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    • 专利摘要:
    the invention provides new pyrazine derivatives of formula (i) or a tautomer or solvate or a pharmaceutically acceptable salt thereof, wherein the substituents are as defined herein. the invention also provides pharmaceutical compositions comprising said compounds and relates to the use of said compounds in the treatment of diseases, for example, cancer.
    公开号:BR112020017283A2
    申请号:R112020017283-9
    申请日:2019-03-01
    公开日:2020-12-15
    发明作者:Christopher Norbert Johnson；John Walter Liebeschuetz；Nicholas John Palmer；Jeffrey David St Denis；David Geoffrey Twigg；Andrew James Woodhead；Ildiko Maria Buck；Gianni Chessari；James Edward Harvey Day；Hideto FUJIWARA；Christopher Charles Frederick Hamlett；Steven Douglas Hiscock；Rhian Sara HOLVEY；Steven Howard
    申请人:Otsuka Pharmaceutical Co., Ltd；Taiho Pharmaceutical Co., Ltd.；
    IPC主号:
    专利说明:

    [0001] [0001] 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
    [0002] [0002] This application relates to patent application GB 1803439.7, filed on March 2, 2018 and patent application GB 1814135.8, filed on August 30, 2018, whose contents are hereby incorporated by reference in their entirety. BACKGROUND OF THE INVENTION
    [0003] [0003] Protein tyrosine phosphatase 2 (SH2) containing Src 2 homology region (SHP2) is a ubiquitously expressed tyrosine phosphatase protein, encoded by the PTPN11 gene. SHP2 contains two N-terminal tandem SH2 domains (N-SH2, C-SH2), a catalytic phosphatase domain (PTP) and a C-terminal tail with 2 tyrosine phosphorylation sites.
    [0004] [0004] SHP2 alternates between active “open” and inactive “closed” forms due to the self-inhibitory interactions between N-SH2 and the PTP domain. This naturally occurring autoinhibition is released when bis-tyrosylphorphylated peptides bind to the N-SH2 domains and SHP2 adopts an “open” conformation, resulting in the activation of the enzyme and exposure of the PTP domain for recognition and catalysis of the substrate.
    [0005] [0005] Mutations in PTPN11 have been linked to several human diseases, including cancer. PTPN11 germline mutations are associated with developmental disorders, such as Noonan syndrome and leopard syndrome, while somatic mutations occur in various types of hematological neoplasms, such as JMML and, more rarely, in solid tumors.
    [0006] [0006] SHP2 is needed to signal downstream receptor tyrosine kinases (eg, EGFR, ALK, PDGFR) and plays a positive role in the regulation of many cellular processes, such as proliferation in response to growth factor and stimulation of cytokines. Previous studies have shown that SHP2 acts upstream of Ras and is necessary for complete and sustained activation of the MAPK pathway. Deregulation of RTK generally leads to a wide variety 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 checkpoint pathways (eg, PD-1) as inhibitory motifs based on immunoreceptor-tyrosine (ITIMs) that bind to SH2 domains SHP2 to mediate a negative signal. Some SHP2 inhibitor compounds have been reported to show inhibitory effect on cancer cell proliferation in vitro and tumor tumor augmentation in a mouse xenograft model (Nature (2016) 535: 148 to 152).
    [0007] [0007] The present invention describes a new series of compounds which selectively inhibit SHP2 and which exhibit anti-cancer activity. SUMMARY OF THE INVENTION
    [0008] [0008] In one aspect, the invention provides a compound of Formula (I): (I)
    [0009] [0009] or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, where:
    [0010] [0010] X is CH or N;
    [0011] [0011] R1 is hydrogen, -CH3 or -CH2OH, but when X is N then R1 is selected from -CH3 and -CH2OH;
    [0012] [0012] R2 and R3 are either:
    [0013] [0013] (i) independently selected from hydrogen and C1-4alkyl; or
    [0014] [0014] (ii) together they form a bridge group with one to three members selected from C1-3alkylene, C2-3 alkenylene, methylene-NRq-methylene and methylene-O-methylene, in which the bridge group is optionally substituted by a group selected from C1-4alkyl, hydroxyl and halogen and Rq is selected from hydrogen, C1-4alkyl, hydroxyl and halogen;
    [0015] [0015] Q is C or N;
    [0016] [0016] where when Q is C then either:
    [0017] [0017] (i) R4 is hydrogen or C1-4alkyl (for example, methyl) optionally substituted by amino (for example, -CH2NH2);
    [0018] [0018] R5 is hydrogen, amino, hydroxyl or C1-4alkyl (for example, methyl) optionally substituted by 1 or 2 groups selected from halogen, hydroxyl (for example, -CH2OH) or amino;
    [0019] [0019] provided that R4 and R5 should not both be selected from amino and C1-4alkyl substituted by amino; or
    [0020] [0020] (ii) R4 and R5 together with Q form a nitrogen-containing heterocyclic ring with four to six members; and
    [0021] [0021] where when Q is N then:
    [0022] [0022] R4 is absent;
    [0023] [0023] R5 is hydrogen; and
    [0024] [0024] R2 and R3 together form the bridge group with one to three members;
    [0025] [0025] R6 and R7 are independently selected from halogen (for example, fluorine), C1-4alkyl (for example, -CH3) and hydroxyl provided that when Q is N, then R6 or R7 are not halogen or hydroxyl;
    [0026] [0026] a is selected from 0, 1 and 2;
    [0027] [0027] b is selected from 0, 1 and 2;
    [0028] [0028] Ring A or is it:
    [0029] [0029] (i) a five-membered nitrogen-containing 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
    [0030] [0030] (ii) a six-membered aromatic nitrogen containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or
    [0031] [0031] (iii) a six membered heterocyclic ring containing non-aromatic nitrogen, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S;
    [0032] [0032] R8 is selected from haloC1-4alkyl (for example, -CF3), -CH3 and halogen (for example, chlorine or fluorine);
    [0033] [0033] R9 is selected from hydrogen, C1-4alkyl (eg, -CH3), haloC1-4alkyl (eg, - CF3) and halogen (eg, chlorine);
    [0034] [0034] R10 are independently selected from halogen, cyano, cyanoC1-4alkyl (eg -CH2- CN), hydroxyl, = O (oxo), C1-4alkyl (eg -CH3, - CH2CH3, and -CH ( CH3) 2), haloC1-4alkyl (for example, -CHF2), C1-4alkoxy (for example, -OCH3, -OCH2CH3 and -OCH (CH3) 2), hydroxylC1-4alkyl (for example, -CH2C (CH3) 2OH , - CH (CH3) CH2OH, -CH (CH3) OH, -CH2CH2OH or -CH2OH), C1-4alkoxyC1-4alkylene (e.g. -CH2-O-CH3 or -CH2-CH2-O-CH3), C1- 4alkylsulfone (for example, -SO2CH3), amino, monoC1-4alkylamino, diC1-4alkylamino (for example, -N (CH3) 2), aminoC1-4alkylene (for example, -CH2NH2), -C0-4alkylene-C (= O ) NH (2-q) (C1-6 alkyl) q), -C1-4alkylene-NHC (= O) C1-6 alkyl, C0-4alkylene sulfonamide (for example, -SO2NRx2 or - CH2SO2NRx2), where Rx is independently selected from H and C1-6alkyl), cycloalkyl with 3 to 6 members, unsaturated heterocyclic group with five or six optionally substituted members containing 1, 2, 3 or 4 hetero atoms selected from O, N, or S where the optional substituent is selected from C1-4alkyl, C1-4alkyl substituted by cycloalkyl with 3 to 6 members, C1-4alkyl substituted by unsaturated heterocyclic group with five or six members optionally substituted containing 1, 2, 3 or 4 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4alkyl, C1-4alkyl substituted by saturated heterocyclic group with four to six members optionally substituted containing 1 or 2 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4alkyl and saturated heterocyclic group with four to six members optionally substituted containing 1 or 2 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4alkyl;
    [0035] [0035] q is selected from 0, 1 or 2; and
    [0036] [0036] c is selected from 0, 1, 2 and 3.
    [0037] [0037] In a second aspect, the invention provides a compound of Formula (I), or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, wherein:
    [0038] [0038] X is CH or N;
    [0039] [0039] R1 is hydrogen, -CH3 or -CH2OH, but when X is N then R1 is selected from -CH3 and -CH2OH;
    [0040] [0040] R2 and R3 are either:
    [0041] [0041] (i) independently selected from hydrogen and C1-4alkyl; or
    [0042] [0042] (ii) together they form a bridge group with one to three members selected from C1-3alkylene, C2-3 alkenylene, methylene-NRq-methylene and methylene-O-methylene, in which the bridge group is optionally substituted by a group selected from C1-4alkyl, hydroxyl and halogen and Rq is selected from hydrogen, C1-4alkyl, hydroxyl and halogen.
    [0043] [0043] Q is C or N;
    [0044] [0044] where when Q is C then either:
    [0045] [0045] (i) R4 is hydrogen or C1-4alkyl (for example, methyl) optionally substituted by amino (for example, -CH2NH2);
    [0046] [0046] R5 is hydrogen, amino or C1-4alkyl (for example, methyl) optionally substituted by 1 or 2 groups selected from halogen, hydroxyl (for example, - CH2OH) or amino;
    [0047] [0047] provided that R4 and R5 should not both be selected from amino and C1-4alkyl substituted by amino; or
    [0048] [0048] (ii) R4 and R5 together with Q form a heterocyclic ring containing nitrogen with four to six members; and
    [0049] [0049] where when Q is N then:
    [0050] [0050] R4 is absent;
    [0051] [0051] R5 is hydrogen; and
    [0052] [0052] R2 and R3 together form the bridge group with one to three members;
    [0053] [0053] R6 and R7 are independently selected from halogen (for example, fluorine), C1-4alkyl (for example, -CH3) and hydroxyl provided that when Q is N, then R6 or R7 are not halogen or hydroxyl;
    [0054] [0054] a is selected from 0, 1 and 2;
    [0055] [0055] b is selected from 0, 1 and 2;
    [0056] [0056] Ring A or is it:
    [0057] [0057] (i) a five-membered nitrogen-containing 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
    [0058] [0058] (ii) a six-membered aromatic nitrogen containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or
    [0059] [0059] (iii) a heterocyclic ring containing six-membered non-aromatic nitrogen, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S;
    [0060] [0060] R8 is selected from haloC1-4alkyl (for example, -CF3), -CH3 and halogen (for example, chlorine or fluorine);
    [0061] [0061] R9 is selected from hydrogen, C1-4alkyl (eg, -CH3), haloC1-4alkyl (eg, - CF3) and halogen (eg, chlorine);
    [0062] [0062] R10 are independently selected from halogen, cyano, cyanoC1-4alkyl (eg, -CH2- CN), hydroxyl, = O (oxo), C1-4alkyl (eg, -CH3 or - CH2CH3), haloC1-4alkyl , C1-4alkoxy (for example, -OCH3), hydroxylC1-4alkyl (for example, -CH2C (CH3) 2OH, - CH (CH3) CH2OH, -CH (CH3) OH, -CH2CH2OH or -CH2OH), C1-4alkoxyC1 - 4 alkylene (for example, -CH2-O-CH3 or -CH2-CH2-O-CH3), C1-4alkylsulfone (for example, -SO2CH3), amino, monoC1-4alkylamino, diC1-4alkylamino (for example, -N ( CH3) 2), aminoC1-4alkylene (for example, -CH2NH2), -C1-4alkylene-C (= O) NH (2-q) (C1-6 alkyl) q), -C1-4alkylene-NHC (= O ) C1-6 alkyl, C0-4alkylene sulfonamide (for example, -SO2NRx2 or -CH2SO2NRx2, where Rx is independently selected from H and C1-6alkyl), and optionally substituted four to six membered heterocyclic group containing 1 or 2 selected hetero atoms among O, N, or S where the optional substituent is selected from among C1-4alkyl;
    [0063] [0063] q is selected from 0, 1 or 2; and
    [0064] [0064] c is selected from 0, 1 and 2.
    [0065] [0065] In a third aspect, the invention provides a compound of Formula (I): (I)
    [0066] [0066] or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, where:
    [0067] [0067] X is CH or N;
    [0068] [0068] R1 is hydrogen, -CH3 or -CH2OH, but when X is N then R1 is selected from -CH3 and -CH2OH;
    [0069] [0069] R2 and R3 are either:
    [0070] [0070] (i) independently selected from hydrogen and C1-4alkyl; or
    [0071] [0071] (ii) together form a bridge group with one to three members selected from C1-3alkylene, C2-3 alkenylene, methylene-NRq-methylene and methylene-O-methylene, in which the bridge group is optionally substituted by a group selected from C1-4alkyl, hydroxyl and halogen and Rq is selected from hydrogen, C1-4alkyl, hydroxyl and halogen;
    [0072] [0072] Q is C or N;
    [0073] [0073] where when Q is C then either:
    [0074] [0074] (i) R4 is hydrogen or C1-4alkyl (for example, methyl) optionally substituted by amino (for example, -CH2NH2);
    [0075] [0075] R5 is hydrogen, amino, hydroxyl or C1-4alkyl (for example, methyl) optionally substituted by 1 or 2 groups selected from halogen, hydroxyl (for example, -CH2OH) or amino;
    [0076] [0076] provided that R4 and R5 should not both be selected from amino and C1-4alkyl substituted by amino; or
    [0077] [0077] (ii) R4 and R5 together with Q form a heterocyclic ring containing nitrogen with four to six members; and
    [0078] [0078] where when Q is N then:
    [0079] [0079] R4 is absent;
    [0080] [0080] R5 is hydrogen; and
    [0081] [0081] R2 and R3 together form the bridge group with one to three members;
    [0082] [0082] R6 and R7 are independently selected from halogen (for example, fluorine), C1-4alkyl (for example, -CH3) and hydroxyl provided that when Q is N, then R6 or R7 are not halogen or hydroxyl;
    [0083] [0083] a is selected from 0, 1 and 2;
    [0084] [0084] b is selected from 0, 1 and 2;
    [0085] [0085] Ring A or is it:
    [0086] [0086] (i) a five-membered nitrogen-containing 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
    [0087] [0087] (ii) a six-membered aromatic nitrogen containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or
    [0088] [0088] (iii) a six membered heterocyclic ring containing non-aromatic nitrogen, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S;
    [0089] [0089] R8 is selected from haloC1-4alkyl (for example, -CF3), -CH3 and halogen (for example, chlorine or fluorine);
    [0090] [0090] R9 is selected from hydrogen, C1-4alkyl (eg, -CH3), haloC1-4alkyl (eg, - CF3) and halogen (eg, chlorine);
    [0091] [0091] R10 are independently selected from halogen, cyano, cyanoC1-4alkyl (eg, -CH2- CN), hydroxyl, = O (oxo), C1-4alkyl (eg, -CH3 and - CH2CH3), haloC1-4alkyl , C1-4alkoxy (for example, -OCH3), hydroxylC1-4alkyl (for example, -CH2C (CH3) 2OH, - CH (CH3) CH2OH, -CH (CH3) OH, -CH2CH2OH or -CH2OH), C1-4alkoxyC1 - 4 alkylene (for example, -CH2-O-CH3 or -CH2-CH2-O-CH3), C1-4alkylsulfone (for example, -SO2CH3), amino, monoC1-4alkylamino, diC1-4alkylamino (for example, -N ( CH3) 2), aminoC1-4alkylene (for example, -CH2NH2), -C1-4alkylene-C (= O) NH (2-q) (C1-6 alkyl) q), -C1-4alkylene-NHC (= O ) C1-6 alkyl, C0-4alkylene sulfonamide (for example, -SO2NRx2 or -CH2SO2NRx2, where Rx is independently selected from H and C1-6alkyl), 3- to 6-membered cycloalkyl, optionally substituted unsaturated heterocyclic group with five or six members containing 1, 2, 3 or 4 heteroatoms selected from O, N, or S where the optional substituent is selected from C 1-4alkyl, C1-4alkyl substituted by 3- to 6-membered cycloalkyl, C1-4alkyl substituted by five or six-membered unsaturated heterocyclic group optionally substituted containing 1, 2, 3 or 4 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4alkyl, C1-4alkyl substituted by saturated heterocyclic group with four to six members optionally substituted containing 1 or 2 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4alkyl and heterocyclic group saturated with four to six optionally substituted members containing 1 or 2 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4alkyl;
    [0092] [0092] q is selected from 0, 1 or 2; and
    [0093] [0093] c is selected from 0, 1, 2 and 3.
    [0094] [0094] 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, methods for the prophylaxis or treatment of a disease or condition as described herein document comprising 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
    [0095] [0095] 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 sub-formulas, subgroups, modalities and examples as defined herein.
    [0096] [0096] "Potency" is a measure of drug activity expressed in terms of the amount needed 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. Effectiveness is the relationship between receptor occupation and the ability to initiate a response at the molecular, cellular, tissue or system level.
    [0097] [0097] The term "inhibitor" refers to an enzyme inhibitor that 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 to allosteric sites in enzymes, or they can interact at exclusive binding sites 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, under different circumstances, manifest in functionally different ways. The inhibitory activity can be reversible or irreversible, depending on the longevity of the inhibitor-enzyme complex, which, in turn, depends on the nature of the inhibitor-enzyme bond.
    [0098] [0098] As used here, the term "mediated", as used, for example, in conjunction with SHP2, as described here (and applied, for example, to various physiological processes, diseases, conditions, conditions, therapies, treatments or interventions) ) is intended to operate in a limited manner, so that the various processes, diseases, states,
    [0099] [0099] The term "treatment", as used here in the context of treating a condition, that is, state, disorder or disease, generally refers to treatment and therapy, whether for a human or an animal (for example, in veterinary applications), in which some desired therapeutic effect is achieved, for example, inhibiting the progress of the condition and includes a reduction in the rate of progress, an interruption in the rate of progress, improvement of the condition, decrease or relief of at least one symptom associated with or caused by the condition being treated and curing the condition. For example, treatment can be the reduction of one or more symptoms of a disorder or the complete eradication of a disorder.
    [0100] [0100] The term “prophylaxis” (ie use of a compound as a prophylactic measure), as used here in the context of treating a condition, condition, disorder or disease, generally refers to prophylaxis or prevention, whether for a human being human or animal (for example, in veterinary applications), in which some desired preventive effect is obtained, for example, in preventing the occurrence of a disease or in 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 delay in the onset of one or more symptoms of the disease, or a decrease in the likelihood of the disease occurring.
    [0101] [0101] References to the prophylaxis or treatment of a disease state or condition such as cancer include within its scope alleviating or reducing the incidence, for example, of cancer.
    [0102] [0102] The combinations of the invention can produce a therapeutically effective effect in relation to the therapeutic effect of the individual compounds / agents when administered separately.
    [0103] [0103] The term 'effective' includes advantageous effects, such as additivity, synergism, reduced side effects, reduced toxicity, increased time to disease progression, increased survival time, sensitization or resensitization from one agent to another or response rate enhanced. Advantageously, an effective effect can allow lower doses of each component or each to be administered to a patient, thereby decreasing the toxicity of 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 of 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 of the combination when presented individually. The term “response rate”, as used here, refers, in the case of a solid tumor, to the extent of the reduction in the size of the tumor at any given time, for example, 12 weeks. So, for example, a 50% response rate means a 50% reduction in tumor size. References in this document to a “clinical response” refer to response rates of 50% or more. A “partial response” is defined here as a response rate of less than 50%.
    [0104] [0104] As used here, the term "combination", 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 “that matches” in this context must be interpreted accordingly.
    [0105] [0105] The association of the two or more compounds / agents in a combination can be physical or non-physical. Examples of physically associated combined compounds / agents include:
    [0106] [0106] • compositions (for example, unit formulations) that comprise the two or more compounds / agents in mixture (for example, within the same unit dose);
    [0107] [0107] • compositions comprising material in which the two or more compounds / are chemically / physically-chemically bonded (for example, crosslinking, molecular agglomeration or bonding to a common vehicle part);
    [0108] [0108] • compositions comprising material in which the two or more compounds / agents are chemically / physically-chemically co-packaged (for example, arranged on or inside lipid vesicles, particles (for example, micro or nanoparticles) or emulsion droplets) ;
    [0109] [0109] • pharmaceutical kits, pharmaceutical packages or patient packages in which the two or more compounds / agents are co-packaged or co-presented (for example, as part of a unit dose set);
    [0110] [0110] Examples of combined compounds / agents not physically associated include:
    [0111] [0111] • material (for example, a non-unit formulation) comprising at least one of the two or more compounds / agents together with instructions for the extemporaneous association of the at least one compound to form a physical association of the two or more compounds / agents ;
    [0112] [0112] • material (for example, a non-unit 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;
    [0113] [0113] • 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 (or others) of the two or more compounds / agents have been (or are being) administered ;
    [0114] [0114] • 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 two or more compounds / agents.
    [0115] [0115] As used here, the term "combination therapy" is intended to define therapies that comprise the use of a combination of two or more compounds / agents (as defined above). Thus, 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 can be administered at the same time or at different times. It will therefore be appreciated that the compounds / agents of the combination can be administered sequentially (for example, before or after) or simultaneously, or in the same pharmaceutical formulation (i.e., together) or in different pharmaceutical formulations (i.e., 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 in relation to the route of administration.
    [0116] [0116] As used herein, the term "pharmaceutical kit" defines a matrix of one or more unit doses of a pharmaceutical composition together with dosing means (eg, measuring device) and / or delivery means (eg, inhaler) or syringe), optionally all contained in packaging. In pharmaceutical kits comprising a combination of two or more compounds / agents, the individual compounds / agents can be unitary or non-unitary formulations. The unit dose (or unit doses) can be contained in a blister pack. The pharmaceutical kit can optionally also include instructions for use.
    [0117] [0117] As used here, the term "pharmaceutical packaging" defines an array of one or more unit doses of a pharmaceutical composition, optionally contained in common outer packaging. In pharmaceutical packages comprising a combination of two or more compounds / agents, the individual compounds / agents can be unitary or non-unitary formulations. The unit dose (or unit doses) can be contained in a blister pack. The pharmaceutical packaging can optionally also include instructions for use.
    [0118] [0118] The term 'optionally substituted', as used here, refers to a group that can be unsubstituted or substituted by a substituent, as defined herein.
    [0119] [0119] The prefix “Cx-y” (where x and y are integers), as used here, refers to the number of carbon atoms in a given group. Thus, a C1-6 alkyl group contains from 1 to 6 carbon atoms, a C3-6 cycloalkyl group contains from 3 to 6 carbon atoms, a C1- 4 alkoxy group contains from 1 to 4 carbon atoms, and so on. against.
    [0120] [0120] The term ‘amino’, as used here, refers to the group -NH2.
    [0121] [0121] The term ‘halo’ or ‘halogen’, as used here, refers to fluorine, chlorine, bromine or iodine, in particular, fluorine or chlorine.
    [0122] [0122] Any and all hydrogen in the compound (as in an alkyl group or when referred to as hydrogen) includes all hydrogen isotopes, in particular 1H and 2H (deuterium).
    [0123] [0123] The term ‘oxo’, as used here, refers to the group = O.
    [0124] [0124] The term 'C1-4alkyl', as used herein as a group or part of a group, refers to a straight or branched saturated hydrocarbon group containing from 1 to 4 carbon atoms, respectively. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like.
    [0125] [0125] The term 'C2-4alkenyl' or 'C2-6alkenyl', as used here as a group or part of a group, refers to a linear or branched hydrocarbon group containing from 2 to 4 or 2 to 6 atoms of carbon, respectively, and containing a carbon-carbon double bond. Examples of such groups include C3-4alkenyl or C3-6alkenyl groups, such as ethylenyl (vinyl), 1-propenyl, 2-propenyl (ally), isopropenyl, butenyl, buta-1,4-dienyl, pentenyl and hexenyl.
    [0126] [0126] The term 'C2-4alkynyl' or 'C2-6alkynyl', as used here as a group or part of a group, refers to a straight or branched hydrocarbon group having 2 to 4 or 2 to 6 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.
    [0127] [0127] The term 'C1-4alkoxy', as used herein as a group or part of a group, refers to a group - O-C1-4alkyl, where C1-4 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy and the like.
    [0128] [0128] The term ‘C3-6cycloalkyl’, as used here, 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.
    [0129] [0129] The term 'C3-6cycloalkenyl', as used here, refers to a partially saturated monocyclic hydrocarbon ring of 3 to 6 carbon atoms having one or more (usually one) carbon-carbon double bond (s) . Examples of such groups include cyclopentenyl, cyclohexenyl and cyclohexadienyl.
    [0130] [0130] The term 'hydroxyC1-4alkyl', as used here as a group or part of a group, refers to a C1-4alkyl group as defined here, where one or more (for example, 1, 2 or 3) that a hydrogen atom is replaced by a hydroxyl group. The term "hydroxyC1-4alkyl" therefore includes monohydroxyC1-4alkyl, and also polyhydroxyC1-4alkyl. There may be one, two, three or more hydrogen atoms replaced by a hydroxyl group, so that hydroxyC1-4alkyl may have one, two, three or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and the like.
    [0131] [0131] The term 'haloC1-4alkyl', as used here as a group or part of a group, refers to a C1-4alkyl group as defined here, where one or more (for example, 1, 2 or 3) that a hydrogen atom is replaced by a halogen. The term 'haloC1-4alkyl' therefore includes monohaloC1-4alkyl and also polyhaloC1-4alkyl. There may be one, two, three or more hydrogen atoms replaced by a halogen, so haloC1-4alkyl may have one, two, three or more halogens. Examples of such groups include fluoroethyl, fluoromethyl, difluoromethyl, trifluoromethyl or trifluoroethyl and the like.
    [0132] [0132] The term 'haloC1-4alkoxy', as used herein as a group or part of a group, refers to an -O-C1-4alkyl group as defined here, where one or more (for example, 1, 2 or 3) that a hydrogen atom is replaced with a halogen. The terms 'haloC1-4alkoxy' therefore include monohaloC1-4alkoxy and also polyhaloC1-4alkoxy. There may be one, two, three or more hydrogen atoms replaced by a halogen, so haloC1-4alkoxy can have one, two, three or more halogens. Examples of such groups include fluoroethyloxy, difluoromethoxy or trifluoromethoxy and the like.
    [0133] [0133] The term "heterocyclyl group", as used here, should include, unless the context otherwise indicates, aromatic and non-aromatic ring systems. Thus, 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 context indicates otherwise, these groups can be monocyclic or bicyclic (including fused, spiro and bridged bicyclic groups) and can contain, for example, 3 to 12 ring members, more usually 5 to 10 members of the ring. The reference to 4 to 7 ring members includes 4, 5, 6 or 7 ring atoms and the 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 usually 3 to 7 or 4 to 7 and preferably 5, 6 or 7 ring members, more preferably 5 or 6 ring members . Examples of bicyclic groups are those that contain 8, 9, 10, 11 and 12 ring members, and more usually 9 or 10 ring members. The heterocyclyl groups can be heteroaryl groups with 5 to 12 ring members, more usually 5 to 10 ring members. When reference is made here to a heterocyclyl group, the heterocyclyl ring may, unless the context otherwise indicates, be optionally substituted, that is, unsubstituted or substituted, by one or more (for example, 1, 2, 3 or 4 in particular one or two) substituents as defined herein.
    [0134] [0134] The heterocyclyl group can be, for example, a monocyclic ring with five or six members or a bicyclic structure formed from fused rings with five and six members or two fused rings with six members or two fused rings with five members. Each ring can contain up to five heteroatoms particularly selected from nitrogen, sulfur and oxygen 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 usually 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 nitrogen atom in the ring. The nitrogen atoms in the heterocyclyl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic, as in the case of an indole nitrogen or pyrrole. In general, the number of basic nitrogen atoms present in the heterocyclyl group, including any substituents on the amino group of the ring, will be less than five.
    [0135] [0135] Heterocyclyl groups can be linked via a carbon atom or a hetero atom (eg, nitrogen). Likewise, heterocyclyl groups can be substituted on a carbon atom or on a hetero atom (for example, nitrogen).
    [0136] [0136] Examples of aromatic five-membered heterocyclyl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanil, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, triazolyl and triazolyl triazolyls and triazolyls and trazolyls and triazolyl and triazolyl and triazolyl.
    [0137] [0137] Examples of six-membered aromatic heterocyclic groups include, without limitation, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
    [0138] [0138] The term "heteroaryl" is used here to denote a heterocyclyl group with an aromatic character. The term "heteroaryl" encompasses polycyclic (for example, 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 linked by the aromatic ring or by a non-aromatic ring.
    [0139] [0139] Examples of heteroaryl groups are monocyclic and bicyclic groups containing five to twelve ring members and more usually five to ten ring members.
    [0140] [0140] Examples of five-membered heteroaryl groups include, without limitation, pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole and tetrazole groups.
    [0141] [0141] Examples of six-membered heteroaryl groups include, without limitation, pyridine, pyrazine, pyridazine, pyrimidine and triazine.
    [0142] [0142] A bicyclic heteroaryl group can be, for example, a group selected from:
    [0143] [0143] a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;
    [0144] [0144] b) a pyridine ring fused to a 5- or 6-membered ring containing 0, 1, 2 or 3 ring heteroatoms;
    [0145] [0145] c) a pyrimidine ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;
    [0146] [0146] d) a pyrrole ring fused to a 5- or 6-membered ring containing 0, 1, 2 or 3 ring heteroatoms;
    [0147] [0147] e) a pyrazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;
    [0148] [0148] f) an imidazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;
    [0149] [0149] g) an oxazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;
    [0150] [0150] h) an isoxazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;
    [0151] [0151] i) a thiazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;
    [0152] [0152] j) an isothiazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 ring heteroatoms;
    [0153] [0153] k) a thiophene ring fused to a 5- or 6-membered ring containing 0, 1, 2 or 3 ring heteroatoms;
    [0154] [0154] l) a furan ring fused to a 5- or 6-membered ring containing 0, 1, 2 or 3 ring heteroatoms;
    [0155] [0155] m) a cyclohexyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; and
    [0156] [0156] n) a cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms.
    [0157] [0157] Particular examples of bicyclic heteroaryl groups containing a five-membered ring fused to another five-membered ring include, without limitation, imidazothiazole (for example, imidazo [2,1-b] thiazole) and imidazoimidazole (for example, imidazo [ 1,2-a] imidazole).
    [0158] [0158] Particular examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, without limitation, benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isole, indole, isol indole, isoindole, indolizine,
    [0159] [0159] Particular examples of bicyclic heteroaryl groups containing two six-membered fused rings include, without limitation, quinoline, isoquinoline, chroman, thiocroman, isochroman, chromene, isochromene, benzodioxan, quinolizine, benzoxazine, pyridopyridine, quinoxaline, quinazoline, quinoline groups. phthalazine, naphthyridine and pteridine.
    [0160] [0160] Examples of polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzthiophene, dihydrobenzofuran, 2,3-dihydrobenzo [1,4] dioxin, benzo [1,3] dioxol, 4,5,6,7-tetrahydrobenzofuran, tetrahydrotriazolopyrazine (e.g. 5,6,7,8-tetrahydro [1,2,4] triazole [4, 3- a] pyrazine), croman, thiocroman, isochroman, chromene, isochromene, benzodioxane, benzoxazine, benzodiazepine and indoline.
    [0161] [0161] A nitrogen containing heteroaryl ring must contain at least one ring nitrogen atom. The nitrogen-containing heteroaryl ring can be linked to N or linked to C. Each ring can, in addition, contain up to about four other heteroatoms particularly selected from nitrogen, sulfur and oxygen. Particularly the heteroaryl ring will contain up to 3 heteroatoms, for example, 1,
    [0162] [0162] Examples of nitrogen-containing heteroaryl groups include, without limitation, monicyclic groups such as pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, pyrazolyl, pyrazolyl, pyrazolyl, pyrazolyl, pyrazolyl, pyrazolyl, pyrazolyl, pyridol, (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, indole , isoindolinyl, purinyl (for example, adenine [6-aminopurine], guanine [2-amino-6-hydroxypurine]), indazolyl, quinolizinyl, benzoxazinyl, benzodiazepinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pyridine and pyridine
    [0163] [0163] Examples of nitrogen-containing polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydroisoquinolinyl, tetrahydroquinolinyl and indolinyl.
    [0164] [0164] The term "non-aromatic" includes, unless the context indicates otherwise, unsaturated ring systems without aromatic character, partially saturated and saturated heterocycly ring systems. The terms "unsaturated" and "partially saturated" refer to rings where the ring structure (or structures) contains atoms that share more than one valence bond, that is, the ring contains at least one multiple bond, for example , a C = C, C ºC or N = C bond. The term "saturated" refers to rings where there are no multiple bonds between 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.
    [0165] [0165] Examples of non-aromatic heterocyclyl groups are groups with 3 to 12 ring members, more usually 5 to 10 ring members. Such groups can be monocyclic or bicyclic, for example, they have 3 to 7 ring members, in particular 4 to 6 ring members. Such groups have in particular 1 to 5 or 1 to 4 hetero-atom ring members (more usually 1, 2 or 3 hetero-atom ring members), generally selected from nitrogen, oxygen and sulfur and oxidized forms thereof. Heterocyclyl groups may contain, for example, cyclic ether parts (for example, as in tetrahydrofuran and dioxane), cyclic thioether parts (for example, as in tetrahydrothiophene and dithian), parts of cyclic amine (for example , in pyrrolidine), cyclic amide parts (for example, as in pyrrolidone), cyclic thioamides, cyclic thioesters, cyclic ureas (for example, as in imidazolidin-2-one), cyclic esters (for example, as butyrolactone), sulfones cyclic (for example, as sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides and combinations thereof (for example, thiomorpholine).
    [0166] [0166] 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, tetrahydronyl, also known as tetrahydrothilan, (e.g., oxan-4-yl), imidazolinyl, imidazolidinonyl, oxazolinyl, thiazolinyl, pyrazolin-2-yl, pyrazolidinyl, piperazinonyl, piperazinyl, and N-alkyl piperazines such as N-methyl piperazinyl. In general, typical non-aromatic heterocyclyl groups include saturated groups, such as piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl and N-alkyl piperazines, such as N-methyl piperazinyl.
    [0167] [0167] 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 linked to N or linked to C. Heterocyclic groups can contain, for example, cyclic amine parts (for example, as in pyrrolidinyl), cyclic amides (such as pyrrolidinonyl, piperidinonyl or caprolactamyl), cyclic sulfonamides (such as isothiazolidinyl 1,1-dioxide, [1,2] thiazinanyl 1,1-dioxide or [1,2] thiazepanyl dioxide) and combinations thereof.
    [0168] [0168] Particular examples of nitrogen-containing, non-aromatic heterocyclyl groups include aziridinyl, morpholinyl, thiomorpholinyl, piperidinyl (e.g., piperidin-1-yl, piperidin-2ila, piperidin-3-yl and piperidin-4-yl), pyrrolidinyl; (for example, pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl), pyrrolidonyl, dihydrothiazolyl, imidazolinyl, imidazolidinonyl, oxazolinyl, thiazolinyl, 6H-1,2,5-thiadiazinyl, pyrazolin-2-yl , pyrazolin-3-yl, pyrazolidinyl, piperazinyl, and N-alkyl piperazines such as N-methyl piperazinyl.
    [0169] [0169] Heterocyclyl groups can be polycyclic fused ring systems or bridged ring systems, such as the bicycloalkane oxa- and aza analogs, tricycloalkanes (for example, 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 to 133, 1992.
    [0170] [0170] Where, in a definition of a cyclic group or ring, it is stated that the cyclic group contains a certain number of members of the heteroatom ring, for example, as in the phrase “a 5- or 6-membered ring containing 0, 1 or 2 members of the nitrogen ring ”, this should be understood as meaning that, in addition to the specified number of members of the specified heteroatom ring, the remaining members of the ring are carbon atoms.
    [0171] [0171] The compound of Formula (I) can contain saturated cyclic groups that can be joined to the rest of the molecule by one or more bonds. When the cyclic group is joined to the rest of the molecule by two or more bonds, these bonds (or two of these bonds) can be made on the same atom (usually a carbon atom) in the ring or at different atoms in the ring. Where bonds are made on the same ring atom, this results in a cyclic group with a single atom (usually a quaternary carbon) attached to two groups. In other words, when the compound of Formula (I) includes a cyclic group, that group can be linked to the rest of the molecule by a bond or to the cyclic group and the rest of the molecule can have an atom in common, for example, a compound spiro.
    [0172] [0172] 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 can be unsubstituted or substituted by 1, 2, 3 or 4 substituents and, in particular, are not substituted or have 1, 2 or 3 substituents, as defined herein. When the cyclic group is saturated, there may be 2 substituents attached to the same carbon (where the substituents are the same ones called geminal desubstitution or 'gem').
    [0173] [0173] A combination of substituents is permitted only if such a combination results in a stable or chemically viable compound (that is, one that will not be substantially altered when kept at 40 ° C or less for at least a week).
    [0174] [0174] The various functional groups and substituents that make up the compounds of the invention are particularly chosen so that the molecular weight of the compound of the invention does not exceed 1,000. More usually, the molecular weight of the compound will be less than 750, for example,
    [0175] [0175] The invention provides a compound of Formula (I): (I)
    [0176] [0176] or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein X, Q, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, a, b, c and A are as defined in this document.
    [0177] [0177] X
    [0178] [0178] X is CH or N.
    [0179] [0179] Therefore, the bicyclic ring in the compound of Formula (I) is a pyrrolopyrazine or a pyrazolopyrazine: pyrrolopyrazine pyrazolopyrazine
    [0180] [0180] In one embodiment, X is CH and the compound is a pyrrolopyrazine. In one embodiment, X is N and the compound is a pyrazolopyrazine.
    [0181] [0181] In particular, X is CH, and the compound of Formula (I) is a compound of Formula (II) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (II)
    [0182] [0182] where Q, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, a, b, c and A are as defined herein.
    [0183] [0183] In particular, X is N, and the compound of Formula (I) is a compound of Formula (IIa) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (IIa)
    [0184] [0184] where Q, R2, R3, R4, R5, R6, R7, R8, R9, R10, a, b, c and A are as defined herein and R1 is -CH3 or -CH2OH.
    [0185] [0185] R1
    [0186] [0186] R1 is hydrogen, -CH3 or -CH2OH, but when X is N then R1 is selected from -CH3 and -CH2OH;
    [0187] [0187] In one mode, R1 is hydrogen or - CH3.
    [0188] [0188] In one embodiment, R1 is hydrogen or - CH2OH.
    [0189] [0189] In one embodiment, R1 is -CH3 or -CH2OH.
    [0190] [0190] In one mode, R1 is -CH3.
    [0191] [0191] In one embodiment, R1 is -CH2OH.
    [0192] [0192] In particular, R1 is hydrogen and X is CH, and the compound of Formula (I) is a compound of Formula (III) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (III)
    [0193] [0193] where R2, R3, R4, R5, R8, R9, R10, a, b, c and A are as defined in this document.
    [0194] [0194] In particular, X is N, and the compound of Formula (I) is a compound of Formula (IIIa) or a tautomer or solvate or a pharmaceutically acceptable salt thereof: (IIIa)
    [0195] [0195] where Q, R2, R3, R4, R5, R6, R7, R8, R9, R10, a, b, c and A are as defined in this document.
    [0196] [0196] In particular, X is N, and the compound of Formula (I) is a compound of Formula (IIIb) or a tautomer or solvate or a pharmaceutically acceptable salt thereof: (IIIb)
    [0197] [0197] where Q, R2, R3, R4, R5, R6, R7, R8, R9, R10, a, b, c and A are as defined in this document.
    [0198] [0198] R2 and R3
    [0199] [0199] R2 and R3 are either:
    [0200] [0200] (i) independently selected from hydrogen and C1-4alkyl; or
    [0201] [0201] (ii) together form a bridge group with one to three members selected from C1-3alkylene, C2-3 alkenylene, methylene-NRq-methylene and methylene-O-methylene, in which the bridge group is optionally substituted by a group selected from C1-4alkyl, hydroxyl and halogen and Rq is selected from hydrogen, C1-4alkyl, hydroxyl and halogen (for example, hydrogen and C1-4alkyl).
    [0202] [0202] In one embodiment, the bridge group is optionally replaced by a group selected from C1-4alkyl, hydroxyl and halogen. In particular, the bridging group is optionally substituted by a group selected from C1-4alkyl, hydroxyl and halogen, but excluding compounds in which a hydroxyl or halogen is in an α position to an N or O atom and excluding compounds in which a group hydroxyl is attached to an alkene carbon.
    [0203] [0203] In one embodiment, R2 and R3 together form a bridge group with one to three members selected from C1-3 alkylene (for example, -CH2-, -CH2-CH2-or - CH2CH2CH2-), C2-3 alkenylene ( for example, -CH = CH-), methylene-NH-methylene (for example, -CH2-NH-CH2-) and methylene-O-methylene (for example, -CH2-O-CH2-), where the group of bridging is optionally substituted by a group selected from C1-4alkyl, hydroxyl or halogen, but excluding compounds in which a hydroxyl or halogen is in an α position to an N or O atom and excluding compounds in which a hydroxyl group is attached to an alkene carbon.
    [0204] [0204] In one embodiment, R2 and R3 together form a bridge group with three members selected from C1-3 alkylene (for example, -CH2-, -CH2-CH2-or -CH2CH2CH2-), C2-3 alkenylene (for example , -CH = CH-), methylene-NH-methylene (for example, -CH2-NH-CH2-) and methylene-O-methylene (for example, -CH2-O-CH2-), where C1-3 alkylene (for example, - CH2-, -CH2-CH2-or -CH2CH2CH2-) or C2-3 alkenylene (for example, -CH = CH-), where the bridge group is optionally substituted by a group selected from C1-4alkyl and halogen. In one embodiment, the halogen substituent is not alpha for the O or N present in the bridge group.
    [0205] [0205] Therefore, the part
    [0206] [0206] is a part as follows, in which the bridge group with one to three members is represented by a curved line:
    [0207] [0207] The bridge group may include one, two or three members of the ring. Therefore, together with the two carbon atoms to which the bridge group is connected and the nitrogen atom between these two carbon atoms in the heterocyclic ring, the bridge group is part of a four-membered ring (when the bridge group includes a ring member), a five member ring (when the bridge group includes two ring members) or a six member ring (when the bridge group includes three ring members).
    [0208] [0208] In one embodiment, the bridge group is C1-3alkylene, for example, -CH2-, -CH2-CH2- or -CH2CH2CH2- where the bridge group is optionally substituted by a group selected from C1-4alkyl, hydroxyl and halogen.
    [0209] [0209] In one embodiment, the bridge group is C1-3alkylene, for example, -CH2-, -CH2-CH2- or -CH2CH2CH2- and the compound of Formula (I) is a compound of Formula (IV) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (IV)
    [0210] [0210] where Q, R1, R4, R5, R6, R7, R8, R9, R10, a, b, c and A are as defined in this document, and d is 0, 1 or 2.
    [0211] [0211] In one embodiment, the bridge group is C2-3 alkenylene, for example, -CH = CH- or -CH2-CH = CH-, where the bridge group is optionally substituted by a group selected from C1-4alkyl , hydroxyl and halogen, but excluding compounds in which a hydroxyl group is attached to an alkene carbon (that is, excluding enoes). In one embodiment, the bridge group is C2-3 alkenylene, for example, -CH = CH- or -CH2-CH = CH-, where the bridge group is optionally substituted by a group selected from C1-4alkyl and halogen.
    [0212] [0212] In one embodiment, the bridge group is C2-3 alkenylene, for example, -CH = CH- or -CH2-CH = CH-.
    [0213] [0213] In one embodiment, the bridge group is methylene-NRq-methylene, for example, -CH2-NH-CH2-, where the bridge group is optionally substituted by a group selected from C1-4alkyl and Rq is selected between hydrogen and C1-4alkyl.
    [0214] [0214] In one embodiment, the bridge group is methylene-NRq-methylene, for example, -CH2-NH-CH2-, optionally substituted by a group selected from C1-4alkyl and Rq is selected from hydrogen and C1-4alkyl.
    [0215] [0215] In one embodiment, the bridge group is methylene-NRq-methylene, for example, -CH2-NH-CH2-, and Rq is selected from hydrogen and C1-4alkyl.
    [0216] [0216] In one embodiment, the bridge group is methylene-NH-methylene, for example, -CH2-NH-CH2-.
    [0217] [0217] In one embodiment, the bridge group is methylene-O-methylene, for example, -CH2-O-CH2-, where the bridge group is optionally substituted by a selected group of C1-4alkyl.
    [0218] [0218] In one embodiment, the bridge group is methylene-O-methylene, for example, -CH2-O-CH2.
    [0219] [0219] The bridge group is optionally substituted by a group selected from C1-4alkyl, hydroxyl and halogen, for example -CH3, in particular, excluding compounds in which a hydroxyl or halogen is in an α position to an N atom or O and excluding compounds in which a hydroxyl group is attached to an alkene carbon.
    [0220] [0220] In particular, the bridge group is not replaced.
    [0221] [0221] In particular, the bridge group is alkylene, for example, -CH2-, -CH2-CH2- or -CH2CH2CH2-, for example, -CH2-CH2-or -CH2CH2CH2-. In particular, the bridge group is unsubstituted alkylene, for example -CH2-, -CH2- CH2- or -CH2CH2CH2-, for example, -CH2-CH2-or -CH2CH2CH2-.
    [0222] [0222] In particular, the bridge group is -CH2- CH2-, and the compound of Formula (I) is a compound of Formula (V) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (V)
    [0223] [0223] where X, Q, R1, R4, R5, R6, R7, R8, R9, R10, a, b, c and A are as defined in this document.
    [0224] [0224] In another mode, R2 and R3 are independently selected from hydrogen and C1-4alkyl.
    [0225] [0225] In one embodiment, R2 and R3 are independently selected from hydrogen and -CH3.
    [0226] [0226] In one embodiment, R2 and R3 are hydrogen.
    [0227] [0227] In a modality, R2 and R3 are either:
    [0228] [0228] (i) hydrogen; or
    [0229] [0229] (ii) together form an alkylene bridge group with one to three members (for example, -CH2- or - CH2-CH2-).
    [0230] [0230] Q, R4 and R5
    [0231] [0231] Q is C or N;
    [0232] [0232] where when Q is C then either:
    [0233] [0233] (i) R4 is hydrogen or C1-4alkyl (for example, methyl) optionally substituted by amino (for example, -CH2NH2);
    [0234] [0234] R5 is hydrogen, amino, hydroxyl or C1-4alkyl (for example, methyl) optionally substituted by 1 or 2 groups selected from halogen, hydroxyl (for example, -CH2OH) or amino;
    [0235] [0235] provided that R4 and R5 should not both be selected from amino and C1-4alkyl substituted by amino; or
    [0236] [0236] (ii) R4 and R5 together with Q form a nitrogen-containing heterocyclic ring with four to six members; and
    [0237] [0237] where when Q is N then:
    [0238] [0238] R4 is absent;
    [0239] [0239] R5 is hydrogen; and
    [0240] [0240] R2 and R3 together form the bridge group with one to three members.
    [0241] [0241] In the mode where Q is C, then R2 and R3 are either:
    [0242] [0242] (i) independently selected from hydrogen and C1-4alkyl; or
    [0243] [0243] (ii) together form a bridge group with one to three members selected from C1-3alkylene, C2-3 alkenylene, methylene-NRq-methylene and methylene-O-methylene, in which the bridge group is optionally substituted by a group selected from C1-4alkyl, hydroxyl and halogen and Rq is selected from hydrogen, C1-4alkyl, hydroxyl and halogen.
    [0244] [0244] In the mode where Q is N then:
    [0245] [0245] R4 is absent;
    [0246] [0246] R5 is hydrogen; and
    [0247] [0247] R2 and R3 together form the one to three membered bridge group as defined here, that is, a one to three membered bridge group selected from C1-3alkylene, C2-3alkenylene, methylene-NRq-methylene and methylene-O-methylene, in which the bridge group is optionally substituted by a group selected from C1-4alkyl, hydroxyl and halogen and Rq is selected from hydrogen, C1-4alkyl, hydroxyl and halogen.
    [0248] [0248] In one embodiment, Q is C or N;
    [0249] [0249] where when Q is C then either:
    [0250] [0250] (i) R4 is hydrogen or C1-4alkyl (for example, methyl) optionally substituted by amino (for example, -CH2NH2);
    [0251] [0251] R5 is hydrogen, amino or C1-4alkyl (for example, methyl) optionally substituted by 1 or 2 groups selected from halogen, hydroxyl (for example, - CH2OH) or amino;
    [0252] [0252] provided that R4 and R5 should not both be selected from amino and C1-4alkyl substituted by amino; or
    [0253] [0253] (ii) R4 and R5 together with Q form a nitrogen-containing heterocyclic ring with four to six members; and
    [0254] [0254] where when Q is N then:
    [0255] [0255] R4 is absent;
    [0256] [0256] R5 is hydrogen; and
    [0257] [0257] R2 and R3 together form the bridge group with one to three members.
    [0258] [0258] In one embodiment, Q is C 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)
    [0259] [0259] where X, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, a, b, c and A are as defined herein.
    [0260] [0260] In a modality Q is C and:
    [0261] [0261] (i) R4 is hydrogen or C1-4alkyl (for example, methyl) optionally substituted by amino (for example, -CH2NH2);
    [0262] [0262] R5 is hydrogen, amino or C1-4alkyl (for example, methyl) optionally substituted by 1 or 2 groups selected from halogen, hydroxyl (for example, - CH2OH) or amino;
    [0263] [0263] provided that R4 and R5 should not both be selected from amino and C1-4alkyl substituted by amino; or
    [0264] [0264] (ii) R4 and R5 together with Q form a nitrogen-containing heterocyclic ring with four to six members.
    [0265] [0265] When Q is C, in one embodiment, R4 is hydrogen or C1-4alkyl (for example, methyl).
    [0266] [0266] When Q is C, in particular R4 is hydrogen or -CH3, for example, hydrogen.
    [0267] [0267] When Q is C, in one embodiment, R5 is hydrogen, amino, or C1-4alkyl (for example, -CH3) optionally substituted by 1 or 2 groups selected from halogen, hydroxyl (for example, -CH2OH) or amino .
    [0268] [0268] When Q is C, in one embodiment, R5 is C1-4alkyl (eg, -CH3) optionally substituted by hydroxyl (eg, -CH2OH) or amino (eg, CH2NH2).
    [0269] [0269] When Q is C, in one embodiment, R5 is amino, hydroxyl or C1-4alkyl (for example, -CH3) replaced by amino or hydroxyl.
    [0270] [0270] When Q is C, in one embodiment, R5 is amino or C1-4alkyl (for example, -CH3) replaced by amino.
    [0271] [0271] When Q is C, in particular R5 is amino or -CH3.
    [0272] [0272] R4 and R5 should not both be selected from amino and C1-4alkyl substituted by amino. In a modality when Q is C, only one of R4 and R5 is amino or C1-4alkyl substituted by amino, that is, one of R4 and R5 is amino or C1-4alkyl substituted by amino and one of R4 and R5 is different from amino and C1-4alkyl substituted by amino.
    [0273] [0273] In one embodiment when Q is C, one of R4 is C1-4alkyl (for example, -CH3) replaced by amino or R5 is amino or C1-4alkyl (for example, -CH3) replaced by amino.
    [0274] [0274] In a modality when Q is C, R4 is hydrogen and R5 is amino or C1-4alkyl (for example, -CH3) replaced by amino.
    [0275] [0275] When Q is C, in particular R5 is amino and the compound of Formula (I) is a compound of Formula (VII) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (VII).
    [0276] [0276] where X, R1, R2, R3, R4, R6, R7, R8, R9, R10, a, b, c and A are as defined in this document.
    [0277] [0277] When Q is C, in a modality R4 is hydrogen or -CH3 and R5 is amino or -CH3.
    [0278] [0278] When Q is C, in particular R4 is hydrogen and R5 is amino.
    [0279] [0279] When Q is C, in one mode, R4 is - CH3 and R5 is amino.
    [0280] [0280] When Q is C and at least one of R2 and R3 is different from hydrogen, then compounds of Formula (I) can exist in more than one stereoisomeric form, for example, (R4, R6 and R7 not shown for simplicity ): (a) (b) (c) (d) (e) (f) (g) (h)
    [0281] [0281] Some of these stereoisomers are pairs of enantiomers:
    [0282] [0282] (a) and (e) (if R2 and R3 are different, otherwise a mesoform);
    [0283] [0283] (b) and (f);
    [0284] [0284] (c) and (g) (if R2 and R3 are different, otherwise a mesoform); and
    [0285] [0285] (d) and (h).
    [0286] [0286] In one embodiment, the compounds of Formula (I) are racemic mixtures. In particular, the compounds of Formula (I) are non-racemic. Typically, at least 55% (for example, at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of Formula (I) is present as a stereoisomer. In particular, 97% (for example, 99%) or more (for example, substantially all) of the total amount of the compound of Formula (I)
    [0287] [0287] In one embodiment, R5 is amino.
    [0288] [0288] When Q is C, R5 is different from hydrogen, and R2 and R3 together form a bridge group, so R5 can either be oriented in the direction of the bridge group or in the opposite direction of the bridge group.
    [0289] [0289] In one mode, R5 is oriented towards the bridge group (R4, R6 and R7 not shown for clarity):
    [0290] [0290] where d is 0, 1 or 2, in particular d is 1.
    [0291] [0291] In one mode, R5 is oriented in the opposite direction of the bridge group (R4, R6 and R7 not shown for clarity):
    [0292] [0292], where d is 0, 1 or 2, in particular d is 1.
    [0293] [0293] In a modality when Q is C, R5 is amino. In a modality when Q is C, R5 is amino and R4 is hydrogen.
    [0294] [0294] In particular, R5 is oriented towards the bridge group, and the compound of Formula (I) is a compound of Formula (VIII) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (VIII)
    [0295] [0295] where X, R1, R4, R5, R6, R7, R8, R9, R10, a, b, c and A are as defined in this document, and d is 0, 1 or 2.
    [0296] [0296] In particular, R5 is oriented towards the bridging group, d is 1, and the compound of Formula (VIII) is a compound of Formula (VIIIa) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (VIIIa)
    [0297] [0297] where X, R1, R4, R5, R6, R7, R8, R9, R10, a, b, c and A are as defined in this document.
    [0298] [0298] When Q is C, in a modality R4 and R5 together with Q form a heterocyclic ring containing nitrogen with four to six members, for example, azetidinyl, pyrrolidinyl or piperidinyl, such as azetidinyl or pyrrolidinyl, and in particular azetidinyl.
    [0299] [0299] In one embodiment, Q is N and R4 is absent, R5 is hydrogen, and R2 and R3 together form the bridge group with one to three members.
    [0300] [0300] In one modality, Q is C or N;
    [0301] [0301] where when Q is C then either:
    [0302] [0302] (i) R4 is hydrogen or C1-4alkyl (for example, methyl) optionally substituted by amino (for example, -CH2NH2);
    [0303] [0303] R5 is hydrogen, amino, or C1-4alkyl (e.g., methyl) optionally substituted by amino;
    [0304] [0304] provided that R4 and R5 should not both be selected from amino and C1-4alkyl substituted by amino; or
    [0305] [0305] (ii) R4 and R5 together with Q form a nitrogen-containing heterocyclic ring with four to six members (for example, azetidine); and
    [0306] [0306] where when Q is N then:
    [0307] [0307] R4 is absent, R5 is hydrogen and R2 and R3 together form the one to three membered alkylene bridge group (for example, -CH2- or -CH2-CH2-).
    [0308] [0308] R6, R7, a and b
    [0309] [0309] R6 and R7 are independently selected from halogen (for example, fluorine), C1-4alkyl (for example, -CH3) and hydroxyl provided that when Q is N, then R6 or R7 is not halogen or hydroxyl;
    [0310] [0310] a is selected from 0, 1 and 2; and
    [0311] [0311] b is selected from 0, 1 and 2.
    [0312] [0312] a is 0, 1 or 2. When a is 0, a CH2 group is present between Q and CHR2. When a is 1, a CHR6 group is present between Q and CHR2. When a is 2, a group C (R6) 2 is present between Q and CHR2.
    [0313] [0313] In one mode, a is 0 or 1. In particular, a is 0. In an alternative mode, a is 1.
    [0314] [0314] b is 0, 1 or 2. When b is 0, a CH2 group is present between Q and CHR3. When b is 1, a CHR7 group is present between Q and CHR3. When b is 2, a group C (R7) 2 is present between Q and CHR3.
    [0315] [0315] In one mode, b is 0 or 1. In particular, b is 0. In an alternative mode, b is 1.
    [0316] [0316] In a modality, a is 1 and b is 0. In an alternative modality, a is 0 and b is 1.
    [0317] [0317] In one embodiment, Q is C and R7 is halogen (for example, fluorine) or hydroxyl.
    [0318] [0318] In particular, a is 0 and b is 0, that is, a CH2 group is present between Q and CHR2 and a CH2 group is present between Q and CHR3, and the compound of Formula (I) is a compound of Formula ( IX) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (IX)
    [0319] [0319] where X, Q, R1, R2, R3, R4, R5, R8, R9, R10, a, b, c and A are as defined in this document.
    [0320] [0320] In one embodiment, R6 and R7 are independently selected from halogen (for example, fluorine), and hydroxyl;
    [0321] [0321] a is selected from 0, 1 and 2; and
    [0322] [0322] b is selected from 0 and 1;
    [0323] [0323] provided that, when Q is N, then a and b are 0.
    [0324] [0324] In a modality, when present, R6 and R7 are halogen (for example, fluorine);
    [0325] [0325] a is selected from 0, 1 and 2; and
    [0326] [0326] b is selected from 0 and 1;
    [0327] [0327] provided that, when Q is N, then a and b are 0.
    [0328] [0328] In one embodiment, a is 1 and R6 is halogen (for example, fluorine) or hydroxyl. In particular, a is 1 and R6 is fluorine.
    [0329] [0329] In one embodiment, a is 1 and R7 is halogen (for example, fluorine) or hydroxyl. In particular, b is 1 and R6 is fluorine.
    [0330] [0330] In one embodiment, a is 1 and b is 1 and R6 and R7 are independently selected from halogen (for example, fluorine) and hydroxyl.
    [0331] [0331] When Q is C, R4 and / or R5 are different from hydrogen, and a and / or b is different from zero, then compounds of Formula (I) can exist in more than one stereoisomeric form.
    [0332] [0332] For example, in the case where R5 is different from hydrogen, a is 1 and b is 0 (R2 and R3 not shown for simplicity): (a) (b) (c) (d)
    [0333] [0333] In particular, in one embodiment, the compound is stereoisomer (a).
    [0334] [0334] For example, in the case where R5 is different from hydrogen, a is 1 and b is 0 (R2 and R3 not shown for simplicity): (a ') (b') (c ') (d')
    [0335] [0335] In the case where R2 and R3 are different from hydrogen, additional stereoisomers are possible. In particular, the following stereoisomers are possible, for example, where R2 and R3 together form the one to three-membered bridge group defined here, for example, C1-3alkylene and in particular -CH2CH2-: (e) (f ) (g) (h) (e ') (f') (g ') (h')
    [0336] [0336] In particular, in one embodiment, the compound is stereoisomer (h) or stereoisomer (e ').
    [0337] [0337] In particular, in one embodiment, the compound is stereoisomer (h) or stereoisomer (e ') and R6 is fluorine and R5 is amino.
    [0338] [0338] In particular, in one embodiment, the compound is stereoisomer (h) or stereoisomer (e ') and R2 and R3 together form a -CH2CH2- group.
    [0339] [0339] In particular, in one embodiment, the compound is stereoisomer (h) or stereoisomer (e ') and R6 is fluorine and R5 is amino and R2 and R3 together form a group - CH2CH2-.
    [0340] [0340] In particular, in one embodiment, the compound is stereoisomer (h) or stereoisomer (e '), for example, where R6 is fluorine.
    [0341] [0341] In particular, in one embodiment, the compound is stereoisomer (h) or stereoisomer (e ') and R6 is fluorine.
    [0342] [0342] In particular, in one embodiment, the compound is stereoisomer (h) or stereoisomer (e ') and R6 is fluorine and R2 and R3 together form a -CH2CH2- group.
    [0343] [0343] In particular, in one embodiment, the compound is a stereoisomer (e '), for example, where R6 is fluorine and R5 is amino.
    [0344] [0344] In particular, in one embodiment, the compound is a stereoisomer (e ') and R6 is fluorine and R5 is amino and R2 and R3 together form a -CH2CH2- group.
    [0345] [0345] In particular, in one embodiment, the compound is a stereoisomer (e '), for example, where R6 is fluorine.
    [0346] [0346] In particular, in one embodiment, the compound is a stereoisomer (e ') and R6 is fluorine.
    [0347] [0347] In particular, in one embodiment, the compound is a stereoisomer (e ') and R6 is fluorine and R2 and R3 together form a -CH2CH2- group.
    [0348] [0348] In particular, the following stereoisomers are possible: (e) (f) (g) (h)
    [0349] [0349] In one embodiment, R5 is amino and R4 is halogen (for example, fluorine).
    [0350] [0350] R8
    [0351] [0351] R8 is selected from haloC1-4alkyl (for example, -CF3), -CH3 and halogen (for example, chlorine or fluorine).
    [0352] [0352] In one mode, R8 is selected from -CH3, chlorine and fluorine.
    [0353] [0353] In one embodiment, R8 is halogen, and the compound of Formula (I) is a compound of Formula (X) or a tautomer or solvate or a pharmaceutically acceptable salt thereof: (X)
    [0354] [0354] where X, Q, R1, R2, R3, R4, R5, R6, R7, R9, R10, a, b, c and A are as defined herein, in particular where halogen is chlorine.
    [0355] [0355] In one mode, R8 is selected from methyl, chlorine and fluorine.
    [0356] [0356] In one mode, R8 is selected from chlorine and fluorine.
    [0357] [0357] In particular, R8 is methyl.
    [0358] [0358] In particular, R8 is chlorine.
    [0359] [0359] R9
    [0360] [0360] R9 is selected from hydrogen, C1-4alkyl (eg, -CH3), haloC1-4alkyl (eg, - CF3) and halogen (eg, chlorine).
    [0361] [0361] In one mode, R9 is selected from hydrogen, -CH3, -CF3 and chlorine.
    [0362] [0362] In one mode, R9 is selected from hydrogen, -CH3, -CF3, chlorine and fluorine.
    [0363] [0363] In particular, R9 is hydrogen and the compound of Formula (I) is a compound of Formula (XI) or a tautomer or solvate or a pharmaceutically acceptable salt thereof: (XI)
    [0364] [0364] where X, Q, R1, R2, R3, R4, R5, R6, R7, R8, R10, a, b, c and A are as defined in this document.
    [0365] [0365] Ring A, R10 and c
    [0366] [0366] Ring A or is it:
    [0367] [0367] (i) a five-membered nitrogen-containing 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
    [0368] [0368] (ii) a six-membered aromatic nitrogen containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or
    [0369] [0369] (iii) a six-membered non-aromatic nitrogen containing heterocyclic ring, in which the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S.
    [0370] [0370] In one embodiment, ring A is a nitrogen-containing heterocyclic ring with five members (for example, an aromatic or non-aromatic ring), or a heterocyclic ring containing aromatic nitrogen with six members, where the heterocyclic ring is optionally contains one or two additional heteroatoms selected from N, O and S.
    [0371] [0371] In one embodiment, ring A is pyrazolyl, thiazolyl, pyrazinyl and pyridyl. This, then, with the fused benzo part forms indazolyl, benzothiazolyl, quinoxalinyl or quinolinyl, respectively.
    [0372] [0372] In one embodiment, ring A is a five-membered nitrogen-containing heterocyclic ring (for example, an aromatic ring or a non-aromatic ring), where the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S.
    [0373] [0373] In one embodiment, ring A is a nitrogen-containing heterocyclic ring with five members (for example, an aromatic ring or a non-aromatic ring), or a heterocyclic ring containing aromatic nitrogen with six members, where the heterocyclic ring is optionally contains one or two additional heteroatoms selected from N, O and S.
    [0374] [0374] In one embodiment, ring A is a five-membered nitrogen-containing heterocyclic ring, in which the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S.
    [0375] [0375] In one embodiment, ring A is a nitrogen-containing heterocyclic ring with five members, in which the heterocyclic ring optionally contains an added hetero atom selected from N, O and S.
    [0376] [0376] In one embodiment, ring A is a five-membered nitrogen-containing heterocyclic ring, where the heterocyclic ring optionally contains an additional heteroatom which is N or S.
    [0377] [0377] In one embodiment, ring A is a heterocyclic ring containing aromatic nitrogen with five members, where the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S.
    [0378] [0378] In one embodiment, ring A is a five-membered nitrogen-containing heterocyclic ring where the heterocyclic ring contains an additional hetero atom which is N.
    [0379] [0379] In one embodiment, ring A is a five-membered aromatic nitrogen containing heterocyclic ring in which the heterocyclic ring contains an additional hetero atom which is N.
    [0380] [0380] In one embodiment, ring A is a five-membered nitrogen-containing heterocyclic ring in which the heterocyclic ring contains an additional heteroatom which is S.
    [0381] [0381] In one embodiment, ring A is a five-membered aromatic nitrogen containing heterocyclic ring in which the heterocyclic ring contains an additional heteroatom which is S.
    [0382] [0382] In one embodiment, ring A is pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl and triazolyl, for example, in which Ring A is thiazolyl or pyrazolyl.
    [0383] [0383] In one embodiment, ring A is a five-membered nitrogen-containing heterocyclic ring (for example, an aromatic ring or a non-aromatic ring), where 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 (XII) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XII)
    [0384] [0384] where X, Q, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, a, b, and c are as defined herein, and 5-Het is a heterocyclic ring containing five-membered nitrogen (for example, an aromatic ring or a non-aromatic ring), where the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S.
    [0385] [0385] In one modality, the part
    [0386] [0386] is selected from the following options in Table I: Table I THE B Ç D AND F G H I J K L M N O P Q
    [0387] [0387] In one modality, the part
    [0388] [0388] is selected from the following options in Table I ’: Table I’ THE B Ç D AND F G H I J K L M N O P Q
    [0389] [0389] In one modality, the part
    [0390] [0390] is selected from the following options in Table I ’’: Table I ’’ THE B Ç D AND F G H I J K L M N O P Q
    [0391] [0391] For example, the part
    [0392] [0392] is selected from options A, B, C, D, E, F, G, H, I, O, P and Q in Table I.
    [0393] [0393] In particular, the part
    [0394] [0394] is selected from options C, D, E, F, G, H, I, O, P and Q in Table I.
    [0395] [0395] In particular, the part
    [0396] [0396] is selected from options D, H, P and
    [0397] [0397] In particular, the part
    [0398] [0398] is selected from:
    [0399] [0399], for example,
    [0400] [0400] In particular, the part
    [0401] [0401] is selected from among
    [0402] [0402] In particular, the compound of Formula (XII) is a compound of Formula (XIIa) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof:
    [0403] [0403] where X, Q, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, a and b are as defined herein, for example, where R10 is C1-4 alkyl.
    [0404] [0404] In particular, the compound of Formula (XIIa) is a compound of Formula (XIIb) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XIIb)
    [0405] [0405] where X, Q, R1, R2, R3, R4, R5, R6, R7, R8, R9, a and b are as defined herein.
    [0406] [0406] In particular, the compound of Formula (XII) is a compound of Formula (XIIc) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof:
    [0407] [0407] where X, Q, R1, R2, R3, R4, R5, R6, R7, R8, R9, a and b are as defined herein.
    [0408] [0408] In particular, the compound of Formula (XII) is a compound of Formula (XIId) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XIId)
    [0409] [0409] where X, Q, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, a and b are as defined herein, for example, where an R10 is C1-4alkyl and the another is halogen (for example, chlorine).
    [0410] [0410] In particular, the compound of Formula (XII) is a compound of Formula (XIIe) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof:
    [0411] [0411] where X, Q, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, a and b are as defined in this document.
    [0412] [0412] In one embodiment, ring A is either:
    [0413] [0413] (i) a six-membered aromatic nitrogen containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or
    [0414] [0414] (ii) a six-membered non-aromatic nitrogen containing heterocyclic ring, in which the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S.
    [0415] [0415] In one embodiment, ring A is a six-membered aromatic nitrogen-containing heterocyclic ring, and the compound of Formula (I) is a compound of Formula (XIII) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof : (XIII)
    [0416] [0416] where X, Q, R1, R2, R3, R4, R5, R6, R7,
    [0417] [0417] (i) a six-membered aromatic nitrogen containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or
    [0418] [0418] (iii) a six-membered non-aromatic nitrogen containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S.
    [0419] [0419] When ring A is a nitrogen-containing six-membered ring, if the ring is aromatic, then the ring can optionally contain one or two additional heteroatoms selected from N, O and S. However, if the nitrogen-containing ring with six members it is non-aromatic, so the ring can optionally contain one or two additional hetero atoms selected from N and S, that is, the ring cannot include an additional hetero atom which is O.
    [0420] [0420] In one embodiment, 6-Het is a six-membered nitrogen-containing heterocyclic ring, where the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S.
    [0421] [0421] 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.
    [0422] [0422] In particular, 6-Het is a six-membered nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains an additional heteroatom selected from N.
    [0423] [0423] In particular, 6-Het is a six-membered nitrogen-containing heterocyclic ring, where the heterocyclic ring contains an additional heteroatom which is N.
    [0424] [0424] In one modality, the part
    [0425] [0425] is selected from the following options in Table II: Table II THE B
    [0426] [0426] In particular, the part
    [0427] [0427] is selected from options D, E and H in Table II, for example, D.
    [0428] [0428] In particular, the part
    [0429] [0429] is selected from:
    [0430] [0430] In particular, the part
    [0431] [0431] is:
    [0432] [0432] In particular, the part
    [0433] [0433] is selected from options E and G in Table II, in particular option G.
    [0434] [0434] In particular, the part
    [0435] [0435] is selected from:
    [0436] [0436] In particular, the part is:.
    [0437] [0437] In one embodiment, the compound of Formula (I) is a compound of Formula (XIIIa) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XIIIa)
    [0438] [0438] where X, Q, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, a and b are as defined in this document.
    [0439] [0439] In one embodiment, the compound of Formula (XIIIa) is a compound of Formula (XIIIb) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XIIIb)
    [0440] [0440] where X, Q, R1, R2, R3, R4, R5, R6, R7, R8, R9, a and b are as defined in this document.
    [0441] [0441] In one embodiment, the compound of Formula (XIII) is a compound of Formula (XIIIc) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XIIIc)
    [0442] [0442] where X, Q, R1, R2, R3, R4, R5, R6, R7, R8, R9, a and b are as defined in this document.
    [0443] [0443] In one embodiment, ring A includes a nitrogen atom adjacent to (that is, directly attached to) the benzene ring and the compound of Formula (I) is a compound of Formula (XIVa) or (XIVb) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, that is: (XIVa) or
    [0444] [0444] where X, Q, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, a, b, c and A are as defined herein.
    [0445] [0445] R10 are independently selected from halogen, cyano, cyanoC1-4alkyl (eg, -CH2- CN), hydroxyl, = O (oxo), C1-4alkyl (eg, -CH3 or - CH2CH3), haloC1-4alkyl , C1-4alkoxy (for example, -OCH3), hydroxylC1-4alkyl (for example, -CH2C (CH3) 2OH, - CH (CH3) CH2OH, -CH (CH3) OH, -CH2CH2OH or -CH2OH), C1-4alkoxyC1 - 4 alkylene (for example, -CH2-O-CH3 or -CH2-CH2-O-CH3), C1-4alkylsulfone (for example, -SO2CH3), amino, monoC1-4alkylamino, diC1-4alkylamino (for example, -N ( CH3) 2), aminoC1-4alkylene (for example, -CH2NH2), -C1-4alkylene-C (= O) NH (2-q) (C1-6 alkyl) q), -C1-4alkylene-NHC (= O ) C1-6 alkyl, C0-4alkylene sulfonamide (for example, -SO2NRx2 or -CH2SO2NRx2, where Rx is independently selected from H and C1-6alkyl), 3 to 6 membered cycloalkyl, unsaturated five or six membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4alkyl, C1-4alkyl substituted by 3- to 6-membered cycloalkyl, C1-4alkyl substituted by five or six-membered unsaturated heterocyclic group optionally substituted containing 1, 2, 3 or 4 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4alkyl, C1-4alkyl substituted by saturated heterocyclic group with four to six members optionally substituted containing 1 or 2 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4alkyl and heterocyclic group saturated with four to six optionally substituted members containing 1 or 2 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4alkyl;
    [0446] [0446] q is selected from 0, 1 or 2; and
    [0447] [0447] c is selected from 0, 1, 2 and 3.
    [0448] [0448] In one embodiment, R10 are independently selected from halogen, cyan, cyanoC1-4alkyl (for example, -CH2-CN), hydroxyl, = O (oxo), C1-4alkyl (for example, -CH3 or -CH2CH3) , haloC1-4alkyl, C1-4alkoxy (for example, -OCH3), hydroxylC1-4alkyl (for example, -CH2C (CH3) 2OH, -CH (CH3) CH2OH, -CH (CH3) OH, -CH2CH2OH or -CH2OH) , C1-4alkoxyC1-4alkylene (for example, -CH2-O-CH3 or -CH2-CH2-O-CH3), C1-4alkylsulfone (for example, -SO2CH3), amino, monoC1-4alkylamino, diC1-4alkylamino (for example , - N (CH3) 2), aminoC1-4alkylene (e.g., -CH2NH2), -C1-4alkylene-C (= O) NH (2-q) (C1-6alkyl) q), -C1-4alkylene- NHC (= O) C1-6 alkyl, C0-4alkylene sulfonamide (for example, - SO2NRx2 or -CH2SO2NRx2, where Rx is independently selected from H and C1-6alkyl), 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-
    [0449] [0449] q is selected from 0, 1 or 2; and
    [0450] [0450] c is selected from 0, 1, and 2.
    [0451] [0451] In one embodiment, R10 are independently selected from halogen, cyan, cyanoC1-4alkyl (for example, -CH2-CN), hydroxyl, = O (oxo), C1-4alkyl (for example, -CH3 or -CH2CH3) , haloC1-4alkyl, C1-4alkoxy (for example, -OCH3), hydroxylC1-4alkyl (for example, -CH2C (CH3) 2OH, -CH (CH3) CH2OH, -CH (CH3) OH, -CH2CH2OH or -CH2OH) , -C1-4alkyleneC1-4alkoxy (for example, -CH2-O-CH3 or -CH2-CH2-O-CH3), C1-4alkylsulfone (for example, -SO2CH3), amino, monoC1-4alkylamino, diC1-4alkylamino (for example, - N (CH3) 2), -C1-4alkyleneamino (e.g., -CH2NH2), -C1-4alkylene-C (= O) NH (2-q) (C1-6 alkyl) q), -C1- 4 alkylene- NHC (= O) C1-6 alkyl, -C0-4alkylenesulfonamide (for example, -SO2NRx2 or -CH2SO2NRx2, where Rx is independently selected from H and C1-6alkyl), and optionally saturated heterocyclic group with four to six members substituted containing 1 or 2 heteroatoms selected from O, N, or S, where the optional substituent is selected from C1-4alkyl.
    [0452] [0452] In a modality c is 2; an R10 is = O (oxo) and an R10 is independently selected from halogen, cyano, cyanoC1-4alkyl (eg, -CH2-CN), hydroxyl, C1-4alkyl (eg, CH3 or -CH2CH3), haloC1-4alkyl , C1-4alkoxy (for example, -OCH3), hydroxylC1-4alkyl (for example, -CH2C (CH3) 2OH, -CH (CH3) CH2OH, -CH (CH3) OH, -CH2CH2OH or -CH2OH), C1-4alkoxyC1 -4alkylene (for example, -CH2-O-CH3 or -CH2-CH2-O-CH3), C1-4alkylsulfone (for example, -SO2CH3), amino, monoC1-4alkylamino, diC1-4alkylamino (for example, -
    [0453] [0453] In a modality, q is 0 or 1. In particular, q is 1. In particular, q is 2.
    [0454] [0454] In one embodiment, c is 0 or 1. In particular, c is 1.
    [0455] [0455] In particular, c is 2. In particular, c is
    [0456] [0456] In one embodiment, R10 are independently selected from halogen, cyan, cyanoC1-4alkyl (for example, -CH2-CN), hydroxyl, = O (oxo), C1-4alkyl (for example, -CH3 or -CH2CH3) , haloC1-4alkyl, C1-4alkoxy (for example, -OCH3), hydroxylC1-4alkyl (for example, -CH (CH3) CH2OH, -CH (CH3) OH, -CH2CH2OH or -CH2OH), diC1-4alkylamino (for example , -N (CH3) 2), and C1-4alkoxyC1-4alkylene (for example, -CH2-O-CH3), for example, where R10 is independently selected from halogen, cyano, hydroxyl, = O (oxo), and C1-4alkyl (for example, -CH3 or - CH2CH3).
    [0457] [0457] In one embodiment, R10 are independently selected from halogen, cyano, cyanoC1-4alkyl (for example, -CH2-CN), hydroxyl, = O (oxo), C1-4alkyl (for example, -CH3 or -CH2CH3) , haloC1-4alkyl, C1-4alkoxy (for example, -OCH3), hydroxylC1-4alkyl (for example, -CH (CH3) CH2OH, -CH (CH3) OH, -CH2CH2OH or -CH2OH) and C1-4alkoxyC1-4alkylene ( for example, -CH2-O-CH3), for example, where R10 is independently selected from halogen, cyano, hydroxyl, = O (oxo), and C1-4alkyl (for example, -CH3 or -CH2CH3).
    [0458] [0458] In one embodiment, R10 are independently selected from halogen, cyan, cyanoC1-4alkyl (for example, -CH2-CN), hydroxyl, = O (oxo), C1-4alkyl (for example, -CH3 or -CH2CH3) , haloC1-4alkyl, C1-4alkoxy (for example, -OCH3), hydroxylC1-4alkyl (for example, -CH (CH3) CH2OH, -CH (CH3) OH, -CH2CH2OH or -CH2OH) and C1-4alkoxyC1-4alkylene ( for example, -CH2-O-CH3), for example, where R10 is independently selected from halogen, cyano, hydroxyl, = O (oxo), and C1-4alkyl (for example, -CH3 or -CH2CH3).
    [0459] [0459] In one embodiment, R10 is independently selected from halogen, cyan, hydroxyl, = O (oxo), and C1-4alkyl (eg, -CH3 or - CH2CH3), for example, where R10 is independently selected from hydroxyl , = O (oxo) and C1-4alkyl (e.g., -CH3).
    [0460] [0460] In one embodiment, R10 are independently selected from halogen (for example, chlorine or fluorine), = O (oxo), C1-4alkyl (for example, -CH3, -CH2CH3, -CH (CH3) 2), C1 -4alkoxy (for example, -OCH3), and diC1-4alkylamino (for example, -N (CH3) 2, for example, where R10 is independently selected from halogen, = O (oxo), and C1-4alkyl (for example , -CH3 or -CH2CH3).
    [0461] [0461] In one embodiment, R10 are independently selected from halogen (for example, chlorine), cyano, cyanoC1-4alkyl (for example, -CH2- CN), C1-4alkoxy (for example, -OCH3, -OCH2CH3 and -OCH (CH3) 2), = O (oxo), C1-4alkyl (for example, -CH3, -CH2CH3 and -CH (CH3) 2), hydroxylC1-4alkyl (for example, -CH2OH, -CH2CH2OH or - CH2C (CH3 ) 2OH), haloC1-4alkyl (for example, -CHF2), diC1-4alkylamino (for example, -N (CH3) 2), C1-4alkoxyC1-4alkylene (for example, -CH2-O-CH3 or -CH2-CH2 -O-CH3), -C0-4alkylene- C (= O) NH (2-q) (C1-6 alkyl) q) (e.g. -CO-N (CH3) 2, -CH2-CH2- CO- N (CH3) 2, -CH2-CO-N (CH3) 2, -CH2-CO-NH (C (CH3) 3) or -CH2-CO-NH (CH3), saturated heterocyclic group with four to six members containing O or N (for example, tetrahydrofuranyl, morpholino, azetidinyl or oxetanyl), and C1-4alkyl (for example, C1 alkyl) substituted by an optionally substituted unsaturated heterocyclic group with five or six members (for example, unsaturated heterocyclic group with five members) containing 1,2, 3 or 4 heteroatoms selected from O, N, and S (for example, N or O), where the optional substituent is selected from C1-4alkyl (for example, -CH3).
    [0462] [0462] In one embodiment, R10 is halogen (for example, chlorine), cyan, C1-4alkyl (for example, -CH3, - CH (CH3) 2 or -CH2CH3), haloC1-4alkyl (for example, -CHF2) , C1-4alkoxy (for example, -OCH3, -OCH2CH3 or -OCH (CH3) 2), C1-4alkoxyC1-4alkene (for example, -CH2OCH3). diC1-4alkylamino (eg, -N (CH3) 2) saturated heterocyclic group with four to six members or optionally substituted (eg, unsubstituted) containing 1 or 2 heteroatoms selected from O or N, where the optional substituent is selected of C1-4alkyl (for example, morpholinyl or azetidinyl).
    [0463] [0463] In one embodiment, R10 is -C0-4alkylene-
    [0464] [0464] In one embodiment, R10 are independently selected from halogen, cyan, hydroxyl, = O (oxo), and C1-4alkyl (for example, -CH3 or - CH2CH3), for example, where R10 is independently selected from C1 -4alkyl (for example, -CH3), halogen or oxo.
    [0465] [0465] In one embodiment, R10 are independently selected from = O (oxo), hydroxyl and C1-4alkyl (for example, -CH3 or -CH2CH3). In particular, R10 are independently selected from = O (oxo), hydroxyl and -CH3.
    [0466] [0466] In particular, c is 1 and R10 are independently selected from = O (oxo), hydroxyl and -CH3.
    [0467] [0467] In particular, c is 1 and R10 is -CH3.
    [0468] [0468] In one embodiment, c is 2 and an R10 is = O (oxo) and an R10 is C1-4alkyl (for example, -CH3 or -CH2CH3).
    [0469] [0469] In one embodiment, R10 is C1-4alkyl (for example, -CH3, -CH2CH3, or -CH (CH3) 2)
    [0470] [0470] In one embodiment, R10 are independently selected from halogen (for example, chlorine), C1-4alkoxy (for example, -OCH3), = O (oxo), C1-4alkyl (for example, -CH3 or -CH2CH3) , hydroxylC1-4alkyl (for example, -CH2CH2OH or -CH2OH), diC1-4alkylamino (for example, -N (CH3) 2), C1-4alkoxyC1-4alkylene (for example, -CH2- O-CH3 or -CH2-CH2 -O-CH3), and saturated heterocyclic group with four to six members containing O (for example, tetrahydrofuran); and
    [0471] [0471] c is selected from 0, 1 and 2.
    [0472] [0472] It should be understood that the above definitions of heterocycles and R10 substituents cover all possible tautomeric forms of the rings. Thus, for example, the following compound can exist in the following tautomeric forms and both fall within the scope of Formula (I): Tautomer A Tautomer B
    [0473] [0473] In addition, for example, the following compound can exist in the following tautomeric forms and both fall within the scope of Formula (I): Tautomer A Tautomer B
    [0474] [0474] In one modality, the part
    [0475] [0475] is selected from:
    [0476] [0476] In one modality, the part
    [0477] [0477] is selected from:
    [0478] [0478] In one modality, the part
    [0479] [0479] is selected from:
    [0480] [0480] In one modality, the part
    [0481] [0481] is selected from:
    [0482] [0482] In one modality, the part
    [0483] [0483] is selected from:
    [0484] [0484] In one modality, the part
    [0485] [0485] is selected from:
    [0486] [0486] In one modality, the part
    [0487] [0487] is selected from:
    [0488] [0488] In one modality, the part
    [0489] [0489] is selected from:
    [0490] [0490] In one modality, the part
    [0491] [0491] is selected from:
    [0492] [0492] In one modality, the part
    [0493] [0493] is selected from:
    [0494] [0494] In one modality, the part
    [0495] [0495] is selected from:
    [0496] [0496] In one modality, the part
    [0497] [0497] is selected from:
    [0498] [0498] In one modality, the part
    [0499] [0499] is selected from:
    [0500] [0500] In one modality, the part
    [0501] [0501] is selected from:
    [0502] [0502] In one modality, the part
    [0503] [0503] is selected from:
    [0504] [0504] In particular, the part
    [0505] [0505] is selected from:
    [0506] [0506] In one modality, the part
    [0507] [0507] is selected from:
    [0508] [0508], for example,
    [0509] [0509] or be selected from:
    [0510] [0510] for example,
    [0511] [0511] In another modality, the part
    [0512] [0512] is selected from:
    [0513] [0513], for example,
    [0514] [0514] or be selected from:
    [0515] [0515] for example, SUBSTITUTE COMBINATIONS
    [0516] [0516] In one embodiment, the compound of Formula (I) is a compound of Formula (XV) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XV)
    [0517] [0517] where Q, R2, R3, R4, R5, R10, c and A are as defined in this document.
    [0518] [0518] 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: (XVI)
    [0519] [0519] where R2, R3, R4, R5, R10, c and A are as defined in this document.
    [0520] [0520] In one embodiment, the compound of Formula (XVI) is a compound of Formula (XVII) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof:
    [0521] [0521] where R2, R3, R4, R5, R6, R10, c and A are as defined in this document.
    [0522] [0522] 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)
    [0523] [0523] where R4, R5, R10, c and A are as defined in this document, and d is 0, 1 or 2 (for example, 1).
    [0524] [0524] 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')
    [0525] [0525] where R4, R5, R6, R10, c and A are as defined in this document, and d is 0, 1 or 2 (for example, 1).
    [0526] [0526] In one embodiment, the compound of Formula (XVIII) is a compound of Formula (XVIIIa) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XVIIIa) where
    [0527] [0527] R4 is hydrogen or C1-4alkyl;
    [0528] [0528] R5 is amino, or C1-4alkyl (e.g., methyl) optionally substituted by amino;
    [0529] [0529] R10 is = O (oxo), C1-4alkyl (for example, -CH3 or -CH2CH3), hydroxylC1-4alkyl (for example, -CH2CH2OH or -CH2OH) or diC1-4alkylamino (for example, -N (CH3 )two);
    [0530] [0530] c is 0 or 1,
    [0531] [0531] d is 0, 1 or 2 (e.g. 1),
    [0532] [0532] and the part
    [0533] [0533] is selected from:
    [0534] [0534] (i) options A, B, C, D, E, F, G, H, I, J, O, P and Q in Table I, and in particular is selected from:
    [0535] [0535] for example,
    [0536] [0536] or (ii) options D, E and H in Table II, and in particular is selected from: H / R10
    [0537] [0537] for example:
    [0538] [0538] In one embodiment, the compound of Formula (XVIII ') is a compound of Formula (XVIIIa') or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XVIIIa ')
    [0539] [0539] where
    [0540] [0540] R4 is hydrogen or C1-4alkyl;
    [0541] [0541] R5 is amino, or C1-4alkyl (e.g., methyl) optionally substituted by amino;
    [0542] [0542] R6 is halogen (for example, fluorine) or hydroxyl;
    [0543] [0543] R10 is = O (oxo), C1-4alkyl (for example, -CH3 or -CH2CH3), hydroxylC1-4alkyl (for example, -CH2CH2OH or -CH2OH) or diC1-4alkylamino (for example, -N (CH3 )two);
    [0544] [0544] c is 0 or 1,
    [0545] [0545] d is 0, 1 or 2 (for example, 1),
    [0546] [0546] and the part
    [0547] [0547] is selected from:
    [0548] [0548] (i) options A, B, C, D, E, F, G, H, I, J,
    [0549] [0549] for example,
    [0550] [0550] or (ii) options D, E and H in Table II, and in particular is selected from:
    [0551] [0551] for example:
    [0552] [0552] In one embodiment, the compound of Formula (I) is a compound of Formula (XV *) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XV *)
    [0553] [0553] where Q, R2, R3, R4, R5, R10, c and A are as defined in this document.
    [0554] [0554] 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: A (R10) c
    [0555] [0555] where R2, R3, R4, R5, R10, c and A are as defined in this document.
    [0556] [0556] In one embodiment, the compound of Formula (XVI *) is a compound of Formula (XVII *) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XVII *)
    [0557] [0557] where R2, R3, R4, R5, R10, c and A are as defined in this document.
    [0558] [0558] In one embodiment, the compound of Formula (XVI *) is a compound of Formula (XVII '*) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XVII ’*)
    [0559] [0559] where R2, R3, R4, R5, R6, R10, c and A are as defined in this document.
    [0560] [0560] 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 *)
    [0561] [0561] where R4, R5, R10, c and A are as defined in this document, and d is 0, 1 or 2 (for example, 1).
    [0562] [0562] In one embodiment, the compound of Formula (XVII *) is a compound of Formula (XVIII ’*) or a tautomer or solvate or a pharmaceutically acceptable salt thereof: (XVIII’ *)
    [0563] [0563] where R4, R5, R6, R10, c and A are as defined in this document, and d is 0, 1 or 2 (for example, 1).
    [0564] [0564] In one embodiment, the compound of Formula (XVIII ’*) is a compound of Formula (XVIIIa’ *) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XVIIIa ’*)
    [0565] [0565] where
    [0566] [0566] R4 is hydrogen or C1-4alkyl;
    [0567] [0567] R5 is amino, hydroxyl or C1-4alkyl (e.g., methyl) optionally substituted by amino;
    [0568] [0568] R6 is halogen (for example, fluorine);
    [0569] [0569] R10 is halogen (for example, chlorine), cyano, C1-4alkyl (for example, -CH3, -CH (CH3) 2 or -CH2CH3), oxo, haloC1-4alkyl (for example, -CHF2), C1 -4alkoxy (for example, -OCH3, -OCH2CH3 or -OCH (CH3) 2), hydroxylC1-4alkyl (for example, -CH2CH2OH), C1-4alkoxyC1-4alkylene (for example, -CH2OCH3). diC1-4alkylamino (eg, -N (CH3) 2) saturated heterocyclic group with four to six members or optionally substituted (eg, unsubstituted) containing 1 or 2 heteroatoms selected from O or N, where the optional substituent is selected C1-4alkyl (for example, morpholinyl or azetidinyl);
    [0570] [0570] c is 0 or 1; and
    [0571] [0571] the part
    [0572] [0572] is as defined here.
    [0573] [0573] In a Formula modality (XVIIIa ’*), the part
    [0574] [0574] is selected from:
    [0575] [0575] (i) options A, B, C, D, E, F, G, H, I, J, O, P and Q in Table I, and in particular is selected from:
    [0576] [0576] for example,
    [0577] [0577] or (ii) options E and G in Table II, and in particular is selected from:
    [0578] [0578] for example:
    [0579] [0579] In one embodiment, the compound of Formula (I) is a compound of Formula (IIa) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (IIa)
    [0580] [0580] where
    [0581] [0581] Q is C or N;
    [0582] [0582] R1 is CH3 or -CH2OH;
    [0583] [0583] R2 and R3 are either:
    [0584] [0584] (i) hydrogen; or
    [0585] [0585] (ii) together form a C1-3 alkylene bridge group with two to three members;
    [0586] [0586] R4 is hydrogen or C1-4alkyl (for example, methyl);
    [0587] [0587] R5 is amino;
    [0588] [0588] or R4 and R5 together with Q (when Q = C), form a heterocyclic ring containing nitrogen with four limbs;
    [0589] [0589] or: (i) a is 1 and b is 0 and R6 is halogen (for example, fluorine) or hydroxyl; or (ii) a is 0 and b is 1 and R7 is halogen (for example, fluorine) or hydroxyl;
    [0590] [0590] R8 is halogen (for example, chlorine or fluorine)
    [0591] [0591] R10 is halogen (for example, chlorine), cyan, C1-4alkyl (for example, -CH3, -CH (CH3) 2 or -CH2CH3),
    [0592] [0592] c is 0 or 1,
    [0593] [0593] d is 0, 1 or 2 (e.g. 1),
    [0594] [0594] and the part
    [0595] [0595] is selected from:
    [0596] [0596] (i) options A, B, C, D, E, F, G, H, I, J, O, P and Q in Table I, and in particular is selected from:
    [0597] [0597] or (ii) options E and G in Table II, and in particular is selected from:
    [0598] [0598] for example:
    [0599] [0599] In an embodiment of the compound of Formula (IIa), R1 is CH3.
    [0600] [0600] In one embodiment, the compound of Formula (IIa) is a compound of Formula (XVIIIa *) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof: (XVIIIa *)
    [0601] [0601] where
    [0602] [0602] R4 is hydrogen or C1-4alkyl (for example, methyl);
    [0603] [0603] R5 is amino;
    [0604] [0604] R6 or R7 is halogen (for example, fluorine);
    [0605] [0605] R8 is halogen (for example, chlorine or fluorine)
    [0606] [0606] R10 is halogen (for example, chlorine), cyano, C1-4alkyl (for example, -CH3, -CH (CH3) 2 or -CH2CH3), haloC1-4alkyl (for example, -CHF2), C1-4alkoxy (for example, -OCH3, -OCH2CH3 or -OCH (CH3) 2), C1-4alkoxyC1-4alkene (for example, -CH2OCH3). diC1-4alkylamino (eg - N (CH3) 2) saturated heterocyclic group with four to six members or optionally substituted (eg, unsubstituted) containing 1 or 2 heteroatoms selected from O or N, where the optional substituent is selected C1-4alkyl (for example, morpholinyl or azetidinyl);
    [0607] [0607] a is 0 or 1;
    [0608] [0608] b is 0 or 1;
    [0609] [0609] c is 0 or 1,
    [0610] [0610] d is 0, 1 or 2 (for example, 1),
    [0611] [0611] and the part
    [0612] [0612] is selected from:
    [0613] [0613] (i) options A, B, C, D, E, F, G, H, I, J, O, P and Q in Table I, and in particular is selected from:
    [0614] [0614] for example,
    [0615] [0615] or (ii) options E and G in Table II, and in particular is selected from:
    [0616] [0616] for example: A PRIVATE GROUP OF COMPOUNDS
    [0617] [0617] In one embodiment, the invention provides a compound of Formula (I): (I)
    [0618] [0618] or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, where:
    [0619] [0619] X is CH or N;
    [0620] [0620] R1 is hydrogen, -CH3 or -CH2OH, but when X is N then R1 is selected from -CH3 and -CH2OH;
    [0621] [0621] R2 and R3 are either:
    [0622] [0622] (i) hydrogen; or
    [0623] [0623] (ii) together form an alkylene bridge group with one to three members (for example, -CH2- or - CH2-CH2-);
    [0624] [0624] Q is C or N;
    [0625] [0625] where when Q is C then either:
    [0626] [0626] (i) R4 is hydrogen, amino or C1-4alkyl (for example, methyl) optionally substituted by amino (for example, -CH2NH2);
    [0627] [0627] R5 is hydrogen, amino or C1-4alkyl (eg, methyl) optionally substituted by amino or hydroxyl;
    [0628] [0628] provided that R4 and R5 should not both be selected from amino and C1-4alkyl substituted by amino; or
    [0629] [0629] (ii) R4 and R5 together with Q form a heterocyclic ring containing nitrogen with four to six members (for example, azetidine); and
    [0630] [0630] where when Q is N then:
    [0631] [0631] R4 is absent, R5 is hydrogen and R2 and R3 together form the one to three membered alkylene bridge group (for example, -CH2- or -CH2-CH2-);
    [0632] [0632] R6 and R7 are independently selected from halogen (for example, fluorine), and hydroxyl;
    [0633] [0633] a is selected from 0, 1 and 2;
    [0634] [0634] b is selected from 0 and 1;
    [0635] [0635] provided that, when Q is N, then a and b are 0;
    [0636] [0636] Ring A or is it:
    [0637] [0637] (i) a five-membered nitrogen containing heterocyclic ring (for example, an aromatic ring or a non-aromatic ring) wherein the heterocyclic ring optionally contains additional hetero atoms selected from N, O and S;
    [0638] [0638] (ii) a six-membered heterocyclic ring containing aromatic or non-aromatic nitrogen, wherein the heterocyclic ring optionally contains an additional hetero atom which is N; or
    [0639] [0639] R8 is selected from halogen (for example, chlorine or fluorine, for example, chlorine);
    [0640] [0640] R9 is hydrogen;
    [0641] [0641] R10 are independently selected from halogen (eg, chlorine), cyan, cyanoC1-4alkyl (eg, -CH2-CN), C1-4alkoxy (eg - OCH3), = O (oxo), hydroxyl, C1-4alkyl (for example, -CH3 or -CH2CH3), hydroxylC1-4alkyl (for example, -CH2CH2OH or - CH2OH), diC1-4alkylamino (for example, -N (CH3) 2), C1-4alkoxyC1-4alkylene (for example, -CH2-O-CH3), -C1-4alkylene-C (= O) NH (2-q) (C1-6 alkyl) q), -C1-4alkylene-NHC (= O) C1-6 alkyl, C1-4alkyl (for example, C1 alkyl) substituted by an optionally substituted five or six-membered unsaturated heterocyclic group (for example, five-membered unsaturated heterocyclic group) containing 2 or 3 heteroatoms selected from O, N, or S, where the optional substituent is selected from C1-4alkyl, and a saturated heterocyclic group with four to six members containing O (for example, tetrahydrofuranyl or oxetanyl);
    [0642] [0642] q is selected from 0, 1 and 2; and
    [0643] [0643] c is selected from 0, 1, 2 and 3.
    [0644] [0644] In one embodiment, the invention provides a compound of Formula (I): (I)
    [0645] [0645] or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, where:
    [0646] [0646] X is CH or N;
    [0647] [0647] R1 is hydrogen, -CH3 or -CH2OH, but when X is N then R1 is selected from -CH3 and -CH2OH;
    [0648] [0648] R2 and R3 are either:
    [0649] [0649] (i) hydrogen; or
    [0650] [0650] (ii) together form an alkylene bridge group with one to three members (for example, -CH2- or - CH2-CH2-);
    [0651] [0651] Q is C or N;
    [0652] [0652] where when Q is C then either:
    [0653] [0653] (i) R4 is hydrogen, amino or C1-4alkyl (for example, methyl) optionally substituted by amino (for example, -CH2NH2);
    [0654] [0654] R5 is hydrogen, amino or C1-4alkyl (eg, methyl) optionally substituted by amino or hydroxyl;
    [0655] [0655] provided that R4 and R5 should not both be selected from amino and C1-4alkyl substituted by amino; or
    [0656] [0656] (ii) R4 and R5 together with Q form a nitrogen-containing heterocyclic ring with four to six members (for example, azetidine); and
    [0657] [0657] where when Q is N then:
    [0658] [0658] R4 is absent, R5 is hydrogen and R2 and R3 together form the one to three membered alkylene bridge group (for example, -CH2- or -CH2-CH2-);
    [0659] [0659] R6 and R7 are independently selected from halogen (for example, fluorine), and hydroxyl;
    [0660] [0660] a is selected from 0, 1 and 2;
    [0661] [0661] b is selected from 0 and 1;
    [0662] [0662] provided that, when Q is N, then a and b are 0;
    [0663] [0663] Ring A or is it:
    [0664] [0664] (i) a five-membered nitrogen-containing heterocyclic ring (for example, an aromatic ring or a non-aromatic ring) wherein the heterocyclic ring optionally contains additional hetero atoms selected from N, O and S;
    [0665] [0665] (ii) a six-membered heterocyclic ring containing aromatic or non-aromatic nitrogen, wherein the heterocyclic ring optionally contains an additional hetero atom which is N; or
    [0666] [0666] R8 is selected from halogen (for example, chlorine or fluorine, for example, chlorine);
    [0667] [0667] R9 is hydrogen;
    [0668] [0668] R10 are independently selected from halogen (for example, chlorine), C1-4alkoxy (for example, -OCH3), = O (oxo), hydroxyl, C1-4alkyl (for example, -CH3 or -CH2CH3), hydroxylC1 -4alkyl (for example, -CH2CH2OH or -CH2OH), diC1-4alkylamino (for example, -N (CH3) 2), C1-4alkoxyC1-4alkylene (for example, -CH2-O-CH3) and saturated heterocyclic group with four to six members containing O (for example, tetrahydrofuranyl or oxetanil); and
    [0669] [0669] c is selected from 0, 1 and 2.
    [0670] [0670] In one embodiment, the invention provides a compound of Formula (I): (I)
    [0671] [0671] or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, where:
    [0672] [0672] X is CH or N;
    [0673] [0673] R1 is hydrogen, -CH3 or -CH2OH, but when X is N then R1 is selected from -CH3 and -CH2OH;
    [0674] [0674] R2 and R3 are either:
    [0675] [0675] (i) hydrogen; or
    [0676] [0676] (ii) together form a one to three membered alkylene bridge group (for example, -CH2-, - CH2-CH2- or -CH2-CH2-CH2-);
    [0677] [0677] Q is C or N;
    [0678] [0678] where when Q is C then either:
    [0679] [0679] (i) R4 is hydrogen, amino or C1-4alkyl (for example, methyl) optionally substituted by amino (for example, -CH2NH2);
    [0680] [0680] R5 is hydrogen, amino, hydroxyl, or C1-4alkyl (for example, methyl) optionally substituted either by amino (for example, -CH2NH2) or hydroxyl (for example, -CH2OH);
    [0681] [0681] provided that R4 and R5 should not both be selected from amino and C1-4alkyl substituted by amino; or
    [0682] [0682] (ii) R4 and R5 together with Q form a nitrogen-containing heterocyclic ring with four to five members (for example, azetidinyl or pyrrolidinyl); and
    [0683] [0683] where when Q is N then:
    [0684] [0684] R4 is absent, R5 is hydrogen and R2 and R3 together form the one to three membered alkylene bridge group (for example, -CH2- or -CH2-CH2-);
    [0685] [0685] R6 and R7 are independently selected from halogen (for example, fluorine), and hydroxyl;
    [0686] [0686] a is selected from 0, 1 and 2;
    [0687] [0687] b is selected from 0 and 1;
    [0688] [0688] provided that, when Q is N, then a and b are 0;
    [0689] [0689] Ring A or is it:
    [0690] [0690] (i) a five-membered nitrogen-containing heterocyclic ring (for example, an aromatic ring or a non-aromatic ring) wherein the heterocyclic ring optionally contains additional heteroatoms selected from N, O and S;
    [0691] [0691] (ii) a six-membered heterocyclic ring containing aromatic or non-aromatic nitrogen, wherein the heterocyclic ring optionally contains an additional hetero atom which is N; or
    [0692] [0692] R8 is selected from halogen (for example, chlorine or fluorine, for example, chlorine) and C1-4alkyl (for example, -CH3);
    [0693] [0693] R9 is selected from hydrogen, halogen (for example, fluorine) and C1-4alkyl (for example, - CH3);
    [0694] [0694] R10 are independently selected from halogen (for example, chlorine or bromine), cyano, cyanoC1-4alkyl (for example, -CH2-CN), C1-4alkoxy (for example, -OCH3, -OCH2CH3 and -OCH (CH3 ) 2), = O (oxo), C1-4alkyl (e.g. -CH3, -CH2CH3 and -CH (CH3) 2), hydroxylC1-4alkyl (e.g. -CH2OH, -CH2CH2OH or -CH2C (CH3) 2OH ), haloC1-4alkyl (for example, -CHF2), diC1-4alkylamino (for example, -N (CH3) 2), C1-4alkoxyC1-4alkylene (for example, -CH2-O-CH3 or -CH2-CH2-O -CH3), -C0-4alkylene-C (= O) NH (2-q) (C1-6 alkyl) q) (e.g., -CO-N (CH3) 2, -CH2-CH2-CO-N ( CH3) 2, -CH2-CO-N (CH3) 2, - CH2-CO-NH (C (CH3) 3) or -CH2-CO-NH (CH3), saturated heterocyclic group with four to six members containing O or N (for example, tetrahydrofuranyl, morpholinyl, azetidinyl or oxetanyl), and C1-4alkyl (for example, C1 alkyl) substituted by an optionally substituted five or six-membered unsaturated heterocyclic group (for example, five-membered unsaturated heterocyclic group) containing 1 , 2, 3 or 4 heteroatoms selected from O, N, and S (for example, N or O), where the optional substituent is selected from C1-4alkyl (for example, -CH3); and
    [0695] [0695] q is selected from 0, 1 and 2; and
    [0696] [0696] c is selected from 0, 1 and 2.
    [0697] [0697] In one modality, the part
    [0698] [0698] is selected from:
    [0699] [0699] In one modality, the part
    [0700] [0700] is selected from:
    [0701] [0701] In one modality, the part
    [0702] [0702] is selected from: PRIVATE COMPOUNDS
    [0703] [0703] In one embodiment, the invention provides a compound of Formula (I) which is one of Examples 1 to 48 or is a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof.
    [0704] [0704] In one embodiment, the invention provides a compound of Formula (I) which is one of Examples 1 to 46 or is a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof.
    [0705] [0705] In one embodiment, the invention provides a compound of Formula (I) which is one of Examples 47 to 48 or is a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof.
    [0706] [0706] In one embodiment, the invention provides a compound of Formula (I) which is one of Examples 1 to 74 or is a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof.
    [0707] [0707] In one embodiment, the invention provides a compound of Formula (I) which is one of Examples 1 to 74 or is a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof.
    [0708] [0708] In one embodiment, the invention provides a compound of Formula (I) which is one of Examples 47 to 74 or is a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof.
    [0709] [0709] In one embodiment, the invention provides a compound of Formula (I) which is one of Examples 1 to 150 or is a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof.
    [0710] [0710] In one embodiment, the invention provides a compound of Formula (I) which is one of Examples 74 to 150 or is a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof.
    [0711] [0711] In one embodiment, the invention provides a compound of Formula (I) that is selected from the following compounds, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:
    [0712] [0712] endo-8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicycle [3.2 .1] octan-3-amine;
    [0713] [0713] endo-8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -3-methyl-8 - azabicycle [3.2.1] octan-3-amine; and
    [0714] [0714] 6- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} - 5-chlorine -2-methyl-3,4-dihydroquinazolin-4-one.
    [0715] [0715] In one embodiment, the invention provides a compound of Formula (I) that is selected from the following compounds, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:
    [0716] [0716] endo-8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicycle [3.2 .1] octan-3-amine;
    [0717] [0717] endo-8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -3-methyl-8 - azabicycle [3.2.1] octan-3-amine;
    [0718] [0718] 6- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} - 5-chlorine -2-methyl-3,4-dihydroquinazolin-4-one; and
    [0719] [0719] (1R, 2S, 3S, 5S) -8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3- yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-amine.
    [0720] [0720] In one embodiment, the invention provides a compound of Formula (I) that is selected from the following compounds, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:
    [0721] [0721] endo-8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicycle [3.2 .1] octan-3-amine;
    [0722] [0722] endo-8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -3-methyl-8 - azabicycle [3.2.1] octan-3-amine;
    [0723] [0723] 6- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} - 5-chlorine -2-methyl-3,4-dihydroquinazolin-4-one;
    [0724] [0724] (1R, 2S, 3S, 5S) -8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3- yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-amine;
    [0725] [0725] {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (3,4-dichloro-2 -methyl-2H-indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol;
    [0726] [0726] {6 - [(1S, 2S, 3S, 5R) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (3,4-dichloro-2 -methyl-2H-indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol;
    [0727] [0727] (1R, 2S, 3S, 5S) -8- [3- (5-chloro-3-methoxyquinoxalin-6-yl) -5-methyl-1H-pyrazol [3,4-b] pyrazin-6- yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-amine;
    [0728] [0728] (6- {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -5-methyl-1H-pyrazole [3,4-b] pyrazin-3-yl} -7-chloro-1,3-benzothiazol-2-yl) methanol;
    [0729] [0729] {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- [3- (azetidin-1- il) -5-chloroquinoxalin-6-yl] -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol;
    [0730] [0730] {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- [7-chloro-2- ( methoxymethyl) - 1,3-benzothiazol-6-yl] -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; and
    [0731] [0731] (1S, 2S, 3S, 5R) -8- [3- (7-chloro-2-methyl-1,3-benzothiazol-6-yl) -5-methyl-1H-pyrazole [3,4- b] pyrazin-6-yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-amine.
    [0732] [0732] In one embodiment, the invention provides a compound of Formula (I) which is the following compound, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:
    [0733] [0733] endo-8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicycle [3.2 .1] octan-3-amine.
    [0734] [0734] In one embodiment, the invention provides a compound of Formula (I) which is the following compound, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:
    [0735] [0735] endo-8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -3-methyl-8 - azabicycle [3.2.1] octan-3-amine.
    [0736] [0736] In one embodiment, the invention provides a compound of Formula (I) which is the following compound, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:
    [0737] [0737] 6- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} - 5-chlorine -2-methyl-3,4-dihydroquinazolin-4-one.
    [0738] [0738] In one embodiment, the invention provides a compound of Formula (I) which is the following compound, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:
    [0739] [0739] (1R, 2S, 3S, 5S) -8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3- yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-amine.
    [0740] [0740] In one embodiment, the invention provides a compound of Formula (I) which is the following compound, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:
    [0741] [0741] {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (3,4-dichloro-2 -methyl-2H- indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol.
    [0742] [0742] In one embodiment, the invention provides a compound of Formula (I) which is the following compound, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:
    [0743] [0743] {6 - [(1S, 2S, 3S, 5R) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (3,4-dichloro-2 -methyl-2H- indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol.
    [0744] [0744] In one embodiment, the invention provides a compound of Formula (I) which is the following compound, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:
    [0745] [0745] (1R, 2S, 3S, 5S) -8- [3- (5-chloro-3-methoxyquinoxalin-6-yl) -5-methyl-1H-pyrazol [3,4-b] pyrazin-6- yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-amine.
    [0746] [0746] In one embodiment, the invention provides a compound of Formula (I) which is the following compound, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:
    [0747] [0747] (6- {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -5-methyl-1H-pyrazole [3,4-b] pyrazin-3-yl} -7-chloro-1,3-benzothiazol-2-yl) methanol.
    [0748] [0748] In one embodiment, the invention provides a compound of Formula (I) which is the following compound, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:
    [0749] [0749] {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- [3- (azetidin-1- il) -5-chloroquinoxalin-6-yl] -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol.
    [0750] [0750] In one embodiment, the invention provides a compound of Formula (I) which is the following compound, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:
    [0751] [0751] {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- [7-chloro-2- ( methoxymethyl) - 1,3-benzothiazol-6-yl] -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol.
    [0752] [0752] In one embodiment, the invention provides a compound of Formula (I) which is the following compound, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:
    [0753] [0753] (1S, 2S, 3S, 5R) -8- [3- (7-chloro-2-methyl-1,3-benzothiazol-6-yl) -5-methyl-1H-pyrazole [3,4- b] pyrazin-6-yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-amine.
    [0754] [0754] For the avoidance of doubt, it should be understood that each general and specific modality and example of a substituent can be combined with each general and specific modality and example of one or more, in particular all,
    [0755] [0755] A reference to a compound of Formula (I), subgroups thereof (for example, Formulas (I), (II), (IIa), (III), (IIIa), (IIIb), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (X), (XI), (XII), (XIIa), (XIIb), (XIIc), (XIId ), (XIIe), (XIII), (XIIIa), (XIIIb), (XIIIc), (XIV), (XIVa), (XIVb), (XV), (XV *), (XVI), (XVI * ), (XVII), (XVII *), (XVII '), (XVII' *), (XVIII), (XVIII '), (XVIIIa), (XVIIIa'), (XVIII *), (XVIII '*) , (XVIIIa *) and (XVIIIa '*)) and any examples also include ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers, unless specified), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof, for example, as discussed 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), subgroups thereof (for example, Formulas (I), (II), (IIa), (III), (IIIa), (IIIb), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (X), (XI), (XII), (XIIa), (XIIb), (XIIc), (XIId ), (XIIe), (XIII), (XIIIa), (XIIIb), (XIIIc), (XIV), (XIVa), (XIVb), (XV), (XV *), (XVI), (XVI * ), (XVII), (XVII *), (XVII '), (XVII' *), (XVIII), (XVIII '), (XVIIIa), (XVIIIa'), (XVIII *), (XVIII '*) , (XVIIIa *) and (XVIIIa '*)) and any example also includes the salts or tautomers or solvates thereof. SALES
    [0756] [0756] Many compounds of Formula (I) can 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 the compounds of Formula (I) include the salt forms of the compounds.
    [0757] [0757] The salts of the present invention can be synthesized from the original compound containing a basic or acidic part by conventional chemical methods, such as 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, these salts can be prepared by reacting the acid or base free forms of these compounds with the base or acid appropriate in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are used.
    [0758] [0758] Acid addition salts (mono- or di-salts) can be formed with a wide variety of acids, inorganic and organic. Examples of acid addition salts include mono- or di-salts formed with an acid selected from acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic acid (eg, L-ascorbic), L-aspartic, benzenesulfonic, benzoic , 4-acetamidobenzoic, butanoic, (+) camphoric, camphor sulfonic, (+) - (1S) - camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclical, dodecyl sulfuric, ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic,
    [0759] [0759] A particular group of salts consists of salts formed of acetic, hydrochloric, hydroiodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isionionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic, methanesulfonic, methanesulfonic (mesylate) , naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic. One salt in particular is the hydrochloride salt.
    [0760] [0760] In one embodiment, the compound is the mesylate or sodium salt.
    [0761] [0761] If the compound is anionic, or has a functional group that can be anionic (for example, -COOH can be -COO-), then a salt can be formed with an organic or inorganic base, generating a suitable cation. Examples of suitable inorganic cations include, without limitation,
    [0762] [0762] 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 the skilled person. Such quaternary ammonium compounds are within the scope of Formula (I).
    [0763] [0763] The compounds of the invention can exist as mono- or di-salts, depending on the pKa of the acid from which the salt is formed.
    [0764] [0764] The salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pages 1 to 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 can be useful, for example, in the purification or separation of the compounds of the invention, are also part of the invention.
    [0765] [0765] In one embodiment of the invention, a pharmaceutical composition is provided which comprises a solution (for example, 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
    [0766] [0766] The compounds of Formula (I) containing an amine function can also form N-oxides. A reference here to a compound of Formula (I) that contains an amine function also includes N-oxide.
    [0767] [0767] When a compound contains several amine functions, one, or more than one, the nitrogen atom 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 heterocyclic group.
    [0768] [0768] N-oxides can be formed by treating the corresponding amine with an oxidizing agent, such as hydrogen peroxide or a per-acid (eg, peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March , 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be produced by the LW Deady procedure (Syn. Comm. 1977, 7, 509 to 514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in a inert solvent, such as dichloromethane.
    [0769] [0769] 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, an N-oxide of pyridine. GEOMETRIC ISOMERS AND TAUTOMERS
    [0770] [0770] The compounds of Formula (I) can exist in several different isomeric and tautomeric geometric forms and references to the compounds of Formula (I) include all of these forms. For the avoidance of doubt, where a compound can exist in one of several isomeric or tautomeric geometric shapes and only one is specifically described or shown, all others are, however, adopted by Formula (I).
    [0771] [0771] For example, certain heteroaryl rings can exist in the two tautomeric forms, such as A and B shown below. For the sake of simplicity, a formula can illustrate one form, but the formula must be adopted as covering both tautomeric forms. The OH N N N N NH N H H
    [0772] [0772] Other examples of tautomeric forms include, for example, keto, enol and enolate forms, such as, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / enediamines, nitrous / oxime, thiocetone / enethiol and nitro / aci-nitro. STEREOISOMERS
    [0773] [0773] Unless mentioned or indicated otherwise, the chemical designation of the compounds denotes the mixture in all possible stereochemically isomeric forms.
    [0774] [0774] Stereocenters are illustrated in the usual way, using lines with 'hash' or 'solid' wedges, for example.
    [0775] [0775] When 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.
    [0776] [0776] 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 their optical isomeric forms (for example, enantiomers , epimers and diastereoisomers), as individual optical isomers, or mixtures (for example, racemic or scalemic mixtures) or two or more optical isomers, unless the context requires otherwise.
    [0777] [0777] Optical isomers can be characterized and identified by their optical activity (that is, as isomers + and -, or del) or they can be characterized in terms of their absolute stereochemistry using the nomenclature "R and S" developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, New York, 1992, pages 109 to 114, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385 to 415.
    [0778] [0778] Optical isomers can be separated by several techniques, including chiral chromatography (chromatography on a chiral support) and these techniques are well known to the person skilled in the art.
    [0779] [0779] 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- tartaric acid (+) - mandelic, (-) - malic acid and (-) - camphor sulfonic acid, separating the diastereoisomers by preferential crystallization and then dissociating the salts to yield the individual enantiomer from the free base.
    [0780] [0780] Additionally, enantiomeric separation can be achieved by covalently attaching an enantiomerically pure chiral auxiliary to the compound and then performing diastereomeric separation using conventional methods, such as chromatography. This is then followed by the cleavage of the aforementioned covalent bond to generate the appropriate enantiomerically pure product.
    [0781] [0781] When the compounds of Formula (I) exist as two or more optical isomeric forms, an enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Thus, in certain circumstances, it may be desirable to use as a therapeutic agent only one of a pair of enantiomers or just one of a plurality of diastereoisomers.
    [0782] [0782] Consequently, the invention provides compositions containing a compound of Formula (I) that has one or more chiral centers, in which at least 55% (for example, at least 60%, 65%, 70%, 75%, 80 %, 85%, 90% or 95%) of the compound of Formula (I) is present as a single optical isomer (for example, enantiomer or diastereoisomer). In a general embodiment, 99% or more (for example, substantially all) of the total amount of the compound of Formula (I) can be present as a single optical isomer (for example, enantiomer or diastereoisomer).
    [0783] [0783] Compounds that encompass double bonds can have an E (entgegen) or Z (zusammen) stereochemistry on said double bond. Substituents in bivalent or (partially) saturated cyclic radicals can have either the cis or trans configuration. The terms cis and trans, when used here, are in accordance with Chemical Abstracts nomenclature (J. Org. Chem. 1970, 35 (9), 2,849 to 2,867), and refer to the position of the substituents on a part of the ring .
    [0784] [0784] Of particular interest are compounds of Formula (I) that are stereochemically pure. When a compound of Formula (I) is, for example, specified as R, this means that the compound is substantially free of the S isomer. If a compound of Formula (I) is, for example, specified as E, it means that the The compound is substantially free of the Z isomer. The terms cis, trans, R, S, EZ are well known to those skilled in the art. ISOTOPIC VARIATIONS
    [0785] [0785] The present invention includes all the pharmaceutically acceptable isotopically labeled compounds of the invention, that is, compounds of Formula (I), in which one or more atoms are replaced by atoms with the same atomic number, but an atomic mass or number of mass other than atomic mass or mass number normally found in nature.
    [0786] [0786] Examples of suitable isotopes for inclusion in the compounds of the invention comprise hydrogen isotopes, such as 2H (D) and 3H (T), carbon, as 11C, 13C and 14C, chlorine, as 36Cl, fluorine, as 18F, iodine, like 123I, 125I and 131I, nitrogen like 13N and 15N, oxygen like 15O, 17O and 18O, phosphorus like 32P, and sulfur like 35S.
    [0787] [0787] Certain isotopically labeled compounds of Formula (I), for example, those that incorporate a radioactive isotope, are useful in studies of the distribution of drugs and / or substrates in tissues. The compounds of Formula (I) can also have valuable diagnostic properties, in that they can be used to detect or identify the formation of a complex between a labeled compound and other molecules, peptides, proteins, enzymes or receptors. Detection or identification methods can use compounds labeled with labeling agents, such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase), etc. The radioactive isotopes tritium, that is, 3H (T) and carbon-14,
    [0788] [0788] Substitution by heavier isotopes, such as deuterium, that is, 2H (D), may provide certain therapeutic advantages resulting from increased metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore, it can be used in some circumstances.
    [0789] [0789] In particular, all references to hydrogen in the application must be constructed to cover 1H and 2H, regardless of whether hydrogen is defined explicitly or whether it is present implicitly to satisfy the valency of the relevant atom (in particular, carbon).
    [0790] [0790] Substitution by positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in positron emission topography (PET) studies to examine target occupation.
    [0791] [0791] 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 attached Examples and Preparations, using appropriate isotopically labeled reagents in place of the unlabeled reagent previously employed. ESTERS
    [0792] [0792] Esters such as carboxylic acid esters, acyloxy esters and phosphate esters of the compounds of Formula (I) carrying a carboxylic acid group or a hydroxyl group are also covered by
    [0793] [0793] In one embodiment of the invention, Formula (I) includes within its scope esters 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 CRYSTALLINE FORMS
    [0794] [0794] Also covered by Formula (I) are any polymorphic forms of the compounds and solvates, such as hydrates, alcoholates and the like.
    [0795] [0795] The compounds of the invention can form solvates, for example, with water (i.e., 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.
    [0796] [0796] Solvates are well known in pharmaceutical chemistry. They can be important for the preparation processes of a substance (for example, in relation to its purification, storage of the substance (for example, its stability) and ease of handling of the substance and are usually formed as part of the isolation stages or purification of a chemical synthesis One skilled in the art can determine by means of standard and long-term techniques whether a hydrate or other solvate has been formed by the isolation conditions or purification conditions used to prepare a particular compound. Examples of these techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (for example, single-crystal X-ray crystallography or X-ray powder diffraction) and solid-state NMR (SS-NMR, also known such as magic angle rotation NMR or MAS-NMR). These techniques are part of the standard analytical tool set of the qualified chemist such as NMR, IR, HPLC and MS.
    [0797] [0797] Alternatively, the person skilled in the art can deliberately form a solvate using crystallization conditions that include an amount of the solvent needed for the specific solvate. After that, the standard methods described here, can be used to establish whether solvates have formed.
    [0798] [0798] In addition, the compounds of the present invention can have one or more polymorphic or amorphous crystalline forms and, as such, should be included in the scope of the invention. COMPLEXES
    [0799] [0799] Formula (I) also includes within its scope complexes (for example, inclusion complexes or clathrates with compounds such as cyclodextrins or complexes with metals) of the compounds. Inclusion complexes, clathrates and metal complexes can be formed using methods well known to those skilled in the art. PRO-DRUGS
    [0800] [0800] Also covered 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).
    [0801] [0801] For example, some prodrugs are esters of the active compound (for example, a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C (= O) OR) is cleaved to produce the active drug. These esters can be formed by esterification, for example, of any of the carboxylic acid groups (-C (= O) OH) in the original compound, with, where appropriate, prior protection from any other reactive group present in the original compound, followed by deprotection if necessary.
    [0802] [0802] Examples of such metabolically labile esters include those of the Formula -C (= O) OR, where R is:
    [0803] [0803] C1-7alkyl (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);
    [0804] [0804] C1-7aminoalkyl (e.g., aminoethyl; 2- (N, N-diethylamino) ethyl; 2- (4-morpholino) ethyl); and acyloxy-C1-7alkyl (e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1- (1-methoxy-1-methyl) ethyl-carbonxyloxyethyl; 1- (benzoyloxy) ethyl; isopropoxy-carbonyloxymethyl; isopropoxycarbonyloxyethyl; cyclohexylcarbonyloxymethyl; 1-cyclohexylcarbonyloxyethyl; cyclohexyloxycarbonyloxymethyl; 1-cyclohexyloxycarbonyloxyethyl; (4-oxanyloxy) carbonyloxymethyl; 1- (4-oxanyloxy) carbonyloxyethyl; (4-tetrahydropyranyl) carbonyloxyethyl).
    [0805] [0805] In addition, some prodrugs are activated enzymatically to produce the active compound, or a compound that, after additional chemical reaction, produces the active compound (for example, as in antigen-directed enzyme prodrug therapy (ADEPT) , enzyme-directed enzyme prodrug therapy (GDEPT) and ligand-driven enzyme prodrug therapy (LIDEPT), etc.). For example, the prodrug can be a sugar derivative or other glycoside conjugate, or it can 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)
    [0806] [0806] 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), (II), (IIa), (III), (IIIa), (IIIb), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (X), (XI ), (XII), (XIIa), (XIIb), (XIIc), (XIId), (XIIe), (XIII), (XIIIa), (XIIIb), (XIIIc), (XIV), (XIVa), (XIVb), (XV), (XV *), (XVI), (XVI *), (XVII), (XVII *), (XVII '), (XVII' *), (XVIII), (XVIII ') , (XVIIIa), (XVIIIa '), (XVIII *), (XVIII' *), (XVIIIa *) and (XVIIIa '*)) and examples thereof, as defined herein, unless the context indicates otherwise.
    [0807] [0807] The compounds of Formula (I) can be prepared according to synthetic methods well known to those skilled in the art.
    [0808] [0808] According to a further aspect of the invention, a process is provided for preparing a compound of Formula (I), or a tautomer, stereoisomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof, which comprises:
    [0809] [0809] (a) coupling a compound of Formula (A) or a protected derivative thereof:
    [0810] [0810] where R1, R2, R3, R4, R5, R6, R7, Q, X, a, b, are as previously defined for the compounds of Formula (I), and P represents a protecting group (such as 2 - (trimethylsilyl) ethoxymethyl; SEM) or is hydrogen, and Z is a metal residue (such as zinc halide, for example, zinc chloride) or an leaving group (such as a halogen, for example, iodine or bromine)
    [0811] [0811] with a compound of Formula (B) or a protected version of it (B)
    [0812] [0812] where R8, R9, R10, A, c, are as defined above for the compounds of Formula (I) and V represents a metal or metalloid residue (such as boronic acid, pinacol boracate, magnesium halide or halide zinc, for example, boronic acid, pinacol boronate) or a leaving group, such as halogen,
    [0813] [0813] followed by an adequate deprotection reaction to remove the protection groups;
    [0814] [0814] (b) couple a compound of Formula (C) or a protected derivative thereof: (C)
    [0815] [0815] where R8, R9, R10, A, c, are as previously defined for the compounds of Formula (I), X is CH, P represents a protecting group (such as 2- (trimethylsilyl) ethoxymethyl; SEM) or is hydrogen, L is leaving group (like chloride),
    [0816] [0816] with a compound of Formula (D) or a protected derivative thereof, wherein R2, R3, R4, R5, R6, R7, Q, a, b, are as previously defined for the compounds of Formula (I) . (D)
    [0817] [0817] (c) reacting a compound of Formula (K) or a protected derivative thereof, (K)
    [0818] [0818] wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, Q, a, b and c are as defined herein for the compound of Formula (I), P represents an amine protecting group (such as 2- (trimethylsilyl) ethoxymethyl; SEM), N, N-dimethylsulfamoyl or hydrogen, L3 is leaving group (such as halogen, for example, bromine) or:
    [0819] [0819] (i) with an organometallic species of Formula CH3M, where M is a metal (for example, CH3-Zn-Hal, where Hal is halogen, for example, chloride, bromide or iodide) in the presence of a catalyst metal (such as (1,3-diisopropylimidazol-2-ylidene) (3-
    [0820] [0820] (ii) with an alkyl boronate (such as potassium (2-trimethylsilyl) -ethoxymethyl trifluoroborate) in the presence of a photoredox catalyst (such as [Ir {dFCF3ppy} 2 (bpy)] PF6), a metal catalyst (as a dimethyl ether glycol complex of nickel (II) chloride), a binder (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 render a compound of Formula (I), where R1 is -CH2OH;
    [0821] [0821] (d) cyclization of a compound of Formula (R), or a protected derivative thereof; (R)
    [0822] [0822] where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Q, a, b, c, A, are as previously defined for the compounds of Formula (I) and L1 a suitable leaving group, such as a halogen, with the use of hydrazine or a protected hydrazine derivative;
    [0823] [0823] in each case, optionally followed by a deprotection step; or
    [0824] [0824] (e) deprotection of a protected derivative of a compound of Formula (I); or
    [0825] [0825] (f) interconversion of a compound of Formula (I) or protected derivative thereof into an additional compound of Formula (I) or protected derivative thereof; or
    [0826] [0826] (g) optionally forming a pharmaceutically acceptable salt of a compound of Formula (I). PREPARATIVE METHODS (A), (B), (C) E (D)
    [0827] [0827] The compounds of Formula (B) were available commercially or are prepared using methods analogous to those described in the examples, for example, the compounds of Formula (B), where V is a boronate residue, are used directly in a single vessel procedure as in general procedure 3 or isolated in a manner similar to the boronates listed in Table 2 and used directly in the reaction as in general procedure 2 (Table 2).
    [0828] [0828] 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 (II) dichloride. Examples of suitable solvents are 1,2-dimethoxyethane or tetrahydrofuran.
    [0829] [0829] When Z is a metallic residue, such as zinc halide, the process typically comprises the reaction of a compound of Formula (A) with a compound of Formula (B) in which V is an leaving group, such as a halogen . Typically, compounds of Formula (A) in which Z is a leaving group, such as a halogen dissolved in a suitable solvent, such as tetrahydrofuran, are treated with a reagent, such as a complex solution of isopropylmagnesium chloride, lithium chloride , for an appropriate time,
    [0830] [0830] The compounds of Formula (D) or protected derivatives thereof are obtained from commercially available starting materials, prepared from procedures in the literature or using methods indicated in the examples described in this application or methods analogous to them .
    [0831] [0831] The compounds of Formula (C) or a protected derivative thereof, in particular where R1 is hydrogen and X is CH, can be obtained by reacting a compound of Formula (E): (E)
    [0832] [0832] Where X is as defined hereinbefore for the compounds of Formula (I) and P represents a suitable amine protecting group (such as 2-
    [0833] [0833] The compounds of Formula (E) are obtained from commercially available starting materials, prepared from procedures in the literature or using methods indicated in the examples described in this patent or analogous methods.
    [0834] [0834] The 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 protected derivative thereof, with the use of a suitable base, such as diisopropylethylamine, in a suitable solvent, such as dimethylsulfoxide or N-methyl-2-pyrrolidinone, at an appropriate temperature, such as 150 ° C.
    [0835] [0835] The compounds of Formula (A) or protected derivatives thereof can be obtained from compounds of Formula (F) while X is CH or protected derivatives thereof (F)
    [0836] [0836] wherein R2, R3, R4, R5, R6, R7, Q, X, a, b, are as defined above for the compounds of Formula (I) and P represents a suitable amine protecting group (such as 2 - (trimethylsilyl) ethoxymethyl; SEM) or is hydrogen,
    [0837] [0837] by introducing a suitable Z-leaving group, such as a halogen, for example, using a suitable halogenating reagent (such as N-iodosuccinimide) followed by an optional protection step to introduce the protection group amine P (such as 2- (trimethylsilyl) ethoxymethyl; SEM)
    [0838] [0838] The compounds of Formula (A), or protected derivatives thereof, in particular where R1 is methyl or CH2OH, can be obtained by reacting a compound of Formula (X ') or protected derivative thereof: (X' )
    [0839] [0839] Where R1 is methyl or CH2OH, P represents a protecting group (such as 2-tetrahydropyran; THP or 2- (trimethylsilyl) ethoxymethyl; SEM) or is hydrogen, and L1 and L2 independently represent starting groups (such as a halide, for example, chlorine, bromine or iodine), with a compound of Formula (D) or protected derivative thereof.
    [0840] [0840] The compounds of Formula (X '), in particular, in which R1 is CH2OH or protected derivatives thereof, can be obtained by reacting a compound of Formula (Y) or protected derivative thereof: (Y)
    [0841] [0841] 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 starting 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-carbazol-9-yl) isophthalonitrile), a peroxide reagent as a tert-butyl peracetate solution , an acid (like TFA), and light source (like a blue LED), in a solvent like DMSO. Alternatively, the reaction can be carried out with an excess of alcohol, such as methanol, in the presence of a metallic salt, such as silver (II) nitrate, a peroxide reagent, such as ammonium persulfate, an acid (such as TFA), in a solvent such as DMSO or water and a heat source (30 to 150 ºC).
    [0842] [0842] Alternatively, compounds of Formula (X '), or protected derivatives thereof, can be obtained by reacting a compound of Formula (W') or protected derivative thereof: (W ')
    [0843] [0843] where P represents a protecting group (such as 2-tetrahydropyran; THP or 2- (trimethylsilyl) ethoxymethyl; SEM) or is hydrogen, and L1 is an leaving group (such as a halogen, for example, iodine or bromine ), with a suitable halogenating agent (such as N-bromosuccinimide or N-iodosuccinimide) to introduce a leaving group such as a halogen (for example, bromine or iodine).
    [0844] [0844] The compounds of Formula (W '), or protected derivatives thereof, in which R1 is methyl, can be obtained by the reaction of a compound of
    [0845] [0845] where P represents a protecting group (such as 2-tetrahydropyran; THP or 2- (trimethylsilyl) ethoxymethyl; SEM) or is hydrogen, and L1 is an leaving group (such as a halogen, for example, iodine or bromine ), with an organometallic residue (such as a kind of organomagnesium, for example, methyl magnesium chloride).
    [0846] [0846] The compounds of Formula (Y '), or protected derivatives thereof, can be obtained by reacting a compound of Formula (Z) or protected derivative thereof: (Z)
    [0847] [0847] where X is N, P represents a protecting group (such as 2-tetrahydropyran; THP or 2- (trimethylsilyl) ethoxymethyl; SEM) or is hydrogen, and L1 is an leaving group (such as a halogen, for example , iodine or bromine), with an oxidizing agent (such as a peroxide reagent, for example, trifluoroperacetic acid).
    [0848] [0848] The compounds of Formula (F), where X = CH, or protected derivatives thereof, can be obtained by reacting a compound of Formula (G) or protected derivatives thereof (G)
    [0849] [0849] wherein R2, R3, R4, R5, R6, R7, Q, a, b, are as previously defined for the compounds of Formula (I), by intramolecular cyclization of the alkoxy vinyl ether and amine with the use of a suitable acid (such as TFA). Under such conditions, one or more protecting groups can also be removed and, therefore, the cyclization step can optionally be followed by a reprotection step, for example, with di-tert-butyl dicarbonate to yield an N-Boc derivative .
    [0850] [0850] The compounds of Formula (G) or protected derivatives thereof can be obtained by reacting a compound of Formula (H) or protected derivative thereof, (H)
    [0851] [0851] where R2, R3, R4, R5, R6, R7, Q, a and b are as previously defined for compounds of Formula (I), where Z is an leaving group (such as a halogen)
    [0852] [0852] with an alkoxy vinyl derivative, such as (E) -1-ethoxyethene-2-boronic acid pinacol ester, by means of metal catalysis (for example, with the use of palladium acetate and a suitable binder, such as 2 -dicyclohexylphosphine-2 ', 6'-dimethoxybiphenyl, i.e., Sphos and a base such as potassium phosphate). The reaction can take place in a suitable solvent or combination of solvents, such as acetonitrile and water,
    [0853] [0853] The compounds of Formula (H) or protected derivatives thereof can be obtained by reacting a compound of Formula (J): (J)
    [0854] [0854] with a compound of Formula (D) or protected derivative thereof, where, Z is an leaving group (like a halogen) and V is leaving group (like a halogen), with a suitable base (like N , N-diisopropylethylamine), in a suitable solvent (such as N-methyl-2-pyrrolidone) at an appropriate temperature (such as 120 ° C).
    [0855] [0855] The compounds of Formula (K), or protected derivatives thereof, can be obtained by reacting a compound of Formula (L) or protected derivative thereof: (L)
    [0856] [0856] wherein R4, R5, R6, R7, Q, X, a, b, are as defined above for the compounds of Formula (I), P represents an amine protecting group (such as 2- (trimethylsilyl) ethoxymethyl; SEM), N, N-dimethylsulfamoyl or is hydrogen, L2 is a leaving group (like halogen, for example, iodine), L3 is a leaving group (like halogen, for example, bromine), with a compound of Formula ( B), using procedures such as those described for (a).
    [0857] [0857] The compounds of Formula (L), or protected derivative thereof, can be obtained by reacting a compound of Formula (M): (M)
    [0858] [0858] where X is as previously defined for the compounds of Formula (I), P represents a suitable protecting group such as 2- (trimethylsilyl) ethoxymethyl (SEM) or N, N-dimethylsulfamoyl, L1 is a leaving group as chloride, L2 is a leaving group like iodine and L3 is leaving group like bromine, with a compound of Formula (D) using procedures like those described for (b).
    [0859] [0859] The compounds of Formula (M) or protected derivatives thereof, can be obtained from commercially available starting materials, prepared from literature procedures or using methods within the examples described in this patent or analogous methods .
    [0860] [0860] Alternatively, compounds of Formula (L), or protected derivatives thereof, can be obtained by reacting a compound of Formula (N) or a protected derivative thereof: (N)
    [0861] [0861] where R2, R3, R4, R5, R6, R7, Q, X, a, b, are as defined above for the compounds of Formula (I), P represents an amine protecting group (as
    [0862] [0862] The compounds of Formula (N) or protected derivatives thereof can be obtained by reacting a compound of Formula (O) or protected derivatives thereof: (O)
    [0863] [0863] wherein R2, R3, R4, R5, R6, R7, Q, X, a, b, are as defined above for the compounds of Formula (I), with a suitable halogenating agent such as N-iodosuccinimide to introduce an output group as a halogen and suitable conditions to introduce the protection group.
    [0864] [0864] The compounds of Formula (O) or protected derivatives thereof, where X is a nitrogen can be obtained by the reaction of a compound of Formula (P): (P)
    [0865] [0865] where R2, R3, R4, R5, R6, R7, Q, a, b, are as defined above for the compounds of Formula (I), L2 is a leaving group like chloride, with a hydrazine derivative suitable as hydrazine hydrate.
    [0866] [0866] The compounds of Formula (P) or protected derivatives thereof can be obtained by reacting a compound of Formula (Q): (Q)
    [0867] [0867] with a compound of Formula (D) or protected derivative thereof, where L1 and L2 are leaving groups such as chloride.
    [0868] [0868] The compounds of Formula (Q) or derivatives protected therefrom, are obtained from commercially available starting materials, or prepared from literature procedures or using methods within the examples described in this patent or analogous methods .
    [0869] [0869] The compounds of Formula (R), or protected derivatives thereof, can be obtained by reacting a compound of Formula (S) or protected derivative thereof: (S)
    [0870] [0870] where R1, R8, R9, R10, A, c, are as defined above for the compounds of Formula (I) and L1 and L2 represent a suitable leaving group, such as a halogen, with a compound of Formula ( D).
    [0871] [0871] The compounds of Formula (S), or protected derivatives thereof, can be obtained by reacting a compound of Formula (T) or protected derivative thereof: (T)
    [0872] [0872] where R1, R8, R9, R10, A, c, are as defined above for the compounds of Formula (I) and L1 and L2 represent a suitable leaving group, such as a halogen, with a suitable oxidizing reagent as manganese (IV) oxide.
    [0873] [0873] The compounds of Formula (T), or protected derivatives thereof, can be obtained by reacting a compound of Formula (U) or protected derivative thereof: (U)
    [0874] [0874] where R1 are as previously defined for the compounds of Formula (I) and L1 and L2 represent suitable leaving groups, such as a halogen, with a compound of Formula (B), where V is a metal or residue of metalloid (like a magnesium halide).
    [0875] [0875] The compounds of Formula (U), or protected derivatives thereof, can be obtained by reacting a compound of Formula (V ') or protected derivative thereof: (V')
    [0876] [0876] where R1, as defined above for the compounds of Formula (I) and L1 and L2 represent suitable leaving groups, such as a halogen, with a suitable oxidizing reagent such as Dess-Martin periodinane.
    [0877] [0877] The compounds of Formula (V), or protected derivatives thereof, can be obtained by reacting a compound of Formula (W) or protected derivative thereof: (W)
    [0878] [0878] where R1, as previously defined for the compounds of Formula (I) and L1 and L2 represents 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-carbazol-9-yl) isophthalonitrile), a peroxide reagent as a tert-butyl peracetate solution, an acid (such as TFA), and a light source (such as a blue LED) , in a solvent like DMSO.
    [0879] [0879] The compounds of Formula (W) or derivatives protected therefrom, are obtained from commercially available starting materials, or prepared from literature procedures or using methods within the examples described in this patent or analogous methods .
    [0880] [0880] The compounds of Formula (T), or protected derivatives thereof, can also be obtained by reacting a compound of Formula (Z ') or protected derivative thereof: (Z ’)
    [0881] [0881] wherein R8, R9, R10, A, c are as defined above 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 2,2,6,6-tetramethylpiperidinylmagnesium chloride complex solution, lithium chloride, for an appropriate time, such as 2.5 h, to complete the metallization. The newly formed organomagnesium species are treated with a compound of Formula (Z ') and allowed to warm up, for example, to room temperature and stirred for a suitable time, such as 18 h.
    [0882] [0882] The compounds of Formula (Z ') or protected derivatives thereof, are prepared using methods within the examples described in this patent or analogous methods. DEPROTECTION OF A PROTECTED DERIVATIVE FROM A COMPOUND OF FORMULA (I)
    [0883] [0883] Process (e) typically comprises any suitable deprotection reaction, the conditions of which will depend on the nature of the protection group. When the protecting group P represents SEM, this deprotection reaction typically comprises the use of a suitable acid in a suitable solvent, followed by the removal of the hydroxymethyl adduct formed during the acid deprotection of the SEM protection 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, for example, water and methanol can be used. The second step involves concentration in a vacuum, followed by dissolving the crude material in a suitable solvent such as methanol and treatment with a suitable disposal reagent such as ethylenediamine in a suitable solvent such as methanol.
    [0884] [0884] Where the protecting group is an N, N-dimethylsulfamoyl group (SO2NMe2), a stronger acid, such as trifluoromethanesulfonic acid, can be used at an appropriate temperature.
    [0885] [0885] Deprotection can be performed according to the procedures described here as general procedures for the preparation of compounds of Formula (I), Methods 1 to 12. FORMATION OF A PHARMACEUTICALLY ACCEPTED SALT FROM A COMPOUND OF FORMULA (I)
    [0886] [0886] Salt formation can be carried out by treating a compound of Formula (I) in the form of free base, dissolved in a suitable solvent, with a stoichiometric amount or an excess of pharmaceutically acceptable organic or inorganic acid, then isolation of the resulting salt by methods well known in the art, for example, evaporation of the solvent or crystallization. GENERAL
    [0887] [0887] 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 appropriate order to achieve the necessary 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:
    [0888] [0888] protection of reactive functions,
    [0889] [0889] deprotection of reactive functions,
    [0890] [0890] halogenation,
    [0891] [0891] dehalogenation,
    [0892] [0892] dealkylation,
    [0893] [0893] alkylation and arylation of amine, aniline, alcohol and phenol,
    [0894] [0894] Mitsunobu reaction in hydroxyl groups,
    [0895] [0895] cicloaddition reactions in appropriate groups,
    [0896] [0896] reduction of nitro, esters, cyan, aldehydes,
    [0897] [0897] transition metal catalyzed coupling reactions,
    [0898] [0898] acylation,
    [0899] [0899] sulfonylation / introduction of sulfonyl groups,
    [0900] [0900] saponification / hydrolysis of ester groups,
    [0901] [0901] amidification or transesterification of ester groups,
    [0902] [0902] esterification or amidification of carboxylic groups,
    [0903] [0903] halogen exchange,
    [0904] [0904] nucleophilic substitution by amine, thiol or alcohol,
    [0905] [0905] reducing amination,
    [0906] [0906] formation of oxime in carbonyl and hydroxylamine groups,
    [0907] [0907] S-oxidation,
    [0908] [0908] N-oxidation, and
    [0909] [0909] salification.
    [0910] [0910] A wide range of well-known functional group interconversions are known to one skilled in the art for converting a precursor compound to a Formula I compound and are described in Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons,
    [0911] [0911] In many of the reactions described above, it may be necessary to protect one or more groups to prevent the reaction from occurring at an undesirable location in the molecule. Examples of protection groups and methods of protecting and deprotecting functional groups can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).
    [0912] [0912] 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 tetra- ether
    [0913] [0913] 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) it 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.
    [0914] [0914] An amine group can be protected, for example, as an amide (-NRCO-R) or a carbamate (-NRCO-OR), for example, as: a methyl amide (-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 (-NHCO-OC (CH3) 2C6H4C6H5, -NH-Bpoc), like a 9-fluorenylmethyl carbamate (-NH-Fmoc), like a 6-nitroveratryl carbamate (-NH-Nvoc) , 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) ethyl carbamate (-NH-Psec).
    [0915] [0915] For example, in the compounds of Formula I contains an amino group, the amino group can be protected by means of a protecting group as defined above, a preferred group is the tert-butyloxycarbonyl group (Boc) while the additional functionality is introduced. When no subsequent modification of the amino group is necessary, the protecting group can be carried out through the reaction sequence to give an N-protected form of a compound of the
    [0916] [0916] Other amine protection groups, such as cyclic amines and heterocyclic NH groups, include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl) groups, benzyl groups, such as a para-methoxybenzyl (PMB) and tetrahydropyranyl (THP) groups .
    [0917] [0917] A carboxylic 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 triC1-7 alkylsilyl-C1-7alkyl ester; or a C5-20 aryl-C1-7 alkyl ester (eg, 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-CH2 NHC (= O) CH3). INSULATION AND PURIFICATION OF THE COMPOUNDS OF THE INVENTION
    [0918] [0918] 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 technique of particular utility in the purification of compounds is preparative liquid chromatography with the use of mass spectrometry as a means of detecting the purified compounds that emerge from the chromatography column.
    [0919] [0919] The preparative LC-MS is a standard and effective method used for the purification of small organic molecules, such as the compounds described here. The 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. The optimization of the preparative gradient LC method will involve variable columns, eluents and volatile modifiers and gradients. Methods for optimizing preparative LC-MS methods and then using them to purify compounds are well known in the art. 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 libraries; J Comb Chem .; 2003; 5 (3); 322-9. An example of such a system for the purification of compounds via preparative LC-MS is described below in the Examples section of this application (under the heading “LC-MS Mass Directed Purification System”).
    [0920] [0920] Methods of recrystallization of compounds of Formula (I) and salt thereof can be performed 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, Publisher Wiley-VCH). 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.
    [0921] [0921] Other examples of methods for purification include sublimation, which includes a heating step under vacuum, for example, with the use of a cold finger, and crystallization by fusion (Crystallization Technology Handbook 2nd Edition, edited by A. Mersmann, 2001 ). BIOLOGICAL EFFECTS
    [0922] [0922] The compound of the invention is expected to be useful in medications or therapy. The compounds of the invention, subgroups and examples thereof, have been shown to inhibit SHP2. This inhibition leads to inhibition of tumor cell proliferation and activation of T cell immune responses against cancer cells, which can be useful in preventing or treating disease states or conditions described herein, for example, 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. Thus, for example, compounds of the invention are expected to be useful in alleviating or reducing the incidence of cancer, preventing or treating SHP2-mediated diseases or conditions, for example, diseases or conditions such as cancers in which activating mutations exist within the components upstream (such as RAS, KRAS and NRAS) from the MAPK pathway or cancers activated by the tyrosine kinase receptor (RTK). The compounds of the present invention can be useful for the treatment of the adult population. The compounds of the present invention can be useful for the treatment of the pediatric population.
    [0923] [0923] The compounds of the present invention have been shown to be good inhibitors of SHP2. The compounds of Formula (I) have the ability to bind SHP2 and exhibit potency for SHP2. The efficacies of the compounds of the present invention were determined against SHP2 using the test protocol described herein and other methods known in the art. More particularly, the compounds of Formula (I) and subgroups thereof have potency for SHP2.
    [0924] [0924] Certain compounds of the invention are those with IC 50 values less than 0.1 µM, in particular less than 0.01 or 0.001 µM.
    [0925] [0925] The SHP2 function has been implicated in many diseases due to its role in cell survival and proliferation, mainly by activating the RAS-ERK signaling pathway, as well as in oncogenesis. As a consequence of their affinity for SHP2, the compounds are expected to be useful in the treatment or prevention of a variety of diseases or conditions, including disorders associated with cell accumulation (eg cancer, autoimmune disorders, inflammation and restenosis), disorders resulting in excessive apoptosis in cell loss (eg, stroke, heart failure, neurodegeneration, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, AIDS, ischemia (stroke, heart attack) myocardium) and osteoporosis or treatment of autoimmune diseases, such as multiple sclerosis (MS).
    [0926] [0926] Therefore, it is also envisaged that the compounds of the invention, as defined herein, may be useful in the treatment of other conditions, such as inflammation,
    [0927] [0927] As a result of their activity against SHP2, it is anticipated that the compounds may be useful in the treatment or prevention of proliferative disorders, such as cancers.
    [0928] [0928] Examples of cancers (and their benign counterparts) that can be treated (or inhibited) include, without limitation, tumors of epithelial origin (adenomas and carcinomas of various types, including adenocarcinomas, squamous carcinomas, transition cell carcinomas and others 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 and biliary system, exocrine pancreas, kidney (for example, renal cell carcinoma), lung (for example, adenocarcinomas, small cell carcinomas, non-small cell carcinomas, bronchialveolar carcinomas and mesotheliomas), head and neck (for example, cancer of the tongue, cavity buccal, larynx, pharynx, nasopharynx, amygdala, salivary glands, nasal cavity and paranasal sinuses), ovary, fallopian tubes, peritoneum, vagina, vulva, penis, testicles, cervix uterus, myometrium, etrium extremity, thyroid (for example, follicular carcinoma of the thyroid), brain, adrenal, prostate, skin and appendages (for example, melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacantoma, dysplastic nevus); haematological malignancies (ie, leukemias, lymphomas) and premalignant haematological diseases and borderline malignancies, including haematological diseases and conditions related to the lymphoid lineage (eg, acute lymphocytic leukemia [ALL], acute lymphocytic leukemia [ALL], leukemia chronic lymphocytic [CLL]), B cell lymphomas such as diffuse large B cell lymphoma [DLBCL], follicular lymphoma, Burkitt's lymphoma, mantle cell lymphoma, T cell lymphoma and leukemia, natural cell lymphoma [NK], Hodgkin's lymphomas, hairy cell leukemia, monoclonal gammopathy of uncertain significance, plasmacytoma, multiple myeloma and post-transplant lymphoproliferative disorders) and hematological diseases and conditions related to myeloid lineage (eg, acute myeloid leukemia [AML], chronic myeloid leukemia [ CML], chronic myelomonocytic leukemia [CML], hypereosinophilic syndrome, myeloproliferative disorders, such as polycythemia vera, thrombocythemia primary and myelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome and promyelocytic leukemia); tumors of mesenchymal origin, for example, soft tissue sarcomas, bones or cartilage, such as osteosarcomas, fibrosarcomas, chondrosarcomas, rhabdomyosarcomas, leiomyosarcomas, liposarcomas, angiosarcomas, Kaposi's sarcoma, Ewing's sarcoma, synovial sarcomas, and synovial sarcomas, ; 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, adrenals, islet cells, parathyroid tumors, carcinoid tumors and medullary thyroid carcinoma); ocular and adnexal tumors (for example, retinoblastoma); germ cells and trophoblastic tumors (for example, teratomas, seminomas, dysgerminomas, hydatiform moles and choriocarcinomas); and pediatric and embryonic tumors (for example, medulloblastoma, neuroblastoma, Wilms' tumor and primitive neuroectodermal tumors); or syndromes, congenital or not, that make the patient susceptible to malignancy (for example, Xeroderma Pigmentoso).
    [0929] [0929] Cell growth is a closely controlled function. Cancer, a condition of abnormal cell growth, results when cells replicate in an uncontrolled manner (increasing in number), grow uncontrollably (getting larger) and / or experience reduced cell death due to apoptosis (programmed cell death), necrosis or anatomy. In one embodiment, abnormal cell growth is selected from uncontrolled cell proliferation, excessive cell growth or reduced programmed cell death. In particular, the condition or disease of abnormal cell growth is cancer.
    [0930] [0930] Thus, in the pharmaceutical compositions, uses or methods of this invention for the treatment of a disease or condition comprising abnormal cell growth (i.e., uncontrolled and / or rapid cell growth), the disease or condition comprising abnormal cell growth in one modality it is cancer.
    [0931] [0931] The compounds of the invention may be useful in the treatment of metastases 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 by the compounds of the invention include primary tumors (i.e., cancer cells at the site of origin), local invasion (cancer cells that penetrate and infiltrate normal surrounding tissues in the local area) and metastatic (or secondary) tumors , that is, tumors that were formed from malignant cells that circulated through the bloodstream (hematogenous dissemination) or via the lymphatics or through the body cavities (transcelelomics) to other sites and tissues of the body. In particular, the compounds of the invention may be useful in the treatment of metastases and metastatic cancers.
    [0932] [0932] In one embodiment, hematological neoplasms are leukemia. In another modality, hematological neoplasms are lymphoma. In one embodiment, cancer is AML. In another modality, cancer is CLL.
    [0933] [0933] 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), 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 large B-cell lymphoma.
    [0934] [0934] 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).
    [0935] [0935] Cancers can be cancers sensitive to treatment with SHP2 inhibitors. Cancers may be those that overexpress SHP2. The cancer may be a wild type SHP2 cancer. The cancer may be a cancer that is SHP2 mutant. In one embodiment, cancer has activating mutations in SHP2.
    [0936] [0936] Particular cancers include hepatocellular carcinoma, melanoma, esophageal, renal, colon, colorectal, lung, for example, NSCLC, mesothelioma or lung adenocarcinoma, breast, bladder, gastrointestinal, ovary and prostate cancer.
    [0937] [0937] Particular cancers include those with activated SHP2 (activating mutations, amplified wild-type overexpression and / or SHP2), for example, hepatocellular carcinoma, breast, lung, colorectal and neuroblastoma.
    [0938] [0938] Specific cancers include those with oncogenic changes in the RAS-RAF-MEK-ERK pathway, including mutant forms of KRAS.
    [0939] [0939] Specific cancers include those in which RTK activity generates disease or resistance to cancer therapies.
    [0940] [0940] The compounds of the invention will be particularly useful in the treatment or prevention of cancers of an associated type or characterized by the presence of high Ras, BRAF and / or MEK signaling.
    [0941] [0941] Elevated levels of Ras, BRAF or MEK signaling are found in many cancers and are associated with a poor prognosis. In addition, cancers with the activation of Ras mutations may also be sensitive to an SHP2 inhibitor. The high levels of Ras signaling and Ras mutations can be identified by the techniques described here.
    [0942] [0942] Another subset of cancers consists of NRas melanoma and NRas AML.
    [0943] [0943] Another subset of cancers consists of KRas lung cancer, KRas pancreatic cancer and KRas colorectal cancer.
    [0944] [0944] In one embodiment, the cancer is colorectal, breast, lung and brain.
    [0945] [0945] In one embodiment, cancer is pediatric cancer.
    [0946] [0946] In one embodiment, cancer is breast cancer, leukemia, lung cancer, liver cancer, gastric cancer, laryngeal cancer or mouth cancer.
    [0947] [0947] If a particular cancer is sensitive to SHP2 inhibitors, it can be determined by a method as set out in the "Diagnostic methods" section.
    [0948] [0948] Another 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.
    [0949] [0949] Certain cancers are resistant to treatment with specific drugs. This may be due to the type of tumor (the most common epithelial neoplasms are inherently chemoresistant and the prostate is relatively resistant to the currently available chemotherapy or radiotherapy regimens) or resistance may appear spontaneously as the disease progresses or as a result of treatment. In this regard, references to the prostate include prostate with resistance to anti-androgenic therapy, in particular abiraterone or enzalutamide, or prostate resistant to castration. Similarly, references to multiple myeloma include multiple myeloma insensitive to bortezomib or refractory multiple myeloma and references to chronic myeloid leukemia include chronic myeloid leukemia insensitive to imitanib and refractory chronic myeloid leukemia. In this respect, references to mesothelioma include mesothelioma with resistance to topoisomerase poisons, alkylating agents, antitubulins, antifolates, platinum compounds and radiation therapy, in particular cisplatin-resistant mesothelioma. References to melanoma include melanomas resistant to treatment with BRAF and / or MEK inhibitors.
    [0950] [0950] The compounds may also be useful in the treatment of tumor growth, pathogenesis, resistance to chemotherapy and radiotherapy, sensitizing cells to chemotherapy and as an antimetastatic agent.
    [0951] [0951] Anti-cancer therapeutic interventions of all types necessarily increase the stress imposed on target tumor cells. SHP2 inhibitors represent a class of chemotherapeutic drugs with the potential to: (i) sensitize malignant cells to drugs and / or anticancer treatments; (ii) alleviate or reduce the incidence of resistance to drugs and / or anticancer treatments; (iii) reversing resistance to drugs and / or anticancer treatments; (iv) enhance the activity of drugs and / or anti-cancer treatments; (v) delay or prevent the appearance of resistance to drugs and / or anticancer treatments.
    [0952] [0952] In one embodiment, the invention provides a compound for use in the treatment of a disease or condition that is mediated by SHP2. In another embodiment, the disease or condition that is mediated by SHP2 is a cancer that is characterized by overexpression and / or increased SHP2 activity.
    [0953] [0953] Another 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.
    [0954] [0954] In one embodiment, a compound is provided for use in the prophylaxis or treatment of an SHP2-mediated disease or condition.
    [0955] [0955] 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, a compound is provided as defined herein.
    [0956] [0956] In one embodiment, a method for the prophylaxis or treatment of cancer is provided that comprises the steps of administering to a mammal a drug that comprises at least one compound, as defined. DIAGNOSTIC METHODS
    [0957] [0957] Before administering a compound of Formula (I), a patient can be scanned to determine whether a disease or condition from which the patient is or may be suffering is one that would be susceptible to treatment with a compound that inhibits SHP2 . The term "patient" includes human and veterinary individuals, such as primates, in particular human patients.
    [0958] [0958] 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 is or may be suffering from is one characterized by a genetic abnormality or abnormal protein expression that leads to the positive regulation of SHP2 levels or positive regulation of a biochemical pathway downstream of SHP2.
    [0959] [0959] Examples of such abnormalities that result in the activation or sensitization of SHP2, loss or inhibition of regulatory pathways that affect the expression of SHP2, positive regulation of receptors or their ligands, cytogenetic aberrations or the presence of mutant variants of receptors or ligands. Tumors with positive regulation of SHP2, in particular overexpression or SHP2 activating mutants, or include activating mutations in a Ras isoform, such as KRAS, may be particularly sensitive to SHP2 inhibitors.
    [0960] [0960] Ras mutations have been detected in cell lines and primary tumors, including, without limitation, melanoma, colorectal cancer, non-small cell lung cancer and pancreatic, prostate,
    [0961] [0961] The term positive regulation includes high expression or overexpression, including amplification of genes (ie, multiple copies of genes), cytogenetic aberration and increased expression by a transcriptional or post-translational effect. Thus, the patient can undergo a diagnostic test to detect a marker characteristic of positive regulation of SHP2. The term diagnosis includes screening. Per marker, genetic markers are included, including, for example, measuring the composition of DNA to identify amplifying SHP2 or the presence of mutations in SHP2, or to identify the presence of mutations in Ras (for example, KRAS). The term marker also includes markers that are characteristic of the positive regulation of SHP2, including protein levels, protein status and mRNA levels of the proteins mentioned above. Gene amplification includes more than 7 copies, as well as gains between 2 and 7 copies.
    [0962] [0962] Diagnostic assays for detecting mutations in KRAS are described in de Castro et al. Br. J. Cancer. July 10, 2012; 107 (2): 345-51. It hurts:
    [0963] [0963] Tests and diagnostic tests are typically conducted on a biological sample (ie, body tissue or body fluids) selected from tumor biopsy samples, blood samples
    [0964] [0964] Methods for identifying and analyzing cytogenetic aberration, genetic amplification, mutations and positive regulation of proteins are known to one skilled in the art. Screening methods can include, without limitation, standard methods, such as DNA sequence analysis by conventional Sanger or next generation methods, polymerase chain reaction with reverse transcriptase (RT-PCR), RNA sequencing (RNAseq), Nanostricted hybridization proximity RNA nCounter assays, or in situ hybridization, such as in situ fluorescence hybridization (FISH) or allele-specific polymerase (PCR) chain reaction. The latest next generation sequencing technologies (NGS), such as massively parallel sequencing, allow for complete exome sequencing or complete genome sequencing.
    [0965] [0965] In RT-PCR screening, the level of mRNA in the tumor is assessed by creating a copy of the mRNA cDNA followed by PCR amplification of the cDNA. PCR amplification methods, primer selection and conditions for amplification are known to one skilled in the art. Nucleic acid manipulations and PCR are performed by standard methods, as described, for example, in Ausubel, F.M. et al., Eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc., or Innis, M.A. et al., 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), 3rd Ed, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, a commercially available kit for RT-PCR (for example, Roche Molecular Biochemicals), or methodology, as set out in US Patents 4,666,828; 4,683,202;
    [0966] [0966] Generally, in situ hybridization comprises the following main steps: (1) fixation of the tissue to be analyzed; (2) prehybridization treatment of the sample to increase the accessibility of the target nucleic acid and reduce non-specific binding; (3) hybridizing the mixture of nucleic acids to the nucleic acid in the biological structure or tissue; (4) post-hybridization washes to remove unbound nucleic acid fragments in hybridization and (5) detection of the hybridized nucleic acid fragments. The probes used in such applications are typically labeled, for example, with radioisotopes or fluorescent reporters. Certain probes are long enough, for example, from about 50, 100 or 200 nucleotides to about 1,000 or more nucleotides, to allow specific hybridization with the target nucleic acid (or nucleic acids) under stringent conditions. Standard methods for performing FISH are described in Ausubel, F.M. et al., 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, pps. 077-088; Series: Methods in Molecular Medicine.
    [0967] [0967] The methods for profiling gene expression are described by (DePrimo et al. (2003), BMC Cancer, 3: 3). Briefly, the protocol is as follows: double-stranded cDNA is synthesized from total RNA using an oligomer (dT) 24 to initiate first strand cDNA synthesis from polyadenylated mRNA, followed by cDNA synthesis from second ribbon with random hexamer initiators. The double-stranded cDNA is used as a model for in vitro transcription of cRNA using biotinylated ribonucleotides. The cRNA is fragmented chemically according to the protocols described by Affymetrix (Santa Clara, CA, USA) and then hybridized overnight with gene-specific oligonucleotide probes in Human Genome Matrices. Alternatively, single nucleotide polymorphism (SNP) arrays, a type of DNA microarray, can be used to detect polymorphisms within a population.
    [0968] [0968] Alternatively, protein products expressed from mRNAs can be analyzed by immunohistochemistry of tumor samples, solid phase immunoassay with microtiter plates, Western blotting, two-dimensional SDS-polyacrylamide electrophoresis, ELISA, cytometry of flow and other methods known in the art for detecting specific proteins, for example,
    [0969] [0969] Abnormal protein levels such as SHP2 can be measured using standard protein assays, for example, the assays described here. Elevated levels or overexpression can also be detected in a tissue sample, for example, tumor tissue by measuring protein levels with an assay like that of Chemicon International. The protein of interest would be immunoprecipitated from the sample lysate and its measured levels. Test methods also include the use of markers.
    [0970] [0970] In other words, the overexpression of SHP2 or mutant SHP2 can be measured by tumor biopsy.
    [0971] [0971] Methods for evaluating gene copy changes include techniques used in cytogenetic laboratories, such as MLPA (Multiplex Lobe-probe Probe Amplification), a multiplexing PCR method that detects abnormal copy numbers or other PCR techniques that can detect amplification, gain and exclusion of genes.
    [0972] [0972] Ex-functional assays can also be used when appropriate, for example, measuring circulating leukemia cells in a cancer patient, to assess the response to the challenge with an SHP2 inhibitor.
    [0973] [0973] Therefore, all of these techniques can also be used to identify tumors particularly suitable for treatment with the compounds of the invention.
    [0974] [0974] Therefore, in a further aspect of the invention includes the use of a compound according to the invention for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition in a patient who has been screened and determined to be suffering from, or at risk of suffering from a disease or condition susceptible to treatment with an SHP2 inhibitor.
    [0975] [0975] 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 that has SHP2 amplification.
    [0976] [0976] Another aspect of the invention includes a compound of the invention for use in the prophylaxis or treatment of cancer in a patient who has a loss of a negative SHP2 regulator.
    [0977] [0977] 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 that has RTK-activated activation of the MAPK signaling pathway.
    [0978] [0978] Magnetic resonance determination of vessel normalization (for example, using magnetic resonance 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.
    [0979] [0979] Thus, an additional aspect of the invention is a method for the diagnosis and treatment of a state or condition of SHP2-mediated disease, wherein the method comprises (i) scanning a patient to determine whether a disease or condition of which the patient is or may be suffering is one that would be susceptible to treatment with SHP2 inhibitor; and (ii) where it is indicated that the disease or condition to which the patient is thus susceptible, subsequently administering to the patient a compound of Formula (I) and subgroups or examples thereof, as defined herein. ADVANTAGES OF THE COMPOUNDS OF THE INVENTION
    [0980] [0980] The compounds of Formula (I) have several advantages over the compounds of the prior art. The compounds of the invention may have particular advantages in one or more of the following aspects:
    [0981] [0981] (i) Higher power;
    [0982] [0982] (ii) Superior in vivo efficacy
    [0983] [0983] (iii) higher PK;
    [0984] [0984] (iv) Superior metabolic stability;
    [0985] [0985] (v) Superior oral bioavailability;
    [0986] [0986] (vi) Superior physical and chemical properties; and / or
    [0987] [0987] (vii) Safety profile or superior therapeutic index (TI). SUPERIOR POWER AND EFFICIENCY IN VIVO
    [0988] [0988] The compounds of Formula (I) have greater affinity for SHP2 and, in particular, greater cell potency against cell lines known to be sensitive to SHP2 antagonists.
    [0989] [0989] Target enhanced engagement is a highly desirable property in a pharmaceutical compound,
    [0990] [0990] The compounds of Formula (I) have improved cell potency and / or improved selectivity for SHP2 cell lines. As a result of increased potency against SHP2, the compounds of the invention may have an increased in vivo efficacy in cancer cell lines and in vivo models. SUPERIOR PK AND METABOLIC STABILITY
    [0991] [0991] The compounds of Formula (I) may have advantageous ADMET properties, for example, better metabolic stability (for example, as determined with mouse liver microsomes), a better P450 profile, short half-life and / or beneficial clearance (for example, low or high clearance). It has also been found that many compounds of Formula (I) have an improved PK profile.
    [0992] [0992] These resources can confer the advantage of having more drug available in the systemic circulation to reach the appropriate site of action to exert its therapeutic effect. Increased drug concentrations to exert pharmacological action on tumors potentially lead to improved efficacy, which allows for reduced doses to be administered. Thus, compounds of Formula (I) should exhibit reduced dosage requirements and should be more easily formulated and administered.
    [0993] [0993] This results in a good separation (‘therapeutic window’) between SHP2 activity and toxic effects. Many compounds of Formula (I) have a reduction in Cmax necessary for effectiveness (due to the better potency of
    [0994] [0994] Potentially, the compounds of the invention have physicochemical properties suitable for oral exposure (oral exposure or AUC). In particular, the compounds of Formula (I) may exhibit improved oral bioavailability or improved reproducibility of oral absorption. Oral bioavailability can be defined as the ratio (F) between the plasma exposure of a compound when administered orally and the plasma exposure of the compound when administered intravenously (i.v.), expressed as a percentage.
    [0995] [0995] Compounds with an oral bioavailability (F-value) greater than 10%, 20% or 30%, more particularly greater than 40%, are particularly advantageous in that they can be administered orally instead of, or also by parenteral administration. SUPERIOR PHYSICAL AND CHEMICAL PROPERTIES
    [0996] [0996] The compounds of Formula (I) may have advantageous physico-chemical properties, in particular chemical stability under acidic conditions and reduced lipophilicity.
    [0997] [0997] Lipophilicity can be measured 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 ionized) in each of the two phases. High lipophilicity is associated with poor drug-like properties, such as low aqueous solubility, poor pharmacokinetic properties (low oral bioavailability), unwanted drug metabolism and high promiscuity. Compounds with ideal lipophilicity may have a greater chance of success in drug development. However, it can be a challenge to achieve reduced logP (or calculated logP, clogP), while maintaining an acceptable level of potency for inhibiting protein-protein interactions (PPI) due to the lipophilic nature of the targets involved. HIGHER SAFETY PROFILE OR THERAPEUTIC INDEX (TI)
    [0998] [0998] In the late 1990s, several drugs, approved by the US FDA, had to be withdrawn from sale in the USA when it was found that they were involved in deaths from heart problems. It was later found that a side effect of these drugs was the development of arrhythmias caused by blocking the hERG channels in cardiac cells. The hERG channel is part of a family of potassium ion channels, the first member of which was identified in the late 1980s in a mutant fruit fly Drosophila melanogaster (see Jan, LY and Jan, YN (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. (1995). A Mechanistic Link Between an Inherited and an Acquired Cardiac Arrhythmia: HERG encodes the Ikr potassium channel. Cell, 81: 299 to 307, and Trudeau, M.C., Warmke, J.W., Ganetzky, B., and Robertson, G.A. (1995). HERG, a Human Inward Rectifier in the Voltage- Gated Potassium Channel Family. Science, 269: 92 to 95.
    [0999] [0999] Compounds that have reduced hERG activity and / or a good separation between hERG activity and activity have a larger 'therapeutic window' or 'therapeutic index'. One method for measuring hERG activity is the plaster loop electrophysiology method. Alternative methods for measuring functional hERG activity include hERG binding assays, which can use commercially available membranes, isolated from cells that stably express the hERG channel or commercially available cell lines expressing the hERG channel.
    [1000] [1000] Compounds may also have an improved Cardiac Safety Index (CSI) [CSI = hERG IC50 / Cmax (unbound)] (Shultz et al, J. Med. Chem., 2011; Redfern et al, Cardiovasc. Res ., 2003). This may be due to an increase in hERG IC50 or a reduction in Cmax required for effectiveness (due to better power and / or PK). Particular compounds can show advantage of CV in vivo.
    [1001] [1001] Particular compounds have reduced hERG ion channel blocking activity. Compounds can have mean IC50 against hERG values greater than 30 times or greater than 40 times or greater than 50 times the IC50 values of compounds in cell proliferation assays. PHARMACEUTICAL FORMULATIONS
    [1002] [1002] Although it is possible to administer the active compound alone, THE SAME is usually presented as a pharmaceutical composition (eg, formulation).
    [1003] [1003] Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods for producing a pharmaceutical composition comprising (for example, admixing) at least one compound of Formula (I) (and subgroups thereof, as defined herein. ), together with one or more pharmaceutically acceptable excipients and, optionally, other therapeutic or prophylactic agents, as described herein.
    [1004] [1004] Pharmaceutically acceptable excipients can be selected from, for example, carriers (for example, a solid, liquid or semi-solid carrier), adjuvants, diluents, fillers or bulking agents, granulating agents, coating agents, release control, binding agents, disintegrants, lubricating agents, preservatives, antioxidants, buffering agents, suspending agents, thickening agents, flavoring agents, sweeteners, flavor-masking agents, stabilizers or any other excipients conventionally used in pharmaceutical compositions. Examples of excipients for various types of pharmaceutical compositions are given in more detail below.
    [1005] [1005] The term "pharmaceutically acceptable", as used herein, refers to compounds, materials, compositions and / or dosage forms that are, within the scope of an appropriate medical judgment, suitable for use in contact with the tissues of a individual (for example, a human subject) without excessive toxicity, irritation, allergic response or other problem or complication, proportional to a reasonable risk / benefit ratio. Each excipient must also be "acceptable" in the sense of being compatible with the other ingredients in the formulation.
    [1006] [1006] 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, USA.
    [1007] [1007] The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, optical, rectal, intravaginal or transdermal administration. When the compositions are intended for parenteral administration, they can 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. Administration can be by bolus injection, short-term infusion or long-term infusion and can be via passive administration or through the use of an appropriate infusion pump or syringe driver.
    [1008] [1008] Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, cosolvents, surfactants, mixtures of organic solvents, cyclodextrin complexing agents, emulsifying agents (to form and stabilize emulsions (formulations), components of liposomes to form liposomes, gelable polymers to form polymeric gels, lyophilization protectors and combinations of agents to, among others, stabilize the active ingredient in a soluble form and make the formulation isotonic with the intended recipient's blood . Pharmaceutical formulations for parenteral administration may also take the form of sterile aqueous and non-aqueous suspensions, which may include suspending and thickening agents (RG Strickly, Solubilizing Excipients in oral and injectable eformulations, Pharmaceutical Research, Vol 21 (2) 2004, pages 201 to 230).
    [1009] [1009] The formulations can be presented in unit dose or multidose containers, for example, ampoules, vials and pre-filled syringes, and can be stored in a freeze-dried (lyophilized) condition, requiring only the addition of the sterile liquid carrier. , for example, water for injections, immediately before use. In one embodiment, the formulation is supplied as an active pharmaceutical ingredient in a vial for subsequent reconstitution with the use of an appropriate diluent.
    [1010] [1010] The pharmaceutical formulation can be prepared by lyophilizing a compound of Formula (I) or subgroups thereof. Lyophilization refers to the freeze-drying procedure of a composition. Freeze drying and freeze drying are therefore used interchangeably here.
    [1011] [1011] Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.
    [1012] [1012] The pharmaceutical compositions of the present invention for parenteral injection may also comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions immediately before 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), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as sunflower oil, saffron, corn oil or olive oil) and injectable organic esters, such as ethyl oleate. Adequate fluidity can be maintained, for example, by the use of thickening materials, such as lecithin, by maintaining the required particle size in the case of dispersions and by using surfactants.
    [1013] [1013] The compositions of the present invention can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. The 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 agents for adjusting tonicity, such as sugars, sodium chloride and the like. The prolonged absorption of the injectable pharmaceutical form can be caused by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.
    [1014] [1014] 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 can be dosed as is or injected into an infusion bag
    [1015] [1015] In another typical embodiment, the pharmaceutical composition is in a form suitable for subcutaneous (s.c.) administration.
    [1016] [1016] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), capsules, tablets, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or adhesives, such as mouth patches.
    [1017] [1017] Thus, tablet compositions may contain a unit dosage of the active compound together with a diluent or inert carrier, such as a sugar or sugar alcohol, for example; lactose, sucrose, sorbitol or mannitol; and / or a non-sugar-based diluent, such as sodium carbonate, calcium phosphate, calcium carbonate or a cellulose or derivative thereof, such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose and starches such as starch of corn. Tablets can also contain standard ingredients such as binding and granulating agents, such as polyvinylpyrrolidone, disintegrants (eg, intumescent crosslinkable polymers, such as cross-linked carboxymethylcellulose), lubricating agents (eg, stearates), preservatives (eg, parabens), antioxidants ( for example, BHT), buffering agents (for example, phosphate or citrate buffers) and effervescent agents, such as citrate / bicarbonate mixtures. Such excipients are well known and need not be discussed in detail here.
    [1018] [1018] The tablets can be designed to release the drug in contact with stomach fluids (immediate-release tablets) or to release in a controlled manner (controlled-release tablets) for an extended period or with a specific region of the gastrointestinal tract.
    [1019] [1019] Capsule formulations can be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid or liquid form. Gelatin capsules can be formed from animal gelatin or synthetic equivalents or plant derivatives thereof.
    [1020] [1020] Solid dosage forms (for example, tablets, capsules, etc.) can be coated or not. Coatings can act as a protective film (for example, a polymer, wax or varnish) or as a mechanism to control drug release or for aesthetic or identification purposes. The coating (for example, a polymer of the Eudragit ™ type) can be designed to release the active component at a desired location in the gastrointestinal tract. Thus, the coating can be selected so as to degrade under certain pH conditions in the gastrointestinal tract, thus selectively releasing the compound in the stomach or ileum, duodenum, fast or colon.
    [1021] [1021] Instead of, or in addition to, a coating, the drug can be presented in a solid matrix comprising a release control agent, for example, a release delay agent that can be adapted 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 polymethacrylate polymer coating, which can be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or release-retardant coating may take the form of an erodible polymer (for example, a maleic anhydride polymer) which is substantially continuously corroded as the dosage form passes through the gastrointestinal tract. In another alternative, the coating can be designed to disintegrate under microbial action in the intestine. As an additional 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 (for example, formulations based on ion exchange resins) can be prepared according to methods well known to those skilled in the art.
    [1022] [1022] The compound of Formula (I) can be formulated with a carrier and administered in the form of nanoparticles, the increased surface area of the nanoparticles aiding their absorption. In addition, 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 on March 13, 2006. Nanoparticles for drug delivery are also described in J. Control. Release, 2003, 91 (1-2),
    [1023] [1023] Pharmaceutical compositions typically comprise from approximately 1% (by weight) to approximately 95% of active ingredient and from 99% (by weight) to 5% (by weight) of a pharmaceutically acceptable excipient or combination of excipients. Typically, the compositions comprise from approximately 20% (by weight) to approximately 90%,% (by weight) of active ingredient and from 80% (by weight) to 10% of a pharmaceutically acceptable excipient or combination of excipients. The pharmaceutical compositions comprise approximately 1% to approximately 95%, typically approximately 20% to approximately 90% active ingredient. The pharmaceutical compositions according to the invention can be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre-filled syringes, pills, tablets or capsules.
    [1024] [1024] The pharmaceutically acceptable excipient (or excipients) can be selected according to the desired physical form of the formulation and can, for example, be selected from diluents (for example, solid diluents such as fillers or bulking agents; and liquid diluents, such as solvents and cosolvents), disintegrants, buffering agents, lubricants, flow aids, release control agents (for example, delaying or delaying release polymers or waxes), binders, granulants, pigments, plasticizers, antioxidants, preservatives , flavorings, flavor masks, tonicity adjusting agents and coating agents.
    [1025] [1025] The person skilled in the art will have the experience necessary to select the appropriate amounts of ingredients for use in formulations. For example, tablets and capsules typically contain 0 to 20% disintegrants, 0 to 5% lubricants, 0 to 5% flow aids and / or 0 to 99% (by weight) of fillers / or bulking agents (depending on drug dose). They may also contain 0 to 10% (by weight) of polymeric binders, 0 to 5% (by weight) of antioxidants, 0 to 5% (by weight) of pigments. In addition, slow-release tablets contain polymers from 0 to 99% (by weight) (depending on the dose). The film layers of the tablet or capsule typically contain 0 to 10% (by weight) of release control polymers (eg delay), 0 to 3% (by weight) of pigments and / or 0 to 2% (in weight) of plasticizers.
    [1026] [1026] Parenteral formulations generally contain 0 to 20% (by weight) of buffers, 0 to 50% (by weight) of cosolvents and / or 0 to 99% (by weight) of Water for Injection (WFI) (depending on dose and freeze dried). Formulations for intramuscular deposits can also contain 0 to 99% (by weight) of oils.
    [1027] [1027] Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired, granulating a resulting mixture and processing the mixture, if desired or necessary, after adding appropriate excipients, in tablets, cores or capsules. of dragees. It is also possible for them to be incorporated into a polymeric or waxy matrix that allows the active ingredients to diffuse or be released in measured quantities.
    [1028] [1028] The compounds of the invention can also be formulated as solid dispersions. Solid dispersions are extremely thin, homogeneous dispersed phases of two or more solids. Solid solutions (molecularly dispersed systems), a type of solid dispersion, are well known for use in pharmaceutical technology (see (Chiou and Riegelman, J. Pharm. Sci., 60, 1,281 to 1,300 (1971)) and are useful in increasing dissolution rates and increased bioavailability of poorly water-soluble drugs.
    [1029] [1029] This invention also provides solid dosage forms that comprise the solid solution described herein. Solid dosage forms include tablets, capsules, chewable tablets and dispersible or effervescent tablets. The known excipients can be mixed with the solid solution to provide the desired dosage form. For example, a capsule can contain the solid solution mixed with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant and a surfactant. In addition, a capsule may contain a bulking agent, such as lactose or microcrystalline cellulose. A tablet can contain the solid solution mixed with at least one disintegrant, a lubricant, a surfactant, a bulking agent and a glidant. A chewable tablet can contain the solid solution mixed with a bulking agent, a lubricant and, if desired, an additional sweetener (such as an artificial sweetener) and suitable flavors. Solid solutions can also be formed by spraying drug solutions and a suitable polymer onto the surface of inert vehicles, such as sugar microspheres (‘non-
    [1030] [1030] Pharmaceutical formulations can be presented to a patient in “patient packs” containing an entire course of treatment in a single pack, usually a blister pack. Patient packaging has an advantage over traditional prescriptions, in which a pharmacist divides the patient's supply of a pharmaceutical product from a bulk supply, as the patient always has access to the package insert contained in the patient's package, which is normally absent in the patient's prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the doctor's instructions.
    [1031] [1031] Compositions for topical use and nasal administration include ointments, creams, sprays, adhesives, gels, liquid drops and inserts (for example, intraocular inserts). Such compositions can be formulated according to known methods.
    [1032] [1032] Examples of formulations for rectal or intravaginal administration include pessaries and suppositories that can, for example, be formed from a moldable or waxy molded material containing the active compound. Active compound solutions can also be used for rectal administration.
    [1033] [1033] Compositions for administration by inhalation can take the form of inhalable powder compositions or liquid or powder sprays, and can be administered in standard form using 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.
    [1034] [1034] The 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 can contain from 1 nanogram to 2 grams of active ingredient, for example, from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, specific subintervals of compound are 0.1 milligrams to 2 grams of active ingredient (more generally 10 milligrams to 1 gram, for example, 50 milligrams to 500 milligrams) or 1 microgram to 20 milligrams (eg 1 microgram to 10 milligrams, for example, 0.1 milligrams to 2 milligrams of active ingredient).
    [1035] [1035] For oral compositions, a unit dosage form can contain from 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.
    [1036] [1036] The active compound will be administered to a patient in need (for example, a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect. TREATMENT METHODS
    [1037] [1037] The compounds of Formula (I) and subgroups as defined herein may be useful in the prophylaxis or treatment of a variety of SHP2-mediated disease states or conditions. Examples of such disease states and conditions are presented above.
    [1038] [1038] The compounds are generally administered to an individual in need of such administration, for example, a human or animal patient, typically human.
    [1039] [1039] The compounds will typically be administered in amounts useful therapeutically or prophylactically and which are generally non-toxic. However, in certain situations (for example, in the case of life-threatening illnesses), 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 administer compounds in amounts associated with a degree of toxicity.
    [1040] [1040] The compounds can be administered for an extended period to maintain beneficial therapeutic effects or they can be administered only for a short period. Alternatively, they can be administered continuously or in a way that provides intermittent dosing (for example, a pulsatile way).
    [1041] [1041] A typical daily dose of the compound of Formula (I) can be 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.
    [1042] [1042] The amount of compound administered and the type of composition used will be proportional to the nature of the disease or physiological condition to be treated and will be at the discretion of the physician.
    [1043] [1043] 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 that acts through a different mechanism to regulate cell growth, thus addressing two of the characteristics of cancer development. Combination experiments can be performed, 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 to 55.
    [1044] [1044] The compounds as defined herein can be administered as the sole therapeutic agent or can be administered in combination therapy with one of the other other compounds (or therapies) to treat a specific disease state, for example, a neoplastic disease such as a cancer as previously defined. For the treatment of the above conditions, the compounds of the invention can advantageously be used in combination with one or more other medicinal agents, more particularly, with other anticancer agents or adjuvants (support agents in therapy) in cancer therapy.
    [1045] [1045] 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 can 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 are sufficient to ensure that an advantageous or synergistic effect is achieved.
    [1046] [1046] It should be appreciated that the typical method and order of administration and the respective amounts and dosage regimes for each component of the combination will depend on the other medicinal agent and compound of the present invention being administered, its route of administration, the specific tumor being treated and the specific host being treated.
    [1047] [1047] The weight ratio of the compound according to the present invention and one or more other anticancer agents, when administered as a combination, can be determined by one skilled in the art. Said reason and exact dosage and frequency of administration depend on the specific compound according to the invention and the other anti-cancer agent (or agents) used, the specific condition to be treated, the severity of the condition to be treated, the age, weight, sex, diet, time of administration and general physical condition of the patient in particular, the mode of administration and other medications the individual may be taking, as is well known to those skilled in the art. In addition, it is evident that the effective daily amount can be reduced or increased depending on the response of the treated subject and / or depending on the judgment of the physician who prescribes the compounds of the present invention.
    [1048] [1048] The compounds of the invention can also be administered in conjunction with non-chemotherapeutic treatments, such as radiation therapy, photodynamic therapy, gene therapy; surgery and controlled diets. Radiotherapy can be for radical, palliative, adjuvant, neoadjuvant or prophylactic purposes.
    [1049] [1049] For use in combination therapy with another chemotherapeutic agent, the compound of Formula (I) and one, two, three, four or more other therapeutic agents can, for example, be formulated together in a dosage form containing two, three, four or more therapeutic agents, that is, in a unitary pharmaceutical composition containing all components. Alternatively, individual therapeutic agents can be formulated separately and presented together in the form of a kit, optionally with instructions for their use.
    [1050] [1050] In another embodiment, the invention provides a combination of a compound as defined herein and another therapeutic agent.
    [1051] [1051] 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.
    [1052] [1052] 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.
    [1053] [1053] In another embodiment, the invention relates to the use of a combination according to the invention in the manufacture of a pharmaceutical composition to inhibit the growth of tumor cells.
    [1054] [1054] In another embodiment, the invention relates to a product containing a compound of Formula I and one or more anti-cancer agents, as a combined preparation for simultaneous, separate or sequential use in the treatment of cancer patients. EXAMPLES SYNTHETIC METHODS
    [1055] [1055] Following methods similar and / or analogous to the general procedures below, the compounds set out below were prepared.
    [1056] [1056] The following synthetic procedures are provided to illustrate the methods used; for a given preparation or step, the precursor used cannot necessarily be derived from the individual batch synthesized according to the step in the description provided.
    [1057] [1057] When a compound is described as a mixture of two diastereoisomers / epimers, the configuration of the stereocenter is unspecified and is represented by straight lines.
    [1058] [1058] As understood by one skilled in the art, synthesized compounds using the protocols as indicated may exist as a solvate, for example, hydrate and / or contain residual solvent or small impurities. The compounds isolated as a salt form can be whole stoichiometric, that is, mono- or di-salts, or of intermediate stoichiometry.
    [1059] [1059] Some of the compounds below are isolated as salt, for example, depending on the acid used in the purification method. Some compounds are isolated as a free base.
    [1060] [1060] Compounds containing a single stereocenter are typically isolated as a single isomer using preparative chiral HPLC (as described in general methods); at (or close to) the final stage of the synthetic sequence. In these cases, stereochemistry is designated according to IUPAC, using lines with wedges
    [1061] [1061] Compounds containing a second stereocenter are typically isolated as a single isomer by preparative achiral and / or chiral HPLC.
    [1062] [1062] Optical isomers can be characterized by their optical activity (that is, as + and - isomers or d and l isomers). The stereocenter can also be designated as “R or S”, according to the nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, New York, 1992, pages 109 to 114 and see also Cahn, Ingold and Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385 to 415.
    [1063] [1063] Optical isomers can be separated by several techniques, including chiral chromatography (chromatography on a chiral support) and these techniques are well known to the person skilled in the art.
    [1064] [1064] As an alternative to chiral chromatography, the optical isomers of basic compounds can be separated by forming diastereoisomeric salts with chiral acids such as (+) - tartaric acid, (-) - pyroglutamic acid, (-) - di-toluoyl acid -L-tartaric acid (+) - mandelic acid, (-) - malic acid and (-) - camphor sulfonic acid, separating the diastereoisomeric salts by preferential crystallization and then dissociating the salts to yield the individual enantiomer from the free base. Likewise, the optical ions of acid compounds can be separated by forming diastereoisomeric salts with chiral amines such as Brucine,
    [1065] [1065] Additionally, enantiomeric separation can be achieved by covalently attaching an enantiomerically pure chiral auxiliary to the compound and then performing diastereomeric separation using conventional methods, such as chromatography. This is then followed by the cleavage of the aforementioned covalent bond to generate the appropriate enantiomerically pure product. Examples may include the production of mentholated esters of an acidic compound.
    [1066] [1066] When the compounds of Formula (I) exist as two or more isomeric optical forms, an enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Thus, in certain circumstances, it may be desirable to use as a therapeutic agent only one of a pair of enantiomers or just one of a plurality of diastereoisomers.
    [1067] [1067] Consequently, the invention provides compositions containing a compound of Formula (I) that has one or more chiral centers, in which at least 55% (for example, at least 60%, 65%, 70%, 75%, 80 %, 85%, 90% or 95%) of the compound of Formula (I) is present as a single optical isomer (for example, enantiomer or diastereoisomer). In a general embodiment, 99% or more (for example, substantially all) of the total amount of the compound of Formula (I) can be present as a single optical isomer (for example, enantiomer or diastereoisomer).
    [1068] [1068] Compounds that encompass double bonds may have an E (entgegen) or Z stereochemistry
    [1069] [1069] Of particular interest are compounds of Formula (I) that are stereochemically pure. When a compound of Formula (I) is, for example, specified as R, this means that the compound is substantially free of the S isomer. If a compound of Formula (I) is, for example, specified as E, it means that the 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.
    [1070] [1070] The terms exo and endo refer to the stereochemistry of a bridged bicycloalkane, as a substituted tropane, described in PAC, 1996, 68, 2193, basic stereochemistry terminology (IUPAC Recommendations 1996). If a substituent, for example, the amino group is oriented towards the highest bridge and receives the description exo; if it is in the opposite direction to the highest numbered bridge, the endo description is given. When there are two substituents on the same carbon atom, the terms exo and endo refer to the substituent with the highest priority. The figure below illustrates the pictorial representation of how the amino tropane is defined in this patent. EXAMPLES
    [1071] [1071] The invention will now be illustrated, but not limited, by reference to the specific modalities described in the examples below. Compounds are named, for example, using an automated naming package, such as AutoNom (CDM), using IUPAC standards, or are named by the chemical supplier. In the examples, the following abbreviations are used. AcOH Acetic acid Aq. Aqueous BOC tert-butyloxycarbonyl BuLi butylithium Cbz Carboxybenzyl DCE 1,2-dichloroethane DCM dichloromethane DIPEA N, N-Diisopropylethylamine DMF N, N-dimethylformamide DMSO dimethyl sulfoxide Et3N triethylamine EtOAc Ethylethyl Ethyl Ethanol Ethanol HPLC High pressure liquid chromatography IPA isopropyl alcohol KOtBu potassium tert-butoxide LED Light emitting diode MeCN acetonitrile MeOH methanol (min) minutes MS NaBH (OAc) mass spectrometry 3 NaOEt sodium triacetoxyborohydride Sodium ethoxide
    [1072] [1072] All starting materials and solvents were obtained from commercial sources or prepared according to the literature citation. Unless otherwise indicated, all reactions were agitated. The organic solutions were routinely dried over anhydrous magnesium sulfate. The hydrogenations were carried out in a Parr hydrogenator, a H Thales cube flow reactor under the indicated conditions or under a hydrogen balloon. The microwave reactions were carried out in a CEM Discover and Smithcreator microwave reactor, heating at a constant temperature with the use of microwave irradiation of variable power. Normal phase column chromatography was performed routinely in an automated flash chromatography system, such as the CombiFlash Companion or CombiFlash RF system, using pre-packaged silica cartridges (230-400 mesh, 40 to 63 µm). SCX was purchased from Supelco and treated with 1M hydrochloric acid before 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% NH3 in MeOH. The purification of silica gel by ion exchange of NH2 was carried out with Strata NH2 columns (55 µm, 70 Å), loaded directly onto the NH2 column and eluting with a solvent such as methanol. Biotage® KP-NH SNAP silica gel columns were purchased from Biotage®. The purification of the reverse phase was performed using Biotage® SNAP Ultra C18 silica gel columns and were purchased from Biotage®. NMR DATA
    [1073] [1073] 1H NMR spectra were acquired on a 400 MHz Bruker Avance III spectrometer, an AL400 (400 MHz; produced by JEOL), a Mercury 400 (400 MHz; produced by Agilent Technologies, Inc.) or a Spectrometer 500 MHz Bruker Avance III HD NMR. The central peaks of chloroform-d, dimethylsulfoxide-d6 or an internal standard of tetramethylsilane were used as references. For NMR data, when the number of protons assigned is less than the theoretical number of protons in the molecule, it is assumed that the apparently missing signal (or signals) is obscured by solvent and / or water peaks. In addition, where the spectra were obtained in protic NMR solvents, NH and / or OH protons exchange with solvent and, therefore, these signals are not normally observed. ANALYTICAL AND PREPARATIVE LC-MS SYSTEMS ANALYTICAL LC-MS SYSTEM AND METHOD DESCRIPTION
    [1074] [1074] In the following examples, the compounds were characterized by mass spectroscopy using the systems and operating conditions set out below. When atoms with different isotopes are present and a single mass is cited, the mass cited for the compound is the monoisotopic mass (that is, 35Cl; 79Br; etc.). SHIMADZU NEXERA
    [1075] [1075] HPLC system: Shimadzu SIL-30AC autosampler / 2x Shimadzu LC-30AD pumps
    [1076] [1076] Mass Spec Detector: Shimadzu LCMS-2020 single quadrupole MS
    [1077] [1077] Second Detector: Shimadzu SPD-M20A diode array detector MS OPERATIONAL CONDITIONS
    [1078] [1078] DC voltage of Qarray: 20V in ES Pos (-20V in ES Neg)
    [1079] [1079] Drying gas flow: 20.0 l / min
    [1080] [1080] DL temperature: 300 ºC
    [1081] [1081] Heat Block Temperature: 350 ºC
    [1082] [1082] Nebulizing Gas Flow: 1.5 l / min
    [1083] [1083] Scan Range: 100 to 750 amu
    [1084] [1084] Ionization Mode: Positive-Negative Electrospray Switching AGILENT SYSTEM 1290 INFINITY II - 6130 LC-MS
    [1085] [1085] HPLC system: Agilent 1290 Infinity II
    [1086] [1086] Mass Spec Detector: Agilent 6130 Single Quadripole
    [1087] [1087] Second Detector: Agilent 1290 Infinity II Diode Array Detector MS OPERATIONAL CONDITIONS
    [1088] [1088] Capillary voltage: 3,000 V
    [1089] [1089] Fragmentor / Gain: 70
    [1090] [1090] Gain: 1
    [1091] [1091] Drying gas flow: 13.0 l / min
    [1092] [1092] Gas Temperature: 350 ºC
    [1093] [1093] Nebulizer pressure: 40 psig
    [1094] [1094] Scan Range: 150 to 1,000 amu
    [1095] [1095] Sheath Gas Temperature: 360 ºC
    [1096] [1096] Sheath Gas Flow: 10.0 l / min
    [1097] [1097] Nozzle Voltage: 300 (+ ve mode) / 1750 (-ve mode)
    [1098] [1098] Ionization Mode: Positive-Negative Switching of Agilent Jet Current Electrospray
    [1099] [1099] LCMS spectra were measured alternatively with an SQD manufactured by Waters Corporation under the following two conditions, and the values of [M + H] + were shown.
    [1100] [1100] MS detection: ESI positive
    [1101] [1101] UV detection: 254 nm
    [1102] [1102] column flow rate: 0.5 ml / min
    [1103] [1103] Mobile phase: water / acetonitrile (0.1% formic acid)
    [1104] [1104] Injection volume: 1 l
    [1105] [1105] Method
    [1106] [1106] Column: Acguity BEH, 2.150 mm, 1.7 m
    [1107] [1107] Gradient:
    [1108] [1108] Time (min) water / acetonitrile (0.1% formic acid)
    [1109] [1109] 0 95/5
    [1110] [1110] 0.1 95/5
    [1111] [1111] 2.1 5/95
    [1112] [1112] 3.0 STOP PREPARATIVE LC-MS SYSTEM AND METHOD DESCRIPTION
    [1113] [1113] The preparative LC-MS is a standard and effective method used for the purification of small organic molecules, such as the compounds described here. The 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. The optimization of the preparative gradient LC method will involve variable columns, eluents and volatile modifiers and gradients. Methods for optimizing preparative LC-MS methods and then using them to purify compounds are well known in the art. 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 libraries; J Comb Chem .; 2003; 5 (3); 322-9.
    [1114] [1114] Various systems for purifying compounds via preparative LC-MS are described below, although one skilled in the art understands that alternative systems and methods to those described can be used. From the information provided herein, or employing alternative chromatographic systems, one skilled in the art can purify the compounds described herein by preparative LC-MS. MASS-DRIVEN PURIFICATION LC-MS SYSTEM
    [1115] [1115] The preparative LC-MS is a standard and effective method used for the purification of small organic molecules, such as the compounds described here. The 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. The optimization of the preparative gradient LC method will involve variable columns, eluents and volatile modifiers and gradients. Methods for optimizing preparative LC-MS methods and then using them to purify compounds are well known in the art. 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 libraries; J Comb Chem .; 2003; 5 (3); 322-9.
    [1116] [1116] Such a system for purifying compounds via preparative LC-MS is described below, although one skilled in the art understands that alternative systems and methods to those described can be used. In particular, methods based on normal preparative phase LC can be used in place of the reverse phase methods described here. Most preparative LC-MS systems use reverse phase LC and volatile acid modifiers, since the approach is very effective for the purification of small molecules and due to the fact that the eluents are compatible with electrospray mass spectrometry by positive ions. Employing other chromatographic solutions, for example, normal phase LC, alternatively buffered mobile phase, basic modifiers etc., as outlined in the analytical methods described above, could be used alternatively to purify the compounds. LC-MS AGILENT 1260 HARDWARE PREPARATIVE SYSTEM:
    [1117] [1117] Self-sampling: G2260A Prep ALS
    [1118] [1118] Pumps: 2x Pumps G1361A Prep for preparative flow gradient, Pump G1311C Quat VL for pumping modifier in prep flow and Pump G1310B Iso to constitute pump flow
    [1119] [1119] UV detector: G1365C 1260 MWD
    [1120] [1120] MS detector: LC-MS Quadrupole G6120B
    [1121] [1121] Fraction collector: 2x G1364B 1260 FC-PS
    [1122] [1122] Active Splitter G1968D SOFTWARE:
    [1123] [1123] Agilent OpenLab C01.06
    [1124] [1124] Operating conditions of MS Agilent:
    [1125] [1125] Capillary voltage: 3000 V
    [1126] [1126] Fragmentor / Gain: 70/1
    [1127] [1127] Drying gas flow: 12.0 l / min
    [1128] [1128] Drying Gas Temperature: 275 ºC
    [1129] [1129] Nebulizer pressure: 40 psig
    [1130] [1130] Vaporizer temperature: 200 ºC
    [1131] [1131] Scan Range: 125 to 800 amu
    [1132] [1132] Ionization Mode: Electrospray
    [1133] [1133] 1. Waters XBridge Prep C18 5m OBD 100x19mm
    [1134] [1134] Typically used for methods based on ammonium bicarbonate
    [1135] [1135] 2. Waters SunFire Prep C18 OBD 5m 100x19mm
    [1136] [1136] Typically used for TFA-based methods
    [1137] [1137] 3. Waters XBridge Prep phenyl 5m OBD 100x19mm
    [1138] [1138] Typically used for methods based on neutral pH based on ammonium acetate
    [1139] [1139] 4. Supelco Ascentis RP-amide 5m 100x21,2mm
    [1140] [1140] Usually used for methods based on formic acid
    [1141] [1141] 5. Phenomenex Synergi Fusion-RP 4m 100x21,2mm
    [1142] [1142] Typically used for methods based on formic acid ELUENTS:
    [1143] [1143] Solvent A: Water
    [1144] [1144] Solvent B: Acetonitrile
    [1145] [1145] Solvent C: Selection of available modifiers:
    [1146] [1146] 2.5% trifluoroacetic acid in water
    [1147] [1147] 2.5% formic acid in water
    [1148] [1148] 250 mM ammonium bicarbonate in pH water
    [1149] [1149] 250 mM ammonium acetate CONSTITUTE SOLVENT:
    [1150] [1150] 90:10 Methanol: Water + 0.2% Formic Acid (for all types of chromatography) METHODS:
    [1151] [1151] According to the analytical trace, the most appropriate type of preparative chromatography was chosen. A typical routine was to perform an analytical LC-MS using the type of chromatography (low or high pH) most suitable for the structure of the compound. Since the analytical trace showed good chromatography, an appropriate preparative method of the same type was chosen. Typical execution conditions for low and high pH chromatography methods were:
    [1152] [1152] Flow rate: 25 ml / min
    [1153] [1153] Gradient: Generally all gradients had an initial step of 0.4 min with 95% A + 5% B (with additional modifier C). Then, according to the analytical trait, a 6.6 min gradient was chosen to achieve good separation (for example, 5% to 50% B for early retention compounds; 35% to 80% B for average retention and so on)
    [1154] [1154] Wash: A 1.6 minute wash step was performed at the end of the gradient
    [1155] [1155] Constitute flow rate: 0.8 ml / min SOLVENT:
    [1156] [1156] All compounds were generally dissolved in 100% MeOH or 100% DMSO
    [1157] [1157] From the information provided, an individual skilled in the art can purify the compounds described herein by preparative LC-MS. WATERS FRACTIONLYNX HARDWARE SYSTEM:
    [1158] [1158] 2767 Double Handle Fraction Collector / Autosampler
    [1159] [1159] preparatory pump 2525
    [1160] [1160] CFO (fluid column organizer) for column selection
    [1161] [1161] RMA (Waters reagent manager) as constitution pump
    [1162] [1162] Waters ZQ Mass Spectrometer
    [1163] [1163] Photodiode Array detector 2996
    [1164] [1164] Waters ZQ SOFTWARE Mass Spectrometer:
    [1165] [1165] Masslynx 4.1
    [1166] [1166] MS Waters operating conditions:
    [1167] [1167] Capillary voltage: 3.5 kV (3.2 kV in negative ES)
    [1168] [1168] Cone voltage: 25 V
    [1169] [1169] Source temperature: 120 ° C
    [1170] [1170] Multiplier: 500 V
    [1171] [1171] Scan Range: 125 to 800 amu
    [1172] [1172] Ionization Mode: Positive Electrospray or Negative Electrospray
    [1173] [1173] Alternatively, preparative reverse phase HPLC column chromatography was performed under the following conditions.
    [1174] [1174] Column: CAPCELL PAK C18 AQ manufactured by SHISEIDO, 30x50 mm, 5 µm
    [1175] [1175] UV detection: 254 nm
    [1176] [1176] column flow rate: 40 ml / min
    [1177] [1177] Mobile phase: water / acetonitrile (0.1% formic acid)
    [1178] [1178] Injection volume: 1.0 ml
    [1179] [1179] Basic gradient method: water / acetonitrile 0% to 50% (8 minutes) AQUIRAL PREPARATIVE CHROMATOGRAPHY
    [1180] [1180] The examples of compounds described were subjected to purification by HPLC, where indicated, using methods developed following the recommendations described in Snyder LR, Dolan JW, High-Performance Gradient Elution The Practical Application of the Linear-Solvent-Strength Model, Wiley, Hoboken, 2007. AQUIRAL PREPARATIVE CHROMATOGRAPHY
    [1181] [1181] Preparative separations using chiral stationary phases (CSPs) are the natural technique to be applied to the resolution of enantiomeric mixtures. Likewise, it can be applied to the separation of diastereomers and achiral molecules. Methods for optimizing preparative chiral separations in CSPs and then using them to purify compounds are well known in the art. Such methods are described in Beesley T. E., Scott R.P.W .; Chiral Chromatography; Wiley, Chichester, 1998. PREPARATION 1: 7-BROMO-3-CHLORINE-5H-PIRROL [2,3-B] PIRAZINE
    [1182] [1182] N-Bromosuccinimide (25.5 g, 0.143 mol) was added gradually to an agitated mixture cooled by 3-chloro-5H-pyrrole [2,3-b] pyrazine ice bath (20 g,
    [1183] [1183] N-Iodosuccinimide (7.88 g, 35 mmol) was added to a solution of 3-chloro-5H-pyrrole [2,3-b] pyrazine (5.36 g, 35 mmol) in DMF (175 ml) to OK. The reaction was stirred for 1 h at RT. Water was added until precipitation occurred. The solid was collected by vacuum filtration, washed with water and dried in a vacuum oven for 24 hours, to yield the title compound (9.06 g). MS: [M + H] + = 279. PREPARATION 3: 3-CHLORINE-7-IODO-5 - {[2- (TRIMETHYLSILYL) ETOXI] METHIL} -5H-PIRROL [2,3-B] PIRAZINE
    [1184] [1184] 3-chloro-7-iodo-5H-pyrrole [2,3-b] pyrazine (9.06 g, 32.6 mmol) was dissolved in THF (163 ml) and sodium hydride (60% in oil mineral, 1.70 g, 42.4 mmoles) was added in portions over 1 hour at 0 to 4 ° C (ice bath). The reaction was warmed to 11 ° C and then cooled to 0 to 4 ° C (ice bath). 2- (trimethylsilyl) ethoxymethyl chloride (7.07 g, 42.4 mmoles) was added by dripping keeping the temperature below 7 ° C and the dark red / orange solution stirred for 1 h and warmed to RT for 2 h. Saturated NH4Cl was added and the mixture extracted with EtOAc (3x). The combined organics were passed through a phase separator and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 50%, EtOAc / petrol) to yield the title compound (13 g), MS: [M + H] + = 410. PREPARATION 4 : 7-BROMO-3-CHLORINE-5 - {[2- (TRIMETHYLSILIL) ETOXI] METHIL} -5H-PIRROL [2,3-B] PIRAZINE
    [1185] [1185] Prepared analogously to 3-chloro-7-iodine-5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazine except for the use of 7-bromo-3 -chloro-5H-pyrrole [2,3-b] pyrazine, to yield the title compound, 1H NMR (400 MHz, DMSO-d6): 8.64 (1H, s), 8.38 (1H, s ), 5.60 (2H, s), 3.54 (2H, t), 0.92-0.77 (2H, m), -0.08--0.10 (9H, m). PREPARATION 5: 3-CHLORINE-7-IODINE-N, N-DIMETHYL-5H-PIRROL [2,3-B] PIRAZIN-5-SULPHONAMIDE
    [1186] [1186] 3-Chloro-7-iodo-5H-pyrrole [2,3-b] pyrazine (5.0 g, 17.93 mmol) was dissolved in THF (89.6 ml) and sodium hydride (60% in mineral oil, 0.932 g, 23.31 mmoles) was added in portions over 1 hour at 0 to 4 ° C (ice bath). Dimethylsulfamoyl chloride (2.5 ml, 23.31 ml) was added by dripping and the solution stirred for 18 h. Saturated NH4Cl was added and the mixture extracted with EtOAc (3x). The combined organics were passed through a phase separator and concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM), to yield the title compound (3.12 g), 1H NMR (400 MHz, DMSO-d6): 8.76 (1H, s), 8.34 (1H, s), 2.97 (6H, s). PREPARATION 6: 8-BENZYL-3-METHYL-8-AZABYCLE [3.2.1] OCTAN-3- OL
    [1187] [1187] To a solution of 8-benzyl-8-azabicyclo [3.2.1] octan-3-one (4.28 g, 19.9 mmol) in THF (47.0 ml) was added 3.0 mol / l of methylmagnesium chloride in THF solution (29.4 ml, 88.4 mmoles) under dry ice-MeCN bath, and the reaction stirred for 30 min at that temperature and then 20 h at RT. A solution of NH4Cl sat. was added at 0 ° C and the mixture was extracted with EtOAc. The combined organic layers were washed with water and sat. Sodium chloride solution, and dried over anhydrous sodium sulfate. After the desiccant was filtered, the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (NH silica gel, gradient elution, 20 to 50%, CH2Cl2: petrol), to yield the title compound (4.50 g) MS: [M + H ] + = 232. PREPARATION 7: N- {ENDO-8-BENZIL-3-METIL-8- AZABICYCLE [3.2.1] OCTAN-3-IL} ACETAMIDE
    [1188] [1188] To a solution of 8-benzyl-3-methyl-8-azabicyclo [3.2.1] octan-3-ol (4.28 g, 18.48 mmoles) in acetonitrile (26 ml) was added conc. Sulfuric acid . (18 ml) by dripping for 15 min. at 0 ° C, and stirred for 18 h at RT. The reaction mixture was poured onto ice (about 200 g), and basified (about pH 10) with 5 mol / l of sodium hydroxide solution (about 100 ml). The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and sat. Sodium chloride solution, and dried over anhydrous sodium sulfate. After the desiccant was filtered, the solvent was removed under reduced pressure. The residue was washed with diethyl ether and petrol, to yield the title compound (2.45 g) MS: [M + H] + = 273. PREPARATION 8: N- {ENDO-8-BENZIL-3-METYL-8- AZABICICLO [3.2.1] OCTAN-3-IL} TERC-BUTYL CARBAMATE
    [1189] [1189] N- {endo-8-benzyl-3-methyl-8-azabicyclo [3.2.1] octan-3-yl} acetamide was added 6 mol / l hydrochloric acid (80 ml) and the mixture stirred for 11 days at 140 ° C. The reaction mixture was basified with 4 mol / l of sodium hydroxide solution at 0 ° C, and 1,4-dioxane (20 ml), and di-tert-butyl dicarbonate (3.93 g, 18.0 mmoles) was added. The reaction was stirred for 1 h at 0 ° C, and 18 h at RT. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and sat. Sodium chloride solution, and dried over anhydrous sodium sulfate. After the desiccant was filtered, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution, 0 to 10% MeOH-DCM) to yield the title compound (3.05 g). MS: [M + H] + = 331. PREPARATION 9: N- {ENDO-3-METHYL-8-AZABICYCLE [3.2.1] OCTAN-3-IL} TERC-BUTYL CARBAMATE
    [1190] [1190] Pd (OH) 2 / C (10% by weight of Pd, 637 mg, 0.454 mmol) was added to a solution of N- {endo-8-benzyl-3-methyl-8-azabicycles [3.2.1 ] octan-3-yl} tert-butyl carbamate (3.0 g, 9.08 mmoles) in MeOH (20 ml) and the reaction subjected to hydrogenation at room pressure and RT for 24 hours. The reaction was filtered through Celite and the filtrate evaporated. The residue was triturated with diethyl ether to yield the title compound (1.86 g). MS: [M + H] + = 241. PREPARATION 10: (1S, 2R, 3R, 5R) -3- (BENZYLAMINE) -2-FLUORO-8- AZABICICLE [3.2.1] OCTANE-8-CARBOXYLATE OF RAC- TERC-BUTILA
    [1191] [1191] To a solution of (1S, 2S, 5R) -2-fluoro-3-oxo-8-azabicyclo [3.2.1] rac-tert-butyl octane-8-carboxylate (10 g, 41.1 mmoles ) in DCE (97.93 ml), benzylamine (4.94 ml, 45.24 mmoles) and sodium triacetoxyborohydride (13.08 g, 61.70 mmoles) were added. After stirring for 18 h at RT, the reaction was divided between DCM (100 ml) and sodium carbonate sat. (200 ml). The organic layer was separated, passed through a phase separator and concentrated in vacuo. The residue was partitioned between diethyl ether (100 ml) and extracted in 0.1 M HCl (3 x 100 ml). The combined aqueous extracts were washed with diethyl ether (300 ml). After basification with 5M NaOH to pH 9, the aqueous phase was extracted with EtOAc (3 x 300 ml), and the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by column chromatography on silica gel (gradient elution, 0 to 50%, EtOAc / petrol) to yield the title compound (1.83 g), 1H NMR (400 MHz, Me-d3- OD): 7.41-7.30 (4H, m), 7.30-7.23 (1H, m), 4.69 (1H, d), 4.50 (1H, s), 4.25 (1H, s), 3.85 (1H, d), 3.80 (1H, d), 3.05-2.82 (1H, m), 1.93 (2H, s), 1.87- 1.79 (1H, m), 1.72 (1H, d), 1.65-1.51 (2H, m), 1.47 (9H, s). PREPARATION 11: (1S, 2R, 3R, 5R) -3-AMINO-2-FLUORO-8- AZABICYCLE [3.2.1] OCTANE-8-CARBOXYLATE OF RAC-TERC-BUTYLE
    [1192] [1192] (1S, 2R, 3R, 5R) -3- (Benzylamino) -2-fluoro-8-azabicyclo [3.2.1] rac-tert-butyl octane-8-carboxylate (0.419 g, 1.25 mmol ) and Pd / C (10%, 0.133 g, 0.13 mmol) were dissolved in glacial acetic acid / ethanol (1: 3, 6.27 ml) and stirred under a 1 bar hydrogen atmosphere for 2 h. The mixture was filtered using a GF / A glass microfiber filter and concentrated in vacuo. The residue was divided between chloroform / IPA (9: 1) (5.0 ml) and sodium bicarbonate sat. (5.0 ml). The aqueous phase was extracted with chloroform / IPA (9: 1) (3x), and the combined organics were passed through a phase separator and concentrated in vacuo, to yield the title compound (305 mg), 1H NMR (400 MHz, DMSO-d6): 4.46-4.37 (1H, m), 4.31 (2H, s), 4.07 (1H, s), 3.00-2.81 (1H, m) , 1.79 (2H, d), 1.64-1.43 (5H, m), 1.43-1.34 (9H, m). PREPARATION 12: (1S, 2R, 3R, 5R) -3- {[(BENZILOXI) CARBONIL] AMINO} -2-FLUORO-8- AZABICICLE [3.2.1] OCTANE-8-CARBOXYLATE OF RAC-TERC-BUTYLE
    [1193] [1193] A (1S, 2R, 3R, 5R) -3-amino-2-fluoro-8-azabicyclo [3.2.1] rac-tert-butyl octane-8-carboxylate (305 mg, 1.25 mmol) dissolved in DCM / THF (8: 1, 6.25 ml), DIPEA (0.653 ml, 3.75 mmoles) and benzyl chloroformate (0.213 ml, 1.50 mmol) were added by cooling. The resulting mixture was stirred at RT for 18 h. A sat. Sodium bicarbonate solution. was added to the reaction mixture, which was extracted with dichloromethane three times. The combined organics were passed through a phase separator and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 40%, EtOAc / petrol) to yield the title compound (487 mg), 1H NMR (400 MHz, DMSO-d6): 7 , 37 (5H, s), 5.77 (1H, s), 5.05 (2H, s), 4.56 (1H, d), 4.35 (1H, s), 4.13 (1H, s), 4.01-3.73 (1H, m), 1.91-1.49 (6H, m), 1.40 (9H, s). PREPARATION 13: N - [(1S, 2S, 3R, 5R) -2-FLUORO-8- AZABICICLE [3.2.1] OCTAN-3-IL] CARBAMATE RAC- HYDROCHLORIDE BENZILA
    [1194] [1194] A (1S, 2R, 3R, 5R) -3- {[(benzyloxy) carbonyl] amino} -2-fluoro-8-azabicyclo [3.2.1] rac-tert-butyl octane-8-carboxylate ( 0.487 g, 1.29 mmol) in DCM (2.15 ml) 4M HCl in 1,4-dioxane (2.15 ml) was added to RT and stirred for 1.5 h. The reaction was concentrated in vacuo, to yield the title compound (404 mg) 1H NMR (400 MHz, Me-d3-OD): 7.49-7.28 (5H, m), 5.14 (2H, s), 4.38-4.24 (1H, m), 4.17-3.98 (2H, m), 2.32-2.06 (4H, m), 2.03 (2H, dd) . GENERAL PROCEDURE 1: N- [ENDO-8- (7-IODO-5 - {[2- (TRIMETHYLSILIL) ETOXI] METHIL} -5H-PIRROL [2,3-B] PIRAZIN-3-IL) - 8-AZABYCLE [3.2.1] OCTAN-3-IL] TERC-BUTYL CARBAMATE
    [1195] [1195] A 30 ml microwave tube was loaded with 3-chloro-7-iodine-5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazine (2 , 90 g, 7.08 mmoles), N- (endo-8-azabicyclo [3.2.1] octan-3-yl) tert-butyl carbamate (3.20 g, 14.2 mmoles) and NMP (6, 0 ml). The vessel was degassed and charged again with N2 (3x). Diisopropylethylamine (2.47 ml, 14.2 mmol) was added and the tube was capped, sealed and heated to 150 ° C for 3 days in a sand bath. After cooling, the reaction was diluted with EtOAc, then washed with brine / aq. sat. (3x). The organic phase was dried (MgSO4) and evaporated. The residue was purified by silica gel column chromatography (gradient elution, 5 to 35% EtOAc / petrol) to yield the title compound (2.59 g). MS: [M + H] + = 600.2.
    [1196] [1196] The compounds in Table 1 below were prepared using procedures analogous to those described in general procedure 1, starting with the appropriate substituted protected pyrrolopyrazine and varying the amine (synthesized as described above with any significant variations indicated below).
    [1197] [1197] A mixture of 4-bromo-2,3-dichloroaniline (10.0 g, 41.5 mmoles) and potassium ethyl xanthate (15.0 g, 93.4 mmoles) in DMF (100 ml) was stirred at 120 ° C for 18 h. The mixture was quenched with aq. 2M (80 ml) and water (400 ml). The mixture was filtered and washed with water to yield the title compound (1.13 g). 1H NMR (400 MHz, DMSO-d6): 14.10 (1H, s), 7.78 (1H, d), 7.19 (1H, d). PREPARATION 15: 6-BROMO-7-CHLORINE-1,3-BENZOTIAZOL
    [1198] [1198] A round-bottom flask loaded with 6-bromo-7-chloro-2,3-dihydro-1,3-benzothiazole-2-thione (1.13 g, 40.3 mmoles), iron powder (12 , 4 g, 221.5 mmoles) and acetic acid (200 ml) at RT was stirred (with mechanical stirrer) at 120 ° C for 2 h. Additional iron powder (24.8 g, 443.0 mmoles) was added and the mixture was stirred at 120 ° C for 2 h. Additional iron powder (12.4 g, 221.5 mmoles) was added and the reaction stirred at 120 ° C for 15 h. The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by recrystallization from EtOAc and then by column chromatography on silica gel (EtOAc: 10% petrol) to yield the title compound (2.7 g) MS: [M + H] + =
    [1199] [1199] To a solution of 4-bromo-3-chloro-2-fluoroaniline (25 g, 111 mmoles) and diisopropylethylamine (48.5 ml, 278 mmoles) in DCM (250 ml) cooled in a bath ice was added acetic anhydride (11.05 ml, 117 mmoles) for 1.5 h. The reaction was warmed to RT and stirred for 24 h. The reaction was washed with HCl (1 M, 250 ml), NaHCO3 (150 ml) and water (100 ml). The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 40% EtOAc / petrol) to yield the title compound (23.8 g). 1H NMR (500 MHz, DMSO-d6) 9.97 (s, 1H), 7.95 - 7.77 (m, 1H), 7.56 (dd, 1H), 2.10 (s, 3H) . PREPARATION 17: 6-BROMO-7-CHLORINE-2-METHYL-1,3-BENZOTIAZOLE
    [1200] [1200] To a solution of N- (4-bromo-3-chloro-2-fluorophenyl) acetamide (1.0 g, 3.77 mmol) in xylene (9.86 ml) was added Lawesson's Reagent (1, 53 g, 2.26 mmol). The reaction was heated to 110 ° C for 18 h. Cesium carbonate (4.11 g, 7.55 mmol) was added and the mixture was stirred at 110 ° C for 18 h. The reaction was cooled to RT and the reaction was diluted with water (500 ml) and ethyl acetate. The organic layer was separated and washed with sat. Brine solution, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (gradient elution,
    [1201] [1201] To a solution of 7-bromo-8-chloro-1,2-dihydroquinolin-2-one (520 mg, 2.0 mmoles) in anhydrous DMF (10 ml) was added sodium hydride (60% in oil mineral, 120 mg, 3.0 mmoles) and the reaction mixture was stirred for 30 min. Iodomethane (0.38 ml, 6.0 mmol) was added and the reaction mixture was stirred for 1 h. Water (20 ml) was added and the product was extracted with EtOAc (2x20 ml). The combined organic layer was washed with brine (2x20 ml), dried (MgSO4), filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 50%, EtOAc / petrol) to yield the title compound (414 mg), MS: [M + H] + = 273 PREPARATION 19: 7-BROMO-8-CHLORINE-N, N-DIMETHYLquinoline-2-AMINE
    [1202] [1202] A solution of 7-bromo-8-chloro-1,2-dihydroquinolin-2-one (1.0 g, 3.87 mmoles) in POCl3 was heated under reflux for 1 h. After cooling, most of the POCl3 was evaporated, ice and NH4OH were added and the product extracted with EtOAc. The organic phase was dried (MgSO4), filtered and evaporated to provide 7-bromo-2,8-dichloroquine (0.79 g), MS: [M + H] + = 278. 7-Bromo-2,8-dichloroquine (250 mg, 0.9 mmol) was dissolved in pyridine (1.5 ml), dimethylamine (40% solution in water, 1.5 ml) was added and the reaction mixture was heated in a sealed tube for 3 h . After cooling, water (10 ml) was added and the product extracted with EtOAc (2 x 15 ml). The organic phase was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 50%, EtOAc / petrol) to yield the title compound (220 mg), MS: [M + H] + = 287. PREPARATION 20 : 6-BROMO-7-CHLORINE-N, N-DIMETHYL-1,3-BENZOTIAZOL-2-AMINE
    [1203] [1203] Carbon disulfide (0.11 ml, 1.81 mmol) and dimethylamine solution (40% by weight in water, 0.29 ml, 2.26 mmol) were added to a suspension of 4-bromo-3 -chloro-2-iodoaniline (500 mg, 1.50 mmol), CuCl2 (202 mg, 1.50 mmol) and K2CO3 (624 mg, 4.51 mmoles) in DMF (5.0 ml) and the reaction heated to 110 ° C for 6 h under N2. After cooling, the reaction was diluted with EtOAc and washed with water (4x) and brine, then dried (MgSO4) and evaporated. The residue was purified by silica gel column chromatography (gradient elution, 0 to 25% EtOAc / petrol) to yield the title compound (362 mg). MS: [M + H] + = 291. PREPARATION 21: 6-BROMO-5-CHLORINE-2-METHYL-3,4- DIIDROQUINAZOLIN-4-ONA
    [1204] [1204] Methyl 6-Amino-3-bromo-2-chlorobenzoate (3.0 g, 13.16 mmol) was dissolved in 4 M / 1,4- HCl
    [1205] [1205] 6-Bromo-5-chloro-2-methyl-3,4-dihydroquinazolin-4-one (0.5 g, 1.83 mmol) and K2CO3 (0.76 g, 5.49 mmol) were dissolved in DMF (7 ml). 2- (Trimethylsilyl) ethoxymethyl chloride (0.388 ml, 2.196 mmoles) was added by dropping and the reaction was stirred at RT overnight. The reaction was diluted with diethyl ether, washed with water and brine. The organic phase was passed through a phase separator and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 20%, EtOAc / petrol) to yield the title compound (0.361 g) as a white solid. MS: [M + H] + = 403. PREPARATION 23: 3 - [(6-AMINO-3-BROMO-2-CHLOROPHENYL) SULFANYL] 2-ETHYLHEXYL PROPANOATE
    [1206] [1206] 4-Bromo-3-chloro-2-iodoaniline (4.80 g,
    [1207] [1207] 3 - [(6-amino-3-bromo-2-chlorophenyl) sulfanyl] 2-ethylhexyl propanoate (1.0 g, 2.4 mmoles) was dissolved in THF (20 ml) and treated with ethoxide 20% sodium in ethanol, stirring for 2 h. Acetic acid (2.24 ml, 39.2 mmoles) and N, N'-carbonyldiimidazole (3.18 g, 19.6 mmoles) were added and stirred for 2 h. The reaction was diluted with EtOAc (20 ml) and washed with aq. sat. (2x 20 ml) and brine (20 ml), then dried over anhydrous sodium sulfate, filtered and evaporated. The residue purified by column chromatography on silica gel (gradient elution, 0 to 50%, EtOAc / petrol) to yield the title compound (294 mg), MS: [M-H] - = 262.
    [1208] [1208] To a suspension of 6-bromo-7-chloro-2,3-dihydro-1,3-benzothiazole-2-one (294 mg, 1.11 mmol) and potassium carbonate (306 mg, 2.22 mmoles) in DMF (4 ml) 2- (trimethylsilyl) ethoxymethyl chloride (297 µl, 1.67 mmol) was added and stirred for 2 h. The reaction was diluted with EtOAc (10 ml) and washed with water (3 x 10 ml) and brine (10 ml). The combined organics were dried over anhydrous sodium sulfate, filtered and evaporated to yield the title compound (448 mg), 1H NMR (400 MHz, DMSO-d6): 7.81 (1H, d), 7.34 (1H, d), 5.37 (2H, s), 3.58 (2H, t), 0.88-0.84 (2H, m), - 0.04--0.08 (9H, m ). PREPARATION 26: 6-BROMO-7-CHLORINE-2- (OXOLAN-3-IL) -1,3- BENZOTIAZOL
    [1209] [1209] DIPEA (0.62 ml, 3.55 mmoles) and tetrahydrofuran-3-carbonyl chloride (0.26 ml, 2.37 mmoles) were added to a solution of 3 - [(6-amino-3- 2-ethylhexyl bromo-2-chlorophenyl) sulfanyl] propanoate (500 mg, 1.18 mmol) in DCM (6 ml) at 0 ° C and the reaction was then allowed to warm to RT and stirred for 16 h. The reaction was divided between DCM and NaHCO3 aq. sat. and the aq. separated extracted with DCM (2x). The combined organics were dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 25%, EtOAc / petrol) to provide the intermediate amide. This residue was re-dissolved in THF (6 ml), NaOEt solution (20% by weight in EtOH, 1.4 ml, 3.55 mmoles) was added and the reaction stirred for 30 min. After cooling to 0 ° C, TFA (2.7 ml, 35.5 mmoles) was carefully added and the reaction then heated to 60 ° C for 4 h. After cooling to 0 ° C, NaHCO3 aq. sat. it was added carefully and the mixture extracted with EtOAc (3x). The combined organics were washed with brine, dried (MgSO4) and evaporated. The residue was purified by silica gel column chromatography (gradient elution, 0 to 25%, EtOAc / petrol) then filtered through NH2 ion exchange silica gel to yield the title compound (271 mg). MS: [M + H] + = 318. PREPARATION 27: 6-BROMO-7-CHLORINE-2- (METOXIMETHIL) -1,3- BENZOTIAZOL
    [1210] [1210] DIPEA (0.82 ml, 4.73 mmoles) and methoxyacetyl chloride (0.32 ml, 3.55 mmoles) were added to a solution of 3 - [(6-amino-3-bromo-2- 2-ethylhexyl chlorophenyl) sulfanyl] propanoate (1.0 g, 2.37 mmoles) in DCM (12 ml) at 0 ° C and the reaction was then allowed to warm to RT and stirred for 1 h. The reaction was divided between
    [1211] [1211] Powdered iron (2.43 g, 43.6 mmol) was added to a solution of 4-bromo-3-chloro-2-nitrophenol (1.10 g, 4.36 mmol) in EtOH (20 ml ) and AcOH (10 ml) and the suspension heated to 90 ° C for 4 h. After cooling, the reaction was filtered, rinsing with EtOAc (~ 100 ml), and the filtrate washed with water (3x) and brine, then dried (MgSO4) and evaporated to yield the title compound (950 mg). MS: [M + H] + = 222 PREPARATION 29: 5-BROMO-4-CHLORINE-2,3-DIHYDRO-1,3-BENZOXAZOL-2- ONA
    [1212] [1212] 1,1′-Carbonyldiimidazole (2.08 g, 12.8 mmol) was added to a solution of 2-amino-4-bromo-3-chlorophenol (950 mg, 4.27 mmol) in THF (22 ml) and the reaction heated to reflux for 2 h. After cooling, the solvent was evaporated and the residue re-dissolved in EtOAc, then washed sequentially with 2M HCl (3x), water and brine. The organic fraction was dried (MgSO4) and evaporated to yield the title compound (1.04 g). MS: [M-H] - = 246 PREPARATION 30: 5-BROMO-4-CHLORINE-3 - {[2- (TRIMEThylSILIL) ETOXI] METIL} -2,3-DIIDRO-1,3-BENZOXAZOL-2-ONA
    [1213] [1213] 2- (Trimethylsilyl) ethoxymethyl chloride (0.53 ml, 3.02 mmol) was added to a suspension of 5-bromo-4-chloro-2,3-dihydro-1,3-benzoxazol-2- one (500 mg, 2.01 mmoles) and K2CO3 (556 mg, 4.03 mmoles) in DMF (7.5 ml) and the reaction stirred at RT under N2 for 3 h. The reaction was diluted with EtOAc and washed with water (3x) and brine, then dried (MgSO4) and evaporated to yield the title compound (752 mg). MS: [M + H] + = 378 PREPARATION 31: 5-BROMO-4-CHLORINE-2-METHYL-2H-INDAZOL
    [1214] [1214] A solution of sodium nitrite (58.6 g, 0.85 mol) in water (98 ml) was added to an ice-cooled 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 aged for 1 h at room temperature. Most of the solvent was evaporated and the residue suspended in water (500 ml) and filtered, washing with water (250 ml x 4), petrol (250 ml x 4) and drying in vacuo at 40 ° C, to yield 5- bromo-4-chloro-1H-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).
    [1215] [1215] Solid trimethyloxonium tetrafluoroborate (258 g, 1.74 mol) was charged to a chilled ice bath solution 5-bromo-4-chloro-1H-indazole (367 g, 1.59 mol) in EtOAc (1 , 9 l) and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with petrol (1.9 l) and aged for 10 min before filtration, washing with petrol (400 ml x 2). The filter cake was combined with sat sodium bicarbonate. (1.5 l), EtOAc (2 l) and the phases were separated. The organic phase was washed with sat. Sodium bicarbonate, dried (MgSO4) and concentrated in vacuo, to yield the title compound (236 g). 1H NMR (400 MHz, DMSO-d6): 8.53 (1H, s), 7.56 (1H, dd), 7.48 (1H, d), 4.20 (3H, s). PREPARATION 32: 5-BROMO-4-CHLORINE-2-ETHYL-2H-INDAZOL
    [1216] [1216] Triethyloxonium hexafluorophosphate (20 g, 80.6 mmoles) was added to 5-bromo-4-chloro-1H-indazole (12.4 g, 53.7 mmoles) in EtOAc (186 ml) and the resulting mixture it was stirred at room temperature overnight. The reaction mixture was quenched with sat. Sodium bicarbonate. (125 ml), and the phases were separated. Aq. it 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 yield the title compound (9.88 g). 1H NMR (400 MHz, DMSO-d6): 8.58 (1H, s), 7.58 (1H, dd), 7.48 (1H, d), 4.49 (2H, q), 1, 52 (3H, t). PREPARATION 33: 5-BROMO-4-FLUORO-2-METHYL-2H-INDAZOL
    [1217] [1217] To a suspension of 5-bromo-4-fluoro-1H-indazole (1.0 g, 4.7 mmoles) in EtOAc (20 ml) was added trimethyloxonium tetrafluoroborate (1.0 g, 7.0 mmoles) ) at room temperature. After stirring at the same temperature for 14.5 h, the mixture was quenched with NaHCO3 aq. sat. and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 0-60% EtOAc / hexane) to yield the title compound (0.91 g), MS: [M + H] + = 230. PREPARATION 34: BORONIC ACID (4-CHLORINE-2-ETHYL-2H-INDAZOL-5-ILA)
    [1218] [1218] Triisopropylborate (10 ml, 43.2 mmoles) was added to a solution of 5-bromo-4-chloro-2-ethyl-2H-indazole (9.1 g, 39.3 mmoles) in THF (45 ml ) and toluene (136 ml), stirring at room temperature under nitrogen. The reaction mixture was cooled to -70 ° C and n-butyllithium (2.5M, 17.3 ml, 43.2 mmoles) was added over 50 min. The reaction was warmed to room temperature, before sudden cooling with 2M hydrochloric acid (65 ml) and stirring overnight. The mixture was filtered, washed with petrol (50 ml) and the solid was dried in vacuo, to yield the title compound (1.4 g) 1H NMR (400 MHz, DMSO-d6): 8.45 (1H, s), 7.50 (1H, dd), 7.28 (1H, d), 4.52 - 4.38 (2H, m), 1.52 (3H, t). PREPARATION 35: 5-BROMO-3,4-DICLORO-2-METHYL-2H-INDAZOL
    [1219] [1219] N-chlorosuccinimide (550 mg, 4.12 mmol) was added to 5-bromo-4-chloro-2-methyl-2H-indazole (1.0 g, 4.12 mmol) in DMF (20.6 ml) to TA. After stirring for 18 h, water was added to effect precipitation. The precipitate was filtered, washed with water and dried in a vacuum oven. The solid was taken up in EtOAc / petrol, filtered and washed with petrol. Dried in a vacuum oven, to yield the title compound (440 mg). MS: [M + H] + = 280. PREPARATION 36: 6-AMINO-3-BROMO-2-CHLOROBENZALDEHYDE
    [1220] [1220] 2-Amino-6-chlorobenzaldehyde (500 mg, 3.22 mmoles) was dissolved in DMF (16 ml) at RT and N-bromosuccinimide (573 mg, 3.22 mmoles) added in one portion. The reaction was stirred for 66 h. Water was added and the precipitate was filtered by vacuum, washing with water and petrol. The solid was dried in a vacuum oven, to yield the title compound (438 mg). MS: [M + H] + = 233. PREPARATION 37: 6-BROMO-5-CHLORINE-3-METHYXY-2-METHYLquinoline NH2 N
    [1221] [1221] A solution of 6-amino-3-bromo-2-chlorobenzaldehyde (582 mg, 2.50 mmol), methoxyacetone (308 mg, 3.50 mmol), and ethanolic KOH in ethanol (10% w / w) v, 0.70 ml) was stirred at RT for 20 min. The precipitate that formed was filtered and dried in a vacuum oven, to yield the title compound (440 mg). MS: [M + H] + = 285. PREPARATION 38: 5-BROMO-2- {2 - [(TERC- BUTYLDIMETHYLSYLIL) OXI] ETHYL} -4-CHLORINE-2H-INDAZOL
    [1222] [1222] 5-Bromo-4-chloro-2H-indazole (2.0 g, 8.70 mmoles) and cesium carbonate (5.67 g, 10.44 mmoles) were combined in NMP (43.39 ml) and heated to 60 ºC. After stirring for 30 min (2-bromoethoxy) -tert-butyldimethylsilane (2.05 ml, 2.29 g, 9.57 mmol) was added. The reaction was stirred for 1 h and cooled to RT. A NH4Cl solution was added and the aqueous phase extracted with EtOAc (3x). The combined organics were passed through a phase separator and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution, 0 to 50%, EtOAc / petrol) to yield the title compound (631 mg), 1H NMR (400 MHz, CDCl3): 8.08 (1H, s), 7.49 (1H, d), 7.44 (1H, d), 4.58-4.46 (2H, m), 4.13-3.98 (2H, m), 0.85 (9H, s), -0.09 (6H, s). PREPARATION 39: 5-BROMO-2- {2 - [(TERC- BUTYldimethylsilyl) OXI] ETHYL} -3,4-DICHLORO-2H-INDAZOL
    [1223] [1223] Prepared from 5-bromo-2- {2- [(tert-butyldimethylsilyl) oxy] ethyl} -4-chloro-2H-indazole using a similar procedure for the preparation of 5-bromo-3, 4-dichloro-2-methyl-2H-indazole to yield the title compound, MS: [M + H] + = 423. PREPARATION 40: 5-BROMO-4-CHLORINE-2-METHYL-2H-INDAZOL-3- CARBALDEHYDE
    [1224] [1224] To 5-bromo-4-chloro-2-methyl-2H-indazole (1.0 g, 4.10 mmol) in THF (8.0 ml), cooled to -78 ºC, lithium diisopropylamide ( 1.0 M, in THF, 7.38 ml, 7.38 mmoles) and the reaction stirred for 90 min. The temperature was increased to 0 ºC (ice bath) and stirred for 25 min. DMF (1.0 ml) was added and the reaction stirred for 30 min. Saturated NH4Cl was added and the reaction extracted with EtOAc (3x). The combined organics were washed with sat. Brine solution. (3x), crossed by a phase separator and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution, 0 to 50%, EtOAc / petrol) to yield the title compound (865 mg), 1H NMR (400 MHz, DMSO-d6): 10 , 63 (1H, s), 7.80 (1H, d), 7.71 (1H, d), 4.43 (3H, s). PREPARATION 41: (5-BROMO-4-CHLORINE-2-METHYL-2H-INDAZOL-3-ILA) METHANOL
    [1225] [1225] 5-Bromo-4-chloro-2-methyl-2H-indazol-3-carbaldehyde (0.707 g, 2.60 mmol) was suspended in methanol / THF (1: 1, 13 ml) at 0 ° C and solid sodium borohydride (0.108 g, 2.86 mmol) was added in portions over 10 min. The resulting mixture was stirred at 0 ° C for 30 min then at RT for another 10 min. The reaction was quenched by the addition of ice. The residue was partitioned between EtOAc and water. The aq. was extracted twice with EtOAc and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo, to yield the title compound (543 mg), 1H NMR (400 MHz, DMSO-d6): 7.54 ( 1H, d), 7.48 (1H, d), 5.44 (1H, t), 5.05 (2H, d), 4.19 (3H, s). PREPARATION 42: 5-BROMO-3 - {[(TERC- BUTYLDIMETHYLSILIL) OXI] METHIL} -4-CHLORINE-2-METHYL-2H-INDAZOL
    [1226] [1226] tert-butylchlorodimethylsilane (0.377 g, 2.50 mmoles) was added to an ice-cooled solution of (5-bromo-4-chloro-2-methyl-2H-indazol-3-yl) methanol (0.653 g, 2.38 mmoles) and imidazole (0.178 g, 2.62 mmoles) in DMF (5.96 ml) under an argon atmosphere. After stirring at room temperature for 2 h, the mixture was brusquely cooled with ice water and extracted with EtOAc (2x). The combined extracts were washed with sat. Brine solution, dried over sodium sulfate and concentrated in vacuo. The raw material was purified by column chromatography on silica gel (gradient elution, 0 to 50%, EtOAc / petrol) to yield the title compound (783 mg), MS: [M + H] + = 389. PREPARATION 43: 4-CHLORINE-2-METHYL-5- (4,4,5,5-TETRAMETHIL-1,3,2-DIOXABOROLAN-2-IL) -2H-INDAZOL
    [1227] [1227] 5-Bromo-4-chloro-2-methyl-2H-indazole (5.0 g, 20.50 mmol), bis (pinacolate) diboro (6.25 g, 24.60 mmol), [1, 1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.750 g, 1.02 mmol) and potassium acetate (6.04 g, 61.50 mmoles) were converted to aqueous paste in 1,4-dioxane (103 ml) and heated to 95 to 100 ° C for 18 h. The reaction was cooled to RT, filtered and washed with EtOAc. The filtrate was concentrated in vacuo and the residue dissolved in toluene and petrol added until precipitation occurred. The suspension was filtered under vacuum suction and the filtrate concentrated in vacuo, to yield the title compound (11.8 g), MS: [M + H] + = 293.
    [1228] [1228] The compounds in Table 2 below were prepared using procedures analogous to those described in preparation 43, starting with the appropriate substituted aryl halide (synthesized as described above with any significant variations indicated).
    [1229] [1229] N- [endo-8- (7-iodo-5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazin-3-yl) - 8-azabicycles [ 3.2.1] tert-butyl octan-3-yl] carbamate (0.500 g, 0.83 mmol), 4-chloro-2-methyl-5- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl) -2H-indazole (0.255 g, 1.34 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.061 g, 0.08 mmol) and carbonate potassium (0.221 g, 1.67 mmol) were dissolved in water (2.78 ml) and 1,2-dimethoxyethane (4.17 ml). The reaction mixture was heated to 95-100 ° C and stirred for 3 h. After cooling to RT, water was added and the aqueous layer extracted with EtOAc (3x). The combined organics were passed through a phase separator and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 50%, EtOAc / petrol) to yield the title compound (261 mg), MS: [M + H] + = 638.
    [1230] [1230] The compounds in Table 3 presented below were prepared in a manner analogous to general procedure 2, using the corresponding aryl halide and boronate or boronic acid, with any significant variations indicated.
    [1231] [1231] 6-Bromo-7-chloro-2- (methoxymethyl) -1,3-benzothiazole (350 mg, 1.2 mmol), bis (pinacolate) diboro (456 mg, 1.8 mmol), [1, 1'- bis (diphenylphosphino) ferrocene] dichloropalladium (II) (175 mg, 0.24 mmol) and potassium acetate (587 mg, 6.0 mmol) were combined in a sealed, 30 ml microwave tube evacuated and filled with nitrogen (x2). 1,4-Dioxane (6 ml) was added and the tube refilled (x2) before heating at 90 ° C for 2 h. After cooling, N- [endo- 8- (7-iodo-5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazin-3-yl) -8-azabicycle [3.2.1] octan-3-yl] tert-butyl carbamate (717 mg, 1.2 mmol), bis (diphenylphosphino) ferrocene] dichloropalladium (II) (175 mg, 0.24 mmol), potassium carbonate ( 992 mg, 7.2 mmoles) and water (3 ml) were added. The reaction was reversed, filled with nitrogen (x2) and heated to 70 ° C for 2 h. After cooling, the reaction was diluted with water and extracted with EtOAc (3x). The combined organics were dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 100%, EtOAc / petrol) to yield the title compound (412 mg). MS: [M + H] + = 685.
    [1232] [1232] The compounds in Table 4 shown below were prepared in a manner analogous to general procedure 3, using the corresponding aryl halides, with any significant variations indicated.
    [1233] [1233] exo-8- [7- (4-Chloro-2-methyl-2H-indazol-5-yl) -5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3- b] pyrazin-3-yl] -8-azabicyclo [3.2.1] octane-3-carbonitrile (69 mg, 0.13 mmol) dissolved in THF (1.26 ml) and LiAlH4 (1.0M in THF, 0.151 ml) added to RT over 10 min. After stirring for 30 min, 1M sodium hydroxide (3.0 ml) was added. The aq. was extracted with EtOAc (3x). The combined organics were passed through a phase separator and concentrated in vacuo, to yield the title compound that was directly used in the next step. MS: [M + H] + = 552. PREPARATION 45: 7- [7- (4-CHLORINE-2-METHYL-2H-INDAZOL-5-IL) -5H- PIRROL [2,3-B] PIRAZIN-3 -IL] -1,7-DIAZASPIRO [3.5] NONANO-1- TERC-BUTYL CARBOXYLATE
    [1234] [1234] A stirred mixture of 7- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5 - {[2- (trimethylsilyl) ethoxy] methyl} -
    [1235] [1235] Prepared by the general Suzuki procedure 2, using 3-chloro-7-iodine-5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazine (1 eq) and 4-chloro-2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole (1 eq), to yield the compound MS title: [M + H] + = 448 PREPARATION 47: N - [(1S, 2R, 3R, 5R) -8- [7- (4-CHLORINE-2-METHYL-2H- INDAZOL-5-IL) - 5 - {[2- (TRIMETHILSILIL) ETOXI] METHIL} -5H- PIRROL [2,3-B] PIRAZIN-3-IL] -2-FLUORO-8- AZABICYCLE [3.2.1] OCTAN-3-IL] CARBAMATE OF RAC-BENZILA
    [1236] [1236] A solution of 4-chloro-5- (3-chloro-5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazin-7-yl) - 2- methyl-2H-indazole (0.188 g, 0.42 mmol), N - [(1S, 2S, 3R, 5R) - 2-fluoro-8-azabicyclo [3.2.1] octan-3-yl] carbamate rac hydrate -benzyl (0.158 g, 0.5 mmol), tris (dibenzylideneacetone) dipaladium (0) -chloroform (22 mg, 0.02 mmol) adduct, dicyclohexyl [2 ', 4', 6'-tris (propan-2 -yl) - [1,1'-biphenyl] -2-yl] phosphane (20 mg, 0.04 mmol) and cesium carbonate (0.507 g, 1.56 mmol) in toluene (4.21 ml) was degassed under nitrogen for 5 min. The reaction was heated to 110 ° C for 18 h. The reaction was diluted with DCM and purified by silica gel column chromatography (gradient elution, 0 to 50%, EtOAc / petrol) to yield the title compound (72 mg), MS: [M + H] + = 690.
    [1237] [1237] Compounds in Table 5 below were prepared in a manner analogous to the synthesis of N - [(1S, 2R, 3R, 5R) - 8- [7- (4-chloro-2-methyl-2H-indazol-5-yl ) -5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazin-3-yl] - 2-fluoro-8-azabicyclo [3.2.1] octan-3-yl ] rac-benzyl carbamate of preparation 47, using the corresponding aryl halide and amine.
    [1238] [1238] Trifluoroacetic acid (0.7 ml) was added to N - [(1S, 2R, 3R, 5R) -8- [7- (4-chloro-2-methyl-2H- indazol-5-yl) - 5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazin-3-yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-yl] carbamate of rac-benzyl (72 mg, 0.10 mmol) dissolved in DCM (0.7 ml and the mixture was stirred for 1.5 h. Additional trifluoroacetic acid (0.5 ml) was added and the reaction stirred for 2 h The reaction was concentrated in vacuo and the residue was dissolved in methanol (1.0 ml) Ethylene diamine was added (1.0 ml) to the reaction and stirred for 2 h The reaction was concentrated in vacuo and water was added to the reaction. The aq. was extracted with ethyl acetate (3x) and the combined organics washed with brine solution and concentrated in vacuo.The residue was purified by column chromatography on silica gel (gradient elution, 0 to 100%, ethyl acetate / petrol 40 to 60 ºC), to yield the title compound (37 mg), MS: [M + H] + = 560. PREPARATION 49: N- [EXO-8- [7- (4-CHLORINE -2-ETIL-2H- INDAZOL-5-IL) -5 - {[2- (TRIMETYLSILIL) ETOXI] METHIL} -5H-PIRROL [2,3- B] PIRAZIN-3-IL] -8-AZABICICLE [3.2.1] OCTAN-3- IL] TERC-BUTYLE CARBAMATE
    [1239] [1239] To a stirred solution of N- [exo-8- (7-iodine-5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazin-3-yl) -8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (0.5 g, 0.834 mmol) (azeotropically dried with dry toluene, x2) in THF (6.68 ml) at 0 ° C lithium chloride and isopropylmagnesium chloride complex solution (1.3 M in THF) (1.41 ml, 1.84 mmol) was added by dripping.
    [1240] [1240] To a solution of 3,5-dibromo-6-chloropyrazin-2-amine (5.0 g, 17.42 mmol) in anhydrous EtOAc (40 ml) was added triethylamine (2.54 ml, 18.29 mmoles) and CuI (0.165 g, 0.87 mmol). The mixture was degassed with bubbling N2 for 20 min, then Pd (PPh3) 4 (0.10 g, 0.87 mmol) was added. The reaction mixture was cooled to 0 ° C, ethinyltrimethylsilane (2.52 ml, 18.29 mmoles) was added slowly and the temperature was allowed to rise to 15 ° C over 3 h. The reaction mixture was diluted with water (30 ml) and extracted with EtOAc (3x). The combined organic layers were dried using a phase separator cartridge then concentrated. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 10%, EtOAc / petrol) to yield the title compound (4.77 g). MS: [M + H] + = 304. PREPARATION 51: 2-BROMO-3-CHLORINE-5H-PIRROL [2,3-B] PIRAZINE
    [1241] [1241] 5-Bromo-6-chloro-3- [2- (trimethylsilyl) ethynyl] pyrazin-2-amine (5.29 g, 17.42 mmol) was dissolved in anhydrous DMF (20 ml) under an atmosphere of nitrogen and cooled to 0 ° C. KOtBu (2.34 g, 20.90 mmoles) was added in portions over 5 min and the reaction mixture was stirred at 0 ° C for an additional 10 min. The reaction was allowed to warm to RT and stirred for 2 h. The reaction was quenched with NH4Cl aq. sat. (20 ml) and more water was added resulting in a precipitate. The precipitate was filtered and washed with water, then dried in a vacuum oven overnight, to yield the title product (3.03 g). MS: [M + H] + = 232. PREPARATION 52: 2-BROMO-3-CHLORINE-7-IODINE-5H-PIRROL [2,3- B] PIRAZINE
    [1242] [1242] 2-Bromo-3-chloro-5H-pyrrole [2,3-b] pyrazine (2.49 g, 10.53 mmol) was dissolved in DMF (20 ml) and N-iodosuccinimide (2.607 g, 11 , 58 mmoles) added to the TA. The reaction was stirred for 1 h at RT. Water was added until precipitation occurred. The solid was collected by vacuum filtration, washed with water and dried in a vacuum oven for 24 hours, to yield the title compound (3.39 g). MS: [MH] + = 357. PREPARATION 53: N - {[1- (2-BROMO-7-IODO-5 - {[2- (TRIMETHILSILIL) ETOXI] METHIL} -5H-PIRROL [2,3-B ] PIRAZIN-3-IL) - 4-METHYLPIPERIDIN-4-IL] METHIL} TERC-BUTYL CARBAMATE
    [1243] [1243] 2-Bromo-3-chloro-7-iodo-5H-pyrrole [2,3-b] pyrazine (1.0 g, 2.8 mmol) was dissolved in DMF (10 ml) and sodium hydride ( 60% in mineral oil, 0.134 g, 3.37 mmoles) was added in portions over 5 min at 0 to 4 ° C (ice bath). The reaction was warmed to RT for 30 min, then cooled to 0 to 4 ° C (ice bath). 2- (trimethylsilyl) ethoxymethyl chloride (0.596 ml, 3.37 mmoles) was added by dripping and the dark red / orange solution stirred for 1 h, then warmed to RT and stirred for 2 h. NH4Cl sat. was added and the reaction was diluted with diethyl ether. The organic phase was washed with water, then brine, dried by passing through a phase separator and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 30%, EtOAc / petrol) to yield 2-bromo-3-chloro-7-iodo-5 - {[2- (trimethylsilyl) ethoxy ] methyl} -5H- pyrrole [2,3-b] pyrazine (0.99 g), which was used directly in the next step.
    [1244] [1244] 2-Bromo-3-chloro-7-iodo-5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazine (0.20 g, 0.40 mmol ) and tert-butyl N - [(4-methylpiperidin-4-yl) methyl] carbamate (0.112 g, 0.488 mmol) were dissolved in NMP (3 ml). Et3N (0.3 ml, 2.1 mmoles) was added and the reaction was heated to 70 ° C in a microwave for 2 h. After cooling, the reaction was diluted with diethyl ether and washed with water, then brine. The organic layer was dried using a phase separator cartridge, then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 50%, EtOAc / petrol) to yield the title compound (0.15 g). MS: [M + H] + = 681. PREPARATION 54: N - ({1- [2-BROMO-7- (4-CHLORO-2-METHYL-2H- INDAZOL-5-IL) -5 - {[2 - (TRIMETHILSILIL) ETOXI] METHIL} -5H-
    [1245] [1245] Prepared according to the general procedure
    [1246] [1246] N - ({1- [2-Bromo-7- (4-chloro-2-methyl-2H-indazol-5-yl) -5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H- pyrrole [2,3-b] pyrazin-3-yl] -4-methylpiperidin-4-yl} methyl) tert-butyl carbamate (0.056 g, 0.077 mmol),
    [1247] [1247] 2-Bromo-3-chloro-7-iodo-5H-pyrrole [2,3-b] pyrazine (2.0 g, 5.61 mmol) was dissolved in anhydrous DMF (10 ml) under an atmosphere of nitrogen and cooled to 0 ° C. NaH (60% in mineral oil, 0.247 g, 6.17 mmoles) was added in small portions, then the reaction was allowed to warm to RT and stirred for 30 min during which time the entire evolution of hydrogen stopped. The reaction was cooled to 0 ° C and dimethylsulfamoyl chloride (0.662 ml, 6.17 mmoles) was added by dropping. The reaction was allowed to warm to RT, stirred for 1 h, then abruptly cooled with aq. sat. (10 ml). The reaction mixture was diluted with EtOAc and washed with water, then brine. The organic layer was dried using a phase separator cartridge, then concentrated under reduced pressure.
    [1248] [1248] 2-Bromo-3-chloro-7-iodo-N, N-dimethyl-5H-pyrrole [2,3-b] pyrazine-5-sulfonamide (0.84 g, 1.82 mmol) and N- [endo-8 -azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (0.82 g, 3.64 mmoles) were dissolved in NMP (7 ml). Et3N (0.716 ml, 5.46 mmoles) was added and the reaction was heated to 60 ° C overnight. After cooling, the reaction diluted with diethyl ether and washed with water, then brine. The organic layer was dried using a phase separator cartridge, then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 70%, EtOAc / petrol) to yield the title compound (0.908 g). MS: [M + H] + = 655. PREPARATION 58: N- [ENDO-8- [2-BROMO-7- (4-CHLORINE-2-METHYL-2H- INDAZOL-5-IL) -5- (DIMETHILSULFAMOIL ) -5H-PIRROL [2,3-B] PIRAZIN- 3-IL] -8-AZABICYCLE [3.2.1] OCTAN-3-IL] TERC- CARBAMATE BUTILLE
    [1249] [1249] Prepared by the general Suzuki procedure 2 using N- [endo-8- [2-bromo-5- (dimethylsulfamoyl) -7-iodo-5H-pyrrole [2,3-b] pyrazin-3- yl] -8- azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (0.908 g, 1.488 mmol), to yield the title compound (0.536 g). MS: [M + H] + = 695. PREPARATION 59: N- [ENDO-8- [7- (4-CHLORINE-2-METHYL-2H-INDAZOL-5-IL) -5- (DIMETHILSULFAMOIL) -2- METHYL-5H-PIRROL [2,3-B] PIRAZIN-3-IL] -8-AZABICYCLE [3.2.1] OCTAN-3-IL] TERC-BUTYL CARBAMATE
    [1250] [1250] N- [endo-8- [2-Bromo-7- (4-chloro-2-methyl-2H-indazol-5-yl) -5- (dimethylsulfamoyl) - 5H-pyrrole [2,3- b ] pyrazin-3-yl] -8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (0.20 g, 0.287 mmol), lithium bromine (0.074 g, 0.863 mmol) and dichloride ( 1,3-diisopropylimidazole-2-ylidene) (3-chloropyridyl) palladium (II) (PEPPSI) (0.014 g, 0.02 mmol) were dissolved in THF (2 ml) and NMP (2 ml). A solution of methylzinc chloride in THF (2M, 0.344 ml, 0.689 mmol) was added and the reaction was stirred at RT for 30 min. NH4Cl sat. was added and the reaction was diluted with diethyl ether and washed with water, then brine. The organic layer was dried using a phase separator cartridge, then concentrated under reduced pressure. The residue was used directly in the next step. MS: [M + H] + = 629. PREPARATION 60: N- [EXO-8- [7- (4-CHLORINE-2-METHYL-2H-INDAZOL-5-IL) -5- (DIMETHILSULFAMOIL) -2- METHYL-5H-PIRROL [2,3-B] PIRAZIN-3-IL] -8-AZABICYCLE [3.2.1] OCTAN-3-IL] TERC-BUTYL CARBAMATE
    [1251] [1251] Prepared in a similar manner to N- [endo-8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5- (dimethylsulfamoyl) - 2-methyl-5H-pyrrole [ 2,3-b] pyrazin-3-yl] -8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate, i.e. preparations; 57.58 and 59, to yield the title compound, MS: [M + H] + = 629 PREPARATION 61: N- {1- [7- (4-CHLORINE-2-METHYL-2H-INDAZOL-5-IL ) -5- (DIMETHILSULFAMOIL) -2-METHYL-5H-PIRROL [2,3-B] PIRAZIN-3-IL] -4- METHYLPIPERIDIN-4-IL} TERC-BUTYL CARBAMATE
    [1252] [1252] Prepared in a similar manner to N- [endo-8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5- (dimethylsulfamoyl) - 2-methyl-5H-pyrrole [ 2,3-b] pyrazin-3-yl] -8-
    [1253] [1253] 3,5-Dichloropyrazine-2-carbaldehyde (2.0 g, 11.29 mmol) was dissolved in DMF (20 ml) and cooled to 0 ° C. Triethylamine (3.14 ml, 22.58 mmoles) was added followed by tert-butyl N- [exo-8-azabicyclo [3.2.1] octan-3-yl] carbamate (2.55 g, 11.29 mmoles ). The reaction was allowed to warm to room temperature overnight, then diluted with diethyl ether and washed with water, then brine. The organic layer was dried by passing through a phase separator cartridge, then concentrated under reduced pressure, to yield the title compound (3.94 g) was used in the next step without further purification. MS: [M + H] + =
    [1254] [1254] Hydrazine hydrate (2.61 ml, 53.72 mmoles) was added to a solution of N- [exo-8- (6-chloro-5-formylpyrazin-2-yl) -8-azabicyclo [3.2. 1] octan-3-yl] tert-butyl carbamate (3.943 g, 10.74 mmoles) in 1.4-
    [1255] [1255] N-Iodosuccinimide (5.927 g, 23.24 mmol) was added to a solution of N- [exo-8- {1H-pyrazol [3,4-b] pyrazin-6-yl} -8-azabicyclo [ 3.2.1] octan-3-yl] tert-butyl carbamate (3.998 g, 11.62 mmoles) in DMF (40 ml). The reaction was heated to 60 ° C for 2 h, then allowed to cool to room temperature. Water was added until precipitation occurred. The solid was collected by vacuum filtration, washed with water and dried in a vacuum oven at 40 ° C overnight to yield the title compound (4.1 g). MS: [M + H] + = 471. PREPARATION 65: N- [EXO-8- {5-BROMO-3-IODO-1H-PIRAZOL [3,4- B] PIRAZIN-6-IL} -8-AZABYCLE [3.2.1] OCTAN-3-IL] TERC-BUTYL CARBAMATE
    [1256] [1256] N-Bromosuccinimide (0.9 g, 5.06 mmol) was added to a solution of N- [exo-8- {3-iodo-1H-pyrazol [3,4-b] pyrazin-6-yl } -8-azabicycle [3.2.1] octan-3-
    [1257] [1257] N- [exo-8- {5-Bromo-3-iodo-1H-pyrazol [3,4-b] pyrazin-6-yl} -8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (1.64 g, 2.99 mmoles) was dissolved in DMF (10 ml) and sodium hydride (60% in mineral oil, 0.229 g, 3.29 mmoles) was added in portions over 5 minutes at 0 to 4 ° C (ice bath). The reaction was warmed to room temperature for 30 minutes, then cooled to 0 to 4 ° C (ice bath). 2- (Trimethylsilyl) ethoxymethyl chloride (0.582 ml, 3.29 mmoles) was added by dripping and the dark red / orange solution stirred for 1 h, then warmed to room temperature and stirred for 2 h. Saturated ammonium chloride was added and the reaction was diluted with diethyl ether. The organic phase was washed with water, then brine, dried by passing through a phase separator and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 30%, EtOAc / petrol) to yield the title compound (1.20 g). MS: No molecular ions were observed under the conditions of MS used. PREPARATION 67: N- [EXO-8- [5-BROMO-3- (4-CHLORINE-2-METHYL-2H- INDAZOL-5-IL) -1 - {[2- (TRIMETHYLSILIL) ETOXI] METHY} -1H - PIRAZOL [3,4-B] PIRAZIN-6-IL] -8-AZABICICLO [3.2.1] OCTAN-3 IL] TERC-BUTYL CARBAMATE
    [1258] [1258] Prepared according to general procedure 2, starting with N- [exo-8- (5-bromo-3-iodo-1 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazole [3,4- b] pyrazin-6-yl) - 8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (1.198 g, 1.76 mmol), to yield the title compound (0.197 g). MS: [M + H] + = 719. PREPARATION 68: N- [EXO-8- [3- (4-CHLORO-2-METHYL-2H-INDAZOL-5-IL) -5-METHYL-1 - {[ 2- (TRIMETHILSILIL) ETOXI] METHIL} -1H- PIRAZOL [3,4-B] PIRAZIN-6-IL] -8-AZABICYCLE [3.2.1] OCTAN-3- IL] TERC-BUTYL CARBAMATE
    [1259] [1259] N- [exo-8- [5-Bromo-3- (4-chloro-2-methyl-2H-indazol-5-yl) -1 - {[2- (trimethylsilyl) ethoxy] methyl} -1H - pyrazole [3,4-b] pyrazin-6-yl] -8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (0.197 g, 0.274 mmol), lithium bromine (0.071 g, 0.823 mmol) and (1,3-diisopropylimidazol-2-ylidene) (3-chloropyridyl) palladium (II) dichloride (PEPPSI) (0.010 g, 0.0137 mmol) were dissolved in THF (2 ml) and NMP (2 ml ). A solution of methylzinc chloride in THF (2M, 0.342 ml, 0.685 mmol) was added and the reaction was stirred at room temperature for 30 minutes.
    [1260] [1260] To an oven-dried microwave vial equipped with a magnetic stirring bar, N- [endo-8- [2-bromo-7- (4-chloro-2-methyl-2H-indazol-5-) was loaded il) -5- (dimethylsulfamoyl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (120 mg, 0 , 17 mmol), [Ir {dFCF3ppy} 2) (bpy)] (PF6) (3.0 mg, 0.003 mmol), NiCl2 · diglyme (1.1 mg, 0.0045 mmol), (2-trimethylsilyl) - potassium ethoxymethyl trifluoroborate (45.3 mg, 0.19 mmol), K2HPO4 (45.2 mg, 0.26 mmol) and 4,4-dithertobutyl bipyridine (1.7 mg, 0.0045 mmol). The flask was evacuated and filled with nitrogen gas (3x), then to the flask was added 1,4-dioxane loaded with nitrogen (3.5 ml) and NMP loaded with nitrogen (0.6 ml). The flask was then irradiated with a blue LED Kessel lamp (34W) overnight. The reaction was concentrated under reduced pressure. To the residue was added 4% aqueous LiCl and EtOAc. The organic phase was separated and aq. was extracted with EtOAc (3x). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 25%, petrol / acetone), to yield the title compound. MS: [M + H] + = 638. PREPARATION 70: 5-BROMO-4-CHLORINE-2-METHYL-2H-1,2,3- BENZOTRIAZOL
    [1261] [1261] To a solution of 6-bromo-7-chloro-1H-1,2,3-benzotriazole (400 mg, 1.72 mmol) in THF (8 ml) was added triphenylphosphine (542 mg, 2.06 mmol), MeOH (0.084 ml, 2.06 mmoles) and bis (2-methoxyethyl) azodicarboxylate (484 mg, 2.06 mmoles) at RT. The mixture was stirred at RT for 2 h. The reaction solution was then concentrated in vacuo, and the residue was purified by column chromatography on silica gel (gradient elution, 10 to 40%, EtOAc / hexane). Fractions containing target product were collected and concentrated in vacuo. The residue was purified by column chromatography on NH silica gel (gradient elution, 0 to 20%, EtOAc / hexane), to yield the title compound (160 mg). MS: [M + H] + = 246, 248. PREPARATION 71: 4-CHLORINE-2-METHYL-5- (4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-IL) - 2H-1,2,3-BENZOTRIAZOL
    [1262] [1262] The mixture of 5-Bromo-4-chloro-2-methyl-2H-1,2,3-benzotriazole (150 mg, 0.609 mmol), bis (pinacolate) diboro (232 mg, 0.913 mmol), complex [ 1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) with dichloromethane (39.8 mg, 0.0487 mmol) and potassium acetate (119 mg, 1.22 mmol) in 1,4-dioxane (1, 5 ml) was degassed, purged with nitrogen, and stirred at 100 ° C for 3 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 column chromatography on NH silica gel (gradient elution, 0 to 70%, EtOAc / hexane), to yield the title compound (155 mg). MS: [M + H] + = 294, 296. PREPARATION 72: N- [ENDO-8- [7- (4-CHLORINE-2-METHYL-2H-1,2,3- BENZOTRIAZOL-5-IL) - 5 - {[2- (TRIMETHILSILIL) ETOXI] METHIL} -5H- PIRROL [2,3-B] PIRAZIN-3-IL] -8-AZABICICLE [3.2.1] OCTAN-3- IL] TERC-BUTYL CARBAMATE
    [1263] [1263] To a suspension of N- (endo-8- (7-iodo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrole [2,3-b] pyrazin-3-yl) - 8-azabicyclo [3.2.1] octan-3-yl) tert-butyl carbamate (50 mg, 0.0834 mmol) and 4-chloro-2-methyl-5- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) -2H-1,2,3-benzotriazole (29.4 mg, 0.100 mmol) in 1,4-dioxane (0.50 ml) and water (0.05 ml ) potassium phosphate (35.4 mg, 0.167 mmol) and 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloromethane (6.81 mg, 0.00834 mmol) complex were added to the RT. The mixture was stirred at 100 ° C for 1 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 diluted with EtOAc and water was added. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 50 to 100%, EtOAc / hexane), to yield the title compound (38 mg). MS: [M + H] + = 639, 641.
    [1264] [1264] To a solution of 5-bromo-4-chloro-1H-indazole (1.00 g, 4.32 mmol) in THF (10 ml) was added N-cyclohexyl-N-methylcyclohexanamine (1.85 ml, 8.64 mmoles) and tert-butyl 2-bromoacetate (1.30 ml, 8.64 mmoles) at RT. The mixture was stirred at 70 ° C for 18 h, diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 5 to 30%, EtOAc / hexane), to yield the title compound (487 mg). MS: [M + H] + = 345, 347. PREPARATION 74: 2- (4-CHLORINE-5- (4,4,5,5-TETRAMETHYL-1,3,2- DIOXABOROLAN-2-IL) -2H -INDAZOL-2-ILA) TERC-BUTYL ACETATE
    [1265] [1265] The mixture of 2- (5-bromo-4-chloro-2H-indazol-2-yl) tert-butyl acetate (480 mg, 1.39 mmol), bis (pinacolate) diboro (529 mg, 2 , 08 mmoles), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane (90.7 mg, 0.111 mmol) and potassium acetate (273 mg, 2.78 mmoles) in 1.4 -dioxane (4.8 ml) was degassed, purged with nitrogen, and stirred at 100 ° C for 18 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, 10 to 30%, EtOAc / hexane), to yield the title compound (423 mg). MS: [M + H] + = 393, 395. PREPARATION 75: ACID 2- (4-CHLORINE-5- (4,4,5,5-TETRAMETHYL 1,3,2-DIOXABOROLAN-2-IL) - 2H-INDAZOL-2-ILA) ACETIC
    [1266] [1266] To a solution of 2- (4-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) acetate tert-butyl (423 mg, 1.08 mmol) in CHCl3 (4.00 ml) TFA (2.00 ml, 26.0 mmoles) was added to RT. The mixture was stirred at 60 ° C for 1 h. The reaction solution was then concentrated in vacuo, the residue was diluted with water and extracted with CHCl3. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the title compound (323 mg). MS: [M + H] + = 337, 339. PREPARATION 76: 2- (4-CHLORINE-5- (4,4,5,5-TETRAMETHYL-1,3,2- DIOXABOROLAN-2-IL) -2H -INDAZOL-2-IL) -N-METHYLACETAMIDE
    [1267] [1267] To a solution of 2- (4-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) acetic acid (100 mg, 0.297 mmol) in THF (2.00 ml) was added Et3N (0.414 ml, 2.97 mmoles), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorin- 2,4,6-trioxide (1.6 M in THF, 0.56 ml, 0.891 mmol) and methylamine (2.0 M in THF, 0.594 ml, 1.19 mmol) at RT. The mixture was stirred at RT for 1 h. The reaction solution was then concentrated in vacuo, and the residue was purified by column chromatography on silica gel (gradient elution, 80 to 100%, EtOAc / hexane), to yield the title compound (50 mg) . MS: [M + H] + = 350, 352. PREPARATION 77: N - [(ENDO-8- (7- {4-CHLORINE-2- [(METHYLCARBAMOIL) METHIL] -2H-INDAZOL-5-IL} - 5 - {[2- (TRIMETHILSILIL) ETOXI] METHIL} -5H-PIRROL [2,3-B] PIRAZIN-3-IL) - 8-AZABICICLE [3.2.1] OCTAN-3-IL] TERC-BUTYL CARBAMATE
    [1268] [1268] To a suspension of N- (endo-8- (7-Iodo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrole [2,3-b] pyrazin-3-yl) - 8-azabicyclo [3.2.1] octan-3-yl) tert-butyl carbamate (50 mg, 0.0834 mmol) and 2- (4-chloro-5- (4,4,5,5-tetramethyl- 1 , 3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) -N-methylacetamide (35.0 mg, 0.100 mmol) in 1,4-dioxane (0.50 ml) and water (0, 05 ml) potassium phosphate (35.4 mg, 0.167 mmol) and 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloromethane (6.81 mg, 0.00834 mmol) complex were added to the OK. The mixture was stirred at 100 ° C for 1 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 diluted with EtOAc and water was added. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 50 to 100%, EtOAc / hexane), to yield the title compound (25 mg). MS: [M + H] + = 695, 697. PREPARATION 78: 3- (5-BROMO-4-CHLORINE-2H-INDAZOL-2-ILA) TERC-BUTYL PROPANOATE
    [1269] [1269] To a solution of 5-bromo-4-chloro-1H-indazole (1 g, 4.32 mmol) in DMF (10 ml) was added K2CO3 (1.19 g, 8.64 mmol) and 3- tert-butyl bromopropanoate (1.44 ml, 8.64 mmoles) at RT. The mixture was stirred at 100 ° C for 2 h, diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 5 to 30%, EtOAc / hexane), to yield the title compound (599 mg). MS: [M + H] + = 359, 361. PREPARATION 79: 3- [4-CHLORINE-5- (4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-IL) -2H -INDAZOL-2-IL] TERC- PROPANOATE BUTILLE
    [1270] [1270] The mixture of tert-butyl 3- (5-bromo-4-chloro-2H-indazol-2-yl) propanoate (599 mg, 1.67 mmol), bis (pinacolate) diboro (634 mg, 2 , 50 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane (109 mg, 0.133 mmol) and potassium acetate (327 mg, 3.33 mmol) in 1.4- dioxane (6 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, 10 to 30%, EtOAc / hexane), to yield the title compound (553 mg). MS: [M + H] + = 407. PREPARATION 80: 3- (5- {3- [endo-3 - {[(tert-Butoxy) carbonyl] amino} -8-azabicyclo [3.2.1] octan-8-yl] -5- {[2- ( trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazin-7-yl} -4-chloro-2H-indazol-2-yl) tert-butyl propanoate
    [1271] [1271] To a suspension of N- (endo-8- (7-iodo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrole [2,3-b] pyrazin-3-yl) - 8-azabicyclo [3.2.1] octan-3-yl) tert-butyl carbamate (100 mg, 0.167 mmol) and 3- [4-chloro-5- (4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl) -2H-indazol-2-yl] tert-butyl propanoate (81.4 mg, 0.200 mmol) in 1,4-dioxane (1.00 ml) and water (0.10 ml) potassium phosphate (70.8 mg, 0.334 mmol) and 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloromethane (13.6 mg, 0.0167 mmol) dichloride complex were added to RT . The mixture was stirred at 100 ° C for 1 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 diluted with EtOAc and water was added. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 50 to 100%, EtOAc / hexane), to yield the title compound (77 mg). MS: [M + H] + = 752, 754. PREPARATION 81: ACID 3- (5- {3- [ENDO-3-AMINO-8-AZABICICLE [3.2.1] OCTAN-8-IL] -5H-PIRROL [2,3-B] PIRAZIN-7-IL} - 4-CHLORINE-2H-INDAZOL-2-ILA) PROPANOIC
    [1272] [1272] To a solution of 3- (5- {3- [endo-3- {[(tert-butoxy) carbonyl] amino} -8-azabicyclo [3.2.1] octan-8-yl] -5- { Tert-butyl [2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazin-7-yl} -4-chloro-2H-indazol-2-yl) propanoate (50.0 mg , 0.0665 mmol) in CHCl3 (1.00 ml) TFA (0.500 ml, 6 mmoles) was added to RT. The mixture was stirred at 60 ° C for 1 h. The reaction was concentrated in vacuo and, to the residue dissolved in methanol (1.00 ml), ethylenediamine (0.200 ml, 3 mmol) was added. The reaction was stirred at RT for 18 h, and the solid that formed was filtered, washed with methanol twice and dried in a vacuum oven, to yield the title compound (18 mg). MS: [M + H] + = 466, 468. PREPARATION 82: 5-BROMO-3,4-DICLORO-1H-INDAZOL
    [1273] [1273] A mixture of 5-bromo-4-chloro-1H-
    [1274] [1274] To a mixture of 4-bromo-3-chloro-2,6-dimethylaniline (4.8 g, 20 mmol), potassium acetate (3.1 g, 31 mmol), acetic acid (1.8 g , 29 mmoles) and toluene (61 ml) tert-butyl nitride (2.5 g, 25 mmoles) was added to RT. The mixture was stirred at 45 ° C overnight. To a mixture was added EtOAc (40 ml) and 1 M NaOH (40 ml). The separated organic layer was washed with brine and concentrated in vacuo. The residue was suspended in toluene and heptane. The precipitate was collected and dried at 50 ° C under reduced pressure, to yield a mixture of 5-bromo-4-chloro-7-methyl-1H-indazole and 5-bromo-6-chloro-7-methyl-1H-indazole (3.4 g). MS: [M + H] + = 245. PREPARATION 84: 5-BROMO-4-CHLORINE-2,7-DIMETHYL-2H-INDAZOL
    [1275] [1275] To a solution of a mixture of 5-bromo-4-chloro-7-methyl-1H-indazole and 5-bromo-6-chloro-7-methyl-1H-
    [1276] [1276] To a mixture of 2-chloro-5,6-difluorobenzaldehyde (5.3 g, 30 mmoles) and sulfuric acid (15 ml) was added N-bromosuccinimide (6.6 g, 37 mmoles) at 60 ° C. The resulting mixture was stirred at the same temperature for 5 h. The mixture was poured onto crushed ice and then extracted with EtOAc. The organic phase was washed with brine and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 20%, EtOAc / hexane), to yield the title compound (6.5 g), 1H-NMR (400 MHz, CDCl3): 10.37 (1H, s), 7.72 (1H, dd). PREPARATION 86: 3-BROMO-2-CHLORINE-5,6-DIFLUOROBENZALDEHYDE O- METIL OXIMA
    [1277] [1277] A mixture of 3-bromo-2-chloro-5,6-
    [1278] [1278] A mixture of 3-bromo-2-chloro-5,6-difluorobenzaldehyde O-methyl oxime (7.1 g, 25 mmol), tetrahydrofuran (25 ml) and hydrazine monohydrate (25 ml) was stirred under reflux for 30 h. To a mixture, EtOAc (120 ml) and water (50 ml) were added. The separated organic layer was concentrated in vacuo. The residue was suspended in EtOAc and hexane. The precipitate was collected and dried at 50 ° C under reduced pressure, to yield the title compound (4.4 g), MS: [M + H] + = 249. PREPARATION 88: 5-BROMO-4-CHLORINE-7 -FLUORO-2-METHYL-2H-INDAZOL
    [1279] [1279] To a solution of 5-bromo-4-chloro-7-fluoro-1H-indazole (1.8 g, 7.4 mmoles) in EtOAc (40 ml) was added trimethyloxonium tetrafluoroborate (1.7 g, 12 mmoles) and the resulting mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc,
    [1280] [1280] Prepared as preparation 43, except using 5-bromo-4-chloro-2,7-dimethyl-2H-indazole to yield the title compound. MS: [M + H] + = 307. PREPARATION 90: 4-CHLORINE-7-FLUORO-2-METHYL 5- (4,4,5,5- TETRAMETHYL 1,3,2-DIOXABOROLAN-2-IL -2H-INDAZOL
    [1281] [1281] Prepared as preparation 43, except for the use of 5-bromo-4-chloro-7-fluoro-2-methyl-2H-indazole to yield the title compound. MS: [M + H] + = 311. PREPARATION 91: N- [ENDO-8- [7- (4-CHLORINE-2,7-DIMETHIL-2H- INDAZOL-5-IL) -5 - {[2- (TRIMETHILSILIL) ETOXI] METHIL} -5H- PIRROL [2,3-B] PIRAZIN-3-IL] -8-AZABICYCLE [3.2.1] OCTAN-3 IL] TERC-BUTYL CARBAMATE N N
    [1282] [1282] Prepared as General Procedure 2, except for the use of 4-chloro-2,7-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) - 2H-indazole to yield the title compound. MS: [M + H] + = 652. PREPARATION 92: N- [ENDO-8- [7- (4-CHLORINE-7-FLUORO-2-METHYL-2H- INDAZOL-5-IL) -5 - {[ 2- (TRIMETHILSILIL) ETOXI] METHIL} -5H- PIRROL [2,3-B] PIRAZIN-3-IL] -8-AZABICYCLE [3.2.1] OCTAN-3- IL] TERC-BUTYL CARBAMATE N N F
    [1283] [1283] Prepared as general procedure 2, except using 4-chloro-7-fluoro-2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) -2H-indazole to yield the title compound. MS: [M + H] + = 656. PREPARATION 93: (1S, 2R, 3S, 5R) -3- (BENZYLAMINE) -2-FLUORO-8- AZABICYCLE [3.2.1] OCTANE-8-CARBOXYLATE RAC-TERC -BUTYL E (1S, 2R, 3R, 5R) -3- (BENZYLAMINE) -2-FLUORO-8- AZABICYCLE [3.2.1] RAC-TERC-BUTYL OCTANE-8-CARBOXYLATE
    [1284] [1284] Sodium triacetoxyborohydride (41 g, 193 mmol) was added in portions to a solution of (±) -tert-butyl 2-fluoro-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (34.8 g, 129 mmoles), acetic acid (11.0 ml, 192 mmoles) and benzylamine (20 ml, 183 mmoles) in dichloromethane (500 ml), then stirred at RT overnight. The mixture was diluted with 10% hydrogen sodium carbonate (500 ml), then extracted with dichloromethane (3 x 500 ml). The combined organic phases were dried (MgSO4), filtered and concentrated under reduced pressure to yield the crude product mixture. Recrystallization from EtOAc: isohexane (800 ml, 1: 3), yielded: PREPARATION 94: (1S, 2R, 3S, 5R) -3- (BENZYLAMINE) -2-FLUORO-8- AZABICICLE [3.2.1] OCTANE- 8-RAC-TERC-BUTYL CARBOXYLATE
    [1285] [1285] (11.6 g). 1H NMR (500 MHz, DMSO-d6) δ: 7.39-7.27 (m, 4H), 7.27-7.19 (m, 1H), 4.51 (br d, 1H), 4 , 38- 4.21 (m, 1H), 4.13-4.04 (m, 1H), 3.83-3.65 (m, 2H), 2.80 (dd, 1H), 2.48 -2.33 (m, 1H), 2.09 (s, 1H), 2.03-1.88 (m, 2H), 1.86-1.69 (m, 2H), 1.56 (d , 1H), 1.37 (s, 9H).
    [1286] [1286] The filtrate, from the above crystallization, was concentrated under reduced pressure to yield a residue (~
    [1287] [1287] (11.9 g). 1H NMR (500 MHz, DMSO-d6) δ: 7.38-7.26 (m, 4H), 7.26-7.15 (m, 1H), 4.66 (dt, 1H), 4, 48- 4.24 (m, 1H), 4.19-4.06 (m, 1H), 3.77 (d, 1H), 3.72 (d, 1H), 2.96-2.72 ( m, 1H), 1.95-1.64 (m, 4H), 1.61-1.43 (m, 3H), 1.38 (s, 9H). PREPARATION 96: (1S, 2R, 3S, 5R) -3-AMINO-2-FLUORO-8- AZABICYCLE [3.2.1] RAC-TERC-BUTYL OCTANE-8-CARBOXYLATE
    [1288] [1288] (1S, 2R, 3S, 5R) -3- (Benzylamino) -2-fluoro-8-azabicyclo [3.2.1] rac-tert-butyl octane-8-carboxylate (18.5 g, 55, 3 mmoles) and 10% palladium on carbon (Type JM 39, 57.3% moisture) (4.0 g, 1.605 mmol) were dissolved in acetic acid / ethanol (1: 3, 200 ml) and stirred under hydrogen at 1 bar for 2 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was treated with aqueous sodium bicarbonate paste (10 g in 100 ml), then extracted with chloroform / IPA (9: 1, 3 x 100 ml). The combined organic phases were concentrated under reduced pressure, to yield the title compound (13.5 g). 1H NMR (500 MHz, DMSO-d6) δ: 4.39-4.15 (m, 2H), 4.07 (m, 1H), 3.11 (dd, 1H), 2.12-1, 88 (m, 4H), 1.83-1.65 (m, 4H), 1.37 (s, 9H). PREPARATION 97: (1S, 2R, 3R, 5R) -3-AMINO-2-FLUORO-8- AZABICYCLE [3.2.1] OCTANE-8-CARBOXYLATE OF RAC-TERC-BUTYLE
    [1289] [1289] The title compound was prepared in a similar manner to rac-tert-butyl (1S, 2R, 3S, 5R) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octane-8-carboxylate with the use of rac-tert-butyl (1S, 2R, 3R, 5R) -3- (benzylamino) -2-fluoro-8-azabicyclo [3.2.1] octane-8-carboxylate (11 g, 32.9 mmoles) to yield the title compound (8.25 g). 1H NMR (500 MHz, DMSO-d6) δ: 4.37 (dt, 2H), 4.38-4.33 (m, 1H), 4.16-4.09 (m, 1H), 2, 95 (dddd, 1H), 1.88-1.76 (m, 3H), 1.66-1.46 (m, 4H), 1.41 (d, J = 0.5 Hz, 9H). PREPARATION 98: (1S, 2R, 3S, 5R) -3- {[(BENZILOXI) CARBONIL] AMINO} -2-FLUORO-8- AZABICICLE [3.2.1] OCTANE-8-CARBOXYLATE OF RAC-TERC-BUTILE
    [1290] [1290] Benzyl chloroformate (10 ml, 70.0 mmol) was added to a cooled (0 ° C) solution of (1S, 2R, 3S, 5R) -3-amino-2-fluoro-8-azabicycles [3.2 .1] rac-tert-butyl octane-8-carboxylate (13.5 g, 52.5 mmoles) and DIPEA (27 ml, 155 mmoles) in THF / DCM (375 ml: 1: 4), then stirred at Overnight overnight. Water (400 ml) was added, then the mixture was extracted with dichloromethane (3 x 400 ml) and the combined organic phases were concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (0 to 30%, EtOAc / isohexane). The purified oil was purified again by column chromatography on silica gel (gradient elution, 0 to 10%, EtOAc / DCM) to yield the title compound (19.5 g). 1H NMR (500 MHz, DMSO-d6) δ: 7.46-7.39 (m, 1H), 7.39-7.34 (m, 4H), 7.34-7.29 (m, 1H ), 5.07 (d, 1H), 5.02 (d, 1H), 4.51 (br d, 1H), 4.38-4.20 (m, 1H), 4.16-4.06 (m, 1H), 3.64-3.49 (m, 1H), 2.23-2.11 (m, 1H), 1.94-1.79 (m, 2H), 1.78-1 , 66 (m, 2H), 1.49-1.43 (m, 1H), 1.38 (s, 9H). PREPARATION 99: (1S, 2R, 3R, 5R) -3- {[(BENZILOXI) CARBONIL] AMINO} -2-FLUORO-8- AZABICICLE [3.2.1] OCTANE-8-CARBOXYLATE OF RAC-TERC-BUTYLE
    [1291] [1291] The title compound was prepared in a similar manner to (1S, 2R, 3S, 5R) -3- {[(benzyloxy) carbonyl] amino} -2-fluoro-8-azabicyclo [3.2.1] octane-8 rac-tert-butyl carboxylate using (1S, 2R, 3R, 5R) -3-amino-2-fluoro-8-azabicyclo [3.2.1] rac-tert-butyl octane-8-carboxylate ( 8.25 g, 32.1 mmoles) to yield the title compound (10.9 g). 1H NMR (500 MHz, DMSO-d6) δ: 7.46-7.26 (m, 6H), 5.11 4.94 (m, 2H), 4.54 (dt, 1H), 4, 43-4.26 (m, 1H), 4.20-4.06 (m, 1H), 3.92-3.72 (m, 1H), 1.99-1.69 (m, 3H), 1.70-1.48 (m,
    [1292] [1292] 3.0 M hydrogen chloride in cyclopentyl methyl ether (130 ml, 390 mmoles) was added to a solution of (1S, 2R, 3S, 5R) -3 - {[((benzyloxy) carbonyl] amino} - 2- rac-tert-butyl fluor-8-azabicyclo [3.2.1] octane-8-carboxylate (14.5 g, 36.4 mmoles) in tert-butyl methyl ether (15 ml), then stirred at RT for 18 h. The mixture was concentrated under reduced pressure, then divided between dichloromethane (200 ml) and saturated hydrogen carbonate solution (200 ml). The organic layer was concentrated under reduced pressure, then purified by column chromatography on silica gel (gradient elution, 0 to 10% (0.7 M ammonia / MeOH) / DCM) to yield the title compound (6, 0 g). 1H NMR (500 MHz, DMSO-d6) δ: 7.41-7.28 (m, 5H), 7.28-7.20 (m, 1H), 5.10-4.97 (m, 2H ), 4.29 (ddd, 1H), 3.69-3.51 (m, 1H), 3.41 (dd, 1H), 3.37-3.29 (m, 1H), 2.30- 2.09 (m, 1H), 2.10-1.97 (m, 1H), 1.77-1.63 (m, 2H), 1.64-1.47 (m, 2H), 1, 30-1.14 (m, 1H). PREPARATION 101: N - [(1S, 2S, 3R, 5R) -2-FLUORO-8- AZABICYCLE [3.2.1] OCTAN-3-IL] CARBAMATE RAC- HYDROCHLORIDE BENZILA
    [1293] [1293] 3.0 M hydrogen chloride in cyclopentyl methyl ether (100 ml, 300 mmoles) was added to a suspension of (1S, 2R, 3R, 5R) -3 - ((((benzyloxy) carbonyl) amino) - (±) - tert-butyl 2-fluoro-8-azabicyclo [3.2.1] octane-8-carboxylate (10.9 g, 27.4 mmoles) in methyl tert-butyl ether (15 ml) and dichloromethane ( 10 ml), then stirred at RT for 18 h. The resulting precipitate was collected by filtration to yield the title compound (8.8 g). 1H NMR (500 MHz, DMSO-d6) δ: 10.28-9.22 (m, 1H), 9.22-8.29 (m, 1H), 7.74-7.59 (m, 1H ), 7.42-7.35 (m, 4H), 7.35-7.29 (m, 1H), 5.07 (d, 1H), 5.04 (d, 1H), 4.83 ( dt, 1H), 4.22-4.12 (m, 1H), 3.99-3.92 (m, 1H), 3.92-3.75 (m, 1H), 2.08-1, 86 (m, 4H), 1.86-1.68 (m, 2H). PREPARATION 102: N - [(1S, 2S, 3S, 5R) -2-FLUORO-8- AZABYCLE [3.2.1] OCTAN-3-IL] BENZILA CARBAMATE (QUICK ELUTION ISOMER)
    [1294] [1294] N - [(1S, 2S, 3S, 5R) -2-Fluoro-8-azabicyclo [3.2.1] octan-3-yl] rac-benzyl carbamate (5.82 g) was dissolved in methanol ( 150 ml), then purified by chiral preparative supercritical fluid chromatography (Lux A1 column, (21.2 mm x 250 mm, 5 µm); 40 ° C, Flow Rate 50 ml / min, BPR 100 BarG, Detection at 210 nm, Volume
    [1295] [1295] From the same chromatography experiment described in preparation 102, the title compound was obtained as the slow eluting isomer (2.99 g). 1H NMR (500 MHz, DMSO-d6) δ: 7.41-7.28 (m, 5H), 7.28-7.20 (m, 1H), 5.10-4.97 (m, 2H ), 4.29 (ddd, 1H), 3.69-3.51 (m, 1H), 3.41 (dd, 1H), 3.37-3.29 (m, 1H), 2.30- 2.09 (m, 1H), 2.10-1.97 (m, 1H), 1.77-1.63 (m, 2H), 1.64-1.47 (m, 2H), 1, 30-1.14 (m, 1H). PREPARATION 104: N - [(1S, 2S, 3S, 5R) -2-FLUORO-8- AZABYCLE [3.2.1] OCTAN-3-IL] CARBAMATE BENZILA CHLORIDRATE
    [1296] [1296] N- fast eluting isomer
    [1297] [1297] Slow eluting isomer N- [(1R, 2R, 3R, 5S) -2-Fluoro-8-azabicyclo [3.2.1] octan-3-yl] benzyl carbamate (3.8 g) was dissolved in dichloromethane (10 ml), then treated with 3.0 M hydrogen chloride in cyclopentyl methyl ether (10 ml, 30.0 mmol) to yield a white solid which was recrystallized from acetonitrile (50 ml) to yield the title compound (3.2 g). 1H NMR (500 MHz, DMSO-d6) δ: 9.34 (br s, 2H), 7.76-7.56 (m, 1H), 7.45-7.27 (m, 5H), 5 .09 (d, 1H), 5.04 (d, 1H), 4.95-4.77 (m, 1H), 4.17-4.06 (m, 1H), 3.98-3.87 (m, 1H), 3.77-3.60 (m, 1H), 2.33 (ddd, 1H), 2.18 (q, 1H), 2.03 - 1.89 (m, 3H), 1.79 (d, 1H). PREPARATION 106: N - [(1S, 2S, 3R, 5R) -2-FLUORO-8-
    [1298] [1298] N - [(1S, 2S, 3R, 5R) -2-fluoro-8-azabicyclo [3.2.1] octan-3-yl] rac-benzyl carbamate (8.8 g) was dissolved in methanol ( 50 mg ml-1), then purified by chiral preparative supercritical fluid chromatography (Lux C2 (4.6 mm x 250 mm, 5 µm); 40 ° C, Flow Rate 50 ml / min, BPR 100 BarG, Detection a 210 nm, Injection Volume 500 µl (25 mg), 35:65 EtOH: CO2 (0.2% by volume of NH3)). The pure fractions were then combined and evaporated to yield the title compound (4.04 g) as the fastest eluting enantiomer. 1H NMR (500 MHz, DMSO-d6) δ: 8.08-7.57 (m, 2), 7.53 (d, 1H), 7.41-7.28 (m, 5H), 5, 04 (d, 1H), 5.02 (d, 1H), 4.67 (dt, 1H), 3.99-3.89 (m, 1H), 3.85-3.67 (m, 2H) , 1.97 - 1.59 (m, 6H). (compound isolated as a partial hydrochloride salt) PREPARATION 107: N - [(1R, 2R, 3S, 5S) -2-FLUORO-8- AZABICYCLE [3.2.1] OCTAN-3-IL] BENZILA CARBAMATE (ISOMER OF SLOW ELUTION)
    [1299] [1299] From the same chromatography experiment described in preparation 106, the title compound was obtained as the slow eluting isomer (4.01 g).
    [1300] [1300] Partial HCl salt of ((1S, 2S, 3R, 5R) -2-fluoro-8-azabicyclo [3.2.1] octan-3-yl) benzyl carbamate (fastest eluting enantiomer) (4, 0 g, 13.65 mmoles) was converted into an aqueous paste into a minimum amount of dichloromethane (10 ml) and tert-butyl methyl ether (50 ml), then treated with 3M hydrogen chloride solution in cyclopentyl methyl ether ( 7 ml, 21.00 mmoles). The mixture was converted to aqueous slurry overnight, then collected by filtration, to yield the title compound (4.19 g). 1H NMR (500 MHz, DMSO-d6) δ: 10.3-8.10 (br m, 2H), 7.65 (d, 1H), 7.46-7.24 (m, 5H), 5 , 18-4.94 (m, 2H), 4.82 (d, J = 47.7 Hz, 1H), 4.25-4.09 (m, 1H), 3.99-3.90 (m , 1H), 3.90-3.75 (m, 1H), 2.08-1.73 (m, 6H). [α] 20D = 15.47 ° (c 1.00, MeOH). PREPARATION 109: N - [(1R, 2R, 3S, 5S) -2-FLUORO-8- AZABICICLE [3.2.1] OCTAN-3-IL] BENZILA CARBAMATE, SALT CHLORIDRATE
    [1301] [1301] N - [(1R, 2R, 3S, 5S) -2-Fluoro-8-azabicyclo [3.2.1] octan-3-yl] benzyl carbamate (slow eluting isomer) (4.0 g, 13 , 65 mmol) was converted into an aqueous slurry into a minimal amount of dichloromethane (10 ml) and tert-butyl methyl ether (50 ml), then treated with 3M hydrogen chloride solution in cyclopentyl methyl ether (7 ml, 21 ml). .00 mmoles). The mixture was converted to aqueous slurry overnight, then collected by filtration, to yield the title compound (4.23 g). 1H NMR (500 MHz, DMSO-d6) δ: 10.3-8.10 (br m, 2H), 7.65 (d, 1H), 7.46-7.24 (m, 5H), 5 , 18-4.94 (m, 2H), 4.82 (d, J = 47.7 Hz, 1H), 4.25- 4.09 (m, 1H), 3.99-3.90 (m , 1H), 3.90-3.75 (m, 1H), 2.08 - 1.73 (m, 6H). [α] 20D = -11.88 ° (c 1.05, MeOH). PREPARATION 110: 6-BROMO-5-CHLORINE-3-METHYL-3,4-DIHYDROQUINAZOLIN-4-ONA
    [1302] [1302] Methyl iodine (0.132 ml, 2.12 mmol) was added to a suspension of 6-bromo-5-chloro-3,4-dihydroquinazolin-4-one (500 mg, 1.93 mmol) and K2CO3 (799 mg, 5.78 mmoles) in DMF (10 ml) and the reaction stirred at RT under N2 for 1.5 h. Water was added and the resulting precipitate collected by vacuum filtration, washing with water, then dried in a vacuum oven, to yield the title compound (470 mg). MS: [M + H] + = 273. PREPARATION 111: 6-BROMO-5-CHLORINE-2,3-DIMETHIL-3,4-
    [1303] [1303] Prepared similarly to 6-bromo-5-chloro-3-methyl-3,4-dihydroquinazolin-4-one, except for the use of 6-bromo-5-chloro-2-methyl-3,4- dihydroquinazolin-4-one to yield the title compound. MS: [M + H] + = 286. PREPARATION 112: 6-BROMO-7-CHLORINE-N, N-DIMETHYL-1,3-BENZOTIAZOL-2-CARBOXAMIDE
    [1304] [1304] DIPEA (0.41 ml, 2.37 mmol) was added to a solution of 2-ethylhexyl 3 - [(6-amino-3-bromo-2-chlorophenyl) sulfanyl] propanoate (500 mg, 1, 18 mmol), N, N-dimethyloxamic acid (139 mg, 1.18 mmol) and hexafluorophosphate 3-oxide 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazole [4,5-b] pyridinium (495 mg, 1.30 mmol) in DMF (6 ml) and the reaction stirred at RT for 16 h. The reaction was diluted with EtOAc and washed sequentially with aq. sat. (2x), H2O (3x) and brine, then dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 25%, EtOAc / petrol) to provide the intermediate amide. This residue was re-dissolved in THF (12 ml), NaOEt solution (20% by weight in EtOH, 1.4 ml, 3.55 mmoles) was added and the reaction stirred for 30 min. After cooling to 0 ° C, TFA (2.7 ml, 35.5 mmoles) was carefully added and the reaction then heated to 60 ° C for 2 h. After cooling to 0 ° C, NaHCO3 aq. sat. was added carefully and the mixture extracted with EtOAc
    [1305] [1305] 5-Bromo-4-chloro-2,3-dihydro-1H-indole-2,3-dione (0.685 g, 2.65 mmol) was dissolved in DCM (7 ml) and cooled to 0 ° C. Diethylamino sulfur trifluoride (1.05 ml, 7.96 mmoles) was added by dripping and the reaction was allowed to warm to RT and stirred overnight. The reaction was diluted with DCM, washed with aq. sat., then brine. The organic phase was dried by passing through a phase separator and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 20%, EtOAc / petrol) to yield the title compound (0.30 g). MS: [MH] - = 281. PREPARATION 114: 5-BROMO-4-CHLORINE-3,3-DIFLUORO-1 - {[2- (TRIMETHYLSILIL) ETOXI] METHIL} -2,3-DIIDRO-1H-INDOL- 2-ONA
    [1306] [1306] 5-Bromo-4-chloro-3,3-difluoro-2,3-dihydro-1H-indole-2-one (0.3 g, 1.06 mmol) was dissolved in DMF (5 ml) and cooled to 0 ° C. Sodium hydride (60% by weight in mineral oil, 0.055 g, 1.38 mmol) was added and the reaction stirred until homogeneous. 2- (Trimethylsilyl) ethoxymethyl chloride (0.243 ml, 1.38 mmol) was added by dropping and the reaction was stirred at RT overnight. The reaction was diluted with Et2O, washed with water, then brine. The organic phase was dried by passing through a phase separator and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution, 0 to 20%, EtOAc / petrol) to yield the title compound (0.392 g). 1H NMR (400 MHz, DMSO-d6): 8.07 (1H, d), 7.27 (1H, d), 5.15 (2H, s), 3.56 (2H, t), 0, 95- 0.85 (2H, m), -0.01--0.16 (9H, m). PREPARATION 115: 5-CHLORINE-2,3-DIMETHIL-6- (4,4,5,5-TETRAMETHYL 1,3,2-DIOXABOROLAN-2-IL) -3,4-DIIDROQUINAZOLIN-4-ONA
    [1307] [1307] Prepared as preparation 43, except using 6-bromo-5-chloro-2,3-dimethyl-3,4-dihydroquinazolin-4-one to yield the title compound. MS:
    [1308] [1308] Prepared as general procedure 2, except for the use of 3-chloro-7-iodo-N, N-dimethyl-5H-pyrrole [2,3-b] pyrazine-5-sulfonamide (5.5 g, 14 , 4 mmoles), 4-Chloro-2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole (70% pure, 7.22 g, 17.3 mmoles), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.105 g, 0.14 mmol), potassium carbonate (3.98 g, 28.83 mmoles), water (48 ml) and 1,2-dimethoxyethane (72 ml) at 70 ° C, MS: [M + H] + = 425 PREPARATION 117: N- [ENDO-8- [7- (5-CHLORINE-2,3 -DIMETHYL-4-OXO- 3,4-DIHYDROQUINAZOLIN-6-IL) -5 - {[2- (TRIMETYLSILYL) ETOXI] METHIL} -5H-PIRROL [2,3-B] PIRAZIN-3-IL] - 8 -AZABICICLO [3.2.1] OCTAN-3-IL] TERC-BUTYL CARBAMATE
    [1309] [1309] Prepared as the general procedure 2, except for the use of 5-chloro-2,3-dimethyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) - 3,4-dihydroquinazolin-4-
    [1310] [1310] Prepared as general procedure 3 except using 6-bromo-5-chloro-3-methyl-3,4-dihydroquinazolin-4-one, MS: [M + H] + = 666 PREPARATION 119: N- [ENDO-8- {7- [7-CHLORINE-2- (DIMETHYLCARBAMOIL) - 1,3-BENZOTIAZOL-6-IL] -5 - {[2- (TRIMETYLSILIL) ETOXI] METIL} -5H- PIRROL [2, 3-B] PIRAZIN-3-IL} -8-AZABYCLE [3.2.1] OCTAN-3 IL] TERC-BUTYL CARBAMATE
    [1311] [1311] Prepared as general procedure 3 except using 6-bromo-7-chloro-N, N-dimethyl-1,3-benzothiazole-2-carboxamide, MS: [M + H] + = 712 PREPARATION 120: N- [ENDO-8- [7- (4-CHLORINE-3,3-DIFLUORO-2-OXO-1- {[2- (TRIMETYLSILIL) ETOXI] METHIL} -2,3-DIIDRO-1H-INDOL-5 -IL) - 5 - {[2- (TRIMETHILSILIL) ETOXI] METHIL} -5H-PIRROL [2,3-B] PIRAZIN-
    [1312] [1312] Prepared as general procedure 3 except using 5-bromo-4-chloro-3,3-difluoro-1 - {[2- (trimethylsilyl) ethoxy] methyl} -2,3-dihydro-1H-indole -2-one, MS: [M + H] + = 805 PREPARATION 121: (3,5-DICLORO-6-METHYLPIRAZIN-2-ILA) METHANOL
    [1313] [1313] To each of the 12 reaction tubes was added TFA (0.40 ml, 5.21 mmoles), 3,5-dichloro-2-methylpyrazine (85 mg, 0.52 mmol), 2.4.5 , 6-tetra (9H-carbazol-9-yl) isophthalonitrile (4 mg, 0.0052 mmol), tert-butyl peracetate solution (50% by weight of odorless mineral alcohol, 0.75 ml, 2.87 mmoles ) and degassed MeOH / DMSO (9: 1.5 ml). Each flask was quickly washed with N2 and then sealed and shaken under blue LED lighting (Kessel lamp, 34W) for 18 h. The contents of the 12 tubes were combined and most of the solvent was evaporated. The residue was divided between EtOAc and aq. sat., the aq. The separated mixture was extracted with EtOAc (2x) and the combined organics were washed with brine (3x), dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 30%, EtOAc / petrol) to yield the title compound (480 mg). MS: [M + H] + = 193. PREPARATION 122: 3,5-DICLORO-6-METHYLPIRAZINE-2-CARBALDEHYDE
    [1314] [1314] To a stirred mixture of (3,5-dichloro-6-methylpyrazin-2-yl) methanol (0.32 g, 1.66 mmol) in DCM (16.6 ml) was added Dess-Martin periodinane (1.05 g, 2.49 mmoles) and the mixture was stirred at RT for 2 h. The reaction was quenched with NaHCO3 aq. sat. and Na2S2O3 aq. sat. EtOAc was added, the phases were separated and the EtOAc layer was washed with aq. sat. (2x). The organic layer was dried (Na2SO4), filtered and concentrated to yield the title compound which was used without further purification. PREPARATION 123: (4-CHLORINE-2-METHYL-2H-INDAZOL-5-ILA) (3,5-DICLORO-6-METHYLPIRAZIN-2-ILA)
    [1315] [1315] To a solution of a lithium chloride and isopropylmagnesium chloride complex solution (1.3 M in THF, 2.58 ml, 3.36 mmoles) in THF (4.48 ml) at 30 ° C was added a solution of 5-bromo-4-chloro-2-methyl-2H-indazole (0.55 g, 2.24 mmoles, 3x toluene azeotropically dried) in THF (4.48 ml) at 30 ° C by dripping during 10 min The mixture was stirred at that temperature for 25 min before being cooled to 0 ° C and a solution of 3,5-dichloro-6-methylpyrazine-2-carbaldehyde (0.319 g, 1.68 mmol, azeotropically dried from 3x THF) in THF (4.48 ml) was added dropwise for 10 min. A 30% brine solution, aq. sat. and EtOAc were added, the phases separated, and the aqueous phase was further extracted with EtOAc (2x). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (gradient elution, 20 to 35%, acetone / petrol) to yield the title compound (0.32 g), MS: [M + H] + = 357. PREPARATION 124: 4-CHLORINE-5- (3,5-DICLORO-6-METHYLPIRAZINE-2-CARBONY) -2-METHYL-2H-INDAZOL
    [1316] [1316] To a stirred solution of (4-chloro-2-methyl-2H-indazol-5-yl) (3,5-dichloro-6-methylpyrazin-2-yl) methanol (0.32 g, 0.895 mmol) in DCM (8.95 ml) at RT manganese (IV) oxide (1.56 g, 17.9 mmoles) was added. The suspension was stirred overnight before being filtered, washed with DCM (3x) and concentrated to yield the title compound (0.221 g) which was used without further purification, MS: [M + H] + = 355 PREPARATION 125: N - [(1R, 2S, 3S, 5S) -8- [6-CHLORINE-5- (4-CHLORINE-2-METHYL-2H-INDAZOL-5-CARBONYL) -3-METHYLPIRAZIN-2- IL] -2-FLUORO- 8-AZABYCLE [3.2.1] OCTAN-3-IL] BENZILA CARBAMATE
    [1317] [1317] To a stirred solution of 4-chloro-5- (3,5-dichloro-6-methylpyrazine-2-carbonyl) -2-methyl-2H-indazole (0.216 g, 0.607 mmol) and DIPEA (0.212 ml, 1.21 mmol) in NMP (0.607 ml) at 0 ° C a solution of N- [(1R, 2R, 3S, 5S) -2-fluoro-8-azabicyclo [3.2.1] octan-3-yl was added ] benzyl carbamate (0.229 g, 0.729 mmol) in NMP (0.607 ml). The mixture was stirred at 0 ° C for 1 h, then allowed to warm to RT and stirred for 24 h. The mixture was diluted with EtOAc / 30% brine / aq. sat., the phases were separated, and the organic phase was washed with 30% brine / aq. sat. (2x), then with NaHCO3 aq. sat .. The organic extract was dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (gradient elution, 23 to 50%, acetone / petrol) to yield the title compound (0.18 g), MS: [M + H] + = 597. PREPARATION 126: N - [(1R, 2S, 3S, 5S) -8- [3- (4-CHLORINE-2-METHYL-2H- INDAZOL-5-IL) -5-METHYL-1H-PIRAZOL [3,4 -B] PIRAZIN-6-IL] -2- FLUORO-8-AZABYCLE [3.2.1] OCTAN-3-IL] BENZILA CARBAMATE
    [1318] [1318] To a stirred solution of N- [(1R, 2S, 3S, 5S) -8- [6-chloro-5- (4-chloro-2-methyl-2H-indazol-5-carbonyl) -3- methylpyrazin-2-yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-yl] benzyl carbamate (0.18 g, 0.301 mmol) in EtOH (6.03 ml) hydrazine monohydrate was added (0.132 ml, 0.603 mmol) and the mixture was heated to
    [1319] [1319] DMF (10.8 ml, 139 mmoles) and water (3.6 ml, 14.34 mmoles) were added to 5-bromo-4-chloro-1H-indazole (3.32 g, 14.34 mmoles) ), gallium (1.5 g, 21.51 mmoles) and aluminum (0.580 g, 21.51 mmoles). 2-bromo-N, N-dimethylacetamide (4.64 ml, 43.0 mmol) was then added and the reaction was stirred at 55 ° C for 64 h. The reaction was diluted with EtOAc (50 ml) and water (50 ml) and filtered. The organic phase was isolated and the aqueous phase further extracted with EtOAc (2 x 50 ml). The combined organic phases were washed with aq. 1M (50 ml) and water (2 x 50 ml), dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (gradient elution, 50 to 100%, EtOAc / isohexanes) to yield the title compound (2.06 g). MS: [M + H] + = 316. PREPARATION 128: N- [ENDO-8- (7- {4-CHLORINE-2- [(DIMETHYLCARBAMOIL) METHIL] -2H-INDAZOL-5-IL} -5- { [2- (TRIMETHILSILIL) ETOXI] METHIL} -5H-PIRROL [2,3-B] PIRAZIN-3-IL) -
    [1320] [1320] ((endo-8- (7-iodine-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrole [2,3-b] pyrazin-3-yl) - 8-azabicycle [3.2 .1] tert-butyl octan-3-yl) carbamate (473 mg, 0.790 mmol) was loaded into a 40 ml vial that was sealed and then evacuated and filled with nitrogen (3x). THF (3 ml) was added and the resulting solution was cooled to 0 ° C before the lithium chloride and isopropylmagnesium chloride complex solution (1.3 M in THF, 1.336 ml, 1.737 mmol) was added by dropping and the resulting solution stirred at 0 ° C for 45 min A solution of zinc (II) chloride (1.9 M in THF, 0.914 ml, 1.737 mmol) was added by dripping and the reaction stirred at 0 ° C for 10 min and then at TA for 45 min 2- (5-bromo-4-chloro-2H-indazol-2-yl) -N, N-dimethylacetamide (250 mg, 0.790 mmol) and SPhos Pd G3 (30.8 mg, 0.039 mmol) were added and the reaction flask evacuated and filled with nitrogen (3x) before being stirred at RT for 24 h. The reaction mixture was diluted with EtOAc (25 ml) and NH4Cl a q. sat. (25 ml). The organic phase was isolated and the aqueous one further extracted with EtOAc (25 ml). The combined organic phases were dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (gradient elution, 50 to 100%, EtOAc / isohexanes) to yield the title compound (164 mg). MS: [M + H] + = 709. PREPARATION 129: 1- (5-BROMO-4-CHLORINE-2H-INDAZOL-2-IL) -2-METHYROPROPAN-2-OL
    [1321] [1321] A mixture of 5-bromo-4-chloro-2H-indazole (6.6 g, 28.5 mmol), 2,2-dimethyloxirane (3.82 ml, 42.8 mmol) and potassium carbonate ( 4.73 g, 34.2 mmoles) in DMF (50 ml) was stirred at RT for 1 h, then at 60 ° C for 11 h, before cooling to RT and allowed to rest over the weekend. The excess solvent was removed under reduced pressure and the residue was placed in water (300 ml) and extracted with EtOAc (3 x 100 ml). The combined organic extracts were dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 30%, EtOAc / isohexanes) to yield the title compound (987 mg). 1H NMR (500 MHz, DMSO-d6): 8.39 (1H, d), 7.59 (1H, dd), 7.47 (1H, d), 4.87 (1H, s), 4, 36 (2H, s), 1.11 (6H, s). PREPARATION 130: 1- (4-CHLORINE-5- (4,4,5,5-TETRAMETHIL-1,3,2-DIOXABOROLAN-2-IL) -2H-INDAZOL-2-IL) -2-METHYLPROPAN-2 -OL
    [1322] [1322] Prepared as preparation 43, except for the use of 1- (5-bromo-4-chloro-2H-indazol-2-yl) -2-methylpropan-2-ol (977 mg, 3.22 mmol). The residue was purified by column chromatography on silica gel (gradient elution, 0 to 5%, MeOH / DCM), to yield the title compound (767 mg). MS: [M + H] + = 351. PREPARATION 131: N- [ENDO-8- {7- [4-CHLORINE-2- (2-HYDROXY-2-METHYROPROPYL) -2H-INDAZOL-5-IL] - 5 - {[2- (TRIMETHILSILIL) ETOXI] METHIL} -5H-PIRROL [2,3-B] PIRAZIN-3-IL} - 8-AZABICICLE [3.2.1] OCTAN-3-IL] TERC-BUTYL CARBAMATE
    [1323] [1323] Prepared as general procedure 2, except using 1- (4-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole -2-yl) -2-methylpropan-2-ol (753 mg, 1.911 mmol) in 1,4-dioxane (12 ml). The crude product was purified by column chromatography on silica gel three times (0 to 50% EtOAc / iso-hexanes, then 40 to 70% EtOAc / iso-hexanes, then 0 to 5% MeOH / DCM) to yield the compound of the title (420 mg). 1H NMR (500 MHz, DMSO-d6): 8.36 (1H, d), 8.16 (1H, s), 7.92 (1H, d), 7.89 (1H, s), 7, 65 (1H, dd), 6.84 (1H, s), 5.57 (2H, s), 4.58 (2H, s), 4.38 (2H, s), 3.62 (2H, t ), 3.43 (1H, s), 2.20 - 2.07 (4H, m), 2.03 - 1.91 (2H, m), 1.76 (2H, d), 1.39 ( 9H, s), 1.14 (6H, s), 0.95 - 0.82 (2H, m), -0.08 (9H, s). PREPARATION 132: 3,4-DICLORO-5- (4,4,5,5-TETRAMETHIL-1,3,2- DIOXABOROLAN-2-IL) -1H-INDAZOL
    [1324] [1324] Prepared as preparation 43, except for the use of 5-bromo-3,4-dichloro-1H-indazole (2.45 g, 9.21 mmol). The crude product was purified by column chromatography on silica gel (gradient elution, 0 to 5%, MeOH / DCM), to yield the title compound (1.95 g). MS: [M + H] + = 313. PREPARATION 133: N- [ENDO-8- [7- (3,4-DICLORO-2H-INDAZOL-5-IL) - 5 - {[2- (TRIMETYLSILIL) ETOXI ] METHIL} -5H-PIRROL [2,3-B] PIRAZIN- 3-IL] -8-AZABICYCLE [3.2.1] OCTAN-3-IL] TERC- CARBAMATE BUTILLE
    [1325] [1325] Prepared as general procedure 2, except for the use of 3,4-dichloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole ( 287 mg, 0.917 mmol) in 1,4-dioxane (12 ml). The crude product was purified by column chromatography on silica gel (gradient elution, 0 to 50%, EtOAc / isohexanes) to yield the title compound (274 mg). MS: [M + H] + = 658. PREPARATION 134: 2- (5-BROMO-4-CHLORINE-2H-INDAZOL-2-ILA) ACETONITRILLA N H N N
    [1326] [1326] 5-Bromo-4-chloro-1H-indazole (5 g, 21.60 mmoles) was dissolved in NMP (2 ml) and bromoacetonitrile
    [1327] [1327] Prepared as preparation 43, except for the use of 2- (5-bromo-4-chloro-2H-indazol-2-yl) acetonitrile (1 g, 3.70 mmol). The crude product was purified by column chromatography on silica gel (gradient elution, 0 to 50%, EtOAc / isohexanes) to yield the title compound (1.31 g). MS: [M + H] + = 318. PREPARATION 136: N- [ENDO-8- {7- [4-CHLORINE-2- (CYANOMETHIL) -2H- INDAZOL-5-IL] -5 - {[2- (TRIMETHILSILIL) ETOXI] METHIL} -5H- PIRROL [2,3-B] PIRAZIN-3-IL} -8-AZABICYCLE [3.2.1] OCTAN-3 IL] TERC-BUTYL CARBAMATE
    [1328] [1328] Prepared as general procedure 2, except using 2- (4-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole -2-yl) acetonitrile (1.059 g, 2.50 mmol). The crude product was dry loaded onto silica (about 8 g) and purified by silica gel column chromatography (gradient elution, 10 to 50%, EtOAc / isohexanes) to yield the title compound (286 mg ). MS: [M + H] + = 663. PREPARATION 137: 5-BROMO-4-CHLORINE-3- (CHLOROMETHYL) -2-METHYL-2H- INDAZOL
    [1329] [1329] To a solution of (5-bromo-4-chloro-2-methyl-2H-indazol-3-yl) methanol (1.21 g, 4.39 mmol) in CHCl3 (100 ml) was added sulfurous dichloride (0.481 ml, 6.59 mmoles). The reaction was heated to 60 ° C for 2 h, before adding SOCl2 (0.2 ml). After an additional 1 h at 60 ° C, the reaction was cooled to RT and the solvent was evaporated. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 50%, EtOAc / isohexanes) to yield the title compound (1.1 g). 1H NMR (500 MHz, DMSO-d6): 7.60 (1H, d), 7.54 (1H, d), 5.45 (2H, s), 4.22 (3H,
    [1330] [1330] To a solution of 5-bromo-4-chloro-3- (chloromethyl) -2-methyl-2H-indazole (1.054 g, 3.59 mmol) in DMSO (15 ml) was added sodium cyanide (0.193) g, 3.94 mmoles) before heating at 60 ° C for 1 h. The reaction was cooled to RT, NaHCO3 aq. sat. (50 ml) was added and extracted with EtOAc (2 x 100 ml). The combined organic extracts were dried (MgSO4) and concentrated to yield the title compound (957 mg). 1H NMR (500 MHz, DMSO-d6): (1H, d), 7.52 (1H, d), 4.73 (2H, s), 4.21 (3H, s). PREPARATION 139: 2- [4-CHLORINE-2-METHYL-5- (4,4,5,5-TETRAMETHYL 1,3,2-DIOXABOROLAN-2-IL) -2H-INDAZOL-3-IL] ACETONITRIL
    [1331] [1331] Prepared as preparation 43, except for the use of 2- (5-bromo-4-chloro-2-methyl-2H-indazol-3-yl) acetonitrile (847 mg, 2.98 mmol). The crude product was purified by silica gel column chromatography (gradient elution, 0 to 5%, MeOH / DCM), to yield the title compound (549 mg). 1H NMR (500 MHz, DMSO-d6): 7.55 (1H, d), 7.44 (1H, d), 4.21 (2H, s), 3.18 (3H, s), 1, 16 (12H, s). PREPARATION 140: N- [ENDO-8- {7- [4-CHLORINE-3- (CYANOMETHIL) -2- METHYL-2H-INDAZOL-5-IL] -5 - {[2- (TRIMETHYLSILIL) ETOXI] METHIL} -
    [1332] [1332] Prepared as general procedure 2, except using 2- (4-chloro-2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-3-yl) acetonitrile (434 mg, 0.916 mmol) and potassium carbonate (380 mg, 2.75 mmol) in 1,4-dioxane (10 ml). The crude product was purified by column chromatography on silica gel (gradient elution, 0 to 90%, EtOAc / isohexanes) to yield the title compound (244 mg). MS: [M + H] + = 677. PREPARATION 141: 4-CHLORINE-2-METHYL 5- (4,4,5,5-TETRAMETHYL 1,3,2-DIOXABOROLAN-2-IL) -2H- INDAZOL-3-CARBALDEHYDE
    [1333] [1333] Prepared as preparation 43, except for the use of 5-bromo-4-chloro-2-methyl-2H-indazol-3-carbaldehyde (1.45 g, 5.30 mmol). The crude product was purified by column chromatography on silica gel (gradient elution, 0 to 10%, MeOH / DCM), to yield the title compound (1.69 g). MS: [M + H] + = 321. PREPARATION 142: N- [ENDO-8- [7- (4-CHLORINE-3-FORMYL-2-METHYL-2H- INDAZOL-5-IL) -5 - {[ 2- (TRIMETHILSILIL) ETOXI] METHIL} -5H- PIRROL [2,3-B] PIRAZIN-3-IL] -8-AZABYCLE [3.2.1] OCTAN-3- IL] TERC-BUTYLE CARBAMATE
    [1334] [1334] Prepared as general procedure 2, except using 4-chloro-2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H- indazole-3-carbaldehyde (285 mg, 0.67 mmol) in 1,4-dioxane (8 ml). The crude product was purified by column chromatography on silica gel (gradient elution, 0 to 50%, EtOAc / isohexanes) to yield the title compound (253 mg). MS: [M + H] + = 666. PREPARATION 143: N- (ENDO-8- (7- (4-CHLORINE-3 - ((E) - (HYDROXYIMINE) METHIL) -2-METHYL-2H-INDAZOL- 5-IL) -5 - ((2- (TRIMETHILSILIL) ETOXI) METHIL) -5H-PIRROL [2,3-B] PIRAZIN-3-IL) - 8-AZABICYCLE [3.2.1] OCTAN-3-ILA) TERC-BUTYLE CARBAMATE
    [1335] [1335] A mixture of N- (endo-8- (7- (4-chloro-3-formyl-2-methyl-2H-indazol-5-yl) -5 - ((2- (trimethylsilyl) ethoxy) methyl ) -5H-pyrrole [2,3-b] pyrazin-3-yl) - 8-azabicyclo [3.2.1] octan-3-yl) tert-butyl carbamate (415 mg, 0.62 mmol), hydrochloride hydroxylamine (87 mg, 1.25 mmol) and sodium carbonate (132 mg, 1.25 mmol) in IPA
    [1336] [1336] A mixture of N- (endo-8- (7- (4-chloro-3- ((E) - (hydroxyimino) methyl) -2-methyl-2H-indazol-5-yl) -5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrole [2,3-b] pyrazin-3-yl) -
    [1337] [1337] A mixture of 5-bromo-4-chloro-2H-indazole (2.305 g, 9.96 mmoles) and 2- (chloromethyl) -1-methyl-1H-imidazole (2.6 g, 19.91 mmoles ) in NMP (50 ml) was stirred at 140 ° C for 24 hours before cooling to RT. The organic phase was washed with aq. sat. (250 ml) and water (2 x 300 ml), dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 100%, EtOAc / iso-hexanes, then washed with 100% (0.03% NH3 in MeOH) / DCM) to yield the compound of the title (1.66 g). MS: [M + H] + = 325. PREPARATION 146: 4-CHLORINE-2 - (((1-METHYL-1H-IMIDAZOL-2-ILA) METHIL) -5- (4,4,5,5-TETRAMETHYL- 1,3,2-DIOXABOROLAN-2-IL) -
    [1338] [1338] Prepared as preparation 43 using 5-bromo-4-chloro-2 - (((1-methyl-1H-imidazol-2-yl) methyl) -2H-indazole (1.66 g, 5, 10 mmoles). The crude product was purified by column chromatography on silica gel twice (0 to 2% MeOH / DCM, then 70 to 100% EtOAc / isohexanes) to yield the title compound (763 mg). MS: [M + H] + = 373. PREPARATION 147: N- (ENDO-8- (7- (4-CHLORINE-2 - ((1-METHYL-1H- IMIDAZOL-2-ILA) METHYL) -2H- INDAZOL-5-IL) -5 - ((2- (TRIMETHILSILIL) ETOXI) METHIL) -5H-PIRROL [2,3-B] PIRAZIN-3-IL) - 8-AZABYCLE [3.2.1] OCTAN-3- ILA) TERC-BUTYLE CARBAMATE
    [1339] [1339] Prepared as general procedure 2, except using 4-chloro-2 - (((1-methyl-1H-imidazol-2-yl) methyl) -5- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) - 2H-indazole (426 mg, 1.14 mmol) in 1,4-dioxane (12 ml). The crude product was purified by column chromatography on silica gel (gradient elution, 0 to 100%, EtOAc / isohexanes) to yield the title compound (413 mg). MS: [M + H] + = 718. PREPARATION 148: 5 - (((5-BROMO-4-CHLORINE-2H-INDAZOL-2-ILA) METHIL) -3-METHYL-1,2,4-OXADIAZOL
    [1340] [1340] Prepared using the same alkylation procedure as preparation 145 using 5- (chloromethyl) -3-methyl-1,2,4-oxadiazole (5 g, 37.7 mmol) to yield the compound of the title (3 g). MS: [M + H] + = 327. PREPARATION 149: 5 - ((4-CHLORINE-5- (4,4,5,5-TETRAMETHYL-1,3,2- DIOXABOROLAN-2-IL) -2H- INDAZOL-2-ILA) METHIL) -3-METHYL-1,2,4- OXADIAZOLE
    [1341] [1341] Prepared as preparation 43 using 5 - ((5-bromo-4-chloro-2H-indazol-2-yl) methyl) -3-methyl-1,2,4-oxadiazole (3 g, 9.16 mmoles). The crude product was purified by column chromatography on silica gel (gradient elution, 0 to 100%, tert-butyl methyl ether / isohexanes) to yield 3 g of an orange oil. The oil was dissolved in tert-butyl methyl ether (50 ml), then extracted with aq. 1M (30 ml, then 10 ml). The aqueous layer was treated with NH4Cl (2.0 g, 37.4 mmoles), then extracted with DCM (3 x 30 ml). The combined organic phases were concentrated under reduced pressure, to yield the title compound (1.4 g). MS: [M + H] + = 375. PREPARATION 150: N- (ENDO-8- (7- (4-CHLORINE-2 - ((3-METHYL-1,2,4- OXADIAZOL-5-ILA) METHYL ) -2H-INDAZOL-5-IL) -5 - ((2- (TRIMETHILSILIL) ETOXI) METHIL) -5H-PIRROL [2,3-B] PIRAZIN-3-IL) - 8-AZABYCLE [3.2.1] OCTAN-3-ILA) TERC-BUTYLE CARBAMATE
    [1342] [1342] Prepared as the general procedure 2, except for the use of 5 - ((4-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H- indazol-2-yl) methyl) -3-methyl-1,2,4-oxadiazole (660 mg, 1.67 mmol), in 1,4-dioxane (12 ml). The crude product was purified by column chromatography on silica gel (gradient elution, 15 to 75% tert-butyl methyl ether / isohexanes) to yield the title compound (460 mg). MS: [M + H] + = 720. PREPARATION 151: 5-BROMO-4-CHLORINE-2 - (((1-METHYL-1H-PIRAZOL-3-ILA) METHIL) -2H-INDAZOL
    [1343] [1343] Prepared using the same alkylation procedure as preparation 145 using 3- (chloromethyl) -1-methyl-1H-pyrazole (4.95 g, 37.9 mmol). The crude product was purified by column chromatography on silica gel (gradient elution, 20 to 100%, EtOAc / isohexanes) to yield the title compound (2.46 g). MS: [M + H] + = 325. PREPARATION 152: 4-CHLORINE-2 - (((1-METHYL-1H-PIRAZOL-3-ILA) METHIL) -5- (4,4,5,5-TETRAMETHYL- 1,3,2-DIOXABOROLAN-2-IL) - 2H-INDAZOL
    [1344] [1344] Prepared as preparation 43 using 5-bromo-4-chloro-2 - (((1-methyl-1H-pyrazol-3-yl) methyl) -2H-indazole (2.44 g, 7, 49 mmoles). The crude product was purified by column chromatography on silica gel (gradient elution, 0 to 5%, MeOH / DCM), to yield the title compound (2.71 g). 1H NMR (500 MHz, DMSO-d6): 8.53 (1H, s), 7.63 (1H, d), 7.52 (1H, d), 7.43 (1H, d), 6, 25 (1H, d), 5.59 (2H, s), 3.80 (3H, s), 1.31 (12H, s). PREPARATION 153: N- (ENDO-8- (7- (4-CHLORINE-2 - (((1-METHYL-1H-PIRAZOL-3-ILA) METHIL) -2H-INDAZOL-5-IL) -5 - (( 2- (TRIMETHILSILIL) ETOXI) METHIL) -5H-PIRROL [2,3-B] PIRAZIN-3-IL) - 8-AZABICYCLE [3.2.1] OCTAN-3-ILA) TERC-BUTYLE CARBAMATE
    [1345] [1345] Prepared as general procedure 2, except using 4-chloro-2 - (((1-methyl-1H-pyrazol-3-yl) methyl) -5- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) - 2H-indazole (435 mg, 1.17 mmol) in 1,4-dioxane (12 ml). The crude product was purified by column chromatography on silica gel twice (20 to 100% EtOAc / isohexanes, then 0 to 3% MeOH / DCM) to yield the title compound (205 mg). MS: [M + H] + = 718. PREPARATION 154: 6-BROMO-5-CHLORINE-2- IODIDE
    [1346] [1346] To a solution of 6-bromo-5-chloroisoquinoline (5.3 g, 21.86 mmoles) in THF (50 ml) was added iodomethane (1.429 ml, 22.95 mmoles). The solution was stirred at RT for 18 h. The precipitate was collected by filtration, washed with THF (50 ml) and the solid was dried in vacuo. The filtrate was stirred for an additional 6 h. Iodomethane (1 ml) was added and the reaction was allowed to stir over the weekend. The precipitate was collected by filtration, washing with THF (40 ml) before combining with the previous batch and drying in vacuo to yield the title compound (4.95 g). 1H NMR (500 MHz, DMSO-d6): 10.10 (1H, s), 8.85 (1H, dd), 8.70 (1H, d), 8.41 (1H, ddd), 8, 38 (1H, dd), 4.48 (3H, s). PREPARATION 155: 6-BROMO-5-CHLORINE-2-METHYL-1,2- DIHYDROISOQUINOLIN-1-ONA
    [1347] [1347] A mixture of 6-bromo-5-chloro-2-methylisoquinoline-2-iodide (4.7 g, 12.23 mmol), cesium carbonate (5.98 g, 18.34 mmol) and Eosin Y (0.423 g, 0.611 mmol) in DMF (300 ml) was stirred under air and irradiated with a 400 W lamp for 10 h. The excess DMF was removed under reduced pressure before adding water (400 ml) and extraction with EtOAc (3 x 210 ml). The organic extracts were dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 50%, EtOAc / isohexanes) to yield the title compound (740 mg). MS: [M + H] + = 272. PREPARATION 156: 5-CHLORINE-2-METHYL 6- (4,4,5,5-TETRAMETHYL 1,3,2-DIOXABOROLAN-2-IL) -1, 2-DIIDROISOQUINOLIN-1-ONA
    [1348] [1348] Prepared as preparation 43 using 6-bromo-5-chloro-2-methyl-1,2-dihydroisoquinolin-1-one (1.01 g, 3.71 mmoles). The crude product was purified by column chromatography on silica gel (gradient elution, 0 to 1%, MeOH / DCM), to yield the title compound (501 mg). 1H NMR (500 MHz, DMSO-d6): 8.18 (1H, d), 7.64 (2H, dd), 6.80 (1H, d), 3.52 (3H, s), 1, 34 (12H, s). PREPARATION 157: (((3R, 4S) -1- (7- (5-CHLORINE-2-METHYL-1-OXO-1,2-DIHYDROISOQUINOLIN-6-IL) -5 - ((2- (TRIMETYLSILIL) ETOXI) METHIL) - 5H-PIRROL [2,3-B] PIRAZIN-3-IL) -3-FLUOROPIPERIDIN-4-ILA) TERC-BUTYL CARBAMATE
    [1349] [1349] Prepared as general procedure 2, except for the use of 5-chloro-2-methyl-6- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) -1, 2-dihydroisoquinolin-1-one (400 mg, 1.16 mmol), N - ((3R, 4S) -3-fluoro-1- (7-iodine-5 - ((2-
    [1350] [1350] 1-bromopyrrolidine-2,5-dione (0.34 g, 1.90 mmol) and (E) -2.2 '- (diazene-1,2-diyl) bis (2-methylpropanonitrile) (0.023 g, 0.142 mmol) were added to a solution of methyl 4-bromo-3-chloro-2-methylbenzoate (0.25 g, 0.949 mmol) in chloroform (5 ml, 0.949 mmol), and the mixture was heated to reflux for 2.5 h, then concentrated on silica. The crude product was purified by column chromatography on silica gel (gradient elution, 0 to 15%, EtOAc in isohexanes) to yield the title compound (0.308 g). 1H NMR (400 MHz, CDCl3): 7.75 (1H, d), 7.70 (1H, d), 5.19 (2H, s), 3.98 (3H, s). PREPARATION 159: 5-BROMO-4-CHLORINE-2-METHYL-2,3-DIIDRO-1H- ISOINDOL-1-ONA
    [1351] [1351] Methyl 4-Bromo-2- (bromomethyl) -3-chlorobenzoate (0.30 g, 0.88 mmol) was suspended in methylamine (33% by weight in EtOH, 1.96 ml, 15.77 mmoles ) and stirred at RT for 30 min. THF (2 ml) was added and the suspension was heated to 50 ° C for 16 h. The mixture was cooled to RT, diluted with aq. 1M (20 ml) and extracted with EtOAc (3 x 50 ml). The combined organic phases were passed through a phase separator and concentrated to yield the title compound (0.220 g). MS: [M + H] +, 260. PREPARATION 160: 4-CHLORINE-2-METHYL 5- (4,4,5,5-TETRAMETHYL 1,3,2-DIOXABOROLAN-2-IL) -2, 3-DIIDRO-1H-ISOINDOL-1-ONA
    [1352] [1352] A mixture of 5-bromo-4-chloro-2-methyl-2,3-dihydro-1H-isoindol-1-one (1.0 g, 3.84 mmol), bis (pinacolate) diboro (2 , 92 g, 11.52 mmoles), potassium acetate (1.130 g, 11.52 mmoles) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane (0.313 g, 0.38 mmol) in 1,4-dioxane (15 ml) was degassed under a flow of N2, then heated at 100 ° C for 18 h, cooled to RT, concentrated and diluted with EtOAc (50 ml). After sonication, the mixture was filtered and concentrated on silica. The residue was purified by column chromatography on silica gel (gradient elution, 1 to 4%, MeOH / DCM), to yield the title compound (1.02 g). 1H NMR (400 MHz, CDCl3): 7.85 (1H, d), 7.74 (1H, d), 4.39 (2H, s), 3.25 (3H, s), 1.41 ( 12H, s). PREPARATION 161: N - (((3R, 4S) -1- (7- (4-CHLORINE-2-METHYL-1-OXO-2,3-DIHYDRO-1H-ISOINDOL-5-IL) -5 - ((2 - (TRIMETHILSILIL) ETOXI) METHIL) - 5H-PIRROL [2,3-B] PIRAZIN-3-IL) -3-FLUOROPIPERIDIN-4-ILA) TERC-BUTYL CARBAMATE
    [1353] [1353] A mixture of N - ((3R, 4S) -3-fluoro-1- (7-iodine-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrole [2,3-b] pyrazin-3-yl) piperidin-4-yl) tert-butyl carbamate (0.5 g, 0.84 mmol), 4-chloro-2-methyl-5- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) -2,3-dihydro-1H-isoindol-1-one (0.42 g, 1.01 mmol), potassium phosphate, tribasic (0.59 g, 2 , 54 mmoles) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane (0.069 g, 0.085 mmol) in 1,4-dioxane (10 ml) and water (2.5 ml) it was degassed under a flow of N2, then heated to 70 ° C for 1 h, cooled to RT, diluted with DCM (10 ml), crossed by a phase separator and concentrated on silica.
    [1354] [1354] To a solution of 5-bromo-4-chloro-1H-1,3-benzodiazole (5 g, 21.60 mmol) in DMF (50.2 ml, 648 mmol) at 0 ° C was added NaH ( 60% by weight in mineral oil, 1.123 g, 28.1 mmoles). The reaction mixture was warmed to RT for 30 min, then iodomethane (1.486 ml, 23.76 mmoles) was added.
    [1355] [1355] A mixture of N - ((3R, 4S) -3-fluoro-1- (7-iodine-5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrole [2,3-b] pyrazin-3-yl) piperidin-4-yl) tert-butyl carbamate (553 mg, 0.93 mmol), 7-chloro-1-methyl-6- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1H-1,3-benzodiazole (268 mg, 0.78 mmol), potassium carbonate (323 mg, 2.34 mmol) and [1,1'-bis complex (diphenylphosphino) ferrocene] dichloropalladium (II) with dichloromethane (63.6 mg, 0.078 mmol) in 1,4-dioxane (12 ml) and water (3 ml) was degassed under a flow of N2. The reaction was heated to 50 ° C for 2 h before cooling to RT, filtering through celite, washing with DCM and MeOH before concentration. The residue was purified by column chromatography on silica gel twice (0 to 100% EtOAc / isohexanes, then 0 to 4% MeOH / DCM) to yield the title compound 176 mg). MS: [M + H] + = 630. PREPARATION 165: 3-CHLORINE-5 - {[2- (TRIMETHYLSILYL) ETOXI] METHIL} - 5H-PIRROL [2,3-B] PIRAZINE
    [1356] [1356] A solution of 3-chloro-5H-pyrrole [2,3-
    [1357] [1357] A suspension of 3-chloro-5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazine (20.0 g, 70.5 mmol), benzophenone imine ( 13.6 ml, 81.0 mmol), [(4,5-bis (diphenylphosphino) -9,9- dimethylxanthene) -2- (2′-amino-1,1′-biphenyl)]] palladium (II) methanesulfonate ( 2.67 g, 2.82 mmoles) and NaOtBu (10.2 g, 106 mmoles) in 1,4-dioxane
    [1358] [1358] To a stirred mixture of 5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazin-3-amine (2.28 g, 8.6 mmol) in HBF4 aq. 48% (11.4 ml) and THF (11.4 ml) at 0 ° C a solution of NaNO2 (0.655 g, 9.5 mmoles, in 2.3 ml of water) was added by dripping over 30 min. After 10 min, the cold mixture was added to a mixture of aq. sat., Na2SO3 aq. sat. and EtOAc. The phases were separated and the EtOAc layer was concentrated. The crude material was dissolved in methyl tert-butyl ether / 10% petrol, crossed through a phase separator and purified by column chromatography on silica gel (gradient elution, 10 to 35%, methyl tert-butyl ether) / petrol) to yield the title compound (1.16 g), MS: [M + H] + = 268. PREPARATION 168: 3-FLUORO-7-IODO-5 - {[2-
    [1359] [1359] To a stirred solution of 3-fluoro-5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazine (1.28 g, 4.79 mmol) in DMF (8.6 ml) to RT was added N-iodosuccinimide (1.51 g, 6.7 mmoles) and the mixture stirred for 1.5 h. The mixture was poured into a mixture of aq. sat. Na2S2O3 and ice water. The resulting solid was collected by filtration and washed with water (3x) and then dried in vacuo to yield the title compound (1.88 g), MS: [M + H] + = 394. PREPARATION 169: 3- FLUORO-7-IODINE-5H-PIRROL [2,3-B] PIRAZINE
    [1360] [1360] A solution of 3-fluoro-7-iodo-5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazine (1.43 g, 3.63 mmoles) in DCM (15 ml) and TFA (10 ml) was stirred at RT for 24 h. The mixture was evaporated. The residue was dissolved in MeOH / aq. and stirred for 1 h. The MeOH was evaporated and the resulting solid was collected by filtration. The solid was washed with water and dried to yield the title compound (0.848 g), MS: [M + H] + = 264. PREPARATION 170: 3-FLUORO-7-IODO-N, N-DIMETHYL-5H-PIRROL [2,3- B] PIRAZINE-5-SULPHONAMIDE
    [1361] [1361] 3-Fluoro-7-iodo-5H-pyrrole [2,3-b] pyrazine (0.848 g, 3.22 mmol) was dissolved in THF / DMF (1: 1, 10 ml) and cooled in a bath of ice. NaH (60% in mineral oil) (0.17 g, 4.19 mmoles) was added and the mixture stirred at RT for 1 h. After re-cooling to 0 ° C, N, N-dimethylsulfamoyl chloride (0.45 ml, 4.19 mmoles) was added and the mixture allowed to warm to RT and stirred overnight. Aq. sat. was added and the mixture extracted with EtOAc. The EtOAc layer was dried (MgSO4) and then evaporated. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 60%, EtOAc / petrol) to yield the title compound (0.72 g), MS: [M + H] + = 371. PREPARATION 171: (1R, 2S, 5S) -2-FLUORO-3-OXO-8- AZABICYCLE [3.2.1] OCTANE-8-CARBOXYLATE RAC-TERC-BUTYL E (1R, 2R, 5S) -2-FLUORO -3-OXO-8-AZABICYCLE [3.2.1] OCTANE-8- RAC-TERC-BUTYL CARBOXYLATE (INSPIRE MIXED)
    [1362] [1362] A solution of (1R, 2R, 5S) -2-fluoro-3-oxo-8-azabicyclo [3.2.1] rac-tert-butyl octane-8-carboxylate (50 g, 195 mmoles) in THF (200 ml) was added dropwise to a suspension of NaOtBu (20 g, 208 mmoles) in THF (200 ml), then stirred at RT for 2 h. The mixture was abruptly cooled with a solution of NH4Cl (20 g, 374 mmol) in water (200 ml), then diluted with saturated brine (800 ml). The mixture was extracted with EtOAc (3 x 500 ml). The combined organic phases were concentrated under reduced pressure, to yield the crude product as a pale yellow oil. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 10%, acetone / isohexane) to yield a 1: 1 mixture of the title compounds (32.2 g). Isomer 1: 1H NMR (500 MHz, DMSO-d6): 4.69 - 4.28 (m, 3H), 2.92 - 2.80 (m, 1H), 2.41 - 2.31 (m , 1H), 2.16 - 1.97 (m, 1H), 1.97 - 1.84 (m, 1H), 1.60 - 1.31 (m, 11H); Isomer 2: 1H NMR (500 MHz, DMSO-d6): 5.05 (dd, J = 47.7, 5.0 Hz, 1H), 4.69 - 4.28 (m, 2H), 2, 79 - 2.68 (m, 1H), 2.42 - 2.28 (m, 1H), 2.17 - 1.82 (m, 2H), 1.72 - 1.25 (m, 11H). PREPARATION 172: (1S, 2S, 3S, 5R) -3- (BENZYLAMINE) -2-FLUORO-8- AZABICYCLE [3.2.1] OCTANE-8-CARBOXYLATE OF RAC-TERC-BUTYL
    [1363] [1363] NaBH (OAc) 3 (65 g, 307 mmoles) was added to a solution of (1R, 2S, 5S) -2-fluoro-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate rac-tert-butyl and (1R, 2R, 5S) -2-fluoro-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate of rac-tert-butyl (1: 1 mixture prepared using the method of Preparation 171, 49.7 g, 184 mmoles), benzylamine (24 ml, 216 mmoles) and acetic acid (12 ml, 210 mmoles) in DCM (500 ml), then stirred at RT for 18 h . A solution of NaHCO3 (100 g, 1,190 mmoles) in water (750 ml) was added, then the mixture was extracted with DCM (3 x 500 ml). The combined organic phases were then
    [1364] [1364] (1S, 2S, 3S, 5R) -3- (Benzylamino) -2-fluoro- 8-azabicyclo [3.2.1] rac-tert-butyl octane-8-carboxylate (27.8 g, 79 mmoles ) and 10% Pd / C (Type JM 39, 57.3% humidity) (6 g, 2.407 mmoles) were dissolved in acetic acid / ethanol (1: 3, 260 ml) and stirred under hydrogen at 1 bar for 18 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was treated with aq. sat. (500 ml), then extracted with chloroform / IPA (9: 1, 3 x 200 ml). The combined organic phases were concentrated under reduced pressure, to yield the title compound (19.6 g). 1H NMR (500 MHz, DMSO-d6): 4.53 (dt, 1H), 4.13 - 4.03 (m, 1H), 4.03 - 3.91 (m, 1H), 3.64 - 3.53 (m, 1H), 2.50 - 2.40 (m, 1H), 2.22 - 2.05 (m, 1H), 1.97 - 1.49 (m, 6H), 1 , 39 (d, 9H). PREPARATION 174: (1S, 2S, 3S, 5R) -3- {[(BENZILOXI) CARBONIL] AMINO} -2-FLUORO-8- AZABICICLE [3.2.1] OCTANE-8-CARBOXYLATE OF RAC-TERC-BUTYLE
    [1365] [1365] Benzyl chloroformate (12 ml, 84 mmoles) was added to an ice bath-cooled solution of (1S, 2S, 3S, 5R) -3-amino-2-fluoro-8-azabicycles [3.2.1] rac-tert-butyl octane-8-carboxylate (19.6 g, 76 mmoles) and DIPEA (30 ml, 172 mmoles) in DCM (150 ml) and THF (50 ml), then stirred at RT for 18 h. Water (300 ml) was added, then the mixture was extracted with DCM (3 x 300 ml) and the combined organic phases were concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 25%, acetone / isohexane), to yield the title compound (28.4 g). 1H NMR (500 MHz, DMSO-d6) δ 7.41 - 7.35 (m, 4H), 7.35 - 7.28 (m, 1H), 7.14 - 6.93 (m, 1H) , 5.23 - 4.89 (m, 2H), 4.85 - 4.65 (m, 1H), 4.22 - 4.07 (m, 2H), 4.07 - 3.97 (m, 1H), 2.29 - 2.17 (m, 1H), 2.08 - 2.02 (m, 1H), 1.99 - 1.79 (m, 2H), 1.80 - 1.64 ( m, 2H), 1.40 (s, 9H). PREPARATION 175: N - [(1S, 2R, 3S, 5R) -2-FLUORO-8- AZABICYCLE [3.2.1] OCTAN-3-IL] CARBAMATE RAC- HYDROCHLORIDE BENZILA
    [1366] [1366] (1S, 2S, 3S, 5R) -3- {[(Benzyloxy) carbonyl] amino} -2-fluoro-8-azabicyclo [3.2.1] rac-tert-butyl octane-8-carboxylate (28 , 4 g, 71.3 mmoles) was dissolved in DCM (100 ml), then added dropwise to a stirred mixture of HCl (3M in cyclopentyl methyl ether, 200 ml, 600 mmoles) and DCM (100 ml). The mixture was stirred at RT for 3 h, then diluted with tert-butyl methyl ether (500 ml) added by dripping. Acetonitrile (50 ml) was added and the mixture was stirred vigorously for 1 h. The resulting solid was collected by filtration and washed with tert-butyl methyl ether (50 ml) followed by isohexane (50 ml) to yield the title compound (21.9 g). 1H NMR (500 MHz, DMSO-d6): 10.08 - 9.28 (m, 2H), 7.46 - 7.14 (m, 6H), 5.21 - 5.00 (m, 3H) , 4.27 - 4.15 (m, 1H), 4.13 - 4.04 (m, 1H), 3.96 - 3.88 (m, 1H), 2.42 (ddd, 1H), 2 , 36 - 2.26 (m, 1H), 2.16 (ddd, 1H), 2.04 - 1.90 (m, 2H), 1.89 - 1.78 (m, 1H). PREPARATION 176: N - [(1S, 2R, 3S, 5R) -2-FLUORO-8- AZABICICLE [3.2.1] OCTAN-3-IL] CARBAMATE BENZILLA HYDROCHLORIDE (QUICK ELUTION ISOMER)
    [1367] [1367] N - [(1S, 2R, 3S, 5R) -2-Fluoro-8-azabicyclo [3.2.1] octan-3-yl] carbamate rac-benzyl hydrochloride (21.9 g) was dissolved in methanol (50 mg / ml), then purified by chiral preparative supercritical fluid chromatography (Lux A1 (4.6 mm x 250 mm, 5 µm); 40 ° C, Flow Rate 50 ml / min, BPR 125 BarG, Detection a 210 nm, Injection Volume 1,000 µl (50 mg), 50:50 MeOH: CO2 (0.7% by volume of DEA)). The pure fractions were combined, then evaporated. The residue was then dissolved in DCM (5 ml), then added dropwise to a stirred mixture of tert-butyl methyl ether (20 ml), isohexane (20 ml) and HCl (3 M in cyclopentyl methyl ether, 2 ml , 6.00 mmoles) to yield a solid which was recrystallized from acetonitrile (15 ml) to yield the title compound (8.7 g). 1H NMR (500 MHz, DMSO-d6) δ 9.82 - 9.29 (m, 2H), 7.62 - 6.86 (m, 6H), 5.25 - 4.87 (m, 3H) , 4.29 - 4.13 (m, 1H), 4.13 - 4.00 (m, 1H), 3.98 - 3.85 (m, 1H), 2.42 (ddd, J = 14, 1, 9.7, 4.7 Hz, 1H), 2.33 - 2.23 (m, 1H), 2.22 - 2.11 (m, 1H), 2.03 - 1.86 (m, 2H), 1.87 - 1.73 (m, 1H). PREPARATION 177: N - [(1R, 2S, 3R, 5S) -2-FLUORO-8- AZABICYCLE [3.2.1] OCTAN-3-IL] CARBAMATE BENZILLA HYDROCHLORIDE (SLOW ELUTION ISOMER)
    [1368] [1368] From the same chromatography experiment described in preparation 176, the title compound was obtained as the slow eluting isomer. The residue was then dissolved in DCM (5 ml), then diluted with tert-butyl methyl ether (20 ml) and treated with HCl (3 M in cyclopentyl methyl ether, 2 ml, 6.00 mmoles) to render a sticky suspension. The suspension was diluted with isohexane (30 ml), stirred for 18 h and collected by filtration to yield the title compound (7.5 g). 1H NMR (500 MHz, DMSO-d6) δ 9.82 - 9.29 (m, 2H), 7.62 - 6.86 (m, 6H), 5.25 - 4.87 (m, 3H) , 4.29 - 4.13 (m, 1H), 4.13 - 4.00 (m, 1H), 3.98 - 3.85 (m, 1H), 2.42 (ddd, J = 14, 1, 9.7, 4.7 Hz, 1H), 2.33 - 2.23 (m, 1H), 2.22 - 2.11 (m, 1H), 2.03 - 1.86 (m, 2H), 1.87 - 1.73 (m, 1H).
    [1369] [1369] The compounds in Table 6 below were prepared using procedures analogous to those described in preparation 43, starting with the appropriate substituted aryl halide (synthesized as described by the indicated preparations) with any significant variations indicated.
    [1370] [1370] Sodium hydride (60% mineral oil, 3.14 g, 78 mmol) was added over 5 min to a solution of 6-chloro-3-iodo-1H-pyrazol [3,4-b] pyrazine ( 20 g, 71.3 mmoles) in THF (300 ml) at 0 ° C. After stirring at 0 ° C for 45 min, 2- (trimethylsilyl) ethoxymethyl chloride (15.2 ml, 86 mmol) was added over 2 min. The mixture was stirred at RT for another 3 h, abruptly cooled with aq. sat. (150 ml), diluted with water (200 ml) and extracted with EtOAc (2 x 150 ml). The combined organic phases were crossed by a phase separator and concentrated. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 25%, EtOAc / isohexane) to yield the title compound (24.2 g). MS: [M + H] + = 411. PREPARATION 179: (6-CHLORINE-3-IODO-1 - {[2- (TRIMETHYLSYL) ETOXI] METHIL} -1H-PIRAZOL [3,4-B] PIRAZIN-5 - ILA) METHANOL
    [1371] [1371] A solution of 6-chloro-3-iodo-1 - ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole [3,4-b] pyrazine (11.5 g, 26.2 mmol) in MeOH (91 ml) and DMSO (100 ml) was bubbled with N2 for 15 min, then silver nitrate (1.78 g, 10.5 mmoles) and TFA (2.02 ml, 26.2 mmoles) were added sequentially. The mixture was heated to 70 ° C and a solution of ammonium persulfate (15.0 g, 65.5 mmoles) in water (33 ml) was added dropwise for 45 min. The mixture was stirred at 70 ° C for a further 2 h, then cooled to RT, diluted with EtOAc (100 ml) and filtered through celite with an EtOAc wash (2 x 50 ml). The filtrate was diluted with aq. sat. (75 ml) and water (300 ml) and divided. The aqueous phase was extracted with EtOAc (2 x 150 ml) and the combined organic phases were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (gradient elution, 5 to 40%, EtOAc / isohexane) to yield the title compound (5.9 g). 1H NMR (500 MHz, CDCl3): 5.83 (2H, s), 5.02 (2H, s), 3.76 - 3.66 (2H, m), 1.02 - 0.88 (2H , m), -0.01 (s, 9H). PREPARATION 180: N - [(1R, 2R, 3S, 5S) -2-FLUORO-8- AZABICICLE [3.2.1] OCTAN-3-IL] TERC-BUTYL CARBAMATE STEP 1: N - [(1R, 2S, 3S, 5S) -2-FLUORO-8- (2,2,2- TRIFLUOROACETYL) -8-AZABICYCLE [3.2.1] OCTAN-3-IL] CARBAMATE BENZILA
    [1372] [1372] To a solution of N - [(1R, 2R, 3S, 5S) -2-fluoro-8-azabicyclo [3.2.1] octan-3-yl] benzyl carbamate (1.0 g, 3.6 mmoles) and Et3N (1.0 ml, 7.2 mmoles) in DCM (15 ml), trifluoroacetic anhydride (0.53 ml, 3.78 mmoles) was added and the reaction mixture was stirred at RT for 1 h. The reaction was diluted with DCM and aq. sat. was added.
    [1373] [1373] To a solution of N - [(1R, 2S, 3S, 5S) -2-fluoro-8- (2,2,2-trifluoroacetyl) -8-azabicyclo [3.2.1] octan-3-yl] benzyl carbamate (1.32 g, 3.53 mmoles) in ethanol (15 ml) were added di-tert-butyl dicarbonate (1.0 g, 4.58 mmoles) and Pd / C (10%, 0, 13 g) and the mixture was hydrogenated for 6 h. The reaction was filtered and the filtrate evaporated. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 40%, EtOAc / petrol) to yield the title compound (1.04 g). 1H NMR (400 MHz, DMSO-d6): 6.98 (1H, d), 4.89-4.21 (3H, m), 3.86 (1H, d), 2.19-1.53 (6H, m), 1.39 (9H, s). STEP 3: N - [(1R, 2R, 3S, 5S) -2-FLUORO-8- AZABICYCLE [3.2.1] OCTAN-3-IL] TERC-BUTYL CARBAMATE
    [1374] [1374] To a solution of N - [(1R, 2S, 3S, 5S) -2-fluoro-8- (2,2,2-trifluoroacetyl) -8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (1.04 g, 3.07 mmoles) in MeOH (15 ml) and H2O (3 ml) was added K2CO3 (2.11 g, 15.35 mmoles) and the mixture was stirred for one day To the other. MeOH was evaporated, H2O was added and the product was extracted with DCM. The organic phase was dried (MgSO4), filtered and evaporated to yield the title compound (0.733 g). 1H NMR (400 MHz, DMSO-d6): 6.75 (1H, d), 4.34 (1H, d), 3.72 - 3.52 (1H, m), 3.46 (1H, s ), 3.35 (1H, s), 2.14 (1H, s), 1.69 (2H, d), 1.60-1.25 (13H, m). PREPARATION 181: N - [(1S, 2R, 3S, 5R) -2-FLUORO-8- AZABICYCLE [3.2.1] OCTAN-3-IL] TERC-BUTYL CARBAMATE
    [1375] [1375] The title compound was prepared using a similar method as in preparation 180 using N- [(1S, 2R, 3S, 5R) -2-fluoro-8-azabicyclo [3.2.1] octan- 3-yl] benzyl carbamate instead of N - [(1R, 2R, 3S, 5S) -2-fluoro- 8-azabicyclo [3.2.1] octan-3-yl] benzyl carbamate to yield the title compound , 1H NMR (400 MHz, DMSO-d6): 6.02 (1H, s), 4.96-4.44 (1H, m), 4.11-3.85 (1H, m), 3, 40 (1H, q), 3.27 (1H, d), 2.35 (1H, s), 2.18-1.97 (1H, m), 1.97-1.83 (1H, m) , 1.83-1.68 (1H, m), 1.68-1.48 (3H, m), 1.39 (9H, s).
    [1376] [1376] The compounds in Table 7 below were prepared using procedures analogous to those described in general procedure 1, starting with the appropriate substituted protected pyrrolopyrazine or pyrazolopyrazine and varying the amine, with any significant variations indicated below.
    [1377] [1377] To a solution of 5-bromo-3,4-dichloro-2-methyl-2H-indazole (30.0 g, 107 mmoles) in THF (450 ml) was added a solution of lithium chloride and chloride complex of isopropylmagnesium (1.3 M in THF, 200 ml, 260 mmoles) at 0 ° C and stirred for 1.5 h. The reaction was cooled to -20 ° C and triisopropyl borate (125 ml, 544 mmoles) was added. After warming to 0 ° C, the reaction was stirred for 1.5 h. Acetic acid (123 ml, 2.1 moles), water (300 ml) and 2-methyltetrahydrofuran (150 ml) were added to the reaction mixture and stirred for 2 h at RT. 5 M NaOH (500 ml) and water (300 ml) were added at 0 ° C and the organic layer was extracted with 3M NaOH (150 ml). The combined aqueous layer was acidified with 6 M HCl (about 400 ml, pH 4) at RT and stirred for 1 h at the same temperature. The precipitate was collected, washed with dil. (pH 3), water and dried at 50 ° C overnight under reduced pressure to yield the title compound (19.8 g). MS: [M + H] + = 246, 248. PREPARATION 183: 3-BROMO-2-CHLORINE-6-IODOANILINE
    [1378] [1378] Sodium dithionite (8.65 g, 49.7 mmoles) in water (30 ml) was added to an ice-cooled solution of 2-chloro-3-bromo-6-iodonitrobenzene (3.00 g , 0.276 mmol) in THF (30 ml) and MeOH (30 ml). The mixture was stirred at RT for 3 h and then partitioned between EtOAc and aq. sat .. The phases were separated, the aqueous phase was extracted with EtOAc and the combined organic phases dried (MgSO4) and concentrated to yield the title compound (1.76 g). 1H NMR (400 MHz, CDCl3): 7.42 (1H, d), 6.78 (1H, d), 4.73 (2H, br, s). PREPARATION 184: 3 - [(2-AMINO-4-BROMO-3-CHLOROPHENYL) SULFANIL] 2-ETHYL HEXYL PROPANOATE
    [1379] [1379] Prepared as preparation 23, except using 3-bromo-2-chloro-6-iodoaniline to yield the title compound. 1H NMR (400 MHz, CDCl3): 7.19 (1H, d), 6.96 (1H, d), 5.04 (2H, s), 4.03 (2H, dd), 3.00 ( 2H, t), 2.57 (2H, t), 1.65-1.53 (1H, m), 1.44-1.25 (9H, m), 0.98-0.85 (6H, m). PREPARATION 185: 5-BROMO-4-CHLORINE-2,3-DIHYDRO-1,3-BENZOTIAZOL-2-ONA
    [1380] [1380] Prepared as preparation 24, except for the use of 2-ethylhexyl 3 - [(2-amino-4-bromo-3-chlorophenyl) sulfanyl] propanoate to yield the title compound. 1H NMR (400 MHz, CDCl3): 8.61-8.43 (1H, m), 7.47-7.41 (1H, m), 7.20 (1H, d). PREPARATION 186: 5-BROMO-4-CHLORINE-3-METHYL-2,3-DIIDRO-1,3-BENZOTIAZOL-2-ONA
    [1381] [1381] Methyl iodide (0.128 ml, 2.05 mmoles) was added to a solution of 5-bromo-4-chloro-2,3-dihydro-1,3-benzothiazole-2-one (291 mg, 1, 02 mmol) and K2CO3 (425 mg, 3.07 mmol) in DMSO (3 ml). The mixture was stirred at RT for 3 days and then divided between EtOAc and water. The phases were separated, the aqueous phase was extracted with EtOAc and combined organic phases washed with brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 20%, EtOAc / petrol) to yield the title compound (208 mg). 1H NMR (400 MHz, CDCl3): 7.47 (1H, d), 7.20 (1H, d), 3.90 (3H, s). PREPARATION 187: 4-BROMO-3-CHLORINE-2-NITROANILINE AND 6-BROMO-3-CHLORINE-2-NITROANILINE
    [1382] [1382] A solution of 3-chloro-2-nitroaniline (25 g, 145 mmoles) and N-bromosuccinimide (25.5 g, 143 mmoles) in AcOH (600 ml) was refluxed for 45 min. After cooling to RT, the reaction mixture was poured into ice water (2 l). The precipitate was collected by filtration, washed with ice water (2 x 200 ml) and dried in a vacuum oven overnight to yield the title compounds (36 g) as a mixture of isomers (4-bromine / 6-bromine in a 9: 1 ratio). 1H NMR (500 MHz, DMSO-d6): 7.56 (1H, d), 6.84 (1H, d), 6.40 (2H, s). PREPARATION 188: 2 - [(4-BROMO-3-CHLORINE-2-
    [1383] [1383] A mixture of 4-bromo-3-chloro-2-nitroaniline and 6-bromo-3-chloro-2-nitroaniline in a ratio of 9: 1 (30 g, 119 mmoles), ethyl bromoacetate (133 ml , 119 mmoles) and K2CO3 (26.4 g, 191 mmoles) was heated to 140 ° C under nitrogen for 30 h. The mixture was cooled to RT, then aq. 1M (250 ml) was added over 10 min. The mixture was stirred for another 10 min, then extracted with DCM (3 x 30 ml). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (gradient elution, 5 to 30%, EtOAc / isohexane). The purified mixture was recrystallized from boiling IPA (70 ml). The solid was filtered, washed with cyclohexane (2 x 50 ml), and dried in a vacuum oven overnight to yield the title compounds (4 g) as a mixture of isomers (4-bromine / 6- bromine in a 9: 1 ratio). MS: [M + H] + =
    [1384] [1384] A mixture of 2 - [(4-bromo-3-chloro-2-
    [1385] [1385] 7-Bromo-8-chloro-1,2,3,4-tetrahydroquinoxalin-2-one and 8-bromo-5-chloro-1,2,3,4-tetrahydroquinoxalin-2-one in a ratio of 9: 1 (3.2 g, 12.2 mmoles) were suspended in 50% by weight of aq. (1.5 ml, 29.3 mmoles) and 3 wt.% Aq. (32 ml, 28.1 mmoles). The reaction mixture was refluxed for 3 h. The mixture was cooled to RT, causing the product to precipitate. AcOH (1.6 ml) was added. The precipitate was collected by filtration, washing with water (2 x 5 ml). The solid was azeotroped with acetonitrile (2 x 20 ml) to yield the title compound (2.8 g). MS: [M + H] + = 259. PREPARATION 191: 7-BROMO-8-CHLORINE-2-METOXYQUINOXALINE
    [1386] [1386] The suspension of 7-bromo-8-chloroquinoxalin-2-ol (2.8 g, 10.8 mmol) and K2CO3 (2.24 g,
    [1387] [1387] To a solution of 7-bromo-8-chloroquinoxalin-2-ol (3 g, 11.6 mmol) in toluene (23 ml) was added phosphorus oxychloride (4.85 ml, 52.0 mmoles) and the reaction mixture was stirred overnight at 70 ° C. The reaction mixture was abruptly cooled by dripping in aq. sat. ice cream (200 ml) and stirred for 2 h at RT. The mixture was then extracted with DCM (3 x 80 ml) and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound (2.5 g). 1H NMR (500 MHz, DMSO-d6): 9.13 (1H, s), 8.22 (1H, d), 8.07 (1H, d). PREPARATION 193: 7-BROMO-8-CHLORINE-2-FLUOROCCHINOXALINE
    [1388] [1388] To a solution of 7-bromo-2,8-dichloroquinoxaline (2.5 g, 8.99 mmoles) in DMSO (19 ml) was added TBAF (1M in THF) (10.8 ml, 10.8 mmoles). The reaction mixture was stirred at 50 ° C for 3 h, then poured into water (150 ml). The precipitate was collected by filtration, washing with water and air drying. The crude product was purified by column chromatography on silica gel (gradient elution, 0 to 15%, EtOAc / isohexane) to yield the title compound (0.85 g). 1H NMR (500 MHz, DMSO-d6): 9.09 (1H, s), 8.19 (1H, d), 8.10 (1H, d). 19F NMR (471 MHz, DMSO-d6): -71.22. PREPARATION 194: 7-BROMO-8-CHLORINE-N, N-DIMETHYLQUINOXALIN-2- THE MINE
    [1389] [1389] To a solution of 7-bromo-8-chloro-2-fluoroquinoxaline (0.85 g, 3.25 mmol) in DMSO (8.5 ml) was added dimethylamine (2 M in THF) (34 ml, 68 mmoles) and the reaction mixture was stirred at RT for 5 h. The mixture was concentrated in vacuo and the DMSO solution was diluted with aq. sat. (30 ml) and extracted with DCM (2 x 20 ml). The combined organic layers were passed through a phase separator and concentrated under reduced pressure to yield the title compound (0.84 g). MS: [M + H] + = 288. PREPARATION 195: N - [(3R, 4S) -1- (6-CHLORINE-5-FORMYL-3-METHYLPIRAZIN-2-IL) -3-FLUOROPIPERIDIN-4-IL ] TERC-BUTYLE CARBAMATE
    [1390] [1390] 3,5-Dichloro-6-methylpyrazine-2-carbaldehyde (0.497 g, 2.6 mmoles) was dissolved in NMP (5 ml) and cooled to 0 ° C. Triethylamine (1.1 ml, 7.8 mmoles) was added followed by tert-butyl N - [(3R, 4S) -3-fluoropiperidin-4-yl] carbamate (0.68 g, 3.12 mmoles). The reaction was allowed to warm to RT and stirred overnight. Aq. sat. was added and the mixture extracted with EtOAc
    [1391] [1391] Hydrazine hydrate (50 to 60%, 1.3 ml, 14.6 mmoles) was added to a solution of N - [(3R, 4S) -1- (6-chloro-5-formyl-3- methylpyrazin-2-yl) -3-fluoropiperidin-4-yl] tert-butyl carbamate (0.49 g, 1.31 mmol) in NMP (3 ml) and the reaction mixture was heated to 100 ° C of a overnight. The reaction mixture was cooled, water was added and the mixture extracted with EtOAc (3x). The combined organics were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 60%, EtOAc / petrol) to yield the title compound (0.212 g), MS: [M + H] + = 351. PREPARATION 197 : N - [(3R, 4S) -3-FLUORO-1- {3-IODO-5-METHYL-1H-PIRAZOL [3,4-B] PIRAZIN-6-IL} PIPERIDIN-4-IL] TERC CARBAMATE -BUTILLE
    [1392] [1392] N-Iodosuccinimide (0.2 g, 0.9 mmol) was added to a solution of N - [(3R, 4S) -3-fluoro-1- {5-methyl-1H-pyrazole [3,4 -b] pyrazin-6-yl} piperidin-4-yl] tert-butyl carbamate (0.212 g, 0.6 mmol) in DMF (3 ml). The reaction was stirred at RT overnight. Additional N-Iodosuccinimide (0.1 g, 0.45 mmol) was added and stirred for 3 h. The reaction mixture was diluted with EtOAc, washed with sat. Na2S2O3. aq., NaHCO3 aq. sat., then brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to yield the title compound (0.25 g), MS: [M + H] + = 477. PREPARATION 198: N - [(3R, 4S) - 3-FLUORO-1- [3-IODO-5-METHYL 1- (OXAN-2-IL) -1H-PIRAZOL [3,4-B] PIRAZIN-6-IL] PIPERIDIN-4-IL] TERC CARBAMATE -BUTILLE
    [1393] [1393] 3,4-dihydro-2H-pyran (0.14 ml, 1.57 mmol) was added to a solution of N - [(3R, 4S) -3-fluoro-1- {3-iodo-5 -methyl-1H-pyrazol [3,4-b] pyrazin-6-yl} piperidin-4-yl] tert-butyl carbamate (0.25 g, 0.52 mmol) and para-toluenesulfonic acid (0.01 g, 0.05 mmol) in DCM (5 ml) at 0 ° C. The reaction was allowed to warm to RT and stirred overnight, then diluted with DCM and washed with aq. sat. and brine. The organic layer was dried by passing through a phase separator, then concentrated. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 50%, EtOAc / petrol) to yield the title compound (0.183 g), MS: [M + H] + = 561. PREPARATION 199 : 6-CHLORINE-3-IODINE-1- (OXAN-2-IL) -1H-
    [1394] [1394] 3,4-dihydro-2H-pyran (9.76 ml, 107 mmoles) was added to a solution of 6-chloro-3-iodo-1H-pyrazole [3,4-b] pyrazine (10 g, 35.7 mmoles) and para-toluenesulfonic acid (0.614 g, 3.57 mmoles) in DCM (100 ml) at 0 ° C. The reaction was allowed to warm to RT and stirred overnight, then diluted with DCM and washed with aq. sat., then brine. The organic layer was dried by passing through a phase separator, then concentrated. The crude product was purified by column chromatography on silica gel (gradient elution, 0 to 20%, ethyl acetate / petrol) to yield the title compound (7 g). 1H NMR (400 MHz, DMSO-d6): 8.79 (1H, s), 5.92 (1H, dd), 3.94 (1H, d), 3.80-3.67 (1H, m ), 2.45-2.17 (1H, m), 2.15-1.91 (2H, m), 1.91-1.68 (1H, m), 1.59 (1H, s), 1.54-1.41 (1H, m). PREPARATION 200: [6-CHLORINE-3-IODINE-1- (OXAN-2-IL) -1H-PIRAZOL [3,4-B] PIRAZIN-5-IL] METHANOL
    [1395] [1395] 6-Chloro-3-iodo-1- (oxan-2-yl) -1H-pyrazole [3,4-b] pyrazine (0.191 g, 0.525 mmol) and tetracis (9H-carbazol-9-yl) benzene-1,3-dicarbonitrile (0.004 g, 0.00525 mmol) were weighed in a microwave flask. Methanol (4 ml) and DMSO (2 ml), which were deoxygenated by bubbling nitrogen for 20 min, were added followed by tert-butyl peracetate (50 wt.% Alcohol, 0.75 ml, 2, 36 mmoles) and TFA (0.4 ml, 5.25 mmoles). The reaction vessel was purged with nitrogen, sealed with a crimp cap and irradiated with a blue LED light overnight. The reaction was concentrated, then diluted with EtOAc and washed with aq. sat., then brine. The organic phase was dried by passing through a phase separator and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (gradient elution, 0 to 30%, ethyl acetate / petrol) to yield the title compound (0.082 g). [M-H] + = 394. PREPARATION 201: 4-CHLORINE-2-ETHYL-5- (4,4,5,5-TETRAMETHYL 1,3,2-DIOXABOROLAN-2-IL) -2H-INDAZOL
    [1396] [1396] Isopropylmagnesium chloride and lithium chloride complex (1.3 M in THF) (5.93 ml, 7.71 mmoles) was added to a solution of 5-bromo-4-chloro-2-ethyl-2H - indazole (1.00 g, 3.85 mmoles) in THF (10 ml) at 0 ° C and the reaction stirred for 4 h. After cooling to -10 ° C using an acetone-ice bath, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.36 ml, 11.6 mmoles ) was added and stirring continued for 30 min at -10 ° C. The reaction was quenched with NH4Cl aq. sat. and H2O and extracted with EtOAc (3x). The combined organics were washed with brine, dried (MgSO4) and evaporated. The residue was suspended in IPA and evaporated, then resuspended in minimum IPA (3 ml) and cooled to 0 ° C. H2O (25 ml) was added by dropping with stirring and the resulting suspension stirred at 0 ° C for 1 h. The solid was collected by filtration, washing initially with a minimum volume of 8: 1 of H2O: IPA (5 ml) and then with petrol (3x). The solid was dried in vacuo to yield the title compound. MS: [M + H] + = 307.
    [1397] [1397] The compounds in Table 8 shown below were prepared in a manner analogous to general procedure 2, using the corresponding aryl halide and boronate or boronic acid with any significant variations indicated).
    [1398] [1398] The compounds in Table 9 presented below were prepared in a manner analogous to general procedure 3, using the corresponding aryl halides, with any significant variations indicated. TABLE 9
    [1399] [1399] 5-Bromo-4-fluoro-2-methyl-2H-indazole (2.6 g, 11.4 mmol) was dissolved in DMF (22.7 ml, 11.4 mmol) and N-chlorosuccinimide (1 , 67 g, 12.5 mmoles) and p-toluenesulfonic acid monohydrate (10 mg) were added. The reaction mixture was stirred at room temperature for 60 h. Water (100 ml) was added to the reaction and the resulting precipitate was filtered. The crude solid was dry loaded onto silica gel and purified by silica gel chromatography (gradient elution, 0 to 20% Hexane / EtOAc) to yield the title compound (0.972 g). MS: [M + H] + = 263. GENERAL PROCEDURES FOR PREPARATIONS OF COMPOUNDS OF FORMULA (I)
    [1400] [1400] The following procedures are illustrative for general methods used in the preparation of Examples 1 to 44 and 45 to 150 listed in Tables 10 and 11 to 17 below. METHOD 1: ENDO-8- [7- (4-CHLORINE-2-METHIL-2H-INDAZOL-5-IL) -5H- PIRROL [2,3-B] PIRAZIN-3-IL] -8-AZABYCLE [3.2 .1] OCTAN-3-AMINA
    [1401] [1401] Trifluoroacetic acid (2.5 ml) was added to N- [endo-8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5 - {[2- (trimethylsilyl ) ethoxy] methyl} -5H-pyrrole [2,3- b] pyrazin-3-yl] -8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (261 mg, 0.45 mmol ) dissolved in DCM (2.5 ml) and the mixture was stirred for 1.0 h. Additional trifluoroacetic acid (1.0 ml) was added and the reaction stirred for 30 min. The reaction was concentrated in vacuo and, to the residue dissolved in methanol (2.0 ml), ethylenediamine was added (2.0 ml). The reaction was stirred for 18 h, and the solid that formed was filtered, washed with methanol twice and dried in a vacuum oven, to yield the title compound (0.09 g). METHOD 2: ENDO-8- [7- (4-CHLORINE-2-METHYL-2H-INDAZOL-5-IL) -2- METHYL-5H-PIRROL [2,3-B] PIRAZIN-3-IL] -8 - AZABICICLO [3.2.1] OCTAN-3-AMINA
    [1402] [1402] N- [endo-8- [7- (4-Chloro-2-methyl-2H-indazol-5-yl) -5- (dimethylsulfamoyl) -2-methyl-5H-pyrrole [2,3-b ] pyrazin-3-yl] -8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate was carefully dissolved in TFA (2 ml) containing water (0.1 ml). Trifluoromethanesulfonic acid (2 ml) was carefully added to the reaction mixture, which was then heated to 90 ° C for 2 h in a microwave. The reaction was diluted with EtOAc (50 ml), washed with aq. sat. to remove acids. The organic layer was dried by passing through a phase separator cartridge, then concentrated under reduced pressure. The residue was purified by column chromatography on KP-NH column (gradient elution, 0 to 10%, EtOAc / methanol) to yield the title compound (0.02 g). METHOD 3: 7- [7- (4-CHLORINE-2-METHYL-2H-INDAZOL-5-IL) -5H- PIRROL [2,3-B] PIRAZIN-3-IL] -1,7-DIAZASPIRO [3.5 ] NONANO
    [1403] [1403] To the mixture of 7- [7- (4-chloro-2-methyl-2H- indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -1,7- diazaspiro [3.5] tert-butyl nonane-1-carboxylate (130 mg, 0.26 mmol), 2,6-lutidine (0.089 ml, 0.77 mmol) and DCM (2.6 ml) was added TMSOTf (0.091 ml, 0.51 mmol) at 0 ° C for 1.5 h. To a reaction mixture, additional 2,6-lutidine (0.089 ml, 0.77 mmol) and TMSOTf (0.091 ml, 0.51 mmol) were added at 0 ° C. The mixture was stirred at 0 ° C for 1.5 h. To a reaction mixture, additional 2,6-lutidine (0.089 ml, 0.77 mmol) and TMSOTf (0.091 ml, 0.51 mmol) were added at 0 ° C. The mixture was stirred at 0 ° C for 1.5 h. The reaction mixture was quenched with NaHCO3 aq. sat. and filtered. The solid was purified by KP-NH column (EtOAc-MeOH = 1: 0 to 4: 1) and triturated with DCM to yield the title compound (64 mg). METHOD 4: RAC- (1S, 2R, 3R, 5R) -8- [7- (4-CHLORINE-2-METHYL-2H- INDAZOL-5-IL) -5H-PIRROL [2,3-B] PIRAZIN- 3-IL] -2-FLUORO-8- AZABYCLE [3.2.1] OCTAN-3-AMINE
    [1404] [1404] To a stirred suspension of Pd (OAc) 2 (7 mg, 0.03 mmol) in anhydrous DCM (0.66 ml) was added triethylamine (37 ul, 0.26 mmol) and Et3SiH (0.211 ml, 1 , 32 mmol) at RT under N2. After stirring at RT for 5 min, N- [(1S, 2R, 3R, 5R) -8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2 , 3-b] pyrazin-3-yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-yl] rac-benzyl carbamate (37 mg, 0.07 mmol) in DCM (0.4 ml) was added to RT under N2. The reaction mixture was stirred at RT for 1 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on KP-NH column (gradient elution, 0 to 5%, Methanol / EtOAc) to yield the title compound (15 mg). METHOD 5: 5- {3- [ENDO-3-AMINO-8-AZABICYCLE [3.2.1] OCTAN-8-IL] -5H-PIRROL [2,3-B] PIRAZIN-7-IL} -4-CHLORINE -2-METHYL-2H- INDAZOL-3-ILA) METHANOL, SULPHONIC METHANIC SALT SALT
    [1405] [1405] N- [endo-8- [7- (3 - {[(tert- Butyldimethylsilyl) oxy] methyl} -4-chloro-2-methyl-2H-indazol-5-yl) -5 - {[2 - tert-butyl (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicyclo [3.2.1] octan-3-yl] carbamate was dissolved in TFA / DCM (1: 1, 3.89 ml) and was stirred for 2h.
    [1406] [1406] N- [endo-8- {7- [7-Chloro-2- (methoxymethyl) - 1,3-benzothiazol-6-yl] -5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H - pyrrole [2,3-b] pyrazin-3-yl} -8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (40 mg, 0.06 mmol) was dissolved in DCM (2 ml), TFA (1 ml) was added and the reaction stirred at room temperature under nitrogen for 16 h.
    [1407] [1407] N - [(1R, 2S, 3R, 5S) -8- [7- (4-Chloro-2-methyl-2H-indazol-5-yl) -5- (dimethylsulfamoyl) -5H-pyrrole [2 , 3- b] pyrazin-3-yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-yl] benzyl carbamate (141 mg, 0.21 mmol) in TFA / trifluoromethanesulfonic acid (1: 1.06 ml) was heated to 90 to 100 ° C for 1 h. The reaction was cooled to RT and was poured into ice, then basified to pH 10 with solid K2CO3. The suspension was extracted with EtOAc (2x), filtered and concentrated in vacuo. The residue was purified by reverse phase column chromatography on C18 silica gel (gradient elution, 5 to 95%, (0.1%, TFA / MeCN) / (0.1%, TFA / water) to yield the title compound (19 mg) METHOD 8 (1R, 2S, 3S, 5S) -8- [3- (4-CHLORO-2-METHYL-2H-INDAZOL-5-IL) -5-METHYL-1H-PIRAZOLE [3,4-B] PIRAZIN-6-IL] -2-FLUORO-8- AZABYCLE [3.2.1] OCTAN-3-AMINA
    [1408] [1408] A mixture of N - [(1R, 2S, 3S, 5S) -8- [3- (4-chloro-2-methyl-2H-indazol-5-yl) -5-methyl-1H-pyrazole [ 3,4- b] pyrazin-6-yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-yl] benzyl carbamate (0.097 g, 0.18 mmol) in methanesulfonic acid (0.776 ml) was stirred at RT for 2 h. The mixture was added carefully to a rapidly stirred aq. sat., water and CHCl3 / IPA (3: 1) and the phases separated, and the aqueous phase was extracted with CHCl3 / IPA (3: 1) (2x). The organic extract was washed with water, dried (Na2SO4), filtered and concentrated. The crude material was ground with a 1: 1 mixture of tert-butyl methyl ether and petrol, then dissolved in EtOH before an excess of HCl (2M in Et2O) was added and the mixture was concentrated to yield the title compound. as the HCl salt (0.0681 g). METHOD 9 ENDO-8- [7- (4-CHLORINE-2-METHIL-2H-1,2,3-BENZOTRIAZOL-5-IL) -5H- PIRROL [2,3-B] PIRAZIN-3-IL] - 8-AZABICICLO [3.2.1] OCTAN-3-AMINA
    [1409] [1409] To a solution of N- [endo-8- [7- (4-chloro-2-methyl-2H-1,2,3-benzotriazol-5-yl) -5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazin-3-yl] - 8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (38.0 mg, 0.0594 mmol) in CHCl3 (1.00 ml) TFA (0.500 ml, 6 mmol) was added to RT. The mixture was stirred at 60 ° C for 1 h. The reaction was concentrated in vacuo and, to the residue dissolved in MeOH (1.00 ml), ethylenediamine (0.200 ml, 3 mmol) was added. The reaction was stirred at RT for 18 h, and the solid that formed was filtered, washed with MeOH twice and dried in a vacuum oven, to yield the title compound (22 mg). METHOD 10 {6 - [(1R, 2S, 3S, 5S) -3-AMINO-2-FLUORO-8- AZABICICLE [3.2.1] OCTAN-8-IL] -3- (3,4-DICLORO-2- METHYL-2H- INDAZOL-5-IL) -1H-PIRAZOL [3,4-B] PIRAZIN-5-IL} METHANOL (EXAMPLE 80) N N
    [1410] [1410] N - [(1R, 2S, 3S, 5S) -8- [3- (3,4-Dichloro-2-methyl-2H-indazol-5-yl) -5- (hydroxymethyl) -1- { [2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol [3,4-b] pyrazin-6-yl] - 2-fluoro-8-azabicyclo [3.2.1] octan-3-yl] tert- carbamate butyl (0.184 g, 0.26 mmol) was dissolved in DCM (1.28 ml) and TFA (1.28 ml) was added by dripping. The reaction was stirred for 1.5 h at RT. A solution of NaHCO3 aq. sat. was added slowly until the aqueous solution reached a basic pH. The aqueous phase was diluted with DCM and EtOAc. The aqueous and organic layers were separated from a formed gum. The gum was dissolved in IPA and aq. (2.0 ml) was added. The solution was stirred for 10 min and then concentrated until a precipitate formed. The precipitate was filtered, washed with water and dried in a vacuum oven at 40 ° C, to yield the title compound (0.095 g). METHOD 11 (3R, 4S) -1- [3- (4-CHLORINE-2-METHYL-2H-INDAZOL-5-IL) -5-METHYL-1H-PIRAZOL [3,4-B] PIRAZIN-6-IL ] -3-FLUOROPIPERIDIN-4-AMINA
    [1411] [1411] A solution of N - [(3R, 4S) -1- [3- (4-chloro-2-methyl-2H-indazol-5-yl) -5-methyl-1- (oxan-2-yl ) -1H-pyrazol [3,4-b] pyrazin-6-yl] -3-fluoropiperidin-4-yl] tert-butyl carbamate (0.066 g, 0.11 mmol) in MeOH (3 ml) and HCl ( 4 M in 1,4-dioxane, 3 ml) was stirred for 2 h. The solvent was evaporated and the residue was triturated with Et2O, to yield the title compound (0.037 g). METHOD 12 {6 - [(1S, 2S, 3S, 5R) -3-AMINO-2-FLUORO-8- AZABICICLE [3.2.1] OCTAN-8-IL] -3- (3,4-DICLORO-2- METHYL-2H- INDAZOL-5-IL) -1H-PIRAZOL [3,4-B] PIRAZIN-5-IL} METHANOL N N
    [1412] [1412] To a solution of N - [(1S, 2S, 3S, 5R) -8- [3- (3,4-dichloro-2-methyl-2H-indazol-5-yl) -5- (hydroxymethyl) -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol [3,4-b] pyrazin-6-yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (0.4 g, 0.554 mmol) in DCM (6 ml) and water (0.24 ml) to RT was added methanesulfonic acid (0.72 ml, 11.1 mmoles). The mixture was stirred rapidly for 30 minutes.
    [1413] [1413] Following methods similar and / or analogous to those described for general procedures for the preparation of compounds of Formula (I) (for example, methods 1 to 12), the compounds shown in Table 10 were prepared from protected N derivatives. -Boc, N-CBz, N-SO2NMe2, SEM or corresponding 2-oxanyl, with any significant variations indicated. The title compounds were isolated directly as the free base or as the appropriate salt without further purification, or purified, for example, using preparative mass-directed HPLC, chromatography, crystallization or grinding and converted 410/546 to the appropriate salt. Example Data Structure Name NMR data Method o MS 1- [exo-8- [7- (4- 1H NMR (400 MHz, DMSO-chloro-2-methyl-d6): 11.65 (1H, s) , 8.44 2H-indazole-5- (1H, s), 8.10 (1H, s), 1, yl) -5H- 7.95 (1H, d), 7.70 (1H, purified pyrrole [ 2.3-s), 7.61 (1H, d), 4.62 by HPLC 1 422 b] pyrazin-3-yl] - (2H, s), 4.21 (3H, s), preparative 8- 2.29 (2H, d), 2.07-1.91 (azabicycle method [3.2.1 (3H, m), 1.81 (2H, d), TFA)] octan-3- 1.57 ( 2H, d), 1.40 (2H, yl] methanamine t).
    [1414] [1414] To a suspension of 5-bromo-4-chloro-1H-indazole (1.0 g, 4.7 mmol) and potassium carbonate (1.79 g, 13 mmol) in DMSO (5 ml) was added 1-bromo-2-methoxy-ethane (0.83 ml, 8.6401 mmoles) at room temperature. After stirring at the same temperature over the weekend, a mixture was diluted with EtOAc and washed with water. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Column chromatography (SNAP Ultra 50 g, gradient elution, 0 to 100% EtOAc in hexane) yielded the title compound (0.45 g, 1.5 mmol, 36%) as a brown solid. MS: [M + H] + = 289, 291, 293 4-CHLORINE-2- (2-METOXYETHIL) -5- (4,4,5,5-TETRAMETHYL-1,3,2- DIOXABOROLAN-2-IL -2H-INDAZOL
    [1415] [1415] To a suspension of 5-bromo-4-chloro-2- (2-methoxyethyl) -2H-indazole (0.45 g, 1.5 mmol) in 1,4-dioxane (10 ml) was added acetate potassium (0.30 g, 3.13 mmol), 4.4.4 ', 4', 5.5.5 ', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane ) (0.59 g, 2.3 mmoles) and 1,1'-Bis (diphenylphosphino) ferrocene-palladium (II) dichloromethane dihydrochloride (0.12 g, 0.15 mmol) complex at room temperature. After stirring at 120 ° C for 4 h, the mixture was diluted with
    [1416] [1416] To a suspension of (endo-8- (7-iodo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrole [2,3-b] pyrazin-3-yl) -8- azabicyclo [3.2.1] octan-3-yl) tert-butyl carbamate (500 mg, 0.83 mmol) and 4-fluoro-2-methyl-5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2H-indazole (680 mg) in 1,4-dioxane (8.0 ml) and water (2.0 ml) potassium carbonate (340 mg, 2.5 mmoles), 1,1'-Bis (diphenylphosphino) ferrocene-palladium (II) complex dichloromethane (68 mg, 0.083 mmol) at room temperature. After stirring at 70 ° C for 8 h, the mixture was diluted with water and EtOAc, and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Column chromatography (SNAP Ultra 50 g, gradient elution, 0 to 100% EtOAc in hexane) yielded a raw material. Then, the raw material was re-purified by SANP Isolute-Flash-NH2 55 g (0 to 100% EtOAc in Hex). Concentration of the fractions yielded the title compound as a pale yellow amorphous (530 mg, 0.77 mmol, 93%). MS: [M + H] + = 682, 684. ENDO-8- (7- (4-CHLORO-2- (2-METOXYETHIL) -2H-INDAZOL-5-IL) -5H- PIRROL [2,3- B] PIRAZIN-3-IL) -8-AZABYCLE [3.2.1] OCTAN-3-AMINE
    [1417] [1417] To a solution of (endo-8- (7- (4-chloro-2- (2-methoxyethyl) -2H-indazol-5-yl) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrole [2,3-b] pyrazin-3-yl) - 8-azabicyclo [3.2.1] octan-3-yl) tert-butyl carbamate (530 mg, 0.77 mmol) in chloroform (2 , 0 ml) TFA (2 ml) was added at room temperature. After stirring at room temperature overnight, the mixture was concentrated in vacuo. The residue was diluted in EtOAc-MeOH, washed with aq. sat. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in MeOH (4.0 ml). Then, ethylenediamine (0.4 ml) was added to the mixture at room temperature. After stirring at 80 ° C for 2 h, the mixture was concentrated in vacuo. The residue was purified by RP-HPLC (SHISEIDO C18AQ, MeCN 0 to 50% in H2O with 0.1% formic acid). The fractions were basified with NaHCO3 aq. sat. and then extracted with CHCl3-MeOH, dried over Na2SO4, filtered and concentrated in vacuo. The residue was suspended in Hexane-EtOAc. The precipitate was collected by filtration, rinsed with hexane and dried at 60 ° C in vacuo to yield the title compound (98 mg, 0.21 mmol, 27%) as a yellow solid. MS: [M + H] + = 452, 454. 1H NMR (DMSO-D6) δ: 11.64 (1H, brs), 8.41 (1H, s), 8.06 (1H, s), 7.92 (1H, d), 7.65 (1H, s), 7.59 (1H, d), 4.59 (2H, t), 4.50-4.48 (2H, brm), 3 , 82 (2H, t), 3.22 (3H, s), 3.15-3.10 (1H, m), 2.38-2.31 (2H, m), 2.09-2.02 (2H, m), 1.96-1.92 (2H, m), 1.71-1.57 (2H, brm), 1.40 (2H, d). EXAMPLE 46. ENDO-8- {7- [4-CHLORINE-2- (OXETAN-3-IL) -2H-INDAZOL-5-IL] -5H-PIRROL [2,3-B] PIRAZIN-3-IL} -8- AZABICICLO [3.2.1] OCTAN-3-AMINA 5-BROMO-4-CHLORINE-2- (OXETAN-3-IL) -2H-INDAZOL
    [1418] [1418] To a suspension of 5-bromo-4-chloro-1H-indazole (1.0 g, 4.3 mmoles) and potassium carbonate (1.79 g, 13 mmoles) in DMSO (5 ml) was added 3-iodooxetane (0.74 ml, 8.6 mmoles) at room temperature. After stirring at 80 ° C for 12 h, the mixture was diluted with EtOAc and washed with water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Column chromatography (SNAP Ultra 50 g, gradient elution, 0 to 100% EtOAc in hexane) yielded the title compound (0.43 g, 1.5 mmol, 34%) as a brown solid. MS: [M + H] + = 287, 289, 291 4-CHLORINE-2- (OXETAN-3-IL) -5- (4,4,5,5-TETRAMETHIL-1,3,2- DIOXABOROLAN-2 -IL) -2H-INDAZOL
    [1419] [1419] To a suspension of 5-bromo-4-chloro-2- (oxetan-3-yl) -2H-indazole (0.43 g, 1.5 mmol) in 1,4-dioxane
    [1420] [1420] To a suspension of (endo-8- (7-iodo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrole [2,3-b] pyrazin-3-yl) -8- azabicyclo [3.2.1] octan-3-yl) tert-butyl carbamate (400 mg, 0.66 mmol) and 4-fluoro-2-methyl-5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2H-indazole (360 mg) in 1,4-dioxane (8.0 ml) and water (2.0 ml) potassium carbonate (270 mg, 2.0 mmoles), 1,1'-Bis (diphenylphosphino) ferrocene-palladium (II) complex dichloromethane (54 mg, 0.066 mmol) at room temperature. After stirring at 70 ° C for 8 h, the mixture was diluted with water and EtOAc, and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Column chromatography (SNAP Ultra 50 g, gradient elution, 0 to 100% EtOAc in hexane) yielded the title compound as a pale yellow amorphous (380 mg, 0.56 mmol, 83%). MS: [M + H] + = 680, 682. ENDO-8- (7- (4-CHLORINE-2- (OXETAN-3-IL) -2H-INDAZOL-5-IL) -5H- PIRROL [2, 3-B] PIRAZIN-3-IL) -8-AZABYCLE [3.2.1] OCTAN-3-AMINE
    [1421] [1421] To a (endo-8- (7- (4-chloro-2- (oxetan-3-yl) -2H-indazol-5-yl) -5 - ((2- (trimethylsilyl) ethoxy) methyl) -5H- pyrrole [2,3-b] pyrazin-3-yl) -8-azabicyclo [3.2.1] octan-3-yl) tert-butyl carbamate (380 mg, 0.55 mmol) in chloroform (3 , 0 ml) TFA (3 ml) was added at room temperature. After stirring at room temperature overnight, TFA (3 ml) was added to the mixture at room temperature. After stirring at 60 ° C for 1 h, the mixture was concentrated in vacuo. The residue was dissolved in MeOH (4 ml) and ethylenediamine (0.6 ml) was added to the mixture at room temperature. After stirring at 60 ° C for 1 h, the mixture was concentrated in vacuo. The residue was purified by RP-HPLC (SHISEIDO C18AQ, MeCN 0 to 50% in H2O with 0.1% formic acid). The fractions were basified with NaHCO3 aq. sat. and then extracted with CHCl3-MeOH, dried over Na2SO4, filtered and concentrated in vacuo. The residue was suspended in Hexane-EtOAc. The precipitate was collected by filtration, rinsed with hexane and dried at 60 ° C in vacuo to yield the title compound (78 mg, 0.17 mmol, 31%) as a yellow solid. MS: [M + H] + = 450, 452. 1H NMR (DMSO-D6) δ: 11.67 (1H, s), 8.58 (1H, s), 8.07 (1H, s), 7.99 (1H, d), 7.68 (1H, s), 7.67 (1H, d), 5.94-5.87 (1H, m), 5.06-4.97 (4H, m), 4.50-4.48 (2H, br m), 3.13-3.12 (1H, m), 2.39-2.31 (2H, m), 2.10-2.03 (2H, m), 1.98-1.88 (2H, m), 1.76-1.56 (2H, br m), 1.40 (2H, d). EXAMPLE 47: 6- {3- [ENDO-3-AMINO-8-AZABICYCLE [3.2.1] OCTAN-8-IL] -5H-PIRROL [2,3-B] PIRAZIN-7-IL} -5-CHLORINE -2-METHYL-1,2-DIHYDROISOQUINOLIN-1-ONA, N- [ENDO-8- [7- (5-CHLORO-2-METHYL-1-OXO-1,2-DIHYDROISOQUINOLIN- 6-IL) SALT -5 - {[2- (TRIMETHILSILIL) ETOXI] METHIL} -5H-PIRROL [2,3- B] PIRAZIN-3-IL] -8-AZABICICLE [3.2.1] OCTAN-3-IL] TERC- CARBAMATE BUTILLE
    [1422] [1422] A mixture of N- [endo-8- (7-iodo-5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazin-3-yl) - 8 -azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (0.500 g, 0.83 mmol), 5-chloro-2-methyl-6- (4,4,5,5-tetramethyl- 1 , 3,2-dioxaborolan-2-yl) -1,2-dihydroisoquinolin-1-one (157 mg, 0.491 mmol), [1,1-bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex, with dichloromethane ( 33.9 mg, 0.042 mmol) and Na2CO3 (132 mg, 1.246 mmol) in 1,4-dioxane (6 ml) and water (1 ml) was degassed under a flow of N2. The reaction was heated to 100 ° C for 1 h. The reaction was cooled to RT, filtered through celite, washed with DCM (10 ml) and MeOH (10 ml) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient elution, 0 to 100% EtOAc / isohexane) to yield the title compound (193 mg), MS: [M + H] + = 665. N- [ENDO-8- [7- (5-CHLORINE-2-METHYL-1-OXO-1,2-DIIDROISOQUINOLIN- 6-IL) -5- (HYDROXIMETHYL) -5H-PIRROL [2,3-B] PIRAZIN-3-IL] -8- AZABICICLO [3.2.1] OCTAN-3-IL] TERC-BUTILA AND N- [ENDO-8- [7- (5-CHLORINE-2-METHYL-1-OXO- CARBAMATE 1,2-DIIDROISOQUINOLIN-6- IL) -5H-PIRROL [2,3-B] PIRAZIN-3-IL] -8-AZABICICLE [3.2.1] OCTAN- 3-IL] TERC-BUTYL CARBAMATE
    [1423] [1423] To a solution of N- [endo-8- [7- (5-chloro-2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl) -5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazin-3-yl] - 8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (177 mg, 0.266 mmol) in THF (3 ml) TBAF (1 M in THF) (0.8 ml, 0.800 mmol) was added. The solution was stirred at 50 ° C for 1 h. The reaction was stirred for another 1 h at this temperature. TBAF (1 M in THF) (0.8 ml, 0.800 mmol) was added and the reaction was stirred at 50 ° C for 1 h, before the addition of TBAF (1 M in THF) (0.8 ml, 0.800 mmol ) and stirring at 50 ° C for another 1 h. The reaction was cooled to 45 ° C and stirred overnight. The reaction was cooled to RT, diluted in DCM (40 ml) and washed with water (2 x 30 ml). The aq. they were extracted with DCM (40 ml) and the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient elution, 0 to 5% MeOH / DCM) to provide the 1: 1 mixture of the title compounds (70 mg). The reaction mixture was carried out without further purification. 6- {3- [ENDO-3-AMINO-8-AZABICICLO [3.2.1] OCTAN-8-IL] -5H- PIRROL [2,3-B] PIRAZIN-7-IL} -5-CHLORINE-2- METHYL-1,2- DIHYDROISOQUINOLIN-1-ONA, SALT DICHYLhydrate
    [1424] [1424] To a solution of N- [endo-8- [7- (5-chloro-2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl) -5- (hydroxymethyl) - 5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate and N- [endo-8- [7- (5-chloro-2 -methyl- 1-oxo-1,2-dihydroisoquinolin-6-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicyclo [3.2.1] octan-3-yl] carbamate of tert-butyl (1: 1 mixture, 70 mg, 0.13 mmol) in THF (1.5 ml) NaOH (2 M, 0.1 ml) was added. After 30 min, HCl (4 M in dioxane, 1 ml) was added and the reaction was stirred at RT for 2 h. The reaction was traversed by an SCX ion exchange column, washing with MeOH and eluting with NH3 / MeOH (0.7 M). The material was stirred in THF (1 ml) with NaOH (2 M, 0.05 ml) for 30 min, before dilution in MeOH and passed through an SCX ion exchange column, washing with MeOH and eluting with NH3 / MeOH ( 0.7 M) and concentrated under reduced pressure. The material was crushed with MeCN (5 ml) and collected by filtration. The residue was placed in 1,4-dioxane (1 ml) and HCl (4 N in dioxane, 1 ml) was added before stirring for 30 min. The precipitate was collected by filtration and concentrated under reduced pressure to yield the title compound (23 mg), MS: [M + H] + = 435. 1H NMR (500 MHz, DMSO- d6) δ 11.98 (1H , d), 8.26 - 8.20 (2H, m), 8.19 (1H, d), 7.99 (2H, d), 7.95 (1H, d), 7.64 (1H, d), 6.88 (1H, d), 4.67 - 4.58 (2H, m), 3.54 (3H, s), 3.24 - 3.11 (1H, m), 2.46 - 2.35 (2H, m), 2.15 - 2.09 (2H, m), 2.02 - 1.94 (2H, m), 1.67 (2H, dd).
    [1425] [1425] The compound of Example 47 is also disclosed herein as the hydrochloride salt, that is, 6- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] - 5H-pyrrole [2,3-b] pyrazin-7-yl} -5-chloro-2-methyl-1,2-dihydroisoquinolin-1-one, hydrochloride salt. EXAMPLE 48. ENDO-8- [3- (4-CHLORINE-2-METHYL-2H-INDAZOL-5-IL) -5-METHYL-1H-PIRAZOL [3,4-B] PIRAZIN-6-IL] -8 - AZABICICLO [3.2.1] OCTAN-3-AMINE, N-[ENDO-8- [3- (4-CHLORINE-2-METHYL-2H-INDAZOL-5-IL) -5-METHYL-1- {[2- (TRIMETHILSILIL) ETOXI] METHIL} -1H-PIRAZOL [3,4-B] PIRAZIN-6- IL] -8-AZABICYCLE [3.2.1] OCTAN-3-IL] TERC-BUTYLE CARBAMATE
    [1426] [1426] Prepare using procedures analogous to N- [exo-8- [3- (4-chloro-2-methyl-2H-indazol-5-yl) -5-methyl-1 - {[2- ( trimethylsilyl) ethoxy] methyl} -1H-pyrazole [3,4-
    [1427] [1427] Example 48 was obtained following the general procedures for the preparation of compounds of Formula (I) using the deprotection method 1.
    [1428] [1428] Following methods similar and / or analogous to those described for the general procedures for the preparation of compounds of Formula (I) (for example, methods 1 to 12), the compounds shown in Table 12 were prepared from the protected derivatives N -Boc, N-Cbz, N-SO2NMe2, 2-oxanyl or corresponding SEM, with any significant variations indicated. The title compounds were isolated directly as the free base or as the appropriate salt without further purification, or purified, for example, using preparative mass-directed HPLC, chromatography, crystallization or grinding and converted to the appropriate salt.
    [1429] [1429] To a solution of 3- (5- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazine- 7-yl} -4-chloro-2H-indazol-2-yl) propanoic (10 mg, 0.0215 mmol) in DMSO (1.00 ml) Et3N (0.0299 ml, 0.215 mmol), 2, 4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorin-2,4,6-trioxide (1.6 M in THF, 0.0270 ml, 0.0429 mmol) and dimethylamine (2, 0 M in THF, 0.210 ml, 0.429 mmol) at RT. The mixture was stirred at RT for 3 days. The reaction solution was then concentrated in vacuo, and the residue was purified by RP-HPLC (SHISEIDO C18AQ, 0 to 50% MeCN in H2O with 0.1% formic acid). The fractions were basified with NaHCO3 aq. sat. and then extracted with CHCl3-MeOH, dried over Na2SO4, filtered and concentrated in vacuo to yield the title compound (1.32 mg). MS: [M + H] + = 493. TABLE 13: EXAMPLES 59 TO 74
    [1430] [1430] Following methods similar and / or analogous to those described for the general procedures for the preparation of compounds of Formula (I) (for example, methods 1 to 13), the compounds shown in Table 12 were prepared from the protected derivatives N -Boc, N-Cbz, N-SO2NMe2, 2-oxanyl or corresponding SEM, with any significant variations indicated. The title compounds were isolated directly as the free base or as the appropriate salt without further purification, or purified, for example, using preparative mass-directed HPLC, chromatography, crystallization or grinding and converted to the appropriate salt.
    [1431] [1431] Following methods similar and / or analogous to those described for the general procedures for the preparation of compounds of Formula (I) (for example, methods 1 to 12), the compounds shown in Table 14 were prepared from the protected derivatives of Corresponding N-Boc, N-CBz, N-SO2NMe2, 2-oxanyl or SEM, with any significant variations indicated. The title compounds were isolated directly as the free base or as the appropriate salt without further purification, or purified, for example, using preparative mass-directed HPLC, chromatography, crystallization or grinding and converted to the appropriate salt.
    [1432] [1432] A solution of isopropylmagnesium chloride and lithium chloride complex (1.3 M in THF) (5.50 ml, 7.14 mmol) was added dropwise to a solution of 5-bromo-3,4- dichloro-2-methyl-2H-indazole (1.0 g, 3.57 mmol, azeotropically dried from toluene 3x) in dry THF (8.78 ml) at 0 ° C and stirred for 3 h. DMF (1.11 ml, 14.3 mmoles) was added by dripping and the reaction warm to RT and stirred for 1 h. The reaction was quenched with NH4Cl aq. sat. (20 ml) and extracted with EtOAc (3 x 20 ml). The combined organics were washed with brine (20 ml), dried (MgSO4) and evaporated. The resulting solid (0.83 g) was triturated with petrol (2 x 50 ml) and azeotroped with THF (3 x 20 ml) to yield the title compound (0.71 g). MS: [M + H] + = 229/231. RAC- (3,4-DICLORO-2-METHIL-2H-INDAZOL-5-ILA) (3,5-DICLORO-6-METHYLPIRAZIN-2-ILA) METHANOL
    [1433] [1433] A 2,2,6,6-tetramethylpiperidinylmagnesium chloride and lithium chloride complex solution (1
    [1434] [1434] Manganese dioxide (1.46 g, 16.8 mmoles) was added to a solution of rac- (3,4-dichloro-2-methyl-2H-indazol-5-yl) (3,5-dichloro -6-methylpyrazin-2-yl) methanol (330 mg, 0.842 mmol) in DCM (8.23 ml) and the reaction stirred at RT for 18 h. The reaction was filtered through Celite, washed with DCM, and the filtrate evaporated to yield the title compound (0.28 g). MS: [M + H] + = 389/391. (1S, 2R, 5R) -2-HYDROXY-3,3-DIMETOXI-8- AZABICYCLE [3.2.1] RAC-TERC-BUTYL OCTANE-8-CARBOXYLATE
    [1435] [1435] To an ice-cooled solution of potassium hydroxide (43 g, 766 mmoles) in anhydrous MeOH (300 ml) was added N-Boc-nortropinone (38 g, 169 mmoles) in MeOH (200 ml) by drip for 25 minutes, keeping the internal temperature in the range 0 to 3 ° C. The mixture was stirred for 20 minutes. Iodobenzene diacetate (83 g, 258 mmoles) was added in portions, then the mixture was allowed to warm to RT and stir for 2 h. The mixture was diluted with water (1 l), then extracted with isohexane (3 x 500 ml). The combined organic phases were dried (MgSO4), filtered and concentrated to yield the title compound (85 g) containing 61 wt% iodobenzene. 1H NMR (500 MHz, DMSO-d6): 4.89 (1H, d), 3.96 (1H, br, s), 3.79 (1H, br, s), 3.61 (1H, br , s), 3.20 (3H, s), 3.19 (3H, s), 2.18 - 1.94 (2H, m), 1.80 - 1.51 (3H, m), 1, 39 (10H, m). (1S, 2R, 5R) -2- (BENZILOXI) -3,3-DIMETOXI-8- AZABICYCLE [3.2.1] RAC-TERC-BUTYL OCTANE-8-CARBOXYLATE
    [1436] [1436] A solution of (1S, 2R, 5R) -2-hydroxy-3,3-dimethoxy-8-azabicyclo [3.2.1] octane-8-carboxylate (85 g, 115 mmol) in THF (100 ml) was added dropwise to a suspension cooled by sodium hydride ice bath (60% in mineral oil, 5 g, 125 mmoles) in THF (200 ml), then stirred at 0 ° C for 20 min. Benzyl bromide (17.4 ml, 146 mmoles) was added by dripping and the mixture was stirred at RT for 18 h. The mixture was diluted with water (1 l), then extracted with isohexane (3 x 500 ml). The organic phases were loaded onto silica gel (1 kg) and purified by column chromatography (gradient elution, 0 to 50%, EtOAc / isohexane) to yield the title compound (47 g). MS: [M + Na] + = 400. (1S, 2R, 5R) -2- (BENZILOXI) -3-OXO-8-AZABICYCLE [3.2.1] OCTANE-8- RAC-TERC-BUTYLE CARBOXYLATE
    [1437] [1437] P-Toluenesulfonic acid monohydrate (1 g, 5.26 mmol) was added to a stirred solution of (1S, 2R, 5R) -2- (benzyloxy) -3,3-dimethoxy-8-azabicyclo [3.2. 1] rac-tert-butyl octane-8-carboxylate (47 g, 100 mmoles) in acetone (400 ml) and water (3 ml, 167 mmoles), then the mixture was stirred at RT for 1 h. The mixture was concentrated, then diluted with aq. sat. (220 ml) and extracted with DCM (2 x 300 ml). The combined organic phases were concentrated. Overnight, the product crystallized and the yellow oil decanted to yield the title compound (31.5 g). 1H NMR (500 MHz, 90 ° C / 363K, DMSO-d6): 7.38 - 7.25 (5H, m), 4.80 (1H, d), 4.60 (1H, d), 4 , 38 - 4.29 (2H, m), 4.02 (1H, d), 2.69 (1H, ddt), 2.27 (1H,
    [1438] [1438] Sodium triacetoxyborohydride (30 g, 142 mmoles) was added to an ice bath cooled solution of (1S, 2R, 5R) -2- (benzyloxy) -3-oxo-8-azabicycles [3.2.1] rac-tert-butyl octane-8-carboxylate (30.5 g, 92 mmoles) and benzylamine (13 ml, 119 mmoles) in DCM (300 ml), then allowed to warm to RT and stir for 2 days. The mixture was diluted with aq. sat. (25 g) and water (250 ml), then extracted with DCM (3 x 200 ml). The combined organic phases were concentrated, then purified by column chromatography on silica gel (gradient elution, 5 to 50%, acetone / isohexane) to yield the title compound (30.5 g). 1H NMR (500 MHz, 90 ° C / 363K, DMSO-d6): 7.42 - 7.20 (10 H, m), 4.58 - 4.48 (2H, m), 4.11 - 3 , 98 (2H, m), 3.83 (1H, d), 3.63 (1H, t), 3.55 (1H, d), 3.16 (1H, t), 2.24 (2H, td), 2.13 (1H, s), 1.91 - 1.58 (4H, m), 1.38 (9H, s). (1S, 2S, 3S, 5R) -3-AMINO-2-HYDROXY-8-AZABYCLE [3.2.1] OCTANE-8-RAC-TERC-BUTYLE CARBOXYLATE
    [1439] [1439] A solution of (1S, 2S, 3S, 5R) -3- (benzylamino) -2- (benzyloxy) -8-azabicyclo [3.2.1] octane-8-rac-tert-butyl carboxylate (7 g , 15.7 mmoles) in ethanol (150 ml) and cyclohexene (50 ml, 494 mmoles) was treated with 5% Pd / C (4 g, 0.801 mmol), then heated to 75 ° C overnight. .
    [1440] [1440] HCl (3 M in cyclopentyl methyl ether, 657 µl, 1.970 mmol) was added slowly to a solution of (1S, 2S, 3S, 5R) -3-amino-2-hydroxy-8-azabicycles [3.2. 1] rac-tert-butyl octane-8-carboxylate (75 mg, 0.310 mmol) in DCM (199 µl), then stirred for 3 h.
    [1441] [1441] Hydrazine monohydrate (6.68 µl, 0.211 mmol) was added to a solution of rac- (1S, 2S, 3S, 5R) -3-amino-8- [6-chloro-5- (3,4- dichloro-2-methyl-2H-indazol-5-carbonyl) -3-methylpyrazin-2-yl] -8-azabicyclo [3.2.1] octan-2-ol (20.9 mg, 0.042 mmol) in EtOH (0.829 ml) and the mixture was heated to 80 ° C for 5 h, then concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 0-10%, NH3 0.7% in MeOH / DCM), to yield the title compound (5.5 mg). MS: [M + H] + = 473/475. 1H NMR (500 MHz, methanol-d4): 7.62 (1H, d), 7.53 (1H, d), 4.46 - 4.41 (1H, m), 4.36 (1H, dd ), 4.20 (3H, s), 4.05 (1H, dd), 3.35 - 3.32 (1H, m), 2.64 (3H, s), 2.47 - 2.35 ( 2H, m2H), 2.13 - 1.95 (3H, m), 1.90 - 1.85 (1H, m). EXAMPLES 91-96: 4-CHLORINE-2-ETHYL-2H-INDAZOL-5-CARBALDEHYDE
    [1442] [1442] Prepared in a similar manner to 3,4-dichloro-2-methyl-2H-indazole-5-carbaldehyde to yield the title compound. RAC- (4-CHLORINE-2-ETYL-2H-INDAZOL-5-ILA) (3,5-DICLORO-6-METHYLPIRAZIN-2-ILA)
    [1443] [1443] Prepared in a similar manner to rac- (3,4-Dichloro-2-methyl-2H-indazol-5-yl) (3,5-dichloro-6-methylpyrazin-2-yl) methanol to yield the compound title. MS: [M + H] + = 371, 373. 4-CHLORINE-5- (3,5-DICLORO-6-METHYLPIRAZINE-2-CARBONY) -2-ETHYL-2H-INDAZOL
    [1444] [1444] Prepared in a similar manner to 3,4-Dichloro-5- (3,5-dichloro-6-methylpyrazine-2-carbonyl) -2-methyl-2H-indazole to yield the title compound. MS: [M + H] + = 369,
    [1445] [1445] Prepared similarly to preparation
    [1446] [1446] Prepared in a similar manner to preparation 125: N - [(1R, 2S, 3S, 5S) -8- [6-Chloro-5- (4-chloro-2-methyl-2H- indazol-5-carbonyl) -3-methylpyrazin-2-yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-yl] benzyl carbamate except stirring at RT for 2 h. Then, the mixture was stirred at 60 ° C overnight. The mixture was further stirred at 80 ° C for 2 h to yield the title compound. MS: [M + H] + = 545, 547 N - [(1R, 2S, 3S, 5S) -8- [6-CHLORINE-5- (3,4-DICLORO-2-METHYL-2H- INDAZOL-5 -CARBONIL) -3-METHYLPIRAZIN-2-IL] -2-FLUORO-8- AZABICYCLE [3.2.1] OCTAN-3-IL] BENZILA CARBAMATE
    [1447] [1447] Prepared similarly to preparation
    [1448] [1448] To a solution of N - [(1R, 2S, 3S, 5S) -8- [6-chloro-5- (3,4-dichloro-2-methyl-2H-indazol-5-carbonyl) -3 - methylpyrazin-2-yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-yl] benzyl carbamate (154 mg, 0.24 mmol) in THF (2.0 ml), hydrated hydrazine ( 0.059 ml, 1.22 mmol) was added to RT. The mixture was stirred at 70 ° C for 2 h. The reaction solution was then concentrated in vacuo, and the residue was purified by column chromatography on silica gel (gradient elution, 20 to 100%, EtOAc / hexane). The crude mixture was dissolved in 1,2-dimethoxyethane (2.0 ml). To the solution, a solution of HCl (4 M in dioxane, 1.0 ml) was added to RT. The solution was stirred at 80 ° C for 1 h. The reaction solution was then concentrated in vacuo, and the residue was purified by silica gel column chromatography (gradient elution, 20 to 100%, EtOAc / hexane) to yield the title compound (40 mg). MS: [M + H] + = 609, 611. 9- [3- (4-CHLORINE-2-METHYL-2H-INDAZOL-5-IL) -5-METHY-1H-
    [1449] [1449] Prepared in a similar manner to N- [(1R, 2S, 3S, 5S) -8- [3- (3,4-dichloro-2-methyl-2H-indazol-5-yl) - 5-methyl- 1H-pyrazol [3,4-b] pyrazin-6-yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-yl] benzyl carbamate, except that the mixture was stirred at 80 ° C for 8 h. Then, the mixture was stirred at RT for 4 days to yield the title compound. MS: [M + H] + = 523. N - [(1R, 2S, 3S, 5S) -8- [3- (4-CHLORO-2-ETYL-2H-INDAZOL-5-IL) -5-METHY -1H-PIRAZOL [3,4-B] PIRAZIN-6-IL] -2-FLUORO-8- AZABICYCLE [3.2.1] OCTAN-3-IL] BENZILA CARBAMATE
    [1450] [1450] Prepared similarly to N- [(1R, 2S, 3S, 5S) -8- [3- (3,4-dichloro-2-methyl-2H-indazol-5-yl) - 5-methyl- 1H-pyrazol [3,4-b] pyrazin-6-yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-yl] benzyl carbamate, except that the mixture was stirred at 90 ° C for 2 h and concentrated in vacuo to yield the title compound. MS: [M + H] + = 589, 591. 7- [3- (4-CHLORINE-2-METHYL-2H-INDAZOL-5-IL) -5-METHYL-1H-PIRAZOL [3,4-B] PIRAZIN-6-IL] -2,7-DIAZASPIRO [3.5] NONANO-2- TERC-BUTYL CARBOXYLATE
    [1451] [1451] Prepared similarly to N- [(1R, 2S, 3S, 5S) -8- [6-chloro-5- (4-chloro-2-methyl-2H-indazol-5-carbonyl) -3- methylpyrazin-2-yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-yl] benzyl carbamate and N- [((1R, 2S, 3S, 5S) -8- [3- (3, 4-dichloro-2-methyl-2H-indazol-5-yl) - 5-methyl-1H-pyrazol [3,4-b] pyrazin-6-yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-yl] benzyl carbamate to yield the title compound. MS: [M + H] + = 523, 525. 6-CHLORINE-1H-4Λ5-PIRAZOL [3,4-B] PIRAZIN-4-ONA
    [1452] [1452] To a suspension of 6-chloro-1H-pyrazole [3,4-b] pyrazine (17.4 g) in acetonitrile (174 ml), urea hydrogen peroxide (22.2 g, 236 mmoles) and anhydride trifluoroacetic (31.3 ml, 225 mmoles) were added at 0 ° C and then the mixture was stirred at RT for 1.5 h. The mixture was diluted with water (200 ml) and the precipitate was collected by filtration and dried under vacuum at 60 ° C, to yield the title compound (10.4 g), MS: [M + H] + = 171, 173. 6-CHLORINE-1- (OXAN-2-IL) -1H-4λ5-PIRAZOL [3,4-B] PIRAZIN-4-ONA
    [1453] [1453] To a suspension of 6-chloro-1H-4λ5-pyrazole [3,4-b] pyrazin-4-one (10.4 g, 61.4 mmoles) in THF (200 ml), 3,4- dihydro-2H-pyran (16.7 ml, 184 mmoles), and p-toluenesulfonic acid monohydrate (0.58 g, 3.06 mmoles) were added and then the mixture was stirred at RT overnight. . The reaction was concentrated in vacuo and the residue was purified by column chromatography on silica gel (gradient elution, 0 to 30%, EtOAc / CHCl3) to yield the title compound (12.9 g), MS: [M + H] + = 255, 257. 6-CHLORINE-5-METHYL-1- (OXAN-2-IL) -1H-PIRAZOL [3,4-B] PIRAZINE
    [1454] [1454] To a solution of 6-chloro-1- (oxan-2-yl) - 1H-4λ5-pyrazol [3,4-b] pyrazin-4-one (12.9 g, 50.5 mmol) in toluene (260 ml), methylmagnesium chloride (3 M in THF, 50.5 ml) was added at 0 ° C. After stirring for 10 min at the same temperature, the mixture was abruptly cooled with aq. sat. and water, the separated organic layer was washed with brine, dried over Na2SO4, filtered and then concentrated in vacuo. The raw material was purified by column chromatography on silica gel (gradient elution, 0 to 40%, EtOAc / hexane) to yield the title compound (5.20 g), MS: [M + H] + = 253 , 255. 6-CHLORINE-5-METHYL-1H-PIRAZOL [3,4-B] PIRAZINE
    [1455] [1455] To a suspension of 6-chloro-5-methyl-1- (oxan-2-yl) -1H-pyrazole [3,4-b] pyrazine (5.20 g) in MeOH (100 ml), HCl (4M in dioxane, 20 ml) was added and then the mixture was stirred at RT overnight. After the concentration of the mixture, the residue was dissolved in MeOH-CHCl3 and then basified with aq. sat. The separated organic layer was dried over Na2SO4, filtered and then concentrated in vacuo. The material was suspended in hexane, collected by filtration and dried under vacuum at 60 ° C, to yield the title compound (3.26 g), MS: [M + H] + = 169, 171. 6-CHLORINE-3 -IODO-5-METHYL-1H-PIRAZOL [3,4-B] PIRAZINE
    [1456] [1456] To a solution of 6-chloro-5-methyl-1H-pyrazole [3,4-b] pyrazine (3.26 g) in DMF (65 ml), N-iodosuccinimide (8.70 g, 38, 7 mmoles) was added and then the mixture was stirred at 50 ° C for 8 h. Then, the mixture was diluted with EtOAc and water. The separated organic layer was washed with water (2x), aq. Na2S2O3. sat., then brine, then dried over Na2SO4, filtered and then concentrated. The crude material was suspended in hexane-CHCl3, collected by filtration and dried under vacuum at 60 ° C to yield the title compound (5.35 g), MS: [M + H] + = 295, 297. 6-CHLORINE -3-IODO-5-METHYL 1- (OXAN-2-IL) -1H-PIRAZOL [3,4- B] PIRAZINE
    [1457] [1457] To a solution of 6-chloro-3-iodo-5-methyl-1H-pyrazole [3,4-b] pyrazine (4.90 g) in THF (98 ml), 3,4-dihydro-2H -pyran (7.55 ml, 83.2 mmoles) and p-toluenesulfonic acid monohydrate (0.317 g, 1.66 mmol) were added, and the mixture was stirred at RT over the weekend. After concentrating the mixture in vacuo, the residue was purified by column chromatography on silica gel (gradient elution, 0 to 25%, EtOAc / hexane) to yield raw material that was suspended in hexane, collected by filtration and dried under vacuum at 60 ° C to yield the title compound (3.6 g), MS: [M + H] + = 379, 381. N - [(1R, 2S, 3S, 5S) -2-FLUORO-8- [3-IODO-5-METIL-1- (OXAN-2-IL) - 1H-PIRAZOL [3,4-B] PIRAZIN-6-IL] -8-AZABICICLE [3.2.1] OCTAN-3 IL] TERC-BUTYLE CARBAMATE
    [1458] [1458] A mixture of 6-chloro-3-iodo-5-methyl-1- (oxan-2-yl) -1H-pyrazol [3,4-b] pyrazine (400 mg, 1.98 mmol), [ (1R, 2R, 3S, 5S) -2-fluoro-8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (387 mg, 1.59 mmol), DIPEA (0.552 ml, 3, 17 mmoles) and NMP (4.0 ml) was stirred at 120 ° C for 6 h. The reaction mixture was cooled to RT, poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 50 to 100%, EtOAc / hexane), to yield the title compound (330 mg). MS: [M + H] + = 587. N - [(1R, 2S, 3S, 5S) -8- [3- (5-CHLORO-3-METOXYQUINOXALIN-6-IL) -5-METHYL 1- ( OXAN-2-IL) -1H-PIRAZOL [3,4-B] PIRAZIN-6-IL] -2- FLUORO-8-AZABICYCLE [3.2.1] OCTAN-3-IL] TERC- CARBAMATE BUTILLE
    [1459] [1459] A mixture of N - [(1R, 2S, 3S, 5S) -2-fluoro-8- [3-iodo-5-methyl-1- (oxan-2-yl) -1H-pyrazole [3, 4- b] pyrazin-6-yl] -8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (75.0 mg, 0.13 mmol), 8-chloro-2-methoxy 7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoxaline (49.2 mg, 0.15 mmol), K3PO4 (40.7 mg, 0.19 mmol) , bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (9.06 mg, 0.01 mmol), 1,4-dioxane (0.75 ml) and water (0.075 ml) was stirred at 80 ° C for 2 h, cooled to RT, poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 100% Hexane / EtOAc) to yield the title compound (100 mg). MS: [M + H] + = 653, 655. N - [(1R, 2S, 3S, 5S) -8- {3- [5-CHLORINE-3- (DIMETHYLAMINE) QUINOXALIN-
    [1460] [1460] A mixture of N - [(1R, 2S, 3S, 5S) -2-fluoro-8- [3-iodo-5-methyl-1- (oxan-2-yl) -1H-pyrazole [3, 4- b] pyrazin-6-yl] -8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (75.0 mg, 0.13 mmol), 8-chloro-N, N- dimethyl-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoxalin-2-amine (51.1 mg, 0.15 mmol), K3PO4 (40.7 mg , 0.19 mmol), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (9.06 mg, 0.01 mmol), 1,4-dioxane (0.75 ml) and water (0.08 ml) was stirred at 80 ° C for 2 h, cooled to RT, poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 100% Hexane / EtOAc) to yield the title compound (160 mg). MS: [M + H] + = 666, 668. TABLE 15: EXAMPLES 91 TO 96
    [1461] [1461] Following methods similar and / or analogous to those described for the general procedures for the preparation of compounds of Formula (I) (for example, methods 1 to 12), the compounds shown in Table 15 were prepared from the derivatives protected from N-Boc, N-
    [1462] [1462] Triethyloxonium tetrafluoroborate (6.23 g, 32.8 mmoles) was added to a solution of 5-bromo-4-fluoro-1H-indazole (4.75 g, 21.9 mmoles) in EtOAc (300 ml ), then stirred at RT for 18 h. Additional triethyloxonium tetrafluoroborate (2 g, 10.5 mmol) was added and stirring continued for 2 h. The mixture was washed with aq. sat. (150 ml) and the aqueous layer was extracted with an additional portion of EtOAc (125 ml). The combined organic phases were concentrated on loose silica gel. The silicate was purified by column chromatography on silica gel (gradient elution, 5 to 50%, EtOAc / isohexane) to yield the title compound (3.17 g). MS: [M + H] + = 243/245. 5-BROMO-3-CHLORINE-2-ETHYL-4-FLUORO-2H-INDAZOL
    [1463] [1463] N-Chlorosuccinimide (1.09 g, 8.15 mmol) was added in portions to 5-bromo-2-ethyl-4-fluoro-2H-indazole (1.5 g, 5.43 mmol) in DMF (20 ml) at 10 ° C. The mixture was then stirred at RT for 1 h, which showed no conversion. P-Toluenesulfonic acid monohydrate (10 mg) was added and stirring continued for 3 h, then briskly cooled with water (90 ml) and sodium thiosulfate (5 g). The resulting mixture was stirred for 30 min, allowed to rest for 30 min, then filtered and dried. The crude product was purified by column chromatography on silica gel (gradient elution, 5 to 25%, EtOAc / isohexane) to yield the title compound (1.5 g). MS: [M + H] + = 279/281. 5-BROMO-4-CHLORINE-2,3-DIMETHIL-2H-INDAZOL
    [1464] [1464] N-butyllithium (2.5M in hexanes, 4 ml, 10.0 mmol) was added to a cooled (-10 ° C) solution of diisopropylamine (1.5 ml, 10.5 mmol) in THF (10 ml ). The mixture was stirred for 10 min before cooling to -78 ° C. To this solution was added a solution of 5-bromo-4-chloro-2-methyl-2H-indazole (2.0 g, 8.15 mmol) in THF (10 ml). The mixture was warmed to 0 ° C for 10 min, then cooled to -78 ° C. Iodomethane (0.66 ml, 10.6 mmoles) was added and the mixture was stirred at -78 ° C for 1 h. The mixture was quenched with aq. sat. (30 ml) and extracted with EtOAc (3 x 30 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography on silica gel (gradient elution, 15 to 75%, EtOAc / isohexane) to yield the title compound (1.7 g). MS: [M + H] + = 259/261/263. 5-BROMO-3,4-DICLORO-2-ETHYL-2H-INDAZOL
    [1465] [1465] Prepared using methods analogous to preparation 35, 5-bromo-3,4-dichloro-2-methyl-2H-indazole to yield the title compound, MS: [M + H] + = 293. 5 -BROMO-2,4-DIMETHIL-2H-INDAZOL
    [1466] [1466] Prepared using methods analogous to preparation 33 5-bromo-4-fluoro-2-methyl-2H-indazole to yield the title compound, MS: [M + H] + = 225. 5-BROMO- 3-CHLORINE-2,4-DIMETHYL-2H-INDAZOL
    [1467] [1467] Prepared using methods analogous to the preparation of 5-bromo-3-chloro-2-ethyl-4-fluoro-2H-indazole to yield the title compound, MS: [M + H] + = 259. 3-CHLORINE-2,4-DIMETHIL-5- (4,4,5,5-TETRAMETHIL-1,3,2-DIOXABOROLAN-2-IL) -2H-INDAZOL
    [1468] [1468] Prepared using methods analogous to preparation 43: 4-chloro-2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H- indazole to yield the title compound, MS: [M + H] + = 307. 5-BROMO-4-CHLORINE-2- (PROPAN-2-IL) -2H-INDAZOL
    [1469] [1469] Potassium tert-Butoxide (3.64 g, 32.4 mmoles) was added to 5-bromo-4-chloro-2H-indazole (7.5 g, 32.4 mmoles) and 2-bromopropane (3 , 05 ml, 32.4 mmoles) at RT in DMF (20 ml). The resulting mixture was then stirred overnight for 16 h, diluted with methyl tert-butyl ether / EtOAc (300 ml, 5: 1), then water (400 ml) was added. The layers were separated and the aqueous one further extracted with tert-butyl methyl ether (100 ml). The combined organics were washed with water (3 x 100 ml), dried by passing through a phase separator and concentrated on loose silica gel. The silicate was purified by column chromatography on silica gel (gradient elution, 0 to 50%, EtOAc / isohexane) to yield the title compound (2.17 g). MS: [M + H] + = 273. 4-CHLORINE-2- (PROPAN-2-IL) -5- (4,4,5,5-TETRAMETYL-1,3,2- DIOXABOROLAN-2-IL) -2H-INDAZOL
    [1470] [1470] Prepared using methods similar to preparation 43: 4-chloro-2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H- indazole to yield the title compound, MS: [M + H] + = 321. N - [(1R, 2S, 3S, 5S) -2-FLUORO-8- [3- (4-FLUORO-2-METHYL- 2H- INDAZOL-5-IL) -5- (HYDROXIMETHIL) -1 - {[2- (TRIMETHYLSILIL) ETOXI] METHIL} -1H-PIRAZOL [3,4-B] PIRAZIN-6-IL] - 8-AZABICICLO [ 3.2.1] OCTAN-3-IL] TERC-BUTYLE CARBAMATE
    [1471] [1471] Prepared as General Procedure 2, except for the use of N - [(1R, 2S, 3S, 5S) -2-fluoro-8- [5- (hydroxymethyl) -3-iodine-1 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol [3,4-b] pyrazin-6-yl] -8-azabicyclo [3.2.1] octan-3-
    [1472] [1472] N-Bromosuccinimide (73 mg, 0.41 mmol) was added to a solution of N - [(1R, 2S, 3S, 5S) -2-fluoro- 8- [3- (4-fluoro-2- methyl-2H-indazol-5-yl) -5- (hydroxymethyl) -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol [3,4-b] pyrazin-6-yl] -8- azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (250 mg, 0.7 mmol) in DMF (6 ml) and the reaction stirred at RT for 1 h. Additional N-bromosuccinimide (0.074 mmol) was added and stirring continued for 30 min. Again, additional N-bromosuccinimide (13 mg, 0.074 mmol) was added and stirring continued for another 1 h. H2 O was added and the resulting precipitate collected by filtration, washing with H2O. This solid was purified by column chromatography on silica gel (gradient elution, 5 to 30%, acetone / petrol) to yield the title compound, MS: [M + H] + = 749. 2-BROMO-3- CHLORINE-5 - {[2- (TRIMETHILSILIL) ETOXI] METHIL} -5H- PIRROL [2,3-B] PIRAZINE
    [1473] [1473] To a mixture of 2-bromo-3-chloro-5H-pyrrole [2,3-b] pyrazine (3.7 g, 15.9 mmol) in DMF (111 ml) at 0 ° C was added NaH (0.76 g, 19.1 mmoles) in portions over 20 min. The reaction was stirred at 0 ° C for 30 min. At the same temperature, 2- (trimethylsilyl) ethoxymethyl chloride (3.39 ml, 19.1 mmoles) was added by dripping. The reaction was allowed to slowly warm to RT in the ice bath before stirring overnight. The reaction mixture was carefully cooled to 0 ° C with aq. sat. (200 ml) and extracted with DCM (3 x 70 ml). The combined organic extracts were concentrated under reduced pressure. The oily residue was diluted with DCM (50 ml) and washed with aq. 1M (100 ml), then brine (50 ml), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 50% DCM / isohexane) to yield the title compound (3.8 g). 1H NMR (500 MHz, DMSO-d6): 8.19 (1H, d), 6.80 (1H, d), 5.60 (2H, s), 3.61 - 3.49 (2H, m ), 0.91 - 0.80 (2H, m), -0.09 (9H, s). 3-CHLORINE-5 - {[2- (TRIMETHILSILIL) ETOXI] METHIL} -5H-PIRROL [2,3- B] METHYL PIRAZINE-2-CARBOXYLATE
    [1474] [1474] To a solution of 2-bromo-3-chloro-5 - {[2-
    [1475] [1475] A mixture of methyl 3-chloro-5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazine-2-carboxylate (1.80 g, 5.27 mmoles) and 1-iodopyrrolidine-2,5-dione (2.50 g, 11.1 mmoles) in DMF (14.3 ml, 184 mmoles) was stirred at RT for 22 h. The reaction mixture was heated to 50 ° C for an additional 5 h, cooled to RT, then brusquely cooled by dripping additionally in a mixture of aq. (5 g in 150 ml) and Na2S2O3 aq. 10% (20 ml). The mixture was extracted with DCM (3 x 20 ml). The combined organics were washed with water (2 x 30 ml), passed through a phase separator and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient elution, 0 to 50%, EtOAc / isohexane) to yield the title compound (1.2 g). MS: [M + H] + = 468. 3 - [(1R, 2S, 3S, 5S) -3 - {[(TERC-BUTOXI) CARBONIL] AMINO} -2-FLUORO- 8-AZABYCLE [3.2.1] OCTAN-8-IL] -7- (3,4-DICLORO-2-METHYL-2H- INDAZOL-5-IL) -5 - {[2- (TRIMETHYLSILIL) ETOXI] METHIL} -5H- PIRROL [2,3 -B] METHYL PIRAZINE-2-CARBOXYLATE
    [1476] [1476] Step 1: Use N - [(1R, 2R, 3S, 5S) -2-fluoro- 8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate, and heat to 120 ° C for 5 h, Step 1 was performed using methods similar to those described in the General Procedure
    [1477] [1477] Step 2: Use (3,4-dichloro-2-methyl-2H-indazol-5-yl) boronic acid, the title compound was prepared using methods similar to those described in General Procedure 2, but using K3PO4 and 1,4-dioxane at 50 ° C instead of K2CO3 and 1,2-dimethoxyethane, respectively. MS: [M + H] + = 748.
    [1478] [1478] Step 3: To a solution of 3- [(1R, 2S, 3S, 5S) -3 - {[(tert-butoxy) carbonyl] amino} -2-fluoro-8-azabicycles [3.2.1] octan -8-yl] -7- (3,4-dichloro-2-methyl-2H- indazol-5-yl) -5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H- pyrrole [2,3- b] methyl pyrazine-2-carboxylate (0.25 g, 0.334 mmol) in THF (2.67 ml) at 0 ° C, lithium aluminum hydride solution (1.0 M in THF) (0.668 ml, 0.668 mmol) per drop. The reaction was stirred at 0 ° C for 10 minutes. The reaction was quenched by the addition of 10% Rochelle salt solution followed by EtOAc. The phases were separated, and the aqueous phase was extracted in EtOAc (x2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. A Biotage column (25 g) eluting with 15% acetone / petrol to 50% acetone / petrol provided N- [(1R, 2S, 3S, 5S) -8- [7- (3,4-dichloro-2- methyl-2H-indazol-5-yl) - 2- (hydroxymethyl) -5 - {[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrole [2,3-b] pyrazin-3-yl] -2- fluoro-8-azabicyclo [3.2.1] octan-3-yl] tert-butyl carbamate (220 mg). MS: [M + H] + = 720. TABLE 16: EXAMPLES 97 TO 123
    [1479] [1479] Following methods similar and / or analogous to those described for the general procedures for the preparation of compounds of Formula (I) (for example, methods 1 to 12), the compounds shown in Table 16 were prepared, with any significant variations indicated . The title compounds were isolated directly as the free base or as the appropriate salt without further purification, or purified, for example, using preparative mass-directed HPLC, chromatography, crystallization or grinding and converted to the appropriate salt.
    [1480] [1480] Prepared using methods analogous to the preparation of 5-bromo-4-chloro-2-methyl-2H-indazol-3-carbaldehyde (preparation 40). 1H NMR (400 MHz, DMSO-d6): 10.66 (1H, s), 7.83 (1H, d), 7.72 (1H, d), 4.84 (2H, q), 1, 47 (3H, t). 4-BROMO-5-CHLORINE-2-ETHYL-2H-INDAZOL-3-CARBONITRIL
    [1481] [1481] Hydroxylamine hydrochloride (943 mg, 13.6 mmol) and Na2CO3 (1.44 g, 13.6 mmol) were added to a suspension of 5-bromo-4-chloro-2-ethyl-2H-indazole- 3- carbaldehyde (2.60 g, 9.04 mmoles) in a mixture of IPA (40 ml), MeOH (40 ml) and H2O (10 ml) and the reaction stirred at 50 ° C overnight. After cooling, most of the solvent was evaporated and additional H2O was added to the remaining aqueous suspension. The precipitated solid was collected under suction and washed on the filter with H2O, then dried in vacuo to provide intermediate oxime as a pale yellow solid (2.52 g). To a solution of this material in MeCN (80 ml) was added copper (II) acetate (753 mg, 4.15 mmoles) and the reaction stirred at 85 ° C for 2 h. After cooling, the solvent was evaporated and the residue purified by silica gel column chromatography (gradient elution, 0 to 20%, EtOAc / petrol) to yield the title compound (2.30 g). 1H NMR (400 MHz, DMSO-d6): 7.86 (1H, d),
    [1482] [1482] Prepared using methods analogous to the preparation of 4-bromo-5-chloro-2-ethyl-2H-indazol-3-carbonitrile. MS: [M + H] + = 270. 4-CHLORINE-2-METHYL-5- (4,4,5,5-TETRAMETHIL-1,3,2-DIOXABOROLAN-2-IL) -2H-INDAZOL-3 -CARBONITRILLA N N
    [1483] [1483] Prepared using methods analogous to the preparation of 4-chloro-2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole MS: [M + H] + = 318. 7-BROMO-8-CHLORINE-2-ETOXYQUINOXALINE
    [1484] [1484] The suspension of 7-bromo-2,8-dichloroquinoxaline (650 mg, 2.34 mmoles) and K2CO3 (1.29 g, 9.36 mmoles) in EtOH (6 ml) was heated under reflux for 3 h , then cooled to RT and divided between EtOAc and water. The separated phases, the aqueous phase was extracted with EtOAc and the combined organic phases washed with brine, dried (MgSO4 + hydrophobic frit) and concentrated to yield the title compound (598 mg). 1H NMR (400 MHz, DMSO-d6): 8.66 (1H, s), 7.94 (1H, d), 7.91 (1H, d), 4.57 (2H, q), 1, 45 (3H, t). 7-BROMO-8-CHLORINE-2- (PROPAN-2-ILOXI) QUINOXALIN
    [1485] [1485] Prepared using methods analogous to the preparation of 7-bromo-8-chloro-2-ethoxyquinoxaline, MS: [M + H] + = 301 2- (AZETIDIN-1-IL) -7-BROMO-8 -CHLOROCQUINOXALINE
    [1486] [1486] Azetidine (0.49 ml, 7.20 mmoles) was added to a solution of 7-bromo-2,8-dichloroquinoxaline (1.00 g, 3.60 mmoles) and triethylamine (1.00 ml, 7 , 20 mmoles) in THF (5 ml) and the mixture immediately turned yellow. Stirred at RT for 80 h and then divided between EtOAc and saturated aqueous NaHCO3. Separate phases, aqueous phase extracted with EtOAc and combined organic phases washed with brine, dried (MgSO4 + hydrophobic frit) and concentrated to yield the title compound (1.05 g). 1H NMR (400 MHz, DMSO-d6): 8.36 (1H, s), 7.71 (1H, d), 7.64 (1H, d), 4.28 (4H, t), 2, 49 - 2.41 (2H, m). TABLE 17: EXAMPLES 124 TO 150
    [1487] [1487] Following methods similar and / or analogous to those described for the general procedures for the preparation of compounds of Formula (I) (for example, methods 1 to 12), the compounds shown in Table 17 were prepared, with any significant variations indicated . The title compounds were isolated directly as the free base or as the appropriate salt without further purification, or purified, for example, with the use of preparative mass directed HPLC, chromatography,
    [1488] [1488] SHP2 activity was monitored by measuring the conversion of the 6,8-difluoromethylumbelliferyl substitute substrate (DiFMUP) to the fluorescent product, 6,8-difluoromethylumbelliferone (DiFMU).
    [1489] [1489] SHP2 was preincubated with test compounds and the activating peptide pIRS1 (H2N-LN (pY) IDLDLV- (PEG) 8- LST (pY) ASINFQK-amide) for 30 min, before the addition of 6 , 8-difluoromethylumbeliferyl (DiFMUP), (Thermo Fisher D6567). Final assay concentrations were 10 pM SHP2, 0.25 µM pIRS1 peptide, 50 µM DiFMUP, 25 mM Bis-Tris propane, pH 7.0, 150 mM NaCl, 0.05% (by volume) Tween-20, TCEP 0.5 mM and 5% (by volume) DMSO. Reaction rates were measured over 30 min by monitoring fluorescence on a BMG Pherastar reader at 360 nm excitation / emission 450 nm. IC50 values were calculated from the normalized dose-response graphs using the four-parameter logistic curve adjustment. CELL PERK INHIBITION TEST
    [1490] [1490] HCC827 cells (ATCC, Manassas, USA) were seeded in 96-well plates at a density of 1 x 105 cells / well in RPMI medium supplemented with 10% FBS and incubated 24h. The compounds were first diluted in DMSO and then in serum-free medium before being added to the cells in triplicate to give a final concentration of 0.1% DMSO. The plates were incubated at 37 ° C for 0.5 hour in a humidified atmosphere of 5% CO2 in air.
    [1491] [1491] After treatment with the compound, the medium was removed and the cells were lysed by adding 50 µl of lysis buffer (Cell Signaling Technology, Beverly, USA) to each well. The plates were then incubated at room temperature for 25 minutes with shaking. PERK levels were measured in lysates using the PathScan® phospho-p44 / 42 MAPK (Thr202 / Tyr204) sandwich ELISA (Cell Signaling Technology, Beverly, USA) according to the kit instructions. Briefly, 50 µl of cell lysate was added to 50 µl of ELISA sample diluent in a 96-well ELISA plate and incubated overnight at 4 ° C. After washing, 100 µl of detection antibody per well was added and the plates incubated for 1 hour at 37 ° C. The plates were washed again and incubated at 37 ° C for 30 minutes with 100 µl of HRP-bound secondary antibody per well. After the final wash, 100 µl per well of TMB substrate was added and the plates incubated at 37 ° C to develop color. Color development was stopped by adding 100 µl per stop solution well. The plates were read at 450 nm in a SpectraMax Gemini reader (Molecular Devices, Uckfield, UK).
    [1492] [1492] The mean signal from the blank wells (no cells added) was subtracted from the signals from each sample well. The pERK levels were then expressed as a “percentage of control”, using samples treated with DMSO as a control. The dose response curves were generated using GraphPad Prism Version 6 (GraphPad Software, La Jolla, USA) and adjusted using the four-parameter logistic curve adjustment.
    [1493] [1493] Where more than one data point was obtained, the table above shows an average (for example, geometric or arithmetic mean) of those data points.
    [1494] [1494] It is clear that it should be understood that the invention is not intended to be restricted to the details of the above modalities, which are described by way of example only. EXAMPLES OF PHARMACEUTICAL FORMULATIONS (I) TABLET FORMULATION
    [1495] [1495] A tablet composition containing a compound of Formula (I) is prepared by mixing an appropriate amount of the compound (for example, 50 to 250 mg) with an appropriate diluent, disintegrant, compression agent and / or glidant . A possible tablet comprises 50 mg of the compound with 197 mg of lactose (BP) as a diluent and 3 mg of magnesium stearate as a lubricant and compaction to form a tablet in a known manner. The compressed tablet can optionally be coated with film. (II) CAPSULE FORMULATION
    [1496] [1496] A capsule formulation is prepared by mixing 100 to 250 mg of a compound of Formula (I) with an equivalent amount of lactose and loading the resulting mixture into standard hard gelatin capsules. An appropriate disintegrant and / or glidant can be included in appropriate amounts as needed. (III) INJECTABLE FORMULATION I
    [1497] [1497] A parenteral composition for administration by injection can be prepared by dissolving a compound of Formula (I) (for example, in the form of a salt) in water containing 10% propylene glycol to give a 1.5% active compound concentration in weight. The solution is then made isotonic, sterilized by filtration or terminal sterilization, placed in an ampoule or vial or pre-filled and sealed syringe. (IV) INJECTABLE FORMULATION II
    [1498] [1498] A parenteral composition for injection is prepared by dissolving a compound of Formula (I) (for example, in the form of salt) (2 mg / ml) and mannitol (50 mg / ml) in water, filtering the sterile solution or by terminal sterilization, and loading in 1 ml sealable vials or pre-filled ampoules or syringes. (V) INJECTABLE FORMULATION III
    [1499] [1499] A formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound of Formula (I) (for example, in the form of salt) in water at 20 mg / ml and then adjusted for isotonicity. The vial is then sealed and autoclaved or placed in an ampoule or pre-filled vial or syringe, sterilized by filtration and sealed. (VI) INJECTABLE FORMULATION IV
    [1500] [1500] A formulation for iv delivery by injection or infusion can be prepared by dissolving the compound of Formula (I) (for example, in the form of salt) in water containing a buffer (for example, 0.2 M acetate, pH 4 , 6) at 20 mg / ml. The vial, ampoule or pre-filled syringe are then sealed and autoclaved or sterilized by filtration and sealed. (VII) FORMULATION FOR SUBCUTANEOUS OR INTRAMUSCULAR INJECTION
    [1501] [1501] A composition for subcutaneous or intramuscular administration is prepared by mixing a compound of Formula (I) with pharmaceutical grade corn oil to yield a concentration of 5 to 50 mg / ml. The composition is sterilized and placed in a suitable container. (VIII) LYOPHILIZED FORMULATION I
    [1502] [1502] Aliquots of the formulated compound of Formula (I) are placed in 50 ml vials and lyophilized. During lyophilization, the compositions are frozen using a one-step freezing protocol at (-45 ° C). The temperature is raised to -10 ºC for annealing, then lowered to freeze at -45 ºC, followed by primary drying at +25 ºC for approximately 3,400 minutes, followed by a secondary drying with increased steps if the temperature is 50 ºC. The pressure during primary and secondary drying is set at 80 millimeters. (IX) LYOPHILIZED FORMULATION II
    [1503] [1503] Aliquots of the formulated compound of Formula (I) or a salt thereof, as defined here, are placed in 50 ml vials and lyophilized. During lyophilization, the compositions are frozen using a one-step freezing protocol at (-45 ° C). The temperature is raised to -10 ºC for annealing, then lowered to freeze at -45 ºC, followed by primary drying at +25 ºC for approximately 3,400 minutes, followed by a secondary drying with increased steps if the temperature is 50 ºC. The pressure during primary and secondary drying is set at 80 millimeters. (X) LYOPHILIZED FORMULATION FOR USE IN ADMINISTRATION I.V. III
    [1504] [1504] A buffered aqueous solution is prepared by dissolving a compound of Formula I in a buffer. The buffered solution is loaded, with filtration to remove particulate material, in a container (such as a Type 1 glass bottle) that is then partially sealed (for example, by means of a Fluorotec stopper). If the compound and the formulation are sufficiently stable, the formulation is sterilized in an autoclave at 121 ºC for an appropriate period of time. If the formulation is not stable to autoclaving, it can be sterilized with a suitable filter and placed in sterile bottles under sterile conditions. The solution is lyophilized using an appropriate cycle. At the conclusion of the lyophilization cycle, the vials are again filled with nitrogen to atmospheric pressure, capped and secured (for example, with an aluminum crimp). For intravenous administration, the lyophilized solid can be reconstituted with a pharmaceutically acceptable diluent, such as 0.9% saline or 5% dextrose. The solution can be dosed as is, or it can be further diluted in an infusion bag (containing a pharmaceutically acceptable diluent, such as 0.9% saline or 5% dextrose), before administration. (XII) POWDER IN A BOTTLE
    [1505] [1505] A composition for oral administration is prepared by carrying a bottle or vial with a compound of Formula (I). The composition is then reconstituted with a suitable diluent, for example, water, fruit juice or commercially available vehicle, such as OraSweet or Syrspend. The reconstituted solution can be dispensed in measuring cups or oral syringes for administration.
    权利要求:
    Claims (37)
    [1]
    1. A compound characterized by being of Formula (I): (I) or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, where: X is CH or N; R1 is hydrogen, -CH3 or -CH2OH, but when X is N then R1 is selected from -CH3 and -CH2OH; R2 and R3 or be: (i) independently selected from hydrogen and C1-4alkyl; or (ii) together they form a bridge group with one to three members selected from C1-3alkylene, C2-3 alkenylene, methylene-NRq-methylene and methylene-O-methylene, where the bridge group is optionally substituted by a group selected from C1-4alkyl, hydroxyl and halogen and Rq is selected from hydrogen, C1-4alkyl, hydroxyl and halogen. Q is C or N; where when Q is C then either: (i) R4 is hydrogen or C1-4alkyl (for example, methyl) optionally substituted by amino (for example, - CH2NH2); R5 is hydrogen, amino, hydroxyl or C1-4alkyl
    (for example, methyl) optionally substituted by 1 or 2 groups selected from halogen, hydroxyl (for example, -CH2OH) or amino; provided that R4 and R5 should not both be selected from amino and C1-4alkyl substituted by amino; or (ii) R4 and R5 together with Q form a four to six membered nitrogen-containing heterocyclic ring; and where when Q is N then: R4 is absent; R5 is hydrogen; and R2 and R3 together form the bridge group with one to three members; R6 and R7 are independently selected from halogen (for example, fluorine), C1-4alkyl (for example, - CH3) and hydroxyl since, when Q is N, then R6 or R7 are not halogen or hydroxyl; a is selected from 0, 1 and 2; b is selected from 0, 1 and 2; Ring A is either: (i) a five-membered nitrogen-containing 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 six-membered aromatic nitrogen containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or (iii) a six-membered non-aromatic nitrogen containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S; R8 is selected from haloC1-4alkyl (for example, -CF3), -CH3 and halogen (for example, chlorine or fluorine); R9 is selected from hydrogen, C1-4alkyl (eg, -CH3), haloC1-4alkyl (eg, -CF3) and halogen (eg, chlorine); R10 are independently selected from halogen, cyano, cyanoC1-4alkyl (eg, -CH2-CN), hydroxyl, = O (oxo), C1-4alkyl (eg, -CH3, - CH (CH3) 2, or -CH2CH3 ), haloC1-4alkyl (for example, -CHF2), C1-4alkoxy (for example, -OCH3, -OCH2CH3 and -OCH (CH3) 2), hydroxylC1-4alkyl (for example, -CH2C (CH3) 2OH, - CH (CH3) CH2OH, -CH (CH3) OH, -CH2CH2OH or -CH2OH), C1-4alkoxyC1-
    4 alkylene (for example, -CH2-O-CH3 or -CH2-CH2-O-CH3), C1-
    4alkylsulfone (e.g. -SO2CH3), amino, monoC1-
    4alkylamino, diC1-4alkylamino (for example, -N (CH3) 2), aminoC1-4alkylene (for example, -CH2NH2), -C1-4alkylene-C (= O) NH (2-q) (C1-6 alkyl) q), -C0-4alkylene-NHC (= O) C1-6 alkyl, C0-4alkylene sulfonamide (for example, -SO2NRx2 or - CH2SO2NRx2), where Rx is independently selected from H and C1-6alkyl), cycloalkyl with 3 to 6-membered, unsaturated heterocyclic group with five or six members optionally substituted containing 1, 2, 3 or 4 heteroatoms selected from O, N, or S where the optional substituent is selected from C1-4alkyl, C1-4alkyl substituted by cycloalkyl with 3 to 6 members, C1-4alkyl substituted by unsaturated heterocyclic group with five or six members optionally substituted containing 1, 2, 3 or 4 heteroatoms selected from O, N, or S, where the optional substituent is selected from C1-4alkyl, C1 -4alkyl substituted by saturated heterocyclic group with four to six members optionally substituted containing 1 or 2 heteroatoms selected from O, N, or S, where the optional substituent is selected from C1-4alkyl and a saturated heterocyclic group with four to six members optionally substituted containing 1 or 2 heteroatoms selected from O, N, or S, where the optional substituent is selected from C1-4alkyl; q is selected from 0, 1 or 2; and c is selected from 0, 1, 2 and 3.
    [2]
    A compound according to claim 1, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that: X is CH or N; R1 is hydrogen, -CH3 or -CH2OH, but when X is N then R1 is selected from -CH3 and -CH2OH; R2 and R3 or be: (i) independently selected from hydrogen and C1-4alkyl; or (ii) together they form a bridge group with one to three members selected from C1-3alkylene, C2-3 alkenylene, methylene-NRq-methylene and methylene-O-methylene, where the bridge group is optionally substituted by a group selected from C1-4alkyl, hydroxyl and halogen and Rq is selected from hydrogen, C1-4alkyl, hydroxyl and halogen. Q is C or N;
    where when Q is C then either: (i) R4 is hydrogen or C1-4alkyl (for example, methyl) optionally substituted by amino (for example, - CH2NH2); R5 is hydrogen, amino or C1-4alkyl (for example, methyl) optionally substituted by 1 or 2 groups selected from halogen, hydroxyl (for example, - CH2OH) or amino; provided that R4 and R5 should not both be selected from amino and C1-4alkyl substituted by amino; or (ii) R4 and R5 together with Q form a four to six membered nitrogen-containing heterocyclic ring; and where when Q is N then: R4 is absent; R5 is hydrogen; and R2 and R3 together form the bridge group with one to three members; R6 and R7 are independently selected from halogen (for example, fluorine), C1-4alkyl (for example, - CH3) and hydroxyl since, when Q is N, then R6 or R7 are not halogen or hydroxyl; a is selected from 0, 1 and 2; b is selected from 0, 1 and 2; Ring A is either: (i) a five-membered nitrogen-containing 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 six-membered aromatic nitrogen containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or (iii) a six-membered non-aromatic nitrogen containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S; R8 is selected from haloC1-4alkyl (for example, -CF3), -CH3 and halogen (for example, chlorine or fluorine); R9 is selected from hydrogen, C1-4alkyl (eg, -CH3), haloC1-4alkyl (eg, -CF3) and halogen (eg, chlorine); R10 are independently selected from halogen, cyano, cyanoC1-4alkyl (eg, -CH2-CN), hydroxyl, = O (oxo), C1-4alkyl (eg, -CH3 or - CH2CH3), haloC1-4alkyl, C1- 4alkoxy (for example, -OCH3), hydroxylC1-4alkyl (for example, -CH2C (CH3) 2OH, - CH (CH3) CH2OH, -CH (CH3) OH, -CH2CH2OH or -CH2OH), C1-4alkoxyC1-
    4 alkylene (for example, -CH2-O-CH3 or -CH2-CH2-O-CH3), C1-
    4alkylsulfone (e.g. -SO2CH3), amino, monoC1-
    4alkylamino, diC1-4alkylamino (for example, -N (CH3) 2), aminoC1-4alkylene (for example, -CH2NH2), -C1-4alkylene-C (= O) NH (2-q) (C1-6 alkyl) q), -C1-4alkylene-NHC (= O) C1-6 alkyl, C0-4alkylene sulfonamide (for example, -SO2NRx2 or -CH2SO2NRx2, where Rx is independently selected from H and C1-
    6alkyl), 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 C1-4alkyl; q is selected from 0, 1 or 2; and c is selected from 0, 1 and 2.
    [3]
    Compound according to claim 1 or 2, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that X is CH.
    [4]
    Compound according to claim 1 or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that X is N.
    [5]
    Compound according to any one of claims 1 to 3, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that R1 is H.
    [6]
    A compound according to any one of claims 1 to 5, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that R2 and R3 together form a bridge group with one to three members selected from among C1-3alkylene, C2-3alkenylene, methylene-NRq-methylene and methylene-O-methylene, where the bridge group is optionally substituted by a group selected from C1-4alkyl, hydroxyl and halogen and Rq is selected from hydrogen and C1- 4alkyl.
    [7]
    A compound according to claim 6, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that R2 and R3 together form a one to three membered bridging group which is C1- 3 alkylene ( for example, -CH2-CH2-).
    [8]
    A compound according to any one of claims 1 to 7, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof,
    characterized by Q being N.
    [9]
    Compound according to any one of claims 1 to 7, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that Q is C.
    [10]
    A compound according to any one of claims 1 to 9, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that R4 is hydrogen or C1-4alkyl (for example, methyl), for example, where R4 is hydrogen.
    [11]
    A compound according to any one of claims 1 to 10, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that R5 is hydrogen, amino, or C1-4alkyl (for example, methyl) optionally substituted by 1 or 2 groups selected from halogen, hydroxyl (for example, -CH2OH) or amino, for example, where R5 is amino or C1-4alkyl (for example, methyl) optionally substituted by 1 or 2 groups selected from halogen, hydroxyl (for example, -CH2OH) or amino (for example, amino).
    [12]
    A compound according to any one of claims 1 to 11, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that it is 0 or 1, for example 0.
    [13]
    A compound according to any one of claims 1 to 12, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that b is 0 or 1, for example, 0.
    [14]
    Compound according to any one of claims 1 to 13, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that to be 1 and R6 is halogen (for example, fluorine) or hydroxyl, for example example, where a is 1 and R6 is fluorine.
    [15]
    A compound according to any one of claims 1 to 14, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that ring A is a five-membered nitrogen-containing heterocyclic ring (for example, a aromatic ring or non-aromatic ring), or a six-membered aromatic nitrogen containing heterocyclic ring, where the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S.
    [16]
    A compound according to any one of claims 1 to 15, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that ring A is a five-membered nitrogen-containing heterocyclic ring (for example, a aromatic ring or a non-aromatic ring), wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S.
    [17]
    17. A compound according to any one of claims 1 to 16, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that ring A is a five-membered heterocyclic ring containing aromatic nitrogen, 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 14, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof,
    characterized in that ring A is either: (i) a six-membered aromatic nitrogen containing heterocyclic ring, in which the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or (ii) a six-membered non-aromatic nitrogen containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S.
    [19]
    19. A compound according to claim 18, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that ring part A is selected from Table I or II herein.
    [20]
    A compound according to claim 19, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that the part is selected from: for example,
    or be selected from: for example,
    [21]
    21. A compound according to any one of claims 1 to 20, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that R8 is selected from -CF3, -CH3 and halogen (for example, chlorine or fluorine), for example, where R8 is selected from halogen (for example, chlorine).
    [22]
    22. A compound according to any one of claims 1 to 21, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that R9 is hydrogen.
    [23]
    23. A compound according to any one of claims 1 to 22, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that R10 is independently selected from halogen, cyano, cyanoC1-4alkyl (for example, - CH2- CN), hydroxyl, = O (oxo), C1-4alkyl (for example, -CH3 or - CH2CH3), haloC1-4alkyl, C1-4alkoxy (for example, -OCH3),
    hydroxylC1-4alkyl (for example, -CH (CH3) CH2OH, -CH (CH3) OH, -CH2CH2OH or -CH2OH) diC1-4alkylamino (for example, -N (CH3) 2), and C1-4alkoxyC1-4alkylene (for example, -CH2-O-CH3), for example, where R10 is independently selected from halogen, cyano, hydroxyl, = O (oxo) and C1-4alkyl (for example, -CH3 or -CH2CH3).
    [24]
    24. A compound according to any one of claims 1 to 23, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that R10 is independently selected from halogen, cyano, hydroxyl, = O (oxo), C1-4alkoxy (for example, -OCH3), diC1-4alkylamino (for example, -N (CH3) 2), and C1-4alkyl (for example, -CH3 or -CH2CH3), for example, where R10 is independently selected among hydroxyl, = O (oxo) and C1-4alkyl (for example, -CH3).
    [25]
    25. A compound according to any one of claims 1 to 24, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, characterized in that c is selected from 0, 1 or 2, for example, where c is 1 or 2.
    [26]
    26. A compound according to claim 1 or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, wherein the compound is characterized by being of Formula (XVIIIa *):
    (XVIIIa *) where R4 is hydrogen or C1-4alkyl (for example, methyl); R5 is amino; R6 or R7 is halogen (for example, fluorine); R8 is halogen (for example, chlorine or fluorine) R10 is halogen (for example, chlorine), cyan, C1-
    4alkyl (e.g. -CH3, -CH (CH3) 2 or -CH2CH3), haloC1-
    4alkyl (for example, -CHF2), C1-4alkoxy (for example, - OCH3, -OCH2CH3 or -OCH (CH3) 2), C1-4alkoxyC1-4alkylene (for example, -CH2OCH3). diC1-4alkylamino (eg, -N (CH3) 2) saturated heterocyclic group with four to six members or optionally substituted (eg, unsubstituted) containing 1 or 2 heteroatoms selected from O or N, where the optional substituent is selected C1-4alkyl (for example, morpholinyl or azetidinyl); a is 0 or 1; b is 0 or 1; c is 0 or 1, d is 0, 1 or 2 (for example, 1), and the part is selected from: (i) options A, B, C, D, E, F, G, H, I, J , O, P and Q in Table I, and in particular is selected from: for example, or (ii) options E and G in Table II, and in particular is selected from: for example:
    [27]
    27. A compound according to claim 1, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, wherein the compound is characterized by being selected from: 1- [exo-8- [7- (4 -chloro-2-methyl-2H-indazol-5-yl) -5H-
    pyrrole [2,3-b] pyrazin-3-yl] -8-azabicyclo [3.2.1] octan-3-yl] methanamine; exo-8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicycle [3.2.1] octan-3-amine; endo-8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicycle [3.2.1] octan-3-amine; 1- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] piperidin-4-amine; 1- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -4-methylpiperidin-4-amine; endo-9- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -9-azabicycle [3.3.1] nonan-3-amine; {4-amino-1- [7- (4-chloro-2-methyl-2H-indazol-5-yl) - 5H-pyrrole [2,3-b] pyrazin-3-yl] piperidin-4-yl} methanol; endo-8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -3-methyl-8-azabicycle [ 3.2.1] octan-3-amine; 4-chloro-5- (3- {3,8-diazabicyclo [3.2.1] octan-8-yl} - 5H-pyrrole [2,3-b] pyrazin-7-yl) -2-methyl-2H- indazole; 7- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -2,7-diazaspiro [3.5] nonane; 1- {1- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -2-methyl-5H-pyrrole [2,3-b] pyrazin-3-yl] -4-methylpiperidin -4-yl} methanamine; rac- (1S, 2R, 3R, 5R) -8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl ] -2-fluoro-8-azabicyclo [3.2.1] octan-3-amine;
    endo-8- [7- (7-chloro-1,3-benzothiazol-6-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicyclo [3.2.1] octan- 3- amine; 1- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -2-methyl-5H-pyrrole [2,3-b] pyrazin-3-yl] -4-methylpiperidin-4- the mine; endo-8- [7- (7-chloro-2-methyl-1,3-benzothiazol-6-yl) - 5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicyclo [3.2. 1] octan-3-amine; 7- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -1,7-diazaspiro [3.5] nonane; endo-8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -2-methyl-5H-pyrrol [2,3-b] pyrazin-3-yl] -8-azabicycle [ 3.2.1] octan-3-amine; 6- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -7-chloro-N, N-dimethyl-1,3-benzothiazole-2-amine; 5- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -4-chloro-2, 3-dihydro-1,3-benzoxazol-2-one; exo-8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -2-methyl-5H-pyrrol [2,3-b] pyrazin-3-yl] -8-azabicyclo [ 3.2.1] octan-3-amine; 6- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -5-chloro-2- methyl-3,4-dihydroquinazolin-4-one; 7- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -8-chloro-N, N-dimethylquinolin-2-amine; 6- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -7-chloro-2, 3-dihydro-1,3-
    benzothiazol-2-one; endo-8- [7- (3,4-dichloro-2-methyl-2H-indazol-5-yl) - 5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicyclo [3.2. 1] octan-3-amine; 7- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -5,5-difluoro-2,7- diazaspiro [3.5] nonane; endo-8- [7- (4-chloro-2-ethyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicycles [3.2.1] octan-3-amine; endo-8- [7- (8-chloro-2-methoxyquinolin-7-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicyclo [3.2.1] octan-3- the mine; exo-8- [7- (4-chloro-2-ethyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicycles [3.2.1] octan-3-amine; (3R, 4R) -1- [7- (4-chloro-2-methyl-2H-indazol-5-yl) - 5H-pyrrol [2,3-b] pyrazin-3-yl] -3-fluoropiperidin- 4-amine; (3S, 4S) -1- [7- (4-chloro-2-methyl-2H-indazol-5-yl) - 5H-pyrrole [2,3-b] pyrazin-3-yl] -3-fluoropiperidin- 4-amine; (3S, 4S) -4-amino-1- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrol [2,3-b] pyrazin-3-yl] piperidin -3-ol; (3S, 4R) -1- [7- (4-chloro-2-methyl-2H-indazol-5-yl) - 5H-pyrrol [2,3-b] pyrazin-3-yl] -3-fluoropiperidin- 4-amine; (3R, 4S) -1- [7- (4-chloro-2-methyl-2H-indazol-5-yl) - 5H-pyrrol [2,3-b] pyrazin-3-yl] -3-fluoropiperidin- 4-amine; {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] - 7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2 , 3-b] pyrazin-2-yl} methanol; 7- {3- [endo-3-amino-8-azabicycles [3.2.1] octan-8-
    yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -8-chloro-1,2-dihydroquinolin-2-one; 2- (5- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -3,4 -dichloro-2H-indazol-2-yl) ethan-1-ol; (5- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -4-chloro-2 -methyl-2H-indazol-3-yl) methanol; endo-8- [7- (4-fluoro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicycles [3.2.1] octan-3-amine; endo-8- {7- [7-chloro-2- (oxolan-3-yl) -1,3-benzothiazol-6-yl] -5H-pyrrol [2,3-b] pyrazin-3-yl} - 8- azabicyclo [3.2.1] octan-3-amine; exo-8- [3- (4-chloro-2-methyl-2H-indazol-5-yl) -5-methyl-1H-pyrazol [3,4-b] pyrazin-6-yl] -8-azabicyclo [ 3.2.1] octan-3-amine; exo-8- [7- (3,4-dichloro-2-methyl-2H-indazol-5-yl) - 5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicyclo [3.2. 1] octan-3-amine; endo-8- [7- (5-chloro-3-methoxy-2-methylquinolin-6-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicycle [3.2.1] octan-3-amine; endo-8- {7- [7-chloro-2- (methoxymethyl) -1,3-benzothiazol-6-yl] -5H-pyrrol [2,3-b] pyrazin-3-yl} -8-azabicycle [ 3.2.1] octan-3-amine; (6- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -7-chloro-1 , 3-benzothiazol-2-yl) methanol; endo-8- {7- [4-chloro-2- (2-methoxyethyl) -2H-indazol-5-
    yl] -5H-pyrrole [2,3-b] pyrazin-3-yl} -8-azabicyclo [3.2.1] octan-3-amine; endo-8- {7- [4-chloro-2- (oxetan-3-yl) -2H-indazol-5-yl] -5H-pyrrol [2,3-b] pyrazin-3-yl} -8- azabicyclo [3.2.1] octan-3-amine; 6- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -5-chloro-2- methyl-1,2-dihydroisoquinolin-1-one; and endo-8- [3- (4-chloro-2-methyl-2H-indazol-5-yl) -5-methyl-1H-pyrazol [3,4-b] pyrazin-6-yl] -8-azabicycle [3.2.1] octan-3-amine; 2- (5- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -4-chlorine -2H-indazol-2-yl) - N, N-dimethylacetamide; endo-8- [7- (4-chloro-7-fluoro-2-methyl-2H-indazol-5-yl) -5H-pyrrol [2,3-b] pyrazin-3-yl] -8-azabicycle [ 3.2.1] octan-3-amine; endo-8- [7- (4-chloro-2-methyl-2H-1,2,3-benzotriazol-5-yl) -5H-pyrrol [2,3-b] pyrazin-3-yl] -8- azabicycles [3.2.1] octan-3-amine; 6- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -5-chloro-2, 3-dimethyl-3,4-dihydroquinazolin-4-one; 1- (5- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -4-chlorine -2H-indazol-2-yl) - 2-methylpropan-2-ol; endo-8- [7- (3,4-dichloro-1H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicyclo [3.2.1] octan- 3- amine; endo-8- [7- (4-chloro-2,7-dimethyl-2H-indazol-5-yl) -
    5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicyclo [3.2.1] octan-3-amine; 6- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -5-chloro-3- methyl-3,4-dihydroquinazolin-4-one; 2- (5- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -4-chlorine -2H-indazol-2-yl) - N-methylacetamide; 3- (5- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -4-chlorine -2H-indazol-2-yl) - N, N-dimethylpropanamide; 6- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -7-chloro-N, N-dimethyl-1,3-benzothiazole-2-carboxamide; 2- (5- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -4-chlorine -2H-indazol-2-yl) - N-tert-butylacetamide; 2- (5- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -4-chlorine -2-methyl-2H-indazol-3-yl) acetonitrile; 5- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -4-chloro-2- methyl-2H-indazole-3-carbonitrile; (1S, 2R, 3R, 5R) -8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] - 2-fluoro-8-azabicyclo [3.2.1] octan-3-amine; (1R, 2S, 3S, 5S) -8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] - 2-fluoro-8-azabicyclo [3.2.1] octan-3-amine; (1S, 2R, 3S, 5R) -8- [7- (4-chloro-2-methyl-2H-indazol-5-
    il) -5H-pyrrole [2,3-b] pyrazin-3-yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-amine; 5- {3- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -4-chloro-3, 3-difluoro-2,3-dihydro-1H-indole-2-one; (1R, 2S, 3R, 5S) -8- [7- (4-chloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] - 2-fluoro-8-azabicyclo [3.2.1] octan-3-amine; endo-8- (7- {4-chloro-2 - [(1-methyl-1H-imidazol-2-yl) methyl] -2H-indazol-5-yl} -5H-pyrrole [2,3-b] pyrazin-3-yl) - 8-azabicyclo [3.2.1] octan-3-amine; endo-8- (7- {4-chloro-2 - [(3-methyl-1,2,4-oxadiazol-5-yl) methyl] -2H-indazol-5-yl} -5H-pyrrole [2, 3-b] pyrazin-3-yl) - 8-azabicyclo [3.2.1] octan-3-amine; endo-8- (7- {4-chloro-2 - [(1-methyl-1H-pyrazol-3-yl) methyl] -2H-indazol-5-yl} -5H-pyrrole [2,3-b] pyrazin-3-yl) - 8-azabicyclo [3.2.1] octan-3-amine; 6- {3 - [(3R, 4S) -4-amino-3-fluoropiperidin-1-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -5-chloro-2-methyl- 1,2-dihydroisoquinolin-1-one; 5- {3 - [(3R, 4S) -4-amino-3-fluoropiperidin-1-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -4-chloro-2-methyl- 2,3-dihydro-1H-isoindol-1-one; (1R, 2S, 3S, 5S) -8- [3- (4-chloro-2-methyl-2H-indazol-5-yl) -5-methyl-1H-pyrazol [3,4-b] pyrazin-6 -yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-amine; (3R, 4S) -1- [7- (7-chloro-1-methyl-1H-1,3-benzodiazol-6-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] - 3-fluoropiperidin-4-amine; (3R, 4S) -1- [3- (4-chloro-2-methyl-2H-indazol-5-yl) -5-
    methyl-1H-pyrazol [3,4-b] pyrazin-6-yl] -3-fluoropiperidin-4-amine; 5- {3 - [(3R, 4S) -4-amino-3-fluoropiperidin-1-yl] -5H-pyrrole [2,3-b] pyrazin-7-yl} -4-chloro-3-methyl- 2,3-dihydro-1,3-benzothiazole-2-one; 6- {3 - [(1S, 2S, 3S, 5R) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -5H-pyrrole [2,3-b] pyrazin -7-yl} - 5-chloro-3-methyl-3,4-dihydroquinazolin-4-one; rac- {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (4-chloro-2-methyl- 2H-indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (4-chloro-2-methyl-2H- indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (3,4-dichloro-2-methyl- 2H-indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6 - [(1S, 2S, 3S, 5R) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (4-chloro-2-methyl-2H- indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (4-chloro-2-ethyl-2H- indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (3-chloro-4-fluoro-2- methyl-2H-indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (5-chloro-3-methoxyquinoxalin- 6- yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6 - [(1S, 2S, 3S, 5R) -3-amino-2-fluoro-8-
    azabicyclo [3.2.1] octan-8-yl] -3- (3,4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl }methanol; {6- [3,8-diazabicyclo [3.2.1] octan-8-yl] -3- (3,4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazole [3,4 -b] pyrazin-5-yl} methanol; {6 - [(1S, 2S, 3S, 5R) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (3-chloro-4-fluoro-2- methyl-2H-indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] - 3- (3,4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazole [3,4-b] pyrazin-5-yl} methanol; rac- (1S, 2S, 3S, 5R) -3-Amino-8- [3- (3,4-dichloro-2-methyl-2H-indazol-5-yl) -5-methyl-1H-pyrazole [3 , 4-b] pyrazin-6-yl] -8-azabicyclo [3.2.1] octan-2-ol; 4-chloro-5- (6- {3,9-diazabicyclo [3.3.1] nonan-9-yl} - 5-methyl-1H-pyrazol [3,4-b] pyrazin-3-yl) -2- methyl-2H-indazole; (1R, 2S, 3S, 5S) -8- [3- (4-chloro-2-ethyl-2H-indazol-5-yl) -5-methyl-1H-pyrazol [3,4-b] pyrazin-6 -yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-amine; (1R, 2S, 3S, 5S) -8- [3- (3,4-Dichloro-2-methyl-2H-indazol-5-yl) -5-methyl-1H-pyrazol [3,4-b] pyrazin -6-yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-amine; 7- [3- (4-chloro-2-methyl-2H-indazol-5-yl) -5-methyl-1H-pyrazol [3,4-b] pyrazin-6-yl] -2,7-diazaspiro [ 3.5] nonane; (1R, 2S, 3S, 5S) -8- [3- (5-chloro-3-methoxyquininoxalin-6-yl) -5-methyl-1H-pyrazol [3,4-b] pyrazin-6-yl] - 2-fluoro-8-azabicyclo [3.2.1] octan-3-amine; 7- {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -5-methyl-1H-pyrazole [3,4 - b] pyrazin-3-yl} -8-chloro-N, N-dimethylquinoxalin-2-amine;
    {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (3-chloro-2-ethyl-4- fluoro-2H-indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (7-chloro-2-methyl-1, 3-benzothiazol-6-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (4-chloro-2,3-dimethyl- 2H-indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (5-chloro-3-methoxy-2- methylquinolin-6-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- [4-chloro-2- (propan-2 -yl) -2H-indazol-5-yl] -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6 - [(1S, 2R, 3S, 5R) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (3,4-dichloro-2-methyl- 2H-indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (3,4-dichloro-2-ethyl- 2H-indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; (1R, 2S, 3S, 5S) -8- [7- (3,4-dichloro-2-methyl-2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl ] -2-fluoro-8-azabicyclo [3.2.1] octan-3-amine; {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (3-bromo-4-fluoro-2- methyl-2H-indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; (1R, 2S, 3S, 5S) -8- [7- (5-chloro-3-methoxyquinoxaline-6-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -2-fluoro- 8- azabicyclo [3.2.1] octan-3-amine;
    endo-8- [7- (5-chloro-3-methoxyquininoxalin-6-yl) -5H-pyrrole [2,3-b] pyrazin-3-yl] -8-azabicyclo [3.2.1] octan-3- the mine; {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (3-chloro-2,4-dimethyl- 2H-indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6 - [(1S, 2S, 3S, 5R) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (5-chloro-3-methoxyquinoxalin- 6- yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; [6- (4-amino-4-methylpiperidin-1-yl) -3- (3,4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin - 5-yl] methanol; (6- {2,8-diazaspiro [4.5] decan-8-yl} -3- (3,4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazole [3,4-b ] pyrazin-5-yl) methanol; [3- (5-chloro-3-methoxyquinoxalin-6-yl) -6- {3,8-diazabicyclo [3.2.1] octan-8-yl} -1H-pyrazol [3,4-b] pyrazin-5 - useful] methanol; {6- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] - 3- (5-chloro-3-methoxyquinoxalin-6-yl) -1H-pyrazole [3,4-b ] pyrazin-5-yl} methanol; {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (7-chloro-1,3-benzothiazole- 6- yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; endo-8- [3- (3,4-dichloro-2-methyl-2H-indazol-5-yl) - 5- (hydroxymethyl) -1H-pyrazol [3,4-b] pyrazin-6-yl] - 8- azabicycles [3.2.1] octan-3-ol; {6- [endo-3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl] -3- (3,4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol;
    {3- [5-chloro-3- (dimethylamino) quinoxalin-6-yl] -6- {3,8-diazabicyclo [3.2.1] octan-8-yl} -1H-pyrazole [3,4-b] pyrazin-5-yl} methanol; {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- [5-chloro-3- (dimethylamino) quinoxalin -6-yl] -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; 8-chloro-7- (6- {3,8-diazabicyclo [3.2.1] octan-8-yl} - 5-methyl-1H-pyrazol [3,4-b] pyrazin-3-yl) -2- methoxyquinoxaline; 1- [3- (5-chloro-3-methoxyquinoxalin-6-yl) -5-methyl-1H-pyrazol [3,4-b] pyrazin-6-yl] -4-methylpiperidin-4-amine; (1S, 2S, 3S, 5R) -8- [3- (5-chloro-3-methoxyquininoxalin-6-yl) -5-methyl-1H-pyrazol [3,4-b] pyrazin-6-yl] - 2-fluoro-8-azabicyclo [3.2.1] octan-3-amine; {3 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -7- (3,4-dichloro-2-methyl- 2H-indazol-5-yl) -5H-pyrrole [2,3-b] pyrazin-2-yl} methanol; {6 - [(1S, 2S, 3S, 5R) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- [7-chloro-2- (dimethylamino) - 1,3-benzothiazol-6-yl] -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; 5- {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -5-methyl-1H-pyrazole [3,4 - b] pyrazin-3-yl} -4-chloro-2-methyl-2H-indazol-3-carbonitrile; 6- [3,9-diazabicyclo [3.3.1] nonan-9-yl] -3- (3,4-dichloro-2-methyl-2H-indazol-5-yl) -1H-pyrazole [3,4- b] pyrazin-5-yl} methanol; 5- {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -5- (hydroxymethyl) -1H-pyrazole [3 , 4-b] pyrazin-3-yl} -4-chloro-2-ethyl-2H-indazol-3-
    carbonitrile; 5- {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -5-methyl-1H-pyrazole [3,4 - b] pyrazin-3-yl} -4-chloro-2-ethyl-2H-indazol-3-carbonitrile; {6- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] - 3- (7-chloro-2-methyl-1,3-benzothiazol-6-yl) -1H-pyrazole [3,4-b] pyrazin-5-yl} methanol; 5- {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -5- (hydroxymethyl) -1H-pyrazole [3 , 4-b] pyrazin-3-yl} -4-chloro-2-methyl-2H-indazol-3-carbonitrile; {6 - [(1S, 2S, 3S, 5R) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- [5-chloro-3- (dimethylamino) quinoxalin -6-yl] -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6- [endo-3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl] -3- [5-chloro-3- (dimethylamino) quinoxalin-6-yl] -1H- pyrazol [3,4-b] pyrazin-5-yl} methanol; (6- {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -5-methyl-1H-pyrazole [3, 4- b] pyrazin-3-yl} -7-chloro-1,3-benzothiazol-2-yl) methanol; {6- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] - 3- [5-chloro-3- (dimethylamino) quinoxalin-6-yl] -1H-pyrazole [3, 4- b] pyrazin-5-yl} methanol; {6- [endo-3-amino-3-methyl-8-azabicyclo [3.2.1] octan-8-yl] -3- (5-chloro-3-methoxyquininoxalin-6-yl) -1H-pyrazole [3 , 4-b] pyrazin-5-yl} methanol; endo-8- [3- (5-chloro-3-methoxyquinoxalin-6-yl) -5-methyl-1H-pyrazol [3,4-b] pyrazin-6-yl] -8-
    azabicycles [3.2.1] octan-3-amine; 7- {6- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] -5-methyl-1H-pyrazol [3,4-b] pyrazin-3-yl} -8- chloro-N, N-dimethylquinoxalin-2-amine; 8-chloro-7- (6- {3,8-diazabicyclo [3.2.1] octan-8-yl} - 5-methyl-1H-pyrazol [3,4-b] pyrazin-3-yl) -N, N-dimethylquinoxalin-2-amine; {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (5-chloro-3-ethoxyquinoxalin- 6- yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; (1R, 2S, 3S, 5S) -8- [3- (5-chloro-3-ethoxyquinoxalin-6-yl) -5-methyl-1H-pyrazol [3,4-b] pyrazin-6-yl] - 2-fluoro-8-azabicyclo [3.2.1] octan-3-amine; {6 - [(1S, 2S, 3S, 5R) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (7-chloro-2-methyl-1, 3-benzothiazol-6-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6 - [(1S, 2S, 3S, 5R) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- (3-chloro-2,4-dimethyl- 2H-indazol-5-yl) -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6- [endo-3-amino-8-azabicyclo [3.2.1] octan-8-yl] - 3- (3-chloro-2,4-dimethyl-2H-indazol-5-yl) -1H-pyrazole [3,4-b] pyrazin-5-yl} methanol; {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- [7-chloro-2- (methoxymethyl) - 1,3-benzothiazol-6-yl] -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- [5-chloro-3- (propan-2 - iloxy) quinoxalin-6-yl] -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol;
    5- {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -5-methyl-1H-pyrazole [3,4 - b] pyrazin-3-yl} -4-chloro-2- (propan-2-yl) -2H-indazol-3-carbonitrile; (1S, 2S, 3S, 5R) -8- [3- (7-chloro-2-methyl-1,3-benzothiazol-6-yl) -5-methyl-1H-pyrazol [3,4-b] pyrazin -6-yl] -2-fluoro-8-azabicyclo [3.2.1] octan-3-amine; {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- [5-chloro-3- (morpholin-4 - ila) quinoxalin-6-yl] -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol; (1R, 2S, 3S, 5S) -8- {3- [5-chloro-3- (morpholin-4-yl) quinoxalin-6-yl] -5-methyl-1H-pyrazole [3,4-b] pyrazin-6-yl} -2-fluoro-8-azabicyclo [3.2.1] octan-3-amine; 5- {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -5- (hydroxymethyl) -1H-pyrazole [3 , 4-b] pyrazin-3-yl} -4-chloro-2- (propan-2-yl) -2H-indazole-3-carbonitrile; and {6 - [(1R, 2S, 3S, 5S) -3-amino-2-fluoro-8-azabicyclo [3.2.1] octan-8-yl] -3- [3- (azetidin-1-yl) -5- chloroquinoxalin-6-yl] -1H-pyrazol [3,4-b] pyrazin-5-yl} methanol.
    [28]
    28. Combination characterized by comprising a compound of Formula (I) according to any one of claims 1 to 27, with one or more (for example, 1 or 2) other therapeutic agents (for example, anticancer agents).
    [29]
    29. Pharmaceutical composition characterized by comprising a compound of Formula (I), according to any one of claims 1 to 27, or a combination, according to claim 28.
    [30]
    A compound according to any one of claims 1 to 27, a combination according to claim 28, or a pharmaceutical composition according to claim 29, characterized in that it is for use in therapy.
    [31]
    A compound according to any one of claims 1 to 27, a combination according to claim 28 or a pharmaceutical composition according to claim 29, characterized in that it is for use in the prophylaxis or treatment of a state of SHP2-mediated disease or condition.
    [32]
    A compound according to any one of claims 1 to 27, a combination according to claim 28, or a pharmaceutical composition according to claim 29, characterized in that it is for use in the prophylaxis or treatment of a state of disease or condition as described in this document.
    [33]
    33. A compound according to any of claims 1 to 27, a combination according to claim 28, or a pharmaceutical composition according to claim 29, characterized in that it is for use in the prophylaxis or treatment of cancer.
    [34]
    34. Use of a compound according to any one of claims 1 to 27, a combination according to claim 28, or a pharmaceutical composition according to claim 29, characterized in that it is for the manufacture of a medicament for use in the prophylaxis or treatment of a disease state or condition as described in this document.
    [35]
    35. Method for the prophylaxis or treatment of a disease or condition, as described in this document, characterized in that it comprises administering to a patient a compound according to any one of claims 1 to 27, a combination, according to claim 28 or a pharmaceutical composition according to claim
    29.
    [36]
    36. A compound according to any one of claims 1 to 27, or a pharmaceutical composition according to claim 29, for use in the prophylaxis or treatment of cancer, wherein the compound is characterized in that it is used in combination with one or more plus other therapeutic agents (for example, anticancer agents) or therapies.
    [37]
    37. Process for the preparation of a compound of Formula (I) according to any one of claims 1 to 27, or a tautomer, stereoisomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, comprising: (a ) coupling a compound of Formula (A) or a protected derivative thereof:
    Z R1 N R2
    X (R6) a
    N
    N N
    P R4 Q 3
    R R5 (R7) b (A) where R1, R2, R3, R4, R5, R6, R7, Q, X, a, b, are as previously defined for the compounds of Formula (I), and P represents a protecting group (such as 2- (trimethylsilyl) ethoxymethyl; SEM) or is hydrogen, and Z is a metal residue (such as zinc halide, for example, zinc chloride) or an leaving group (such as a halogen, for example , iodine or bromine) with a compound of Formula (B) or a protected version of it
    (B) where R8, R9, R10, A, c, are as defined above for the compounds of Formula (I) and V represents a metal or metalloid residue (such as boronic acid, pinacol boracate, magnesium halide or halide zinc, for example, boronic acid, pinacol boronate) or a leaving group, such as halogen, followed by an appropriate deprotection reaction to remove the protecting groups; (b) coupling a compound of Formula (C) or a protected derivative thereof:
    (C) where R8, R9, R10, A, c, are as previously defined for the compounds of Formula (I), X is CH, P represents a protecting group (such as 2- (trimethylsilyl) ethoxymethyl; SEM) or is hydrogen, L is leaving group (as chloride), with a compound of Formula (D) or a protected derivative thereof, where R2, R3, R4, R5, R6, R7, Q, a, b, are as defined previously for the compounds of
    Formula (I);
    (D) (c) reacting a compound of Formula (K) or a protected derivative thereof,
    (K) where R2, R3, R4, R5, R6, R7, R8, R9, R10, Q, a, b and c are as defined herein for the compound of Formula (I), P represents an amine protecting group (such as 2- (trimethylsilyl) ethoxymethyl; SEM), N, N-dimethylsulfamoyl or hydrogen, L3 is leaving group (such as halogen, for example, bromine): (i) with an organometallic species of Formula CH3M, where M is a metal (for example, CH3-Zn-Hal, where Hal is halogen, for example, chloride, bromide or iodide) in the presence of a metal catalyst (such as (1,3-diisopropylimidazole-2-ylidene) (dichloride 3-chloropyridyl) palladium (II)) to yield a compound of Formula (I), wherein R1 is -CH3; or (ii) with an alkyl boronate (such as potassium (2-trimethylsilyl) -ethoxymethyl trifluoroborate) in the presence of a photoredox catalyst (such as [Ir {dFCF3ppy} 2 (bpy)] PF6), a metal catalyst (such as nickel (II) chloride dimethyl ether glycol complex), a binder (such as 4,4'-di-tert-butyl-2,2′-dipyridyl), a base (such as dipotassium phosphate) and a source of light (such as a blue LED), to render a compound of Formula (I), where R1 is -CH2OH; (d) cyclisation of a compound of Formula (R), or a protected derivative thereof;
    (R) where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Q, a, b, c, A, are as previously defined for the compounds of Formula (I) and L1 represents a suitable leaving group, such as a halogen, with 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 protected derivative thereof into an additional compound of Formula (I) or protected derivative thereof; or (g) optionally forming a pharmaceutically acceptable salt of a compound of Formula (I).
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    公开号 | 公开日 | 专利标题
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    MA52421A|2021-01-06|
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    JP2021514962A|2021-06-17|
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    PH12020551305A1|2021-10-25|
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    EP3463343A4|2016-05-31|2019-10-23|Board of Regents, University of Texas System|Heterocyclic inhibitors of ptpn11|EP3463343A4|2016-05-31|2019-10-23|Board of Regents, University of Texas System|Heterocyclic inhibitors of ptpn11|
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    SG11202100199UA|2018-08-10|2021-02-25|Navire Pharma Inc|6--3--2-methylpyrimidin-4-one derivatives and related compounds as ptpn11inhibitors for treating cancer|
    EP3853233A1|2018-09-18|2021-07-28|Nikang Therapeutics, Inc.|Tri-substituted heteroaryl derivatives as src homology-2 phosphatase inhibitors|
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    WO2021085653A1|2019-10-31|2021-05-06|Taiho Pharmaceutical Co., Ltd.|4-aminobut-2-enamide derivatives and salts thereof|
    TW202128688A|2019-11-08|2021-08-01|美商銳新醫藥公司|Bicyclic heteroaryl compounds and uses thereof|
    WO2021106231A1|2019-11-29|2021-06-03|Taiho Pharmaceutical Co., Ltd.|A compound having inhibitory activity against kras g12d mutation|
    WO2021215545A1|2020-04-24|2021-10-28|Taiho Pharmaceutical Co., Ltd.|Anticancer combination therapy with n--2-amino)methyl)-1h-imidazole-5-carboxamide inhibitor of kras-g12c|
    WO2021215544A1|2020-04-24|2021-10-28|Taiho Pharmaceutical Co., Ltd.|Kras g12d protein inhibitors|
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    法律状态:
    2021-12-07| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    优先权:
    申请号 | 申请日 | 专利标题
    GB1803439.7|2018-03-02|
    GBGB1803439.7A|GB201803439D0|2018-03-02|2018-03-02|Pharmaceutical compounds|
    GB1814135.8|2018-08-30|
    GBGB1814135.8A|GB201814135D0|2018-08-30|2018-08-30|Pharmaceutical compounds|
    PCT/IB2019/051641|WO2019167000A1|2018-03-02|2019-03-01|Pharmaceutical compounds|
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