moL) drop by drop, then stirred at -60 °C for 2 h. The reaction mixture was poured into water (800 mL), extracted with EtOAc (2 x 500 mL), washed with brine, dried over Na2SÜ4, concentrated in vacuo to give the crude product. It was used in the next step without purification. Step 3: 1-Tere-butyl 4-ethyl 4-[(2S)-2-[(terobutyldimethylsilyl)oxy]-1-hydroxypropyl]piperidine-1,4-dicarboxylate A solution of diisopropylamine (65.0 g, 0.64 mol) in THF (400 mL) was cooled to −20 °C. n-BuLi (2.5 M, 224 mL, 0.56 mol) was added dropwise, then stirred at −10 °C for 1 h. 1-Tere-butyl 4-ethylpiperdine-1,4-dicarboxylate (110.0 g, 0.43 mol) in THF (200 mL) was added dropwise at -10 °C, then stirred at -10 °C at room temperature for 1 h under N2. (2S)-2-[(tertbutyldimethylsilyl)ox¡]propanal (120.0 g, 0.64 mol) in THF (200 mL) was added dropwise at -10 °C, then stirred at -10 °C to 0 °C for 2 h. The reaction mixture was poured into saturated NH4Cl (1 L), extracted with EtOAc (2 x 500 mL), the combined EtOAc phase was washed with brine, dried over Na2SO4, concentrated in vacuo, purified by column of silica (petroleum ether / EtOAc=50 / 1 to 30 / 1 to 20 / 1) to give the product (70.0 g, 37%) as a yellow oil,1H NMR (400 MHz, CDCI3) δ: 4.29-4.09 (m, 2H), 4.063.88 (m, 2H), 3.79 (d, 1H), 3.60-3.48 (m, 1 H), 2.78 (s, 2H), 2.66-2.25 (m, 1H), 2.24- 1.94 (m, 2H), 1.74 (m, 2H), 1.50-1.37 (m, 9H), 1.34-1.18 (m, 5H), 1.12 (d, 3H), 0.91 (s, 10H), 0.04 (s, 6H). Step 4: Tere-butyl 4-[(2S>2-\[(tere-butyldimethylsilyl)oxy]-1-hydroxypropyl]-4-(hydroxymethyl)piperidine-1carboxylate To the solution of 4-ethyl 4-[(2S)-2-[(tert-but¡ld¡methylsil¡l)ox¡]-1-hydroxy¡prop¡l]p¡perídin- 1-Tere-butyl 1,4-dicarboxylate (70.0 g, 0.157 mol) in THF (700 mL) was added to LIBH4 (2 M, 118 mL, 0.236 mol) at 0 °C, then stirred at room temperature overnight. . The mixture was poured into water (500 mL), stirred at room temperature for 20 minutes, extracted with EtOAc (2 x 300 mL), washed with brine, dried over Na2SO4, concentrated in vacuo to give the crude product. (60.0g). It was used in the next step without purification. Step 5: Tere-butyl 4-[(2S)-1,2-dihydroxypropyl]-4-(hydroxymethyl)piperidine-1-carboxylate To a cold (0 °C) solution of 4-[(2S)-2-\ / / tert-butyldimethyls¡l¡l)ox¡]-1-hydroxyprop¡l]-4(hydroxymethyl)piperidin -l -carboxylate tere-butyl (60.0 g, 0.149 mol) in THF (600 mL), TBAF (1 M, 223 mL, 0.223 mol) was added and stirred at room temperature for 2 h. NaHCOs (aqueous, 600 mL) was added, stirred at room temperature for 10 minutes, extracted with EtOAc (2 x 300 mL), washed with brine, dried over Na2SO4, concentrated in vacuo, purified by a silica (DCM / MeOH=100 / 1 to 50 / 1 to 30 / 1) to give the product (37.0 g, 86%) as a yellow oil, 1H NMR (400 MHz, CDCI3) δ: 4.02-3.87 (m, 1H), 3.74 (m, 4H), 3.36 (d, 4H), 3.10 (s, 2H), 1.66 (s, 3H), 1.40 (s, 10H), 1.31 (s, 3H). Step 6: Tere-butyl (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate οη«ι ηη / ζζηζ / Ε / γ 137 To an ice-cooling solution of tere-butyl 4-[(2S)-1,2-dihydroxypropyl]-4-(hydroxymethyl)piperidi-tcarboxylate (37.0 g, 0.127 mol) in THF (400 mL) NaH (17.8 g, 0.44 mol) was added in portions, then a solution of TsCl (25.5 g, 0.134 mol) in THF (200 mL) was added and the reaction mixture was stirred at 0 °C for 2 hours The reaction mixture was poured into ice and NH4CI (aqueous, 600 mL), extracted with EtOAc (3 x 400 mL), washed with brine, dried over Na2SO4, concentrated in vacuo, purified by silica column ( DCM / MeOH=100 / 1 to 50 / 1 to 30 / 1) to give the product (20.0 g, 58%) as a yellow oil, 1H NMR (400 MHz, CDCI3) δ: 3.94-3.57 (m, 4H) , 3.45 (d, 1H), 2.96 (s, 2H), 1.70 (s, 3H), 1.42 (s, 10H), 1.29 (m, 4H). Step 7: terobutyl (3S)-3-methyl-4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate To an ice-cooling solution of tere-butyl (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8carboxylate (20.0 g, 0.074 mol) in DCM (200 mL) was added to DMP (37.5 g, 0.088 mol) in portions. The reaction mixture was stirred at room temperature for 1 h, poured into NaHCOs (aqueous), extracted with DCM, washed with brine, dried over Na2SO4, concentrated in vacuo to give the product (19.0 g, 95%). ) like a yellow oil. It was used directly in the next stage. Step 8: (3S,4S>3-methyl-4-[(2-methylpropane-2-sulfinyl)amino]-2-oxa-8-azaspiro[4.5]decane-8carboxylate tere-butyl The solution of tere-butyl (3S)-3-methyl-4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (11.0 g, 0.04 mol) in THF (250 mL) was added (fi)-2-methylpropane-2-sulfinamide (9.9 g, 0.08 mol), Ti(0Et)4 (36.5 g, 0.16 mol) and the reaction mixture was stirred at 75 °C overnight. The reaction mixture was cooled to -10 °C, LÍBH4 (2 M, 30 mL, 0.06 mol) was added dropwise, then stirred at -10 °C for 1 h. The reaction mixture was poured into ice and NH4CI (aqueous, 300 mL) and EtOAc (300 mL), stirred at room temperature for 20 minutes and then filtered through celite. The reaction mixture was extracted with EtOAc (2 x 300 mL), washed with brine, dried over Na2SO4, concentrated in vacuo, purified using a silica column (petroleum ether / EtOAc=10 / 1 to 5 / 1 to 3 / 1 to 2 / 1) to give the product (7.0 g, 47%),1H NMR (400 MHz, DMSO-ofe) δ: 5.07 (d, J = 11.0 Hz, 1H), 4.06 (s, 1H), 3.74 (m, 3H), 3.37 (d, 3H), 2.84 (s, 2H), 1.69-1.50 (m, 2H), 1.39 (s, 11H), 1.15 (s, 9H), 1.06 (m , 3H). Step 9: (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride To the solution of (3S,4S)-3-methyl-4-[(2-methylpropane-2-sulfínl)amino]-2-oxa-8-azaspiro[4.5]decane8 -Tere-butyl carboxylate (5.8 g, 15.5 mmol) in MeOH (20 mL) was added to HCl / dioxane (4 M, 39 mL, 155 mmol), then stirred at 50 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was dissolved in water (50 mL), extracted with EtOAc (3 x 40 mL). The aqueous phase was lyophilized to give the HCl salt of the product (4.0 g) as a yellow solid. MS: [M+H]+= 171.1H NMR (400 MHz, DMSO-rt) δ: 4.44 (m, 1H), 4.05-3.88 (m, 2H), 3.67 (s, 1H), 3.58-3.39 (m , 2H), 3.22-3.01 (m, 2H), 1.98 (m, 4H), 1.34 (s, 3H). οη«ι ηη / ζζηζ / Ε / γ 138 Preparation 26:1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate tere-butyl --. .CHO Boc. --x Boc, f Y í n >Stage2N η OHBoc'N-'\ OH , A J * k 4 ...................*· k A-4 - ----* i I . / Boc' -- 'i \ \...- \ ..l \ / ! / on«i nn / zznz / Ε / γ Step 1: tere-butyl 4-formyl-4-(prop-2-en-1-yl)piperidine-1-carboxylate The reaction mixture of tere-butyl 4-form¡lp¡perídin-1-carboxylate (1200.0 g, 5.63 mol) in THF (10 L) was cooled to -25 °C, then bromide was added. of allyl (816.5 g, 6.75 mol), followed by tBuOK (757.8 g, 6.75 mol) in portions. The reaction mixture was stirred at -25 °C ~ -15 °C for approximately 45 minutes, then poured into ice NH4Cl (aqueous, 8 L), extracted with EtOAc, washed with brine, dried over Na2SÜ4 and concentrated in vacuo. The crude product was purified by silica column (petroleum ether / EtOAc=50 / 1 to 20 / 1 to 10 / 1) to give the title compound (920.0 g, 64.5%) as a colorless oil.1H NMR (CDCI3 ): 9.49 (1H, s), 5.63 (1H, m), 5.09 (2H, m), 3.79 (2H, m), 2.96 (2H, m), 2.23 (2H, d), 1.93 (2H, m) , 1.44 (10H, m). Step 2: Tere-butyl 4-(1-hydroxyprop-2-en-1-yl)-4-(prop-2-en-1-yl)piperidine-1-carboxylate A solution of tere-butyl 4-formyl-4-(prop-2-en-1-yl)piper¡din-1-carboxylate (400.0 g, 1.58 mol) in THF (4 L) was cooled to -60° C, magnesium bromide (1.90 L, 1.90 mol) was added, then it was stirred at room temperature for 1 h. The mixture was poured into NH4Cl (aqueous, 5 L), extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated in vacuo to give the product (426.0 g, 95.8%) as a brown oil. 1H NMR (CDCI3): 5.93 (2H,m), 5.24 (2H, m), 5.07 (2H, t), 4.00 (91H, d), 3.69 (2H, m), 3.12 (2H, m), 2.30 (1H , m), 2.19(1 H, m), 1.74 (1 H, m), 1.60-1.53 ​​(2H, m) 1.49 (11H, m). Step 3: terobutyl 1-hydroxy-8-azaspiro[4.5]dec-2-ene-8-carboxylate To the solution of tere-butyl 4-(1-hydroxy¡prop-2-en-1-¡l)-4-(prop-2-en-1-¡l)peridine-1-carboxylate (10.0 g, 35.3 mmol) in toluene (150 mL), Grubbsll (0.91 g, 1.07 mmol) was added and the reaction was stirred at 90 °C for 7 h. The mixture was purified by silica column (petroleum ether / EtOAc=20 / 1 to 10 / 1 to 5 / 1) to give the desired product (7.1 g, 78.9%) as a brown oil. 1H NMR (CDCI3): 5.92 (1H, m), 5.83 (1H, m), 4.30 (1h, s), 3.58 (2H, m), 3.16 (2H, m), 2.22 (2H, dd), 1.74 ( 2H, m), 1.46-1.76 (12H, m). Step 4:1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate tere-butyl A solution of tere-butyl 1-hydroxy-8-azaspiro[4.5]dec-2-ene-8-carboxylate (100.0 g, 0.39 mol) in DCM (600 mL) was cooled to 0°C, Dess Martin (184 g, 0.43 mol) was then added and the mixture was stirred at RT for 1 h. The reaction mixture was poured into NaHCOs (1.8 L) and NaHSOs (1.5 L), extracted with DCM, the combined DCM phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product. The crude product was poured into ether of 139 petroleum / EtOAc=4:1 and stirred overnight, filtered and concentrated in vacuo to give the title compound (57.6 g, 58%) as a pale red solid, 1H NMR (CDCb): 7.6(1 H, m), 6.18 (1H, m), 4.09 (2H, br s), 2.90 (2H, m), 2.61 (2H, s), 1.77 (2H, m), 1.46 (9H, s), 1.27 ( 2H, d). Preparation 27: (1R>1-\{[(ferc-butoxy)carbonyl]amino}-3,3-difluoro-8-azaspiro[4.5]decane-8carboxylate tere-butyl or Etapq 1 P Q ° ” ΜΛ * M) ' • ,7< / ÓTBSÓTBS Eioc q9 E'apaá Ν'wg Stage5 HnA,^Eías3g ^'N^aN''% NHBocV'T \ .A A.4 % '--------- A, \ -----* AA \ < 2 'L / < / : / Y υ 1'AF OH0 0F Step 1: Tere-butyl (3ff)-3-hydroxy-1-oxo-8-azaspiro[4.5]decane-8-carboxylate The reaction was carried out in three batches. A mixture of CuCl (0.59 g, 6.0 mmol), (S)-Tol-BINAP (4.05 g, 6.0 mmol), t-BuONa (0.57 g, 6.0 mmol) in THF (450 mL) was stirred at room temperature for 30 minutes. B2pin2 (55.6 g, 0.22 mol) in THF (250 mL) was added, stirred at room temperature for 15 minutes. Tere-butyl 1-oxo-8azaspiro[4.5]dec-2-ene-8-carboxylate (50.0 g, 0.2 mol) in THF (250 mL) and MeOH (12.7 g, 0.4 mol) were added and the reaction mixture It was stirred at room temperature overnight. Water (1 L) and NaBOs (153.1 g, 0.99 mol) were added and the reaction mixture was stirred at RT for 1 h. The three batches were combined, filtered, extracted with EtOAc, washed with brine, dried over Na2SÜ4 and concentrated in vacuo to obtain the crude product. The crude product was suspended in EtOAc and stirred at 0°C for 1 h, filtered and dried to give a part of the product (79.3 g). The filtrate was concentrated in vacuo, purified by silica column (petroleum ether / EtOAc=20 / 1 to 10 / 1 to 3 / 1) to give the other part of the product (37.5 g) as a white solid. 1H NMR (CDCb): 4.62 (1H, m), 3.89 (2H, m), 3.03 (2H, m), 2.63 (1H, dd), 2.43 (1H, dd), 2.10 (1H, m), 1.63 ( 3H, m), 1.45 (9H, s), 1.30 (3H, m). Stage 2: (3R>3-\f(tert-butyldimethylsilyl)oxy]-1-oxo-8-azaspiro[4.5]decane-8-carboxylate tere-butyl To a solution of tere-butyl (3fi)-3-hydroxyl-1-oxo-8-azaspiro[4.5]decane-8-carboxylate (100.0 g, 0.37 mol) in DMF (900 mL) added (37.9 g, 0.56 mol), TBSCI (67.2 g, 0.46 mol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water (5 L), extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated in vacuo, purified by silica column (petroleum ether / EtOAc=20 / 1 at 10 / 1 to 3 / 1) to give the product (118.7 g, 79.4%) as a yellow oil. on«l 00177077B / Y 1401H NMR (CDCI3): 4.44 (1Η, m), 3.83 (2Η, d), 2.95 (2H, m), 2.31 (1H, dd), 2.27 (1H, dd), 2.03 (2H, m), 1.93 (1H, m), 1.71 (1 H, m), 1.40 (9H, s), 1.21 (2H, m), 0.82 (9H, s), 0.03 (9H, s). Step 3: (1R,3R)-3-[(tert-butyldimethylsilyl)oxy]-1-[(2-methylpropane-2-sulfinyl)amino]-8azaspiro[4.5]decane-8-carboxylate tere-butyl To a solution of (3ñ>3-\[(tert-but¡ld¡met¡ls¡l¡l)ox¡]-1-oxo-8-azaspiro[4.5]decane-8-carboxylate tere-butyl (120.0 g, 0.31 mol) in THF (2 L), sulfinamide (75.8 g, 0.61 mol), Ti(OEt)4 (285.4 g, 1.25 mol) were added and the reaction mixture was stirred at 65 ° C overnight. The reaction mixture was cooled to -60 °C, UBH4 (940 mL, 0.94 mol) was added dropwise and stirred at -60 °C for 3 h. The reaction mixture was poured into NH4CI (aqueous), extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated in vacuo, purified by silica column (petroleum ether / EtOAc=10 / 1 to 5 / 1 to 3 / 1 ) to give the product (59.7 g, 39%) as a yellow oil, 1H NMR (CDCh): 4.29 (1H, m), 3.90 (2H, d), 3.76 (1H, m), 3.30 (1H, m) , 3.02 (2H, m), 2.33 (1H, m), 1.60-1.80 (7H, m), 1.44 (9H, s), 1.20 (9H, s), 0.86 (9H, s), 0.034 (6H, s ). Step 4: Tere-butyl (1fi,3fi)-3-hydroxy-1-[(2-methylpropane-2-sulfinyl)amino]-8-azaspiro[4.5]decane-8carboxylate To a solution of (1F?,3F?)-3-[(tert-but¡ld¡met¡ls¡l¡l)ox¡]-1-[(2-methylpropane-2-sulf¡n¡ l)amino]-8azaspiro[4.5]decane-8-carboxylate (38.0 g, 77.74 mmol) in THF (230 mL) TBAF (155.5 mL, 155.5 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours The reaction mixture was poured into water, extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated in vacuo, purified by silica column (DCM / MeOH=50 / 1 to 30 / 1 to 20 / 1) to give the desired product (26.1 g, 89.7%) as a brown oil, 1H NMR (DMSO-de): 5.06 (1H, m), 4.68 (1H, d), 4.03 (1H, m), 3.78 ( 2H, m), 3.06 (1H, m),2.73 (2H, m),2.15 (1H, m), 1.61 (4H, m), 1.39 (10 H, m),1.26 (2H, m),1.20 ( 9H, s). Step 5: Tere-butyl (1 R)-1-[(2-methylpropane-2-sulfinyl)amino]-3-oxo-8-azaspiro[4.5]decane-8carboxylate To the solution of (1 fi.Sfíj-S-hydroxy-l-[(2-methylpropane-2-sulfiníl)amino]-8-azaspiro[4.5]decane-8carboxylate of tere-butyl (23.3 g, 0.062 mol) in DCM (500 mL) Dess-Martin (39.6 g, 0.093 mol) was added at 0 ° C and the mixture was stirred at 0 ° C for 2 h. The reaction mixture was quenched with saturated aqueous NaHCOs, was filtered through Celite. The filtrate was extracted with DCM, the combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica column (CH2Cl2 / MeOH=50 / 1 at 40 / 1 to 30 / 1 v / v) to give the product (21.44 g, 92.4%) as a yellow oil. Step 6: Tere-butyl (1R)-1-{[(tert-butoxy)carbonyl]amino}-3-oxo-8-azaspiro[4.5]decane-8-carboxylate To the solution of (1 F?)-1-[(2-methylpropane-2-sulfányl)amino]-3-oxo-8-azaspiro[4.5]decane-8carboxylate of tere-butyl (10.00 g, 0.027 mol) in dioxane (200 mL), HCl (6 M in dioxane, 200 mL) was added at room temperature, then the mixture was stirred at room temperature for 3 h. The reaction mixture was neutralized with solid NaHCOs to PH=9, Boc2O (23.44 g, 0.11 mol) was added. Mix ΟΠΑΙ ηη / 77Π7 / Ε / Υ was stirred at RT while maintaining PH>9. The mixture was quenched with saturated aqueous NaHCOs, filtered through Celite. The filtrate was extracted with DCM, the combined organic layers washed with brine, dried over Na2SO4, concentrated in vacuo. The residue was purified by silica column (DCM / MeOH=50 / 1 to 40 / 1 to 30 / 1) to give the product (21.44 g, 92.4%) as a yellow oil. Step 7: tert-butyl (1 R>1-{[(tert-butoxy)carbonyl]amino}-3,3-difluoro-8-azaspiro[4.5]decane-8-carboxylate To the solution of tere- butyl (1.00 g, 2.71 mmol) in DCM (20 mL) Deoxo Fluor (2.40 g, 10.85 mmol) was added at 0 °C, then the mixture was allowed to warm to RT and then stirred at 5 °C overnight . The mixture was quenched with saturated aqueous NaHCOs in an ice water bath, extracted with EtOAc, the combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo. The resulting residue was purified by silica column (petroleum ether / EtOAc=20 / 1 to 15 / 1 to 10 / 1 v / v) to give the product (600.0 mg, 56.6%) as a white solid, 1H NMR ( CDCIs): 4.55 (1H, d), 4.01-3.93 (3H, m), 2.85 (2H, d), 2.56 (1H, m), 2.26 (1H, m), 2.02 (2H, m), 1.66 (1H , m), 1.44 (21H, s),19F NMR (CDCh): -86.45 (d). Preparation 28: (1R>4,4-difluoro-8-azaspiro[4.5]decane-1-amine οη«ι ηη / 77Π7 / Ε / γ To a solution of tert-butyl (1phy)-1-{[(tert-butoxy)carbonyl]amino}-3,3-difluoro-8-azaspiro[4.5]decane-8-carboxylate (543 mg, 1.39 mmol ) in DCM (4 mL) was added TFA (4 mL) and the solution was stirred overnight. The solvent was evaporated to provide the bis-TFA salt of the title compound which was used without further purification, 1H NMR (400 MHz, Me-d3-OD): 3.69 (1H, t), 3.54-3.36 (2H, m ), 3.22-3.08 (2H, m), 2.93-2.77 (1H, m), 2.69-2.53 (1H, m), 2.52-2.35 (2H, m), 2.15-2.03 (1H, m), 1.97-1.77 (3H, m). Preparation 29: tert-butyl N-[(1R,3R>3-(trifluoromethyl)-8-azaspiro[4.5]decan-1-yl]carbamate Stage 3 stage 4 NHBoc HN f Stage 5 ¡ 142 Step 1: benzyl 1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate To the mixture of tere-butyl 1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate (30.0 g, 0.20 mol) in DCM (1000 mL) TFA (150 mL) was added, then The mixture was stirred at RT overnight. The mixture was concentrated in vacuo to give the impure intermediate which was used directly in the next step. To the mixture of the impure intermediate in THF (100 mL) and H2O (400 mL) NaHCOs (50.4 g, 0.60 mol) was added to adjust the pH of the solution to 8-9. The mixture was cooled to 0°C and the solution of Cbz-CI (51.2 g, 0.30 mol) in THF (100 mL) was added dropwise. The reaction mixture was allowed to warm to RT after the addition was complete with stirring overnight. The reaction mixture was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo. The resulting residue was purified by silica column (petroleum ether / EtOAc-10 / 1 to 2 / 1) to give the product (49.5 g, 87.5%) as a brown oil. Step 2: Benzyl 1-oxo-3-(trifluoromethyl)-8-azaspiro[4.5]decane-8-carboxylate A solution of benzyl 1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate (10.8 g, 37.9 mmol) in THF (150 mL) was cooled to 0 °C, then trimethyl( trifluoromethyl)silane (6.5 g, 45.4 mmol), TBAF (0.76 mL, 0.76 mmol). The mixture was stirred at 0°C for 1.5 h. The mixture was quenched with 2 M aqueous HCl (40 mL) at 0 °C. The solution was diluted with saturated aqueous NH4Cl and extracted with EtOAc, the combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo. The resulting residue was purified by silica column (petroleum ether / EtOAc=10 / 1 to 3 / 1) to give the product (4.4 g, 32.6%) as a yellow oil. Step 3: Benzyl (1ff,3R)-1-[(2-methylpropane-2-sulfinyl)amino]-3-(trifluoromethyl)-8azaspiro[4.5]decane-8-carboxylate A solution of benzyl 1-oxo-3-(trifluorome...

Claims

1. A compound of formula (I): oη«ι ηη / 77P7 / E / γ or a tautomer or a pharmaceutically acceptable solvate or salt thereof, wherein: R1 is hydrogen or hydroxyl; R2 and R3 are independently selected from hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, Ci-4 hydroxyalkyl and -CN; X is O or CR4R5; R4 and R5 are independently selected from hydrogen, halogen, hydroxyl, Ci-4 alkyl, Ci-4 alkoxy and Ci-4 haloalkyl; R6 and R7 are hydrogen, Ci-4 alkoxy or halogen (for example, chlorine or fluorine), or R6 and R7 are joined to form ring A which is optionally substituted with one or more (for example, 1, 2, or 3) R10 groups; Ring A is: (i) a five-membered heterocyclic ring containing nitrogen (for example, an aromatic ring or a non-aromatic ring) wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S, or (ii) a six-membered aromatic heterocyclic ring containing nitrogen,wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or (ii) a six-membered non-aromatic heterocyclic ring containing nitrogen, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S; R8 is selected from C1-4 haloalkyl (for example, -CF3), -CH3 and halogen (for example, chlorine or fluorine); R9 is selected from hydrogen, C1-4 alkyl (for example, -CH3), C1-4 haloalkyl (for example, -CF3) and halogen (for example, chlorine); R10 is independently selected from halogen, cyano, Ci-4 cyanoalkyl (e.g., -CH2-CN), hydroxyl, =0 (oxo), Ci-4 alkyl (e.g., -CH3, -CH(CH3)2 or -CH2CH3), Ci-4 haloalkyl (e.g., CHF2), C1-4 alkoxy (e.g., -OCH3, -OCH2CH3 and -OCH(CH3)2), C1-4 hydroxyalkyl (e.g., CH2C(CH3)2OH, -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH or -CH2OH), Ci-4 alkoxy, Ci-4 alkylene (e.g., -CH2-O-CH3 or -CH2-CH2-O-CH3),C1-4 alkylsulfone (e.g., -SO2CH3), amino, C1-4 monoalkylamino, C1-4 dialkylamino (e.g., -N(CH3)2), C1-4 aminoalkylene (e.g., CH2NH2), -alkylene Ci-4-C(=O)NH(2-q)(Ci-e)q alkylene), -alkylene Co-4-NHC(=O) C1-6 alkyl, C0-4 alkylene sulfonamide (e.g., -SO2NRX2 or -CHESChNRA), wherein Rx is independently selected from H and Ci-β alkyl), 3- to 6-membered cycloalkyl, optionally substituted five- or six-membered unsaturated heterocyclic group containing 1, 2, 3, or 4 heteroatoms selected from O, N, or S, wherein the optional substituent is selected from C1-4 alkyl, C1-4 alkyl substituted with 3- to 6-membered cycloalkyl members, C1-4 alkyl substituted with an optionally substituted five- or six-membered unsaturated heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4 alkyl,C1-4 alkyl substituted with an optionally substituted saturated four- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from O, N, or S, wherein the optional substituent is selected from C1-4 alkyl and an optionally substituted saturated four- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from O, N, or S, wherein the optional substituent is selected from C1-4 alkyl; and q is selected from 0, 1, or 2.

2. A compound of formula (I) according to claim 1, wherein X is O.

3. A compound of formula (I) according to claim 1, wherein X is CR4R5, and R4 and R5 are independently selected from hydrogen, halogen, and C1-4 alkyl optionally substituted with one or more halogens (e.g., C1 alkyl optionally substituted with one or more halogens).

4. A compound of formula (I) according to any one of claims 1 or 3, wherein X is CR4R5, and R4 is hydrogen and R5 is selected from halogen (for example, fluorine, chlorine, bromine or iodine, in particular fluorine) and halomethyl (for example, monohalomethyl, dihalomethyl and trihalomethyl, wherein halo is selected from fluorine, chlorine, bromine or iodine).

5. A compound of formula (I) according to any of claims 1 to 4, wherein R1 is hydroxyl.

6. A compound of formula (I) according to any of claims 1 to 4, wherein R1 is hydrogen.

7. A compound of formula (I) according to any one of claims 1 to 6, wherein R2 is hydrogen and R3 is selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl and -CN.

8. A compound of formula (I) according to any one of claims 1 to 7, wherein R2 is hydrogen and R3 is C1-4 alkyl, for example, -CH3.

9. A compound of formula (I) according to any one of claims 1 to 8, wherein R8 is selected from -CH3, chlorine, and fluorine.

10. A compound of formula (I) according to any one of claims 1 to 9, wherein R8 is chlorine.

11. A compound of formula (I) according to any one of claims 1 to 10, wherein R9 is hydrogen.

12. A compound of formula (I) according to any one of claims 1 to 11, wherein R6 and R7 are hydrogen or halogen (for example, chlorine or fluorine).

13. A compound of formula (I) according to any one of claims 1 to 11, wherein R6 and R7 are joined to form a ring A which is optionally substituted by one or more (e.g., 1, 2, or 3) R10 groups; wherein the ring A is: (i) a five-membered heterocyclic ring containing nitrogen (e.g., an aromatic ring or a non-aromatic ring) wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O, and S, or (ii) a six-membered aromatic heterocyclic ring containing nitrogen, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O, and S; or (iii) a six-membered non-aromatic heterocyclic ring containing nitrogen, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S.

14. A compound of formula (I) according to claim 13, wherein ring A is a five-membered heterocyclic ring containing nitrogen (e.g., an aromatic ring or a non-aromatic ring), or a six-membered aromatic heterocyclic ring containing nitrogen, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O, and S.

15. A compound according to claim 14, wherein ring A is a five-membered heterocyclic ring containing nitrogen (e.g., an aromatic ring or a non-aromatic ring), wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S.

16. A compound according to claim 15, or a pharmaceutically acceptable tautomer, salt or solvate thereof, wherein ring A is a nitrogen-containing five-membered aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S.

17. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable tautomer, salt or solvate thereof, wherein ring A is: (i) a nitrogen-containing, six-membered aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or (ii) a nitrogen-containing, six-membered, non-aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S.

18. A compound according to any one of claims 1 to 12, wherein the remainder οη«ι ηη / 77Π7 / E / γ 192 is selected from Table I or Table II in the present description.

19. A compound according to claim 18, or a pharmaceutically acceptable tautomer, salt, or solvate thereof, wherein the R group is selected from: £>^^7 HN·__ R9 / R9 / yvm yy / R8 / R8 , for example, N r9 J / 1 yy / R8 or is selected from: ________ < vO / R8 for example, V-θ' / R8 R7 9 1 ll y^R6 / R8 / Λ MH / R10 R9 / 9 's / · H / N R9 b / r8 R10)c __(R10)c N 0 / R8 N===:\ —OCHS R9 / -N(CH3)2 yy / R8 193 20. A compound according to any one of claims 1 to 19, wherein R10 is independently selected from halogen, cyano, C1-4 cyanoalkyl (e.g., -CH2-CN), hydroxyl, oxo, C1-4 alkyl (e.g., -CH3 or -CH2CH3), C1-4 haloalkyl, C1-4 alkoxy (e.g., -OCH3), C1-4 hydroxyalkyl (e.g., -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH or -CH2OH), C1-4 dialkylamino (e.g., -N(CH3)2), and C1-4 alkoxy alkylene (e.g., -CH2-O-CH3), wherein R10 is independently selected from halogen, cyano, hydroxyl, oxo and C1-4 alkyl (e.g., -CH3 or -CH2CH3).

21. A compound according to any one of claims 1 to 20, wherein R10 is independently selected from halogen, cyano, hydroxyl, =0 (oxo), C1-4 alkoxy (e.g., -OCH3), C1-4 dialkylamino (e.g., -N(CH3)2), and C1-4 alkyl (e.g., -CH3 or -CH2CH3), e.g., wherein R10 is independently selected from hydroxyl, =0 (oxo) and C1-4 alkyl (e.g., -CHs).

22. A compound according to claim 1 or a pharmaceutically acceptable tautomer, salt or solvate thereof, wherein R6 and R7 are joined to form ring A and the compound of formula (I) is a compound of formula (XVIII): κ (XVIII).

23. A compound indicated with the indication 1, or a tautómer, salt or solvate pharmaceutically acceptable of the same, whereby the compound is selected from: (1 R,3R)-8-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1 Hp¡razolo[3,4-b]pyraz¡n-6-yl]-3-(tr¡fluoromethyl)-8azaespiro[4.5]decan-1 -amine; (1 R)-8-[3-(4-chloro-2-met¡l-2H-indazol-5-¡l)-5-met¡l-1 H-pyrazolo[3,4-b]pyraz¡n-6-¡l]-3,3-difluoro-8azaespiro[4.5]decane-1 -amine; (4S)-8-[3-(4-chloro-2-methyl-2H-indazol-5-¡l)-5-methyl-1 H-pyrazolo[3,4-b]p¡raz¡n-6-yl]-2-oxa-8azaespiro[4.5]decane-4-amine; (4S)-8-[3-(3,4-dichloro-2-met¡l-2H-¡ndazol-5-¡l)-5-methyl-1 H-pyrazolo[3,4-b]pyraz¡n-6-¡l]-2-oxa-8azaespiro[4.5]decane-4-amine; (4S)-8-[3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1 H-pyrazolo[3,4-b]p¡razin-6-¡l]-2-oxa-8azaespiro[4.5]decane-4-amine; (3S,4S)-8-[3-(4-chloro-2-methyl-2H-¡ndazol-5-¡l)-5-met¡l-1 H-pyrazolo[3,4-b]p¡raz¡n-6-¡l]-3-methyl-2-oxa-8azaespiro[4.5]decane-4-amine; 194 {6-[(1 R)-1 -am¡no-3,3-d¡fluoro-8-azaesp¡ro[4.5]decan-8-yl]-3-(4-chloro-2-met¡l-2H-¡ndazol-5-¡lo)-1 Hpyrazolo[3,4-b]pyraz¡n-5-¡l}methanol; {6-[(3S,4S)-4-am¡no-3-met¡l-2-oxa-8-azasp¡ro[4.5]decane-8-¡l]-3-(3,4-dichloro-2-met¡l-2H-indazol-5-¡l)-1 Hpyrazolo[3,4-b)methl-5-l-5; (3S,4S)-8-[3-(5-chloro-3-methoxyquinoxal¡n-6-¡l)-5-methyl-1 H-pyrazolo[3,4-b]pyrazine-6-¡l]-3-methyl-2-oxa-8azaespiro[4.5]decane-4-amine; (3S,4S)-8-{3-[5-chloro-3-(dimethylam¡no)qu¡noxalin-6-yl]-5-met¡l-1 H-pyrazolo[3,4-b]p¡raz¡n-6-¡l}-3-methyl-2-oxa8-azaespiro[4.5-]aminadecane; (4S)-8-{3-[5-chloro-3-(d¡methylam¡no)qu¡noxal¡n-6-¡l]-5-met¡l-1 H-pyrazolo[3,4-b]p¡razin-6-¡l}-2-oxa-8azaespiro[4.5]decane-amine; 7-{6-[(1 R)-1-amino-8-azaesp¡ro[4.5]decan-8-¡l]-5-met¡l-1H-p¡razolo[3,4-b]p¡raz¡n-3-¡l}-8-chloro-N,Dimethylquinoxaline-2-amine; (4S)-8-[3-(5-chloro-3-methoxyquinoxal¡n-6-¡l)-5-met¡l-1 H-pyrazolo[3,4-b]pyrazin-6-¡l]-2-oxa-8azaespiro[4.5]decane-4-amine; (1 R)-8-[3-(5-chloro-3-methoxyquinoxal¡n-6-¡l)-5-met¡l-1 H-pyrazolo[3,4-b]p¡raz¡n-6-yl]-8-azaespro[4.5]decane-1amine; (1 R)-8-[3-(3,4-d¡chloro-2-methyl-2H-¡ndazol-5-¡l)-5-met¡l-1 H-pyrazolo[3,4-b]p¡raz¡n-6-¡l]-8-azaespiro[4.5]decane1-amine; {6-[(1 R)-1-am¡no-3,3-d¡fluoro-8-azaesp¡ro[4.5]decane-8-¡l]-3-(3,4-dichloro-2-met¡l-2H-¡ndazol-5-¡l)-1 Hpyrazolo[3,4-b]p-methl-5-l-5; {6-[(3S,4S)-4-am¡no-3-met¡l-2-oxa-8-azaesp¡ro[4.5]decane-8-¡l]-3-[5-chloro-3-(dimeth¡lam¡no)qu¡noxal¡n-6-¡l]1 H-pyrazolo[3,4-b]p¡raz¡n-5-¡l}methanol; {6-[(3C,4C)-4-amino-3-methyl-2-oxa-8-azaespiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-1 H-pyrazolo[3,4b]pyrazine-5-yl}methanol; (3S,4S)-8-[3-(3-chloro-2-fluorophen¡l)-5-met¡l-1H-p¡razolo[3,4-b]p¡raz¡n-6-¡l]-3-met¡l-2-oxa-8azaespiro[4.5]decane-4-amine; {6-[(1 R,3S)-1 -am¡no-3-fluoro-8-azaesp¡ro[4.5]decane-8-¡l]-3-(3,4-dichloro-2-met¡l-2H-¡ndazol-5-¡l)-1 Hpyrazolo[3,4-b]p¡no-meth-ol}-an; {6-[(3S,4S)-4-am¡no-3-met¡l-2-oxa-8-azaesp¡ro[4.5]decane-8-¡l]-3-(4-chloro-2,3-dimeth¡l-2H-¡ndazol-5-¡l)-1 Hpyrazolo[3,4-b]p¡raz¡n-5-¡l}methanol; {6-[(3S,4S)-4-am¡no-3-met¡l-2-oxa-8-azaesp¡ro[4.5]decan-8-¡l]-3-(5-chloro-3-methoxyqu¡noxal¡n-6-¡l)-1 Hpyrazolo[3,4-b]p¡raz¡n-5-¡l}methanol; {6-[(3S,4S)-4-am¡no-3-met¡l-2-oxa-8-azaesp¡ro[4.5]decan-8-¡l]-3-(3-chloro-2-fluorofen¡l)-1H-p¡razolo[3,4b]pyrazin-5-¡l}methanol; {6-[(3S,4S)-4-am¡no-3-met¡l-2-oxa-8-azaespiro[4.5]decan-8-¡l]-3-(2-chlorophen¡l)-1 H-pyrazolo[3,4-b]pyraz¡n-5¡IJmetanol; (3S,4S)-8-{3-[3-(azetidin-1 -¡l)-5-chloroquinoxal¡n-6-¡l]-5-met¡l-1 H-pyrazolo[3,4-b]pyraz¡n-6-¡lo}-3-met¡l-2-oxa8-azaespiro[4.5]decan-4-amine; y on«l 0017707IRIM 195 (3S,4S)-8-{3-[5-chloro-3-(morpholin-4-yl)quinoxalin-6-yl]-5-methyl-1 H-pyrazolo[3,4-b]pyraz¡n-6-¡l}-3-met¡l-2-oxa-8azaespiro[4.5]decan-4-amine.

24. A combination that includes a compound of formula (I) as defined in any of the indications 1 to 23 with one or more (for example, 1 or 2) of other therapeutic agents (for example, agents against cancer).

25. A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 23 or a combination as defined in claim 24.

26. A compound as defined in any of claims 1 to 23, a combination according to claim 24, or a pharmaceutical composition according to claim 25 for use in therapy.

27. A compound as defined in any of claims 1 to 23, a combination according to claim 24 or a pharmaceutical composition according to claim 25 for use in the prophylaxis or treatment of a disease state or condition mediated by SHP2.

28. A compound as defined in any of claims 1 to 23, a combination according to claim 24, or a pharmaceutical composition according to claim 25 for use in the prophylaxis or treatment of a disease state or condition as described herein.

29. A compound as defined in any of claims 1 to 23, a combination according to claim 24, or a pharmaceutical composition according to claim 25 for use in cancer prophylaxis or treatment.

30. The use of a compound as defined in any of claims 1 to 23, a combination according to claim 24, or a pharmaceutical composition according to claim 25 for the manufacture of a medicament for use in the prophylaxis or treatment of a disease state or condition as described herein.

31. A method for the prophylaxis or treatment of a disease or condition as described herein comprising administering to a patient a compound as defined in any of claims 1 to 23, a combination according to claim 24, or a pharmaceutical composition according to claim 25.

32. A compound as defined in any of claims 1 to 23, or a pharmaceutical composition according to claim 24 for use in cancer prophylaxis or treatment, wherein the compound is used in combination with one or more other therapeutic agents (e.g., anticancer agents) or therapies.

33. A compound as defined in any of claims 1 to 23 for use in combination therapy with one or more other therapeutic agents (e.g., anticancer agents) or therapies.

34. A process for the preparation of a compound of formula (I) as defined in any one of claims 1 to 23, or a pharmaceutically acceptable tautomer, stereoisomer, salt or solvate thereof, comprising: (a) coupling a compound of formula (A) or a protected derivative thereof: wherein X, R1, R2 and R3 are as defined above in this description for compounds of formula (I), and P represents a protecting group (such as 2-tetrahydropyran; THP or 2-(trimethylsilyl)ethoxymethyl;SEM) or is hydrogen, and Z is a metal residue (such as zinc halide, for example, zinc chloride) or a leaving group (such as a halogen, for example, iodine or bromine) with a compound of formula (B) or a protected version thereof (B) wherein R6, R7, R8 and R9 are as defined above in the present description for compounds of formula (I) and V represents a metal or metalloid residue (such as boronic acid, pinacol boronate, magnesium halide or zinc halide, for example, boronic acid, pinacol boronate) or a leaving group such as a halogen, followed by a suitable deprotection reaction to remove the protecting groups; or (b) coupling a compound of formula (C) or a protected derivative thereof: wherein R1, R6, R7, R8 and R9 are as defined above in the present description for compounds of formula (I), X is CH, P represents a protecting group (such as 2-tetrahydropyran; THP or 2-(trimethylethyl)ethoxymethyl;SEM) or is hydrogen, L is a leaving group (such as chloride), with a compound of formula (D) or a protected derivative thereof, wherein X, R2 and R3 are as defined above in this description for compounds of formula (I) on«i ηη / ζζηζ / E / γ (D), or (c) reacting a compound of formula (K) or a protected derivative thereof, wherein X, R2, R3, R6, R7, R8 and R9 are as defined in this description for the compound of formula (I), P represents an amine protecting group (such as 2-tetrahydropyran; THP or 2-(trimethylsilyl)ethoxymethyl;SEM), N,N-dimethylsulfamoyl or hydrogen, L3 is a leaving group (such as halogen, for example, bromine): (i) with an organometallic species of the formula CH3M, where M is a metal (for example, CHs-ZnHal, where Hal is a halogen, for example, chloride, bromide or iodide) in the presence of a metallic catalyst (such as (1,3-diisopropylimidazol-2-lydene)(3-chloropyridyl)palladium(II) dichloride) to give a compound of formula (I) wherein R1 is H; or (i) with an alkyl boronate (such as potassium (2-trimethylsilyl)-ethoxymethyl trifluoroborate) in the presence of a photoredox catalyst (such as [lr{dFCF3ppy}2(bpy)]PF6), a metal catalyst (such as the nickel(ll) and ethylene glycol dimethyl ether chloride complex), a ligand (such as 4,4'-di-tert-butyl-2,2'-dipyridyl), a base (such as dipotassium phosphate) and a light source (such as a blue LED), to give a compound of formula (I) wherein R1 is OH;or (d) cyclization of a compound of formula (R), or a protected derivative thereof; 198 wherein X, R1, R2, R3, R6, R7, R8 and R9 are as defined above in this description for compounds of formula (I) and L1 represents a suitable leaving group, such as a halogen, by the use of hydrazine or a protected hydrazine derivative; in each case optionally followed by a deprotection step; or (e) deprotection of a protected derivative of a compound of formula (I); or (f) interconversion of a compound of formula (I) or a protected derivative thereof into a further compound of formula (I) or a protected derivative thereof; or (g) optionally the formation of a pharmaceutically acceptable salt of a compound of formula (I).

35. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable tautomer, stereoisomer, salt or solvate thereof as defined in claim 38, wherein the compound of formula (A) is produced by reacting a compound of formula (Xj) or a protected derivative thereof: (X') wherein R1 is as defined in claim 1, P represents a protecting group (such as 2-tetrahydropyran; THP or 2-(trimethylsilyl)ethoxymethyl; SEM) or is hydrogen, and L1 and L2 independently represent leaving groups (such as a halide, for example, chlorine, bromine or iodine); with a compound of formula (D) or a protected derivative thereof: wherein X, R2 and R3 are as defined in claim 1.