Indazolyl triazole derivatives, kit, and pharmaceutical composition

专利摘要:
INDAZOLYL TRIAZOLE DERIVATIVES AS IRAK INHIBITORS. The present invention relates to compounds of Formula I) which are used for the treatment of inflammation and autoimmune disorders.
公开号:BR112013015460B1
申请号:R112013015460-8
申请日:2011-12-16
公开日:2022-01-25
发明作者:Catherine Jorand-Lebrun；Stefano Crosignani；Jerome Dorbais；Tania Grippi- Vallotton；Adeline Pretre
申请人:Merck Serono S.A.；
IPC主号:

专利说明:

[0001] The present invention relates to indazolyltriazole derivatives of Formula (I) as IRAK inhibitors and their use in the treatment of cancer, and other diseases related to IRAK overexpression, such as rheumatoid arthritis, systemic lupus erythematosus or lupus nephritis. background
[0002] Kinases catalyze the phosphorylation of proteins, lipids, sugars, nucleosides and other cellular metabolites and play key roles in all aspects of eukaryotic cell physiology. Especially, protein kinases and lipid kinases participate in signaling events that control cell activation, growth, differentiation and survival in response to extracellular mediators or stimuli, such as growth factors, cytokines or chemokines. In general, protein kinases are classified into two groups, those that preferentially phosphorylate tyrosine residues and, preferably, those that phosphorylate serine and/or threonine.
[0003] Kinases are important therapeutic targets for anti-inflammatory drug development (Cohen, 2009. Current Opinion in Cell Biology 21, 1-8), eg kinases that are involved in orchestrating the innate and adaptive immune response. Kinase targets of particular interest are members of the IRAK family.
[0004] Interleukin-1 receptor-associated kinases (IRAKs) are critically involved in the regulation of intracellular signaling networks that control inflammation (Ringwood and Li, 2008. Cytokine 42, 1-7). IRAKs are expressed in many cell types and can mediate signals from various cellular receptors, including toll-like receptors (TLR). IRAK4 is thought to be the initial activated protein kinase downstream of the interleukin-1 receptor (IL-1) and toll-like receptors (TLR), except TLR3, and initiates signaling in the innate immune system via rapid activation of IRAK1 and slower activation of IRAK2. IRAK1 was first identified by biochemical purification of IL-1 dependent kinase activity, which co-immunoprecipitates with the IL-1 type 1 receptor (Cao et al, 1996 Science 271 (5252): 1128-1131). IRAK2 was identified by searching the human expressed sequence label (EST) database for sequences homologous to IRAKI (Muzio et al, 1997 Science 278 (5343): 1612-5). IRAK3 (also called IRAKM) was identified using a murine EST sequence encoding a polypeptide with significant homology to IRAK1 to screen a phytohaemagglutinin-activated peripheral blood leukocyte (PBL) cDNA library (Wesche et al. , 1999. J. Biol. Chem. 274 (27): 19403-10). IRAK4 was identified by database search for IRAK-like and PCR-like sequences of a universal cDNA library (Li et al., 2002. Proc. Natl. Acad. Sci. USA 99(8):5567-5572).
[0005] Mice expressing a catalytically inactive mutant of IRAK4 instead of the wild-type kinase are completely resistant to septic shock caused by various TLR agonists and are impaired in their response to IL-1. Children who lack IRAK4 activity due to a genetic defect suffer from recurrent infections with pyogenic bacteria. It appears that IRAK- and IL-1RS-dependent TLRs are vital for childhood immunity against some pathogenic bacteria, but play a redundant role in protective immunity to most adult infections. Therefore IRAK4 inhibitors may be useful for treating chronic inflammatory diseases in adults without making them too susceptible to viral and bacterial infections (Cohen, 2009. Current Opinion in Cell Biology 21, 1-8). Potent IRAK4 inhibitors have been developed ( Buckley et al., 2008. Bioorg Med Chem Lett. 18(12):3656-60 ). IRAK1 is essential for TLR7- and TLR9-mediated activation of IRF7 and interferon-alpha (IFN-α) production, suggesting that IRAK1 inhibitors may be useful for the treatment of systemic lupus erythematosus (SLE). IRAK2 is activated downstream of IRAK4 and plays a role in pro-inflammatory cytokine production. Therefore, IRAK2 inhibitors may be useful for inflammatory diseases. Summary of the invention
[0006] According to one aspect of the invention, compounds of Formula (I) are provided. According to another aspect of the invention, there are provided compounds of Formula (I) which are suitable for the treatment and/or prevention of IRAK-related disorders. According to another aspect of the invention there are provided compounds which are capable of modulating, especially inhibiting IRAK activity or function in disease states in mammals, especially in humans.
[0007] According to another aspect of the invention, methods are provided for the treatment and/or prevention of diseases selected from inflammatory autoimmune disorders, cardiovascular disorders, neurodegenerative disorders, bacterial and viral infections, allergy, asthma, pancreatitis, multiple organs, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, graft rejection, lung injury, respiratory disease, and ischemic conditions.
[0008] In another aspect, the present invention provides compounds of Formula (I), which are selective for IRAK-4 and/or IRAK-1 over the other isoforms.
[0009] According to another aspect of the invention there is provided a kit or kit comprising at least one compound of Formula (I), preferably in combination with immunomodulatory agents. Preferably, the kit consists of separate packages of: (a) an effective amount of a compound of Formula (I) and/or pharmaceutically usable derivatives, solvates, salts, hydrates and stereoisomers thereof, including mixtures thereof in all proportions, and (b) an effective amount of an additional medicament active ingredient.
[00010] According to another aspect of the invention, there is provided a process for the synthesis of compounds of Formulas (I) and related Formulas.
whereQ denotes Ar or Het,
[00011] E denotes -(CH2)mCO-, -(CH2)mSO2, -(CH2)q-, -(CH2)mNHCO-, or a single bond,
[00012] R1 denotes H, OH, NH-C1-C6-alkyl, OC1-C6-alkyl, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cyc, Hal, Het1, O-Het1 , CO-Het1, NH-Het1, CO-Ar1, O-Ar1, Ar1, NH-Ar1, -(CH2)qHet1, -CONH-(CH2)qHet1, -CONH-Het1, -(CH2)qO-Het1, -(CH2)qO-Ar1, -(CH2)qAr1, -CONH-(CH2)qAr1, -CONH-Ar1, -CONHC3-C6-cycloalkyl, -(CH2)qHal, -(CH2)qCyc, CF3, -( CH2)sNH-(CH2)q-Het1, -(CH2)sNH-(CH2)q-Ar1, wherein NH-C1-C6-alkyl, OC1-C6-alkyl, C1-C6-alkyl, C2-C6- alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl may be substituted by 1 to 3 groups independently selected from OC1-C3-alkyl, OH, CONH2, NH2,
[00013] R2 denotes H, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Hal, CF3, preferably H,
[00014] R3 denotes Het1, Ar1, NRaRb, COOH, -(CH2)qHet1, -(CH2)qAr1, -(CH2)qNRaRb, -(CH2)qCOOH, or C1-C6-alkyl wherein 1 to 3 atoms of hydrogen can be independently substituted by OH or CF3.
[00015] R4 denotes H, C1-C6-alkyl, C2-C6-alkenyl, Hal;
[00016] Ra denotes H, C1-C6-alkyl, linear, branched or cyclic
[00017] Rb denotes H, Hetb, Arb, -CO-Hetb, -CO-Arb, a C3-C8-cycloalkylal or a linear or branched alkyl having 1 to 6 carbon atoms, wherein 1 to 3 hydrogen atoms may be substituted by Hetb, Arb, NH2, N(C1-C6-alkyl)2, NH(C1-C6-alkyl), N(C1-C6-alkyl)(3-C8-cycloalkyl), NH(C3-C8- cycloalkyl), O(C1-C6-alkyl), CN, OH, CF3, Hal,n is 0, 1, 2, 3 or 4,m is 0, 1, 2,3 or 4,q is 1, 2, or 3,s' is 0, 1, 2 or 3,
[00018] Hal denotes Cl, Br, I, F, preferably Cl or F.
[00019] Ar denotes bicyclic or divalent monocyclic fused arylene group having 6 to 14 carbon atoms, which may be further substituted by 1 to 4 substituents selected from Hal, C1-C6-alkyl, -(CH2)mOC1- C6-alkyl, CN, OH, NO2, CF3, -(CH2)mCOOH, -(CH2)mCOOC1-C6-alkyl;
[00020] Het denotes an unsaturated, saturated or monocyclic divalent aromatic or bicyclic fused heterocyclic group having 1 to 5 heteroatoms independently selected from N, O, S and/or a -C=O group, which may be further substituted by 1 to 4 substituents selected from Hal, C1-C6-alkyl, -(CH2)mOC1-C6-alkyl, CN, OH, NO2, CF3, -(CH2)mCOOH, -(CH2)mCOOC1-C6-alkyl;
[00021] Ar1 denotes an aromatic, monocyclic or bicyclic carbocyclic ring, having 6 to 14 carbon atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, -CF3, -OCF3, -NO2, -CN, perfluoroalkyl, Hal , -CF3, -OCF3, -NO2, -CN, perfluoroalkyl, C1-C6-linear or branched alkyl, cycloalkyl, -OH, -OC1-C6-alkyl, -COC1-C6-alkyl, -NH2, -COH , -COOH, -CONH2, an Rb group such as -CH2θ(C1-C6-alkyl), -SO2NRaRb or SO2(C1-C6-alkyl).
[00022] Het1 denotes a saturated, or unsaturated, monocyclic or bicyclic (fused, bridged, or spiro) aromatic heterocyclic ring having 1 to 4 heteroatoms independently selected from N, O, S and/or a CO group, which is unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, -CF3, -OCF3, -NO2, -CN, perfluoroalkyl, C1-C6-linear or branched alkyl, C3-C8-cycloalkyl, -OH, -OC1-C6-alkyl -NH2, -N(C1-C6-alkyl)2, -COH, -COOH, -CONH2, -COC1-C6-alkyl, -NHCO(C3-C6-cycloalkyl), an Rb group such as -CH2O(C1-C6) -alkyl), -SO2NRaRb or SO2(C1-C6 alkyl).
[00023] Hetb denotes a saturated, or unsaturated, monocyclic or bicyclic (fused or spiro) aromatic heterocyclic ring having 1 to 4 heteroatoms independently selected from N, O, S and/or a CO group, which is unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, -CF3, -OCF3, -NO2, -CN, perfluoroalkyl, -OH, -OC1-C6-alkyl, -NH2, -COH, -COOH, -CONH2, or by a C1-C6-alkyl linear or branched in which 1 to 3 hydrogen atoms can be replaced by NH2, N(C1-C6-alkyl)2, NH(C1-C6-alkyl), N(C1-C6-alkyl)(3-C8-cycloalkyl) ), NH(C3-C8-cycloalkyl), O(C1-C6-alkyl), CN, OH, CF3, Hal, C3-C8-cycloalkyl, or by a 4- to 8-membered heterocyclic ring containing a heteroatom selected from from O, S and N,
[00024] Arb denotes an aromatic, monocyclic or bicyclic carbocyclic ring having 6 to 14 carbon atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, -CF3, -OCF3, -NO2, -CN, perfluoroalkyl, Hal, -CF3, -OCF3, -NO2, -CN, perfluoroalkyl, -OH, -OC1-C6-alkyl, -NH2, -COH, -COOH, -CONH2, or by a linear or branched C1-C6-alkyl that 1 to 3 hydrogen atoms can be replaced by NH2, N(C1-C6-alkyl)2, NH(C1-C6-alkyl), N(C1-C6-alkyl)(C3-C8-cycloalkyl), NH( C3-C8-cycloalkyl), O(C1-C6-alkyl), CN, OH, CF3, Hal, C3-C8-cycloalkyl, or by a 4- to 8-membered heterocyclic ring containing a heteroatom selected from O , S and N,
[00025] Cyc denotes a saturated or unsaturated carbocyclic ring having 3 to 8 carbon atoms, preferably 5 or 6 carbon atoms, wherein 1 to 5 H atoms are replaced by Hal, -CF3, -OCF3, -NO2, - CN, perfluoroalkyl, Hal, -CF3, -OCF3, -NO2, -CN, perfluoroalkyl, C1-C6-linear or branched alkyl, cycloalkyl, -OH, -OC1-C6-alkyl, -COC1-C6-alkyl, -NH2, -COH, -COOH, -CONH2, an Rb group such as -CH2O(C1-C6-alkyl), -SO2NRaRb or SO2(C1-C6-alkyl).
[00026] and pharmaceutically acceptable derivatives, solvates, tautomers, salts, hydrates
[00027] and stereoisomers thereof, including mixtures thereof in all proportions.
[00028] In another embodiment, Formula (I) encompasses compounds of sub-Formulas (Ia) and (Ib)

[00029] In another embodiment, the present invention provides compounds of Formula (I) and related Formulas (Ia) and (Ib) wherein
[00030] Q denotes Ar, preferably phenylene. E denotes -(CH2)mCO-,R1 denotes H, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cyc, Hal, Het1, O-Het1, O-Ar1, Ar1, -(CH2)qHet1, -(CH2)qO-Het1, -(CH2)qO-Ar1, -(CH2)qAr1, -(CH2)qHal, -(CH2)qCyc, CF3,R2 denotes H , C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl,Hal, CF3, preferably H,R3denotes Het1 or NRaRb, preferably Het1,R4denotes H,
[00031] Wherein Ra, Rb, Het1, Ar, Ar1, m are as defined above.
[00032] In another embodiment, the present invention provides compounds of Formula (I) and related Formulas (Ia) and (Ib) wherein Q denotes Ar, preferably phenylene. E denotes -(CH 2 )mCO-,R 1 , R 2 are both H ,R3denotes Het1 or NRaRb, preferably Het1,R4denotes H,
[00033] Wherein Ra, Rb, Het1, Ar, m are as defined above.
[00034] In another embodiment, the present invention provides a compound of Formulas (Ic), (Id) or (Ie)

[00035] Wherein R1, R3, R2, E, n are as defined above.
[00036] In another embodiment, the present invention provides compounds of Formula (If):

[00037] In another embodiment, the group E in Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If)
[00038] denotes -(CH2)mCO- or -(CH2)mNHCO-, where m is as defined above. preferably,
[00039] m is 0, 1 or 2, more preferably m is 0 or 1.
[00040] In another embodiment, the E group in Formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) is -(CH2)q- or a single bond , where q is as defined above. Preferably q is 1.
[00041] In another embodiment, in the case Q is Ar, and is disubstituted in the para or meta positions.
[00042] In another embodiment, the present invention provides compounds of Formula (If) wherein R2 is as defined above, preferably H,Q is Ar,E is -CO-, -(CH2)- or a bond, R3 is Het1 ,
[00043] R1 is selected from H, F, -CH3, Het1, -(CH2)q-Het1, -NH-Het1, -CONH-(CH2)qHet1, -CONH-Het1, -CONH-Ar1, or a C2-C6-alkenyl that can be substituted by 1 to 3 groups independently selected from OC1-C3-alkyl, OH, CONH2, and NH2, where q is as defined above.
[00044] In other embodiments Het1 denotes a saturated, or unsaturated 5- to 12-membered monocyclic or bicyclic (fused or spiro) heterocyclic ring having 1 to 3 heteroatoms independently selected from N, and a CO group, which is unsubstituted or monosubstituted, or disubstituted by C3-C8-cycloalkyl, -OH, -OC1-C6-alkyl, -NH2, -N(C1-C6-alkyl)2, -COHetb, Hetb, Arb or a linear or branched having 1 to 6 carbon atoms in which 1 to 3 hydrogen atoms can be independently replaced by Hetb, Arb, OH, CF3,
[00045] In another embodiment, Hetb denotes a 5- or 6-membered saturated or aromatic ring having 1 nitrogen atom, optionally substituted with 1 to 3 substituents selected from C1-C6-alkyl, OH, Hal. Preferably, Hetb denotes a pyridine ring or a pyrrolidine ring.
[00046] In another embodiment, Arb denotes a phenyl ring optionally substituted by 1 to 3 substituents selected from Hal, preferably F, OH.
[00047] In another embodiment, in the case Q is Ar, it denotes a phenylene in which 1 H atom can be replaced by a group selected from C1-C6-alkyl, O-C1-C6-alkyl or CF3 .
[00048] In another embodiment, in the case Q is Het, it denotes a monocyclic or unsaturated 5- or 6-membered divalent aromatic heterocylic group having 1 or 2 nitrogen atoms.
[00049] In another embodiment, only 1 of Ra and Rb in Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) denotes H and the remaining group as the meaning defined under Formula (I).
[00050] "C1-C6-alkyl" or "a C1-C6-alkyl group" denotes a straight-chain or branched alkyl having 1 to 6 carbon atoms.
[00051] "C1-C3-alkyl" or "a C1-C3-alkyl group" denotes a straight-chain or branched alkyl having 1 to 3 carbon atoms.
[00052] "C1-C6-alkyl" or "C1-C3-alkyl" may also include halo-alkyl. Halo-alkyl contains 1 to 10 halogen atoms, preferably 1 to 3 halogen atoms. Halo-alkyl contains, for example, a -CF3, -CHF2 or -CH2F group.
[00053] "C2-C6-alkenyl" or "a C2-C6-alkenyl group" denotes a straight or branched carbon chain having 2 to 6 carbon atoms and 1 to 3 double bonds.
[00054] "C2-C6-alkynyl" or "a C2-C6-alkynyl group" denotes a straight or branched carbon chain having 2 to 6 carbon atoms and 1 to 3 tripe bonds.
[00055] A "leaving group" denotes a chemical moiety that can be removed or replaced by another chemical group.
[00056] Throughout the specification, the term leaving group preferably denotes Cl, Br, I or a reactively modified OH group, such as, for example, an activated ester, an imidazolide or alkylsulfonyloxy having 1 to 6 carbon atoms. (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6 to 10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy).
[00057] Radicals of this type for activating the carboxyl group in typical acylation reactions are described in the literature (e.g. in standard works such as Houben-Weila, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg- Thieme-Verlag, Stuttgart).
[00058] Activated esters are advantageously formed in situ, for example, by the addition of HOBt or N-hydroxysuccinimide.
[00059] The following abbreviations refer to the abbreviations used below:
[00060] AcNH2 (Acetamide), AcOH (Acetic acid), 9-BBN (9-Borabicyclo 3.3.1 nonane), BINAP (2,2'-bis(disphenylphosphino)-1,1'-binaphthalene), BOP (Hexafluorophosphate of benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium) dba (dibenzylidene acetone), tBu (tert-Butyl), tBuOK (potassium tert-butoxide), CDI (1,1'-Carbonyldiimidazole), COMU (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbene hexafluorophosphate), DBU (1,8-Dizabicyclo[5.4.0]undec-7-ene), DCM (Dichloromethane), DIAD ( Diisobutylazodicarboxylate), DIEA (Diisopropyl Ethylamine), DMA (Dimethyl Acetamide), DMAP (4-Dimethylaminopyridine), DMSO (Dimethyl Sulfoxide), DMF (N,N-Dimethylformamide), EDC (1-Ethyl Hydrochloride -3-(3-dimethylaminopropyl)carbodiimide), EtOAc (Ethyl Acetate), EtOH (Ethanol), g (gram), cHex (Cyclohexane), HPLC (High Performance Liquid Chromatography), h (hour) , MHz (Megahertz), MeOH (Methanol), min (minute), mL (milliliter), mmol (millimol), mM (millimolar), mp (melting point), MS (Mass Spectrometry), MW (Microwave), NMM (N-Methyl Morpholine), NMR (Nuclear Magnetic Resonance), NBS (N-Bromosuccinimide), PBS (Phosphate Buffered Saline), PMB (Paramethoxybenzyl ), TA (room temperature), SPA (Scintillation Proximity Assay), TBAF (TetraButyl Ammonium FIuoride), TBTU (N,N,N',N'-Tetramethyl-O-(benzotriazol-1-yl)uroniotetrafluoroborate), TEA ( Triethyl amine), TFA (Trifluoroacetic Acid), THF (Tetrahydrofuran), PetEther (Petroleum Ether), TBME (Tert-Butyl Methyl Ether), TLC (Thin Layer Chromatography), TMS (Trimethylsilyl), TMSI ( trimethylsilyl iodide), UV (Ultraviolet).
[00061] In general, compounds according to Formula (I) and related Formulas of the present invention can be prepared from readily available starting materials. If such starting materials are not commercially available, they can be prepared by standard synthetic techniques. In general, synthetic routes for any individual compound of Formula (I) and related Formulas will depend on the particular substituents on each molecule, such factors being appreciated by those skilled in the art. The following general methods and procedures described in the examples below can be used to prepare compounds of Formula (I) and related Formulas. The reaction conditions described in the following schemes, such as temperatures, solvents or co-agents, are given as examples only and are not restrictive. It will be appreciated that when typical or preferred experimental conditions (i.e., reaction temperatures, time, moles of reagents, solvents, etc.) are given, other experimental conditions may also be used, unless otherwise indicated. Optimal reaction conditions may vary with the particular reagents or solvents used, but such conditions can be determined by those skilled in the art using routine optimization procedures. For all protection and deprotection methods, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter GM Wuts in "Protective Groups in Organic Synthesis", Wiley Interscience, 3rd Edition 1999.
[00062] Depending on the nature of Q, E, R1, R2, R3, Ra, Rb, n, m, q, different synthetic strategies can be selected for the synthesis of compounds of Formula (I). In the process illustrated in the following schemes, Q, E, R1, R2, R3, Ra, Rb, n, m, Q, are as defined above in the description, unless otherwise indicated.
[00063] Generally, the triazole-indazole compounds of Formula (I) and related Formulas (Ia) and (Ib), wherein Q, E, R1, R2, R3, Ra, Rb, n, m, q are defined as above can be prepared by 1,3-dipolar cycling between an alkyne of general Formula (II) wherein R1, R2, n are as defined above and the PG1 is H or a nitrogen protecting group such as, but not limited to tert-butyloxycarbonyl, acetyl, tetrahydropyran, PMB and an azide of general Formula (III), as described in Scheme 1, and wherein Q, E and R3 are as defined above. General protocols for such cycloaddition are given below in the examples, using conditions and methods well known to those skilled in the art. This reaction is preferably carried out with Cu(II) salts such as copper sulfate pentahydrate or copper acetate in the presence of a reducing agent such as sodium ascorbate or copper metal as a catalyst system in a mixture of tert-butanol, THF , dioxane or acetonitrile, with water. Organic solvent such as THF, toluene, DCM, acetonitrile, in the presence of a stoichiometric amount of Cu(I) salt, such as CuI, Cu(CH3CN)4PF6, CuBr(PPh3)4 or CuIP(OEt)3 or Cu(II) salts and an excess of a base such as TEA, DIEA, 2,6-lutidine, pyridine can also be used. The cycloaddition can be carried out at a temperature rising from TA to 150°C under thermal conditions or MW in 15 minutes to 72h. In the case PG1 is a nitrogen protecting group, the cycloaddition is followed by a suitable deprotection step. Suitable conditions of the deprotection step may be, for example, hydrolysis under acidic conditions, using, for example, hydrochloric acid in dioxane, at room temperature or at a temperature of 20°C to 100°C. Scheme 1

[00064] These conditions are applicable to any compound of General Formula (I).
[00065] Alkyne compounds of general Formula (II) wherein R1, R2, n, PG1 are as defined above can be obtained by coupling a compound of Formula (IV) wherein R1, n and PG1 are as defined above and X denotes triflate or halide, preferably bromide or iodide with a compound of Formula (V) wherein R2' is a protecting group such as but not limited to Me3Si, or R2 when R2 is defined as above but preferably not H, as outlined in Scheme 2. General protocols for such coupling are given below in the examples, using conditions and methods well known to those skilled in the art to carry out such coupling. This reaction is preferably carried out with a suitable catalyst such as but not limited to dichlorobis(triphenylphosphine)palladium(II) or 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II), Pd(OAc)2, Pd2(dba )3, Pd(Cl)2(PPh3)2 or Pd/C in the presence or absence of an additional ligand, such as but not limited to P(tBu)3, P(oTol)3, PPh3, BINAP. The reaction may also be carried out in the presence of a suitable copper salt such as but not limited to copper(I) iodide, copper(I) bromide or copper(I) chloride. The reaction can be carried out in the presence or absence of bases such as TEA, DIEA, NMM, piperidine, Cs 2 CO 3 , sodium phosphate, in the presence or absence of a suitable solvent such as THF, ACN, DMF or acetone. This coupling reaction can be carried out at a temperature between about 20°C to about 100°C, preferably at about 70°C, for a few hours, such as one hour to 24 h. For a list of conditions described for the coupling of an aryl alkyne with an aryl or heteroaryl triflate or halide, see also Chem. Rev. 2007, 107, 874-892.Scheme 2

[00066] The method for preparing alkyne compounds of Formula (II) selected below: 3-ethynyl-1H-indazol 3-ethynyl-5-methyl-1H-indazol 4-(3-ethynyl-1H-indazol-5-yl tert-butyl tert-butyl 3-ethynyl-5-(hydroxymethyl)-1H-indazole-1-carboxylate tert-butyl 3-ethynyl-5-methyl-1H-indazole-1-carboxylate 5-)piperidine-1-carboxylate tert-butyl-1-carboxylate bromo-3-ethynyl-1H-indazole is more particularly described in the examples.
[00067] Compounds of General Formula (IV) can be obtained by standard halogenation conditions when X is I, Cl, Br by treatment of indazole (VI) wherein R1, n and PG1 are as defined above with X2 or NBX in a solvent such as DCM, DMF, Acetonitrile, THF or AcOH at temperatures rising from 0°C to 100°C for 1h to 48h as outlined in Scheme 3. Scheme 3

[00068] Compounds of General Formula (VI) wherein R1, n and PG1 are as defined above are commercially available or can be obtained following standard indazole formation procedures described in the literature (e.g. Synthesis, 1972, 375; Bioorg.Med .Chem.Lett., 2001, 11, 1153-1156; Bioorg.Med.Chem., 2008, 16, 1966-1982).
[00069] Indazoles Formula (VI) and Related Formulas wherein R1, n and PG1 are as defined above may be converted to alternative Indazoles of Formula (VI) and Related Formulas wherein R1, n and PG1 are as defined above , employing suitable interconversion techniques well known to those skilled in the art.
[00070] Indazole compounds of General Formula (VIa) wherein R1 is selected from C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cyc, Het1, Ar1, -(CH2)qHet1, -(CH2)qO-Het1, -(CH2)qO-Ar1, -(CH2)qAr1, -(CH2)qCyc, -(CH2)qNH-(CH2)q-Het1, -(CH2)qNH-(CH2) q-Ar1, wherein NH-C1-C6-alkyl, OC1-C6-alkyl, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, may be substituted by 1 to 3 groups independently selected from of OC1-C3-alkyl, OH, CONH2, NH2, R4 is as defined above and PG1 is as defined above can be prepared by coupling reaction between indazole compounds of general Formula (VIb) wherein LG1 is a leaving group such as Cl, Br, I or a sulfonate ester such as triflate, and boronic acid or ester derivatives of Formula (VII) wherein R is H or an alkyl group and R 1 is as defined above, to give indazole compounds of General Formula (VIc) wherein R1 and PG1 are as defined above, following or not following, by a reduction of the resulting double bond c as outlined in Scheme 4. General protocols for such coupling are given below in the Examples, using conditions and methods well known to those skilled in the art to carry out such coupling. In a typical procedure, indazole (VIb) and boronic acid or ester (VII) are heated in a suitable solvent, such as THF, toluene or dioxane, in the presence or absence of water as a co-solvent, in the presence of a base, such as Cs2CO3, K2CO3, CsF, and with a suitable catalyst such as but not limited to dichlorobis(triphenylphosphine)palladium(II), Pd(PPh3)4 or 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II), Pd (OAc)2, Pd2(dba)3, Pd(Cl)2(PPh3)2 or Pd/C in the presence or absence of an additional ligand, such as but not limited to P(tBu)3, P(oTol)3 , PPh3, BINAP. This coupling reaction can be carried out at a temperature between about 20°C to about 150°C, preferably at about 120°C, for a few minutes to a few hours, possibly under microwave irradiation. The reduction step is normally carried out under hydrogen pressure, between 1 and 60 bars, at a temperature ranging from RT to 80°C in the presence of a suitable catalyst such as Pd/C, Pt2O or Ra-Ni. Other hydrogen sources such as ammonium formate can be used. R1 in Formula (VII) and (VIc) may be synthetic precursors of R1 in Formula (VIa).Scheme 4

[00071] The above-mentioned conditions are applicable for example in the reaction of Scheme 4a wherein indazole compounds of general Formula (VIa') wherein Rc is H, C1-C6-alkyl, -CONRaRb, SO2NRaRb and PG1 is as defined above can be prepared by coupling reaction between indazole compounds of general Formula (VIb') wherein LG1 is a leaving group such as Cl, Br, I or a sulfonate ester such as triflate, and boronic acid or ester derivatives of Formula (VII') wherein R is H or an alkyl group and Rc is as defined above.Scheme 4a

[00072] The method for preparing Indazole derivatives of Formula (VIa) selected below: tert-butyl 4-(1H-indazol-5-yl)piperidine-1-carboxylate is more particularly described in the examples.
[00073] Alternatively, indazole compounds of general Formula (VIa) wherein R1, R4, and PG1 are as defined above may be prepared by coupling reaction between an indazole compound of general Formula (VId) wherein R is H or an alkyl group and PG1 is as defined above and is composed of General Formula (VIIa) wherein R1 is as defined above and LG2 is sulfonate ester such as triflate, following or not following by a reduction of the resulting double bond as outlined in Scheme 5. General protocols that can be used for such a transformation are the same as defined above. Scheme 5

[00074] The above-mentioned conditions are applicable for example in the reaction of Scheme 5a wherein indazole compounds of general Formula (VIa') in which Rc is H, alkyl, amide, sulfonamide and PG1 is as defined above can be prepared by reaction coupling between an indazole compound of general Formula (VId') wherein R is H or an alkyl group and PG1 is as defined above and compound of general Formula (VIIa') wherein Rc is as defined above and LG2 is ester of sulfonate such as triflate.Scheme 5a

[00075] Azide compounds of General Formula (III) wherein Q, E and R3 are as defined above can be prepared from amines of General Formula (VIII) wherein Q, E and R3 are as defined above as outlined in the scheme 6. General protocols for such reactions are given below in the Examples, using conditions and methods well known to those skilled in the art. As an example, a two-step process can be used where amines (VIII) are first treated with sodium nitrite in a strong acid such as but not limited to AcOH, TFA or H2SO4 followed by NaN3 in water at temperature rising from 0° C for TA. A pot procedure using tert-butylnitrite and TMS-azide in a solvent such as EtOAc at RT for 1h to 12h can also be used for such a transformation. For a list of conditions described for the formation of azides see also Angew. Chem. Int. Ed., 2005, 44, 5188-5244.Scheme 6

[00076] Alternatively, compounds of general Formula (IIIa) wherein Q, m, Ra, Rb are as defined above may be prepared by coupling a carboxylic acid of Formula (IX) wherein Q and m are as defined above with an amine of general Formula (X) wherein Ra, Rb are as defined above as outlined in Scheme 7. General protocols for such coupling are given below in the Examples, using conditions and methods well known to those skilled in the art. Standard coupling agents such as TBTU, COMU, EDC or isobutyl chloroformate can be used in the presence or absence of a base such as DIEA, TEA or NMM in a suitable solvent such as DMF, Acetonitrile, THF or DCM at temperature rising from about 0°C to 50°C, preferably at 0°C for a time of 30 minutes to a few hours. Alternatively, a carboxylic acid derivative (such as acyl chloride) can be coupled with the amine (X), using conditions and methods well known to those skilled in the art, in the presence of a base such as pyridine or DIEA in a suitable solvent such as toluene, DCM, THF or DMF, at temperature rising from about 0°C to RT, preferably RT, for a few hours.Scheme 7Q-(CH2)m-COOHN3 + HNRaRb QQ —(CH2)— CONRaRb

[00077] Triazole-indazole Compounds of Formula (I) and Related Formulas, wherein Q, E, R1, R2, R3, R4, Ra, Rb, n, m, q are as defined above, may be converted into alternative compounds of Formula (I) and related Formulas wherein Q, E, R1, R2, R3, R4, Ra, Rb, n, m, q are as defined above, employing suitable interconversion techniques well known to those versed in the technique.
[00078] Pyridine compounds of General Formula (Ie') wherein the group ER3 denotes NRaRb and wherein R1, n, R2, Ra, Rb are as defined above and PG1 is H or a nitrogen protecting group such as, but not limited to tert-butyloxycarbonyl, acetyl, tetrahydropyran, PMB can be prepared by reacting an a-chloropyridine compound of general Formula (Ie') wherein R 1 , n, R 2 and PG 1 are as defined above, and wherein the group ER3 denotes Cl, and an amine of general Formula (X) wherein Ra and Rb are as defined above as outlined in Scheme 8. General protocols of such a reaction are given below in the Examples, using conditions and methods well known to those skilled in the art. technique. This reaction is preferably carried out at temperature rising from RT to 250°C in the presence or absence of a base such as Cs2CO3, K2CO3, TEA or DIEA and in a solvent such as DMF, DMSO, THF or the amine HNRaRb.Scheme 8

[00079] The method for preparing pyridine derivatives of Formula (e') selected below: 3-[1-(6-morpholin-4-ylpyridin-3-yl)-1H-1,2,3-triazol-4- yl]-1H-indazole is more particularly described in the examples.
[00080] Amide compounds of General Formula (I') wherein R3 denotes NRaRb and E denotes -(CH2)mCO, and R1, R2, R4, Q, Ra, Rb, m, n are as defined above, and PG1 is H or a nitrogen protecting group such as, but not limited to, tert-butyloxycarbonyl, acetyl, tetrahydropyran, PMB may be prepared by coupling a carboxylic acid compound of General Formula (I') wherein R3 denotes - (CH2 )mCOOH and E denotes -(CH2)q or a single bond, and R1, R2, R4, Q, m, n, q, and PG1 are as defined above and an amine of general Formula (X) wherein Ra and Rb are as defined above as outlined in Scheme 9. General protocols of such a reaction are given below in the Examples, using conditions and methods well known to those skilled in the art. Standard coupling agents such as TBTU, COMU, EDC or isobutyl chloroformate can be used in the presence or absence of a base such as DIEA, TEA or NMM in a suitable solvent such as DMF, Acetonitrile, THF or DCM at temperature rising from about 0°C to 50°C, preferably at 0°C for a time of 30 minutes to a few hours. Alternatively, a carboxylic acid derivative (such as acyl chloride) can be coupled with the amine HNRaRb, using conditions and methods well known to those skilled in the art, in the presence of a base such as pyridine or DIEA in a suitable solvent. such as toluene, DCM, THF or DMF, at temperature rising from about 0°C to RT, preferably RT, for a few hours.Scheme 9

[00081] The method for preparing amide derivatives of Formula (I') selected below:
[00082] 3-{1-[4-(2-morpholin-4-yl-2-oxoethyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol
[00083] 3-{1-[4-(2-oxo-2-pyrrolidin-1-ylethyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole
[00084] 3-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}-N,N-dimethylpropanamide
[00085] 3-{1-[4-(3-morpholin-4-yl-3-oxopropyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol
[00086] 3-{1-[4-(3-oxo-3-pyrrolidin-1-ylpropyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole
[00087] 3-(1-{4-[3-(4-methylpiperazin-1-yl)-3-oxopropyl]phenyl}-1H-1,2,3-triazol-4-yl)-1H-indazole
[00088] 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-2-methoxy-N,N-dimethylbenzamide
[00089] 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}pyrrolidin-3-ol
[00090] 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}-N,N-dimethylpyrrolidin-3-amine
[00091] (1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}piperidin-4-yl)methanol
[00092] 1-(1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}piperidin-3-yl)-N,N -dimethylmethanamine
[00093] 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}piperidin-3-ol
[00094] 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-N-(1-methyl-2-oxopyrrolidin-3-yl)benzamide
[00095] 3-{1-[3-Methoxy-4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole
[00096] 3-(1-{4-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]phenyl}-1H-1,2,3-triazol-4-yl)-1H-indazole
[00097] 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}piperidin-4-ol
[00098] 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}-N,N-dimethylpiperidin-4-amine
[00099] 3-[1-(4-{[3-(pyrrolidin-1-ylcarbonyl)piperidin-1-yl]carbonyl}phenyl)-1H-1,2,3-triazol-4-yl]-1H- indazole
[000100] 3-[1-(4-{[3-(morpholin-4-ylmethyl)piperidin-1-yl]carbonyl}phenyl)-1H-1,2,3-triazol-4-yl]-1H- indazole
[000101] 1-[(1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}piperidin-3-yl)methyl]pyrrolidin -2-one
[000102] 2-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}-8-methyl-2,8-diazaspiro[5.5] undecane
[000103] 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-N-[(1-methylpiperidin-3-yl)methyl]benzamide
[000104] 3-{1-[3-(2-morpholin-4-yl-2-oxoethyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol
[000105] 3-(1-{3-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]phenyl}-1H-1,2,3-triazol-4-yl)-1H-indazole
[000106] 3-{1-[3-(2-oxo-2-pyrrolidin-1-ylethyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole
[000107] 3-{1-[3-(3-morpholin-4-yl-3-oxopropyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol
[000108] 3-{1-[3-(3-oxo-3-pyrrolidin-1-ylpropyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole
[000109] 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-N-[2-(1-methylpyrrolidin-2-yl)ethyl]benzamide
[000110] 1-(1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}piperidin-4-yl)-N,N -dimethylmethanamine
[000111] 2-(1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}piperidin-2-yl)-N,N -dimethylethanamine
[000112] (3R)-1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}piperidin-3-ol
[000113] (3S)-1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}piperidin-3-ol
[000114] 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-N-[1-(1-methylpiperidin-4-yl)-1H- pyrazol-4-yl]benzamide
[000115] ((2S)-1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}pyrrolidin-2-yl)methanol
[000116] (1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}piperidin-2-yl)methanol
[000117] N-cyclohexyl-N-(2-hydroxyethyl)-4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzamide
[000118] 3-[1-(4-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}phenyl)-1H-1,2,3-triazol-4-yl]-1H- indazole
[000119] 3-(1-{4-[(4-methoxypiperidin-1-yl)carbonyl]phenyl}-1H-1,2,3-triazol-4-yl)-1H-indazole
[000120] 6-Methyl-2-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5- yl)methyl]pyridazin-3(2H)-one
[000121] 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-N-[1-(2-morpholin-4-ylethyl)-1H- pyrazol-4-yl]benzamide
[000122] 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-N-[1-(1-methylpyrrolidin-3-yl)-1H- pyrazol-4-yl]benzamide
[000123] 3-[1-(4-{[3-(2-methoxyethyl)piperidin-1-yl]carbonyl}phenyl)-1H-1,2,3-triazol-4-yl]-1H-indazole
[000124] 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}azetidin-3-ol
[000125] 3-{1-[4-({3-[(2-methyl-1H-imidazol-1-yl)methyl]piperidin-1-yl}carbonyl)phenyl]-1H-1,2,3- triazol-4-yl}-1H-indazole
[000126] 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-N-(1-methylpiperidin-4-yl)benzamide
[000127] 2-(1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}piperidin-2-yl)ethanol
[000128] 3-[1-(4-{[3-(methoxymethyl)piperidin-1-yl]carbonyl}phenyl)-1H-1,2,3-triazol-4-yl]-1H-indazole
[000129] N-(2-hydroxybutyl)-4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzamide
[000130] 3-(1-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}-1H-1,2,3-triazol-4-yl)-1H-indazole
[000131] 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-N-[1-(8-methyl-8-azabicyclo[3.2.1] ]oct-3-yl)-1H-pyrazol-4-yl]benzamide
[000132] 3-[1-(4-{[3-(1H-imidazol-1-ylmethyl)piperidin-1-yl]carbonyl}phenyl)-1H-1,2,3-triazol-4-yl]- 1H-indazole
[000133] 3-(1-{4-[(3-methoxypiperidin-1-yl)carbonyl]phenyl}-1H-1,2,3-triazol-4-yl)-1H-indazole
[000134] is more particularly described in the examples.
[000135] Compounds of General Formula (I') wherein E denotes -(CH2)q, R3 is NRaRb, and R1, R2, R4, Q, q, Ra, Rb, n are as defined above and PG1 is H or a nitrogen protecting group such as, but not limited to tert-butyloxycarbonyl, acetyl, tetrahydropyran, PMB may be prepared by reductive amination between an aldehyde compound of general Formula (XI) wherein R1, R2, R4, Q, q, m and PG1 are as defined above and an amine of general Formula (X) wherein Ra and Rb are as defined above as outlined in Scheme 10. General protocols of such a reaction are given below in the Examples, using conditions and methods well known to those versed in the technique. Standard reducing agents such as sodium triacetoxyborohydride or sodium cyanoborohydride can be used in suitable solvents such as DCM, 1,2-dichloroethane at temperature rising from RT to 70°C for a few hours, such as one hour to 24 hours. Scheme 10

[000136] The method for preparing amine derivatives of Formula (I') selected below:
[000137] 5-Methyl-3-{1-[4-(pyrrolidin-1-ylmethyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole
[000138] 5-Methyl-3-{1-[4-(morpholin-4-ylmethyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole
[000139] N-methyl-1-{4-[4-(5-methyl-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}methanamine
[000140] 5-Methyl-3-(1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-1H-1,2,3-triazol-4-yl)-1H-indazole
[000141] N,N-Dimethyl-1-{4-[4-(5-methyl-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}methanamine
[000142] 5-Methyl-3-{1-[4-(piperazin-1-ylmethyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol
[000143] is more particularly described in the examples.
[000144] Amide compounds of General Formula (I') wherein E denotes -(CH2)mCO-, and R1, R2, R3, R4, m, n are as defined above and PGi is H or a nitrogen protecting group such as, but not limited to tert-butyloxycarbonyl, acetyl, tetrahydropyran, PMB can be prepared by coupling an amine compound of general Formula (XIII) wherein R 1 , R 2 , R 4 , Q, m, n and PG 1 are as defined above and an acid of general Formula (XII) wherein R3 is as defined above as outlined in Scheme 11. General protocols of such a reaction are given below in the Examples, using conditions and methods well known to those skilled in the art. Standard coupling agents such as TBTU, COMU, EDC or isobutyl chloroformate can be used in the presence or absence of a base such as DIEA, TEA or NMM in a suitable solvent such as DMF, Acetonitrile or THF or DCM at temperature rising from about 0°C to 50°C, preferably at 0°C for a time of 30 minutes to a few hours. Alternatively, a carboxylic acid derivative (such as acyl chloride, R3COCl) can be coupled with the amine (XIII), using conditions and methods well known to those skilled in the art, in the presence of a base such as pyridine or DIEA in a suitable solvent such as toluene, DCM, THF or DMF, at temperature rising from about 0°C to RT, preferably RT, for a few hours.Scheme 11

[000145] The method for preparing amide derivatives of Formula (I') selected below:
[000146] N-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzyl}cyclopentane carboxamide
[000147] N-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzyl}acetamide
[000148] N-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzyl}isonicotinamide
[000149] N-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzyl}-2-morpholin-4-ylacetamide
[000150] N-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzyl}tetrahydro-2H-pyran-4-carboxamide is more particularly described in the examples.
[000151] Pyridazinone compounds of General Formula (Ifb) wherein Q, E, R2, R3 are as defined above, PG1 is is H or a nitrogen protecting group such as, but not limited to tert-butyloxycarbonyl, acetyl, tetra -hydropyran, PMB and Rd is H, C1-C6-alkyl, Ar1, or Het1 can be prepared following the synthetic route outlined in Scheme 12. A preferred synthetic route involves the reaction of an alcohol compound of general Formula (If') wherein R1 denotes CH2OH and Q, E, R2, R3, PG1 are as defined above with a pyridazinone compound of General Formula (XIV) wherein Rd is as defined above under Mitsunobu reaction conditions. General protocols of such a reaction are given below in the Examples, using conditions and methods well known to those skilled in the art. This reaction is preferably carried out in a solvent such as DCM, THF, DMF at a temperature rising from 0°C to 50°C, preferably at RT in the presence of a phosphine, such as, but not limited to triphenylphosphine, and an azadicarboxylate. , such as, but not limited to, diisopropylazadicarboxylate. A second synthetic pathway involves the reaction of compound of general Formula (If') wherein R1 denotes CH2Hal, preferably CH2Br, and Q, E, R2, R3 and PG1 are as defined above or (If') wherein R1 denotes CH2LG3 and Q, E, R2, R3, PG1 are as defined above and LG3 is a leaving group such as Cl, Br, I, or a sulfonate ester such as mesylate with a pyridazinone (XIV) wherein Rd is as defined above. General protocols of such a reaction are given below in the Examples, using conditions and methods well known to those skilled in the art. This reaction is preferably conducted in the presence of a base such as but not limited to NaH, tert-BuOK, NaOEt, K2CO3, Cs2CO3 in a solvent such as THF, ACN, DMF, EtOH at temperature rising from RT to 80°C. Intermediate of general formula (If') wherein R1 denotes CH2Br can be obtained by bromination of a methyl compound of general formula (If') wherein R1 is CH3 and wherein Q, E, R2, R3, PG1 are as defined above, using conditions and methods well known to those skilled in the art, in the presence of a suitable bromine source such as NBS or Br2, a radical initiator such as AIBN, benzoylperoxide, or light in a suitable solvent such as CCl4, HCl3 , ACN at temperature rising from about RT to 120°C for a few hours. A preferred condition for this transformation is described in Synlett, (2005), 18, 2837-2842 and uses NBS in the presence of ZrCl4 in DCM. Intermediate of General Formula (If') wherein R1 is CH2LG3 can be obtained by sulfonylation or halogenation using conditions and methods well known to those skilled in the art. Standard conditions for the sulfonylation use appropriate sulfonyl chloride in the presence of a base such as TEA, DIEA or pyridine in a solvent such as DCM or THF at a temperature rising from 0°C to 50°C, preferably at RT. Standard condition for halogenation uses SOCl2, POCl3, PCl5 in a solvent such as DCM at a temperature rising from 0°C to 60°C, preferably at RT for a few hours.Scheme 12

[000152] The above-mentioned method is also suitable for the preparation of compounds of Formula (I) and related Formulas in which R1 is attached to another position of the imidazole ring, for example 4, 6 or 7-positions.
[000153] The method for preparing amide derivatives of Formula (Ifb) selected below:
[000154] 6-(3,5-Difluorophenyl)-2-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}- 1H-indazol-5-yl)methyl]pyridazin-3(2H)-one
[000155] 2-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-yl)methyl] pyridazin-3(2H)-one
[000156] 2-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-yl)methyl] -6-pyridin-4-ylpyridazin-3(2H)-one
[000157] 6-Methyl-2-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5- yl)methyl]pyridazin-3(2H)-one
[000158] is more particularly described in the examples.
[000159] Indazoles of Formula (If')) wherein R1 is an Ar1, Het1, C2-C6-alkenyl, C2-C6-alkynyl, or Cyc and PG1 is as defined above can be prepared by Suzuki- Miyura between an indazole of Formula (If'), wherein LG1 is Cl, Br, I or a sulfonate ester such as triflate, and a boronic acid or ester of Formula (XV) wherein R1 is as defined above and R is H or an alkyl group (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; Takahiro I. and Toshiaki M., Tetrahedron Lett. 2005, 46, 3573-3577) as outlined in scheme 13. General protocols for such coupling are given below in the Examples, using conditions and methods well known to those skilled in the art to carry out such coupling. In a typical procedure, indazole (If') where R1 is LG1 and boronic acid or ester (XV) are heated in a suitable solvent, such as THF, toluene or dioxane, in the presence or absence of water as a co-solvent, in the presence of a base, such as Cs2CO3, K2CO3, CsF, and with an appropriate catalyst such as but not limited to dichlorobis(triphenylphosphine)palladium(II), Pd(PPh3)4 or 1,1'-bis(diphenylphosphine) )ferrocenedichloro palladium(II), Pd(OAc)2, Pd2(dba)3, Pd(Cl)2(PPh3)2 or Pd/C in the presence or absence of an additional ligand, such as but not limited to P(tBu )3, P(oTol)3, PPh3, BINAP. This coupling reaction can be carried out at a temperature between about 20°C to about 150°C, preferably at about 120°C, for a few minutes to a few hours, possibly under microwave irradiation. 13

[000160] Conditions described above are applicable to a reaction of Scheme 13a where R1, PG1, R2, Q, E, R3 are as defined above. Scheme 13a

[000161] The above-mentioned method is also suitable for the preparation of compounds of Formula (I) and related Formulas in which R1 is attached to another position of the imidazole ring, for example positions 4, 6 or 7.
[000162] The method for preparing amide derivatives of Formula (If') selected below:
[000163] 5-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2 ,3-triazol-4-yl}-1H-indazole
[000164] 5-(1-Methyl-1H-pyrazol-4-yl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl }-1H-indazole
[000165] 5-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2 ,3-triazol-4-yl}-1H-indazole
[000166] is more particularly described in the examples.
[000167] Indazoles of Formula (Ifc) wherein Q, E, R2, R3 and PG1 are as defined above and Rc is H, C1-C6-alkyl, -CONRaRb, SO2NRaRb can be prepared by reacting a compound of general Formula (XVII) wherein Q, E, R2, R3 and PG1 are as defined above with a compound of general Formula (XVI) wherein Rc is as described above and LG3 is a leaving group such as Cl, Br, I, or a sulfonate ester such as a mesylate as outlined in Scheme 14. General protocols of such a reaction are given below in the Examples, using conditions and methods well known to those skilled in the art. This reaction is preferably carried out in a solvent such as DCM, THF, DMF, ACN in the presence of a base such as K2CO3, NaHCO3, Cs2CO3 in the presence or absence of KI or NaI at the temperature rising from 0°C to 100°C, possibly under microwave irradiation.Scheme 14

[000168] The above-mentioned method is also suitable for the preparation of compounds of Formula (I) and related Formulas in which R1 is attached to another position of the imidazole ring, for example positions 4, 6 or 7.
[000169] The method for preparing Indazole derivatives of Formula (Ifc) selected below:
[000170] 5-[1-(2-fluoroethyl)piperidin-4-yl]-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4- yl}-1H-indazole
[000171] 5-(1-Acetylpiperidin-4-yl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H- indazole
[000172] According to a further general process, compounds of Formula I can be converted to alternative compounds of Formula I, employing suitable interconversion techniques as described hereinafter in the Examples.
[000173] If the above presented general synthetic methods are not applicable to obtain compounds according to Formula I and/or intermediates necessary for the synthesis of compounds of Formula I, suitable methods of preparation known to one skilled in the art should be used. In general, the synthetic pathways for any individual compound of Formula I will depend on the specific substituents on each molecule and upon availability of read-through of the necessary intermediates; again such factors being appreciated by those versed in the common technique. For all methods of protection, deprotection, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter GM Wuts in "Protective Groups in Organic Synthesis", Wiley -Interscience, 1991.
[000174] The group QE-R3 in Formula (I) and related Formulas (Ia), (Ib), (Ic), (Id), (Ie) and (If) preferably denote one of the following















[000175] The group R1 in Formula (I) and related Formulas (Ia), (Ib), (Ic), (Id), (Ie) and (If) preferably denote H, Halogen such as F, Cl or Br, Methyl , trifluoromethyl, methoxy, hydroxy or one of the following groups:



[000176] In a preferred embodiment, the present invention provides compounds of Formula (I) and related Formulas wherein the group QE-R3 is selected from


[000177] And wherein the R1 group is selected from H, OH, -CH3,F, Cl, or one of the following groups:

[000178] Preferred compounds of the present invention are selected from the following group:













































[000179] Compounds of this invention can be isolated in association with solvent molecules by crystallization from an appropriate solvent or by evaporation of an appropriate solvent.
[000180] Pharmaceutically acceptable anionic salts of compounds of Formula (I), which contain a basic center, can be prepared in a conventional manner. For example, a solution of the free base can be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt is isolated either by filtration or by vacuum evaporation of the reaction solvent.
[000181] Pharmaceutically acceptable cationic salts of compounds of Formula (I), which contain an acidic center, can be prepared in a conventional manner. For example, a solution of the free acid can be treated with a suitable base, either neat or in a suitable solution, and the resulting salt is isolated either by filtration or by vacuum evaporation of the reaction solvent. In some cases, salts can be prepared by mixing a solution of the acid with a solution of an alkaline or alkaline salt (such as sodium ethylhexanoate, magnesium oleate), employing a solvent in which the alkaline or alkaline earth salt is used. of the compounds of Formula (I) precipitate, or may otherwise be isolated by concentration and addition of a non-solvent.
[000182] Both types of salts can be formed or interconverted using ion exchange resin techniques.
[000183] Depending on the conditions used, reaction times are generally between a few minutes and 14 days. The reaction temperature is between about -30°C and about 140°C, normally between -10°C and 90°C, in particular between about 0°C and 70°C.
[000184] Compounds of Formula (I) and related Formulas, furthermore, can be obtained by releasing compounds of Formula (I) from one of their functional derivatives by treatment with a sovolysis agent or hydrogenolysis.
[000185] Preferred starting materials for solvolysis or hydrogenolysis are those which correspond to Formula I and related Formulas, but which contain corresponding protected amino and/or hydroxyl groups, rather than one or more amino groups and and/or free hydroxyl groups, preferably those bearing an amino protecting group instead of an H atom attached to an N atom, in particular those bearing an R*-N group, where R* represents an amino protecting group , instead of an HN group, and/or those that have a hydroxyl protecting group instead of the H atom of a hydroxyl protecting group, e.g. those that correspond to Formula I but which carry a -COOR** group, where R** denotes a hydroxyl protecting group, rather than a -COOH group.
[000186] It is also possible for a plurality of - the same or different - protected amino and/or hydroxyl groups to be present in the starting material molecule. If the protecting groups present are different from each other, they can in many cases be selectively cleaved.
[000187] The term "amino protecting group" is known in general terms, and refers to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easily removed after the desired chemical reaction has been carried out. performed elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted acyl, aryl or substituted aralkoxymethyl or aralkyl groups. Since amino protecting groups are removed after the desired reaction (or sequence of reactions), their type and size are furthermore not essential, however preference is given to those having 1-20, in particular 1-8, carbon atoms. The term "acyl group" is to be understood in the broadest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and above all aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl and FMOC; sulfonyl and aryl, such as Mtr. Preferred amino protecting groups are BOC and Mtr, even more CBZ, Fmoc, benzyl and acetyl.
[000188] The term "hydroxyl protecting group" is also known in general terms, and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easily removed after the desired chemical reaction has been carried out in others. molecule sites. Typical of such groups are those mentioned above, in addition also unsubstituted alkyl or substituted aryl groups, aralkyl or acyl groups. The nature and size of the hydroxyl protecting groups is not crucial as they are removed again after the desired chemical reaction or reaction sequence, preference is given to groups with 1-20, in particular 1-10 carbon atoms. Examples of hydroxyl protecting groups are, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butyl are particularly preferred.
[000189] Compounds of Formula I and related Formulas are released from their functional derivatives - depending on the protecting group used - for example strong inorganic acids such as hydrochloric acid, perchloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, TFA or sulfonic acids, such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, in addition, also alcohols, such as methanol, ethanol or isopropanol, and water. Mixtures of the above-mentioned solvents are additionally suitable. TFA is preferably used in excess without adding an additional solvent, and perchloric acid is preferably used as a mixture of acetic acid and 70% perchloric acid in a 9:1 ratio. The reaction temperatures for cleavage are advantageously between about 0 and about 50°C, preferably between 15 and 30°C (room temperature).
[000190] The BOC, OtBut and Mtr groups can, for example, preferably be cleaved using TFA in dichloromethane or with about 3 to 5 N HCl in dioxane at 15-30°C and the Fmoc group it can be cleaved using a solution of about 5 to 50% dimethylamine, diethylamine or piperidine in DMF at 15-30°C.
[000191] Protecting groups that can be removed by hydrogenolysis (e.g. CBZ, benzyl or the release of the amidino group from the oxadiazole derivative thereof) can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble metal catalyst such as palladium, advantageously on a support such as carbon). Suitable solvents are those indicated hereinabove, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is generally carried out at temperatures between about 0 and 100°C and pressures between about 1 and 200 bar, preferably at 2030°C and 1-10 bar. A hydrogenolysis of the CBZ group succeeds, for example, on 5 to 10% Pd/C in methanol or with ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°C.
[000192] Examples of suitable inert solvents are hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene, chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, trifluoromethylbenzene, chloroform or dichloromethane, alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane, glycol ethers such as monomethyl or monoethyl ethylene glycol ether or ethylene glycol dimethyl ether (diglyme), ketones such as acetone or butanone, amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethyl formamide (DMF), nitriles such as acetonitrile; sulfoxides such as dimethylsulfoxide (DMSO), carbon disulfide; carboxylic acids such as formic acid or acetic acid, nitro compounds such as nitromethane or nitrobenzene, esters such as ethyl acetate, or mixtures of said solvents.
[000193] Esters can be hydrolyzed, for example, using HCl, H2SO4, or using LiOH, NaOH or KOH in water, water / THF, water / THF / ethanol or water / dioxane, at temperatures between 0 and 100°C.
[000194] Free amino groups may further be acylated in a conventional manner, using an acyl chloride or anhydride or alkylated using an unsubstituted alkyl group or substituted halide, advantageously in an inert solvent such as dichloromethane or THF and/or in the presence of a base, such as triethylamine or pyridine, at temperatures between -60°C and 30°C.
[000195] Formula (I) and related Formulas also cover optically active forms (stereoisomers), enantiomers, racemates, diastereomers and their hydrates and solvates of these compounds. The term "solvates of compounds" is taken to mean adduction of inert solvent molecules to the compounds that form due to their mutual attractive force. Solvates are, for example, mono- or dihydrates or alcoholates.
[000196] The term "pharmaceutically usable derivatives" is taken to mean, for example, the salts of compounds of Formula I and so-called prodrug compounds.
[000197] The term "prodrug derivatives" is used to mean compounds of Formula I which have been modified with, for example, alkyl or acyl groups, sugars or oligopeptides, and which are rapidly cleaved in the body to form the active compounds. Preferably, "prodrug", as one of the compounds of Formula I, refers to derivative compounds that are rapidly transformed in vivo to give the parent compound of Formula I, such as, for example, by hydrolysis in blood. T. Higuchi and V. Stella provide an in-depth discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975). Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited by E.B. Roche, Pergamon Press: New York (1987). These references, and any others cited throughout this specification, are intended to be incorporated herein by reference.
[000198] These also include biodegradable polymeric derivatives of the compounds according to the invention, as described, for example, in Int. J. Pharm. 115, 61-67 (1995).
[000199] Formula (I) and related Formulas also encompass mixtures of the compounds of Formula I, e.g. mixtures of two diastereomers, e.g. in a ratio of 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.
[000200] These are particularly preferably mixtures of stereoisomeric compounds.
[000201] Pharmaceutical formulations may be administered in the form of dosage units, which comprise a predetermined amount of active ingredient per dosage unit. Such a unit may comprise, for example, 0.5mg to 1g, preferably 1mg to 700mg, especially preferably 5mg to 100mg, of a compound according to the invention, depending on the disease condition. treatment, the method of administration and the age, weight and condition of the patient, or in pharmaceutical formulations may be administered in the form of dosage units comprising a predetermined amount of active ingredient per dosage unit. Preferred unit dosage formulations are those comprising a daily dose or part of a dose, as indicated above, or a corresponding fraction of an active ingredient. Furthermore, pharmaceutical formulations of this type can be prepared using a process, which is generally known in the pharmaceutical art.
[000202] Pharmaceutical formulations may be adapted for administration by any suitable method desired, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral methods ( including subcutaneous, intramuscular, intravenous or intradermal). Such formulations may be prepared using processes known in the pharmaceutical field, for example by combining the active ingredient with the excipient(s) or with the adjuvant(s).
[000203] Pharmaceutical formulations adapted for oral administration may be administered as separate units, such as, for example, capsules or tablets, powders or granules, solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods, or liquid water-in-oil or liquid water-in-oil emulsions.
[000204] Thus, for example, in the case of oral administration in the form of a tablet or capsule, the active ingredient component may be combined with an oral, non-toxic, pharmaceutically acceptable inert excipient such as, for example, , ethanol, glycerol, water and the like. Powders are prepared by grinding the compound to a suitable fine size and mixing it with a similarly ground pharmaceutical excipient such as, for example, an edible carbohydrate, such as, for example, starch or mannitol. A flavoring, preservative, dispersant and coloring agent may also be present.
[000205] Capsules are produced by preparing a powder mixture as described above and filling in the form of gelatine shells. Glidants and lubricants, such as, for example, highly dispersed silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, may be added to the powder mixture prior to the filling operation. A disintegrant or solubilizer, such as, for example, agar, calcium carbonate or sodium carbonate, may also be added in order to improve the availability of the drug after the capsule has been made.
[000206] Furthermore, if desired or necessary, suitable binders, lubricants and disintegrators as well as coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as, for example, glucose or beta-lactose, corn sweeteners, natural and synthetic rubber, such as, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a mixture of powders, granulating or dry pressing the mixture, adding a lubricant and a disintegrant, and pressing the mixture into tablets. A powder mixture is prepared by mixing the sprayed compound in a suitable manner with a diluent or a base as described above, and optionally with a binder, such as, for example, carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a dissolution retardant such as, for example, paraffin, an absorption accelerator, such as, for example, a quaternary salt, and/or an absorptive, such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymeric materials and pressing it through a sieve. As an alternative to granulation, powder mixing can be performed by means of a compression machine, giving non-uniformly shaped pieces, which are divided into shaped granules. The granules can be lubricated by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to tablet molding forms. The lubricated mixture is then compressed into tablets. The active ingredients can also be combined with a free-flowing inert excipient and then pressed to directly tablet without performing granulation or dry pressing steps. A clear or opaque protective layer consisting of a sealing layer of shellac, a layer of sugar or polymeric material and a gloss layer of wax may be present. Dyes can be added to these coatings in order to be able to distinguish between different dosage units.
[000207] Oral liquids, such as, for example, solutions, syrups and elixirs, can be prepared in unit dosage form so that a given amount comprises a predetermined amount of the compounds. Syrups can be prepared by dissolving the compounds in an aqueous solution with a suitable flavor, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions may be formulated by dispersing the compounds in a non-toxic vehicle. Solubilizers and emulsifiers, such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives, such as, for example, peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like, can also be added.
[000208] Dosage unit formulations for oral administration may, if desired, be encapsulated in microcapsules. The formulation may also be prepared in such a way that release is prolonged or delayed, such as, for example, by coating or embedding the particulate material in polymers, waxes and the like.
[000209] The compounds of Formula (I) and related Formulas, and their salts, solvates and physiologically functional derivatives thereof and the other active ingredients may also be administered in the form of liposome delivery systems such as, for example, small vesicles unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as, for example, cholesterol, stearylamine or phosphatidylcholines.
[000210] The compounds of Formula (I) and related Formulas and their salts, solvates and physiologically functional derivatives thereof and the other active ingredients may also be delivered using monoclonal antibodies as individual vehicles to which the molecules of the compound are coupled. The compounds can also be coupled to soluble polymers as target drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine substituted with palmitoyl radicals. The compounds may further be coupled to a class of biodegradable polymers which are suitable for carrying out the controlled release of a drug, for example polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals , polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
[000211] Pharmaceutical formulations adapted for transdermal administration can be administered as self-contained patches for prolonged close contact with the epidermis of the recipient. Thus, for example, the active ingredient can be delivered from the patch by iontophoresis, as described in general terms in Pharmaceutical Research, 3 (6), 318 (1986).
[000212] Pharmaceutical compounds adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
[000213] For the treatment of the eye or other external tissues, eg mouth and skin, the formulations are preferably applied as a topical ointment or cream. In the case of an ointment formulation, the active ingredient may be employed with either a paraffinic or a water-miscible cream base. Alternatively, the active ingredient may be formulated into a cream with an oil-in-water cream base or a water-in-oil base.
[000214] Pharmaceutical formulations adapted for topical application to the eye include eye drops, where the active ingredient is dissolved or suspended in a suitable vehicle, especially in an aqueous solvent.
[000215] Pharmaceutical formulations adapted for topical application in the mouth include troches, lozenges and mouthwashes.
[000216] Pharmaceutical formulations adapted for rectal administration may be administered in the form of suppositories or enemas.
[000217] Pharmaceutical formulations adapted for nasal administration in which the carrier substance is a solid include a coarse powder having a particle size, for example, in the range of 20,500 microns, which is administered as it is made, i.e. by rapid inhalation through the nasal passages from a container containing the powder held close to the nose. Formulations suitable for administration as a nasal spray or nasal drops with a liquid carrier substance include solutions of the active ingredient in water or oil.
[000218] Pharmaceutical formulations adapted for administration by inhalation encompass finely particulate dusts or mists that can be generated by various types of pressurized aerosol dispensers, nebulizers or insufflators.
[000219] Pharmaceutical formulations adapted for vaginal administration may be administered in the form of pessaries, tampons, creams, gels, pastes, foams or spray formulations.
[000220] Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions comprising antioxidants, buffers, bacteriostatics and solutes, whereby the formulation is made isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may include suspending media and thickeners. The formulations may be administered in single-dose or multi-dose containers, e.g., sealed ampoules and vials, and stored in a freeze-dried (lyophilized) state, so that only the addition of the sterile liquid vehicle, e.g., water for injection immediately before use is required.
[000221] Injection solutions and suspensions prepared according to the recipe can be prepared from sterile powders, granules and tablets.
[000222] This goes without saying that, in addition to the components particularly mentioned above, the formulations may also contain other agents customary in the art with respect to the particular type of formulation, thus, for example, formulations which are suitable for oral administration may include flavors .
[000223] A therapeutically effective amount of a compound of Formula (I) and related Formulas and the other active ingredient depends on a number of factors, including, for example, the age and weight of the animal, the disease condition that requires precise treatment, and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the attending physician or veterinarian. However, an effective amount of a compound is generally in the range of 0.1 to 100 mg/kg body weight of the recipient (mammal) per day, and particularly typically in the range 1 to 10 mg/kg body weight. body per day. Thus, the actual amount per day for a 70 kg adult mammal is generally between 70 and 700 mg, where this amount may be administered as a single dose per day or generally in a series of codoses (such as, for example, two, three, four, five or six) per day, so the total daily dose is the same. An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as the fraction of the effective amount of the compound per se.
[000224] The present invention further relates to a method for treating a subject suffering from an IRAK-related disorder, comprising administering to said subject an effective amount of a compound of Formula I and related Formulas. The present invention preferably relates to a method, wherein the IRAK-associated disorder is an autoimmune disorder or condition associated with a hyperactive immune response or cancer. The present invention further relates to a method of treating a subject suffering from an immunoregulatory abnormality, comprising administering to said subject a compound of Formula (I) and related Formulas, in an amount that is effective to treat the condition. said immunoregulatory abnormality. The present invention preferably relates to a method wherein the immunoregulatory abnormality is a chronic autoimmune inflammatory disease or selected from the group consisting of: allergic diseases, amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus, chronic rheumatoid arthritis, diabetes mellitus type I, inflammatory bowel disease, cirrhosis of the bile ducts, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmopathy, and asthma . The present invention further relates to a method wherein the immunoregulatory abnormality is bone marrow or organ transplant rejection or graft-versus-host disease. The present invention further relates to a method wherein the immunoregulatory abnormality is selected from the group consisting of: organ or tissue transplantation, graft-versus-host diseases caused by transplantation, autoimmune syndromes including rheumatoid arthritis , systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin disorders, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, corneal epithelial dystrophy, corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergies, respiratory tract disease reversible obstructive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or inveterate asthma, late asthma and airway hyperresponsiveness, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture syndrome , hemolytic-uremic syndrome, diabetic nephropathy, myositis multiplex, Guillain-Barre syndrome, Ménière's disease, polyneuritis, multiple neuritis type, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red blood cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, aneritroplasia, osteoporosis, sarcoidosis, lung fibroid, idiopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarthritis nodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren's disease, adiposis, eosinophilic fasciitis, gingival lesions, periodontium, alveolar bone, substantia ossea dentis, glomerulonephritis, male pattern alopecia or senile alopecia preventing hair removal or providing hair germination and/or promoting hair production and hair growth, muscular dystrophy, pyoderma and Sezary syndrome, Addison's disease, ischemia-reperfusion damage from organ injury, which occurs after preservation, transplantation, or ischemic disease, endotoxin shock, pseudomembranous colitis, acute renal failure, ischemic colitis caused by drugs or radiation, chronic renal failure, lung toxinosis caused by oxygen or drugs lung, lung cancer, pulmonary emphysema, cataract, siderosis, retinitis pigmentosa, senile macular degeneration, vitreous scarring, chemical corneal burn, dermatitis erythema multiforme, linear dermatitis IgA Ballous and cementum dermatitis, gingivitis, periodontitis , sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, carcinoma metastasis and hypobaropathy, disease caused by histamine or leukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial liver resection , acute liver necrosis, necrosis caused by toxins, viral hepatitis, shock or anoxia, hepatitis B, non-A/non-B hepatitis, cirrhosis, alcoholic cirrhosis, liver failure, fulminant liver failure, late-onset liver failure, "acute over chronic" liver failure, increased chemotherapeutic effect, cytomegalovirus infection, by HCMV, AIDS, cancer, senile dementia, Parkinson's disease, trauma and chronic bacterial infection.
[000225] Preferably, disorders associated with IRAK are selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type I diabetes, type II diabetes, inflammatory disease Intestinal disease (Cronh's disease and ulcerative colitis), Hyperimmunoglobulinemia D and periodic fever syndrome, Cryopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, Still and Adult-onset disease, Gout, Pseudogout, SAPHO syndrome, of Castleman, Sepsis, Stroke, atherosclerosis, celiac disease, DIRA (IL-1 receptor antagonist deficiency), Alzheimer's disease, Parkinson's disease, cancer.
[000226] Preferred compounds of Formula (I) and related Formulas have an IC50 for binding to IRAK of less than about 5 µM, preferably less than about 1 µM, and even more preferably less than about 0.100 μM
[000227] Compounds according to Formula to Formula (I) and related Formulas can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that when typical or preferred experimental conditions (i.e., reaction temperatures, time, moles of reagents, solvents, etc.) are given, other experimental conditions may also be used, unless otherwise indicated. Optimal reaction conditions may vary with the particular reagents or solvents used, but such conditions can be determined by those skilled in the art using routine optimization procedures.
[000228] In general, the routes of synthesis for any individual compound of Formula (I) and related Formulas will depend on the particular substituents of each molecule and the ready availability of necessary intermediates; again such factors being appreciated by those skilled in the art.
[000229] The compounds of the present invention can be isolated in association with solvent molecules by crystallization from evaporation of an appropriate solvent. Pharmaceutically acceptable acid addition salts of compounds of Formula (I) and related Formulas which contain a basic center can be prepared in a conventional manner. For example, a solution of the free base can be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt is isolated either by filtration or by vacuum evaporation of the reaction solvent. Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of the compound of Formula (I) and related Formulas, which contain an acidic center, with a suitable base. Both types of salts can be formed or interconverted using ion exchange resin techniques.
[000230] If the above set of general methods of synthesis is not applicable to obtain compounds according to Formula (I) and/or intermediate products necessary for the synthesis of compounds of Formula (I), suitable methods of preparation are known by one skilled in the art should be used. In general, the routes of synthesis for any individual compound of Formula (I) will depend on the particular substituents of each molecule and the ready availability of necessary intermediates; again such factors being appreciated by those versed in the art. For all protection and deprotection methods, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter GM Wuts in "Protective Groups in Organic Synthesis”, Wiley Interscience, 3rd Edition 1999.
[000231] In what follows, the present invention shall be illustrated by means of some examples, which are not interpreted to be seen as limiting the scope of the invention. General:
[000232] The HPLC data provided in the examples described below were obtained as follows.
[000233] Condition A: Waters XbridgeTM C8 Column 50 mm x 4.6 mm at a flow rate of 2 mL/min; 8 min gradient H2O:CH3CN:TFA from 100:0:0.1% to 0:100:0.05%.
[000234] Condition B: Waters XbridgeTM C8 Column 50 mm x 4.6 mm at a flow rate of 2 mL/min; 8 min H2O:CH3CN gradient from 100:0 to 0:100.
[000235] UV detection (maxplot) for all conditions.
[000236] The MS data provided in the examples described below were obtained as follows: Mass spectr: LC/MS Waters ZMD (ESI).
[000237] The NMR data provided in the examples provided below were obtained as follows: 1H-NMR: Bruker DPX-300MHz or Bruker AV-400MHz.
[000238] Preparative HPLC purifications were performed with a Waters mass directed auto-purification Fractionlynx equipped with a 19x100 mm 5 μm Sunfire Prep C18 OBD column, unless otherwise noted. All HPLC purifications were performed with a gradient of ACN/H2O or ACN/H2O/HCOOH (0.1%).
[000239] Microwave chemistry was performed in a Biotage EmrysTM Optimiser or InitiatorTM Sixty single-mode microwave reactor.
[000240] The compounds of the invention were named according to the standards used in the "ACD / Name Batch" program of Advanced Chemistry Development Inc., ACD / Labs (Version 7.00). Product version: 7.10, build: September 15, 2003.
[000241] Compounds according to Formula (I) can be prepared from readily available starting materials by various methods of synthesis, using solid phase and solution phase chemical protocols or solid phase protocols or of mixed solution. Examples of synthetic pathways are described below in the examples. Unless otherwise indicated, compounds of Formula (I) and related Formulas obtained as a racemic mixture may be separated to provide an enantiomerically enriched mixture, or a pure enantiomer.
[000242] Commercially available starting materials used in the following experimental description were purchased from Aldrich or Sigma or ABCR unless otherwise noted. SPE cartridges were purchased from IST and used the following supplier recommendations. Intermediate 1: 3-ethynyl-1H-indazolStep a) Formation of tert-butyl 3-[(trimethylsilyl)ethynyl]-1H-indazole-1-carboxylate

[000243] A mixture of tert-butyl 3-iodo-1H-indazole-1-carboxylate (prepared as described in J.Med.Chem. (2008), 51(12), 3460-3465); (34 g; 99 mmol; 1.00 eq.), (trimethylsilyl)acetylene (16.6 mL; 119 mmol; 1.20 eq.), PdCl2(PPh3)2 (2.77 g; 3.95 mmol; 0.04 eq.) and TEA (41 mL) was heated overnight at 50°C. A reaction mixture was then diluted with DCM and washed three times with a saturated aqueous solution of NH4Cl. Organic layer was dried over magnesium sulfate, filtered and concentrated. This crude was solubilized in DCM and the precipitate obtained was filtered off through a pad of celite. Purification by flash chromatography on silica (Heptane/EtOAc; gradient from 98:2 to 2:98) provided the title compound as a beige solid (20 g, 69% yield). 1H NMR (300 MHz, DMSO-d6) δ: 8.12 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.70 (m,1H), 7.46 (m,1H), 1.65 (s, 9H), 0.32 (s, 9H). Step b) Formation of 3-ethynyl-1H-indazole

[000244] Potassium carbonate (880 mg, 6.4 mmol, 0.1 eq.) was added to a solution of tert-butyl 3-[(trimethylsilyl)ethynyl]-1H-indazole-1-carboxylate (20 g; 63.6 mmol ; 1.0 eq.) in EtOH (400 mL) and a reaction mixture was stirred overnight at RT. Solvent was removed under vacuum while maintaining bath temperature below 25°C. The residue was dissolved in Et2O, washed with water (twice) and brine (four times). Organic layer was dried over magnesium sulfate, filtered and concentrated to give the title compound as a brown solid (7.1 g, 80%). 1H NMR (300 MHz, DMSO-d6) δ: 13.44 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.59 (d; J = 8.5 Hz, 1H), 7.41 (m, 1H), 7.22 (m, 1H), 4.50 (s, 1H). Intermediate 2: 3-ethynyl-5-methyl-1H-indazolStep a) Formation of tert-butyl 3-iodo-5-methyl-1H-indazole-1-carboxylate

[000245] To a suspension of 3-iodo-5-methyl-1H-indazole (ChemBridge Corp.; 6.0 g; 23.3 mmol; 1.0 eq.) in acetonitrile (180 mL) was added DMAP (568 mg; 4.65 mmol). ; 0.20 eq.), di-tert-butyldicarbonate (6.1 g; 28 mmol; 1.2 eq.) and TEA (3.87 mL). A reaction mixture was stirred overnight at RT. Acetonitrile was removed under reduced pressure and the residue was dissolved in EtOAc. The resulting solution was washed with water and brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a brown solid (8.32 g; 99.9 %).1H NMR (300 MHz, DMSO-d6) δ: 7.95 (d, J = 8.7 Hz, 1H), 7.52 (dd, J =8.7, 1.4 Hz, 1H), 7.33-7.31 (1H, m), 2.47 (s, 3H), 1.64 (s, 9H). ) Formation of tert-butyl 5-methyl-3-[(trimethylsilyl)ethynyl]-1H-indazole-1-carboxylate

[000246] Tert-butyl 3-iodo-5-methyl-1H-indazole-1-carboxylate (8.3 g; 23.2 mmol; 1.0 eq.), (trimethylsilyl)acetylene (6.8 mL; 48.8 mmol; 2.1 eq.), Pd(OAc)2 (521 mg; 2.3 mmol; 0.1 eq.), triphenylphosphine (1.22 g; 4.65 mmol; 0.2 eq.) and copper iodide (442 mg; 2.32 mmol; 0.1 eq. .) in TEA (57 mL). A reaction mixture was degassed and stirred at 80°C under N2 for 1 hour. Et2O was added and the reaction mixture was filtered through a pad of celite. The filtrate was then washed twice with a saturated aqueous solution of NH4Cl and brine, dried over magnesium sulfate, filtered and concentrated. This crude was purified by flash chromatography on silica (Heptane/EtOAc, gradient from 100:0 to 10:90) to give the title compound as a beige solid. 1 H NMR (300 MHz, DMSO-d6) δ : 8.00 (d , J = 8.6 Hz, 1H), 7.56-7.55 (m, 1H), 7.50 (dd, J = 8.6 Hz, 1.5 Hz, 1H), 2.47 (s, 3H), 1.64 (s, 9H), 0.33-0.31 (m, 9H).Step c) Formation of 3-ethynyl-5-methyl-1H-indazole

[000247] The title compound was obtained, following procedure described for intermediate 1, step b), but starting from 5-methyl-3-[(trimethylsilyl)ethynyl]-1H-indazole-1-carboxylate (2.63 g; 8.01 mmol; 1.0 eq.) as a beige solid (1.25 g, 100% yield).1H NMR (300 MHz, DMSO-d6) δ 13.30 (brs, 1H), 7.49-7.46 (m, 2H), 7.25 ( dd, J = 8.7 Hz, 1.1 Hz, 1H), 4.46 (s, 1H), 2.42 (s, 3H). HPLC (Condition A): RT 3.07 min (96.4% purity). Intermediate 3 : 4-(4-azidobenzoyl)morpholine

[000248] TBTU (1.28 g; 3.98 mmol; 1.3 eq.) was added to a cold (0°C) solution of 4-azidobenzoic acid (500 mg; 3.06 mmol; 1.0 eq.) and DIEA (1.2 mL; 7.05 mmol ; 2.3 eq.) in DMF (10 mL). After 15 min, morpholine (324 μl; 3.68 mmol; 1.2 eq.) was added and the reaction mixture was stirred at RT for 3 hours. A reaction mixture was diluted with EtOAc and washed twice with a saturated aqueous solution of NaHCO3 then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give the title compound as a beige solid (710 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ 7.46 (d, J= 8.6 Hz , 2H), 7.18 (d, J=8.6 Hz, 2H), 3.59-3.47 (m, 8H). HPLC (Condition A): RT 2.21 min (98.2% purity). Intermediate 4: 1-(4-azidobenzoyl)-3-(pyrrolidin-1-ylmethyl)piperidine

[000249] The title compound was obtained, following procedure described for intermediate 3, but starting from 4-azidobenzoic acid (200 mg; 1.23 mmol; 1.0 eq.) and 3-pyrrolidin-1-ylmethyl-piperidine dihydrochloride ( Chemical Diversity Labs, 254 mg; 1.05 mmol; 0.86 eq.) as a beige oil (421 mg, 100 %).MS (ESI+): 314.2 (92% purity). 1H NMR (300 MHz, DMSO-d6) δ 7.51 -7.37 (m, 2H), 7.20-7.08 (m, 2H), 2.69 (s, 2H), 2.50-2.10 (m, 6H), 1.92-1.32 (m, 10H), 1.25-1.12 (m, 1H) . Intermediate 5: 4-azido-N-{[(2R)-1-ethylpyrrolidin-2-yl]methyl}benzamide

[000250] The title compound was obtained, following procedure described for intermediate 3, but starting from 4-azidobenzoic acid (305 mg; 1.87 mmol; 1.0 eq.) and 1-[(2R)-1-ethylpyrrolidin-2 - yl]methanamine (TCI, 200 mg; 1.56 mmol; 1.0 eq.) as an oil.MS (ESI+): 274.1, (ESI-) 272.1 (100% purity). Intermediate 6: 4-azido-N-{ [(2S)-1-ethylpyrrolidin-2-yl]methyl}benzamide

[000251] The title compound was obtained, following procedure described for intermediate 3, but starting from 4-azidobenzoic acid (305 mg; 1.87 mmol; 1.0 eq.) and 1-[(2S)-1-ethylpyrrolidin-2 - yl]methanamine (TCI, 200 mg; 1.56 mmol; 1.0 eq.) as an oil.MS (ESI+): 274.1, (ESI-) 272.1 (82% purity). Intermediate 7: 4-[2-(4-) azido-1H-pyrazol-1-yl)ethyl]pyridineStep a) Formation of 4-[2-(4-nitro-1H-pyrazol-1-yl)ethyl]pyridine

[000252] DIAD (7.27 mL; 37.2 mmol; 1.1 eq.) was slowly added to a solution of 4-(2-hydroxyethyl)pyridine (4.2 g; 34.1 mmol; 1.0 eq.), 4-nitro-1H- pyrazole (3.86 g; 34.1 mmol; 1.0 eq.) and triphenylphosphine (9.84 g; 37.5 mmol; 1.1 eq.) in THF (120 mL) kept under Nitrogen at 0°C. A reaction mixture was allowed to warm to RT and left O/N. THF was removed under reduced pressure and the crude was purified by flash chromatography on silica (EtOAc:heptane, gradient from 50:50 to 100:0) to provide the title compound in quantitative yield. MS(ESI+): 219.0, (ESI-) 272.1 (92.2% purity). 1H NMR (400 Mz, DMSO-d6) δ 8.80 (s, 1H), 8.44-8.43 (m, 2H), 8.24 (s, 1H ), 7.18-7.17 (m, 2H), 4.50-4.48 (t, J = 7.04 Hz, 2H), 3.19-3.17 (t, J = 7.0 Hz, 2H).Step b) Formation of 1-(2-pyridin) -4-ylethyl)-1H-pyrazol-4-amine

[000253] A solution of 4-[2-(4-nitro-1H-pyrazol-1-yl)ethyl]pyridine (9.9 g; 34 mmol; 1.0 eq.) in MeOH (250 mL) in the presence of a catalytic amount of Pd/C was hydrogenated under 14 bars of H2 at RT. Upon completion, a reaction mixture was filtered through a pad of celite and concentrated. The crude was purified by flash chromatography on silica (DCM:MeOH, gradient from 100:0 to 80:20) to give the title compound as a brown solid (3.26 g, 51%). MS(ESI+): 189.0 (87.9% purity). 1H NMR (400 Mz, DMSO-d6) δ 842-8.41 (d, J = 5.9Hz, 2H), 7.15-7.14 (d, J = 5.8Hz, 2H) , 6.96 (s, 1H), 6.91(s, 1H), 4.21-4.19 (t, J = 7.4 Hz, 2H), 3.99 (brs, 2H), 3.05-3.03 (t, J = 7.1 Hz, 2H, t ).Step c) Formation of 4-[2-(4-azido-1H-pyrazol-1-yl)ethyl]pyridine

[000254] To a cold (0°C) solution of 1-(2-Pyridin-4-yl-ethyl)-1H-pyrazol-4-ylamine (300 mg; 2.66 mmol; 1.0 eq.) in AcOH (2.0 mL ) and H2SO4 (1.0 mL) was added dropwise a solution of sodium nitrite (220 mg; 3.19 mmol; 1.2 eq.) in water (1.50 mL) and the reaction mixture was stirred at 0°C for 1 hour. A solution of sodium azide (207 mg; 3.2 mmol; 1.2 eq.) in water (1.5 mL) was then added dropwise at 0°C and the reaction mixture was stirred at 0°C for 2 hours. A reaction mixture was then poured into ice water, basified to pH = 10-11 with NaOH (5N) and extracted with EtOAc (twice). Combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a dark oil, which was used without further purification in the next step. MS (ESI+): 215.0 (98.7% purity). Intermediate 8: 4-[4-(5-methyl-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzaldehyde

[000255] 3-Ethynyl-5-methyl-1H-indazole (1.0 g; 6.4 mmol; 1.0 eq.) and 4-azidobenzaldehyde (prepared as described in Chem.Med.Chem. (2009), 4(7), 1182 -1188; 1.30 g; 7.04 mmol; 1.1 eq.) were dissolved in 1,4-dioxane (15 mL). D-(-)-isoascorbic acid sodium salt (127 mg; 0.64 mmol; 0.10 eq.) followed by a solution of copper sulfate pentahydrate (32 mg; 0.13 mmol; 0.02 eq.) in water (1.5 mL) were added and the reaction mixture was stirred at 90°C for 3.5 hours. To complete the reaction more D-(-)-isoascorbic acid sodium salt (127 mg; 0.64 mmol; 0.10 eq.) and copper sulfate pentahydrate (32 mg; 0.13 mmol; 0.02 eq.) were added again and a reaction mixture was heated at 100°C for 8h. 1,4-dioxane was removed under reduced pressure and the residue was sonicated in a mixture of EtOAc and water (1:1). The resulting solid was filtered and dried to give the title compound as a beige solid (1.94 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ: 13.29 (brs, 1H), 10.11 (s, 1H), 9.46 (s, 1H), 8.34 (d, J= 8.6 Hz, 2H), 8.18 (d, J = 8.6 Hz, 2H), 8.14 (m, 1H), 7.51 (d, J= 8.4 Hz, 1H), 7.28 (dd, J= 8.4 Hz, 1.4 Hz, 1H), 2.49 (s, 3H). Intermediate 9 : 3-[1-(6-chloropyridin-3-yl)-1H-1,2,3-triazol-4-yl]-1H-indazole Step a) Formation of 5-azido-2-chloropyridine

[000256] 5-Amino-2-chloropyridine_(2.28 g; 17.7 mmol; 1.0 eq.) was dissolved in TFA (7 mL). Sodium nitrite (1.35 g; 19.5 mmol; 1.1 eq.) was then added portion by portion to this solution maintained at 0°C. Reaction mixture was stirred at 0°C for 30 min before the addition of an ice cold solution of sodium azide (1.15 g; 17.7 mmol; 1.0 eq.) in water (8 mL). It was stirred at 0°C for 1 h. TFA was then removed and the residue was dissolved in EtOAc. The organic phase was washed with saturated aqueous NaHCO3 solution, brine, dried over magnesium sulfate, filtered and concentrated. The crude obtained was purified by flash chromatography on silica (heptane:EtOAc, gradient from 95:5 to 80:20) to give the title compound as a brown oil (1.89 g, 69%). 1 H NMR (300 Mz , DMSO-d6) δ 8.23 (dd, J = 0.6, 2.9 Hz, 1H), 7.68 (dd, J = 2.9, 8.6 Hz, 1H), 7.54 (dd, J = 0.6, 8.6 Hz, 1H).Step b ) Formation of 3-[1-(6-chloropyridin-3-yl)-1H-1,2,3-triazol-4-yl]-1H-indazol

[000257] 3-Ethynyl-1H-indazole (249 mg; 1.75 mmol; 1.0 eq.) and 5-azido-2-chloropyridine (270 mg; 1.75 mmol; 1.0 eq.) were dissolved in 1,4-dioxane (11 mL). D-(-)-isoascorbic acid sodium salt (69 mg; 0.35 mmol; 0.2 eq.) was added followed by copper sulfate pentahydrate (17.5 mg; 0.07 mmol; 0.04 eq.) in water (3.7 mL ) and a reaction mixture was heated at 80°C for 2 days. The precipitate obtained was filtered, washed with water and EtOAc and dried under vacuum to give the title compound as a beige powder. mp = 272-280°C.1H NMR (300 Mz, DMSO-d6) δ 13.40 (s, 1H), 9.44 (s, 1H), 9.16 (d, J = 2.8 Hz, 1H), 8.56 (dd, J = 2.9, 8.8 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.44 (m, 1H ), 7.26 (m, 1H). HPLC (Condition A): RT 3.30 min (100% purity). Intermediate 10: 3-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]phenyl}propanoic

[000258] 3-(4-azidophenyl)propanoic acid (Bachem, 672 mg; 3.5 mmol; 1.0 eq.) and 3-ethynyl-1H-indazole (500 mg; 3.5 mmol; 1.0 eq.) were dissolved in 1.4 -dioxane (7.5 mL). D-(-)-isoascorbic acid sodium salt (139 mg; 0.70 mmol; 0.2 eq.) followed by a solution of copper sulfate pentahydrate (35 mg; 0.14 mmol; 0.04 eq.) in water (0.75 mL) were added. A reaction mixture was stirred at 90°C for 48h. Dioxane was partially removed under reduced pressure, water was added and the mixture was extracted with EtOAc (three times). Combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude obtained was sonicate in DCM (5 ml) and heptane (10 ml). The resulting solid was filtered and dried under high vacuum to give the title compound as a brown solid (875 mg, 75%). 1H NMR (300 Mz, DMSO-d6) δ: 13.37 (brs, 1H), 9.27 (s, 1H), 8.35 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.46-7.41 (m, 1H), 7.27-7.22 (m, 1H), 2.92 (t, J = 7.5 Hz , 2H), 2.60 (t, J = 7.5 Hz, 2H). HPLC (Condition A): RT 3.14 min (93.5% purity). MS (ESI+): 334.2, MS (ESI-): 332.2. Intermediate 11: 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoic acid

[000259] 4-azidobenzoic acid (252 mg; 1.55 mmol; 1.1 eq.) and 3-ethynyl-1H-indazole (200 mg; 1.4 mmol; 1.0 eq.) were dissolved in 1,4-dioxane (3 ml). D-(-)-isoascorbic acid sodium salt (28 mg; 0.14mmol; 0.1 eq.) followed by a solution of copper sulfate pentahydrate (7 mg; 0.03 mmol; 0.02 eq.) in water (0.75 mL) were added and a reaction mixture was stirred at 90°C for 48h. Reaction mixture was diluted with EtOAc and extracted with NaOH (0.1N). Aqueous phase was filtered, acidified to pH 4-5 by addition of HCl (5N) and the precipitate thus obtained was filtered, washed with water and dried under reduced pressure at 50°C to yield the title compound as a white solid (453 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ 13.53 (s, 1H), 9.57 (s, 1H), 8.49 (d, J = 8.1 Hz, 1H), 8.42- 8.24 (m, 3H), 8.13-8.03 (m, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.63-7.50 (m, 1H), 7.45-7.29 (m, 2H). Intermediate 12: Acid 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-2-methoxybenzoic Step a) Formation of 4-[4-(1H-indazol-3-yl )-1H-1,2,3-triazol-1-yl]-2-methoxybenzoate methyl

[000260] The title compound was prepared following procedure described for intermediate 10, but starting from methyl 4-azido-2-methoxybenzoic carboxylic acid (prepared as described in JOC, 1983, 48(25), p5041-43; 324 mg; 1.41 mmol; 1.0 eq.) and 3-ethynyl-1H-indazole (200 mg; 1.41 mmol; 1.0 eq.) as a residue that was used directly in the next step (363 mg, 74%).MS (ESI+) : 456.4, MS (ESI-): 454.5.Step b) Formation of 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-2-methoxybenzoic acid

[000261] Methyl 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-2-methoxybenzoate (363 mg; 1.04 mmol; 1.0 eq.) suspended in MeOH (8 mL) was treated with sodium hydroxide (8.3 mL, 1N; 8.3 mmol; 8.0 eq.) and stirred at RT until all the solid dissolved (3 h). MeOH was removed under reduced pressure, the resulting solution was made acidic by adding 1N HCl and extracted with DCM (3 times). Combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a beige solid (249 mg, 71%).MS (ESI+): 336.1, MS (ESI-): 334.2. Intermediate 13: [1-(4-azidobenzoyl)piperidin-3-yl]methanol

[000262] The title compound was obtained following procedure described for intermediate 3, but starting from azidobenzoic acid (700 mg; 4.3 mmol; 1.0 eq.) and 3-(hydroxymethyl)piperidine (533 μl; 4.7 mmol; 1.1 eq. .) as an oil (1.12 g; 100%). 1H NMR (300 MHz, DMSO-d6) δ: 7.41 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 4,564.28 (m, 2H), 3.68-3.47 (m , 1H), 3.29 (m, 1H), 3.12-2.94 (m, 1H), 2.822.54 (m, 2H), 1.74-1.39 (m, 4H), 1.26-1.13 (m, 1H). HPLC (Condition A): RT 2.40 min (89.4% purity).MS (ESI+): 261.1.Intermediate 14: [1-(4-azidobenzoyl)piperidin-3-yl]methanolStep a) Acid Formation (4-azidophenyl) acetic

[000263] The title compound was obtained, following procedure described for intermediate 7, step c), but starting from Methyl(4-aminophenyl) acetate (1.0 g; 6.05 mmol; 1.0 eq.) as a beige powder. (790 mg, 74%). 1H NMR (300 MHz, DMSO-d6): 137.29 (d, J = 8.5 Hz, 2H), 7.06 (d, J = 8.5 Hz, 2H), 3.57 (s, 2H). Step b) Acid Formation {4 -[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}acetic

[000264] The title compound was obtained, following procedure described for intermediate 10, but starting from 3-ethynyl-1H-indazole (300 mg; 2.11 mmol; 1.0 eq.) and (4-azidophenyl)acetic acid (374 mg; 2.11 mmol; 1.0 eq.) as a white solid (525 mg; 78%). 1H NMR (300 MHz, DMSO-d6): 13.35 (brs, 1H), 12.47 (bs, 1H), 9.29 (s, 1H), 8.36 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.601 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.47-7.41 (m, 1H), 7.28-7232 (m, 1H), 3.71 ( s, 2H). HPLC (Condition A): RT 2.99 min (93.1% purity). Intermediate 15: {3-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}acetic acid

[000265] The title compound was obtained, following procedure described for intermediate 10, but starting from (3-azidophenyl)acetic acid (prepared as described in J.Med.Chem. (2005), 48(23), 7153 -7165; 586 mg; 3.31 mmol; 1.0 eq.) and 3-ethynyl-1H-indazole (470 mg; 3.31 mmol; 1.0 eq.) as a brown solid (880 mg; 83.3%).1H NMR (300 MHz, DMSO-d6): 13.36 (brs, 1H), 12.51 (brs, 1H), 9.31 (s, 1H), 8.36 (dt, J = 8.2 Hz, 1.0 Hz, 1H), 8.01 (t, J = 1.8 Hz, 1H), 7.967.93 (m, 1H), 7.63-7.55 (m, 2H), 7.47-7.41 (m, 2H), 7.28-7.23 (m, 1H), 3.76 (s, 2H). Intermediate 16:4 -(4-azido-2-fluorobenzoyl)morpholineStep a) Formation of 3-fluoro-4-(morpholin-4-ylcarbonyl)aniline

[000266] The title compound was obtained, following procedure described for intermediate 3, but starting from 4-amino-2-fluorobenzoic acid (150 mg; 0.97 mmol; 1.0 eq.) and morpholine (102 µl; 1.16 mmol; 1.2 eq.) as a pale orange oil (200 mg, 92.0%). 1H NMR (300 MHz, DMSO-d6) δ 7.04 (t, J = 8.4 Hz, 1H), 6.41 (dd, J = 8.4 Hz, 2.1 Hz, 1H), 6.31 (dd, J = 13.0 Hz, 2.1 Hz, 1H), 3.26-3.36 (m, 8H). HPLC (Condition A): RT 1.42 min (96.3% purity).Step b) Formation of 4-(4-azido-2-fluorobenzoyl)morpholine

[000267] Tert-butyl nitrite (0.16 mL; 1.34 mmol; 1.5 eq.) was added to a solution of 3-fluoro-4-(morpholin-4-ylcarbonyl)aniline (200 mg; 0.89 mmol; 1.0 eq.) in AcOEt (6 mL) kept at -10°C. A reaction mixture was stirred at -10°C for 10 minutes before the addition of azidotrimethylsilane (0.14 mL; 1.07 mmol; 1.2 eq.). Reaction mixture was stirred at RT for 2 hours and concentrated under reduced pressure to give the title compound as a pale orange oil (220 mg, 99%).1H NMR (300 MHz, DMSO-d6): δ: 7.45 (t , J = 8.0 Hz, 1H), 7.15 (dd, J = 11.0 Hz, 2.1 Hz, 1H), 7.06 (dd, J = 8.0 Hz, 2.1 Hz, 1H), 3.64-3.63 (m, 4H), 3.52 ( t, J = 4.6 Hz, 2H), 3.23 (t, J = 4.6 Hz, 2H). MS (ES+): 2521.1; RT 1.02 min (purity = 92%). Intermediate 17: tert-Butyl 4-(3-ethynyl-1H-indazol-5-yl)piperidine-1-carboxylateStep a) Formation of 4-(1H-indazol-5- tert-butyl yl)-3,6-dihydropyridine-1(2H)-carboxylate

[000268] A suspension of 5-bromoindazole (Combi-blocks; 3.0 g; 15.2 mmol; 1.0 eq.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) tert-Butyl -3,6-dihydropyridine-1(2H)-carboxylate (Frontier Scientific; 6.59 g; 21.3 mmol; 1.4 eq.), 1,1'-bis-(diphenylphosphino)ferrocene (1.11 g; 1.52 mmol; 0.1eq.) and potassium carbonate (6.31 g; 45.7 mmol; 3.0 eq.) in degassed dioxane (60 mL) and water (30 mL) was heated at 90°C for 24h. A reaction mixture was cooled, diluted with DCM and filtered through a pad of celite. Water was added to the filtrate and the aqueous phase was extracted three times with DCM. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was absorbed onto silica and purified by flash silica chromatography (heptane/EtOAc, gradient from 80:20 to 30:70) to give the title compound as an off-white solid. 1 H NMR (300 MHz, DMSO-d6 ) δ 13.04 (brs, 1H), 8.04 (s, 1H), 7.78-7.71 (m, 1H), 7.53-7.44 (m, 2H), 6.14 (s, 1H), 4.10-3.92 (m, 2H), 3.56 (t, J = 5.7 Hz, 2H), 2.60-2.51 (m, 2H), 1.41 (s, 9H). HPLC (Condition A): RT 4.42 min (93.6% purity). MS (ES+): 341.2. MS (ES-): 298.2.Step b) Formation of tert-butyl 4-(1H-indazol-5-yl)piperidine-1-carboxylate

[000269] A solution of tert-butyl 4-(1H-indazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg; 0.67 mmol; 1.0 eq.) in MeOH ( 6 mL) was hydrogenated (10 bars) on a Paar instrument in the presence of Pd/C (10% Pd humidified at 50% H2O; 7.11 mg; 0.07 mmol; 0.10 eq.) at RT. After 12h, a reaction mixture was filtered through a pad of celite and the filtrate was concentrated to dryness to give the title compound as a gray foam (200mg; 99%).1H NMR (300MHz, DMSO-d6) δ 12.94 (brs, 1H), 7.98 (s, 1H), 7.56 (s, 1H), 7.49-7.43 (m, 1H), 7.28-7.22 (m, 1H), 4.18-4.02 (m, 2H), 2.99 -2.67 (m, 3H), 1.83-1.73 (m, 2H), 1.65-1.46 (m, 2H), 1.42 (s, 9H).Step c) Formation of 4-(3-iodo-1H-indazol-5 tert-butyl -yl)piperidine-1-carboxylate

[000270] KOH pellets (141.5 mg; 2.52 mmol; 3.8 eq.) were added in small portion over 10 min to a solution of tert-butyl 4-(1H-indazol-5-yl)piperidine-1-carboxylate ( 200 mg; 0.66 mmol; 1.0 eq.) and iodine (0.34 g; 1.33 mmol; 2.0 eq.) in dry DMF (6 mL). A reaction mixture was stirred O/N at RT. It was then poured into a saturated solution of Na2S2O3 (100 mL) and extracted three times with ether. Combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow foam (225 mg, 79%). 1H NMR (300 MHz, DMSO-d6) δ 13.41 (brs, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.35 (dd, J = 8.7, 1.3 Hz, 1H), 7.20 (s, 1H) , 4.26-3.94 (m, 2H), 2.93-2.74 (m, 3H), 1.99-1.70 (m, 2H), 1.67-1.47 (m, 2H), 1.42 (s, 9H). HPLC (Condition A): RT 5.10 min (100% purity).Step d) Formation of tert. -butyl

[000271] A solution of tert-butyl 4-(3-iodo-1H-indazol-5-yl)piperidine-1-carboxylate (218.mg; 0.51mmol; 1.0eq.), di-tert-butyldicarboxylate (145 mg; 0.66 mmol; 1.3 eq.), dimethylamino-4-pyridine (12.5 mg; 0.10 mmol; 0.20eq.) and TEA (86.0 μl; 0.61 mmol; 1.2 eq.) in acetonitrile (6.5 ml) was stirred at TA O/N. Acetonitrile was removed under reduced pressure, the residue was diluted with water and extracted three times with ether. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (heptane/EtOAc, gradient from 90:10 to 75:25) to give the title compound as a colorless oil (200 mg, 74%). 1 H NMR (300 MHz, DMSO-d6) δ 7.99 (d, J = 8.7 Hz, 1H), 7.62 (dd, J = 1.6, 8.7 Hz, 1H), 7.35 (s, 1H), 4.18-4.03 (m, 2H), 2.96-2.73 (m, 3H), 1.87-1.75 (m, 2H), 1.64 (s, 9H). 1.61-1.48 (m, 2H), 1.42 (s, 9H). (Condition A): RT 6.33 min (99.8% purity).Step e) Formation of 5-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-[(trimethylsilyl)ethynyl]-1H-indazole -1-tert-butyl carboxylate

[000272] A suspension of tert-butyl 5-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-iodo-1H-indazol-1-carboxylate (200 mg; 0.38 mmol; 1.0 eq.), (Trimethylsilyl)acetylene (53 μl; 0.38 mmol; 1.0 eq.), TEA (158 μl) and bis(triphenylphosphine)palladium(II) chloride (10.7 mg; 0.02 mmol; 0.04 eq.) was heated at 70°C for overnight in a sealed tube. A reaction mixture was diluted with EtOAc and washed with a saturated solution of NH4Cl and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to give the title compound as a brown gum (200 mg, 100%). 1 H NMR (300 MHz, DMSO-d6) δ 8.04 (d, J = 8.7 Hz , 1H), 7.63-7.54 (m, 2H), 4.15-4.04 (m, 2H), 2.99-2.74 (m, 3H), 1.86-1.74 (m, 2H), 1.64 (s, 9H), 1.61-1.52 (m, 2H), 1.42 (s, 9H), 0.32 (s, 9H).Step f) Formation of tert-butyl 4-(3-ethynyl-1H-indazol-5-yl)piperidine-1-carboxylate

[000273] A solution of tert-butyl 5-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-[(trimethylsilyl)ethynyl]-1H-indazol-1-carboxylate (189 mg; 0.38 mmol; 1.0 eq.) and potassium carbonate (5.3 mg; 0.04 mmol; 0.1 eq.) in EtOH (3.8 mL) was stirred at RT O/N. EtOH was removed under reduced pressure and the residue was diluted with ether, washed with water then brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash silica chromatography (heptane/EtOAc, gradient from 90:10 to 60:40) to give the title compound as a beige solid (118 mg, 95%). 1 H NMR (300 MHz, DMSO-d6) δ 13.35 (brs, 1H), 7.55-7.47 (m, 2H), 7.33 (dd, J = 1.6, 8.6 Hz, 1H), 4.48 (s, 1H), 4.15-4.03 (m, 2H) , 2.93-2.71 (m, 3H), 1.86-1.74 (m, 2H), 1.65-1.45 (m, 2H), 1.42 (s, 9H). HPLC (Condition A): RT 4.78 min (99.1% purity). Intermediate 18: 3-{3-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]phenyl} propanoic

[000274] The title compound was obtained, following procedure described for intermediate 10, but starting from 3-(3-azidophenyl)propanoic acid (prepared as described in J.Med.Chem (1994), 37(12), 1841-1849, 570 mg; 2.98 mmol; 1.0 eq.) and 3-ethynyl-1H-indazole (424 mg; 2.98 mmol; 1.0 eq.) as a brown solid. 1 H NMR (300 MHz, DMSO-d6): 13.36 (brs, 1H), 12.51 (brs, 1H), 9.32 (s, 1H), 8.36 (dt, J = 1.0, 8.2 Hz, 1H), 7.96 (t, J = 2.0 Hz, 1H), 7.90-7.87 ( m, 1H), 7.61 (dt, J = 8.4 Hz, 1.0 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.477.38 (m, 2H), 7.28-7.23 (m, 1H), 2.97 (t, J = 7.6 Hz, 2H), 2.68 (t, J = 7.6 Hz, 2H). Intermediate 19: 4-(4-azido-2-chlorobenzoyl)morpholine

[000275] The title compound was obtained, following procedure described for intermediate 16, sep b), but starting from 3-chloro-4-(morpholin-4-ylcarbonyl)aniline (Enamina, 1.40 g; 5.8 mmol; 1.0 eq.) as a beige solid (1.5 g, 97%). 1H NMR (300 MHz, DMSO-d6) δ: 7.41 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.18 (dd, J = 8.3 Hz, 2.2 Hz, 1H) , 3.64-3.63 (m, 4H), 3.52 (t, J = 4.7 Hz, 2H), 3.12 (t, J = 4.7 Hz, 2H). HPLC (Condition A): RT 2.81 min (83% purity). Intermediate 20: tert-butyl 3-ethynyl-5-(hydroxymethyl)-1H-indazole-1-carboxylateStep a) 3-bromo-5-formyl formation tert-butyl -1H-indazole-1-carboxylate

[000276] The title compound was obtained, following procedure described for intermediate 17, step d), but starting from 3-bromo-1H-indazole-5-carboxaldehyde (1.09 g; 4.84 mmol; 1.0 eq.) as a white solid (1.2 g, 76%). 1H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.38-8.33 (m, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.17 (dd, J = 1.5, 8.8 Hz, 1H), 1.66 (s, 9H). HPLC (Condition A): RT 4.07 min (96.6% purity). MS (ESI+): 325.1, 327.1.Step b) Formation of tert-butyl 3-bromo-5-(hydroxymethyl)-1H-indazole-1-carboxylate

[000277] Sodium borohydride (395 mg; 10.4 mmol; 2.9 eq.) was added in one portion to a solution of tert-butyl-3-bromo-5-formyl-1H-indazole-1-carboxylate (1.20 g ; 3.58 mmol; 1.0 eq.) in DMF (30 mL). A reaction mixture was stirred for 3 h then poured into HCl (0.1N solution) and extracted with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow solid (1.19 g, 100%). 1 H NMR (300 MHz, DMSO-d6) δ 8.05 ( d, J = 8.7 Hz, 1H), 7.69-7.60 (m, 2H), 4.66 (s, 2H), 1.65 (s, 9H). HPLC (Condition A): RT 3.65 min (81.6% purity). MS (ESI+): 327.1, 329.1.Step c) Formation of tert-butyl 5-(hydroxymethyl)-3-[(trimethylsilyl)ethynyl]-1H-indazole-1-carboxylate

[000278] A mixture of trimethylsilylacetylene (1.60 mL; 11.3 mmol; 2.1 eq.), tert-butyl 3-bromo-5-(hydroxymethyl)-1H-indazole-1-carboxylate (1.80 g; 5.50 mmol; 1.0 eq.) , Pd(OAc) 2 (54 mg; 0.24 mmol; 0.04 eq.), triphenylphosphine (115 mg; 0.44 mmol; 0.08 eq.) and copper iodide (62 mg; 0.33 mmol; 0.06 eq.) in TEA (50 mL ) was degassed then refluxed for 3h. After cooling, it was poured into HCl (0.1N solution) and extracted with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a brown oil (2.6g). 1 H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J = 8.7 Hz, 1H), 7.71 (s, 1H), 7.60 (dd, J = 1.6, 8.7 Hz, 1H), 5.41 (t, J = 5.7 Hz, 1H), 4.66 (d, J = 5.7 Hz, 2H), 1.65 (s, 9H), 0.32 (s, 9H). MS (ESI+): 345.2.Step d) Formation of tert-butyl 3-ethynyl-5-(hydroxymethyl)-1H-indazole-1-carboxylate

[000279] TBAF (10 mL of 1.0 M solution in THF; 10 mmol; 2.5 eq.) was added in one portion to a solution of 5-(hydroxymethyl)-3-[(trimethylsilyl)ethynyl]-1H-indazol- tert-butyl 1-carboxylate (2.6 g; 3.92 mmol; 1.0 eq.) in THF (30 mL). A reaction mixture was stirred at RT for 30 min and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica (n-heptane/EtOAc, gradient from 80:20 to 50:50) to give the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J = 8.7 Hz, 1H), 7.74 (s, 1H), 7.61 (dd, J = 1.5, 8.7 Hz, 1H), 5.41 (t, J = 5.6 Hz, 1H), 4.88 (s, 1H) , 4.66 (d, J = 5.6 Hz, 2H), 1.65 (s, 9H). HPLC (Condition A): RT 3.29 min (81.6% purity). MS (ESI+): 273.0. Intermediate 21: 5-(bromomethyl)-3-{1-[4-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-1 -tert-butyl carboxylateStep a) Formation of tert-butyl 3-ethynyl-5-methyl-1H-indazole-1-carboxylate

[000280] The title compound was obtained, following procedure described for intermediate 17, step d), but starting from 3-ethynyl-5-methyl-1H-indazole (1.05 g; 6.72 mmol; 1.0 eq) as a solid orange (1.66 g, 96 %). 1 H NMR (300 MHz, DMSO-d6) δ 8.00 (d, J = 8.7 Hz, 1H), 7.60 (s, 1H), 7.50 (dd, J = 1.4, 8.7 Hz, 1H), 4.86 (s, 1H), 2.46 (s, 3H), 1.65 (s, 9H). HPLC (Condition A): RT 4.56 min (94.3% purity). MS (ESI+): 257.2.Step b) Formation of 3-{1-[4-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-5-methyl-1H-indazol-1 - tert-butyl carboxylate

[000281] Copper sulfate pentahydrate (0.08 g; 0.33 mmol; 0.06 eq.) was added to a solution of tert-butyl-3-ethynyl-5-methyl-1H-indazole-1-carboxylate (1.55 g; 6.03 mmol; 1.0 eq.), methyl 4-azidobenzoate (prepared as described in JOC (2006), 71(15), 5822-5825; 1.20 g; 6.77 mmol; 1.1 eq.) and Sodium salt of acid D-(-)-isoascorbic acid (0.24 g; 1.22 mmol; 0.20 eq.) in DMF (15 mL) and water (0.50 mL). A reaction suspension was heated in MW at 80°C for 45 min then poured into HCl (0.1 N solution) and extracted with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (n-heptane/EtOAc, gradient from 90:10 to 60:40) to give the title compound as a yellow solid. 1H NMR (300 MHz, DMSO) δ 9.66 (s, 1H), 8.35-8.25 (m, 3H), 8.20 (d, J = 8.8 Hz, 2H), 8.05 (d, J = 8.7 Hz, 1H), 7.54 (dd, J = 1.5, 8.7 Hz, 1H), 3.91 (s, 3H), 2.53 (s, 3H), 1.69 (s, 9H). HPLC (Condition A): RT 5.07 min (96.8% purity). MS (ESI+): 434.4.Step c) Formation of 5-(bromomethyl)-3-{1-[4-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole -1-tert-butyl carboxylate

[000282] Zirconium tetrachloride (23 mg; 0.10 mmol; 0.1 eq.) was added in one portion to a solution of NBS (160 mg; 0.90 mmol; 0.9 eq.) in DCM (10 mL) at 0°C . A solution of tert-butyl 3-{1-[4-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-5-methyl-1H-indazol-1-carboxylate (434 mg ; 1.00 mmol; 1.0 eq.) in DCM (10 mL) was then added dropwise to a reaction mixture which was subsequently stirred at RT for 16h. A reaction mixture was then diluted with DCM and washed sequentially with saturated NaHCO3 and brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow solid (392 mg, 76%) 1H NMR ( 300 MHz, DMSO) δ 9.70 (s, 1H), 8.62 (d, J = 1.0 Hz, 1H), 8.30 (d, J = 8.8 Hz, 2H), 8.21 (d, J = 8.8 Hz, 2H), 8.16 (d, J = 8.8 Hz, 1H), 7.79 (dd, J = 8.8 Hz, 1.7, 1H), 4.99 (s, 2H), 3.92 (s, 3H), 1.70 (s, 9H). MS (ESI+): 512.3.Intermediate 22: 5-(hydroxymethyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H tert-butyl -indazole-1-carboxylate

[000283] The title compound was obtained, following procedure described for intermediate 21, step b), but starting from tert-butyl-3-ethynyl-5-(hydroxymethyl)-1H-indazole-1-carboxylate (557 mg ; 1.68 mmol; 1.0 eq.) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.49 (s, 1H), 8.20 (d, J = 8.6 Hz, 2H), 8.12 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.65 (dd, J = 1.5, 8.7 Hz, 1H), 5.44 (t, J = 5.7 Hz, 1H), 4.71 (d, J = 5.7 Hz, 2H), 3.78-3.35 (m, 11H), 1.70 (s, 9H). HPLC (Condition A): RT 3.42 min (94.9% purity). MS (ESI+): 505.3. Intermediate 23: 4-[4-azido-2-(trifluoromethyl)benzoyl]morpholineStep a) Formation of 4-(morpholin-4-ylcarbonyl)-3-(trifluoromethyl)aniline

[000284] The title compound was obtained, following procedure described for intermediate 3, but starting from 4-amino-2-(trifluoromethyl)benzoic acid (1.00 g; 4.87 mmol; 1.0 eq.) and morpholine (515 µl; 5.85 mmol; 1.2 eq.) as an oil (1.36 g, 100 %).1H NMR (300 MHz, DMSO-d6) δ 7.05 (d, J = 8.2 Hz, 1H), 6.89 (s, 1H), 6.79 ( d, J = 8.2 Hz, 1H), 5.81 (brs, 2H), 3.74-3.35 (m, 6H), 3.29-2.97 (m, 2H).Step b) Formation of 4-[4-azido-2-( trifluoromethyl)benzoyl]morpholine

[000285] The title compound was obtained, following procedure described for intermediate 16, step b), but starting from 4-(morpholin-4-ylcarbonyl)-3-(trifluoromethyl)aniline (730 mg; 2.66 mmol; 1.0 eq.) as an orange oil (837 mg, quantitative). HPLC (Condition A): RT 3.56 min (77.0% purity). MS (ESI+): 301.1. Intermediate 24: 4-(4-azido-3-fluorobenzoyl)morpholineStep a) Formation of 2-fluoro-4-(morpholin-4-ylcarbonyl)aniline

[000286] The title compound was obtained, following procedure described for intermediate 3, but starting from 4-Amino-3-fluorobenzene carboxylic acid (Apollo Scientific, 500 mg; 3.22 mmol; 1.0 eq.) and morpholine (340 μl ; 3.87 mmol; 1.2 eq.) as an orange solid (643 mg, 89%). 1H NMR (300 MHz, DMSO-d6) δ 7.08 (dd, J = 1.8, 12.0 Hz, 1H), 7.00 (dd, J = 1.8, 8.2 Hz, 1H), 6.81-6.69 (m, 1H), 5.59 ( brs, 2H), 3.66-3.53 (m, 4H), 3.53-3.43 (m, 4H). HPLC (Condition A): RT 1.21 min (96.7% purity).Step b) Formation of 4-(4-azido-3-fluorobenzoyl)morpholine

[000287] The title compound was obtained, following procedure described for intermediate 16, step b), but starting from 2-fluoro-4-(morpholin-4-ylcarbonyl)aniline (643 mg; 2.87 mmol; 1.0 eq. ) as an orange oil (729 mg, 100%).1H NMR (300MHz, DMSO-d6) δ 7.41-7.18 (m, 3H), 3.77-3.11 (m, 8H). HPLC (Condition A): RT 3.02 min (84.7% purity). Intermediate 25: 1-(1-Methylpyrrolidin-3-yl)-1H-pyrazol-4-amineStep a) Formation of 4-nitro-1-pyrrolidin hydrochloride -3-yl-1H-pyrazole

[000288] A solution of HCl (4N in dioxane, 50 mL, 150 mmol, 3.4 eq.) was added to a solution of tert-butyl-3-(4-nitro-1H-pyrazol-1-yl)pyrrolidine-1 -carboxylate (prepared as described in Tetrahedron Lett. (2008), 49(18), 2996-2998, 13 g, 46 mmol, 1 eq.) in dry dioxane (75 mL) at 0°C. A reaction mixture was then stirred at RT for 5h. It was concentrated under reduced pressure to give the title compound as an off-white solid (9.5 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ 9.73 (brs, 1H), 9.46 (brs, 1H), 9.07 (s, 1H), 8.37 (s, 1H), 5.24 (m, 1H), 3.50-3.72 ( m, 3H), 2.28-2.49 (m, 3H). Step b) Formation of 1-(1-Methylpyrrolidin-3-yl)-4-nitro-1H-pyrazole

[000289] To a solution of formic acid (50ml) and solution of Formaldehyde (50ml) was added 4-Nitro-1-pyrrolidin-3-yl-1H-pyrazole hydrochloride (10g). A reaction mixture was heated at 100°C for 16h. A reaction mixture was concentrated under reduced pressure. The residue was triturated with acetonitrile (150 mL), the solid filtered and the filtrate concentrated. The crude material was basified with ammonia solution, extracted with ethyl acetate, dried over sodium sulfate and evaporated to yield (7g, 78%) as a pale yellow liquid. 1H NMR (400 Mz, DMSO-d6) δ 8.85 ( s, 1H), 8.24 (s, 1H), 5.24 (m, 1H), 2.75-2.81 (m, 3H), 2.33-2.49 (m, 2H), 2.27 (s, 3H), 2.12 (m, 1H) .Step c) Formation of 1-(1-Methylpyrrolidin-3-yl)-1H-pyrazol-4-amine

[000290] A solution of 1-(1-Methylpyrrolidin-3-yl)-4-nitro-1H-pyrazole (3.0 g, 18 mmmol, 1 eq.) in methanol (40 mL) was hydrogenated (3 bars) in the presence from Ra-Ni (1g) to RT. After 3h, the catalyst was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a brown liquid. 1H NMR (400 MHz, DMSO-d6) δ 7.06 (s, 1H), 6.85 (m, 1H) , 4.67 (m, 1H), 3.82 (brs, 2H), 2.63-2.74 (m, 2H), 2.58-2.61 (m, 1H), 2.38-2.44 (m, 1H), 2.21-2.28 (m, 1H), 2.27 (s, 3H), 1.89-1.97 (m, 1H).Intermediate 26: 3-ethynyl-5-bromo-1H-indazolStep a) Formation of 5-bromo-3-[(trimethylsilyl)ethynyl]-1H-indazole -1- tert-butyl carboxylate

[000291] The title compound was obtained, following procedure described for intermediate 2, step a), but starting from tert-butyl 5-bromo-3-iodo-1H-indazole-1-carboxylate (J & W Phar - mLab, 16 g, 37 mmol) as a white solid (10 g, 67%): 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 8.9 Hz, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.81(dd, J = 1.9, 8.9 Hz, 1H), 1.63 (s, 9H), 0.31 (s, 9H).Step b) Formation of 3-ethynyl-5-bromo-1H-indazole

[000292] The title compound was obtained, following procedure described for intermediate 1, step b), but starting from tert-5-bromo-3-[(trimethylsilyl)ethynyl]-1H-indazole-1-carboxylate butyl (16 g, 0.04 mol) as a white solid (7g, 78%).1H NMR (400MHZ, DMSO-d6) δ 13.63 (s, 1H), 7.87 (brs, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.53 (dd, J = 1.8, 8.8 Hz, 1H), 4.55 (s, 1H). Intermediate 27:3-(4-azido-1H-pyrazol-1-yl)-8-methyl- 8-azabicyclo[3.2.1]octaneStep a) Formation of 8-Methyl-3-(4-nitro-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1]octane

[000293] To a solution of 4-Nitro-1H-pyrazole (10 g, 88.4 mmol) in DCM:DMF (3:1, 400 mL) was added Tropina (12.5 g, 88.4 mmol, 1 eq.), triphenyl phosphine (69.5 g, 265 mmol), followed by di-tert-butyl azodicaboxylate (61 g, 265 mmol) portion by portion at 10-15°C. A reaction mixture was stirred at RT for 4 days. It was then concentrated under reduced pressure. The crude was purified by flash chromatography on silica (PetEther/EtOAc) to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s,1H), 8.31 (s,1H) ), 4.92-4.86 (m, 1H), 3.99 (m, 2H), 2.66-2.56 (m, 5H), 2.26-2.17 (m, 4H), 2.062.01 (m, 2H). 1-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-amine

[000294] Ammonia was bubbled for 15 min into a solution of 8-Methyl-3-(4-nitro-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1]octane (3.4 g, 14.4 mmol) in MeOH (300 mL). The solution was then hydrogenated (3 bars) in the presence of Ra-Ni (2 g) at RT. After 2h, the catalyst was filtered and the filtrate was concentrated under reduced pressure. The solid was purified by trituration in acetonitrile (25 mL) to give the title compound as a white solid (2.2 g, 75%). 1H NMR (400 MHz, DMSO-d6) δ 7.08 (brs,1H), 6.87 ( brs, 1H), 4.49 (brs, 1H), 3.84 (s, 2H), 2.61 (s, 3H), 2.42-2.36 (m, 2H), 2.19-2.16 (t, 2H), 2.06-1.97 (m, 4H).Step c) Formation of 3-(4-azido-1H-pyrazol-1-yl)-8-methyl-8-azabicyclo[3.2.1]octane

[000295] The title compound was prepared following procedure described for intermediate 7, step c), but starting from 1-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-1H -pyrazol-4-ylamine (124 mg; 0.60 mmol; 1.0 eq.) as a dark oil (139 mg; 100%) which was used without further purification in the next step. MS (ESI+): 233.0.Intermediate 28: tert-Butyl 4-(4-amino-1H-pyrazol-1-yl)azepane-1-carboxylateStep a) Formation of 4-(4-nitro-1H-pyrazol-1 tert-butyl -yl)azepane-1-carboxylate

[000296] The title compound was obtained, following procedure described for intermediate 26, step a), but starting from 4-Nitro-1H-pyrazole (2.36 g, 20.9 mmol) and 4-hydroxyazepane-1-carboxylate (J & W PharmLab, 4.5 g, 20.9 mmol) as a white solid (4.5 g, 70%).1H NMR: (400 MHz, DMSO-d6) δ 8.91 (s,1H), 8.25 (s,1H), 4.49- 4.41 (m, 1H), 3.60-3.53 (m, 1H), 3.41-3.38 (m, 2H), 3.27-3.31 (m, 1H), 2.08-2.01 (m, 2H), 1.97-1.90 (m, 2H ), 1.87-1.83 (m, 1H), 1.66-1.63 (m, 1H), 1.40 (s, 9H).Step b) Formation of 4-(4-amino-1H-pyrazol-1-yl)azepane-1 - tert-butyl carboxylate

[000297] A solution of tert-butyl 4-(4-nitro-1H-pyrazol-1-yl)azepane-1-carboxylate (4.5 g, 15.5 mmol) in methanol (250 mL) was hydrogenated (3 bars) at presence of Palladium on Carbon (10%, 2g) at RT. After 3h, a reaction mixture was filtered through a pad of celite and concentrated under reduced pressure to give the title compound as a brown solid (3.8 g, 95%). 1H NMR: (400 MHz, DMSO-d6) δ 6.99 (s, 1H), 6.86 (s, 1H), 4.05 (m, 1H), 3.94 (m, 2H), 3.85 (m, 2H), 2.85 (brs , 2H), 1.86 (m, 2H), 1.65 (m, 2H), 1.40 (s, 9H). Intermediate 29: 3-[1-(4-Bromo-phenyl)-1H-[1,2,3] triazol-4-yl]-1H-indazole

[000298] To a solution of 3-Ethynyl-1H-indazole (6.0 g, 42.2 mmol) in dioxane (60 mL) was added 4-Azidobromobenzene (Ukrorgsynthesis Ltd., 9.19 g, 46.4 mmol), D-acid sodium salt -(-)- Iso ascorbic acid (0.83 g, 4.2 mmol) and a solution of CuSO4.5H2O (0.21 g, 0.8 mmol) in water (10 mL). A reaction mixture was heated at 80°C for 3 days. After completion of the reaction, a reaction mixture was cooled to RT, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was recrystallized from methanol and dried under vacuum to give the title compound as a brown solid (9.0 g, 63%).1H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 9.36 (s, 1H), 8.35-8.33 (d, J = 8.1 Hz, 1H), 8.06-8.02 (m, 2H), 7.86-7.82 (m, 2H), 7.61-7.59 (d, J = 8.4 Hz, 1H ), 7.45-7.41(m, 1H), 7.26-7.22 (m, 1H). Intermediate 30: 4-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazole tert-butyl -1-yl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate

[000299] The title compound was obtained, following procedure described for intermediate 7, step a), but starting from 3-[1-(4-Bromo-phenyl)-1H-[1,2,3]triazol- 4-yl]-1H-indazole (400 mg; 1.2 mmol; 1.0 eq.) and 1-N-Boc-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine (545 mg; 1.76 mmol; 1.5 eq.) as a brown solid (515 mg, 99%). HPLC (max scheme) 97.3%; TA 4.95min. UPLC/MS: (MS+) 443.3, (MS-) 441.3. Intermediate 31: 4-(4-azidophenyl)-1-(3,3,3-trifluoropropyl)piperidine Step a) Formation of 4-(4-nitrophenyl) tert-butyl -3,6-dihydropyridine-1(2H)-carboxylate

[000300] A mixture of 4-nitrophenylboronic acid pinacol ester (4.5 g; 18.1 mmol; 1.2 eq.), 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)- tert-butyl carboxylate (5.0 g; 15.1 mmol; 1.0 eq.) and sodium carbonate (1.07 g, 10.1 mmol, 5 eq.) were dissolved in DME (50 mL) and water (25 mL). The mixture was degassed for 5min with nitrogen before the addition of Pd(PPh3)4 (349 mg; 0.30 mmol; 0.02 eq.) and heated to 80°CO/N. Water (100 mL) was added and the aqueous phase was extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash silica chromatography (EtOAc:heptane, 10:90) to give the title compound as a yellow solid (3.3g, 72%).1H NMR (300MHz, DMSO-d6) δ 8.24-8.17 (m, 2H), 7.65-7.68 (m, 2H), 6.45 (brs, 1H), 4.06 (m, 2H), 3.56 (t, 2H), 2.55-2.48 (m, 2H), 1.43 (s, 9H ).Step b) Formation of 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[000301] Hydrogen chloride (20 mL of a 4N solution in dioxane) was added dropwise to a solution of tert. -butyl (3.0 g; 9.86 mmol; 1.0 eq.) in toluene (15 mL). A reaction mixture was stirred at RT for 3h. The suspension formed was filtered, washed with toluene (10 mL) and dried under vacuum to give the title compound as a white solid (1.96g, 97%). UPLC/MS: (MS+) 205.3.Step c) Formation of 4-(4-nitrophenyl)-1-(3,3,3-trifluoropropyl)-1,2,3,6-tetrahydropyridine

[000302] Sodium triacetoxyborohydride (6.2 g, 29.4 mmol, 2 eq.) was added to a solution of 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine (3.0 g; 14.7 mmol; 1.0 eq.), DIEA (2.5 mL; 14.7 mmol; 1.0 eq.) and 3,3,3-Trifluoropropanal (2.4 mL; 29.4 mmol; 2.0 eq.) in DCE (60 mL). A reaction mixture was heated at 50°C for 2h and cooled by adding a saturated solution of NH4Cl (50 mL). The phases were separated and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated to give a brown crude. Purification by flash chromatography on silica (EtOAc:heptane) gave the title compound as a yellow solid (2.0g, 45%). UPLC/MS: (MS+) 301.4. Step d) Formation of 4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]aniline

[000303] In Paar autoclave, a solution of 4-(4-nitrophenyl)-1-(3,3,3-trifluoropropyl)-1,2,3,6-tetrahydropyridine (2.6 g; 8.66 mmol; 1.0 eq. .) in EtOAc (52 mL) was hydrogenated at 25 bars O/N in the presence of Pd/C (wet, 10%, 0.26 g; 2.44 mmol; 0.28 eq.). Reaction mixture was filtered through a pad of celite. The filtrate was then concentrated under reduced pressure to give the title compound as a brown oil (2.33g, 99%). UPLC/MS: (MS+) 273.4. Step d) Formation of 4-(4-azidophenyl)-1-(3,3,3-trifluoropropyl)piperidine

[000304] The title compound was obtained, following procedure described for intermediate 7, step c), but starting from 4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]aniline (500 mg ; 1.84 mmol; 1.0 eq.) as a yellow oil (550 mg, 100%). UPLC/MS: (MS+) 299.4, (MS-) 301.4. Intermediate 32: 3-[4-(4-azidophenyl)piperidin-1-yl]-1,1,1-trifluoropropan-2-ol Step a) Formation of 1,1,1-trifluoro-3-[4-(4-nitrophenyl)-3,6-dihydropyridin-1(2H)-yl]propan-2-ol

[000305] 1,2-Epoxy-3,3,3-trifluoropropane, tech., 85% (2.32 g; 17.63mmol; 1.20 eq.) was added to a suspension of 4-(4-nitrophenyl)-1,2 ,3,6-tetrahydropyridine (3.0 g; 14.7 mmol; 1.0 eq.) in DMF (60 mL) and DIEA (2.5 mL, 14.7 mmol, 1 eq.). A reaction mixture was heated at 45°C for 4h. It was then allowed to cool to RT and diluted with water (50 mL) and EtOAc (100 mL). Organic layer was washed with a saturated solution of NH4Cl (2 x 50 mL) and water, dried over magnesium sulfate, filtered and concentrated to give the expected compound as an orange solid (3.6 g, 77%). UPLC/MS: (MS+) 317.3, (MS-) 315.3.Step b) Formation of 3-[4-(4-aminophenyl)piperidin-1-yl]-1,1,1-trifluoropropan-2-ol

[000306] The title compound was obtained, following procedure described for intermediate 31, step d), but starting from 1,1,1-trifluoro-3-[4-(4-nitrophenyl)-3,6-di -hydropyridin-1(2H)-yl]propan-2-ol (3.6 g; 11.4 mmol; 1.0 eq.) as a yellow solid (3.2 g, 98%). UPLC/MS: (MS+) 289.4.Step c) Formation of 3-[4-(4-azidophenyl)piperidin-1-yl]-1,1,1-trifluoropropan-2-ol

[000307] The title compound was obtained, following procedure described for intermediate 7, step c), but starting from 3-[4-(4-aminophenyl)piperidin-1-yl]-1,1,1-trifluoropropan -2-ol (500 mg; 1.84 mmol; 1.0 eq.) as a brown oil (570 mg, 99%). UPLC/MS: (MS+) 315.4. Intermediate 33: 1-(4-azidobenzoyl)-N,N-dimethylpiperidin-4-amine

[000308] The title compound was described for intermediate 3, but azidobenzoic (3.0 g; 18.4 mmol; 1.0 eq.) and 4-(dimethylamino)piperidine (2.36 g; 18.4 mmol; 1.0 eq.) as an orange oil (3.65 eq.) g, 73%).1H NMR (300 MHz, DMSO-d6) δ 7.52 - 7.36 (m, 2H), 7.25 - 7.09 (m, 2H), 4.61 - 4.20 (m, 1H), 3.75 - 3.37 (m, 2H), 1H), 3.14 - 2.72 (m, 2H), 2.45 - 2.27 (m, 1H), 2.19 (s, 6H), 1.94 - 1.61 (m, 2H), 1.44 - 1.23 (m, 2H). Intermediate 34: 1 -{4-[4-(5-bromo-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}-N,N-dimethylpiperidin-4-amine

[000309] The title compound was obtained, following procedure described for intermediate 10 but starting from 5-Bromo-3-ethynyl-1H-indazole (1.5 g; 6.8 mmol; 1.0 eq.) and 1-(4-azidobenzoyl )-N,N-dimethylpiperidin-4-amine (1.85 g; 6.8 mmol; 1.0 eq.) as a yellow powder (1.36g, 37%). HPLC (max scheme) 99.8%; TA 3.36min. UPLC/MS: (MS+) 496.2. Intermediate 35 : 4-(4-azidobenzyl)morpholine

[000310] The title compound was obtained, following procedure described for intermediate 7, step c), but starting from 4-morpholin-4-ylmethyl-phenylamine (1.06 g; 5.51 mmol; 1.0 eq.) as a yellow oil (1.21g, 100%).1H NMR (300MHz, DMSO-d6) δ 7.34 (d, J=8.4Hz, 2H), 7.07 (d, J=8.4Hz, 2H), 3.62 - 3.49 (m, 4H) ), 3.43 (s, 2H), 2.41 - 2.23 (m, 4H). HPLC (max scheme) 97.2%; RT 1.36min. Intermediate 36 : Methyl 3-ethynyl-1H-indazole-5-carboxylate

[000311] The title compound was obtained, following procedure described for intermediate 1 but starting from methyl 1H-indazole-5-carboxylate as a yellow solid (3.80 g; 91.11%). 1H NMR (400 MHz, DMSO) δ 13.78 (s, 1H), 8.33-8.32 (t, J = 0.68 Hz, 1H), 7.97-7.95 (m, 1H), 7.70-7.67 (m, 1H), 4.64 (s, 1H), 3.87(s , 3H). Intermediate 37: 5-[(3-chloro-6-oxopyridazin-1(6H)-yl)methyl]-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1 tert-butyl ,2,3-triazol-4-yl}-1H-indazol-1-carboxylate

[000312] DIAD (0.35 mL; 1.80 mmol; 2.3 eq.) was added dropwise over 1 min to a solution of 6-chloropyridazin-3(2H)-one (153 mg; 1.17 mmol; 1.5 eq.), 5 tert-butyl -(hydroxymethyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-1-carboxylate ( 393 mg; 0.78 mmol; 1.0 eq.) and triphenylphosphine (430 mg; 1.64 mmol; 2.1 eq.) in DCM (15 mL). A reaction mixture was stirred at RT for 16 h, then diluted with DCM and sequentially washed with the 1N HCl solution and brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash silica chromatography (EtOAc: n-heptane, gradient from 30:70 to 90:10) to give the title compound as a white solid (316 mg, 66%). 1 H NMR (300 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.54 (s, 1H), 8.19 (d, J = 8.6 Hz, 2H), 8.14 (d, J = 8.8 Hz, 1H), 7.75 - 7.64 (m, 3H ), 7.60 (d, J = 9.7 Hz, 1H), 7.13 (d, J = 9.7 Hz, 1H), 5.42 (s, 2H), 3.64 (s, 8H), 1.69 (s, 9H). HPLC (max scheme) 98.6%; TA 4.10min. UPLC/MS: (MS+) 617.1, (MS-) 675.1. Intermediate 38: (1S,4S)-5-(4-azidobenzyl)-2-oxa-5-azabicyclo[2.2.1]heptaneStep a) Formation of (1S,4S)-5-(4-nitrobenzyl)-2-oxa-5-azabicyclo[2.2.1]heptane

[000313] The title compound was obtained, following procedure described for intermediate 31, step c), but starting from 4-nitrobenzaldehyde (500 mg; 3.31 mmol; 1.0 eq.) and (1S,4S)-2-Oxa-5 - azabicyclo2.2.1heptane HCl (Active Scientific, 538 mg; 3.97 mmol; 1.20eq.) as a yellow oil (843 mg, 100%).1H NMR (300 MHz, DMSO-d6) δ 8.26 - 8.12 (m, 2H ), 7.68 - 7.50 (m, 2H), 4.36 (brs, 1H), 3.93 (d, J = 7.6 Hz, 1H), 3.86 (d, J = 2.9 Hz, 2H), 3.54 (dd, J = 7.5, 1.8 Hz, 1H), 3.47 (brs, 1H), 2.74 (dd, J = 9.9, 1.7 Hz, 1H), 2.42 (d, J = 9.9 Hz, 1H), 1.88 - 1.78 (m, 1H), 1.67 - 1.56 (m, 1H).Step b) Formation of 4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]anilineChiral

[000314] A solution of (1S,4S)-5-(4-nitrobenzyl)-2-oxa-5-azabicyclo[2.2.1]heptane (943 mg; 4.03 mmol; 1.0 eq.) in EtOAc (10 mL) was hydrogenated under 10 bars H 2 in the presence of Pd/C (wet, 10%, 43 mg, 0.40 mmol; 0.1 eq.) O/N. The crude was filtered through a pad of celite, concentrated under reduced pressure and purified by flash silica chromatography (DCM:MeOH:NH4OH, 96:3:1) to give the title compound as a yellow oil ( 80 mg, 10%). 1 H NMR (300 MHz, DMSO-d6) d 6.95 (d, J = 8.4 Hz, 2H), 6.54 - 6.44 (m, 2H), 4.91 (s, 2H), 4.31 (s, 2H), 1H), 3.87 (d, J = 7.4 Hz, 1H), 3.58 - 3.41 (m, 3H), 3.35 (d, J = 8.1 Hz, 1H), 2.66 (dd, J = 9.9, 1.7 Hz, 1H), 2.34 (d, J = 10.0 Hz, 1H), 1.74 (dd, J = 9.5, 2.1 Hz, 1H), 1.54 (d, J = 9.5 Hz, 1H).Step c) Formation of (1S,4S)-5 -(4-azidobenzyl)-2-oxa-5-azabicyclo[2.2.1]heptane

[000315] The title compound was obtained, following procedure described for intermediate 7, step c), but starting from 4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5 -ylmethyl]aniline (80 mg; 0.39 mmol; 1.0 eq.) as a yellow oil (110 mg, 100%). 1H NMR (300 MHz, CDCl3) δ 7.40 - 7.30 (m, 2H), 7.08 - 6.92 (m, 2H), 4.43 (brs, 1H), 4.12 (d, J = 7.4 Hz, 1H), 3.75 (d, 1H), J = 3.5 Hz, 2H), 3.66 (dd, J = 7.8, 1.8 Hz, 1H), 3.46 (brs, 1H), 2.87 (dd, J = 10.2, 1.7 Hz, 1H), 2.62 - 2.54 (m, 1H ), 1.92 (dd, J = 9.8, 2.1 Hz, 1H), 1.84 - 1.68 (m, 1H). Intermediate 39: 3-(4-azidophenyl)-8-cyclohexyl-8-azabicyclo[3.2.1]octane Step a) Formation of 3-(4-nitrophenyl)-8-azabicyclo[3.2.1]oct-2 tert-butyl -ene-8-carboxylate

[000316] A mixture of 1-bromo-4-nitrobenzene (2.0 g; 9.9 mmol; 1.0 eq.), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) tert-butyl -8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (4.3 g; 12.9 mmol; 1.30eq.), PdCl2(dppf) (724 mg; 0.99 mmol; 0.1 eq.) and potassium carbonate (4.1 g; 29.7 mmol; 3.0 eq.) in 1,4-dioxane (20 mL) and water (10 mL) was heated to 90°C under an O/N nitrogen atmosphere. A reaction mixture was filtered through a pad of celite. The cake was washed with dichloromethane, phases were separated and the organic phase was washed with water and brine. The organic phase was then dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash silica chromatography (heptane/EtOAc, gradient from 90:10 to 80:20) to give the title compound as a yellow solid (1.97 g; 60%). 1 H NMR (300 MHz, DMSO- d6-d6) δ: 8.17 (d, J= 9.0 Hz, 2H), 7.69 (d, J= 9.0 Hz, 2H), 6.84 (d, J= 5.3 Hz, 1H), 4.43 (t, J= 5.3 Hz , 1H), 4.35 (m, 1H), 2.97 (d, J= 17.5 Hz, 1H), 2.32 (d, J= 17.5 Hz, 1H), 2.15 (m, 1H), 1.95-1.88 (m, 2H) , 1.71-1.58 (m, 1H), 1.37 (s, 9H). HPLC (max scheme) 89.0%; TA %4.66min. UPLC/MS: (MS+) 331.3.Step b) Formation of 3-(4-nitrophenyl)-8-azabicyclo[3.2.1]oct-2-ene

[000317] Hydrogen chloride (22 mL of a 4N solution in dioxane) was added to a solution of 3-(4-nitrophenyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate of tert-butyl (1.97 g; 5.96 mmol; 1.0 eq.) in DCM (20 mL) and the reaction mixture was stirred at RT. After 1h, a reaction mixture was diluted with DCM and the organic phase was washed with 1N NaOH and brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow solid (1.05g, 76%).1H NMR (300 MHz, DMSO-d6) δ 8.16 (d, J= 9.0 Hz, 2H), 7.65 (d, J= 9.0 Hz, 2H), 6.82 (dt, J= 6.0 Hz, 1.5 Hz, 1H), 3.74 -3.69 (m, 2H), 2.76 (dd, J= 17.5 Hz, 4.5 Hz, 1H), 2.17 (dd, J= 17.5 Hz, 1.5 Hz, 1H), 1,921.68 (m, 3H), 1.56-1.46 (m, 1H). HPLC (max scheme) 91.7%; TA %1.84min. UPLC/MS: (MS+) 231.2.Step c) Formation of 8-cyclohexyl-3-(4-nitrophenyl)-8-azabicyclo[3.2.1]oct-2-ene

[000318] Sodium triacetoxyborohydride (460 mg, 2.17 mmol, 2.0 eq.) was added to a solution of 3-(4-nitrophenyl)-8-azabicyclo[3.2.1]oct-2-ene (250 mg; 1.1 mmol ; 1.0 eq.) and cyclohexanone (168 μl; 1.63 mmol; 1.5 eq.) in DCE (10.00 mL) and a reaction mixture was heated to 50°C under nitrogen atmosphere. After 1h, a reaction mixture was poured into a saturated solution of NaHCO3. Aqueous phase was extracted twice with DCM and combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (DCM:MeOH, gradient from 100:0 to 90:10) to give the title compound as a beige solid (220 mg, 65%). 1 H NMR (300 MHz, DMSO- d6) δ 8.17 (d, J= 8.9 Hz, 2H), 7.68 (d, J= 8.9 Hz, 2H), 6.68 (d, J= 5.4 Hz, 1H), 3.79-3.68 (m, 2H), 2.80- 2.75 (m, 1H), 2.31 (m, 1H), 2.07-1.66 (m, 8H), 1.52 (m, 2H), 1.23-1.09 (m, 5H). HPLC (max scheme) 100.0%; TA %3.01min. UPLC/MS: (MS+) 313.4. Step d) Formation of 4-(8-cyclohexyl-8-azabicyclo[3.2.1]oct-3-yl)aniline

[000319] A solution of 8-cyclohexyl-3-(4-nitrophenyl)-8-azabicyclo[3.2.1]oct-2-ene (230 mg; 0.74 mmol; 1.0 eq.) in EtOH (7 mL) was passed twice at 1 mL/min through the H-Cube using a Pd/C cartridge under full H 2 at 25°C. The solution was then concentrated under reduced pressure to give the title compound as a 66:33 mixture of the endo:exo isomers (163 mg; 78%). 1 H NMR (DMSO) δ 6.94 (d, J= 8.3 Hz, 1.3 H), 6.87 (d, J= 8.3 Hz, 0.7H), 6.48-6.45 (m, 2H), 4.78 (bs, 2H), 3.47 (m, 2H), 2.84-2.70 (m, 1H), 2.19- 2.07 (m, 2H), 1.90-1.82 (m, 3H), 1.72-1.63 (m, 5H), 1.54-1.46 (m, 2H), 1.40-1.33 (m, 2H), 1.27-0.98 (m, 5H ). HPLC (max scheme) 65.3%; TA %2.25min. UPLC/MS: (MS+) 285.4.Step e) Formation of 3-(4-azidophenyl)-8-cyclohexyl-8-azabicyclo[3.2.1]octane

[000320] The title compound was obtained following procedure described for intermediate 7, step c), but starting from 4-(8-cyclohexyl-8-azabicyclo[3.2.1]oct-3-yl)aniline ( 175 mg; 0.62 mmol; 1.0 eq.) as a 66:33 mixture of endo:exo isomers (140 mg, 73%).1H NMR (300 MHz, DMSO-d6-d6): δ 7.37 (d, J=8.5 Hz, 1.3H), 7.30 (d, J=8.5 Hz, 0.7H), 7.05-7.00 (m, 2H), 3.53 (m, 2H), 3.00-2.89 (m, 1H), 2.28-2.19 (m, 2H), 1.95-1.85 (m, 3H), 1.72 (m, 5H), 1.59-1.49 (m, 2H), 1.39-1.35 (m, 2H), 1.28-1.11 (m, 5H). HPLC (max scheme) 91.8%; TA %3.08min. UPLC/MS: (MS+) 311.4. Intermediate 40: 1-(4-Methoxybenzyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4- yl}-1H-indazol-5-olStep a) Formation of 5-bromo-1-(4-methoxybenzyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2, 3-triazol-4-yl}-1H-indazole

[000321] 4-Methoxybenzylchloride (1.13 mL; 8.27 mmol; 1.5 eq.) was added dropwise to a solution of {4-[4-(5-Bromo-1H-indazol-3-yl)-[1 ,2,3] triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (2.5 g; 5.5 mmol; 1.0 eq.) and KOH (0.34 g; 6.07 mmol; 1.1 eq.) in acetone (75 mL) and DMF (25 mL). A reaction mixture was stirred at RT O/N. It was then diluted with 0.1N HCl solution and extracted three times with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (DCM:MeOH, gradient from 100:0 to 90:10) to give the title compound as an orange oil (4.1g, 100%). UPLC/MS: (MS+) 573.0.Step b) Formation of 1-(4-methoxybenzyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol- 4-yl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

[000322] A mixture of 5-bromo-1-(4-methoxybenzyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl} -1H-indazole (200 mg; 0.35 mmol; 1.0 eq.), bis-(pinacolato)diboron (133 mg; 0.52 mmol; 1.5 eq.), potassium acetate (103 mg; 1.05 mmol; 3.0 eq.) and PdCl2 (dppf) (25 mg, 0.03 mmol, 0.1 eq.) in dioxane (5 mL) was heated O/N in a sealed tube to 90°C. Solvent was then removed under reduced pressure and the crude was purified by flash silica chromatography (DCM:MeOH) to give the title compound as a brown solid (220 mg, 100%). UPLC/MS: (MS+) 624.2.Step c) Formation of 1-(4-methoxybenzyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol- 4-yl}-1H-indazol-5-ol

[000323] A solution of 1-(4-methoxybenzyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-5-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (239 mg; 0.39 mmol; 1.0 eq.) and hydrogen peroxide (52 mg, 1.54 mmol, 4 eq. .) in EtOAc (4.8 mL) was stirred O/N at RT. Solvent was removed under reduced pressure and the crude was purified by preparative HPLC to give the title compound as a white powder (135 mg, 69%). UPLC/MS: (MS+) 511.1. Intermediate 41: [3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1-(tetra -hydro-2H-pyran-2-yl)-1H-indazol-5-yl]methanolStep a) Formation of 3-ethynyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5 -methyl carboxylate

[000324] PTSA (0.99 g; 5.77 mmol; 0.11 eq.) was added to a solution of 3-ethynyl-1H-indazole-5-carboxylic acid methyl ester (10.1 g; 50.2 mmol; 1.0 eq.) and 3, 4-dihydro-2H-pyran (10.5 mL; 116 mmol; 2.3 eq.) in DME (100 mL). A reaction mixture was refluxed for 3 h, then cooled and concentrated. The residue was redissolved in DCM and washed sequentially with NaHCO3 (sat) and NaCl (sat) solutions, dried over magnesium sulfate, filtered and concentrated. The crude was triturated with Et2O to give the title compound as a yellow solid (7.9 g, 54%).
[000325] 1 H NMR (300 MHz, DMSO-d6) δ 8.33 (dd, J = 1.5, 0.8 Hz, 1H), 8.05 (dd, J = 8.9, 1.5 Hz, 1H), 7.94 (dd, J = 8.9, 0.8 Hz, 1H), 5.96 (dd, J = 9.5, 2.4 Hz, 1H), 4.75 (s, 1H), 3.95 - 3.84 (m, 4H), 3.82 - 3.70 (m, 1H), 2.43 - 2.26 (m , 1H), 2.09 - 1.94 (m, 2H), 1.84 - 1.65 (m, 1H), 1.65 - 1.50 (m, 2H). HPLC (max scheme) 98.4%; TA %3.92min. UPLC/MS: (MS+) 201.2.Step b) Formation of 3-Ethynyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylic acid

[000326] Sodium hydroxide (100 mL; 5.0 M; 500 mmol; 18.1 eq.) was added in one portion to a solution of 3-ethynyl-1-(tetrahydro-2H-pyran-2-yl)-1H methyl -indazole-5-carboxylate (7.9 g; 27.7 mmol; 1.0 eq.) in DMF (100 mL) and MeOH (100 mL). A reaction mixture was stirred at RT for 1h, then poured into a 1N HCl solution (pH 1) and extracted with DCM. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The brown solid obtained was triturated with MeOH to give the title compound as a red solid (4.83g, 65%).
[000327] 1H NMR (300 MHz, DMSO-d6) δ 13.09 (s, 1H), 8.35 - 8.28 (m, 1H), 8.04 (dd, J = 8.9, 1.5 Hz, 1H), 7.90 (dd, J = 8.9, 0.6 Hz, 1H), 5.95 (dd, J = 9.5, 2.3 Hz, 1H), 4.73 (s, 1H), 3.94 - 3.84 (m, 1H), 3.83 - 3.69 (m, 1H), 2.43 - 2.27 (m, 1H), 2.09 - 1.93 (m, 2H), 1.83 - 1.65 (m, 1H), 1.64 - 1.52 (m, 2H). HPLC (max scheme) 99.5%; TA %3.17min. UPLC/MS: (MS-) 269.3.Step c) Formation of [3-ethynyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl]methanol

[000328] BOP (3.18 g; 7.19 mmol; 1.20 eq.) was added to a solution of 3-ethynyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylic acid ( 1.97 g; 5.97 mmol; 1.0 eq.) in DIEA (7 mL; 41.2 mmol; 6.9 eq.) and THF (350 mL). After 1 h, DMA (100 mL) was added in one portion followed by sodium borohydride (0.70 g; 18.5 mmol; 3.1 eq.). A reaction mixture was stirred at RT for 20 min, diluted with EtOAc and washed sequentially with 1N HCl, NaHCO3 (sat) and NaCl (sat) solutions, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (EtOAc: n-heptane, gradient from 10:90 to 50:50) gave the title compound as a clear oil (1.26 g, 78.2%).
[000329] 1H NMR (300 MHz, DMSO-d6) δ 7.75 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 0.6 Hz, 1H), 7.43 (dd, J = 8.7, 1.5 Hz, 1H ), 5.87 (dd, J = 9.5, 2.3 Hz, 1H), 5.29 (t, J = 5.8 Hz, 1H), 4.62 (d, J = 5.8 Hz, 2H), 4.58 (s, 1H), 3.93 - 3.82 (m, 1H), 3.80 - 3.68 (m, 1H), 2.44 - 2.27 (m, 1H), 2.08 - 1.91 (m, 2H), 1.83 - 1.64 (m, 1H), 1.63 - 1.51 (m, 2H) . HPLC (max scheme) 95.2%; TA %2.78min. UPLC/MS: (MS+) 257.2.Step d) Formation of [3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl]methanol

[000330] The title compound was obtained, following procedure described for intermediate 10, but starting from [3-ethynyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl ]methanol (1.39 g; 5.42mmol; 1.0 eq.) and 4-(4-azidobenzoyl)morpholine (1.89 g; 8.14 mmol; 1.5 eq) as a yellow solid (1.87g, 71%).
[000331] 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.33 (d, J = 0.6 Hz, 1H), 8.18 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 8.7 Hz, 2H), 7.47 (dd, J = 8.7, 1.5 Hz, 1H), 5.98 - 5.90 (m, 1H), 5.31 (t, J = 5.7 Hz , 1H), 4.67 (d, J = 5.7 Hz, 2H), 3.98 - 3.89 (m, 1H), 3.85 - 3.73 (m, 1H), 3.71 - 3.36 (m, 8H), 2.59 - 2.42 (m, 1H) ), 2.15 - 1.97 (m, 2H), 1.88 - 1.71 (m, 1H), 1.68 - 1.51 (m, 2H). HPLC (max scheme) 92.9%; TA %2.99min. UPLC/MS: (MS+) 489.5.Example 1: 3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

[000332] The title compound was obtained, following procedure described for intermediate 10, but starting from 4-(4-azidobenzoyl)morpholine (710 mg; 3.1 mmol; 1.0 eq.) and 3-ethynyl-1H-indazole ( 435 mg; 3.1 mmol; 1.0 eq.). After purification by preparative HPLC, it was obtained as a white solid.
[000333] 1H NMR (300 Mz, DMSO-d6) δ: 13.39 (brs, 1H), 9.40 (s, 1H), 8.37 (dt, J = 8.2, 1.0 Hz, 1H), 8.16 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.62 (dt, J = 8.4, 1.0 Hz, 1H), 7.48-7.42 (m, 1H), 7.297.24 (m, 1H), 3.64 (m, 6H), 3.41 (m, 2H). HPLC (Condition A): RT 2.90 min (99.3% purity). MS (ESI+): 375.2, MS (ESI-): 373.2.Example 2: 3-[1-(4-{[3-(pyrrolidin-1-ylmethyl)piperidin-1-yl]carbonyl}phenyl)-1H- 1,2,3-triazol-4-yl]-1H-indazole

[000334] The title compound was prepared following procedure described for intermediate 10, but starting from 1-(4-azidobenzoyl)-3-(pyrrolidin-1-ylmethyl)piperidine (420 mg; 1.34 mmol; 1.0 eq.) and 3-ethynyl-1H-indazole (190 mg; 1.34 mmol; 1.0 eq.). After purification by preparative HPLC, it was obtained as the formic acid salt. The salt was solubilized in DCM and washed with a saturated solution of NaHCO3 then brine. Organic phase was dried over magnesium sulfate, filtered and concentrated. The resulting oil was suspended in EtOH, and concentrated to dryness to give the title compound as a yellow powder.
[000335] 1H NMR (300 Mz, DMSO-d6) δ: 13.37 (s, 1H), 9.37 (s, 1H), 8.36 (d, J = 8.1 Hz, 1H), 8.15 (d, J = 8.7 Hz, 2H), 7.61 (m, 3H), 7.43 (m, 1H), 7.26 (m, 1H), 4.48 (m, 0.4H), 4.25 (m, 0.6H), 3.70 (m, 0.6H), 3.52 ( m, 0.4H), 3.04 (m, 0.4H), 2.91 (m, 0.6H), 2.74 (m, 0.4H), 2.202.43 (m, 4H), 2.02 (m, 0.6H), 1.69 (m , 6H), 1.48 (m, 4H), 1.20 (m, 1H). HPLC (Condition A): RT 2.69 min (99.9% purity). MS (ESI+): 456.4, MS (ESI-): 454.5.Example 3: N-{[(2R)-1-ethylpyrrolidin-2-yl]methyl}-4-[4-(5-methyl-1H-indazole) - 3-yl)-1H-1,2,3-triazol-1-yl]benzamide

[000336] The title compound was obtained, following the procedure described for intermediate 10, but starting from 4-azido-N {[(2R)-1-ethylpyrrolidin-2-yl]methyl}benzamide (158 mg; 0.58 mmol; 1.0 eq.) and 3-ethynyl-5-methyl-1H-indazole (90 mg; 0.58 mmol; 1.0 eq.). After purification by preparative HPLC, it was obtained as a white powder.
[000337] 1H NMR (300 Mz, DMSO-d6) δ: 13.36 (brs, 1H), 9.43 (s, 1H), 8.61 (t, J = 6.0 Hz, 1H), 8.2-8.07 (m, 5H), 7.51 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 3.50-3.41 (m, 1H), 3.16-3.03 (m, 2H), 2.93-2.81 (m , 1H), 2.70-2.59 (m, 1H), 2.37-2.26 (m, 1H), 2.16 (dd, J = 16.8, 8.6 Hz, 1H), 1.88-1.78 (m, 1H), 1.71-1.57 (m , 3H), 1.07 (t, J = 7.2 Hz, 3H). HPLC (Condition B): RT 1.61 min (95.0% purity). MS (ESI+): 430.4, MS (ESI-): 428.4.Example 4: N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-4-[4-(5-methyl-1H-indazole) - 3-yl)-1H-1,2,3-triazol-1-yl]benzamide

[000338] The title compound was obtained, following procedure described for intermediate 10, but starting from 4-azido-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}benzamide (197 mg; 0.58 mmol; 1.0 eq.) and 3-ethynyl-5-methyl-1H-indazole (90 mg; 0.58 mmol; 1.0 eq.). After purification by preparative HPLC, it was obtained as a white powder.
[000339] 1H NMR (300 Mz, DMSO-d6): δ: 13.28 (brs, 1H), 9.40 (s, 1H), 8.60 (t, J = 6.0 Hz, 1H), 8.20-8.07 (m, 5H) , 7.51 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 3.50-3.41 (m, 1H), 3.15-3.01 (m, 2H), 2.92-2.80 ( m, 1H), 2.65-2.58 (m, 1H), 2.35-2.24 (m, 1H), 2.13 (dd, J = 16.8 Hz, 8.6 Hz, 1H), 1.86-1.77 (m, 1H), 1.71-1.57 (m, 3H), 1.07 (t, J = 7.2 Hz, 3H). HPLC (Condition A): RT 2.81 min (100.0% purity). MS (ESI+): 430.4, MS (ESI-): 428.4.Example 5: 3-{1-[1-(2-pyridin-4-ylethyl)-1H-pyrazol-4-yl]-1H-1,2 ,3-triazol-4-yl}-1H-indazole

[000340] The title compound was obtained, following procedure described for intermediate 10, but starting from 4-[2-(4-azido-1H-pyrazol-1-yl)ethyl]pyridine (136 mg; 0.63 mmol; 1.0 eq.) and 3-ethynyl-1H-indazole (90 mg; 0.63 mmol; 1.0 eq.). After purification by preparative HPLC, it was obtained as a beige powder.
[000341] 1H NMR (300 Mz, DMSO-d6): 13.32 (s, 1H), 9.04 (s, 1H), 8.48-8.46 (m, 3H), 8.32 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 0.6 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.43 (ddd, J = 8.0, 5.8, 1.0 Hz, 1H), 7.27-7.22 (m, 3H), 4.52 ( t, J = 7.1 Hz, 2H), 3.28 (t, J = 7.1 Hz, 2H). HPLC (Condition A): RT 2.12 min (100.0% purity). MS (ESI+): 357.2, MS (ESI-): 355.2.Example 6: 5-methyl-3-{1-[4-(pyrrolidin-1-ylmethyl)phenyl]-1H-1,2,3-triazol- 4-yl}-1H-indazole

[000342] Sodium cyanoborohydride (166 mg; 2.64 mmol; 4.0 eq.) was added to a solution of 4-[4-(5-methyl-1H-indazol-3-yl)-1H-1,2,3- triazol-1-yl]benzaldehyde (200 mg; 0.66 mmol; 1.0 eq.) and pyrrolidine (1.64 mL; 19.8 mmol; 30 eq.) in DMA (4 mL) and the reaction mixture was stirred at RT. After 12 h, as no product was detected, sodium borohydride (100 mg; 2.64 mmol; 4.0 eq.) was added and the reaction mixture was stirred at RT for 1 h. Reaction was quenched with water and extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC provided the title compound as a formic acid salt. It was dissolved in MeOH and passed through an SPE-NH2 cartridge. Fractions containing the desired compound were concentrated to dryness providing a yellow gum, which was sonicated twice in 3 mL of Et2O. The suspension obtained was concentrated then dried overnight under high vacuum to give the title compound as a beige solid.
[000343] 1H NMR (300 Mz, DMSO-d6) δ: 13.245 (brs, 1H), 9.26 (s, 1H), 8.14-8.13 (m, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 1H), 7.27 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 3.67 (s, 2H), 2.49-2.45 ( m, 7H), 1.74-1.70 (m, 4H). HPLC (Condition A): RT 2.63 min (99.5% purity). MS (ESI+): 359.2, MS (ESI-): 357.3.Example 7: 5-Methyl-3-{1-[4-(morpholin-4-ylmethyl)phenyl]-1H-1,2,3-triazol- 4-yl}-1H-indazole

[000344] The title compound was obtained, following procedure described by example 6, but starting from 4-[4-(5-methyl-1H-indazol-3-yl)-1H-1,2,3-triazole -1-yl]benzaldehyde (200 mg; 0.66 mmol; 1.0 eq.) and morpholine (1.7 mL; 19.8 mmol; 30 eq.) as a beige solid.
[000345] 1H NMR (300 Mz, DMSO-d6) δ: 13.23 (brs, 1H), 9.26 (s, 1H), 8.14-8.13 (m, 1H), 8.01(d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 1H), 7.27 (dd, J = 8.5, 1.5 Hz, 1H), 3.60 (t, J = 4.5 Hz, 4H), 3.56 (s, 2H), 2.47 (s, 3H), 2.40 (t, J = 4.5 Hz, 4H). HPLC (Condition A): RT 2.54 min (98.6% purity). MS (ESI+): 375.2, MS (ESI-): 373.3. Example 8: N-Methyl-1-{4-[4-(5-methyl-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}methanamine

[000346] The title compound was obtained following procedure described by example 6, but starting from 4-[4-(5-methyl-1H-indazol-3-yl)-1H-1,2,3-triazol- 1-yl]benzaldehyde (200 mg; 0.66 mmol; 1.0 eq.) and methylamine (6.6 mL of a 2.00 M solution in THF; 13.2 mmol; 20 eq.) as a white solid.
[000347] 1H NMR (300 Mz, DMSO-d6) δ: 13.25 (brs, 1H), 9.27 (s, 1H), 8.28 (brs, 1H), 8.14-8.13 (m, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 1H), 7.27 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 3.87 (s, 2H), 2.48 (s, 3H), 2.37 (s, 3H). HPLC (Condition A): RT 2.45 min (98.4% purity). MS (ESI+): 319.1, MS (ESI-): 317.2.Example 9: 5-methyl-3-(1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-1H-1,2 ,3-triazol-4-yl)-1H-indazole

[000348] The title compound was obtained following procedure described by example 6, but starting from 4-[4-(5-methyl-1H-indazol-3-yl)-1H-1,2,3-triazol- 1-yl]benzaldehyde (200 mg; 0.66 mmol; 1.0 eq.) and methyl piperazine (2.2 mL; 19.8 mmol; 30 eq.) as a beige solid.
[000349] 1H NMR (DMSO-d6) δ : 13.21 (brs, 1H), 9.25 (s, 1H), 8.148.13 (m, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.54 (d , J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 1H), 7.27 (dd, J = 8.5, 1.5 Hz, 1H), 3.55 (s, 2H), 2.47 (s, 3H), 2.40 -2.34 (m, 8H), 2.16 (s, 3H). HPLC (Condition A): RT 2.29 min (90.9% purity). MS (ESI+): 388.3, MS (ESI-): 386.4.Example 10: N,N-dimethyl-1-{4-[4-(5-methyl-1H-indazol-3-yl)-1H-1, 2,3-triazol-1-yl]phenyl}methanamine

[000350] The title compound was obtained following procedure described by example 6, but starting from 4-[4-(5-methyl-1H-indazol-3-yl)-1H-1,2,3-triazol- 1-yl]benzaldehyde (180 mg; 0.59 mmol; 1.0 eq.) and dimethylamine (8.9 mL of a 2M solution in THF; 17.8 mmol; 30 eq.) as a beige solid.
[000351] 1H NMR (300 Mz, DMSO-d6) δ: 13.23 (brs, 1H), 9.27 (s, 1H), 8.14 (m, 1H), 8.01(d, J = 8.6 Hz, 2H), 7.54 ( d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.6 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1.5 Hz, 1H), 3.48 (s, 2H), 2.48 (s, 3H) , 2.19 (s, 6H). HPLC (Condition A): RT 2.53 min (97.3% purity). MS (ESI+): 333.2, MS (ESI-): 331.3.Example 11: 5-Methyl-3-{1-[4-(piperazin-1-ylmethyl)phenyl]-1H-1,2,3-triazol- 4-yl}-1H-indazole

[000352] Sodium triacetoxyborohydride (279 mg; 1.32 mmol; 2.0 eq.) was added to a solution of tert-butyl-1-piperazinecarboxylate (1.22 g; 6.59 mmol; 10 eq.) and 4-[4-(5- methyl-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzaldehyde (200 mg; 0.66 mmol; 1.0 eq.) in DMA (4 mL) and a reaction mixture was stirred overnight at TA. Sodium triacetoxyborohydride (279 mg; 1.32 mmol; 2.0 eq.) and glacial acetic acid (75.42 μl; 1.32 mmol; 2.00 eq.) then sodium cyanoborohydride (83 mg; 1.32 mmol; 2. eq.) were added to complete the reaction which was quenched with water and extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting gum was stirred at RT in a solution of HCl in dioxane (5 mL, 4N) for 2 hours.
[000353] A reaction mixture was basified to pH = 9-10 and extracted with EtOAc. Organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC provided the title compound as a formic acid salt. It was dissolved in MeOH and passed through an SPE-NH2 cartridge. Fractions containing the desired compound were concentrated to dryness providing a yellow gum, which was sonicated twice in 3 mL of Et2O. The suspension obtained was concentrated then dried overnight under high vacuum to give the title compound as a beige solid.
[000354] 1H NMR (300 Mz, DMSO-d6) δ: 13.23 (brs, 1H), 9.25 (s, 1H), 8.14-8.13 (m, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 3.52 (s, 2H), 2.72-2.69 ( m, 4H), 2.487 (s, 3H), 2.32-2.30 (m, 4H). HPLC (Condition A): RT 2.22 min (95.4% purity). MS (ESI+): 374.3, MS (ESI-): 372.3.Example 12: 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl] phenyl}methanamineStep a) Formation of tert-butyl {4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzyl}carbamate

[000355] The title compound was obtained, following procedure described for intermediate 10, but starting from tert-butyl 4-azidobenzyl)carbamate (prepared as described in Organic Letters (2003), 5(14), 2571-2572 ,; 1.12 g; 4.51 mmol; 1.0 eq.) and 3-ethynyl-1H-indazole (641 mg; 4.51 mmol; 1.0 eq.) as a white powder.
[000356] 1H NMR (DMSO-d6) δ 13.35 (brs, 1H), 9.28 (s, 1H), 8.36 (d, J= 8.2, 1H), 8.00 (d, J=8.4 Hz, 2H), 7.60 ( d, J = 8.4 Hz, 1H), 7.54-7.41 (m, 4H), 7.28-7.20 (m, 1H), 4.22 (d, J = 6.0 Hz, 2H), 1.41 (s, 9H). HPLC (Condition A): RT 3.95 min (95.1% purity). MS (ESI+): 391.3, MS (ESI-): 389.3.Step b) Formation of 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol- 1-yl]phenyl}methanamine.

[000357] A solution of tert-butyl {4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzyl}carbamate (1.17 g; 3.00 mmol; 1.0 eq.) in HCl solution in 1,4-dioxane (7.5 mL, 4N) was stirred at RT. After 48h, a reaction mixture was concentrated to dryness providing a thick solid, which was sonicated in a 1:1 mixture of DCM/MeOH. The suspension obtained was concentrated to dryness to give the title compound as a beige solid (967 mg, 98%). HPLC (Condition A): RT 2.08 min (95.3% purity). MS (ESI+): 291.1, MS (ESI-): 289.2. Preparative HPLC purification of 50 mg of this crude provided a pure sample (35 mg):
[000358] 1H NMR (300 Mz, DMSO-d6) δ: 13.40 (brs, 1H), 9.33 (s, 1H), 8.36 (dt, J = 8.2 Hz, J = 1.0 Hz, 1H), 8.07 (d, 1H), J = 8.5 Hz, 2H), 7.68 (d, J = 8.5 Hz, 2H), 7.62 (dt, J = 8.2 Hz, 1.0 Hz, 1H), 7.47-7.42 (m, 1H), 7.29-7.24 (m, 1H), 4.02 (s, 2H). HPLC (Condition A): RT 2.06 min (97.5% purity). MS (ESI+): 291.1, MS (ESI-): 289.1.Example 13:N-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl] benzyl}cyclopentanecarboxamide

[000359] TBTU (185 mg; 0.58 mmol; 1.3 eq.) was added to a cold (0°C) solution of c-cyclopentane carboxylic acid (53 μl; 0.49 mmol; 1.1 eq.) in DMF (2.9 mL). After 10 min, a solution of 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}methanamine (145 mg; 0.44 mmol; 1.0 eq.) and DIEA (174 μl; 1.02 mmol; 2.3 eq.) in DMF (2.9 mL) was added and the reaction mixture was stirred overnight at RT. DCM was added and the reaction mixture was washed with a saturated aqueous solution of NH4Cl and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude was purified by preparative HPLC to yield the title compound as a white solid.
[000360] 1H NMR (300 Mz, DMSO-d6) δ: 13.36 (brs, 1H), 9.28 (s, 1H), 8.41 (t, J = 6.0 Hz, 1H), 8.36 (dt, J = 8.2 Hz, 1.0 Hz, 1H), 8.00 (d, J = 8.6 Hz, 2H), 7.60 (dt, J = 8.2 Hz, 1.0 Hz, 1H), 7.49-7.41 (m, 3H); 7.28-7.23 (m, 1H), 4.35 (d, J = 6.0 Hz, 2H), 2.70-2.59 (m, 1H), 1,841.49 (m, 8H). HPLC (Condition A): RT 3.59 min (97.6% purity). MS (ESI+): 387.3, MS (ESI-): 385.4.Example 14:N-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl] benzyl}acetamide

[000361] To a solution of 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}methanamine (190 mg; 0.58 mmol; 1.0 eq.) and TEA (242 µl; 1.74 mmol; 3.0 eq.) in DMF (3.8 ml) was added acetyl chloride (46 µl; 0.70 mmol; 1.2 eq.) and the reaction mixture was stirred overnight at RT . Reaction mixture was diluted with DCM and washed with water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC provided the title compound as a white solid.
[000362] 1H NMR (300 Mz, DMSO) δ: 13.36 (brs, 1H), 8.29 (s, 1H), 8.47 (t, J = 5.9 Hz, 1H), 8.36 (dt, J = 8.0 Hz, J= 1.0 Hz, 1H), 8.01 (d, J = 8.6 Hz, 2H), 7.60 (dt, J = 8.4 Hz, J = 1.0 Hz, 1H), 7.49 (d, J = 8.6 Hz, 2H), 7.47-7.41 (m, 1H), 7.28-7.23 (m, 1H), 4.34 (d, J = 5.9 Hz, 2H), 1.90 (s, 3H). HPLC (Condition A): RT 2.81 min (97.7% purity). MS (ESI+): 333.2, MS (ESI-): 331.2.Example 15: N-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl] benzyl}isonicotinamide

[000363] The title compound was obtained following procedure described by example 14, but starting from 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1 -yl]phenyl}methanamine (190 mg; 0.58 mmol; 1.0 eq.) and isonicotinoyl chloride hydrochloride (124. mg; 0.70 mmol; 1.2 eq.) as a white solid.
[000364] 1H NMR (300Mz, DMSO): 13.36 (brs, 1H), 9.45 (t, J = 6.0 Hz, 1H), 9.29 (s, 1H), 8.77-8.75 (m, 2H), 8.36 (dt, J = 8.0 Hz, 1.0 Hz, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.84-7.82 (m, 2H), 7.62-7.52 (m, 3H), 7.46-7.41 (m, 1H), 7.28-7.23 (m, 1H), 4.60 (d, J = 6.0 Hz, 2H). HPLC (Condition A): RT 2.49 min (100.0% purity). MS (ESI+): 396.3, MS (ESI-): 394.3.Example 16: N-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl] benzyl}-2-morpholin-4-ylacetamide

[000365] The title compound was obtained following procedure described by example 13, but starting from 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1 -yl]phenyl}methanamine (150 mg; 0.46 mmol; 1.0 eq.) and 4-morpholinoacetic acid (Scientific Matrix, 73 mg; 0.50 mmol; 1.1 eq.) as a white solid.
[000366] 1H NMR (300 Mz, DMSO-d6): 13.36 (brs, 1H), 9.29 (s, 1H), 8.45 (t, J = 6.0 Hz, 1H), 8.36 (d, J = 8.0 Hz, 1H ), 8.00 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.6 Hz, 2H), 7.47-7.41 (m, 1H), 7.28-7.23 (m, 1H), 4.39 (d, J = 6.0 Hz, 2H), 3.63 (t, J = 4.6 Hz, 4H), 3.01 (s, 2H), 2.45 (t, J = 4.6 Hz, 4H). HPLC (Condition A): RT 2.50 min (99.6% purity). MS (ESI+): 418.4, MS (ESI-): 416.5.Example 17: N-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl] benzyl}tetrahydro-2H-pyran-4-carboxamide

[000367] The title compound was obtained following procedure described by example 14, but starting from 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1 -yl]phenyl}methanamine (190 mg; 0.58 mmol; 1.0 eq.) and tetrahydro-2H-pyran-4-carbonyl chloride (104 mg; 0.70 mmol; 1.2 eq.) as a white solid.
[000368] 1H NMR (300 Mz, DMSO-d6) δ: 13.36 (brs, 1H), 9.29 (s, 1H), 8.45 (t, J= 6.0 Hz, 1H), 8.35 (dt, J= 8.1 Hz, 1.0Hz, 1H), 8.00 (d, J=8.6Hz, 2H), 7.61 (dt, J=8.5Hz, 1.0HZ, 1H), 7.49-7.71 (m, 3H), 7.287.23 (m, 1H) , 4.36 (d, J = 6.0 Hz, 2H), 3.91-3.85 (m, 2H), 3.36-3.28 (m, 2H), 2.46-2.39 (m, 1H), 1.67-1.59 (m, 4H). HPLC (Condition A): RT 2.93 min (98.9% purity). MS (ESI+): 403.3, MS (ESI-): 401.3.Example 18: 3-{1-[4-(2-morpholin-4-yl-2-oxoethyl)phenyl]-1H-1,2,3- triazol-4-yl}-1H-indazole

[000369] COMU (151 mg; 0.41 mmol; 1.3 eq.) was added in a solution of {4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1- yl]phenyl}acetic acid (100 mg; 0.31 mmol; 1.0 eq.) and DIEA (69 μl; 0.41 mmol; 1.3 eq.) in DMF (4 mL). After 1-2 min, morpholine (33 μl; 0.38 mmol; 1.2 eq.) was added and the reaction mixture was stirred overnight at RT. EtOAc was added and the reaction mixture was washed twice with a saturated aqueous solution of NaHCO3. The organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC provided the title compound as a white solid.
[000370] 1H NMR (300 Mz, DMSO-d6) δ: 13.36 (brs, 1H), 9.29 (s, 1H), 8.36 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.5 Hz, 1H), 7.49-7.41 (m, 3H), 7.28-7.23 (m, 1H), 3.84 (s, 2H), 3.58-3.55 (m, 6H), 3.49 -3.46 (m, 2H). HPLC (Condition A): RT 2.97 min (98.8% purity). MS (ESI+): 389.3, MS(ESI-): 387.3.Example 19: 3-{1-[4-(2-oxo-2-pyrrolidin-1-ylethyl)phenyl]-1H-1,2,3- triazol-4-yl}-1H-indazole

[000371] The title compound was obtained following procedure described by example 18, but starting from {4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1- yl]phenyl}acetic acid (120 mg; 0.38 mmol; 1.0 eq.) and pyrrolidine (37 μl; 0.45 mmol; 1.2 eq.) as a beige solid.
[000372] 1H NMR (300 Mz, DMSO-d6) δ: 13.35 (brs, 1H), 9.29 (s, 1H), 8.36 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.49-7.42 (m, 3H), 7.28-7.23 (m, 1H), 3.74 (s, 2H), 3.52 (t, J = 6.7 Hz, 2H ), 3.32 (t, J = 6.7 Hz, 2H), 1.90 (quint., J = 6.7 Hz, 2H), 1.78 (quint., J = 6.7 Hz, 2H). HPLC (Condition A): RT 3.29 min (94.3% purity). MS (ESI+): 373.25, MS (ESI-): 371.3. Example 20: 3-[1-(6-morpholin-4-ylpyridin-3-yl)-1H-1,2,3-triazol-4-yl]-1H-indazol

[000373] A suspension of 3-[1-(6-chloropyridin-3-yl)-1H-1,2,3-triazol-4-yl]-1H-indazole (13 mg; 0.04 mmol; 1.0 eq.) in morpholine (0.5 mL) was heated in MW at 120°C for 4.5 h. The precipitate obtained was filtered, washed with Et2O and dried under vacuum at 50°C to yield the title compound as a beige solid.
[000374] 1H NMR (DMSO-d6) δ: 13.33 (s, 1H), 9.18 (s, 1H), 8.74 (d, J= 2.8 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.16 (dd, J = 2.6, 9.1 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.43 (m, 1H), 7.23 (m, 1H), 7.07 (d, J = 9.1 Hz, 1H ), 3.72 (m, 4H), 3.55 (m, 4H). HPLC (Condition A): RT 3.21 min (97.3% purity). MS (ESI+): 348.3, MS (ESI-): 346.3.Example 21: 3-{4-[4-(1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]phenyl }-N,N-dimethylpropanamide

[000375] TBTU (188 mg; 0.58 mmol; 1.3 eq.) was added to a cold (0°C) solution of 3-{4-[4-(1H-indazol-3-yl)-1H-1 acid, 2,3-triazol-1-yl]phenyl}propanoic acid (150 mg; 0.45 mmol; 1.0 eq.) and DIEA (176 µl; 1.03 mmol; 2.3 eq.) in DMF (3 ml). After 10 min, dimethylamine (270 µl at 2.00 M in THF; 0.54 mmol; 1.20 eq.) was added and the reaction mixture was stirred overnight at RT. The resulting solid was filtered and purified by preparative HPLC to yield the title compound as a brown solid.
[000376] 1H NMR (300 Mz, DMSO-d6) δ: 13.34 (brs, 1H), 9.26 (s, 1H), 8.36 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.62-7.59 (m, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.46-7.41 (m, 1H), 7.28-7.23 (m, 1H), 2.96 (s, 3H), 2.93 -2.88 (m, 2H), 2.83 (s, 3H), 2.70-2.65 (m, 2H). HPLC (Condition A): RT 3.23 min (92.2% purity). MS (ESI+): 361.3, MS (ESI-): 359.3.Example 22: 3-{1-[4-(3-morpholin-4-yl-3-oxopropyl)phenyl]-1H-1,2,3- triazol-4-yl}-1H-indazole

[000377] The title compound was obtained following procedure described by example 21, but starting from 3-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol- 1-yl]phenyl}propanoic acid (150 mg; 0.45 mmol; 1.0 eq.) and morpholine (47 μl; 0.54 mmol; 1.2 eq.) as a brown solid.
[000378] 1H NMR (300 Mz, DMSO-d6) δ: 13.35 (brs, 1H), 9.27 (s, 1H), 8.36 (d, J = 8.21 Hz, 1H), 7.95 (d, J = 8.6 Hz, 2H), 7.60 (dt, J = 8.5 Hz, 1.0 Hz, 1H), 7.50 (d, J = 8.6 Hz, 2H), 7.47-7.41 (m, 1H), 7.28-7.23 (m, 1H), 3.54- 3.51 (m, 4H), 3.46-3.43 (m, 4H), 2.95-2.90 (m, 2H), 2.73-2.68 (m, 2H). HPLC (Condition A): RT 3.14 min (98.2% purity). MS (ESI+): 403.3, MS (ESI-): 401.5.Example 23: 3-{1-[4-(3-oxo-3-pyrrolidin-1-ylpropyl)phenyl]-1H-1,2,3- triazol-4-yl}-1H-indazole

[000379] The title compound was obtained following procedure described by example 13, but starting from 3-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol- 1-yl]phenyl}propanoic acid (150 mg; 0.45 mmol; 1.0 eq.) and pyrrolidine (45 µl; 0.54 mmol; 1.2 eq.) as a beige solid.
[000380] 1H NMR (300 Mz, DMSO-d6) δ: 13.35 (brs, 1H), 9.27 (s, 1H), 8.35 (dt, J = 8.1 Hz, 1.0 Hz, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.61 (dt, J = 8.5 Hz, 1.0 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.46-7.41 (m, 1H), 7.28-7.23 (m, 1H) , 3.38 (t, J = 6.7 Hz, 2H), 3.29 (t, J = 6.7 Hz, 2H), 2.92 (t, J = 7.5 Hz, 2H), 2.61 (t, J = 7.5 Hz, 2H), 1.89 -1.71 (m, 4H). HPLC (Condition A): RT 3.49 min (99.3% purity). MS (ESI+): 387.3, MS (ESI-): 385.4.Example 24: 3-(1-{4-[3-(4-methylpiperazin-1-yl)-3-oxopropyl]phenyl}-1H-1, 2,3-triazol-4-yl)-1H-indazole

[000381] The title compound was obtained following procedure described by example 13, but starting from 3-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol- 1-yl]phenyl}propanoic acid (150 mg; 0.45 mmol; 1.0 eq.), 1-methylpiperazine (60 µl; 0.54 mmol; 1.2 eq.) as a beige solid.
[000382] 1H NMR (300 Mz, DMSO-d6) δ: 13.35 (brs, 1H), 9.27 (s, 1H), 8.35 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.46-7.41 (m, 1H), 7.28-7.23 (m, 1H), 3.43 (m, 4H ), 2.94-2.89 (m, 2H), 2.72-2.67 (m, 2H), 2.27 (m, 4H), 2.18 (s, 3H). HPLC (Condition A): RT 2.45min (99.5% purity). MS (ESI+): 416.4, MS (ESI-): 414.4.Example 25: 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-2- methoxy-N,N-dimethylbenzamide

[000383] The title compound was obtained following procedure described by example 13, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]-2-methoxybenzoic acid (70 mg; 0.21 mmol; 1.0 eq.) and dimethylamine (156 μl of a 2.0 M solution in THF; 0.31 mmol; 1.5 eq.) as a thick white solid.
[000384] 1H NMR (300 Mz, DMSO-d6) δ: 13.39 (s, 1H), 9.46 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 1.9 Hz, 1H), 7.71 (dd, J = 8.1 Hz, 1.9 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.48-7.41 (m, 2H), 7.27 (ddd, J = 8.4, 6.8, 0.7 Hz, 1H), 3.97 (s, 3H), 3.02 (s, 3H), 2.82 (s, 3H). HPLC (Condition A): RT 3.05 min (99.7% purity). MS (ESI+): 363.2, MS (ESI-): 361.3.Example 26: 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl] benzoyl}pyrrolidin-3-ol

[000385] A solution of TBTU (137 mg; 0.33 mmol; 1.3 eq.) and 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) in DMF (2 mL) was stirred for 1 h at RT before adding DIEA (111 μl; 0.66 mmol; 2.0 eq.) and 3-pyrrolidinol (43 mg; 0.49 mmol; 1.5 eq.). A reaction mixture was stirred at RT overnight. It was then diluted with DCM and washed with a saturated aqueous solution of NaHCO 3 . Organic phase was dried over magnesium sulfate, filtered and concentrated. The crude was purified by preparative HPLC to yield the title compound as a yellow solid.
[000386] 1H NMR (300 Mz, DMSO-d6) δ 13.38 (s, 1H), 9.41 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.15 (d, J = 8.7 Hz, 2H ), 7.78 (dd, J = 3.2, 8.6 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.51-7.39 (m, 1H), 7.27 (t, J = 7.1 Hz, 1H), 4.32 (brd, J = 26.0 Hz, 1H), 3.76-3.54 (m, 2H), 3.54-3.20 (m, 3H), 2.06-1.75 (m, 2H). HPLC (Condition A): RT 2.58 min (96.7% purity). MS (ESI+): 375.2, MS (ESI-): 373.2.Example 27: 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl] benzoyl}-N,N-dimethylpyrrolidin-3-amine

[000387] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 3-dimethylamino pyrrolidine (56 mg, 0.49, 1.5 eq.). Purification by flash chromatography on silica (DCM:MeOH:NH4OH, gradient from 100:0:0 to 90:10:0.1) gave the title compound as a yellow powder.
[000388] 1H NMR (300 Mz, DMSO-d6) δ 13.37 (s, 1H), 9.39 (s, 1H), 8.36 (d, J = 8.2 Hz, 1H), 8.13 (d, J = 8.3 Hz, 2H ), 7.83-7.72 (m, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.53-7.36 (m, 1H), 7.33-7.19 (m, 1H), 3.77-3.18 (m, 5H), 2.78-2.60 (m, 1H), 2.24-1.92 (m, 6H), 1.82-1.69 (m, 1H). HPLC (Condition A): RT 2.20 min (90.1% purity). MS (ESI+): 402.3, MS (ESI-): 400.3. Example 28: (1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}piperidin-4-yl)methanol

[000389] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 4-piperinyl methanol (Alfa Aesar, 57 mg, 0.49 mmol, 1.5 eq.). Purification by flash chromatography on silica (DCM:MeOH:NH4OH, gradient from 100:0:0 to 90:10:0.1) gave the title compound as a beige powder.
[000390] 1H NMR (300 Mz, DMSO-d6) δ 13.37 (s, 1H), 9.38 (s, 1H), 8.36 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 8.6 Hz, 2H ), 7.67-7.56 (m, 3H), 7.50-7.38 (m, 1H), 7.31-7.19 (m, 1H), 4.52 (t, J = 5.1 Hz, 1H), 3,713.52 (m, 1H), 3.39-3.22 (m, 2H), 1.92-1.51 (m, 4H), 1.30-1.01 (m, 4H). HPLC (Condition A): RT 2.84 min (91.8% purity). MS (ESI+): 403.3, MS (ESI-): 401.2.Example 29: 1-(1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1 -yl]benzoyl}piperidin-3-yl)-N,N-dimethylmethanamine

[000391] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and N-Dimethyl-1-piperidin-3-ylmethanamine (Scientific Matrix, 70 mg, 0.49, 1.5 eq.). Purification by flash chromatography on silica (DCM:MeOH:NH4OH, gradient from 100:0:0 to 90:10:0.1) gave the title compound as a yellow powder.
[000392] 1H NMR (300 Mz, DMSO-d6) δ 13.37 (s, 1H), 9.39 (s, 1H), 8.36 (d, J = 8.1 Hz, 1H), 8.14 (d, J = 8.6 Hz, 2H ), 7.70-7.56 (m, 3H), 7.50-7.36 (m, 1H), 7.25 (t, J = 7.5 Hz, 1H), 3.31 (s, 6H), 2.45-1.90 (m, 6H), 1.89- 1.32 (m, 4H), 1.31-1.08 (m, 1H). HPLC (Condition A): RT 2.43 min (96.2% purity). MS (ESI+): 430.4, MS (ESI-): 428.3.Example 30:1 -{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl ]benzoyl}piperidin-3-ol

[000393] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 3-hydroxypiperidine (50 mg, 0.49, 1.5 eq.). The crude obtained was suspended in acetonitrile, filtered and dried to give the title compound as a beige powder.
[000394] 1H NMR (300 Mz, DMSO-d6) δ 13.38 (s, 1H), 9.39 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.14 (d, J = 8.6 Hz, 2H ), 7.75-7.57 (m, 3H), 7.51-7.39 (m, 1H), 7.27 (t, J = 7.5 Hz, 1H), 5.10-4.81 (m, 1H), 4.21 (brs, 0.5H), 3.77 (brs, 0.5H), 3.62-3.37 (m, 1H), 3.09 (brs, 1H), 2.011.26 (m, 6H). HPLC (Condition A): RT 2.79 min (93.7% purity). MS (ESI+): 389.3, MS (ESI-): 387.3.Example 31: 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-N- (1-methyl-2-oxopyrrolidin-3-yl)benzamide

[000395] The title compound was obtained following the procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1 acid -yl]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 3-amino-1-methylpyrrolidin-2-one (Chem Bridge Corp., 56 mg, 0.49 mmol, 1.5 eq.). The crude obtained was suspended in acetonitrile, filtered and dried to give the title compound as a beige powder.
[000396] 1H NMR (300 Mz, DMSO-d6) δ 13.38 (s, 1H), 9.43 (s, 1H), 8.94 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 8.1 Hz, 1H ), 8.21 (d, J = 8.8 Hz, 2H), 8.11 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.50-7.38 (m, 1H), 7.31-7.15 (m, 1H), 4.74-4.52 (m, 1H), 3.42-3.32 (m, 2H), 2.77 (s, J = 7.8 Hz, 3H), 2.44-2.27 (m, 1H), 2.13-1.85 (m , 1H). HPLC (Condition A): RT 2.69 min (92.2% purity). MS (ESI+): 402.3, MS (ESI-): 400.3.Example 32: 5-Methyl-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol- 4-yl}-1H-indazole

[000397] Copper sulfate pentahydrate (70 mg; 0.28 mmol; 0.07 eq.) was added to a solution of 3-ethynyl-5-methyl-1H-indazole (665 mg; 4.26 mmol; 1.00eq.), 4- (4-azidobenzoyl)morpholine (987 mg; 4.25 mmol; 1.0 eq.) and D-(-)-isoascorbic acid sodium salt (283 mg; 1.43 mmol; 0.34 eq.) in DMF (15 mL) and water ( 0.5 ml). A reaction suspension was heated in MW at 80°C for 40 min then poured into HCl solution (1N) and extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give a yellow solid (1.38 g, 83%).
[000398] 1H NMR (300 Mz, DMSO-d6) δ: 13.25 (s, 1H), 9.36 (s, 1H), 8.20-8.10 (m, 3H), 7.68 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.6 Hz, 1H), 7.28 (dd, J = 1.4, 8.6 Hz, 1H), 3.74-3.36 (m, 8H), 2.48 (s, 3H). HPLC (Condition A): RT 3.21 min (98.6% purity). MS (ESI+): 389.2, MS (ESI-): 387.2.Example 33: (1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl ]benzoyl}pi-peridin-3-yl)methanol

[000399] The title compound was obtained following procedure described for intermediate 10, but starting from (4-azidobenzoyl)piperidin-3-yl]methanol (1.12 g; 4.30 mmol; 1.0 eq.) and 3-ethynyl-1H -indazole (612 mg; 4.30 mmol; 1.0 eq.) as a white solid.
[000400] 1H NMR (300 Mz, DMSO-d6): 13.38 (brs, 1H), 9.39 (s, 1H), 8.36 (dt, J = 8.1 Hz, 1.0 Hz, 1H), 8.14 (d, J = 8.6 Hz, 2H), 7.65-7.60 (m, 3H), 7.47-7.42 (m, 1H), 7.28-7.23 (m, 1H), 4.62-4.35 (m, 2H), 3.74-3.53 (m, 1H), 3.38-3.25 (m, 1H), 3.10-2.56 (m, 3H), 1.77-1.47 (m, 4H), 1.281.12 (m, 1H). HPLC (Condition A): RT 2.93 min (97.2% purity). MS (ESI+): 403.3, MS (ESI-): 401.4.Example 34: 3-{1-[3-methoxy-4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol- 4-yl}-1H-indazole

[000401] The title compound was obtained following procedure described by example 14, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]-2-methoxybenzoic acid (70 mg; 0.21 mmol; 1.0 eq.) and morpholine (27 μl; 0.31 mmol; 1.5 eq.) as a white solid.
[000402] 1H NMR (300 Mz, DMSO-d6) δ: 13.41 (s, 1H), 9.46 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 1.9 Hz, 1H), 7.71 (dd, J = 8.1, 1.9 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.48-7.42 (m, 2H), 7.27 (ddd, J = 8.4, 6.8, 0.7 Hz , 1H), 3.97 (s, 3H), 3.65 (bs, 4H), 3.55 (t, J = 4.6 Hz, 2H), 3.22-3.18 (m, 2H). HPLC (Condition A): RT 3.02 min (99.3% purity). MS (ESI+): 405.3, MS (ESI-): 403.3.
[000403] The following compounds were prepared according to procedures described for example 1 or example 26 above:



Example 70: 3-(1-{4-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]phenyl}-1H-1,2,3-triazol-4-yl)-1H-indazol

[000404] The title compound was obtained, following procedure described by example 18, but starting from {4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1 -yl]phenyl}acetic acid (120 mg; 0.38 mmol; 1.0 eq.) and N-methyl piperazine (50 μl; 0.45 mmol; 1.2 eq.). A reaction mixture was eluted through an SPE-NH2 column before purification by preparative HPLC which gave the title compound as a beige powder.

[000405] 1H NMR (300 MHz, DMSO-d6) δ 13.36 (brs, 1H), 9.30 (s, 1H), 8.36 (d, J= 8.2 Hz, 1H), 8.00 (d, J= 8.5 Hz, 2H ), 7.61 (d, J = 8.5 Hz, 1H), 7.48-7.41 (m, 3H), 7.28-7.23 (m, 1H), 3.86 (s, 2H), 3.67 (m, 4H), 2.73 (m, 1H), 4H), 2.48 (m, 3H). HPLC (Condition A): RT 2.30 min (99.4% purity). MS (ESI+): 402.3, MS (ESI-): 400.4.Example 71: 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl] benzoyl}piperidin-4-ol

[000406] The title compound was obtained, following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1- yl]benzoic acid (100 mg; 0.33 mmol; 1.0eq.) and 4-hydroxypiperidine (50 mg, 0.49 mmol, 1.5 eq.) as a brown oil.
[000407] 1H NMR (300 MHz, DMSO-d6) δ 13.37 (s, 1H), 9.38 (s, 1H), 8.36 (d, J = 8.2 Hz, 1H), 8.18-8.08 (m, 2H), 7.68 -7.56 (m, 3H), 7.50-7.37 (m, 1H), 7.30-7.18 (m, 1H), 4.82 (d, J = 3.9 Hz, 1H), 4.01 (brs, 1H), 3.83-3.65 (m , 1H), 3.51 (brs, 1H), 3.24 (brs, J = 12.5 Hz, 2H), 1.77 (brs, 2H), 1.39 (brs, 2H). HPLC (Condition A): RT 2.65 min (92.6% purity). MS (ESI+): 389.3, MS (ESI-): 387.2.Example 72: 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl] benzoyl}-N,N-dimethylpiperidin-4-amine

[000408] The title compound was obtained, following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1- yl]benzoic acid (100 mg; 0.33 mmol; 1.0eq.) and 4-dimethylaminopiperidine (FluoroChem, 63 mg, 0.49 mmol, 1.5eq.) as a colorless oil.
[000409] 1H NMR (300 MHz, DMSO-d6) δ 13.39 (s, 1H), 9.40 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.23-8.10 (m, 3H), 7.71 -7.57 (m, 3H), 7,517.39 (m, 1H), 7.32-7.20 (m, 1H), 4.47 (brs, 1H), 3.66 (brs, 1H), 3,222.72 (m, 2H), 2.62 -2.43 (m, 1H), 2.27 (s, 6H), 1.99-1.64 (m, 2H), 1.541.26 (m, 2H). HPLC (Condition A): RT 2.27 min (99.6% purity). MS (ESI+): 416.3, MS (ESI-): 414.3.Example 73:3-[1-(4-{[3-(pyrrolidin-1-ylcarbonyl)piperidin-1-yl]carbonyl}phenyl)-1H- 1,2,3-triazol-4-yl]-1H-indazole

[000410] The title compound was obtained, following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1- yl]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 3-Piperidinyl(1-pyrrolidinyl)methanone (90 mg, 0.49 mmol, 1.5 eq.) as a white solid.
[000411] 1H NMR (DMSO) δ 1H NMR (300 MHz, DMSO-d6) δ 13.38(s, 1H), 9.39 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.15 (d, 1H), J = 8.5 Hz, 2H), 7.72-7.57 (m, 3H), 7.51-7.39 (m, 1H), 7.32-7.21 (m, 1H), 4.57-4.28 (m, 1H), 3.70-3.37 (m, 1H), 2H), 3.31-3.03 (m, 4H), 2.99-2.58 (m, 2H), 2.02-1.40 (m, 8H). HPLC (Condition A): RT 3.26 min (99.3% purity). Example 74: 3-[1 -(4-{[3-(morpholin-4-ylmethyl)piperidin-1-yl]carbonyl}phenyl)-1H- 1,2,3-triazol-4-yl]-1H-indazole

[000412] The title compound was obtained, following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1- yl]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 4-Piperidin-3-ylmethyl-morpholine; dihydrochloride (126 mg, 0.49 mmol, 1.5 eq.) as a brown solid.
[000413] 1H NMR (300 MHz, DMSO-d6) δ 13.39 (s, 1H), 9.40 (s, 1H), 8.38 (d, J = 8.1 Hz, 1H), 8.14 (d, J = 8.6 Hz, 2H ), 7.69-7.57 (m, 3H), 7.51-7.39 (m, 1H), 7.27 (t, J = 7.5 Hz, 1H), 4.56-4.21 (m, 1H), 3,803.46 (m, 2H), 3.46-3.21 (m, 2H), 3.12-2.56 (m, 2H), 2.45-1.94 (m, 6H), 1.91-1.04 (m, 6H). HPLC (Condition A): RT 2.47 min (97.9% purity). Example 75: 1-[(1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol- 1-yl]benzoyl}piperidin-3-yl)methyl]pyrrolidin-2-one

[000414] The title compound was obtained, following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1- yl]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 1-(3-Piperidinylmethyl)-2-pyrrolidinone (90 mg, 0.49 mmol, 1 eq.) as a brown solid.
[000415] 1H NMR (300 MHz, DMSO-d6) δ 13.39 (s, 1H), 9.39 (s, 1H), 8.36 (d, J = 8.2 Hz, 1H), 8.14 (d, J = 8.5 Hz, 2H ), 7.72-7.57 (m, 3H), 7.48-7.37 (m, 1H), 7.25 (t, J = 7.5 Hz, 1H), 4.40-4.15 (m, 1H), 3.61-3.26 (m, 3H), 3.24-2.59 (m, 5H), 2.34-1.56 (m, 6H), 1.56-1.07 (m, 2H). HPLC (Condition A): RT 3.12 min (91.6% purity). Example 76: 24-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl }-8-methyl-2,8-diazaspiro[5.5]undecane

[000416] The title compound was obtained, following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1- yl]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 2-Methyl-2,8-diazaspiro[5.5]undecane (83 mg, 0.49 mmol, 1.5 eq.) as a brown solid. 1
[000417] H NMR (300 MHz, DMSO-d6) δ 13.38 (s, 1H), 9.40 (s, 1H), 8.36 (d, J = 8.2 Hz, 1H), 8.13 (d, J = 8.6 Hz, 2H ), 7.62 (t, J = 8.0 Hz, 3H), 7.50-7.37 (m, 1H), 7.25 (t, J = 7.6 Hz, 1H), 4.05-3.63 (m, 1H), 3.57-3.09 (m, 4H), 2.45-0.73 (m, 14H). HPLC (Condition A): RT 2.60 min (92.2% purity). Example 77: 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-N- [(1-methylpiperidin-3-yl)methyl]benzamide

[000418] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 3-(Aminomethyl)-1-methylpiperidine (63 mg, 0.49 mmol, 1.5 eq.) as a white solid.
[000419] 1H NMR (300 MHz, DMSO-d6) δ 13.39 (s, 1H), 9.42 (s, 1H), 8.65 (t, J = 5.7 Hz, 1H), 8.36 (d, J = 8.2 Hz, 1H ), 8.18 (d, J = 8.8 Hz, 2H), 8.08 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.50-7.38 (m, 1H), 7.25 (t , J = 7.5 Hz, 1H), 3.27-3.05 (m, 2H), 2.66 (dd, J = 9.3, 31.9 Hz, 2H), 2.12 (s, 3H), 1.93-1.53 (m, 5H), 1.53- 1.33 (m, 1H), 1.04-0.81 (m, 1H). HPLC (Condition A): RT 2.43 min (86.1% purity). MS (ESI+): 416.3, MS (ESI-): 414.3.Example 78: 3-{1-[3-(2-morpholin-4-yl-2-oxoethyl)phenyl]-1H-1,2,3- triazol-4-yl}-1H-indazole

[000420] The title compound was obtained following procedure described by example 70, but starting from {3-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1- yl]phenyl}acetic acid (200 mg; 0.63 mmol; 1.0 eq.) and morpholine (66 μl; 0.75 mmol; 1.2 eq.) as a white powder.
[000421] 1H NMR (300 MHz, DMSO-d6) δ 13.36 (brs, 1H), 9.30 (s, 1H), 8.36 (dt, J= 8.0 Hz, 1.0 Hz, 1H), 7.96-7.90 (m, 2H ), 7.63-7.54 (m, 2H), 7.47-7.41 (m, 1H), 7.37 (dt, J=1.0, 8.0 Hz, 1H), 7.28-7.23 (m, 1H), 3.88 (s, 2H), 3.58-3.55 (m, 6H), 3.50-3.47 (m, 2H). HPLC (Condition A): RT 3.01 min (99.0% purity). MS (ESI-): 387.4.Example 79: 3-(1-{3-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]phenyl}-1H-1,2,3-triazol-4 -yl)-1H-indazole

[000422] The title compound was obtained following procedure described by example 70, but starting from {3-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1- yl]phenyl}acetic acid (200 mg; 0.63 mmol; 1.0 eq.) 1-methylpiperazine (84 μl; 0.75 mmol; 1.2 eq.) as a beige powder.
[000423] 1H NMR (300 Mhz, DMSO-d6) δ 13.37 (brs, 1H), 9.30 (s, 1H), 8.36 (dt, J=8.1 Hz, 1.0 Hz, 1H), 7.96 (m, 1H), 7.93-7.90 (m, 1H), 7.61 (dt, J= 8.4 Hz, 1.0 Hz, 1H), 7.56 (t, J= 8.0 Hz, 1H), 7.47-7.41 (m, 1H), 7.37-7.35 (m , 1H), 7.28-7.23 (m, 1H), 3.87 (s, 2H), 3.55 (t, J= 4.8 Hz, 2H), 3.49 (t, J= 4.8 Hz, 2H), 2.31-2.26 (m, 4H), 2.18 (s, 3H). HPLC (Condition A): RT 2.31 min (98.9% purity). MS (ESI+): 402.3, MS (ESI-): 400.3.Example 80: 3-{1-[3-(2-morpholin-4-ylethyl)phenyl-1H-1,2,3-triazol-4-yl }-1H-indazole

[000424] LAH (1M in THF, 107 μl; 0.26 mmol; 2.0 eq.) was added dropwise to a cold (0°C) solution of 3-{1-[3-(2-morpholin-4-yl -2-oxoethyl)phenyl-1H-1,2,3-triazol-4-yl}-1H-indazole (50 mg, 0.13 mmol, 1 eq.) in dry THF (1 mL). A reaction mixture was allowed to warm to RT and stirred overnight. Water was added and the reaction mixture was extracted three times with EtOAc. Combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude was purified by preparative HPLC to give the title compound as a beige powder.
[0004251 1H NMR (300 MHz, DMSO-d6) δ 13.37 (brs, 1H), 9.31 (s, 1H), 8.37 (dt, J = 8.2 Hz, 1.0 Hz, 1H), 7.96 (t, J = 1.5 Hz , 1H), 7.907.87 (m, 1H), 7.61 (dt, J = 1.0, 8.4 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.47-7.41 (m, 1H), 7.40- 7.38 (m, 1H), 7.28-7.23 (m, 1H), 3.59 (t, J = 4.6 Hz, 4H), 2.91-2.86 (m, 2H), 2.64-2.59 (m, 2H), 2.47 (t, J = 4.6 Hz, 4H). HPLC (Condition A): RT 2.47 min (95.5% purity). MS (ESI+): 375.2, MS (ESI-): 373.3. Example 81: 3-{1-[3-fluoro-4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol

[000426] The title compound was obtained following procedure described for intermediate 10, but starting from 3-ethynyl-1H-indazole (114 mg; 0.80 mmol; 1.0 eq.) and 4-(4-azido-2-fluorobenzoyl )morpholine (200 mg; 0.80 mmol; 1.0 eq.) as a yellow powder.
[000427] 1H NMR (300 MHz, DMSO) δ : 13.41 (brs, 1H), 9.44 (s, 1H), 8.36 (dt, J= 8.2 Hz, 1.0 Hz, 1H), 8.14 (dd, J= 10.5 Hz , 2.0 Hz, 1H), 8.06 (dd, J= 8.2 Hz, 2.0 Hz, 1H), 7.71 (t, J= 7.8 Hz, 1H), 7.62 (dt, J= 8.5 Hz, 1.0 Hz, 1H), 7.47 -7.43 (m, 1H), 7.29-7.24 (m, 1H), 3.68 (m, 1H), 3.68 (m, 4H), 3.57 (t, J = 4.5 Hz, 2H), 3.32 (m, 2H). HPLC (Condition A): RT 3.22 min (100.0% purity). MS (ESI+): 393.3, MS (ESI-): 391.3.Example 82: 3-{1-[3-(2-oxo-2-pyrrolidin-1-ylethyl)phenyl]-1H-1,2,3- triazol-4-yl}-1H-indazole

[000428] The title compound was obtained following procedure described by example 70, but starting from {3-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1- yl]phenyl}acetic acid (200 mg; 0.63 mmol; 1.0 eq.) and pyrrolidine (62 μl; 0.75 mmol; 1.2 eq.) as a white solid.
[000429] 1 H NMR (300 MHz, DMSO-d6): 13.37 (brs, 1H), 9.29 (s, 1H), 8.36 (dt, J = 8.1 Hz, 1.0 Hz, 1H), 7.96 (t, J = 1.8 Hz, 1H), 7,937.90 (m, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7,477.41 (m, 1H), 7.38 (d , J = 7.8 Hz, 1H), 7.28-7.23 (m, 1H), 3.79 (s, 2H), 3.54 (t, J = 6.7 Hz, 2H), 3.32 (t, J = 6.7 Hz, 2H), 1.90 (quint., J = 6.7 Hz, 2H), 1.79 (quint., J = 6.7 Hz, 2H).Example 83: 3-{1-[3-(2-pyrrolidin-1-ylethyl)phenyl]-1H- 1,2,3-triazol-4-yl}-1H-indazole

[000430] The title compound was obtained following procedure described by example 80, but starting from 3-{1-[3-(2-oxo-2-pyrrolidin-1-ylethyl)phenyl]-1H-1,2 ,3-triazol-4-yl}-1H-indazole (40 mg; 0.11 mmol; 1.00eq.) as a white solid.
[000431] 1H NMR (300 MHz, DMSO-d6) δ 13.55 (brs, 1H), 9.33 (s, 1H), 8.37 (dt, J= 8.0 Hz, 1.0 Hz, 1H), 8.27 (s, 1H), 7.98 (t, J= 1.78 Hz, 1H), 7.92-7.89 (m, 1H), 7.62 (dt, J= 8.4 Hz, 1.0 Hz, 1H), 7.55 (t, J= 8.0 Hz, 1H), 7.47- 7.39 (m, 2H), 7.29-7.24 (m, 1H), 2.94 (m, 4H), 2.76-2.72 (m, 4H), 1.78-1.74 (m, 4H). HPLC (Condition A): RT 2.56 min (95.8% purity). MS (ESI+): 359.2, MS (ESI-): 357.3.Example 84: 3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl} -5-piperidin-4-yl-1H-indazolStep a) Formation of 4-(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl }-1H-indazol-5-yl)piperidine-1-carboxylate tert-butyl hydrochloride

[000432] The title compound was obtained following procedure described for Intermediate 10, but starting from 4-(4-azidobenzoyl)morpholine (83 mg; 0.36 mmol; 1.0 eq.) and 4-(3-ethynyl-1H- tert-butyl indazol-5-yl)piperidine-1-carboxylate (116 mg; 0.36 mmol; 1.0 eq.) as a brown gum.
[000433] 1H NMR (300 MHz, DMSO-d6) δ 13.30 (brs, 1H), 9.37 (s, 1H), 8.20 - 8.10 (m, 3H), 7.74 - 7.64 (m, 2H), 7.54 (d, 3H), J = 8.5 Hz, 1H), 7.37 (dd, J = 8.6, 1.6 Hz, 1H), 4.23-4.02 (m, 2H), 3.79-3.35 (m, 8H), 3.01-2.71 (m, 3H), 1.94 -1.77 (m, 2H), 1.70-1.49 (m, 2H), 1.43 (s, 9H). HPLC (Condition A): RT 4.53 min (purity 100.0%).Step b) Formation of 3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol- 4-yl}-5-piperidin-4-yl-IH-indazole

[000434] To a solution of 4-(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-yl tert-butyl)piperidine-1-carboxylate (40 mg; 0.07 mmol; 1.0 eq.) in 1,4-dioxane (3.0 mL) and water (1.0 mL) was added hydrogen chloride (1 mL of a 4N solution). in dioxane, 4.00 mmol; 56 eq.). The resulting solution was stirred at TA for 12h. Solvent was removed under reduced pressure, the residue was redissolved in ACN and water and lyophilized to give the title compound as a yellow solid (40 mg, 100%).
[000435] 1H NMR (300 MHz, DMSO) δ 13.38 (brs, 1H), 9.37 (s, 1H), 8.96 (brs, 1H), 8.76 (brs, 1H), 8.23 (s, 1H), 8.19-8.09 (m, 2H), 7,757.53 (m, 3H), 7.34 (dd, J = 1.4, 8.7 Hz, 1H), 3.80-3.52 (m, 5H), 3.533.21 (m, 3H), 3.04 (d , J = 5.3 Hz, 4H), 2.15-1.75 (m, 5H). HPLC (Condition A): RT 2.44 min (93.2% purity). MS (ES+): 458.5, MS (ESI-): 456.5.Example 85: 3-{1-[3-(3-morpholin-4-yl-3-oxopropyl)phenyl]-1H-1,2,3- triazol-4-yl}-1H-indazole

[000436] The title compound was obtained following procedure described by example 70, but starting from 3-{3-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol- 1-yl]phenyl}propanoic acid (200 mg; 0.60 mmol; 1.0 eq.) and morpholine (63 μl; 0.72 mmol; 1.2 eq.) as a beige solid.
[000437] 1 H NMR (300 MHz, DMSO-d6): 13.36 (brs, 1H), 9.31 (s, 1H), 8.36 (d, J= 8.0 Hz, 1H), 7.97 (t, J= 1.7 Hz, 1H ), 7.89-7.86 (m, 1H), 7.61 (dt, J= 8.4 Hz, 1.0 Hz, 1H), 7.54 (t, J= 8.0 Hz, 1H), 7.47-7.39 (m, 2H), 7.28-7.23 (m, 1H), 73.53-3.50 (m, 4H), 3.46-3.44 (m, 4H), 2,982.93 (m, 2H), 2.77-2.72 (m, 2H). HPLC (Condition A): RT 3.21 min (99.2% purity). MS (ESI+): 403.3, MS (ESI-): 401.4.Example 86: 3-{1-[3-(3-morpholin-4-ylpropyl)phenyl]-1H-1,2,3-triazol-4- yl}-1H-indazole

[000438] The title compound was obtained following procedure described by example 80, but starting from 3-{1-[3-(3-morpholin-4-yl-3-oxopropyl)phenyl]-1H-1,2 ,3-triazol-4-yl}-1H-indazole (75 mg; 0.17 mmol; 1.0 eq.) as a yellow solid.
[000439] 1 H NMR (300 MHz, DMSO-d6): 11.30 (bs, 1H), 9.32 (s, 1H), 8.36 (dt, J=8.0 Hz, 1.0 Hz, 1H), 7.99 (m, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.63-7.55 (m, 2H), 7.46-7.40 (m, 2H), 7.28-7.23 (m, 1H), 3.96-3.80 (m, 4H), 3.45- 3.41 (m, 2H), 3.15-2.99 (m, 4H), 2.80 (t, J=7.6 Hz, 2H), 2.20-2.10 (m, 2H). HPLC (Condition A): RT 2.65 min (97.3% purity). MS (ESI+): 389.3, MS (ESI-): 387.4.Example 87: 3-{1-[3-(3-oxo-3-pyrrolidin-1-ylpropyl)phenyl]-1H-1,2,3- triazol-4-yl}-1H-indazole

[000440] The title compound was obtained following procedure described by example 70, but starting from 3-{3-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol- 1-yl]phenyl}propanoic acid (200 mg; 0.60 mmol; 1.0 eq.) and pyrrolidine (59 μl; 0.72 mmol; 1.2 eq.) as a beige solid.
[000441] 1 H NMR (300 MHz, DMSO-d6): 13.36 (bs, 1H), 9.301 (s, 1H), 8.36 (d, J= 8.0 Hz, 1H), 7.96 (t, J= 1.8 Hz, 1H ), 7.89-7.86 (m, 1H), 7.61 (dt, J= 8.6 Hz, 1.0 Hz, 1H), 7.53 (t, J= 8.0 Hz, 1H), 7.47-7.39 (m, 2H), 7.317.23 (m, 1H), 3.39 (t, J= 6.7 Hz, 2H), 3.29 (t, J= 6.7 Hz, 2H), 2.98-2.93 (m, 2H), 2.68-2.63 (m, 2H), 1.89- 1.80 (m, 2H), 1.79-1.70 (m, 2H). HPLC (Condition A): RT 3.50 min (97.7% purity). MS (ESI+): 387.3, MS (ESI-): 385.3.Example 88: 3-{1-[3-(3-pyrrolidin-1-ylpropyl)phenyl]-1H-1,2,3-triazol-4- yl}-1H-indazole

[000442] The title compound was obtained following procedure described by example 80, but starting from 3-{1-[3-(3-oxo-3-pyrrolidin-1-ylpropyl)phenyl]-1H-1,2 ,3-triazol-4-yl}-1H-indazole (80 mg; 0.18 mmol; 1.0 eq.) as a yellow solid.
[000443] 1H NMR (300 MHz, DMSO-d6): 13.40 (bs, 1H), 10.83 (bs, 1H), 9.33 (s, 1H), 8.36 (dt, J=8.0 Hz, 1.0 Hz, 1H), 7.98 (m, 1H), 7.937.90 (m, 1H), 7.63-7.55 (m, 2H), 7.47-7.40 (m, 2H), 7.28-7.23 (m, 1H), 3.56-3.50 (m, 2H ), 3.17-3.10 (m, 2H), 2.99-2.93 (m, 2H), 2.81 (t, J=7.5 Hz, 2H), 2.14-1.84 (m, 6H). HPLC (Condition A): RT 2.75 min (98.3% purity). MS (ESI+): 373.3, MS (ESI-): 371.4.Example 89: 3-{1-[3-chloro-4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol- 4-yl}-1H-indazole

[000444] The title compound was obtained following procedure described for Intermediate 10, but starting from 4-(4-azido-2-chlorobenzoyl)morpholine (1.50 g; 5.62 mmol; 1.0 eq.) and 3-ethynyl-1H - indazole (0.80 g; 5.62 mmol; 1.0 eq.) as a beige powder.
[000445] 1 H NMR (300 MHz, DMSO-d6) δ : 13.41 (brs, 1H), 9.46 (s, 1H), 8.37-8.33 (m, 2H), 8.17 (dd, J= 8.4 Hz, 2.1 Hz, 1H), 7.69 (d, J= 8.4 Hz, 1H), 7.62 (dt, J= 1.0, 8.4 Hz, 1H), 7.47-7.42 (m, 1H), 7.29-7.24 (m, 1H), 3.73- 3.65 (m, 4H), 3.57 (t, J= 4.5 Hz, 2H), 3.22 (t, J= 4.5 Hz, 2H). HPLC (Condition A): RT 3.42 min (98.8% purity). MS (ESI+): 409.3, MS(ESI-): 407.3.Example 90: 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-N- [2-(1-methylpyrrolidin-2-yl)ethyl]benzamide

[000446] The title compound was obtained following procedure described by example 70, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (150 mg; 0.49 mmol; 1.0 eq.) and 1-(pyridin-4-yl)-1H-pyrazol-4-amine (60 mg mg; 0.47 mmol; 0.95 eq.) as a white powder.
[000447] 1H NMR (300 MHz, DMSO-d6) δ 13.40 (s, 1H), 9.42 (s, 1H), 8.74 (t, J = 4.3 Hz, 1H), 8.34 (d, J = 7.8 Hz, 1H ), 8.20 (d, J = 7.8 Hz, 2H), 8.09 (d, J = 7.8 Hz, 2H), 7.61 (d, J = 8.5 Hz, 1H), 7.44 (t, J = 7.1 Hz, 1H), 7.25 (t, J = 6.4 Hz, 1H), 3.37 (m, 3H), 2.95 (m, 1H), 2.79 (m, 1H), 2.64 (s, 3H), 2.21 (m, 1H), 2.07 (m , 1H), 1.85 (m, 2H), 1.63 (m, 2H). HPLC (Condition A): RT 2.51 min (99.2% purity). MS (ESI+): 416.3, MS (ESI-): 414.4.Example 91: 1-(1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1 -yl]benzoyl}piperidin-4-yl)-N,N-dimethylmethanamine

[000448] The title compound was obtained following procedure described by example 70, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (150 mg; 0.49 mmol; 1.0 eq.) and 1-(pyridin-4-yl)-1H-pyrazol-4-amine (66 mg; 0.47 mmol; 0.95 eq.) as a white powder.
[000449] 1H NMR (300 MHz, DMSO-d6) δ 13.38 (s, 1H), 9.39 (s, 1H), 8.35 (d, J = 7.9 Hz, 1H), 8.14 (d, J = 8.8 Hz, 2H ), 7.63 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 4.48 (brs, 1H), 3.60 (m, 2H), 270-2.83 (m, 3H), 2.58 (s, 6H), 1.96 (m, 1H), 1.75 (m, 2H), 1.16 (m, 2H) . HPLC (Condition A): RT 2.86 min (93.1% purity). MS (ESI+): 430.4, MS(ESI-): 428.4.Example 92:2-(1 -{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol- 1-yl]benzoyl}piperidin-2-yl)-N,N-dimethylethanamine

[000450] The title compound was obtained following procedure described by example 70, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (150 mg; 0.49 mmol; 1.0 eq.) and 1-(pyridin-4-yl)-1H-pyrazol-4-amine (73 mg; 0.47 mmol; 0.95 eq.) as a white powder.
[000451] 1H NMR (300 MHZ, DMSO) δ 13.37 (s, 1H), 9.39 (s, 1H), 9.14 (brs, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.25 (t, J = 7.4 Hz, 1H), 4.75 (s, 1H), 3.08 (m, 4H), 2.82 (s, 6H), 2.24 (m, 1H), 1.43-1.84 (m, 7H). HPLC (Condition A): RT 2.12 min (96.9% purity). MS (ESI+): 444.4, MS (ESI-): 442.4.Example 93: (3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl }-1H-indazol-5-yl)methanol

[000452] The title compound was obtained following procedure described by example 21, step b), but starting from tert-butyl 3-ethynyl-5-(hydroxymethyl)-1H-indazole-1-carboxylate (557 mg; 1.68 mmol; 1.0 eq.) and 4-(4-azidobenzoyl)morpholine (390 mg, 1.51 mmol, 0.9 eq.) as a white solid.
[000453] 1H NMR (300 MHz, DMSO-d6) δ 13.32 (s, 1H), 9.37 (s, 1H), 8.31 (s, 1H), 8.15 (d, J = 8.5 Hz, 2H), 7.69 (d , J = 8.5 Hz, 2H), 7.56 (d, J = 8.6 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 4.66 (s, 2H), 3.86-3.25 (m, 8H). HPLC (Condition A): RT 2.25 min (95.4% purity). MS (ESI+): 405.3, MS(ESI-): 403.3.Example 94: 6-(3,5-difluorophenyl)-2-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]- 1H-1,2,3-triazol-4-yl}-1H-indazol-5-yl)methyl]pyridazin-3(2H)-oneStep a) Formation of 4-[4-(5-{[3-) (3,5-difluorophenyl)-6-oxopyridazin-1(6H)-yl]methyl}-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoic

[000454] Sodium hydride (34 mg; 0.78 mmol; 2.0 eq.) was added in one portion to a solution of 6-(3,5-Difluoro-phenyl)-2H-pyridazin-3-one (106 mg; 0.51 mmol; 1.3 eq.) in DMF (3 mL). After 10 min a solution of tert 5-(bromomethyl)-3-{1-[4-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-1-carboxylate -butyl (392 mg; 0.38 mmol; 1.0 eq.) in DMF (3 mL) was added dropwise over 2 min and the reaction solution stirred for 4 h at RT. A reaction mixture was then poured into a saturated solution of NaHCO3 and extracted with EtOAc. Combined organic phases were dried over magnesium sulfate, filtered and concentrated to give a yellow solid. This solid was redissolved in NaOH (5N, 0.5 mL) and DMSO (2 mL) and heated in MW for 10 min at 80°C. Reaction mixture was poured into saturated NaHCO3 solution and washed with EtOAc. The basic aqueous phase was acidified to pH 1 with 1N HCl and extracted with EtOAc. Combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow solid (218 mg, 100%).
[000455] 1H NMR (300 MHz, DMSO-d6) δ 13.43 (s, 1H), 9.44 (s, 1H), 8.47 (s, 1H), 8.29-8.09 (m, 6H), 7.68 (d, J = 7.2 Hz, 2H), 7.63 - 7.47 (m, 2H), 7.40 - 7.30 (m, 1H), 7.14 (d, J = 9.8 Hz, 1H), 5.52 (s, 2H). HPLC (Condition A): RT 3.87 min (52.8% purity). MS (ESI+): 526.2, MS (ESI-): 524.2.Step b) Formation of 6-(3,5-difluorophenyl)-2-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl) ]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-yl)methyl]pyridazin-3(2H)-one

[000456] 4-[4-(5-{[3-(3,5-Difluorophenyl)-6-oxopyridazin-1(6H)-yl]methyl}-1H-indazol-3-yl)-1H-1 acid ,2,3-triazol-1-yl]benzoic acid (218 mg; 0.22mmol; 1.0 eq.) was added in one portion to a suspension of 1,1'-carbonyldiimidazole (97 mg; 0.60 mmol; 2.7 eq.) in DMF (20 ml). The reaction suspension was heated at 100C° for 20 min then morpholine (100 μl; 1.15 mmol; 5.2 eq.) was added in one portion. A reaction mixture was heated at 100°C for 16 h. It was allowed to cool to RT, poured into HCl (1N solution) and extracted with EtOAc. Combined organic phases were washed sequentially with saturated aqueous NaHCO3 solution and brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by preparative HPLC to give the title compound as a white solid.
[000457] 1H NMR (300 MHz, DMSO-d6) δ 13.42 (s, 1H), 9.38 (s, 1H), 8.48 (s, 1H), 8.23-8.08 (m, 3H), 7.75-7.64 (m, 4H), 7.61 (d, J = 8.6 Hz, 1H), 7.57-7.48 (m, 1H), 7.42-7.28 (m, 1H), 7.13 (d, J = 9.8 Hz, 1H), 5.51 (s, 2H ), 3.64 (s, 8H). HPLC (Condition A): RT 3.78 min (97.7% purity). MS (ESI-): 593.7.Example 95: 2-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H- indazol-5-yl)methyl]pyridazin-3(2H)-oneStep a) Formation of 3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4- tert-butyl yl}-5-[(6-oxopyridazin-1(6H)-yl)methyl]-1H-indazol-1-carboxylate

[000458] DIAD (0.30 mL; 1.54 mmol; 2.3 eq.) was added dropwise over 1 min to a solution of 5-(hydroxymethyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl] tert-butyl -1H-1,2,3-triazol-4-yl}-1H-indazol-1-carboxylate (340 mg; 0.67 mmol; 1.0 eq.), 3(2H)-pyridazinone (100 mg; 1.04 mmol; 1.5 eq.) and triphenylphosphine (354 mg; 1.35 mmol; 2.0 eq.) in DCM (15 mL). A reaction mixture was stirred for 4h at RT then poured into HCl (0.1N solution) and extracted with DCM. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (20:80 to 90:10 gradient, MeOH pure) to give the title compound as a yellow solid.
[000459] 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.52 (s, 1H), 8.19 (d, J = 8.6 Hz, 2H), 8.13 (d, J = 8.7 Hz, 1H ), 7.98 (dd, J = 1.6, 3.9 Hz, 1H), 7.77-7.61 (m, 3H), 7.45 (dd, J = 3.9 Hz, 1H), 7.01 (dd, J = 9.5 Hz, 1.6, 1H) , 5.46 (s, 2H), 3.76-3.35 (m, 8H), 1.69 (s, 9H). HPLC (Condition A): RT 3.74 min (91.1% purity). MS (ESI-): 483.4.Step b) Formation of 2-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}- 1H-indazol-5-yl)methyl]pyridazin-3(2H)-one

[000460] A solution of 3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-5-[(6-oxopyridazin-1(6H) )-yl)methyl]-1H-indazol-1-carboxylate tert-butyl (202 mg; 0.32 mmol; 1.00 eq.) and HCl (6.00 mL of a 4N solution in dioxane; 24 mmol; 76 eq.) in MeOH (4 mL) was stirred at RT for 3h. A reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC to give the title compound as a white solid. HPLC (Condition A): RT 2.67 min (98.1% purity). MS (ESI+): 483.3, MS (ESI-): 481.3.Example 96: (3R)-1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol- 1-yl]benzoyl}piperidin-3-ol

[000461] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (153 mg; 0.50 mmol; 1.0eq.) and (R)-(+)-3-hydroxypiperidine hydrochloride (83 mg; 0.60 mmol; 1.2 eq.) as a white solid.
[000462] 1H NMR (300 MHz, DMSO-d6) δ 13.39 (brs, 1H), 9.39 (brs, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.14 (d, J = 8.6 Hz, 2H ), 7.73-7.57 (m, 3H), 7.51-7.39 (m, 1H), 7.27 (t, J = 7.5 Hz, 1H), 5.15-4.78 (m, 1H), 4.34-3.68 (m, 1H), 3.63-3.36 (m, 2H), 3.20-2.85 (m, 2H), 2.06-1.59 (m, 2H), 1.56-1.28 (m, 2H). HPLC (Condition A): RT 3.27 min (92.6% purity). HPLC (Condition C): RT 12.69 min (96.9% purity). MS (ESI+): 389.3, MS (ESI-): 387.4.Example 97: (3S)-1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol- 1-yl]benzoyl}piperidin-3-ol

[000463] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (153 mg; 0.50 mmol; 1.0eq.) and (S)-3-hydroxypiperidine hydrochloride (83 mg; 0.60 mmol; 1.2 eq.) as a white solid.
[000464] 1H NMR (300 MHz, DMSO-d6) δ 13.39 (brs, 1H), 9.39 (brs, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.14 (d, J = 8.6 Hz, 2H ), 7.73-7.57 (m, 3H), 7.51-7.39 (m, 1H), 7.27 (t, J = 7.5 Hz, 1H), 5.15-4.78 (m, 1H), 4.34-3.68 (m, 1H), 3.63-3.36 (m, 2H), 3.20-2.85 (m, 2H), 2.06-1.59 (m, 2H), 1.56-1.28 (m, 2H). HPLC (Condition A): RT 3.25 min (purity 88.1%). MS (ESI+): 389.3, MS (ESI-): 387.4.Example 98: 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-N- [1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]benzamide

[000465] The title compound was obtained following procedure described by example 70, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (183 mg; 0.60 mmol; 1.0 eq.) and 1-(1-Methyl-piperidin-4-yl)-1H-pyrazol-4-ylamine (130 mg; 0.72 mmol; 1.2 eq.) as a white solid .
[000466] 1H NMR (300 MHz, DMSO-d6) δ 13.41 (brs, 1H), 10.62 (brs, 1H), 9.46 (s, 1H), 8.38 (d, J = 8.2 Hz, 1H), 8.32-8.14 (m, 4H), 8.10 (s, 1H), 7.69-7.58 (m, 2H), 7.46 (t, J = 7.1 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 4.25-3.99 ( m, 1H), 2.87 (d, J = 13.7 Hz, 2H), 2.21 (s, 3H), 2.15-1.86 (m, 6H). HPLC (Condition A): RT 3.07 min (98.6% purity). MS (ESI+): 468.3, MS (ESI-): 466.3.Example 99: ((2S)-1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazole -1-yl]benzoyl}pyrrolidin-2-yl)methanol

[000467] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100 mg; 0.33 mmol; 1.0eq.) and L-prolinol (50 mg, 0.49 mmol, 1.5 eq.) as a white solid.
[000468] 1H NMR (300 MHz, DMSO-d6) δ 13.38 (s, 1H), 9.40 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.15 (d, J = 8.5 Hz, 2H ), 7.87-7.67 (m, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.51-7.39 (m, 1H), 7.27 (t, J = 7.5 Hz, 1H), 4.83 (t, J = 5.7 Hz, 1H), 4.27-4.09 (m, 1H), 3.73-3.35 (m, 3H), 3.10 (s, 1H), 2.07-1.60 (m, 4H). HPLC (Condition A): RT 3.07 min (99.2% purity). MS (ESI+): 389.3, MS (ESI-): 387.3.Example 100 : (1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl ]benzoyl}piperidin-2-yl)methanol

[000469] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100mg; 0.33 mmol; 1.0 eq.) and 2-piperidine methanol (57 mg, 0.49 mmol, 1.5 eq.) as a beige oil.
[000470] 1H NMR (300 MHz, DMSO-d6) δ 13.38 (s, 1H), 9.38 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 8.5 Hz, 2H ), 7.73-7.57 (m, 3H), 7.57-7.39 (m, 1H), 7.36-7.21 (m, 1H), 4.92-4.77 (m, 1H), 4.55-4.19 (m, 1H), 3.85-3.57 (m, 2H), 3.01-2.66 (m, 1H), 2.03-1.10 (m, 7H).HPLC (Condition A): RT 3.05 min (94.3% purity). MS (ESI+): 403.3, MS (ESI-): 401.3.Example 101: 3-{1-[4-(morpholin-4-ylcarbonyl)-3-(trifluoromethyl)phenyl]-1H-1,2,3- triazol-4-yl}-1H-indazole

[000471] The title compound was obtained following procedure described for intermediate 10, but starting from 4-[4-azido-2-(trifluoromethyl)benzoyl]morpholine (244 mg; 0.57 mmol; 1.0 eq.) and 3-ethynyl-1H-indazole (81 mg; 0.57 mmol; 1.0 eq.) as a white solid.
[000472] 1 H NMR (300 MHz, DMSO-d6): 13.42 (brs, 1H), 9.58 (s, 1H), 8.54 (d, J= 2.0 Hz, 1H), 8.47 (dd, J= 8.3 Hz, 2.0 Hz, 1H), 8.36 (dt, J= 8.0 Hz, 1.0 Hz, 1H), 7.82 (d, J= 8.3 Hz, 1H), 7.62 (dt, J= 8.3 Hz, 1.0 Hz, 1H), 7.48-7.43 (m, 1H), 7.30-7.25 (m, 1H), 3.75-3.57 (m, 5H), 3.473.40 (m, 1H), 3.27-3.13 (m, 2H). HPLC (Condition A): RT 3.43 min (99.3% purity). MS (ESI+): 443.3, MS (ESI-): 413.3.Example 102: 3-{1-[2-fluoro-4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol- 4-yl}-1H-indazole

[000473] The title compound was obtained following procedure described for intermediate 10, but starting from 4-(4-azido-3-fluorobenzoyl)morpholine (143 mg; 0.57 mmol; 1.0 eq.) and 3-ethynyl-1H - indazole (81 mg; 0.57 mmol; 1.0 eq.) as a beige solid.
[000474] 1 H NMR (300 MHz, DMSO-d6): 12.39 (brs, 1H), 9.10 (d, J=2.0 Hz, 1H), 8.34 (dt, J= 8.0 Hz, 1.0 Hz, 1H), 8.04 ( t, J= 8.0 Hz, 1H), 7.73 (dd, J= 1.5, 10.1 Hz, 1H), 7.62 (dt, J= 1.0, 8.5 Hz, 1H), 7.52 (dd, J= 1.5, 8.0 Hz, 1H ), 7.47-7.42 (m, 1H), 7.29-7.24 (m, 1H), 3.67-3.60 (m, 6H), 3.42 (m, 2H). HPLC (Condition A): RT 2.99 min (99.6% purity). MS (ESI+): 393.2, MS (ESI-): 391.2.Example 103: 2-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol- 4-yl}-1H-indazol-5-yl)methyl]-6-pyridin-4-ylpyridazin-3(2H)-oneStep a) Formation of 3-{1-[4-(methoxycarbonyl)phenyl]-1H- tert-Butyl 1,2,3-triazol-4-yl}-5-[(6-oxo-3-pyridin-4-ylpyridazin-1(6H)-yl)methyl]-1H-indazol-1-carboxylate

[000475] Sodium hydride (106 mg; 2.43 mmol; 7.4 eq.) was added in one portion to a solution of 6-pyridin-4-ylpyridazin-3(2H)-one (176 mg; 1.02 mmol; 3.1 eq. ) in DMF (6 mL). After 10 min a solution of tert 5-(bromomethyl)-3-{1-[4-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-1-carboxylate -butyl (565 mg; 0.33 mmol; 1.0 eq.) in DMF (6 mL) was added dropwise over 2 min and the reaction solution stirred for 4 h at RT. A reaction mixture was then poured into saturated NaHCO3 solution and extracted with EtOAc. Combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude was purified by preparative HPLC to give the title compound as a yellow solid.
[000476] 1H NMR (300 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.75-8.62 (m, 3H), 8.30 (d, J = 8.8 Hz, 2H), 8.24 - 8.18 (m, 3H) , 8.15 (d, J = 9.2 Hz, 1H), 7.93 (dd, J = 1.6, 4.6 Hz, 2H), 7.78 - 7.72 (m, 1H), 7.19 (d, J = 9.8 Hz, 1H), 5.59 ( s, 2H), 3.92 (s, 3H), 1.68 (s, 9H). MS (ESI+): 605.3.Step b) Formation of 4-(4-{5-[(6-oxo-3-pyridin-4-ylpyridazin-1(6H)-yl)methyl]-1H-indazol-3 acid -yl}-1H-1,2,3-triazol-1-yl)benzoic

[000477] 3-{1-[4-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-5-[(6-oxo-3-pyridin-4-ylpyridazin-1( tert-Butyl 6H)-yl)methyl]-1H-indazol-1-carboxylate (88 mg; 0.10 mmol; 1.0 eq.) was suspended in NaOH (5N solution, 0.50 mL), DMF (6 mL) and EtOH (6 mL). The suspension was heated in MW at 80°C for 10 min. A reaction mixture was allowed to cool to RT and brought to pH 6 by addition of HCl (1N solution). The resulting solution was passed through an SCX-2 column and concentrated to give the title compound as a yellow solid (65 mg, 100%).
[000478] 1H NMR (300 MHz, DMSO-d6) δ 13.41 (brs, 1H), 9.28 (s, 1H), 8.70 (dd, J = 1.6, 4.5 Hz, 2H), 8.50 (s, 1H), 8.17 (d, J = 9.8 Hz, 1H), 8.04 (d, J = 8.7 Hz, 2H), 7.99-7.88 (m, 4H), 7.58 (d, J = 9.0 Hz, 2H), 7.55-7.47 (m, 1H), 7.17 (d, J = 9.8 Hz, 1H), 5.54 (s, 2H). HPLC (Condition A): RT 2.34 min (93.1% purity). MS (ESI+): 491.3, MS (ESI-): 489.4.Step c) Formation of 2-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3- triazol-4-yl}-1H-indazol-5-yl)methyl]-6-pyridin-4-ylpyridazin-3(2H)-one

[000479] The title compound was obtained following procedure described by example 94, step b), but starting from 4-(4-{5-[(6-oxo-3-pyridin-4-ylpyridazin-1( 6H)-yl)methyl]-1H-indazol-3-yl}-1H-1,2,3-triazol-1-yl)benzoyl (65 mg; 0.12 mmol; 1.0 eq.) and morpholine (4 mL; 46 mmol; 372 eq.) to give the title compound as a white solid.
[000480] 1H NMR (300 MHz, DMSO-d6) δ 13.42 (s, 1H), 9.38 (s, 1H), 8.70 (dd, J = 1.6, 4.6 Hz, 2H), 8.50 (s, 1H), 8.16 (d, J = 6.0 Hz, 1H), 8.14 (d, J = 3.0 Hz, 1H), 7.92 (dd, J = 1.6, 4.6 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.17 (d, J = 9.8 Hz, 1H), 5.53 (s, 2H), 3.64 (s, 8H). HPLC (Condition A): RT 2.24 min (98.8% purity). MS (ESI+): 560.3, MS (ESI-): 558.2.Example 104: 5-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-{1-[4- (morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

[000481] A suspension of {4-[4-(5-Bromo-1H-indazol-3-yl)-[1,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (150 mg; 0.33 mmol; 1.0 eq.), 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid, pinacol ester (Boron Molecular, 221 mg; 0.99 mmol; 3.0 eq.) , PdCl2(PPh3)2 (23 mg; 0.03 mmol; 0.10eq.), cesium fluoride (151 mg; 0.99 mmol; 3.0 eq.) in dioxane (3 mL) and water (1.5 mL) was degassed with a stream of nitrogen and heated in MW at 150°C for 10 min. A reaction mixture was filtered through a pad of celite, water was added to the filtrate. Aqueous phase was extracted three times with DCM using separator tubes. Combined organic phases were concentrated under reduced pressure and the crude was purified by flash chromatography on silica (DCM/MeOH, gradient from 100:0 to 90:10) to give the title compound as a yellow powder.
[000482] 1H NMR (300 MHz, DMSO) δ 13.36 (brs, 1H), 9.39 (s, 1H), 8.31 (s, 1H), 8.15 (d, J = 8.0 Hz, 2H), 7.78-7.47 (m , 4H), 6.32-6.11 (m, 1H), 3.84-3.49 (m, 6H), 3.46-3.25 (m, 2H), 3.11-2.98 (m, 2H), 2.71-2.58 (m, 4H), 2.30 (s, 3H). HPLC (Condition A): RT 2.22 min (94.5% purity). MS (ESI+): 470.3, MS(ESI-): 468.3.Example 105:5-(1-acetylpiperidin-4-yl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H- 1,2,3-triazol-4-yl}-1H-indazole

[000483] To a solution of 3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-5-piperidin-4-yl-1H- indazole (100 mg; 0.22 mmol; 1.0 eq.) in Pyridine (1.5 mL) was added acetyl chloride (15 μl; 0.22 mmol; 1.0 eq.). A reaction mixture was stirred at room temperature O/N. Acetyl chloride (15 μl; 0.22 mmol; 1.0 eq.) was added back to the reaction mixture to complete the reaction. Pyridine was removed under reduced pressure and DCM was added to the residue. DCM layer was washed with saturated NH4Cl solution and brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by preparative chromatography to give the title compound as a white foam.
[000484] 1H NMR (300 MHz, DMSO-d6) δ 13.30 (brs, 1H), 9.37 (s, 1H), 8.23-8.07 (m, 3H), 7.74-7.64 (m, 2H), 7.55 (d, J = 8.6 Hz, 1H), 7.37 (dd, J = 8.7 Hz, 1.4, 1H), 4.66-4.50 (m, 1H), 3.97 (d, J = 13.2 Hz, 1H), 3.79-3.34 (m, 8H ), 3.25-3.09 (m, 1H), 3.03-2.86 (m, 1H), 2.72-2.55 (m, 1H), 2.06 (s, 3H), 1.96-1.44 (m, 4H). HPLC (Condition A): RT 3.09 min (94.3% purity).
[000485] MS (ESI+): 500.3, MS (ESI-): 498.3.Example 106: 5-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-3-{1- [4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

[000486] A suspension of {4-[4-(5-Bromo-1H-indazol-3-yl)-[1,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (100 mg; 0.22 mmol; 1.0 eq.), 1-Benzyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6 -tetrahydro-pyridine; hydrochloride (J&W Pharm Lab, 222 mg; 0.66 mmol; 3.00eq.), Pd2Cl2(PPh3)2 (15 mg; 0.02 mmol; 0.1 eq.), potassium carbonate (91 mg; 0.66 mmol; 3.0 eq.) in dioxane (2 mL) and water (1 mL) was degassed with nitrogen flow and heated in MW at 150°C for 10 min. A reaction mixture was filtered through a pad of celite, water was added to the filtrate. Aqueous phase was extracted three times with DCM using separator tubes. Combined organic phases were concentrated under reduced pressure and the crude was purified by flash chromatography on silica (DCM/MeOH, gradient from 100:0 to 90:10) to give the title compound as a yellow powder.
[000487] 1H NMR (300 MHz, DMSO-d6) δ 13.37 (brs, 1H), 9.39 (s, 1H), 8.30 (s, 1H), 8.22-8.10 (m, 2H), 7.76-7.65 (m, 2H), 2H), 7.65-7.50 (m, 2H), 7.42-7.31 (m, 4H), 7.31-7.22 (m, 1H), 6.30-6.10 (m, 1H), 3.78-3.50 (m, 8H), 3.47- 3.37 (m, 2H), 3.18-3.07 (m, 2H), 2.77-2.56 (m, 4H). HPLC (Condition A): RT 2.87 min (97.5% purity). MS (ESI+): 546.4, MS (ESI-): 544.3.Example 107: N-cyclohexyl-N-(2-hydroxyethyl)-4-[4-(1H-indazol-3-yl)-1H-1 ,2,3-triazol-1-yl]benzamide

[000488] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and N-cyclohexylethanolamine (70 mg, 0.49 mmol, 1.5 eq.) as a white solid.
[000489] 1H NMR (300 MHz, DMSO-d6) δ 13.38 (s, 1H), 9.40 (s, 1H), 8.37 (d, J = 8.2 Hz, 1H), 8.14 (d, J = 8.3, 2H) , 7.67-7.54 (m, 3H), 7.51-7.39 (m, 1H), 7.35-7.21 (m, 1H), 4.86-4.70 (m, 1H), 3.56 (brs, 2H), 3.47-3.26 (m, 1H), 3H), 1.90-1.33 (m, 8H), 1.11-0.90 (m, 2H). HPLC (Condition A): RT 3.58 min (99.6% purity). MS(ESI+): 431.3, MS (ESI-): 429.3.Example 108: : 3-[1-(4-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}phenyl)-1H -1,2,3-triazol-4-yl]-1H-indazole

[000490] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and (S)-(()-2-(methoxymethyl)pyrrolidine (56 mg, 0.49 mmol, 1.5 eq.) as a white solid.
[000491] 1H NMR (300 MHz, DMSO-d6) δ 13.39 (s, 1H), 9.41 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.15 (d, J = 8.6 Hz, 2H ), 7.74 (d, J = 8.4, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.51-7.39 (m, 1H), 7.27 (t, J = 7.5 Hz, 1H), 4.29 (brs, 1H), 3.67-3.57 (m, 1H), 3.57-3.21 (m, 5H), 3.04 (brs, 1H), 2.11-1.62 (m, 4H). HPLC (Condition A): RT 3.33 min (99.8% purity). MS (ESI+): 403.3, MS (ESI-): 401.3.Example 109: 3-(1-{4-[(4-methoxypiperidin-1-yl)carbonyl]phenyl}-1H-1,2,3-triazole -4-yl)-1H-indazole

[000492] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 4-methoxypiperidine (567 mg, 0.49 mmol, 1.5 eq.) as a white solid.
[000493] 1H NMR (300 MHz, DMSO-d6) δ 13.39 (s, 1H), 9.40 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.6 Hz, 2H ), 7.71-7.57 (m, 3H), 7.51-7.39 (m, 1H), 7.27 (t, J = 7.5 Hz, 1H), 3.94 (brs, 1H), 3.61-3.41 (m, 2H), 3.39- 3.17 (m, 2H), 3.28 (s, 3H), 1.88 (brs, 2H), 1.49 (brs, 2H). HPLC (Condition A): RT 3.19 min (99.8% purity).MS (ESI+): 403.3, MS (ESI-): 401.2.Example 110: 6-methyl-2-[(3-{1 -[4-( morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-yl)methyl]pyridazin-3(2H)-oneStep a) 4-( 4-{5-[(3-methyl-6-oxopyridazin-1(6H)-yl)methyl]-1H-indazol-3-yl}-1H-1,2,3-triazol-1-yl)benzoic acid

[000494] The title compound was obtained following procedure described by example 94, step a), but starting from 6-methyl-3(2H)-pyridazinone (107 mg; 0.97 mmol; 2.9 eq.) and 5-( tert-butyl bromomethyl)-3-{1-[4-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-1-carboxylate (565 mg; 0.33 mmol; 1.0 eq.) as a yellow solid.
[000495] 1H NMR (300 MHz, DMSO-d6) δ 13.44 (s, 1H), 9.40 (s, 1H), 8.35 (s, 1H), 8.23 - 8.12 (m, 4H), 7.58 (d, J = 8.7, 1H), 7.43 (dd, J = 8.7, 1.5, 1H), 7.35 (d, J = 9.5, 1H), 6.93 (d, J = 9.5, 1H), 5.35 (s, 2H), 2.26 (s , 3H). HPLC (Condition A): RT 3.07 min (77.9% purity). MS (ESI-): 426.4.Step b) Formation of 6-methyl-2-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4 -yl}-1H-indazol-5-yl)methyl]pyridazin-3(2H)-one

[000496] The title compound was obtained following procedure described by example 94, step b), but starting from 4-(4-{5-[(3-methyl-6-oxopyridazin-1(6H)-yl) )methyl]-1H-indazol-3-yl}-1H-1,2,3-triazol-1-yl)benzoic acid (35 mg; 0.06 mmol; 1.0 eq.) as a white solid. HPLC (Condition A): RT 2.98 min (97.5% purity).
[000497] MS (ESI+): 357.2, MS (ESI-): 355.2.Example 111: 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl] -N-π-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]benzamide

[000498] The title compound was obtained following procedure described by example 70, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (101 mg; 0.33 mmol; 1.0 eq.) and 1-(2-Morpholin-4-yl-ethyl)-1H-pyrazol-4-ylamine; dihydrochloride (purchased from UkrOrgSynthesis Building Blocks, 107 mg; 0.40 mmol; 1.2 eq.) as a white solid.
[000499] 1H NMR (300 MHz, DMSO-d6) δ 13.42 (brs, 1H), 10.62 (brs, 1H), 9.46 (s, 1H), 8.38 (d, J = 8.1 Hz, 1H), 8.24 (q , J = 8.9 Hz, 4H), 8.14 (s, 1H), 7.62 (d, J = 7.3 Hz, 2H), 7.52-7.39 (m, 1H), 7.28 (t, J = 7.5 Hz, 1H), 4.24 (t, J = 6.5 Hz, 2H), 3.63-3.48 (m, 4H), 2.71 (t, J = 6.5 Hz, 2H), 2.47-2.34 (m, 4H). HPLC (Condition A): RT 3.06 min (94.0% purity). MS (ESI+): 484.3, MS(ESI-): 482.2.Example 112: 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-N- π-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl]benzamide

[000500] The title compound was obtained following procedure described by example 70, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (101 mg; 0.33 mmol; 1.0 eq.) and 1-(1-Methyl-pyrrolidin-3-yl)-1H-pyrazol-4-ylamine (66 mg; 0.40 mmol; 1.2 eq.) as a beige powder .
[000501] 1H NMR (300 MHz, DMSO-d6) δ 13.41 (brs, 1H), 10.63 (brs, 1H), 9.46 (s, 1H), 8.38 (d, J = 8.1 Hz, 1H), 8.32-8.12 (m, 5H), 7.63 (t, J = 4.2 Hz, 2H), 7.52-7.39 (m, 1H), 7.28 (t, J = 7.6 Hz, 1H), 4.99-4.81 (m, 1H), 2.86- 2.67 (m, 3H), 2.48-2.33 (m, 2H), 2.31 (s, 3H), 2.04 (s, 1H). HPLC (Condition A): RT 3.09 min (95.1% purity). MS (ESI+): 545.3, MS(ESI-): 452.2.Example 113: 3-[1 -(4-{[3-(2-methoxyethyl)piperidin-1-yl]carbonyl}phenyl)-1H-1, 2,3-triazol-4-yl]-1H-indazole

[000502] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 3-(2-methoxyethyl) piperidine. HCl (ChemBridge Corporation, 70 mg; 0.49 mmol; 1.5 eq.) as a white solid.
[000503] 1H NMR (300 MHz, DMSO-d6) δ 13.38 (s, 1H), 9.40 (s, 1H), 8.37 (d, J = 8.2 Hz, 1H), 8.15 (d, J = 8.4 Hz Hz, 2H), 7.73-7.57 (m, 3H), 7.51-7.38 (m, 1H), 7.33-7.20 (m, 1H), 4.45-4.23 (m, 1H), 3.48-3.39 (m, 1H), 3.34 ( s, 3H), 3.29-2.98 (m, 4H), 1.84 (brd, J = 11.7 Hz, 1H), 1,781.56 (m, 2H), 1.56-1.11 (m, 4H). HPLC (Condition A): RT 3.62 min (100.0% purity). MS (ESI+): 431.3, MS (ESI-): 429.3.Example 114:1 -{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl ]benzoyl}azetidin-3-ol

[000504] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 3-hydroxyazetidine hydrochloride (ChemBridge Corporation, 54 mg; 0.49 mmol; 1.5 eq.) as a white powder.
[000505] 1H NMR (300 MHz, DMSO-d6) δ 13.39 (s, 1H), 9.42 (s, 1H), 8.37 (d, J = 8.3 Hz, 1H), 8.17 (d, J = 8.7 Hz, 2H ), 7.88 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.51-7.39 (m, 1H), 7.27 (t, J = 7.5 Hz, 1H), 5.81 (d , J = 5.8 Hz, 1H), 4.62-4.43 (m, 2H), 4.39-4.23 (m, 1H), 4.19-4.03 (m, 1H), 3.83 (brd, J = 8.4 Hz, 1H). HPLC (Condition A): TA2.59 min (100.0% purity). MS (ESI+): 361.2, MS(ESI-): 359.1.Example 115: 3-{1-[4-({3-[(2-methyl-1H-imidazol-1-yl)methyl]piperidin-1- yl}carbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

[000506] The title compound was obtained following the procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1 acid -yl]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 3-[(2-Methyl-1H-imidazol-1-yl)methyl]piperidine (88 mg; 0.49 mmol; 1.5 eq.) as a white solid .
[000507] 1H NMR (DMSO-d6) δ 13.41 (s, 1H), 9.40 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.14 (brs, 2H), 7.62 (m, 3H) , 7.51-7.38 (m, 1H), 7.27 (m, 2.5H), 7.00 (m, 1.5H), 4.53-2.73 (m, 6H), 2.46-2.20 (m, 3H), 2.04 (brs, 1H) , 1.90-1.59 (m, 2H), 1.59-1.10 (m, 2H). HPLC (Condition A): RT 2.59 min (98.5% purity). MS (ESI+): 467.3, MS(ESI-): 465.2.Example 116: 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-N- (1-methylpiperidin-4-yl)benzamide

[000508] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 4-amino-1-methylpiperidine (56 mg; 0.49 mmol; 1.5 eq.) as a white solid.
[000509] 1H NMR (DMSO-d6) δ 13.41 (s, 1H), 9.46 (s, 1H), 8.65 (d, J = 7.5 Hz, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.22 (d, J = 8.8 Hz, 2H), 8.12 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.5 Hz, 1H), 7.50 - 7.40 (m, 1H), 7.327.20 (m, 1H), 4.07 (brs, 1H), 3.49 (d, J = 11.4 Hz, 2H), 3.23 - 3.03 (m, 2H), 2.86 - 2.71 (m, 3H), 2.08 (m, 2H), 1.86-1.66 (m, 2H). HPLC (Condition A): RT 2.39 min (97.9% purity). MS (ESI+): 402.3, MS(ESI-): 400.3.Example 117: 2-(1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1 -yl]benzoyl}piperidin-2-yl)ethanol

[000510] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 2-piperidine ethanol (63 mg; 0.49 mmol; 1.5 eq.) as a white solid.
[000511] 1H NMR (300 MHz, DMSO-d6) δ 13.21 (s, 1H), 9.22 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H ), 7.52-7.38 (m, 3H), 7.35-7.22 (m, 1H), 7.16-7.01 (m, 1H), 4.77-4.53 (m, 1H), 4.37-4.11 (m, 2H), 3.39-3.08 (m, 2H), 2.50-2.21 (m, 1H), 1.89-1.19 (m, 6H), 1.13-1.02 (m, 2H). HPLC (Condition A): RT 3.17 min (94.4% purity). MS (ESI+): 417.2, MS(ESI-): 415.2.Example 118 3-[1 -(4-{[3-(methoxymethyl)piperidin-1-yl]carbonyl}phenyl)-1H-1,2,3 -triazol-4-yl]-1H-indazole

[000512] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 3-methoxymethyl-piperidine hydrochloride (81 mg; 0.49 mmol; 1.5 eq.) as a white solid.
[000513] 1H NMR (300 MHz, DMSO-d6) δ 13.39 (s, 1H), 9.40 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.15 (d, J = 8.0 Hz, 2H ), 7.73-7.56 (m, 3H), 7.55-7.35 (m, 1H), 7.27 (t, J = 7.5 Hz, 1H), 4.55-4.16 (m, 1H), 3.79-3.45 (m, 1H), 3.42-2.81 (m, 7H), 2.79-2.59 (m, 1H), 1.92-1.14 (m, 4H). HPLC (Condition A): RT 3.49 min (98.9% purity). MS (ESI+): 417.2, MS (ESI-): 415.2.Example 119: N-(2-hydroxybutyl)-4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazole -1-yl] benzamide

[000514] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 1-amino-2-butanol (44 mg; 0.49 mmol; 1.5 eq.) as a white solid.
[000515] 1H NMR (300 MHz, DMSO-d6) δ δ 13.41 (s, 1H), 9.42 (s, 1H), 8.61 (t, J = 5.7 Hz, 1H), 8.37 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 8.8 Hz, 2H), 8.12 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.51 - 7.39 (m, 1H), 7.27 ( t, J = 7.5 Hz, 1H), 4.78 (d, J = 5.2 Hz, 1H), 3.58 (m, 1H), 3.35 (m, 1H), 3.22 (m, 1H), 1.48 (m, 1H), 1.34 (m, 1H), 0.92 (t, J = 7.4 Hz, 3H). HPLC (Condition A): RT 2.91 min (purity 100.0%). MS (ESI+): 377.2, MS(ESI-): 375.2.Example 120: 3-(1 -{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}-1H-1,2 ,3-triazol-4-yl)-1H-indazole

[000516] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 4-(1-pyrrolidinyl) piperidine (76 mg; 0.49 mmol; 1.5 eq.) as a white solid.
[000517] 1H NMR (300 MHz, DMSO-d6) δ 13.39 (s, 1H), 9.40 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.19-8.07 (m, 2H), 7.72 -7.57 (m, 3H), 7.52-7.39 (m, 1H), 7.27 (t, J = 7.5 Hz, 1H), 4.38-4.15 (m, 1H), 3.713.49 (m, 1H), 3.23-2.91 (m, 2H), 2.57-2.42 (m, 4H), 2.33-2.17 (m, 1H), 2.02-1.73 (m, 2H), 1.73-1.59 (m, 4H), 1.42 (d, J = 9.8 Hz , 2H). HPLC (Condition A): RT 2.43 min (98.2% purity). MS (ESI+): 442.3, MS (ESI-): 440.3.Example 121: 5-[1-(2-fluoroethyl)piperidin-4-yl]-3-{1-[4-(morpholin-4-ylcarbonyl) phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

[000518] A suspension of 1-bromo-2-fluoro-ethane (Avocado Research, 26 mg; 0.21 mmol; 0.95 eq.), 3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H- 1,2,3-triazol-4-yl}-5-piperidin-4-yl-1H-indazole (100 mg; 0.22 mmol; 1.0 eq.) and NaHCO 3 (257 mg; 3.06 mmol; 14 eq.) in DMF (2 mL) was heated in MW at 100°C for 3h. EtOAc and water were added to the reaction mixture. The two phases were separated and the aqueous phase was extracted with EtOAc twice. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (DCM/MeOH, gradient from 100:0 to 90:10) to give the title compound as a beige solid.
[000519] 1H NMR (300 MHz, DMSO-d6) δ 13.29 (brs, 1H), 9.38 (s, 1H), 8.28-8.05 (m, 3H), 7.69 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 4.57 (dt, J = 48.0 Hz, 4.8, 2H), 3.88-3.37 (m, 8H), 3.18-2.91 ( m, 2H), 2.85-2.56 (m, 3H), 2.28-2.06 (m, 2H), 1,941.61 (m, 4H). HPLC (Condition A): RT 5.96 min (93.8% purity). MS (ESI+): 504.3, MS (ESI-): 502.3.Example 122: 5-bromo-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol- 4-yl}-1H-indazole

[000520] The title compound was obtained following procedure described for intermediate 21, step b), but starting from 4-(4-azidobenzoyl)morpholine (3.47 g; 15 mmol; 1.1 eq.) and 5-Bromo-3 -ethynyl-1H-indazole (3.0 g; 13.6 mmol; 1.0 eq.) as a yellow solid.
[000521] 1H NMR (300 MHz, DMSO-d6) δ 13.60 (s, 1H), 9.45 (s, 1H), 8.55 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 7.69 (d , J = 8.1 Hz, 2H), 7,657.53 (m, 2H), 3.79-3.35 (m, 8H). HPLC (Condition A): RT 3.50 min (99.1% purity). MS (ESI+): 453.3, 455.3, MS (ESI-): 451.3, 453.3.Example 123:5-(1-methyl-1H-pyrazol-4-yl)-3-{1-[4-(morpholin-4) -ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

[000522] The title compound was obtained following procedure described by example 104, but starting from {4-[4-(5-Bromo-1H-indazol-3-yl)-[1,2,3]triazol- 1-yl]-phenyl}-morpholin-4-yl-methanone (120 mg; 0.26 mmol; 1.0 eq.) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (83 mg; 0.40 mmol; 1.5 eq.) as a beige powder (87 mg, 72%).
[000523] 1H NMR (300 MHz, DMSO-d6) δ 13.37 (brs, 1H), 9.41 (s, 1H), 8.42 (s, 1H), 8.24-8.10 (m, 3H), 7.91 (s, 1H) , 7.77-7.56 (m, 4H), 3.90 (s, 3H), 3.77-3.36 (m, 8H). HPLC (Condition A): RT 3.25 min (98.7% purity). MS (ESI+): 455.3, MS (ESI-): 453.3.Example 124:5-(1-methylpiperidin-4-yl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H- 1,2,3-triazol-4-yl}-1H-indazole

[000524] 5-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2 ,3-triazol-4-yl}-1H-indazole (20 mg; 0.04 mmol; 1.0 eq.) was dissolved in MeOH (3 mL) and Pd/C (moistened, 50% water; 100 mg) was added. A reaction mixture was hydrogenated at RT for two days on a Parr instrument (35 bars). Reaction mixture was filtered through a pad of celite and dried under vacuum to give the title compound as a beige solid (14mg, 70%).
[000525] 1H NMR (300 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.25-8.09 (m, 3H), 7.73-7.62 (m, 2H), 7.64-7.49 (m, 1H), 7.40- 7.29 (m, 1H), 3.81-3.39 (m, 8H), 2.98-2.56 (m, 4H), 2.22 (s, 3H), 2.06-1.66 (m, 5H). HPLC (Condition A): RT 3.86 min (87.8% purity). MS (ESI+): 472.3, MS(ESI-): 470.2.Example 125: 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-N- [1-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl]benzamide

[000526] The title compound was obtained following procedure described by example 70, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (101 mg; 0.33 mmol; 1.0 eq.) and 1-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-ylamine (82 mg; 0.40 mmol; 1.2 eq.) as a beige solid.
[000527] 1H NMR (300 MHz, DMSO-d6) δ 13.42 (brs, 1H), 10.63 (brs, 1H), 9.46 (s, 1H), 8.38 (d, J = 8.2 Hz, 1H), 8.23 ( q, J = 8.9 Hz, 4H), 8.13 (s, 1H), 7.68-7.58 (m, 2H), 7.52-7.39 (m, 1H), 7.27 (t, J = 7.4 Hz, 1H), 4.64-4.46 (m, 1H), 3.33 (d, J = 13.3 Hz, 2H), 2.35 (s, 3H), 2.221.95 (m, 4H), 1.91-1.69 (m, 4H). HPLC (Condition A): RT 3.18 min (88.1% purity). MS (ESI+): 494.3, MS (ESI-): 492.4.Example 126:3-[1 -(4-{[3-(1H-imidazol-1-ylmethyl)piperidin-1-yl]carbonyl}phenyl)- 1H-1,2,3-triazol-4-yl]-1H-indazole

[000528] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100 mg; 0.33 mmol; 1.0eq.) and 3-Imidazol-1-ylmethyl-piperidine; dihydrochloride (117 mg; 0.49 mmol; 1.5 eq.) as a white solid.
[000529] 1H NMR (DMSO-d6) δ 13.41 (s, 1H), 9.42 (s, 1H), 8.37 (d, J= 8.2 Hz, 1H), 8.12 (m, 2H), 7.65 (m, 3H) , 7.62 (d, J = 8.4 Hz, 1H), 7.45 (m, 1H), 7.27 (m, 1.5H), 6.74-7.15 (m, 1.5H), 2.70-4.5 (m, 6H), 2.03 (m , 1H), 1.67 (m, 2H), 1.45 (m, 1H), 1.24 (m, 1H). HPLC (Condition A): RT 2.55 min (97.8% purity). MS (ESI+): 453.3, MS (ESI-): 451.3.Example 127: 3-(1-{4-[(3-methoxypiperidin-1-yl)carbonyl]phenyl}-1H-1,2,3-triazole -4-yl)-1H-indazole

[000530] The title compound was obtained following procedure described by example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (100 mg; 0.33 mmol; 1.0eq.) and 3-Methoxy-piperidine; hydrochloride (ChemCollect GmbH, 74 mg; 0.49 mmol; 1.5 eq.) as a white solid.
[000531] 1H NMR (300 MHz, DMSO) δ 13.38 (s, 1H), 9.40 (s, 1H), 8.37 (d, J = 8.3 Hz, 1H), 8.15 (d, J = 8.3 Hz, 2H), 7.72-7.55 (m, 3H), 7.45 (t, J = 7.5 Hz, 1H), 7.27 (t, J = 7.4 Hz, 1H), 4.09-3.65 (m, 1H), 3.57-3.18 (m, 5H) , 3.10 (brs, 1H), 2.03-1.21 (m, 5H). HPLC (Condition A): RT 3.22 min (99.5% purity). MS (ESI+): 403.2, MS (ESI-): 401.2.Example 128: 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-hydrochloride N-(1-piperidin-4-yl-1H-pyrazol-4-yl)benzamideStep a) Formation of 4-[4-({4-[4-(1H-indazol-3-yl)-1H-1, tert-Butyl 2,3-triazol-1-yl]benzoyl}amino)-1H-pyrazol-1-yl]piperidine-1-carboxylate

[000532] The title compound was obtained following procedure described by example 70, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (101 mg; 0.33 mmol; 1.0 eq.) and 4-(4-amino-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (105 mg; 0.40 mmol; 1.2 eq.) like a pink powder.
[000533] 1H NMR (300 MHz, DMSO-d6) δ 13.41 (brs, 1H), 10.63 (brs, 1H), 9.46 (s, 1H), 8.38 (d, J = 8.3 Hz, 1H), 8.23 (dd , J = 8.4, 18.6 Hz, 4H), 8.12 (s, 1H), 7.71-7.56 (m, 2H), 7.46 (t, J = 7.7 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H) , 4.38 (s, 1H), 4.05 (d, J = 13.3 Hz, 2H), 2.91 (br s, 2H), 2.09-1.92 (m, 2H), 1.90-1.66 (m, 2H), 1.43 (s, 9H). HPLC (Condition A): RT 4.60 min (95.7% purity). MS (ESI+): 554.3, MS (ESI-): 552.3.Step b) Formation of 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl hydrochloride ]-N-(1-piperidin-4-yl-1H-pyrazol-4-yl)benzamide

[000534] To a solution of 4-[4-({4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}amino)-1H- tert-butyl pyrazol-1-yl]piperidine-1-carboxylate (100 mg; 0.18 mmol; 1.0 eq.) in dioxane (3 mL) was added 4N 1,4-dioxane solution (450 μl of a solution at 4N in dioxane; 1.80 mmol; 10 eq.) and a drop of water. The resulting suspension was stirred at RT O/N. Solvent was removed under reduced pressure and the residue suspended in ACN and filtered to give the title compound as a beige solid (64 mg, 72%).
[000535] 1H NMR (300 MHz, DMSO-d6) δ 13.45 (brs, 1H), 10.75 (s, 1H), 9.46 (s, 1H), 9.19-8.73 (m, 2H), 8.38 (d, J = 8.1 Hz, 1H), 8.32-8.18 (m, 4H), 8.15 (s, 1H), 7.71 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.52-7.39 (m, 1H), 7.27 (t, J = 7.5 Hz, 1H), 4.64-4.42 (m, 1H), 3.48-3.30 (m, 2H), 3.05 (s, 2H), 2.27-2.05 (m, 4H). HPLC (Condition A): RT 3.06 min (95.7% purity). MS (ESI+): 454.4, MS (ESI-): 452.3.Example 129: N-(1-Azepan-4-yl-1H-pyrazol-4-yl)-4-[4-(1H-indazol- 3-yl)-1H-1,2,3-triazol-1-yl]benzamideStep a) Formation of 4-[4-({4-[4-(1H-indazol-3-yl)-1H-1, tert-Butyl 2,3-triazol-1-yl]benzoyl}amino)-1H-pyrazol-1-yl]azepane-1-carboxylate

[000536] The title compound was obtained following procedure described by example 70, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl acid ]benzoic acid (101 mg; 0.33 mmol; 1.0 eq.) and 4-(4-Amino-pyrazol-1-yl)-azepane-1-carboxylic acid tert-butyl ester (111 mg; 0.40 mmol; 1.2 eq.) as a beige solid.
[000537] 1H NMR (300 MHz, DMSO-d6) δ 13.41 (brs, 1H), 10.62 (brs, 1H), 9.46 (s, 1H), 8.38 (d, J = 8.2 Hz, 1H), 8.23 (dd , J = 8.8, 19.4 Hz, 4H), 8.09 (s, 1H), 7.62 (d, J = 6.2 Hz, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.28 (t, J = 7.5 Hz , 1H), 4.34 (s, 1H), 3.70-3.50 (m, 1H), 3.48-3.35 (m, 2H), 3.32-3.15 (m, 1H), 2.16-1.55 (m, 6H), 1.44 (s , 9H). HPLC (Condition A): RT 4.69 min (99.0% purity). MS (ESI+): 568.3, MS (ESI-): 566.3.Step b) Formation of N-(1-azepan-4-yl-1H-pyrazol-4-yl)-4-[4-(1H-indazol- 3-yl)-1H-1,2,3-triazol-1-yl]benzamide hydrochloride

[000538] The title compound was obtained following procedure described by example 128, step b), but starting from 4-[4-({4-[4-(1H-indazol-3-yl)-1H-1 tert-Butyl ,2,3-triazol-1-yl]benzoyl}amino)-1H-pyrazol-1-yl]azepane-1-carboxylate (100 mg; 0.18 mmol; 1.0 eq.) as a beige solid (84 mg, 95%).
[000539] 1H NMR (300 MHz, DMSO-d6) δ 13.43 (brs, 1H), 10.72 (brs, 1H), 9.46 (s, 1H), 9.25-8.88 (m, 2H), 8.38 (d, J = 8.1 Hz, 1H), 8.33-8.09 (m, 5H), 7.71-7.58 (m, 2H), 7.52-7.40 (m, 1H), 7.27 (t, J = 7.5 Hz, 1H), 4.56 (d, J = 5.4 Hz, 1H), 3.45-3.02 (m, 4H), 2.40-2.10 (m, 4H), 2.051.71 (m, 2H). HPLC (Condition A): RT 3.12 min (96.1% purity). MS (ESI+): 468.3, MS (ESI-): 466.4.Example 131: 4-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1- Hydrochloride tert-butyl yl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate

[000540] Hydrogen chloride (6.0 mL of a 4N solution in dioxane) was added to a suspension of 4-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazole tert-butyl -1-yl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate (505 mg; 1.14 mmol; 1.0 eq.) in dioxane (6.0 mL). The resulting light brown suspension was stirred at 35°C for 3h. It was then concentrated to dryness and the resulting beige solid was suspended in dioxane, filtered, washed several times with Et2O and dried in vacuo at 40°C to give the title compound as a beige solid (379 mg, 87.7%).
[000541] 1H NMR (300 MHz, DMSO-d6) δ 13.43 (brs, 1H), 9.52 - 9.14 (m, 3H), 8.36 (d, J = 8.1, 1H), 8.10 (d, J = 8.0, 2H ), 7.75 (d, J = 8.1, 2H), 7.62 (d, J = 8.5, 1H), 7.44 (t, J = 7.6, 1H), 7.26 (t, J = 7.2, 1H), 6.37 (s, 1H), 3.96 - 3.67 (m, 2H), 3.45 - 3.18 (m, 2H), 2.93 - 2.57 (m, 2H).Example 132: 3-[1-(4-piperidin-4-ylphenyl)-1H- 1,2,3-triazol-4-yl]-1H-indazole hydrochlorideStep a) Formation of 4-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1 tert-butyl -yl]phenyl}piperidine-1-carboxylate

[000542] In a Parr reactor, Pd/C (10% wet Pd, 50% water, 24 mg, 0.23 mmol, 0.1 eq.) was suspended in a solution of 4-{4-[4-(1H- tert-butyl indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate (1.0 g; 2.26 mmol; 1.0 eq.) and ammonium formate (2.85 g; 45.2 mmol; 20 eq.) in THF (55 mL). A reaction mixture was stirred for 48h at 70°C. It was then filtered through a pad of celite, the cake was washed several times with THF and the filtrate was concentrated to dryness. The resulting residue was partitioned between DCM and water. Organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM: MeOH, gradient from 100:0 to 95:5) gave the title compound as a white foam (950 mg g; 94.5%).
[000543] 1H NMR (300 MHz, DMSO-d6) δ 13.36 (brs, 1H), 9.27 (s, 1H), 8.36 (d, J = 8.2 Hz, 1H), 8.01 - 7.93 (m, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.56 - 7.39 (m, 3H), 7.30 - 7.20 (m, 1H), 4.27 - 3.94 (m, 2H), 3.01 - 2.63 (m, 3H), 1.96 - 1.70 (m, 2H), 1.69 - 1.47 (m, 2H), 1.43 (s, 9H). 1H HPLC (max scheme) 97.2%; TA 5.33min. UPLC/MS: (MS+) 445.2, (MS-) 443.2.Step b) Formation of 3-[1-(4-piperidin-4-ylphenyl)-1H-1,2,3-triazol-4-yl Hydrochloride ]-1H-indazole

[000544] The title compound was obtained, following procedure described by example 131, but starting from 4-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol- tert-Butyl 1-yl]phenyl}piperidine-1-carboxylate (900 mg; 2.02 mmol; 1.0 eq.) as a white powder (700 mg; 90.8%).
[000545] 1H NMR (300 MHz, DMSO-d6) δ 13.43 (brs, 1H), 9.29 (s, 1H), 9.17 - 8.72 (m, 2H), 8.36 (d, J = 8.1 Hz, 1H), 8.07 - 7.94 (m, 2H), 7.67 - 7.56 (m, 1H), 7.55 - 7.38 (m, 3H), 7.32 - 7.19 (m, 1H), 3.51 - 3.24 (m, 2H), 3.19 - 2.84 (m, 1H), 3H), 2.15 - 1.73 (m, 4H). HPLC (max scheme) 99.4%; TA 2.62min. UPLC/MS: (MS+) 345.2, (MS-) 343.1.Example 133: 3-(1,4-[1-(2-fluoroethyl)piperidin-4-yl]phenyl}-1H-1,2,3- triazol-4-yl)-1H-indazole

[000546] 1-bromo-2-fluoroethane (30 mg; 0.24 mmol; 0.9 eq.) was added to a suspension of 3-[1-(4-piperidin-4-ylphenyl)-1H-1,2, 3-triazol-4-yl]-1H-indazole (100 mg; 0.26 mmol; 1.0 eq.) and NaHCO 3 (331 mg; 3.94 mmol; 15 eq.) in dry DMF (2 mL). A reaction mixture was heated in MW at 100°C for 3h. It was then diluted with water and extracted with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM: MeOH, gradient from 100:0 to 90:10) gave the title compound as a white solid (40 mg, 39%).
[000547] 1H NMR (300 MHz, DMSO-d6) δ 13.36 (brs, 1H), 9.27 (s, 1H), 8.41 - 8.31 (m, 1H), 8.01 - 7.92 (m, 2H), 7.64 - 7.58 ( m, 1H), 7.55 - 7.38 (m, 3H), 7.30 - 7.20 (m, 1H), 4.56 (dt, J = 47.8, 4.9 Hz, 2H), 3.09 - 2.96 (m, 2H), 2.75 - 2.54 ( m, 3H), 2.22 - 2.07 (m, 2H), 1.88 - 1.61 (m, 4H). HPLC (max scheme) 99.8%; RT 2.64min.UPLC/MS: (MS+) 391.1, (MS-) 389.2Example 134: 3-{1-[4-(1-acetylpiperidin-4-yl)phenyl]-1H-1,2,3-triazole -4-yl}-1H-indazole Step a) Formation of 1-acetyl-3-{1-[4-(1-acetylpiperidin-4-yl)phenyl]-1H-1,2,3-triazol-4- yl}-1H-indazole

[000548] Acetyl chloride (17 μl; 0.25 mmol; 0.95 eq.) was added to a solution of 3-[1-(4-piperidin-4-ylphenyl)-1H-1,2,3-triazol-4- yl]-1H-indazole (100 mg; 0.26 mmol; 1.0 eq.) in pyridine (1.50 mL). a reaction mixture was stirred at RT for 1h. Acetyl chloride (9 μl; 0.13 mmol; 0.5 eq.) was added again and the reaction mixture was stirred at RT for 1h. It was concentrated under reduced pressure and the residue was diluted with DCM. Water was added, the two phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM:MeOH, gradient 100:0 to 90:10) gave the title compound as a beige solid (85 mg, 76%). HPLC (max scheme) 96.2%; TA 4.08min. UPLC/MS: (MS+) 429.2.Step b) Formation of 3-{1-[4-(1-acetylpiperidin-4-yl)phenyl]-1H-1,2,3-triazol-4-yl}-1H -indazole

[000549] A solution of 1-acetyl-3-{1-[4-(1-acetylpiperidin-4-yl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole (85 mg; 0.20 mmol; 1.0 eq.) and potassium carbonate (274 mg; 1.98 mmol; 10 eq.) in MeOH (1.0 mL) and DCM (1.00 mL) was stirred at RT for 1h. It was then diluted with water. Aqueous phase was separated and extracted with DCM. Combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a white powder (35mg, 46%).
[000550] 1H NMR (300 MHz, DMSO-d6) δ 13.35 (brs, 1H), 9.28 (s, 1H), 8.41 - 8.31 (m, 1H), 8.03 - 7.93 (m, 2H), 7.64 - 7.58 ( m, 1H), 7.55 - 7.39 (m, 3H), 7.30 - 7.20 (m, 1H), 4.64 - 4.47 (m, 1H), 4.02 - 3.84 (m, 1H), 3.23 - 3.07 (m, 1H), 2.98 - 2.81 (m, 1H), 2.68 - 2.54 (m, 1H), 2.05 (s, 3H), 1.92 - 1.76 (m, 2H), 1.74 - 1.39 (m, 2H). HPLC (max scheme) 98.5%; TA 3.90min. UPLC/MS: (MS+) 387.2, (MS-)385.2.Example 135: 6-fluoro-3-(1-{4-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]phenyl} -1H-1,2,3-triazol-4-yl)-1H-indazole

[000551] The title compound was obtained, following procedure described for intermediate 10, but starting from 3-ethynyl-6-fluoro-1H-indazole (60 mg; 0.37 mmol; 1.0 eq.) and 4-(4- azidophenyl)-1-(3,3,3-trifluoropropyl)piperidine (112 mg; 0.37 mmol; 1.0 eq.) as an amorphous beige foam (38 mg; 22%).
[000552] 1H NMR (300 MHz, DMSO-d6-d6) δ: 13.43 (brs, 1H), 9.29 (s, 1H), 8.38 (dd, J = 8.9, 5.4 Hz, 1H), 8.07 - 7.89 (m , 2H), 7.61 - 7.43 (m, 2H), 7.40 (dd, J = 9.5, 1.9 Hz, 1H), 7.15 (td, J = 9.3, 2.1 Hz, 1H), 3.18 - 2.99 (m, 2H), 2.85 - 2.52 (m, 5H), 2.34 - 2.11 (m, 2H), 1.95 - 1.54 (m, 4H). HPLC (Condition A): RT 3.21 min (93.0% purity). UPLC/MS: (MS+) 459.5, (MS-) 457.5.Example 136: 1,1,1-trifluoro-3-(4-{4-[4-(6-methyl-1H-indazol-3-yl) -1H-1,2,3-triazol-1-yl]phenyl}piperidin-1-yl)propan-2-ol

[000553] The title compound was obtained, following procedure described for intermediate 10, but starting from 3-ethynyl-6-methyl-1H-indazole (60 mg; 0.38 mmol; 1.0 eq.) and 3-[4- (4-azidophenyl)piperidin-1-yl]-1,1,1-trifluoropropan-2-ol (121 mg; 0.38 mmol; 1.0 eq.) as a white foam (53 mg; 29%).
[000554] 1H NMR (300 MHz, DMSO-d6-d6) δ 13.18 (brs, 1H), 9.24 (s, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.01 - 7.90 (m, 2H) , 7.57 - 7.45 (m, 2H), 7.37 (s, 1H), 7.09 (d, J = 8.4 Hz, 1H), 4.27 - 4.06 (m, 1H), 3.12 - 2.92 (m, 3H), 2.70 - 2.52 (m, 3H), 2.48 (s, 3H), 2.29 - 2.07 (m, 2H), 1.89 - 1.58 (m, 4H). HPLC (Condition A): RT 3.22 min (94.7% purity). UPLC/MS: (MS+) 471.5, (MS-) 469.5.Example 137: 4-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl] phenyl}piperidin-3-ol hydrochlorideStep a) Formation of 3-hydroxy-4-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl} tert-butyl piperidine-1-carboxylate

[000555] To a stirred solution, borane-methyl sulfide complex (587 μl of a 2.0 M solution in THF; 1.18 mmol; 1.3 eq.) in THF (6.0 mL) kept at 0°C under a nitrogen atmosphere was A solution of 4-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}-3,6-dihydropyridine- tert-Butyl 1(2H)-carboxylate (400 mg; 0.90 mmol; 1.0 eq.) in THF (6.0 mL). A reaction mixture was stirred at RT for 12h. Additional borane-methyl sulfide complex (135 μl of a 2.00 M solution in THF; 0.27 mmol; 0.3 eq.) was added and the reaction mixture was stirred at RT for 1 additional hour. A reaction mixture was then cooled to 0°C before the dropwise addition of NaOH (3.6 mL) followed by hydrogen peroxide (615 μl). It was then allowed to warm to RT and stirred O/N. A reaction mixture was then diluted with water and extracted with DCM (four times). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (EtO-Ac:heptanes, gradient from 90:10 to 40:60) to give the title compound as a white foam (90mg, 22%). HPLC (max scheme) 96.4%; TA %4.16min. UPLC/MS: (MS+) 461.4, (MS-) 459.5.Step b) Formation of 4-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol- 1-yl]phenyl}piperidin-3-ol

[000556] The title compound was obtained, following procedure described by example 131, but starting from 3-hydroxy-4-{4-[4-(1H-indazol-3-yl)-1H-1,2, tert-butyl 3-triazol-1-yl]phenyl}piperidine-1-carboxylate (85 mg; 0.18 mmol; 1.0 eq.) as a white solid (70 mg, 96%). 9:1 mixture of cis and trans isomers:
[000557] 1H NMR (300 MHz, DMSO-d6) δ 13.41 (brs, 1H), 9.29 (s, 1H), 9.27 - 9.04 (m, 2H), 8.37 (d, J = 8.1 Hz, 1H), 8.13 - 7.95 (m, 2H), 7.66 - 7.57 (m, 1H), 7.52 - 7.39 (m, 2H), 7.32 - 7.19 (m, 1H), 4.61 (brs, 1H), 3.98 (td, J = 10.6, 4.4 Hz, 1H), 3.47 - 2.56 (m, 6H), 2.13 - 1.71 (m, 2H). HPLC (max scheme) 96.0%; TA %2.36min. UPLC/MS: (MS+) 361.3, (MS-) 359.4.Example 138: N,N-dimethyl-1-(4-{4-[5-(2-methylprop-1-en-1-yl)-1H -indazol-3-yl]-1H-1,2,3-triazol-1-yl}benzoyl)piperidin-4-amine

[000558] A mixture of 1-{4-[4-(5-bromo-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}-N,N-dimethylpiperidin -4-amine (160 mg; 0.32 mmol; 1.0 eq.), 1-{4-[4-(5-bromo-1H-indazol-3-yl)-1H-1,2,3-triazol-1- yl]benzoyl}-N,N-dimethylpiperidin-4-amine (160 mg; 0.32 mmol; 1.0 eq.), PdCl2dppf (24 mg; 0.03 mmol; 0.1 eq.) and potassium carbonate (224 mg; 1.62 mmol; 5.0 eq.) in dioxane (1 mL) and water (1 mL) was heated to 80°CO/N in a sealed tube. A reaction mixture was then filtered through a pad of celite and the filtrate was extracted twice with DCM. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM: MeOH, gradient form 90:10 to 50:50) gave the title compound as a brown powder (68 mg, 45%).
[000559] 1H NMR (DMSO) δ 13.35 (s, 1H), 9.37 (s, 1H), 8.21 (s, 1H), 8.17-8.11 (m, 2H), 7.68-7.62(m, 2H), 7.55 ( d, J = 8.7 Hz, 1H), 7.35-7.29 (m, 1H), 6.47-6.43 (m, 1H), 4.54-4.38 (m, 1H), 3.73-3.55 (m, 1H), 3.18-2.74 ( m, 2H), 2.42-2.29 (m, 1H), 2.19 (s, 6H), 1.93 (s, 3H), 1.90 (s, 3H), 1.88-1.61 (m, 2H), 1.47-1.29 (m, 2H), 2H). HPLC (max scheme) 98.0%; TA 3.71min. UPLC/MS: (MS+) 470.3, (MS-) 468.3.Example 139: 1 -{4-[4-(5-Isobutyl-1H-indazol-3-yl)-1H-1,2,3-triazol- 1-yl]benzoyl}-N,N-dimethylpiperidin-4-amine

[000560] The title compound was obtained, following procedure described by example 132, but starting from N,N-dimethyl-1-(4-{4-[5-(2-methylprop-1-en-1- yl)-1H-indazol-3-yl]-1H-1,2,3-triazol-1-yl}benzoyl)piperidin-4-amine (65mg; 0.14mmol; 1.0eq.) as a white foam (26mg , 40%).
[000561] 1H NMR (300 MHz, DMSO-d6) δ 13.28 (brs, 1H), 9.35 (s, 1H), 8.17 - 8.06 (m, 3H), 7.73 - 7.60 (m, 2H), 7.52 (d, J = 8.5 Hz, 1H), 7.27 (dd, J = 9.8 Hz, 1H), 4.59 - 4.35 (m, 1H), 3.90 - 3.25 (m, 1H), 3.26 - 2.72 (m, 2H), 2.62 (d , J = 7.1 Hz, 2H), 2.47 - 2.35 (m, 1H), 2.22 (s, 6H), 2.03 - 1.63 (m, 3H), 1.53 - 1.28 (m, 2H), 0.91 (d, J = 6.6 Hz, 6H). HPLC (max scheme) 98.0%; TA 3.82min. UPLC/MS: (MS+) 472.3, (MS-) 470.3.Example 140: 3-{1-[1-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol- 4-yl]-1H-1,2,3-triazol-4-yl}-1H-indazole

[000562] The title compound was obtained, following procedure described for intermediate 10, but starting from 3-(4-azido-1H-pyrazol-1-yl)-8-methyl-8-azabicyclo[3.2.1] octane (139 mg; 0.6 mmol; 1.0 eq.) and 3-ethynyl-1H-indazole (85 mg; 0.60 mmol; 1.00eq.) as a yellow solid (40mg, 16%).
[000563] 1H NMR (300 MHz, DMSO-d6) δ 13.33 (s, 1H), 9.05 (s, 1H), 8.56 (s, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.23 (s , 1H), 8.11 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.49 - 7.38 (m, 1H), 7.25 (t, J = 7.4 Hz, 1H), 4.76 - 4.54 (m, 1H), 3.43 (br s, 2H), 2.39 (s, 3H), 2.22 (t, J = 11.9 Hz, 2H), 2.08 (d, J = 10.1 Hz, 2H), 1.96 (d, J = 10.2 Hz , 2H), 1.86 - 1.71 (m, 2H). HPLC (max scheme) 98.5%; TA 2.70min. UPLC/MS: (MS+) 375.2, (MS-) 373.1.Example 141: 3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-hydrochloride yl}-5-(piperidin-4-ylmethyl)-1H-indazolStep a) Formation of 4-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3- tert-butyl triazol-4-yl}-1H-indazol-5-yl)methyl]piperidine-1-carboxylate

[000564] A degassed solution of 1-N-Boc-4-methylenepiperidine (48 mg; 0.24 mmol; 1.1 eq.) and 9-BBN (0.5M 0.44 mL of a 0.5 M solution in THF; 0.22 mmol; 1.0 eq.) in THF (0.5 mL) was heated at 80°C for 1 h in a sealed tube. This solution was allowed to cool to RT and cannulated into a degassed mixture of 5-bromo-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl} -1H-indazole (100 mg; 0.22 mmol; 1.0 eq.), PdCl2dppf (1 mg; 0.001 mmol; 0.01 eq.) and potassium carbonate (76 mg; 0.55 mmol; 2.5 eq.) in DMF (1 mL) and water (0.1 ml). The resulting mixture was heated to 65°C O/N. As the reaction was not completed, a second borane solution was prepared (from 0.24 mmol of 1-N-Boc-4-methylene-piperidine) and added to a reaction mixture which was heated at 65°C overnight. A reaction mixture was poured into water and extracted twice with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM:MeOH, gradient from 100:0 to 90:10) gave the title compound as a yellow powder (110 mg, 87%).
[000565] 1H NMR (300 MHz, DMSO-d6) δ 13.29 (brs, 1H), 9.36 (s, 1H), 8.21 - 8.08 (m, 3H), 7.74 - 7.65 (m, 2H), 7.56 - 7.48 ( m, 1H), 7.32 - 7.23 (m, 1H), 4.04 - 3.81 (m, 2H), 3.79 - 3.36 (m, 8H), 2.83 - 2.56 (m, 3H), 1.84 - 1.50 (m, 3H), 1.49 - 1.39 (m, 1H), 1.37 (s, 9H), 1.21 - 0.91 (m, 2H). HPLC (max scheme) 86.0%; TA 4.36 min. UPLC/MS: (MS-) 470.2 (M-tBuOCO). Step b) Formation of 3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-5-(piperidin-4-ylmethyl)-hydrochloride 1H-indazole

[000566] The title compound was obtained, following procedure described by example 131, but starting from 4-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2, tert-Butyl 3-triazol-4-yl}-1H-indazol-5-yl)methyl]piperidine-1-carboxylate (100 mg; 0.17 mmol; 1.0 eq.) as a beige solid (31 mg, 35%) . 1H NMR (300 MHz, DMSO-d6) δ 13.34 (brs, 1H), 9.37 (s, 1H), 8.84 - 8.66 (m, 1H), 8.57 - 8.35 (m, 1H), 8.15 (d, J = 7.7 Hz, 3H), 7.69 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 3.92 - 3.30 (m, 8H), 3.23 (d, J = 11.1Hz, 2H), 2.50 (s, 4H), 1.99 - 1.65 (m, 3H), 1.51 - 1.28 (m, 2H). HPLC(max scheme) 93.2%; TA 2.21min. UPLC/MS: (MS-) 470.2.Example 142: 3-{1-[4-(morpholin-4-ylmethyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol- Methyl 5-carboxylate

[000567] The title compound was obtained, following procedure described for intermediate 10, but starting from 5-(benzyloxy)-3-ethynyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole ( 400 mg; 2.0 mmol; 1.0 eq.) and 4-(4-azidobenzoyl)morpholine (436 µl; 2.0 mmol; 1.0 eq.) as a white solid (508 mg, 61%).
[000568] 1H NMR (300 MHz, DMSO-d6) δ 13.73 (s, 1H), 9.38 (s, 1H), 9.10 (s, 1H), 8.07 - 7.96 (m, 3H), 7.71 (dd, J = 8.8, 0.7 Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H), 3.92 (s, 3H), 3.68 - 3.52 (m, 6H), 2.46 - 2.29 (m, 4H). HPLC (max scheme) 97.7%; TA 2.45min. UPLC/MS: (MS+) 419.1, (MS-) 417.1.Example 143: N-(1-methylpiperidin-4-yl)-3-{1-[4-(morpholin-4-ylmethyl)phenyl]-1H- 1,2,3-triazol-4-yl}-1H-indazole-5-carboxamideStep a) Formation of 3-{1-[4-(morpholin-4-ylmethyl)phenyl]-1H-1,2,3 acid - triazol-4-yl}-1H-indazole-5-carboxylic acid

[000569] A solution of methyl 3-{1-[4-(morpholin-4-ylmethyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-carboxylate (351 mg; 0.84 mmol; 1.0 eq.) and lithium hydroxide (201 mg; 8.4 mmol; 10 eq.) in THF (3.5 mL) and water (3.5 mL) was stirred O/N at 40°C. A 5N HCl solution was then added and the precipitate was filtered, washed with water and dried under reduced pressure at 40°CO/N to give the title compound as a white powder (366 mg, 100%). UPLC/MS: (MS+) 405.1, (MS-) 403.1.Step b) Formation of N-(1-methylpiperidin-4-yl)-3-{1-[4-(morpholin-4-ylmethyl)phenyl] - 1H-1,2,3-triazol-4-yl}-1H-indazole-5-carboxamide

[000570] The title compound was obtained, following procedure described for intermediate 3, but starting from 3-{1-[4-(morpholin-4-ylmethyl)phenyl]-1H-1,2,3-triazole acid -4-yl}-1H-indazole-5-carboxylic acid (50 mg; 0.12 mmol; 1.0 eq.) and 4-amino-1-methylpiperidine (64 mg; 0.56 mmol; 4.5 eq.) as a white solid (33mg, 53%).
[000571] 1H NMR (300 MHz, DMSO-d6) δ 13.61 (s, 1H), 9.41 (s, 1H), 8.90 (s, 1H), 8.67 (d, J = 6.9 Hz, 1H), 8.04 (d , J = 8.5 Hz, 2H), 7.95 (dd, J = 8.8, 1.5 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 4.18 - 3.99 (m, 1H), 3.68 - 3.53 (m, 4H), 3.47 - 3.25 (m, 6H), 3.13 - 2.91 (m, 2H), 2.72 (s, 3H), 2.47 - 2.32 (m, 2H), 2.11 - 1.80 (m, 4H). HPLC (max layout) 100.0%; TA %1.60min. UPLC/MS: (MS+) 501.2, (MS-) 499.2.Example 144: 6-(4-hydroxyphenyl)-2-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H- 1,2,3-triazol-4-yl}-1H-indazol-5-yl)methyl]pyridazin-3(2H)-one

[000572] A suspension of PdCl2(PPh3)2 (10 mg; 0.01 mmol; 0.11 eq.), 5-[(3-chloro-6-oxopyridazin-1(6H)-yl)methyl]-3-{1- tert-butyl [4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-1-carboxylate (79 mg; 0.13 mmol; 1.0 eq.) , 4-hydroxyphenylboronic acid (35 mg; 0.25 mmol; 2.0 eq.) and cesium fluoride (65 mg; 0.43 mmol; 3.3 eq.) in DMF (2.0 mL) and water (1.0 mL) was degassed with argon in a tube sealed and heated in MW at 120°C for 1.5 h. The mixture was then filtered through a pad of celite. The filtrate was diluted with EtOAc. The phases were separated and the organic phase was washed with 1N HCl solution, dried over magnesium sulfate, filtered and concentrated. Purification of the crude by preparative HPLC gave the title compound as a white solid (9 mg, 9%).
[000573] 1H NMR (300 MHz, DMSO-d6) δ 13.40 (s, 1H), 9.85 (br, 1H), 9.38 (s, 1H), 8.46 (s, 1H), 8.18 - 8.12 (m, 2H) , 7.98 (d, J = 9.8 Hz, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 1H), 7.54 - 7.46 (m, 1H), 7.05 (d, J = 9.7 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 5.46 (s, 2H), 3.75 - 3.43 (m, 8H). HPLC (max scheme) 98.6%; TA 3.14min. UPLC/MS: (MS+) 575.1, (MS-) 573.0.Example 145: 3-(1-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl ]phenyl}-1H-1,2,3-triazol-4-yl)-1H-indazole

[000574] The title compound was obtained, following procedure described for intermediate 10, but starting from 3-Ethynyl-1H-indazole (74 mg; 0.52 mmol; 1.0 eq.) and (1S,4S)-5-( 4-azidobenzyl)-2-oxa-5-azabicyclo[2.2.1]heptane (120 mg; 0.52 mmol; 1.0 eq.) as a yellow solid (79 mg, 40%).
[000575] 1H NMR (300 MHz, DMSO-d6) δ 13.36 (s, 1H), 9.29 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 8.6 Hz, 2H ), 7.66 - 7.53 (m, 3H), 7.49 - 7.39 (m, 1H), 7.30 - 7.20 (m, 1H), 4.38 (brs, 1H), 3.96 (d, J = 7.4 Hz, 1H), 3.82 ( d, J = 3.3 Hz, 2H), 3.56 (dd, J = 7.5, 1.8 Hz, 1H), 3.49 (brs, 1H), 2.77 (dd, J = 9.9, 1.6 Hz, 1H), 2.45 (d, J = 9.9 Hz, 1H), 1.84 (dd, J = 9.4, 1.8 Hz, 1H), 1.62 (d, J = 9.6 Hz, 1H). HPLC (max scheme) 98.4%; TA 2.32min. UPLC/MS: (MS+) 373.3, (MS-) 371.2.Example 146: 3-(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4 -yl}-1H-indazol-6-yl)prop-2-yn-1-ol

[000576] A mixture of {4-[4-(6-Bromo-1H-indazol-3-yl)-[1,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (150 mg; 0.33 mmol; 1.0 eq.), propargyl alcohol (39 μl; 0.66 mmol; 2.0 eq.) and Pd(PPhβ)4 (19 mg, 0.02 mmol, 0.05 eq.) in pyrrolidine (1.5 mL) was heated. O/N at 80°C in a sealed tube. A reaction mixture was then diluted with DCM and washed with a saturated solution of NH4Cl (three times) and brine. Organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC gave the title compound as a beige solid (40 mg, 28%).
[000577] 1H NMR (300MHz, DMSO-d6-d6): 13.50 (brs, 1H), 9.42 (s, 1H), 8.34 (dd, J=8.5Hz, 1.0Hz, 1H), 8.15 (d, J = 8.6 Hz, 2H), 7,707,67 (m, 3H), 7.28 (dd, J= 8.5 Hz, 1.0 Hz, 1H), 5.40 (t, J= 6.0 Hz, 1H), 4.35 (d, J= 6.0 Hz, 2H), 3.64 (m, 6H), 3.47 (m, 2H).
[000578] HPLC (max scheme) 94.4%; TA %2.65min. UPLC/MS: (MS+) 429.1, (MS-) 427.2.Example 147: 3-(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4 -yl}-1H-indazol-6-yl)propan-1-ol

[000579] A solution of 3-(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-6-yl) prop-2-yn-1-ol (40 mg; 0.09 mmol; 1.0 eq.) in DCM (2.0 mL) and MeOH (2.0 mL) was passed through a Pd/C cartridge at RT with complete H2 to 1 mL /min in the H-cube. Solvents were removed under reduced pressure and the crude obtained was purified by preparative HPLC to give the title compound as a white solid (15mg, 37%).
[000580] 1H NMR (300MHz, DMSO-d6) δ 13.23 (brs, 1H), 9.37 (s, 1H), 8.24 (d, J= 8.3 Hz, 1H), 8.15 (d, J= 8.6 Hz, 2H) , 7.68 (d, J= 8.6 Hz, 2H), 7.37 (m, 1H), 7.12 (dd, J= 8.3 Hz, 1.1 Hz, 1H), 4.52 (t, J= 5.1 Hz, 1H), 3.64 (m , 6H), 3.42 (m, 2H), 2.94-2.75 (m, 4H), 1.85-1.72 (m, 2H). HPLC (max scheme) 98.3%; TA %2.69min. UPLC/MS: (MS+) 433.1, (MS-) 431.2.Example 148: N-(1-methylpiperidin-3-yl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H- 1,2,3-triazol-4-yl}-1H-indazol-5-amine

[000581] LiHMDS (1.99 mL of a 1.0 M in THF; 1.99 mmol; 4.5 eq.) was added to a degassed suspension of {4-[4-(5-Bromo-1H-indazol-3-yl)-[1 ,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (200 mg; 0.44 mmol; 1.0 eq.), 3-amino-1-methylpiperidine dihydrochloride, 98% (99 mg; 0.53 mmol; 1.2 eq.), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl][2-( 2-aminoethyl)phenyl]palladium(II), (7.0 mg; 0.01 mmol; 0.02 eq.) and dicyclohexyl-(2',4',6'-triisopropyl-3,6-dimethoxy-biphenyl-2 -yl)-phosphane (5.0 mg; 0.01 mmol; 0.02 eq.) in DMF (500 µl). A reaction mixture was then heated to 70°C O/N. As the reaction was not completed, additional 3-amino-1-methylpiperidine dihydrochloride (99 mg; 0.53 mmol; 1.2 eq.), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4' -6'-tri-i-propyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (7.0 mg; 0.01 mmol; 0.02 eq.), dicyclohexyl-(2') ,4',6'-triisopropyl-3,6-dimethoxy-biphenyl-2-yl)-phosphane (5.0 mg; 0.01 mmol; 0.02 eq.) and LiHMDS (1.99 mL of a 1.0 M in THF; 1.99 mmol ; 4.5 eq.) were added and the reaction mixture was heated again at 70°C for 12h. It was diluted with DCM and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC gave the title compound as a brown solid (10 mg, 5%).
[000582] 1 H NMR (300 MHz, DMSO-d6-d6): 12.96 (brs, 1H), 9.26 (s, 1H), 8.14 (d, J= 8.6 Hz, 2H), 7.68 (d, J= 8.6 Hz , 2H), 7.36-7.33 (m, 1H), 6.96-6.92 (m, 2H), 5.36 (m, 1H), 3.64-3.55 (m, 11H), 3.00 (m, 1H), 2.73 (m, 1H ), 2.23 (m, 3H), 1.99-1.59 (m, 3H), 1.30 (m, 1H). HPLC (max scheme) 94.3%; TA 1.99 min. UPLC/MS: (MS+) 487.3, (MS-) 485.3.Example 149: N,N-dimethyl-1-(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2 ,3-triazol-4-yl}-1H-indazol-5-yl)pyrrolidin-3-amineStep a) formation of (4-{4-[5-Bromo-1-(tetrahydro-pyran-2-yl) )-1H-indazol-3-yl]-[1,2,3]triazol-1-yl}-phenyl)-morpholin-4-yl-methanone

[000583] The title compound was obtained, following procedure described for intermediate 41, step a), but starting from {4-[4-(5-Bromo-1H-indazol-3-yl)-[1,2,3 ]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (1.8 g; 3.99 mmol; 1.0 eq.) as a white solid (1.61 g, 75%).
[000584] 1H NMR (300 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.57 (d, J = 1.5 Hz, 1H), 8.24 - 8.13 (m, 2H), 7.86 (d, J = 8.9 Hz , 1H), 7.73 - 7.68 (m, 2H), 7.68 - 7.63 (m, 1H), 6.04 - 5.93 (m, 1H), 3.94 (d, J = 11.7 Hz, 1H), 3.86 - 3.75 (m, 1H) ), 3.53 (d, J = 68.4 Hz, 8H), 2.47 - 2.37 (m, 1H), 2.16 - 1.97 (m, 2H), 1.88 - 1.70 (m, 1H), 1.68 - 1.55 (m, 2H). UPLC/MS: (MS+) 537.4.Step b) Formation of N,N-dimethyl-1-[3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazole -4-yl}-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl]pyrrolidin-3-amine

[000585] A mixture of 4-{4-[5-Bromo-1-(tetrahydro-pyran-2-yl)-1H-indazol-3-yl]-[1,2,3]triazol-1- yl}-phenyl)-morpholin-4-yl-methanone (150 mg; 0.28 mmol; 1.0 eq.), 3-(dimethylamino)pyrrolidine (38 mg; 0.33 mmol; 1.2 eq.), 2-2-dicyclohexylphosphino -2',6'-di-i-propoxy-1,1'-biphenyl (13 mg; 0.03mmol; 0.1 eq.), Chloro(2-dicyclohexylphosphino-2',6'-di-i-propoxy -1,1'-biphenyl)[2-(2-aminoethylphenyl)] palladium(II), methyl-t-butylether (23 mg; 0.03 mmol; 0.1 eq.) and sodium tert-butoxide (134 mg; 1.40 mmol ; 5.0 eq.) in dry THF (3.0 mL) was heated in a sealed tube in MW at 100°C for 15 min. It was diluted with DCM and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated. purification by flash chromatography (DCM:MeOH, gradient from 100:0 to 90:10) gave the title compound as a brown liquid (110 mg, 69%).
[000586] 1H NMR (DMSO) δ 9.32 (s, 1H), 8.16 (d, J= 8.7 Hz, 2H), 7.69-7.63 (m, 3H), 7.26 (d, J= 2.0 Hz, 1H), 6.99 (dd, J= 9.0 Hz, 2.0 Hz, 1H), 5.84 (dd, J= 10.0 Hz, 2.0 Hz, 1H), 3.95-3.91 (m, 1H), 3.82-3.30 (m, 13H), 2.88-2.80 (m, 1H), 2.50-2.41 (m, 1H), 2.23 (s, 6H), 2.19 (m, 1H), 2.08-2.01 (m, 2H), 1.94-1.75 (m, 2H), 1.60 (m , 2H). HPLC (max scheme) 98.8%; TA %2.74min. UPLC/MS: (MS+) 571.6.Step c) Formation of N,N-dimethyl-1-(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazole -4-yl}-1H-indazol-5-yl)pyrrolidin-3-amine
[000587] Hydrogen chloride (0.72 mL of a 4N solution in dioxane) was added to a solution of N,N-dimethyl-1-[3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]- 1H-1,2,3-triazol-4-yl}-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl]pyrrolidin-3-amine (110 mg; 0.19 mmol ; 1.0 eq.) in DCM (1.1 mL) and MeOH (0.55 mL). A reaction mixture was stirred at RT O/N. Solvents were then removed under reduced pressure and the residue was purified by preparative HPLC to give the title compound as a yellow powder (65mg, 69%).
[000588] 1H NMR (300 MHz, MeOD): 8.98 (s, 1H), 8.14 (d, J= 8.7 Hz, 2H), 7.73 (d, J= 8.7 Hz, 2H), 7.53 (d, J= 9.1 Hz, 1H), 7.48 (d, J= 2.0 Hz, 1H), 7.13 (dd, J= 8.1 Hz, 2.0 Hz, 1H), 3.80-3.68 (m, 9H), 3.633.43 (m, 4H), 2.84 (s, 6H), 2.61-2.51 (m, 1H), 2.30-2.21 (m, 1H). HPLC (max scheme) 96.0%; TA %2.12min. UPLC/MS: (MS+) 487.4, (MS-) 485.3. Example 150: 2,2,2-Trifluoro-1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}ethanol

[000589] A mixture of 1-(4-bromophenyl)-2,2,2-trifluoroethane-1-ol (296 mg; 1.16 mmol; 1.1 eq.), 3-Ethynyl-1H-indazole (150 mg; 1.06 mmol ;1.0 eq.), sodium azide (75 mg; 1.16 mmol; 1.1 eq.), D-(-)-isoascorbic acid sodium salt (21 mg; 0.11 mmol; 0.1 eq.), copper iodide (20 mg; 0.11 mmol; 0.1 eq.) and trans-1,2-bis(methylamino)cyclohexane (22 mg; 0.16 mmol; 0.15 eq.) in DMSO (2.6 mL) and water (0.5 mL) was heated in a sealed tube at 70°C for 48h.
[000590] A reaction mixture was poured into a saturated NH4OH solution and extracted with DCM (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC gave the title compound as a beige solid (100 mg, 26%).
[000591] 1H NMR (DMSO) δ 13.38 (brs, 1H), 9.33 (s, 1H), 8.36 (dt,J= 8.0 Hz, 1.0 Hz, 1H), 8.12 (d, J= 8.7 Hz, 2H), 7.75 (d, J= 8.7 Hz, 2H), 7.61 (dt, J= 8.4 Hz, 1.0 Hz, 1H), 7.47-7.42 (m, 1H), 7.29-7.23 (m, 1H), 7.05 (bs, 1H ), 5.34 (q, J=7.2 Hz, 1H). HPLC (max scheme) 100.0%; TA %3.83min. UPLC/MS: (MS+) 360.4, (MS-) 358.4.Example 151& 152 : 3-(1-{4-[(3-exo)-8-cyclohexyl-8-azabicyclo[3.2.1]oct- 3-yl]phenyl}-1H-1,2,3-triazol-4-yl)-1H-indazol and 3-(1-{4-[(3-endo)-8-cyclohexyl-8-azabicyclo [3.2.1]oct-3-yl]phenyl}-1H-1,2,3-

[000592] The title compound was obtained following procedure described for intermediate 10, but starting from 3-(4-azidophenyl)-8-cyclohexyl-8-azabicyclo[3.2.1]octane (135 mg; 0.43 mmol; 1.0 eq.) and 3-ethynyl-1H-indazole (62 mg; 0.43 mmol; 1.0 eq.) as a 70:30 mixture of the endo:exo isomer (110.00 mg; 38%). The two isomers were separated by SFC using a chiralpak IA column (250x20 mm, 5 μm) with 50% EtOH containing 0.1% DIEA at 80 mL/min.
[000593] First eluting compound: exo isomer, beige solid, 20 mg. 1H NMR (300 MHz, DMSO-d6-d6): 13.36 (brs, 1H), 9.27 (s, 1H), 8.35 (d, J= 8.1 Hz, 1H), 7.98 (d, J= 8.1 Hz, 2H) , 7.60 (d, J= 8.4 Hz, 1H), 7.54 (d, J= 8.1 Hz, 2H), 7.47-7.41 (m, 1H), 7.28-7.23 (m, 1H), 4.40-3.61 (m, 2H ), 3.15 (m, 1H), 2.10-1.69 (m, 10H), 1.58 (m, 3H), 1.31-1.08 (m, 6H).
[000594] Second eluting compound: endo isomer, beige solid, 40 mg. 1H NMR (300 MHz, DMSO-d6-d6): 13.35 (brs, 1H), 9.27 (s, 1H), 8.36 (d, J= 8.1 Hz, 1H), 7.94 (d, J= 8.6 Hz, 2H) , 7.62-7.57 (m, 3H), 7.46-7.41 (m, 1H), 7.28-7.22 (m, 1H), 3.56 (m, 2H), 3.09 (quint., J=7.2 Hz, 1H), 2.36- 2.20 (m, 3H), 1.90-1.86 (m, 2H), 1.79-1.72 (m, 4H), 1.621.57 (m, 2H), 1.45-1.41 (m, 2H), 1.29-1.06 (m, 6H ).Example 153: 3-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-yl) oxy]propan-1-olStep a) Formation of 3-[(1-(4-methoxybenzyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazole -4-yl}-1H-indazol-5-yl)oxy]propan-1-ol

[000595] A solution of 1-(4-methoxybenzyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole -5-ol (60 mg; 0.12mmol; 1.0 eq.), 3-bromo-1-propanol (24 mg; 0.18 mmol; 1.5 eq.) and cesium carbonate (77 mg; 0.24 mmol; 2.0 eq.) in DMF (1.2 mL) was stirred at RT O/N. A reaction mixture was then diluted with DCM and washed with brine. Organic phase was dried over magnesium sulfate, filtered and concentrated. Purification of the crude by preparative HPLC gave the title compound as a white powder (43 mg, 64%). UPLC/MS: (MS+) 569.2.Step b) Formation of: 3-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl }-1H-indazol-5-yl)oxy]propan-1-ol

[000596] A solution of 3-[(1-(4-methoxybenzyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl} -1H-indazol-5-yl)oxy]propan-1-ol (43mg; 0.08mmol; 1.0eq.) and anisole (124mL, 1.13mmol, 15eq.) in TFA (2mL) and water (2.7mL ) was stirred at RT for 48 h. Reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to give the title compound as a brown gum (10.5 mg, 31%).
[000597] 1H NMR (300 MHz, DMSO-d6) δ 13.25 (s, 1H), 9.35 (s, 1H), 8.15 (d, J = 8.6 Hz, 2H), 7.77 - 7.72 (m, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 9.0 Hz, 1H), 7.10 (dd, J = 9.0, 2.4 Hz, 1H), 4.61 (t, J = 5.2 Hz, 1H), 4.21 - 4.06 (m, 2H), 3.78 - 3.24 (m, 10H), 2.02 - 1.82 (m, 2H). HPLC (max scheme) 97.2%; RT %2.63min.UPLC/MS: (MS+) 449.1, (MS-) 447.1.Example 154: (4S)-4-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H -1,2,3-triazol-4-yl}-1H-indazol-5-yl)methoxy]dihydrofuran-2(3H)-one

[000598] A solution of methanesulfonic anhydride (113 mg; 0.65 mmol; 1.6 eq.) in DCM (3.0 mL) was added dropwise over 1 min to a solution of [3-{1-[4-(morpholin-4 -ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl]methanol (194 mg; 0.40 mmol; 1.0 eq.) in DIEA (1.0 mL; 5.9 mmol; 15 eq.) and DCM (3.0 mL) containing activated molecular sieves. After 10 min, a solution of (S)-3-hydroxy-g-butyrolactone (160 mg; 1.57 mmol; 4 eq.) in DCM (1.0 mL) was added dropwise over 2 min. A reaction mixture was then stirred for 16 h at RT. It was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was redissolved in MeOH (2 mL) and hydrogen chloride (8 mL of a 4N solution in dioxane) was added. A reaction mixture was stirred at RT for 3h and then concentrated under reduced pressure. Purification by preparative HPLC gave the title compound as a white solid (14 mg, 7%). 1H NMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 9.38 (s, 1H), 8.33 (s, 1H), 8.15 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.6 Hz, 1H), 7.49 - 7.37 (m, 1H), 4.69 (s, 2H), 4.47 - 4.34 (m, 3H), 3.82 - 3.40 (m, 8H ), 2.88 (dd, J = 17.8, 5.7 Hz, 1H), 2.56 (d, J = 17.8 Hz, 1H). HPLC (max scheme) 96.5%; TA %2.59min. UPLC/MS: (MS+) 489.5, (MS-) 487.6.
[000599] Examples 155 to 299 described in Table 1 can be prepared following the methods and techniques described in the examples above. Table 1:



































Example 300: In Vitro Assays IRAKI Enzyme Assays:
[000600] IRAK1 is a purified recombinant human enzyme (His- TEV-IRAK1 (194-712))
[000601] In this assay, IRAK-1 hydrolyzes ATP and autophosphorylates. ATP consumption format:
[000602] Measurement of IRAK-1 inhibition is done in 384-well format based on luminescent assay (PKLight® ATP Detection Reagent Lonza: based on Basel CH LT07-501). This PKLight® assay is based on bioluminescent measurement of ATP remaining in the wells after kinase activity and luciferase activity which generates light from ATP and luciferin.
[000603] His-TEV-IRAK-1 (30ng/well), ATP (1.5μM) and compounds in DMSO (range of concentrations from 20μM to 1nM) or controls (2% DMSO) are incubated for 2 hours at 30° C in assay buffer: 50mM Hepes pH7.0, 0.1% free fatty acid BSA, 2mM Dithiothreitol DTT, 10mM MgCl 2 , 0.5mM EGTA, 0.01% Triton-X-100.
[000604] Kinase reaction is stopped by adding PKLight® ATP Detection Reagent mix according to supplier's instructions. Luminescent signal is then measured after 1 hour incubation time with a luminometer (BMG Pherastar reader or equivalent). Flashplate Format:
[000605] Measurement of IRAK-1 inhibition is performed on streptavidins coated 384-well FlashPlate (PerkinElmer #SMP410A).
[000606] His-TEV-IRAK-1 (15ng/well), ATP (1 μM, [33P]ATP 0.25μCi/well) and compounds in DMSO (range of concentrations from 20μM to 1nM) or controls (2% of DMSO) are incubated for 3 hours at 30°C in assay buffer: 50mM Hepes pH7.0, 0.1% fatty acid-free BSA, 2mM Dithiothreitol DTT, 10mM MgCl2, 0.5mM EGTA, Triton-X- 100 to 0.01%. Kinase reaction is stopped by adding EDTA. Supernatants are discarded, plates are washed three times with 150 mM NaCl and radioactivity is then measured in a Microbeta Trilux reader. IRAK4 Enzyme Assay:
[000607] IRAK4 is a purified recombinant human enzyme (His-TEV-IRAK1 (194-712)
[000608] IRAK4 hydrolyzes ATP, autophosphorylates and phosphorylates a generic Serine/Theonine peptide substrate (STK: 61ST1BLC from CisBio International based in Bagnols/Cèze FR). ATP consumption format:
[000609] Measurement of IRAK-4 inhibition is done in 384-well format based on luminescent assay (Lonza PKLight® ATP Detection Reagent: based on Basel CH LT07-501). This PKLight® assay is based on luminescent measurement of ATP remaining in the wells after kinase activity and luciferase activity which generates light from ATP and luciferin.
[000610] His-TEV-IRAK4 (8ng/well), ATP (2μM), STK1-biotin peptide (300nM) and compounds in DMSO (range of concentrations from 20μM to 1nM) or controls (2% DMSO) are incubated by 2 hours at 30°C in assay buffer: 50mM Hepes pH7.0, 0.1% fatty acid-free BSA, 2mM Dithiothreitol DTT, 10mM MgCl2, 0.5mM EGTA, 0.01% Tween-20, 5mM MnCl2 .
[000611] Kinase reaction is stopped by adding PKLight® ATP ATP Detection reagent mix according to supplier instructions. Luminescent signal is then measured after 1 hour incubation time with a luminometer (BMG Pherastar reader or equivalent). Flashplate format:
[000612] Measurement of IRAK-4 inhibition is performed on streptavidin coated 384-well FlashPlate (PerkinElmer #SMP410A). His-TEV-IRAK4 (20ng/well), ATP (2μM, [33P]ATP 0.25μCi/pθ9θ), STK1-biotin peptide (300nM) and compounds in DMSO (concentration range from 20μM to 1nM) or controls (2 % DMSO) are incubated for 3 hours at 30°C in assay buffer: 50mM Hepes pH7.0, 0.1% fatty acid-free BSA, 2mM Dithiothreitol DTT, 10mM MgCl2, 0.5mM EG-TA, 0.01% Tween-20, 5mM MnCl2.
[000613] Kinase reaction is stopped by addition of EDTA. Sibrenatant is discarded, plates are washed three times with 150 mM NaCl and radioactivity is then measured in a Microbeta Trilux reader. Functional Assay of IRAK IL8 Secretion:
[000614] THP1 cells are human monocytes derived from acute monocytic leukemia. IL1β receptor expressed on the surface membrane of THP1 cells induced IL8 release. IRAKs are signaling kinases downstream of TLRs and TNF, IL-18, IL-33 and IL-1 Receptors.
[000615] In cells, IRAK4 is upstream of IRAK1.
[000616] The human IL8 kit, provided by CysBio International based on Bagnols/Cèze FR, allows the quantitative determination of IL-8 in cell culture supernatants.
[000617] Anti-cytokine IL8 antibodies are respectively labeled with Europium Cryptate and XL665. Upon binding to IL-8 molecules, the two antibodies are brought into close proximity, allowing TERF (Fluorescent Resonance Energy Transfer) to occur. This TERF increases proportionally to IL-8 concentrations and is converted to IL8 pg amounts.
[000618] THP-1 cells are cultured on Day 1 in 384-well plates with RPMI 1640 at a density of 30,000 cells/well. Compounds 4x/2% DMSO (range of concentrations from 20μM to 1nM) and 4x IL1β at 100ng/ml final are added to cells overnight at 37°C, 5% CO 2 . Measurement of IL-8 secretion is done by mixing on Day 2 10μl of supernatant with 10μl of a mixture solution of europium cryptate and XL665 (v:v) as described by the supplier.
[000619] HTRF (Homogeneous Time-Resolved Fluorescence) signal is measured after 3 hours incubation time at 30°C with a BMG Pherastar reader or equivalent. Results are summarized in Table 2 below:


















































*: 1mM < IC50 < 5 mM**: 0.1 mM < IC50 < 1 mM***: IC50 < 0.1 mMn.d: not determined Example 301: Functional Assay of IRAK IL-6 Secretion in Human PBMC
[000620] Human PBMCs from healthy volunteers were purified from the buffy coats of heparinized whole blood by Ficoll-Hypaque density centrifugation. Isolated PBMCs were washed twice in PBS, counted, and cultured at a density of 7x10 4 cells/well in 180 L of complete RPMI 1640 medium containing 10% heat-inactivated FBS. PBMC was pre-incubated for 1h with serial dilutions of test article dissolved in DMSO (0.33% final DMSO concentration) at 37°C in a 5% CO2 incubator. PBMC was then stimulated with 10 ng/ml IL1- ( final volume 200 l) and incubation was continued for 18-20 h. The collected foam supernatants and IL-6 was quantified using the Duo-set ELISA kit (R&DSystems) following the manufacturer's instructions. Results are summarized in Table 3 below:



*: 200 nM < IC50 < 2 mM**: IC50 < 200 nMExample 302: LPS-induced cytokine release in mice
[000621] Female C57B6 mice (8-10 weeks 4-6 mice/group) were dosed po with vehicle (40% Kleptose in water), reference compound dexamethasone (1 mg/kg) or three different doses of compound 1 (10, 30 and 60 mg/kg to 10mL/kg). 30 minutes after compound administrations mice were injected ip with LPS (0111:B4, 1 mg/kg). 2 hours after LPS injection mice were sacrificed. Serum was collected; Cytokine levels (TNF-α and IL-6) were detected by ELISA or CBA. Compound 1 dose-dependently inhibits LPS-induced TNFα and IL-6 release in mice is shown in Table 4 below.Table 4: LPS-induced TNFα inhibition and IL-6 release in mice
Example 303: Preparation of a Pharmaceutical FormulationFormulation 1 - Tablets
[000622] A compound of Formula (I) is mixed as a dry powder with a dry gelatin binder in a weight ratio of approximately 1:2. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active compound according to the invention per tablet) in a tablet press. Formulation 2 - Capsules
[000623] A compound of Formula (I) is mixed as a dry powder with a starch diluent in a weight ratio of approximately 1:1. The mixture is filled with 250 mg capsules (125 mg of active compound according to the invention per capsule).Formulation 3 - Liquid
[000624] A compound of Formula (I) (1250 mg), sucrose (1.75 g) and xanthan gum (4 mg) are mixed, passed through a U.S. mesh No. 10, and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavoring, and coloring are diluted with water and added with stirring. Sufficient water is then added to produce a total volume of 5 mL.Formulation 4 - Tablets
[000625] A compound of Formula (I) is mixed as a dry powder with a dry gelatin binder in a weight ratio of approximately 1:2. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active compound according to the invention per tablet) in a tablet press. Formulation 5 - Injection
[000626] A compound of Formula (I) is dissolved in an injectable aqueous medium of sterile buffered saline at a concentration of approximately 5 mg/mL.

权利要求:
Claims (3)
[0001]
1. Compound, characterized by the fact that it presents Formula (I),
[0002]
2. Kit, characterized in that it consists of separate packages of: (a) an effective amount of a compound of Formula (I), as defined in claim 1, and/or pharmaceutically usable derivatives, solvates, salts, hydrates and stereoisomers thereof, including mixtures thereof in all proportions, and (b) an effective amount of an additional medicament active ingredient.
[0003]
3. Pharmaceutical composition, characterized in that it comprises at least one of the compounds of Formula (I), as defined in claim 1.

类似技术:

---

公开号 | 公开日 | 专利标题

---

AU2011347711B2|2017-02-02|Indazolyl triazole derivatives as IRAK inhibitors

---

JP6128449B2|2017-05-17|Kinase inhibitor

---

US7622471B2|2009-11-24|Pyrazole derivatives having a pyridazine and pyridine functionality

---

EA038972B1|2021-11-16|Dimethoxyphenyl substituted indole compounds as tlr7, tlr8 or tlr9 inhibitors

---

JP6189434B2|2017-08-30|Pyrimidine pyrazolyl derivatives

---

AU2014291711A1|2016-02-11|Autotaxin inhibitors comprising a heteroaromatic ring-benzyl-amide-cycle core

---

JP5837482B2|2015-12-24|Pyrazole oxadiazole derivative

---

JP2012507512A|2012-03-29|Amyloid β modulator

---

BR112014018868B1|2021-02-09|aromatic heterocyclic compound containing nitrogen, pharmaceutical composition comprising said compound and use thereof

---

JP6527163B2|2019-06-05|Pyrimidine pyrazolyl derivatives and their use as IRAK inhibitors

---

WO2011058149A1|2011-05-19|Tricyclic pyrazol amine derivatives

---

JP2016501242A|2016-01-18|Pyridine-2-amide useful as a CB2 agonist

---

AU2014298017A1|2016-02-11|Heterobicycloaryl RORc2 inhibitors and methods of use thereof

---

HUE029594T2|2017-03-28|Trpv4 antagonists

---

TW201904959A|2019-02-01|Heterocyclic compound

---

US20120142685A1|2012-06-07|Organic compounds

---

BR122021014375B1|2021-11-30|PROCESS FOR PREPARATION OF INDAZOLYL TRIAZOLE DERIVATIVES

---

TW201910325A|2019-03-16|Indole derivatives and uses thereof

同族专利:

---

公开号 | 公开日

---

AR084507A1|2013-05-22|

---

US20130274241A1|2013-10-17|

---

CN103429585B|2015-07-08|

---

CN103429585A|2013-12-04|

---

WO2012084704A1|2012-06-28|

---

RS55165B1|2017-01-31|

---

KR101842098B1|2018-03-26|

---

MX2013007149A|2013-10-30|

---

HUE029617T2|2017-03-28|

---

CA2822166A1|2012-06-28|

---

ES2592713T3|2016-12-01|

---

PL2655357T3|2016-12-30|

---

US9073892B2|2015-07-07|

---

BR112013015460A2|2016-09-20|

---

ZA201305483B|2014-06-25|

---

SI2655357T1|2016-10-28|

---

EP2655357B1|2016-06-22|

---

EA201300730A1|2013-12-30|

---

AU2011347711A1|2013-08-01|

---

SG191205A1|2013-07-31|

---

PT2655357T|2016-09-28|

---

AU2011347711B2|2017-02-02|

---

HRP20161127T1|2016-11-18|

---

JP2014500286A|2014-01-09|

---

KR20130133252A|2013-12-06|

---

IL226912A|2017-01-31|

---

LT2655357T|2016-10-10|

---

EP2655357A1|2013-10-30|

---

JP6007189B2|2016-10-12|

---

HK1191938A1|2014-08-08|

---

CA2822166C|2019-10-29|

---

EA023544B1|2016-06-30|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

ZA200503242B|2002-10-24|2006-10-25|Celgene Corp|Treatment of pain with JNK inhibitors|

---

US20040087642A1|2002-10-24|2004-05-06|Zeldis Jerome B.|Methods of using and compositions comprising a JNK inhibitor for the treatment, prevention, management and/or modification of pain|

---

US20050090529A1|2003-07-31|2005-04-28|Pfizer Inc|3,5 Disubstituted indazole compounds with nitrogen-bearing 5-membered heterocycles, pharmaceutical compositions, and methods for mediating or inhibiting cell proliferation|

---

US6984652B2|2003-09-05|2006-01-10|Warner-Lambert Company Llc|Gyrase inhibitors|

---

CN101208333A|2005-04-29|2008-06-25|细胞基因公司|Solid forms of 1-)-3-benzene|

---

RU2487873C2|2007-06-08|2013-07-20|Эбботт Лэборетриз|5-substituted indazole as kinase inhibitors|AR045563A1|2003-09-10|2005-11-02|Warner Lambert Co|ANTIBODIES DIRECTED TO M-CSF|

---

WO2012087772A1|2010-12-21|2012-06-28|Schering Corporation|Indazole derivatives useful as erk inhibitors|

---

US9643955B2|2012-12-20|2017-05-09|Merck Sharp & Dohme Corp.|2-pyridyloxy-3-nitrile-4-substituted orexin receptor antagonists|

---

EP2934516A4|2012-12-20|2016-07-20|Merck Sharp & Dohme|3-ester-4-substituted orexin receptor antagonists|

---

LT2953944T|2013-02-07|2017-07-10|Merck Patent Gmbh|Pyridazinone-amides derivatives|

---

SI2953952T1|2013-02-07|2017-10-30|Merck Patent Gmbh|Macrocyclic pyridazinone derivatives|

---

TWI667233B|2013-12-19|2019-08-01|德商拜耳製藥公司|Novel indazolecarboxamides, processes for their preparation, pharmaceutical preparations comprising them and their use for producing medicaments|

---

MX2016009011A|2014-01-10|2017-01-23|Aurigene Discovery Tech Ltd|Indazole compounds as irak4 inhibitors.|

---

DK3094329T3|2014-01-13|2018-11-19|Aurigene Discovery Tech Ltd|BICYCLIC HETEROCYCLYL DERIVATIVES AS IRAC4 INHIBITORS|

---

EP3200789B1|2014-09-30|2019-11-06|Merck Sharp & Dohme Corp.|Inhibitors of irak4 activity|

---

US9943516B2|2014-09-30|2018-04-17|Merck Sharp & Dohme Corp.|Inhibitors of IRAK4 activity|

---

WO2016053771A1|2014-09-30|2016-04-07|Merck Sharp & Dohme Corp.|Inhibitors of irak4 activity|

---

EP3200788B1|2014-09-30|2019-09-18|Merck Sharp & Dohme Corp.|Inhibitors of irak4 activity|

---

JO3705B1|2014-11-26|2021-01-31|Bayer Pharma AG|Novel substituted indazoles, processes for preparation thereof, pharmaceutical preparations comprising them and use thereof for production of medicaments|

---

WO2016096709A1|2014-12-16|2016-06-23|Eudendron S.R.L.|Heterocyclic derivatives modulating activity of certain protein kinases|

---

ES2861351T3|2015-04-22|2021-10-06|Rigel Pharmaceuticals Inc|Pyrazole compounds and method of making and using the compounds|

---

TW201701879A|2015-04-30|2017-01-16|拜耳製藥公司|Combinations of IRAK4 inhibitors|

---

EP3195865A1|2016-01-25|2017-07-26|Bayer Pharma Aktiengesellschaft|Combinations of inhibitors of irak4 with inhibitors of btk|

---

JP6947743B2|2016-03-03|2021-10-13|バイエル・ファルマ・アクティエンゲゼルシャフト|A novel 2-substituted indazole, a method for producing the indazole, a pharmaceutical preparation containing the novel 2-substituted indazole, and its use for producing a drug.|

---

EP3219329A1|2016-03-17|2017-09-20|Bayer Pharma Aktiengesellschaft|Combinations of copanlisib|

---

JP6821701B2|2016-04-29|2021-01-27|バイエル・ファルマ・アクティエンゲゼルシャフト|N- [2--6--2H-indazole-5-yl] -6-pyridin-2-carboxamide Crystal morphology|

---

BR112018072246A2|2016-04-29|2019-02-12|Bayer Pharma Aktiengesellschaft|indazole synthesis|

---

PT3464266T|2016-06-01|2021-11-23|Bayer Pharma AG|Substituted indazoles useful for treatment and prevention of allergic and/or inflammatory diseases in animals|

---

JOP20180011A1|2017-02-16|2019-01-30|Gilead Sciences Inc|PYRROLO[1,2-b] PYRIDAZINE DERIVATIVES|

---

CN111194319A|2017-10-19|2020-05-22|拜耳动物保健有限责任公司|Use of fused heteroaromatic pyrrolidones for treating and preventing diseases in animals|

---

EP3704108A4|2017-10-31|2021-08-25|Curis, Inc.|Compounds and compositions for treating hematological disorders|

---

WO2019111218A1|2017-12-08|2019-06-13|Cadila Healthcare Limited|Novel heterocyclic compounds as irak4 inhibitors|

---

EP3731869A4|2017-12-26|2021-09-22|Kymera Therapeutics, Inc.|Irak degraders and uses thereof|

---

GB201801226D0|2018-01-25|2018-03-14|Redx Pharma Plc|Modulators of Rho-associated protein kinase|

---

WO2019213506A1|2018-05-04|2019-11-07|Incyte Corporation|Salts of an fgfr inhibitor|

---

TW202136268A|2018-07-13|2021-10-01|美商基利科學股份有限公司|Pyrrolo[1,2-b]pyridazine derivatives|

---

AU2019389174A1|2018-11-30|2021-07-01|Kymera Therapeutics, Inc.|Irak degraders and uses thereof|

---

CA3129601A1|2019-02-11|2020-08-20|Merck Patent Gmbh|Indazolyl-isoxazole derivatives for the treatment of diseases such as cancer|

---

WO2021084022A1|2019-10-31|2021-05-06|F. Hoffmann-La Roche Ag|Hydropyrazino[1,2-d][1,4]diazepine compounds for the treatment of autoimmune disease|

法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

---

2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

---

2019-12-17| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

---

2019-12-24| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

---

2021-06-08| B350| Update of information on the portal [chapter 15.35 patent gazette]|

---

2021-06-22| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

---

2021-08-24| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

---

2021-11-30| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

---

2022-01-25| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 16/12/2011, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |

优先权:

---

申请号 | 申请日 | 专利标题

---

US201061424890P| true| 2010-12-20|2010-12-20|

---

EP10195867|2010-12-20|

---

US61/424,890|2010-12-20|

---

EP10195867.6|2010-12-20|

---

PCT/EP2011/073015|WO2012084704A1|2010-12-20|2011-12-16|Indazolyl triazole derivatives as irak inhibitors|

---