Novel sulfonamides or sulfones and their use as neuroprotective and / or neurorestorative agents

Abstract

The present invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt and / or solvate thereof. The invention further relates to the use of the compounds of the invention as neuroprotective and / or neurorestorative agents, in particular for use in the treatment of neurological disorders.

Description

NOVEL SULFONAMIDES OR SULFONES AND THEIR USE AS NEUROPROTECTIVE AND / OR NEURORESTORATIVE AGENTS FIELD OF INVENTION

[0001] The present invention relates to novel polycyclic sulfonamides or sulfones, wherein the sulfonamide or sulfone group is bond to a bicyclic heteroaryl. The compounds of the invention are useful as neuroprotective and / or neurorestorative agents, in particular for use in the treatment of neurological disorders. BACKGROUND OF INVENTION

[0002] Neurological disorders (NDs) are heterogeneous diseases affecting the autonomic, peripheral and central nervous system of the body. Amongst the Central Nervous System (CNS) diseases, Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), dementia, stroke, head trauma, brain tumor, pain and epilepsy are always the most challenging diseases to be addressed. Compounds actives for treating CNS might also be relevant to other diseases, for example diseases of the peripheral nervous system, eyes, spinal cord and enteric system.

[0003] The incidence of NDs is expected to increase dramatically in the 21stcentury, in particular due to increased life expectancy and demographic changes. Some of these diseases are characterized by age-related gradual decline in neurological functions. In medicine, neurological diseases are the world's important and common cause of disability-adjusted life years, or years of healthy life lost due to death or disability. CNS diseases represent the largest and fastest growing therapeutic domain of unmet medical need, and it is being recognized as a global public health challenge and become a major global health priority. Adequate neurological diagnosis represents an immense challenge, and patients are more concerned about the development of new effective treatments to treat pathophysiology or symptoms. Neurological disorders affect millions of people worldwide and cause permanent damage. They are progressive diseases with symptomsthat can degenerate overtime. Although there is generally no definitive cure, supporting treatments exist. The goal of these treatments is mainly to reduce symptoms and preserve the quality of life of the patient as long as possible.

[0004] Neurons are postmitotic cells that must live for a lifetime. While young neurons have proper functioning of self-healing protective mechanisms, aging or external or internal insults disturb them, eventually leading to neurodegeneration. These external / internal hazards are traumatic injuries or excitotoxic compounds, reactive oxygen species (ROS), protein aggregates, and other toxic molecules. Fortunately, cells have an intrinsic machinery that blocks death by activating resilience mechanisms or promoting regeneration pathways. Dysfunctionality or insufficiency of these self-healing mechanisms has also been described in neurodegenerative diseases.

[0005] Among natural self-healing agents, the glial cell line-derived neurotrophic factor (GDNF) acts as a potent neurotrophic factor, promoting survival in different neuronal populations such as spinal motor neurons, retinal cells, central noradrenergic neurons, or sympathetic neurons, among others. Likewise, GDNF (and other proteins of the GDNF family of neurotrophic factors such as neurturin, artemin and persephin) acts as a powerful trophic factor favoring, not only the survival and plasticity, but also the proliferation, differentiation, and protection of dopaminergic neurons, as well as the synthesis of dopamine and dopaminergic transmission in the developing and adult brain. GDNF can promote neuroprotection through MAP kinase / ERK, Src kinase and PI3 kinase / AKT pathways by inducing several neuroprotective signaling cascade, including the activation of the transcription factor Elk1 through the activation of the GFRα1-RET receptor complex.

[0006] The field of applications for these proteins is vast. Pre-clinical and clinical trials have been carried out to evaluate the effect of neurotrophic factors of the GDNF family for the prevention, treatment or management of Parkinson’s disease, chronic pain, Alzheimer’s disease, amyotrophic lateral sclerosis, neuropathy, depression, stroke, and these proteins were even suggested as male contraceptives. However, the clinical application of GDNF is hampered by its poor pharmacokinetic properties, the fact that itdoes not cross the blood-brain barrier and thus the necessity for intracranial delivery via stereotaxic surgery, varying biological activity, and high price.

[0007] Blood-brain barrier penetrating small-molecule compounds that target the GDNF receptor complex and mimic GDNF biological effects in neurons may be an avenue to overcome these issues and translate to greater efficacy in the clinic. Superior tissue penetration of such compounds could promote survival in all affected neuronal pathways.

[0008] It was surprisingly found out by the Applicants that novel polycyclic sulfonamides or sulfones of formula (I) showed potent GFRα1-RET activity in a luciferase assay, thereby opening the way to overcoming the limitations of available therapeutic solutions. SUMMARY

[0009] An object of the present invention is a compound of formula (I)or a pharmaceutically acceptable salt and / or solvate thereof; wherein W, RA-RD, R1-R4, A1-A5and R10are as defined hereinafter and / or as defined in the claims.

[0010] According to one embodiment, the compound is selected from the compounds of Table 1 herein, and pharmaceutically acceptable salts and / or solvates thereof.

[0011] Another object of the present invention is a pharmaceutical composition comprising a compound according to the invention and at least one pharmaceutically acceptable carrier.

[0012] Another object of the present invention is a compound according to the invention or a pharmaceutical composition according to the invention for use as a medicament. Another object of the present invention is a compound according to the invention or a pharmaceutical composition according to the invention for use in the treatment of a neurological disorder.

[0013] Another object of the present invention is a process for manufacturing a compound according to the invention. DEFINITIONS

[0014] In the present invention, the following terms have the following meanings: Chemical definitions

[0015] Where chemical substituents are combinations of chemical groups, the point of attachment of the substituent to the molecule is by the last chemical group recited on the right of the name of the substituent. For example, an arylalkyl substituent is linked to the rest of the molecule through the alkyl moiety and it may by represented as follows: “aryl-alkyl-”.

[0016] Unless otherwise indicated, the compounds were named using BIOVIA Draw 2021 (Dassault, France).

[0017] The definitions herein referring to the optional or mandatory substitution of a specified group apply both to the substituted group considered as such or to the same group comprised in another chemical moiety, which can both be substituted as set forth herein. For example,(C1-C8) alkyl, (C1-C8) alkyl-O- or cycloalkyl-(C1-C8) alkyl-NH-; wherein the alkyl is optionally substituted by at least one F” means that any alkyl group present in the structure of Rxmay optionally substituted by at least one F, including said (C1-C8) alkyl as such (e.g., CF3), the alkyl comprised in said (C1-C8) alkyl-O- (e.g., OCF3) and the alkyl comprised in said cycloalkyl-(C1-C8) alkyl-NH- (e.g., cyclopropyl-CH2-CHF-CH2-NH-).

[0018] “Alkoxy” refers to an alkyl-O- group.

[0019] “Alkyl” refers to a saturated linear or branched hydrocarbon chain, typically comprising from 1 to 16 carbon atoms, preferably from 1 to 12 carbon atoms, more preferably from 1 to 8 carbon atoms, furthermore preferably from 1 to 6 carbon atoms. Alkyl groups may be monovalent or polyvalent (i.e., “alkylene” groups, which are divalent alkyl groups, are encompassed in “alkyl” definition). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g., n-pentyl, iso-pentyl), and hexyl and its isomers (e.g., n-hexyl, iso-hexyl). Particular examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl (including methylene, ethylene, n-propylene, n-butylene and n-butylene).

[0020] “Amine” refers to derivatives of ammonia (NH3), wherein one or more hydrogen atoms have been replaced by a substituent such as, for example, alkyl or aryl. “Amino” refers to the -NH2 group.

[0021] “Aryl” refers to a cyclic, polyunsaturated, aromatic hydrocarbyl group comprising at least one aromatic ring and comprising from 5 to 12 carbon atoms, preferably from 6 to 10 carbon atoms. Aryl groups may be monovalent or polyvalent (e.g., divalent). Aryl groups may have a single ring (e.g., phenyl) or multiple aromatic rings fused together (e.g., naphthyl) or linked covalently. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocycloalkyl or heteroaryl) fused thereto. This definition of “aryl” encompasses the partially hydrogenated derivatives of the carbocyclic systems enumerated herein, as long as at least one ring is aromatic. Aryls may optionally be substituted by at least one group such as, for example, halogen (e.g., F or Cl), (C1-C8) alkyl (e.g., methyl) or nitrile (CN). Non-limiting examples of aryl groups include phenyl, biphenyl, biphenylenyl, 5- or 6- tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1- 2-, 3-, 4- or 5-acenaphthylenyl, 3-, 4- or 5-acenaphthenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8- tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, and 1-, 2-, 3-, 4- or 5-pyrenyl. A particular example of aryl group is phenyl.

[0022] “Benzylidene” refers to a phenyl group bond to a moiety through an exo carbon-carbon double bound, i.e., =CH-Ph bond to a carbon atom. The moiety is typically cyclic such as, for example, an heterocycloalkyl.

[0023] “Cycloalkyl” refers to a cyclic alkyl group, typically comprising from 3 to 15 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, further more preferably from 3 to 6 carbon atoms. Cycloalkyl groups may be monovalent or polyvalent (e.g., divalent). This definition of “cycloalkyl” encompasses polycyclic cycloalkyls (e.g., bicycles) and bridged cycloalkyl structures, including cycles bound together through one atom (“spiro”) or through two atoms. This definition of “cycloalkyl” encompasses cycloalkyls including a cyclic alkyl group substituted by at least one non-cyclic alkyl, such as, for example, a (C1-C8) alkyl (preferably, (C1-C4) alkyl, (e.g., methyl). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycoheptyl, cyclooctanyl, cyclononanyl, cyclodecanyl, norbornyl, adamantyl, bicyclo[2.2.2]octanyl, bicyclo[4.4.0]decanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[2.1.1]hexane, 2,3-dihydro-1H- indenyl, 1,2,3,4-tetrahydronaphthalenyl, decahydronaphthalenyl, 1,2,3,4- tetrahydronaphthalenyl, and octahydropentalenyl.

[0024] “Cx-Cy” or “(Cx-Cy)” preceding the name of a group means that the group comprises from x to y carbon atoms, in accordance to common terminology in the chemistry field.

[0025] “Halogen” refers to a fluorine, chlorine, bromine or iodine atom.

[0026] “Heteroalkyl” refers to an alkyl group as defined herein, wherein one or more carbon atoms are replaced by a heteroatom selected from oxygen, nitrogen and sulfur, and wherein the resulting heteroalkyl group comprises at least one carbon atom. In heteroalkyl groups, the heteroatoms are bound along the alkyl chain only to carbon atoms, i.e., each heteroatom is separated from any other heteroatom by at least one carbon atom, typically by at least two carbon atoms. Heteroalkyl groups may be monovalent or polyvalent (e.g., divalent). The nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized (e.g., sulfur may be oxidized as SO or SO2). Heteroalkyl groups may further include one or more =O and / or =S groups. In one embodiment, at least two carbon atoms are replaced by a heteroatom. In one embodiment, the heteroalkyl is bound to another group or molecule through a carbon atom, i.e., the binding atom is not selected among the heteroatoms included therein. In one embodiment, the heteroalkyl is bound to another group or moleculethrough one of the heteroatoms included therein. When substituted by one or more other group(s), an heteroalkyl may be substituted either through a carbon atom or through a heteroatom (e.g., nitrogen), unless otherwise specified. Non-limiting examples of heteroalkyl include alkoxy, ethers and polyethers (e.g., polyethylene glycol), secondary and tertiary amines and polyamines, thioethers and polythioethers, and combinations thereof.

[0027] “Heteroaryl” refers to aromatic rings or aromatic ring systems comprising from 5 to 15 carbon atoms, preferably from 4 to 12 carbon atoms, more preferably from 3 to 10 carbon atoms, having one or two rings that are fused together or linked covalently, wherein at least one ring is aromatic, and wherein one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and / or sulfur atoms. Heteroaryl groups may be monovalent or polyvalent (e.g., divalent). The nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized (e.g., the heteroatom is substituted by oxo (=O) for sulfur atom or (→O) for nitrogen atom). This definition of “heteroaryl” encompasses the partially hydrogenated derivatives of the carbocyclic systems enumerated herein, as well as ring systems including one or more fused non-aromatic cycloalkyl and / or heterocycloalkyl ring(s), as long as at least one ring is aromatic. In one embodiment, the heteroaryl is bound to another group or molecule through a carbon atom, i.e., the binding atom is not selected among the heteroatoms included therein. In one embodiment, the heteroaryl is bound to another group or molecule through one of the heteroatoms included therein. When substituted by one or more other group(s), an heteroaryl may be substituted either through a carbon atom or through a heteroatom (e.g., nitrogen), unless otherwise specified. Heteroaryls may optionally be substituted by at least one group such as, for example, halogen (e.g., F or Cl), (C1-C8) alkyl (preferably, (C1-C4) alkyl, e.g., methyl) or nitrile (CN). Non-limiting examples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, tetrazinyl, imidazo[2,1- b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3- d][l,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[l,5-a]pyridinyl, indolyl, indolizinyl,isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1,2,3- benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[l,2-a]pyridinyl, 6-oxo- pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin- l(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and quinoxalinyl. Non-limiting examples of heteroaryl groups comprising at least one fused non-aromatic ring include 2,3-dihydrobenzofuranyl, benzo[d][1,3]dioxolyl, indolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 1,2,3,4-tetrahydroquinoxaline, 3,4-dihydro-2H-benzo[b][1,4]thiazine and 2,3-dihydrobenzo[b][1,4]oxathiine.

[0028] “Heteroarylidene” refers to a heteroaryl group bond to a moiety through an exo carbon-carbon double bound, i.e., =CH-heteroaryl bond to a carbon atom. The moiety is typically cyclic such as, for example, an heterocycloalkyl.

[0029] “Heterocycloalkyl” refers to a cyclic heteroalkyl group, typically comprising from 2 to 15 carbon atoms, preferably from 2 to 11 carbon atoms, more preferably from 2 to 7 carbon atoms, furthermore preferably from 2 to 6 carbon atoms. Heterocycloalkyl groups may be monovalent or polyvalent (e.g., divalent). Heterocycloalkyl groups are typically 3- to 7-membered, preferably 5- or 6-membered. Heterocycloalkyl are typically monocyclic or bicyclic, preferably monocyclic. This definition encompasses polycyclic heterocycloalkyls (e.g., bicycles) and bridged heterocycloalkyl structures, including cycles bound together through one atom (“spiro”) or through two atoms. The nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized (e.g., the heteroatom is substituted by oxo (=O) for sulfur atom or (→O) for nitrogen atom). In one embodiment, the heterocycloalkyl is bound to another group or molecule through a carbon atom, i.e., the binding atom is not selected among the heteroatoms included therein. In one embodiment, the heterocycloalkyl is bound to another group or molecule through one of the heteroatoms included therein. When substituted by one or more other group(s), an heterocycloalkyl may be substituted either through a carbon atom or through a heteroatom (e.g., nitrogen), unless otherwisespecified. Heterocycloalkyls may optionally be substituted by at least one group such as, for example, halogen (e.g., F or Cl), (C1-C8) alkyl (preferably, (C1-C4) alkyl, e.g., methyl), nitrile (CN) or =O. Non-limiting examples of heterocycloalkyl include aziridine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, azepane, azocane, octahydro-1H-isoindole, decahydroisoquinoline, tetrahydrofuran, tetrahydropyran, tetrahydroisoquinoline (e.g., 1,2,3,4-tetrahydroisoquiline), hexahydropyridazine, hexahydropyrazine, hexahydropyrimidine, decahydroquinoline, octahydropyrrolo[3,4- c]pyrrole, isoindoline, 1,2,3,4-tetrahydroquinoline and oxetane.

[0030] “Prodrug” refers to a pharmacologically acceptable derivative of a therapeutic agent (e.g., a compound according to the invention) whose in vivo biotransformation product is the therapeutic agent (active drug). Prodrugs are typically characterized by increased bioavailability and are readily metabolized in vivo into the active compounds. Non-limiting examples of prodrugs include amide prodrugs and carboxylic acid ester prodrugs.

[0031] “Solvate” refers to molecular complex comprising a compound along with stoichiometric or sub-stoichiometric amounts of one or more molecules of one or more solvents, typically the solvent is a pharmaceutically acceptable solvent such as, for example, ethanol. The term “hydrate” refers to a solvate when the solvent is water (H2O).

[0032] “Ylidene” refers to CH group involved in an exo carbon-carbon double bound with another moiety. The moiety is typically cyclic such as, for example, an heterocycloalkyl. General definitions

[0033] “About” is used herein to mean approximately, roughly, around, or in the region of. The term “about” preceding a figure means plus or less 10 % of the value of the figure. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth by 10%.

[0034] “Administration", or a variant thereof (e.g., “administering”), means providing a therapeutic agent alone or as part of a pharmaceutically acceptable composition, to the patient in whom / which the condition, symptom, or disease is to be treated.

[0035] “Comprise” or a variant thereof (e.g., “comprises”, “comprising”) is used herein according to common patent application drafting terminology. Hence, “comprise” preceded by an object and followed by a constituent means that the presence of a constituent in the object is required (typically as a component of a composition), but without excluding the presence of any further constituent(s) in the object. Moreover, any occurrence of “comprise” or a variant thereof herein also encompasses narrower expression “substantially consist of”, further narrower expression “consist of” and any variants thereof (e.g., “consists of”, “consisting of”), and may be replaced thereby, unless otherwise stated.

[0036] “GDNF family receptor alpha-1”, “GFRα1”, or “GDNFRα1”, also named “RET ligand 1” or “TGF-beta-related neurotrophic factor receptor 1”, is a protein from the GDNFR family that acts as a receptor for GDNF. It mediates the GDNF-induced autophosphorylation and activation of the RET receptor. In humans, GFRα1 is encoded by the GFRA1 gene. An exemplary amino acid sequence of human GFRα1 is given in SEQ ID NO: 1, in which amino acid residues 1-24 correspond to the signal peptide and amino acid residues 430-465 correspond to the propeptide which is removed in mature form. SEQ ID NO: 1 MFLATLYFALPLLDLLLSAEVSGGDRLDCVKASDQCLKEQSCSTKYRTLRQCV AGKETNFSLASGLEAKDECRSAMEALKQKSLYNCRCKRGMKKEKNCLRIYWS MYQSLQGNDLLEDSPYEPVNSRLSDIFRVVPFISDVFQQVEHIPKGNNCLDAAK ACNLDDICKKYRSAYITPCTTSVSNDVCNRRKCHKALRQFFDKVPAKHSYGML FCSCRDIACTERRRQTIVPVCSYEEREKPNCLNLQDSCKTNYICRSRLADFFTNC QPESRSVSSCLKENYADCLLAYSGLIGTVMTPNYIDSSSLSVAPWCDCSNSGND LEECLKFLNFFKDNTCLKNAIQAFGNGSDVTVWQPAFPVQTTTATTTTALRVK NKPLGPAGSENEIPTHVLPPCANLQAQKLKSNVSGNTHLCISNGNYEKEGLGAS SHITTKSMAAPPSCGLSPLLVLVVTALSTLLSLTETS

[0037] “Human” refers to a male or female human subject at any stage of development, including neonate, infant, juvenile, adolescent and adult.

[0038] “Neuroprotective” refers to the protection of a neuronal cell from insults, events, or conditions that would normally result in a loss of neuronal cell’s functions, and ultimately, neuronal cell death. Such insults, events, or conditions include, without limitation, neuronal stress, for instance, caused by hypoxia or ischemia; traumatic injuries; and exposure to toxic molecules, for instance, to abnormal misfolded proteins, protein aggregates, excitotoxins, reactive oxygen species, endoplasmic reticulum stressors, mitochondrial stressors, Golgi apparatus antagonists and the like. The term also characterizes the detectable biological activity of a compound in reducing the amount or level of neuronal cell’s loss of functions and / or neuronal cell death.

[0039] “Neurorestorative” refers to the restoration or rescue of a neuronal cell and in particular of its functions, from the effect of an insult, event, or condition that would normally result in a loss of neuronal cell’s functions if not in neuronal cell death.

[0040] “Patient” refers to a subject who / which is awaiting the receipt of, or is receiving medical care or was / is / will be the object of a medical procedure, or is monitored for the development of the targeted disease or condition, such as, for example, a neurological disorder.

[0041] “Pharmaceutically acceptable” means that the ingredients of a composition are compatible with each other and not deleterious to the subject to which / whom it is administered.

[0042] “Pharmaceutically acceptable carrier” refers to an excipient that does not produce an adverse, allergic or other untoward reaction when administered to an animal, preferably a human. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory offices, such as, e.g., FDA Office or EMA. Examples of pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (for example sodium carboxymethylcellulose), polyethylene glycol, polyacrylates, waxes, polyethylene- polyoxypropylene- block polymers, polyethylene glycol and wool fat.

[0043] “Pharmaceutical composition” refers to a composition comprising at least one therapeutic agent (e.g., a compound according to the present invention) and at least one pharmaceutically acceptable carrier.

[0044] “Proto-oncogene tyrosine-protein kinase receptor Ret”, or in short “RET”, also named “cadherin family member 12”, is a receptor tyrosine kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation. RET is activated upon (i) binding of a neurotrophic factor of the GDNF family (e.g., GDNF, neurturin, artemin or persephin) to a receptor of the GDNFR family (e.g., GFRα1, GFRα2, GFRα3 or GFRα4), then (ii) complex formation between RET and the receptor of the GDNFR family, (iii) dimerization and (iv) trans-autophosphorylation. An exemplary amino acid sequence of human RET is given in SEQ ID NO: 2, in which amino acid residues 1-28 correspond to the signal peptide. SEQ ID NO: 2 MAKATSGAAGLRLLLLLLLPLLGKVALGLYFSRDAYWEKLYVDQAAGTPLLY VHALRDAPEEVPSFRLGQHLYGTYRTRLHENNWICIQEDTGLLYLNRSLDHSS WEKLSVRNRGFPLLTVYLKVFLSPTSLREGECQWPGCARVYFSFFNTSFPACSS LKPRELCFPETRPSFRIRENRPPGTFHQFRLLPVQFLCPNISVAYRLLEGEGLPFR CAPDSLEVSTRWALDREQREKYELVAVCTVHAGAREEVVMVPFPVTVYDEDD SAPTFPAGVDTASAVVEFKRKEDTVVATLRVFDADVVPASGELVRRYTSTLLP GDTWAQQTFRVEHWPNETSVQANGSFVRATVHDYRLVLNRNLSISENRTMQL AVLVNDSDFQGPGAGVLLLHFNVSVLPVSLHLPSTYSLSVSRRARRFAQIGKVC VENCQAFSGINVQYKLHSSGANCSTLGVVTSAEDTSGILFVNDTKALRRPKCAE LHYMVVATDQQTSRQAQAQLLVTVEGSYVAEEAGCPLSCAVSKRRLECEECG GLGSPTGRCEWRQGDGKGITRNFSTCSPSTKTCPDGHCDVVETQDINICPQDCL RGSIVGGHEPGEPRGIKAGYGTCNCFPEEEKCFCEPEDIQDPLCDELCRTVIAAAVLFSFIVSVLLSAFCIHCYHKFAHKPPISSAEMTFRRPAQAFPVSYSSSGARRPSL DSMENQVSVDAFKILEDPKWEFPRKNLVLGKTLGEGEFGKVVKATAFHLKGR AGYTTVAVKMLKENASPSELRDLLSEFNVLKQVNHPHVIKLYGACSQDGPLLLI VEYAKYGSLRGFLRESRKVGPGYLGSGGSRNSSSLDHPDERALTMGDLISFAW QISQGMQYLAEMKLVHRDLAARNILVAEGRKMKISDFGLSRDVYEEDSYVKRS QGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIPPERLFNLL KTGHRMERPDNCSEEMYRLMLQCWKQEPDKRPVFADISKDLEKMMVKRRDY LDLAASTPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYGMSDPNW PGESPVPLTRADGTNTGFPRYPNDSVYANWMLSPSAAKLMDTFDS

[0045] “Selected from” is used herein according to common patent application drafting terminology, to introduce a list of elements among which one or more item(s) is (are) selected. Any occurrence of “selected from” in the specification may be replaced by “selected from the group comprising or consisting of” and reciprocally without changing the meaning thereof.

[0046] “Subject” refers to an animal, typically a warm-blooded animal, preferably a mammal, more preferably a primate, furthermore preferably a human. In one embodiment, the subject is a “patient” as defined herein. In one embodiment, the subject is affected, preferably is diagnosed, with a disease. In one embodiment, the subject is at risk of developing a disease. Examples of risks factor include, but are not limited to, genetic predisposition, or familial history of the disease.

[0047] “Therapeutic agent”, “active pharmaceutical ingredient” and “active ingredient” refer to a compound for therapeutic use and relating to health. Especially, a therapeutic agent (e.g., a compound according to the present invention) may be indicated for treating a disease (e.g., a neurological disorder). An active ingredient may also be indicated for improving the therapeutic activity of another therapeutic agent.

[0048] “Therapeutically effective amount” (in short “effective amount”) refers to the amount of a therapeutic agent (e.g., a compound according to the present invention) that is sufficient to achieve the desired therapeutic, prophylactic or preventative effect in the patient to which / whom it is administered, without causing significant negative or adverse side effects to said patient. A therapeutically effective amount may be administered priorto the onset of the disease for a prophylactic or preventive action. Alternatively, or additionally, the therapeutically effective amount may be administered after initiation of the disease for a therapeutic action.

[0049] “Treating”, “treatment” or “alleviation” refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder (herein a “disease”) (e.g., a neurological disorder). Those in need of treatment include those already with the disease as well as those prone to have the disease or those in whom the condition or disease is to be prevented. A patient is successfully “treated” for a disease if, after receiving a therapeutic amount of a therapeutic agent (e.g., a compound according to the present invention), the patient shows observable and / or measurable reduction in or absence of one or more of the following: reduction in the number of pathogens; reduction in the percent of total cells that are pathogenic; and / or relief to some extent, one or more of the symptoms associated with the specific disease; reduced morbidity and mortality, and improvement in quality of life issues. The above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician. DETAILED DESCRIPTION

[0050] An object of the present invention is a compound of formula (I)or a pharmaceutically acceptable salt and / or solvate thereof;wherein W represents CH or N; RA, RB, RCand RDeach independently represents hydrogen, F, Cl, CH3, CF3, CHF2 or CH2F, provided that at least one among RA, RB, RCand RDdoes not represent hydrogen (i.e., the phenyl or pyridinyl is substituted, in other words, the phenyl or pyridinyl cannot be unsubstituted); R1represents hydrogen or (C1-C8) alkyl, wherein the alkyl is optionally substituted by at least one OH, (C1-C3) alkoxy or F; and R2, R3and R4represents hydrogen; or R1and R4form together -CH2-O-CH2- or -CH2-CH2-, wherein the -CH2-CH2- is optionally substituted by at least one F, OH or OCH3; and R2and R3each represents hydrogen; A1and A2each independently represents N or C; and A3, A4and A5each independently represents N, NR11, C or CR12; provided that at least one among A1, A2, A3, A4and A5represents N or NR11; wherein each R11represents independently hydrogen, (C1-C8) alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1-C8) alkyl-, heterocycloalkyl-(C1-C8) alkyl-, aryl-(C1-C8) alkyl- or heteroaryl- (C1-C8) alkyl-; and each R12represents independently hydrogen, (C1-C8) alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1-C8) alkyl-, heterocycloalkyl-(C1-C8) alkyl-, aryl-(C1-C8) alkyl- or heteroaryl- (C1-C8) alkyl-; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl in R11or R12(i.e., any alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl that is represented by R11or R12or that is part of any substituent thereof) isoptionally substituted by at least one F, Cl, OH, =O, (C1-C8) alkyl, (C1-C8) alkyl-O- or NR13R14; wherein R13and R14each independently represents hydrogen or (C1-C8) alkyl; and R10represents NR5R6or C(R5)(R6)(R9); wherein R5represents hydrogen, (C1-C8) alkyl, CH3 substituted by one to three (C1-C8) alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl- (C1-C8) alkyl; wherein the alkyl or cycloalkyl in R5is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, NR17R18, CO2H, R17R18N-C(O)-, R17O-NR18-, heterocycloalkyl, aryl or heteroaryl; wherein R17and R18each independently represents hydrogen or (C1-C8) alkyl; wherein the heterocycloalkyl, aryl or heteroaryl (i.e., any heterocycloalkyl, aryl or heteroaryl that is represented by R5or that is part of any substituent thereof) is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR19R20, CO2H, R19R20N-C(O)-, R19O-NR20-, (C1-C8) alkyl-CO2-, R19R20N-(C1-C8) alkyl-, R19O2C-(C1-C8) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl- (C1-C8) alkyl-; wherein R19and R20each independently represents hydrogen or (C1-C8) alkyl; R6represents hydrogen, (C1-C8) alkyl, CH3substituted by one to three (C1-C8) alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl- (C1-C8) alkyl; wherein the alkyl or cycloalkyl in R6is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, NR21R22, CO2H, R21R22N-C(O)-, R21O-NR22-, heterocycloalkyl, aryl or heteroaryl; wherein R21and R22each independently represents hydrogen or (C1-C8) alkyl;wherein the heterocycloalkyl, aryl or heteroaryl (i.e., any heterocycloalkyl, aryl or heteroaryl that is represented by R6or that is part of any substituent thereof) is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR23R24, CO2H, R23R24N-C(O)-, R23O-NR24-, (C1-C8) alkyl-CO2-, R23R24N-(C1-C8) alkyl-, R23O2C-(C1-C8) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl- (C1-C8) alkyl-; wherein R23and R24each independently represents hydrogen or (C1-C8) alkyl; or R5and R6form together with the carbon atom or nitrogen atom to which they are bound a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl (i.e., the cycloalkyl or heterocycloalkyl that is formed by R5, R6and the carbon atom to which they are bound) is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR25R26, CO2H, (C1-C8) alkyl-CO2-, R25R26N-C(O)-, R25O-NR26-, R25R26N-(C1-C8) alkyl-, R25O2C-(C1-C8) alkyl-, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1-C8) alkyl-, heterocycloalkyl-(C1-C8) alkyl-, aryl-(C1-C8) alkyl-, heteroaryl- (C1-C8) alkyl-, aryl-cycloalkyl-, cycloalkyl-O-, heterocycloalkyl-O-, aryl- O-, heteroaryl-O-, cycloalkyl-(C1-C8) alkyl-O-, heterocycloalkyl- (C1-C8) alkyl-O-, aryl-(C1-C8) alkyl-O-, heteroaryl-(C1-C8) alkyl-O-, cycloalkyl-NR25-, heterocycloalkyl-NR25-, aryl-NR25-, heteroaryl-NR25-, cycloalkyl-(C1-C8) alkyl-NR25-, heterocycloalkyl-(C1-C8) alkyl-NR25-, aryl-(C1-C8) alkyl-NR25-, heteroaryl-(C1-C8) alkyl-NR25-, benzylidene, heteroarylidene, aryl-(C1-C8) alkyl-ylidene- or heteroaryl-(C1-C8) alkyl- ylidene-; wherein R25and R26each independently represents hydrogen or (C1-C8) alkyl; wherein the heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylidene (i.e., any heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylidene that is part of any substituent of the heterocycloalkyl formed by R5, R6and the nitrogen atom to which they are bound) isoptionally substituted at least one F, Cl, (C1-C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR27R28, CO2H, R27R28N-C(O)-, R27O-NR28-, (C1-C8) alkyl-CO2-, R27R28N-(C1-C8) alkyl-, R27O2C-(C1-C8) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl- (C1-C8) alkyl-; wherein R27and R28each independently represents hydrogen or (C1-C8) alkyl; and R9represents hydrogen, (C1-C8) alkyl, CH3 substituted by one to three (C1-C8) alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl- (C1-C8) alkyl; wherein the alkyl or cycloalkyl in R9is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, NR29R30, CO2H, R29R30N-C(O)-, R29O-NR30-, heterocycloalkyl, aryl or heteroaryl; wherein R29and R30each independently represents hydrogen or (C1-C8) alkyl; wherein the heterocycloalkyl, aryl or heteroaryl (i.e., any heterocycloalkyl, aryl or heteroaryl that is represented by R9or that is part of any substituent thereof) is optionally substituted by at least one F, Cl, CF3, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR31R32, CO2H, R31R32N-C(O)-, R31O-NR32-, (C1-C8) alkyl-CO2-, R31R32N-(C1-C8) alkyl-, R31O2C-(C1-C8) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl-(C1-C8) alkyl-; wherein R31and R32each independently represents hydrogen or (C1-C8) alkyl.

[0051] In any one of the following embodiments directed to specific limitations to the structure of the compounds of formula (I), any alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylidene may independently be optionally substituted as indicated under formula (I) herein, unless otherwise specified.

[0052] In the above formula (I) as represented herein, both the five-membered ring (formed by A1, A2, A3, A4and A5, wherein at least one among A1, A2, A3, A4and A5represents N or NR11) and the six-membered ring to which the five-membered heteroaryl is fused (substituted by the nitrogen of the piperazine and the SO2) are aromatic, as represented by the circle in the center of each ring. Consequently, the five-membered ringis an heteroaryl and the six-membered ring is either heteroaryl or phenyl, depending on the position of the nitrogen heteroatom(s). Moreover, the five-membered ring and the six-membered ring form together a bicyclic heteroaryl (specifically, a [6,5] bicyclic heteroaryl).

[0053] According to one preferred embodiment, W represents CH. According to one particular embodiment, W represents N.

[0054] According to one embodiment, at least one among RA, RB, RCand RDrepresents hydrogen. In one embodiment, exactly one among RA, RB, RCand RDrepresents hydrogen. In one embodiment, exactly two among RA, RB, RCand RDrepresents hydrogen. In one embodiment, exactly three among RA, RB, RCand RDrepresents hydrogen.

[0055] In one embodiment, at least one among RAand RCrepresents hydrogen. In one preferred embodiment, RArepresents hydrogen. In one preferred embodiment, RCrepresents hydrogen. In one further preferred embodiment, RAand RCeach represents hydrogen.

[0056] According to one embodiment, at least one among RA, RBand RDrepresents F or Cl. In one embodiment, at least one among RBand RDrepresents F or Cl. In one particular embodiment, RBand RDeach independently represents F or Cl. In one particular embodiment, RBrepresents F. In one particular embodiment, RBrepresents Cl. In one particular embodiment, RDrepresents F. In one particular embodiment, RDrepresents Cl. In one particular embodiment, RArepresents F. In one preferred embodiment, RBrepresents F. In one particular embodiment, RDrepresents CH3. In one preferred embodiment, RDrepresents Cl. In one further preferred embodiment, RBrepresents F and RDrepresents Cl.

[0057] As defined under formula (I) hereinabove, R1may represents (C1-C8) alkyl, wherein the alkyl is optionally substituted by at least one OH, (C1-C3) alkoxy or F, i.e., the (C1-C8) alkyl in R1is optionally substituted by at least one group, and the group may be OH, (C1-C3) alkoxy or F. According to one embodiment, R1represents (C1-C8) alkyl,wherein the alkyl is substituted by at least one group selected from OH, (C1-C3) alkoxy and F. According to one preferred embodiment, the alkyl is not substituted.

[0058] According to one embodiment, R1represents hydrogen or (C1-C8) alkyl, wherein the alkyl is optionally substituted by at least one OH, (C1-C3) alkoxy or F; and R2, R3and R4represents hydrogen. In one preferred embodiment, R1represents hydrogen or methyl. In one further preferred embodiment, R1, R2, R3and R4each represents hydrogen. In one further preferred embodiment, R1represents methyl.

[0059] According to one embodiment, R1and R4form together -CH2-O- CH2- or -CH2-CH2. In one embodiment, R1and R4form together -CH2-CH2-. In one embodiment, the -CH2-CH2- is optionally substituted by at least one F, OH or OCH3. In one preferred embodiment, the -CH2-CH2- is not substituted.

[0060] According to one embodiment, A1, A2, A3, A4and A5form together a five-membered heteroaryl selected from the following formulaewherein R11and R12are each independently as defined under formula (I) herein; and wherein the dotted lines represent the points of fusion of the five-membered heteroaryl to the six-membered ring (heteroaryl or phenyl) to which it is fused.

[0061] In one embodiment, A1, A2, A3, A4and A5form together a five-membered heteroaryl selected from the following formulaewherein each R11and R12are each independently as defined under formula (I) herein; and wherein the dotted lines represent the points of fusion of the five-membered heteroaryl to the six-membered ring to which it is fused.

[0062] In one preferred embodiment, A1, A2, A3, A4and A5form together a five-membered heteroaryl selected from the following formulaewherein each R11and R12are each independently as defined under formula (I) herein; and wherein the dotted lines represent the points of fusion of the five-membered heteroaryl to the six-membered ring to which it is fused.

[0063] In one further preferred embodiment, A1, A2, A3, A4and A5form together a five-membered heteroaryl selected from the following formulaewherein each R11and R12are each independently as defined under formula (I) herein; and wherein the dotted lines represent the points of fusion of the five-membered heteroaryl to the six-membered ring to which it is fused.

[0064] In one embodiment, A1, A2, A3, A4and A5form together a five-membered heteroaryl selected from the following formulaewherein each R11and R12are each independently as defined under formula (I) herein; and wherein the dotted lines represent the points of fusion of the five-membered heteroaryl to the six-membered ring to which it is fused.

[0065] In one preferred embodiment, A1, A2, A3, A4and A5form together a five-membered heteroaryl selected from the following formulaewherein each R11and R12are each independently as defined under formula (I) herein; and wherein the dotted lines represent the points of fusion of the five-membered heteroaryl to the six-membered ring to which it is fused.

[0066] In one further preferred embodiment, A1, A2, A3, A4and A5form together a five-membered heteroaryl selected from the following formulaewherein each R11and R12are each independently as defined under formula (I) herein; and wherein the dotted lines represent the points of fusion of the five-membered heteroaryl to the six-membered ring to which it is fused.

[0067] In the above formulae, the dotted lines thus represent the points of fusion of the five-membered heteroaryl (formed by A1, A2, A3, A4and A5) to the six-membered ring (heteroaryl or phenyl) to which the five-membered heteroaryl is fused. Any possible orientation of said fusion is encompassed, i.e., any one of the two dotted lines on the right or on the left of the formulae may represent the fusion through any one of A1or A2groups, regardless of the orientation of the drawing. In other words, the orientation of the formulae as drawn is not to be construed as a structural limitation thereof. Typically, the dotted line represented on the left corresponds to the point of fusion of the phenyl through the A1group and the dotted line represented on the right corresponds to point of fusion of the phenyl through the A2group, i.e., the orientation of the formulae as drawn is the same as the orientation of formula (I) as drawn.

[0068] According to one preferred embodiment, the five-membered heteroaryl (formed by A1, A2, A3, A4and A5) and the six-membered ring (heteroaryl or phenyl) form together a bicyclic heteroaryl selected from [1,2,4]triazolo[1,5-a]pyridine, [1,2,4]triazolo[4,3-a]pyridine, benzimidazole, benzotriazole, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, indazole and indole. In one preferred embodiment, the bicyclic heteroaryl is selected from benzimidazole, imidazo[1,5-a]pyridine, indazole and indole.

[0069] According to one embodiment, A3represents NR11or CR12, wherein R11and R12are as defined under formula (I) herein. In one embodiment, R11and / or R12do / does not represent hydrogen. According to one embodiment, A4represents NR11or CR12, wherein R11and R12are as defined under formula (I) herein. In one embodiment, R11and / or R12do / does not represent hydrogen.

[0070] According to one embodiment, A5represents NR11or CR12, wherein R11and R12are as defined under formula (I) herein. In one embodiment, A5represents NR11or CR12, wherein R11and R12are as defined under formula (I) herein, provided that R11and / or R12do / does not represent hydrogen. In one preferred embodiment, A5represents NR11orCR12, wherein R11and R12are as defined under formula (I) herein, provided that R11and R12each does not represent hydrogen. In one further preferred embodiment, R11and R12each independently represents methyl, ethyl, isobutyl, hydroxymethyl, hydroxyethyl, hydroxybutyl (preferably, 2-hydroxy-2-methyl-propyl), methoxyethyl, ethyl-O-C(O)-, cyclobutyl or cyclopropyl. In one further preferred embodiment, R11and R12each independently represents methyl, ethyl, hydroxymethyl, hydroxyethyl, methoxyethyl, ethyl-O-C(O)- or cyclopropyl.

[0071] According to one embodiment, A3and A4each independently represents N, NH, C or CH. In one embodiment, A3represents N, NH, C or CH. In one embodiment, A4represents N, NH, C or CH.

[0072] In accordance with the definitions under formula (I) herein, R11and / or R12may represent a carboxylic acid or ester, i.e., an alkyl substituted by one oxo (=O) and further substituted by either hydroxyl (OH) or alkoxy (alkyl-O-). According to one embodiment, R11and R12each independently represents hydrogen, (C1-C8) alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1-C8) alkyl-, heterocycloalkyl- (C1-C8) alkyl-, aryl-(C1-C8) alkyl- or heteroaryl-(C1-C8) alkyl-; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl in R11or R12is optionally substituted by at least one F, Cl, OH, =O, (C1-C8) alkyl (preferably, (C1-C4) alkyl), (C1-C8) alkyl-O- (preferably, (C1-C4) alkyl-O-) or NR13R14, wherein R13and R14each independently represents hydrogen or (C1-C8) alkyl (preferably, hydrogen or (C1-C4) alkyl). In one embodiment, R11and R12each independently represents hydrogen, (C1-C8) alkyl, cycloalkyl or cycloalkyl-(C1-C8) alkyl-; wherein the alkyl or cycloalkyl in R11or R12is optionally substituted by at least one F, Cl, OH, =O, (C1-C8) alkyl, (C1-C8) alkyl-O- or NR13R14, wherein R13and R14each independently represents hydrogen or (C1-C8) alkyl. In one particular embodiment, R11and R12each independently represents hydrogen, (C1-C8) alkyl or cycloalkyl; wherein the alkyl or cycloalkyl in R11or R12is optionally substituted by at least one F, Cl, OH, =O, (C1-C8) alkyl, (C1-C8) alkyl-O- or NR13R14, wherein R13and R14each independently represents hydrogen or (C1-C8) alkyl. In one particular embodiment, R11and R12each independently represents hydrogen, (C1-C4) alkyl or (C3-C4) cycloalkyl; wherein the alkyl or cycloalkylin R11or R12is optionally substituted by at least one F, Cl, OH, =O, (C1-C8) alkyl, (C1-C8) alkyl-O- or NR13R14, wherein R13and R14each independently represents hydrogen or (C1-C8) alkyl. In one embodiment, R11and R12each independently represents hydrogen, (C1-C4) alkyl or (C3-C4) cycloalkyl; wherein the alkyl or cycloalkyl in R11or R12is optionally substituted by at least one F, Cl, OH, =O, (C1-C4) alkyl, (C1-C4) alkyl-O- or NR13R14, wherein R13and R14each independently represents hydrogen or (C1-C4) alkyl. In one preferred embodiment, R11and R12each independently represents hydrogen, methyl, ethyl, isobutyl, hydroxymethyl, hydroxyethyl, hydroxybutyl (preferably, 2-hydroxy-2-methyl-propyl), methoxyethyl, ethyl-O-C(O)-, cyclobutyl or cyclopropyl. In one further preferred embodiment, R11and R12each independently represents methyl, ethyl, isobutyl, hydroxymethyl, hydroxyethyl, hydroxybutyl (preferably, 2-hydroxy-2-methyl-propyl), methoxyethyl, ethyl-O-C(O)-, cyclobutyl or cyclopropyl. In one preferred embodiment, R11and R12each independently represents hydrogen, methyl, ethyl, hydroxymethyl, hydroxyethyl, methoxyethyl, ethyl-O-C(O)- or cyclopropyl. In one further preferred embodiment, R11and R12each independently represents methyl, ethyl, hydroxymethyl, hydroxyethyl, methoxyethyl, ethyl-O-C(O)- or cyclopropyl.

[0073] According to one embodiment, R10represents NR5R6. According to one different embodiment, R10represents C(R5)(R6)(R9).

[0074] According to one aspect of the present invention, R10represents NR5R6or C(R5)(R6)(R9), wherein R5, R6and R9are defined as follows.

[0075] According to one embodiment, R5represents hydrogen, (C1-C8) alkyl, cycloalkyl or cycloalkyl-(C1-C8) alkyl- (including deuterated derivatives thereof). In one preferred embodiment, R5represents hydrogen or (C1-C8) alkyl. In one embodiment, R5represents hydrogen. In one embodiment, R5represents (C1-C8) alkyl. In one embodiment, the alkyl or cycloalkyl is optionally substituted by at least one halogen (preferably, F). In one embodiment, the alkyl or cycloalkyl is not substituted. In one particular embodiment, R5represents methyl, trideuteriomethyl (CD3) or ethyl.In one further preferred embodiment, R5represents hydrogen, methyl, trideuteriomethyl (CD3) or ethyl.

[0076] According to one embodiment, R6represents hydrogen, (C1-C8) alkyl, cycloalkyl or cycloalkyl-(C1-C8) alkyl- (including deuterated derivatives thereof). According to one preferred embodiment, R6does not represents hydrogen. In one preferred embodiment, R6represents (C1-C8) alkyl or cycloalkyl. In one embodiment, the alkyl or cycloalkyl is optionally substituted by at least one halogen (preferably, F). In one embodiment, the alkyl or cycloalkyl is optionally substituted by one or two halogen(s) (preferably, one or two F). In one embodiment, the alkyl or cycloalkyl is not substituted. In one further preferred embodiment, R6represents ethyl, propyl (preferably, n-propyl), 3-fluoropropyl (preferably, 3-fluoro n-propyl), butyl (preferably, tert-butyl) or difluorocyclobutyl (preferably, 3,3-difluorocyclobutyl).

[0077] According to one embodiment, R5and R6each independently represents hydrogen, (C1-C8) alkyl, cycloalkyl or cycloalkyl-(C1-C8) alkyl- (including deuterated derivatives thereof). In one preferred embodiment, R5represents hydrogen or (C1-C8) alkyl and / or R6represents (C1-C8) alkyl or cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by at least one halogen (preferably, F). In one further preferred embodiment, R5represents hydrogen, methyl, trideuteriomethyl (CD3) or ethyl and / or R6represents ethyl, propyl (preferably, n-propyl), 3-fluoropropyl (preferably, 3-fluoro n-propyl), butyl (preferably, tert-butyl) or difluorocyclobutyl (preferably, 3,3-difluorocyclobutyl). In one embodiment, R5represents hydrogen. In one particular embodiment, R5represents hydrogen and R6represents (C1-C8) alkyl (preferably, butyl; more preferably, tert-butyl). In one particular embodiment, R5and R6each independently represents (C1-C8) alkyl (preferably, ethyl).

[0078] According to one embodiment, R5and R6form together with the carbon atom or nitrogen atom to which they are bound a cycloalkyl or an heterocycloalkyl. In one preferred embodiment, R5and R6form together with the carbon atom to which they are bound a cycloalkyl. In one preferred embodiment, R5and R6form together with the nitrogen atom to which they are bound a pyrrolidine, piperidine or piperazine. In one embodiment, the cycloalkyl or heterocycloalkyl is optionally substituted by atleast one halogen (preferably, F). In one embodiment, the cycloalkyl or heterocycloalkyl is optionally substituted by at least one phenyl, benzyl or phenylethyl; wherein the phenyl, benzyl or phenylethyl is optionally substituted by at least one halogen (preferably, Cl or F; more preferably, Cl). In one particular embodiment, R5and R6form together with the nitrogen atom to which they are bound a pyrrolidine, pyrrolidine substituted by one or two halogen(s) (preferably, one or two F; more preferably, two F), piperidine, phenylpiperidine, piperazine or phenylethyl-piperazine substituted by one halogen (preferably, one Cl ; preferably, the halogen substitutes the phenyl). In one further preferred embodiment, R5and R6form together with the nitrogen atom to which they are bound a cyclopentyl, difluoropyrrolidine (preferably, 3,3-difluoropyrrolidine), phenyl-piperidine (preferably, 4-phenyl-piperidin-1-yl) or (chlorophenyl)ethyl-piperazine (preferably, 4-(4-chlorophenyl)ethyl]piperazin-1-yl).

[0079] In one embodiment, R9represents hydrogen or (C1-C8) alkyl. In one embodiment, R9represents (C1-C8) alkyl. In one embodiment, the alkyl is not substituted. In one preferred embodiment, R9represents hydrogen.

[0080] In one particular embodiment, R5and R6each independently represents hydrogen, (C1-C8) alkyl, cycloalkyl or cycloalkyl-(C1-C8) alkyl- (including deuterated derivatives thereof), and R9represents hydrogen. In one preferred embodiment, R5represents hydrogen or (C1-C8) alkyl and / or R6represents (C1-C8) alkyl or cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by at least one halogen (preferably, F), and R9represents hydrogen. In one further preferred embodiment, R5represents hydrogen, methyl, trideuteriomethyl (CD3) or ethyl and / or R6represents ethyl, propyl (preferably, n-propyl), 3-fluoropropyl (preferably, 3-fluoro n-propyl), butyl (preferably, tert-butyl) or difluorocyclobutyl (preferably, 3,3-difluorocyclobutyl), and R9represents hydrogen. In one embodiment, R5represents hydrogen. In one particular embodiment, R5represents hydrogen and R6represents (C1-C8) alkyl (preferably, butyl; more preferably, tert-butyl), and R9represents hydrogen. In one particular embodiment, R5and R6each independently represents (C1-C8) alkyl (preferably, ethyl), and R9represents hydrogen.

[0081] According to one aspect of the present invention, R10represents NR5R6, wherein R5and R6are defined as follows.

[0082] According to one embodiment, R5represents hydrogen, (C1-C8) alkyl, cycloalkyl or cycloalkyl-(C1-C8) alkyl- (including deuterated derivatives thereof). In one preferred embodiment, R5represents hydrogen or (C1-C8) alkyl. In one embodiment, R5represents hydrogen. In one embodiment, R5represents (C1-C8) alkyl. In one embodiment, the alkyl or cycloalkyl is optionally substituted by at least one halogen (preferably, F). In one embodiment, the alkyl or cycloalkyl is not substituted. In one particular embodiment, R5represents methyl, trideuteriomethyl (CD3) or ethyl. In one further preferred embodiment, R5represents hydrogen, methyl, trideuteriomethyl (CD3) or ethyl.

[0083] According to one embodiment, R6represents hydrogen, (C1-C8) alkyl, cycloalkyl or cycloalkyl-(C1-C8) alkyl- (including deuterated derivatives thereof). According to one preferred embodiment, R6does not represents hydrogen. In one preferred embodiment, R6represents (C1-C8) alkyl or cycloalkyl. In one embodiment, the alkyl or cycloalkyl is optionally substituted by at least one halogen (preferably, F). In one embodiment, the alkyl or cycloalkyl is optionally substituted by one or two halogen(s) (preferably, one or two F). In one embodiment, the alkyl or cycloalkyl is not substituted. In one further preferred embodiment, R6represents ethyl, propyl (preferably, n-propyl), 3-fluoropropyl (preferably, 3-fluoro n-propyl), butyl (preferably, tert-butyl) or difluorocyclobutyl (preferably, 3,3-difluorocyclobutyl).

[0084] According to one embodiment, R5and R6each independently represents hydrogen, (C1-C8) alkyl, cycloalkyl or cycloalkyl-(C1-C8) alkyl- (including deuterated derivatives thereof). In one preferred embodiment, R5represents hydrogen or (C1-C8) alkyl and / or R6represents (C1-C8) alkyl or cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by at least one halogen (preferably, F). In one further preferred embodiment, R5represents hydrogen, methyl, trideuteriomethyl (CD3) or ethyl and / or R6represents ethyl, propyl (preferably, n-propyl), 3-fluoropropyl (preferably, 3-fluoro n-propyl), butyl (preferably, tert-butyl) or difluorocyclobutyl (preferably, 3,3-difluorocyclobutyl). In one embodiment, R5represents hydrogen. Inone particular embodiment, R5represents hydrogen and R6represents (C1-C8) alkyl (preferably, butyl; more preferably, tert-butyl). In one particular embodiment, R5and R6each independently represents (C1-C8) alkyl (preferably, ethyl).

[0085] According to one embodiment, R5and R6form together with the nitrogen atom to which they are bound an heterocycloalkyl. In one preferred embodiment, R5and R6form together with the nitrogen atom to which they are bound a pyrrolidine, piperidine or piperazine. In one embodiment, the heterocycloalkyl is optionally substituted by at least one halogen (preferably, F). In one embodiment, the heterocycloalkyl is optionally substituted by at least one phenyl, benzyl or phenylethyl; wherein the phenyl, benzyl or phenylethyl is optionally substituted by at least one halogen (preferably, Cl or F; more preferably, Cl). In one particular embodiment, R5and R6form together with the nitrogen atom to which they are bound a pyrrolidine, pyrrolidine substituted by one or two halogen(s) (preferably, one or two F; more preferably, two F), piperidine, phenylpiperidine, piperazine or phenylethyl-piperazine substituted by one halogen (preferably, one Cl ; preferably, the halogen substitutes the phenyl). In one further preferred embodiment, R5and R6form together with the nitrogen atom to which they are bound a difluoropyrrolidine (preferably, 3,3-difluoropyrrolidine), phenyl-piperidine (preferably, 4-phenyl-piperidin-1-yl) or (chlorophenyl)ethyl-piperazine (preferably, 4-(4-chlorophenyl)ethyl]piperazin-1-yl).

[0086] According to one aspect of the present invention, R10represents C(R5)(R6)(R9); and R5, R6and R9are defined as follows.

[0087] According to one embodiment, R5represents hydrogen, (C1-C8) alkyl, cycloalkyl or cycloalkyl-(C1-C8) alkyl- (including deuterated derivatives thereof). In one preferred embodiment, R5represents hydrogen or (C1-C8) alkyl. In one embodiment, R5represents hydrogen. In one embodiment, R5represents (C1-C8) alkyl. In one embodiment, the alkyl or cycloalkyl is optionally substituted by at least one halogen (preferably, F). In one embodiment, the alkyl or cycloalkyl is not substituted. In one particular embodiment, R5represents methyl or ethyl. In one further preferred embodiment, R5represents hydrogen, methyl or ethyl.

[0088] According to one embodiment, R6represents hydrogen, (C1-C8) alkyl, cycloalkyl or cycloalkyl-(C1-C8) alkyl- (including deuterated derivatives thereof). According to one preferred embodiment, R6does not represents hydrogen. In one preferred embodiment, R6represents (C1-C8) alkyl. In one embodiment, the alkyl is optionally substituted by at least one halogen (preferably, F). In one preferred embodiment, the alkyl is not substituted. In one further preferred embodiment, R6represents ethyl or butyl (preferably, tert-butyl).

[0089] According to one embodiment, R5and R6each independently represents hydrogen, (C1-C8) alkyl, cycloalkyl or cycloalkyl-(C1-C8) alkyl- (including deuterated derivatives thereof). In one preferred embodiment, R5represents hydrogen or (C1-C8) alkyl and / or R6represents (C1-C8) alkyl. In one further preferred embodiment, R5represents hydrogen, methyl or ethyl and / or R6represents ethyl or butyl (preferably, tert-butyl). In one embodiment, R5represents hydrogen. In one particular embodiment, R5represents hydrogen and R6represents (C1-C8) alkyl (preferably, butyl; more preferably, tert-butyl). In one particular embodiment, R5and R6each independently represents (C1-C8) alkyl (preferably, ethyl).

[0090] According to one embodiment, R5and R6form together with the carbon atom to which they are bound a cycloalkyl or an heterocycloalkyl. In one preferred embodiment, R5and R6form together with the carbon atom to which they are bound a cycloalkyl. In one embodiment, the cycloalkyl or the heterocycloalkyl is optionally substituted by at least one halogen (preferably, F). In one preferred embodiment, the cycloalkyl or the heterocycloalkyl is not substituted. In one further preferred embodiment, R5and R6form together with the nitrogen atom to which they are bound a cyclopentyl.

[0091] In one embodiment, R9represents hydrogen or (C1-C8) alkyl. In one embodiment, R9represents (C1-C8) alkyl. In one embodiment, the alkyl is not substituted. In one preferred embodiment, R9represents hydrogen.

[0092] In one particular embodiment, R5and R6each independently represents hydrogen, (C1-C8) alkyl, cycloalkyl or cycloalkyl-(C1-C8) alkyl- (including deuteratedderivatives thereof), and R9represents hydrogen. In one preferred embodiment, R5represents hydrogen or (C1-C8) alkyl and / or R6represents (C1-C8) alkyl, and R9represents hydrogen. In one further preferred embodiment, R5represents hydrogen, methyl or ethyl and / or R6represents ethyl or butyl (preferably, tert-butyl), and R9represents hydrogen. In one embodiment, R5represents hydrogen. In one particular embodiment, R5represents hydrogen and R6represents (C1-C8) alkyl (preferably, butyl; more preferably, tert-butyl), and R9represents hydrogen. In one particular embodiment, R5and R6each independently represents (C1-C8) alkyl (preferably, ethyl), and R9represents hydrogen.

[0093] According to one embodiment, at least one heterocycloalkyl present in the compound of formula (I) is a water-solubilizing group, i.e., the presence of this group in the molecule increases the solubility thereof in water, compared with the same molecule not comprising the heterocycloalkyl.

[0094] According to one embodiment, the compound of formula (I) is a compound of formula (I-a)or a pharmaceutically acceptable salt and / or solvate thereof; wherein W, RB, RD, R1-R4, A1-A5and R10are as defined under formula (I) herein.

[0095] In one embodiment, W in formula (I-a) represents CH. In one embodiment, RBand RDin formula (I-a) each independently represents F or Cl. In one particular embodiment, RBrepresents F and RDrepresents Cl.

[0096] According to one embodiment, the compound of formula (I) is selected from the compounds of Table 1 below, and pharmaceutically acceptable salts and / or solvates thereof. Table 1 Cpd Structure Name (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[6-[(4- phenyl-1- 001 piperidyl)sulfonyl]imidazo [1,2-a]pyridin-8-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[6-[(4- phenyl-1- piperidyl)sulfonyl]- 002 [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[6- (2,2- dimethylpropylsulfonyl)im 003 idazo[1,2-a]pyridin-8-yl]- 3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[6- (2,2- dimethylpropylsulfonyl)- 004 [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[5-[(4- phenyl-1- 005 piperidyl)sulfonyl]-1H- indol-7-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanoneCpd Structure Name N-tert-butyl-7-[(1S,5R)-3- (2-chloro-4-fluoro- benzoyl)-3,8- 006 diazabicyclo[3.2.1]octan- 8-yl]-N- (trideuteriomethyl)-1H- indole-5-sulfonamide N-tert-butyl-7-[(1S,5R)-3- (2-chloro-4-fluoro- benzoyl)-3,8- 007 diazabicyclo[3.2.1]octan- 8-yl]-1-cyclopropyl- indole-5-sulfonamide N-tert-butyl-7-[(1S,5R)-3- (2-chloro-4-fluoro- 008 benzoyl)-3,8- diazabicyclo[3.2.1]octan- 8-yl]-1H-indole-5- sulfonamide N-tert-butyl-7-[(1S,5R)-3- (2-chloro-4-fluoro- benzoyl)-3,8- 009 diazabicyclo[3.2.1]octan- 8-yl]-N,1-dimethyl-indole- 5-sulfonamide N-tert-butyl-7-[(1S,5R)-3- (2-chloro-4-fluoro- 010 benzoyl)-3,8- diazabicyclo[3.2.1]octan- 8-yl]-N-methyl-1H-indole- 5-sulfonamide (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[5- (2,2- 011 dimethylpropylsulfonyl)- 1H-indol-7-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanoneCpd Structure Name (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[5- (2,2- 012 dimethylpropylsulfonyl)- 1-methyl-indol-7-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[1- cyclopropyl-5-(2,2- 013 dimethylpropylsulfonyl)in dol-7-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[5-[(4- phenyl-1- 014 piperidyl)sulfonyl]-1H- indazol-7-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone N-tert-butyl-7-[(1S,5R)-3- (2-chloro-4-fluoro- benzoyl)-3,8- 015 diazabicyclo[3.2.1]octan- 8-yl]-1H-indazole-5- sulfonamide N-tert-butyl-7-[(1S,5R)-3- (2-chloro-4-fluoro- benzoyl)-3,8- 016 diazabicyclo[3.2.1]octan- 8-yl]-1-cyclopropyl- indazole-5-sulfonamide (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[5- (3,3-difluoropyrrolidin-1- 017 yl)sulfonyl-1H-indazol-7- yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanoneCpd Structure Name (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[5-[4- [2-(4- chlorophenyl)ethyl]piperaz in-1-yl]sulfonyl-1H- 018 indazol-7-yl]-3,8- diazabicyclo[3.2.1]octan- 3- yl]methanone;hydrochlori de (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[5-[4- [2-(4- chlorophenyl)ethyl]piperaz in-1-yl]sulfonyl-1- 019 cyclopropyl-indazol-7-yl]- 3,8- diazabicyclo[3.2.1]octan- 3- yl]methanone;hydrochlori de (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[5- (2,2- 020 dimethylpropylsulfonyl)- 1H-indazol-7-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[5- (2,2- dimethylpropylsulfonyl)- 021 1-methyl-indazol-7-yl]- 3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[1- cyclopropyl-5-(2,2- 022 dimethylpropylsulfonyl)in dazol-7-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanoneCpd Structure Name (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[5- (2,2- dimethylpropylsulfonyl)- 023 1-(2- hydroxyethyl)indazol-7- yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[5- (2,2- dimethylpropylsulfonyl)- 024 1-(2- methoxyethyl)indazol-7- yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1R,5S)-8-[6-[(4- phenyl-1- 025 piperidyl)sulfonyl]-3H- benzotriazol-4-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[6-[(4- phenyl-1- 026 piperidyl)sulfonyl]-1H- benzimidazol-4-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- O Cl O O phenyl)-[(1S,5R)-8-[3- N S N N methyl-6-[(4-phenyl-1- 027 piperidyl)sulfonyl]benzimi F N N dazol-4-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanoneCpd Structure Name N-tert-butyl-7-[(1S,5R)-3- (2-chloro-4-fluoro- benzoyl)-3,8- 028 diazabicyclo[3.2.1]octan- 8-yl]-1H-benzimidazole-5- sulfonamide N-tert-butyl-7-[(1S,5R)-3- (2-chloro-4-fluoro- benzoyl)-3,8- 029 diazabicyclo[3.2.1]octan- 8-yl]-1-cyclopropyl- benzimidazole-5- sulfonamide N-tert-butyl-7-[(1S,5R)-3- (2-chloro-4-fluoro- benzoyl)-3,8- 030 diazabicyclo[3.2.1]octan- 8-yl]-N-methyl-1H- benzimidazole-5- sulfonamide (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[6-[4- [2-(4- chlorophenyl)ethyl]piperaz in-1-yl]sulfonyl-1H- 031 benzimidazol-4-yl]-3,8- diazabicyclo[3.2.1]octan- 3- yl]methanone;hydrochlori de (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[6-[4- [2-(4- chlorophenyl)ethyl]piperaz in-1-yl]sulfonyl-3- 032 cyclopropyl-benzimidazol- 4-yl]-3,8- diazabicyclo[3.2.1]octan- 3- yl]methanone;hydrochlori deCpd Structure Name (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[6- (2,2- dimethylpropylsulfonyl)- 033 3H-benzimidazol-4-yl]- 3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[6- (2,2- 034 dimethylpropylsulfonyl)- 3-methyl-benzimidazol-4- yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[3- cyclopropyl-6-(2,2- 035 dimethylpropylsulfonyl)be nzimidazol-4-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[6- (2,2- dimethylpropylsulfonyl)- 036 3-ethyl-benzimidazol-4- yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7-[(4- phenyl-1- piperidyl)sulfonyl]- 037 [1,2,4]triazolo[4,3- a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanoneCpd Structure Name (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7-[(4- phenyl-1- 038 piperidyl)sulfonyl]imidazo [1,2-a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7-[(4- phenyl-1- 039 piperidyl)sulfonyl]imidazo [1,5-a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone 5-[(1S,5R)-3-(2-chloro-4- fluoro-benzoyl)-3,8- 040 diazabicyclo[3.2.1]octan- 8-yl]-N,N-diethyl- imidazo[1,5-a]pyridine-7- sulfonamide 5-[(1S,5R)-3-(2-chloro-4- fluoro-benzoyl)-3,8- 041 diazabicyclo[3.2.1]octan- 8-yl]-3-cyclopropyl-N,N- diethyl-imidazo[1,5- a]pyridine-7-sulfonamide N-tert-butyl-5-[(1S,5R)-3- (2-chloro-4-fluoro- benzoyl)-3,8- 042 diazabicyclo[3.2.1]octan- 8-yl]imidazo[1,5- a]pyridine-7-sulfonamideCpd Structure Name N-tert-butyl-5-[(1S,5R)-3- (2-chloro-4-fluoro- benzoyl)-3,8- diazabicyclo[3.2.1]octan- 043 8-yl]-N- (trideuteriomethyl)imidazo [1,5-a]pyridine-7- sulfonamide N-tert-butyl-5-[(1S,5R)-3- (2-chloro-4-fluoro- benzoyl)-3,8- 044 diazabicyclo[3.2.1]octan- 8-yl]-3-methyl- imidazo[1,5-a]pyridine-7- sulfonamide N-tert-butyl-5-[(1S,5R)-3- (2-chloro-4-fluoro- benzoyl)-3,8- 045 diazabicyclo[3.2.1]octan- 8-yl]-3-cyclopropyl- imidazo[1,5-a]pyridine-7- sulfonamide N-tert-butyl-5-[(1S,5R)-3- (2-chloro-4-fluoro- benzoyl)-3,8- 046 diazabicyclo[3.2.1]octan- 8-yl]-3-cyclopropyl-N- methyl-imidazo[1,5- a]pyridine-7-sulfonamide N-tert-butyl-5-[(1S,5R)-3- (2-chloro-4-fluoro- benzoyl)-3,8- diazabicyclo[3.2.1]octan- 047 8-yl]-3-cyclopropyl-N- (trideuteriomethyl)imidazo [1,5-a]pyridine-7- sulfonamideCpd Structure Name (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7- (3,3-difluoropyrrolidin-1- 048 yl)sulfonylimidazo[1,5- a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[3- cyclopropyl-7-(3,3- 049 difluoropyrrolidin-1- yl)sulfonyl-imidazo[1,5- a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone 5-[(1S,5R)-3-(2-chloro-4- fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan- 050 8-yl]-N-(3- fluoropropyl)imidazo[1,5- a]pyridine-7-sulfonamide 5-[(1S,5R)-3-(2-chloro-4- fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan- 051 8-yl]-N-(3-fluoropropyl)- N-methyl-imidazo[1,5- a]pyridine-7-sulfonamide 5-[(1S,5R)-3-(2-chloro-4- fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan- 052 8-yl]-3-cyclopropyl-N-(3- fluoropropyl)imidazo[1,5- a]pyridine-7-sulfonamideCpd Structure Name 5-[(1S,5R)-3-(2-chloro-4- fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan- 053 8-yl]-3-cyclopropyl-N-(3- fluoropropyl)-N-methyl- imidazo[1,5-a]pyridine-7- sulfonamide 5-[(1S,5R)-3-(2-chloro-4- fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan- 054 8-yl]-N-(3,3- difluorocyclobutyl)imidaz o[1,5-a]pyridine-7- sulfonamide 5-[(1S,5R)-3-(2-chloro-4- fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan- 055 8-yl]-N-(3,3- difluorocyclobutyl)-N- methyl-imidazo[1,5- a]pyridine-7-sulfonamide 5-[(1S,5R)-3-(2-chloro-4- fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan- 8-yl]-3-cyclopropyl-N- 056 (3,3- difluorocyclobutyl)imidaz o[1,5-a]pyridine-7- sulfonamide 5-[(1S,5R)-3-(2-chloro-4- fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan- 057 8-yl]-3-cyclopropyl-N- (3,3-difluorocyclobutyl)- N-methyl-imidazo[1,5- a]pyridine-7-sulfonamideCpd Structure Name (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7-[4- [2-(4- chlorophenyl)ethyl]piperaz in-1- 058 yl]sulfonylimidazo[1,5- a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan- 3- yl]methanone;hydrochlori de (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7-[4- [2-(4- chlorophenyl)ethyl]piperaz in-1-yl]sulfonyl-3- 059 cyclopropyl-imidazo[1,5- a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan- 3- yl]methanone;hydrochlori de (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7- (2,2- dimethylpropylsulfonyl)im 060 idazo[1,2-a]pyridin-5-yl]- 3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7- (2,2- 061 dimethylpropylsulfonyl)im idazo[1,5-a]pyridin-5-yl]- 3,8- diazabicyclo[3.2.1]octan- 3-yl]methanoneCpd Structure Name (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7- (2,2- dimethylpropylsulfonyl)- 062 3-methyl-imidazo[1,5- a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[3- cyclopropyl-7-(2,2- 063 dimethylpropylsulfonyl)im idazo[1,5-a]pyridin-5-yl]- 3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7- (2,2- dimethylpropylsulfonyl)- 064 3- (hydroxymethyl)imidazo[1 ,5-a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone ethyl 5-[(1S,5R)-3-(2- chloro-4-fluoro-benzoyl)- 3,8- diazabicyclo[3.2.1]octan- 065 8-yl]-7-(2,2- dimethylpropylsulfonyl)im idazo[1,5-a]pyridine-3- carboxylate (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7- (2,2- dimethylpropylsulfonyl)- 066 3-(2- hydroxyethyl)imidazo[1,5- a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanoneCpd Structure Name (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7- (2,2- dimethylpropylsulfonyl)- 067 3-(2- methoxyethyl)imidazo[1,5 -a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-(7- cyclopentylsulfonylimidaz 068 o[1,5-a]pyridin-5-yl)-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7-(1- ethylpropylsulfonyl)imida 069 zo[1,5-a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7- [(1SR)-1- methylpropyl]sulfonylimid 070 azo[1,5-a]pyridin-5-yl]- 3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[4-[3-cyclopropyl- 7-(2,2- 071 dimethylpropylsulfonyl)im idazo[1,5-a]pyridin-5- yl]piperazin-1- yl]methanoneCpd Structure Name (2-chloro-4-fluoro- phenyl)-[4-[7-(2,2- dimethylpropylsulfonyl)- 072 3-methyl-imidazo[1,5- a]pyridin-5-yl]piperazin-1- yl]methanone (2-chloro-4-fluoro- phenyl)-[(3S)-4-[7-(2,2- 073 dimethylpropylsulfonyl)- 3-methyl-imidazo[1,5- a]pyridin-5-yl]-3-methyl- piperazin-1-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[5- (2,2- dimethylpropylsulfonyl)- 074 1-(2-hydroxy-2-methyl- propyl)indazol-7-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone [(1S,5R)-8-[5-(2,2- dimethylpropylsulfonyl)- 1-(2- methoxyethyl)indazol-7- 075 yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]-(4- fluorophenyl)methanone (2-chlorophenyl)- [(1S,5R)-8-[5-(2,2- dimethylpropylsulfonyl)- 1-(2- 076 methoxyethyl)indazol-7- yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanoneCpd Structure Name (2-chloro-4,5-difluoro- phenyl)-[(1S,5R)-8-[5- (2,2- dimethylpropylsulfonyl)- 077 1-(2- methoxyethyl)indazol-7- yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone [(1S,5R)-8-[5-(2,2- dimethylpropylsulfonyl)- 1-(2- methoxyethyl)indazol-7- 078 yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]-(4-fluoro-2-methyl- phenyl)methanone (3-chloro-5-fluoro-2- pyridyl)-[(1S,5R)-8-[5- (2,2- dimethylpropylsulfonyl)- 079 1-(2- methoxyethyl)indazol-7- yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7- (2,2- dimethylpropylsulfonyl)- 080 3-(2-hydroxy-2-methyl- propyl)imidazo[1,5- a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7- (2,2- dimethylpropylsulfonyl)- 081 3-ethyl-imidazo[1,5- a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanoneCpd Structure Name (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7- (2,2- dimethylpropylsulfonyl)- 082 3-isobutyl-imidazo[1,5- a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[3- cyclobutyl-7-(2,2- 083 dimethylpropylsulfonyl)im idazo[1,5-a]pyridin-5-yl]- 3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7- (3,3-difluoropyrrolidin-1- yl)sulfonyl-3-methyl- 084 imidazo[1,5-a]pyridin-5- yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7- (3,3-difluoropyrrolidin-1- yl)sulfonyl-3-ethyl- 085 imidazo[1,5-a]pyridin-5- yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro- phenyl)-[(1S,5R)-8-[7- (3,3-difluoropyrrolidin-1- yl)sulfonyl-3-isobutyl- 086 imidazo[1,5-a]pyridin-5- yl]-3,8- diazabicyclo[3.2.1]octan- 3-yl]methanoneCpd Structure Name (2-chloro-4-fluoro Cl F - O F phenyl)-[(1S,5R)-8-[7- N O (3,3-difluoropyrrolidin-1- N N S yl)sulfonyl-3-(2- 087 F O hydroxyethyl)imidazo[1,5- N H O a]pyridin-5-yl]-3,8- N diazabicyclo[3.2.1]octan- 3-yl]methanone F (2-chloro-4-fluoro- Cl O F phenyl)-[(1S,5R)-8-[3- N O cyclobutyl-7-(3,3- N 088 N S difluoropyrrolidin-1- F O yl)sulfonyl-imidazo[1,5- N a]pyridin-5-yl]-3,8- N diazabicyclo[3.2.1]octan- 3-yl]methanone

[0097] All references herein to a compound of the invention (e.g., “compound of formula (I)”) include references to salts, solvates, multi component complexes and liquid crystals thereof. All references herein to a compound of the invention include references to polymorphs and crystal habits thereof. All references herein to a compound of the invention include references to isotopically-labelled compounds thereof, including deuterated compounds thereof. All references herein to a compound of the invention include references to stereoisomers thereof. All references herein to a compound of the invention include references to pharmaceutically acceptable prodrugs thereof.

[0098] In particular, the compounds of the invention may be in the form of pharmaceutically acceptable salts. According to one embodiment, the compound of the invention is a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate,saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)- morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. When a compound contains an acidic group as well as a basic group the compound may also form internal salts, and such compounds are within the scope of the invention. When a compound contains a hydrogen-donating heteroatom (e.g., NH), the invention also encompasses salts and / or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule. Pharmaceutically acceptable salts of compounds of the invention may be prepared by one or more of these methods: (i) by reacting the compound with the desired acid; (ii) by reacting the compound with the desired base; (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using the desired acid; and / or (iv) by converting one salt of the compound to another by reaction with an appropriate acid or by means of a suitable ion exchange column. All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

[0099] In particular, the compounds of the invention may be in the form of pharmaceutically acceptable solvates. According to one embodiment, the compound of the invention is a pharmaceutically acceptable solvate. According to one embodiment, the compound of the invention is a pharmaceutically acceptable salt and solvate.

[0100] In particular, the compounds of the invention may include at least one asymmetric center(s) and thus may exist as different stereoisomeric forms. Accordingly, all references herein to a compound of the invention include all possible stereoisomers and include not only the racemic compounds, but the individual enantiomers and their non-racemic mixtures as well. Non-racemic mixtures may comprise any amounts of eachdistinct stereoisomer, for example one stereoisomer may be preponderant (e.g., a 90 / 10 or 80 / 20 mixture), or the enantiomeric ratio may be close to a racemic mixture (e.g., a 40 / 60 mixture). When a compound is desired as a single enantiomer, such single enantiomer may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be carried out by any suitable method known in the art. Pharmaceutical composition

[0101] Another object of the present invention is a composition comprising a compound according to the invention, as described herein. According to one embodiment, the composition further comprises at least one pharmaceutically acceptable carrier, so that the composition is a “pharmaceutical composition” as defined herein.

[0102] In a first embodiment, the pharmaceutical composition comprises the compound according to the invention as sole therapeutic agent. In a second embodiment, the pharmaceutical composition further comprises at least another therapeutic agent such as, for example, a therapeutic agent suitable for treating a neurological disorder.

[0103] Another object of the present invention is a medicament comprising a compound according to the invention, as described herein. Kit

[0104] Another object of the present invention is a kit of parts (in short “kit”) comprising a compound or composition according to the invention, as described herein. According to one embodiment, the kit comprises a manufacture such as, for example, a package or a container. According to one embodiment, the kit comprises instructions for use. The kit may be promoted, distributed, or sold as a unit for performing the methods of the present invention.

[0105] According to one embodiment, the kit comprises: a pharmaceutical composition comprising the compound according to the invention, and another separatepharmaceutical composition comprising at least another therapeutic agent such as, for example, a therapeutic agent suitable for treating a neurological disorder. Medical use of the compound

[0106] Another object of the present invention is a compound or a composition according to the invention, as described herein, for use as a medicament.

[0107] Another object of the present invention is a compound or a composition according to the invention, as described herein, for use in the treatment of a neurological disorder.

[0108] Another object of the present invention is a method for treating a neurological disorder in a subject in need thereof. Another object of the present invention is the use of a compound or a composition according to the invention, as described herein, in the manufacture of a medicament for the treatment of a neurological disorder. Another object of the present invention is the use of a compound or a composition according to the invention, as described herein, for treating a neurological disorder.

[0109] According to one embodiment, the method or the use comprises a step of administering to a subject a therapeutically effective amount of a compound, a composition or a medicament according to the invention, as described herein.

[0110] According to one embodiment, the neurological disorder to be treated by the method or the use of the invention is: - a disease or a disorder associated with defective neurogenesis such as, for example, Hirschsprung disease, schizophrenia, Ataxia telangiectasia, age-related decline of nervous system performance, or a neurodevelopmental disorder; - a neurodegenerative disease or disorder, such as, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Fronto- temporal dementia, retinal neurodegenerative diseases, neuro-ophthalmic diseases, neurotrophic keratitis, Charcot-Marie-Tooth disease, Spinal Muscular Atrophy, epilepsy (e.g., an epilepsy disorder, or a seizure disorder, or a chronic neurological disorder presenting with epilepsy), dementia, age-related decline of nervous systemperformance, a prion disease, Creutzfeldt-Jacob disease, Multiple System Atrophy (Shy Drager Syndrome), Multiple sclerosis, or Guillain-Barre syndrome; - a disease or a disorder associated with nerve injury or neurotoxicity, such as, for example, head injury, brain damage, traumatic brain injury, peripheral nerve injury, traumatic peripheral nerve injury, peripheral neuropathy, nerve transplantation complications, spinal cord injury, traumatic spinal cord injury, severance of nerves or nerve damage, severance of cerebrospinal nerve cord, a damage to brain or nerve cells, syringomyelia, optic neuropathy, trauma, stroke, ischemia, stroke, ischemic stroke, neurotoxicity caused by alcohol or substance abuse (e.g., ecstasy, methamphetamine etc.), or aphasia; - a neurodevelopmental disorder, such as, for example, Rett syndrome, X-linked mental retardation, fragile X syndrome, Down's syndrome, Autism Spectrum Disorder, Hirschsprung's disease, Tourette syndrome, childhood learning disorder, an attention deficit disorder, Attention Deficit Hyperactivity Disorder (ADHD), Angelman syndrome, micropreemie, schizophrenia, Language disorder, preterm birth, perinatal arterial ischemic stroke, spina bifida, mental retardation, nonsyndromic X-linked mental retardation, Ondine syndrome, or WAGR syndrome; - a neuropsychiatric disorder such as, for example, depression, Major Depressive Disorder, schizophrenia, schizophrenic form disorder, schizoaffective disorder, delusional disorder, anxiety, anxiety disorders, panic disorder, phobias, an obsessive-compulsive disorder, a post‑traumatic stress disorder, a bipolar disorder, anorexia nervosa, bulimia nervosa, anhedonia, apathy, dementia, substance- induced dementia, a motor and / or tic disorder characterized by motor and / or vocal tics (e.g., Tourette’s disorder), a substance use behavior, addiction, mood disorders, suicidality, cancer-related psychiatric symptoms, Alzheimer’s disease, Huntington’s disease, Fronto-temporal dementia, or a reward deficiency syndrome (RDS); - a movement disorder, such as, for example, Parkinson’s disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, a motor and tic disorder characterized bymotor and / or vocal tics (e.g., Tourette’s disorder), an ataxia, ataxias muscular rigidity (spasticity), Charcot-Marie-Tooth disease, Spinal Muscular Atrophy, Werdnig-Hoffmann disease, or chronic proximal spinal muscular atrophy; - a pain disorder, such as, for example, neuralgia, trigeminal neuralgia, chronic pain, inflammatory pain, pain associated with arthritis, fibromyalgia, back pain, cancer- associated pain, pain associated with digestive disease, pain associated with Crohn’s disease, pain associated with autoimmune disease, pain associated with endocrine disease, pain associated with diabetic neuropathy, phantom limb pain, spontaneous pain, chronic post-surgical pain, chronic, temporomandibular pain, causalgia, post-herpetic neuralgia, AIDS-related pain, complex regional pain syndromes type I and II, trigeminal neuralgia, chronic back pain, pain associated with spinal cord injury, pain associated with drug intake and recurrent acute pain, neuropathic pain, or inappropriate neuronal activity resulting in neurodysthesia in a disease such as diabetes, an MS and a motor neuron disease; - an ophthalmic disease or an ocular disorder such as, for example, a retinal disorder, retinal neurodegenerative diseases, Retinitis Pigmentosa, Non-Arthritic Anterior Ischemic Optic Neuropathy (NAION), macular degeneration, age-related macular degeneration, glaucoma, diabetic retinopathy, optic neuropathy and retinal degeneration, neuro-ophthalmic diseases, age-related cataract, primary open-angle glaucoma (POAG), retinal ganglion cell damage, ocular hypertension, ischemic optic neuropathy, macular telangiectasia, cystoid macular edema, Macular Telangiectasia Type 2, neurotrophic keratitis, or strabismus; - a disorder of the enteric system or a gastro-intestinal disorder, such as, for example, a disorder of intestinal motility, constipation, Hirschsprung’s disease, Inflammatory Bowel Disease, Intestinal Neuronal Dysplasia, ulcerative colitis, Achalasia, Esophageal spasm, duodenal ulcer, Zollinger-Ellison Syndrome, hypersecretion of gastric acid, malabsorptive disorder or intestinal inflammation; - a progressive muscular dystrophy, such as, for example, Duchenne, Becker, Emery- Dreifuss, Landowy-Dejerine, scapulohumeral, limb-girdle, Von Graefe-Fuchs, oculopharyngeal, myotonic and congenital, a congenital or acquired myopathy,Charcot-Marie-Tooth disease, Werdnig-Hoffmann disease, or chronic proximal spinal muscular atrophy; - a disease or a disorder associated with defective long-term or short-term memory, such as, for example, memory loss, benign forgetfulness, or Alzheimer’s disease; - an autoimmune disorder such as, for example, multiple sclerosis, autoimmune encephalomyelitis, autoimmune encephalitis, autoimmune hemolytic anemia, chronic lymphocytic leukemia, Churg-Strauss syndrome, anti-N-methyl-D- aspartate receptor (NMDAR) encephalitis, Thyroid-associated orbitopathy, autoimmune thyroiditis, Guillain-Barré syndrome, or autoimmune thrombocytopenic purpura; - a neuro-ontological disease or disorder such as, for example, cochlear sensory cell damage, defective auditory perception, hearing loss, or tinnitus; - a sleep disorder, such as, for example, narcolepsy, restless leg syndrome, Obstructive sleep apnea, chronic insomnia disorder, paradoxical sleep deprivation or REM sleep deprivation; - a cerebrovascular disease or a neurovascular disease, such as, for example, early brain injury (EBI) after subarachnoid hemorrhage (SAH), cerebral ischemia, stroke, hypoxic-ischemic brain injury, perinatal arterial ischemic stroke, or neovascular Age-related macular degeneration (nvAMD); - a substance abuse disorder, such as, for example, substance dependence, substance abuse and the sequalae of substance abuse dependence, substance-induced psychological disorder, substance withdrawal and substance-induced dementia or amnestic disorder; - a neuronal reaction to viral infection, Trypanosoma infection, a neurological deficit associated with AIDS, obesity, temporomandibular joint dysfunction, aphasia, Bell’s palsy, encephalitis, a kidney disease or renal dysfunction, phaeochromocytoma, a metabolic syndrome, cancer, eczema, thrombocytopenia; hypoplasia; disseminated intravascular coagulation (DIC); myelodysplasia; immune thrombocytopenic purpura (ITP), HIV induced ITP, a neuro-oncologicaldisease or disorder, neuro-immunological disease or disorder, multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), type I neurofibromatosis, Scleroderma, an epidermal and stromal wound healing disorder and / or a scarring disorder; or - a disease or disorder associated with aging and / or senescence.

[0111] According to one embodiment, the neurological disorder is epilepsy, such as, for example, Dravet syndrome, benign Rolandic epilepsy, frontal lobe epilepsy, infantile spasms, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy, childhood absence epilepsy (e.g., pyknolepsy), febrile seizures, progressive myoclonus epilepsy of Lafora, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, Generalized Epilepsy with Febrile Seizures (GEFS+), Severe Myoclonic, Epilepsy of Infancy (SMEI), Benign Neonatal Familial Convulsions (BFNC), West Syndrome, Ohtahara Syndrome, early myoclonic encephalopathies, migrating partial epilepsy, infantile epileptic encephalopathies, Tuberous Sclerosis Complex (TSC), focal cortical dysplasia, Type I Lissencephaly, Miller-Dieker Syndrome, Angelman’s syndrome, Fragile X syndrome, epilepsy in autism spectrum disorders, epilepsy in subcortical band heterotopia, epilepsy in Walker-Warburg syndrome, epilepsy in Alzheimer’s disease, post-traumatic epilepsy, progressive myoclonus epilepsies, reflex epilepsy, Rasmussen’s syndrome, temporal lobe epilepsy, limbic epilepsy, status epilepticus, abdominal epilepsy, massive bilateral myoclonus, catamenial epilepsy, Jacksonian seizure disorder, Unverricht-Lundborg disease, or photosensitive epilepsy.

[0112] According to one embodiment, the composition or the medicament according to the invention, as described herein, is to be administered to a subject, and may be formulated using methods well-known in the art. Non-limiting examples of forms adapted for administration include solutions (such as, for example, sterile aqueous solutions), gels, dispersions, emulsions, suspensions and solid forms suitable for using to prepare solutions or suspensions upon the addition of a liquid prior to use (such as, for example, powder or liposomal forms).

[0113] The composition or the medicament according to the invention, as described herein, may be administered using administration route well-known in the art such as, for example, parenterally, orally, by inhalation, spray, rectally, nasally, or via an implanted reservoir.

[0114] It will be however understood that the total daily usage of the compound, the composition or the medicament will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disease being treated and the severity of the disease; activity of the compound employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific therapeutic agent employed; the duration of the treatment; drugs used in combination or coincidental with the specific therapeutic agent employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. The total dose required for each treatment may be administered by multiple doses or in a single dose.

[0115] In one embodiment, the dosage of the compound is about 0.01 to 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg / kg per day; more preferably about 0.5 to about 100 mg / kg per day. A suitable dosage level may be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dosage may be about 0.05 to 0.5, about 0.5 to 5 or about 5 to 50 mg / kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing from about 1.0 to 1000 milligrams of the active ingredient, particularly about 1.0, about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, and about 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[0116] According to a first embodiment, the composition or the medicament according to the invention, as described herein, is to be administered as sole therapeutic agent. According to a second embodiment, the composition or the medicament according to the invention, as described herein, is to be administered before at least another therapeutic agent, concomitantly with at least another therapeutic agent, and / or after at least another therapeutic agent. In one embodiment, the other therapeutic agent is suitable for treating a neurological disorder.

[0117] Another object of the present invention is a method of promoting neuronal cell’s survival and / or neuronal cell’s functions. Another object of the present invention is a compound or a composition according to the invention, as described herein, for use in promoting neuronal cell’s survival and / or neuronal cell’s functions. According to one embodiment, the method or the use comprises a step of contacting a neuronal cell with a therapeutically effective amount of a compound, a composition or a medicament according to the invention, as described herein. The method or the use may be in vitro, ex vivo or in vivo.

[0118] Another object of the present invention is a method of rescuing neuronal cell’s functions after the neuronal cell has been subjected to insults, events, or conditions detrimental to neuronal cell’s functions. Another object of the present invention is a compound or a composition according to the invention, as described herein, for use in rescuing neuronal cell’s functions after the neuronal cell has been subjected to insults, events, or conditions detrimental to neuronal cell’s functions. Such insults, events, or conditions include, without limitation, neuronal stress, for instance, caused by hypoxia or ischemia; traumatic injuries; and exposure to toxic molecules, for instance, to abnormal misfolded proteins, protein aggregates, excitotoxins, reactive oxygen species,endoplasmic reticulum stressors, mitochondrial stressors, Golgi apparatus antagonists and the like. According to one embodiment, the method or the use comprises a step of contacting a neuronal cell with a therapeutically effective amount of a compound, a composition or a medicament according to the invention, as described herein. The method or the use may be in vitro, ex vivo or in vivo.

[0119] Another object of the present invention is a method of binding or modulating GFRα1 using a compound or a composition according to the invention, as described herein. Another object of the present invention is a compound or a composition according to the invention, as described herein, for binding or modulating GFRα1. According to one preferred embodiment, the compound or a composition is for activating GFRα1. In one embodiment, GFRα1 is human GFRα1, preferably with SEQ ID NO: 1.

[0120] Another object of the present invention is a method of activating the GFRα1 / RET signaling pathway using a compound or a composition according to the invention, as described herein. Another object of the present invention is a compound or a composition according to the invention, as described herein, for activating the GFRα1 / RET signaling pathway.

[0121] Another object of the present invention is a method of detecting GFRα1 in a sample, using a compound or a composition according to the invention, as described herein. Another object of the present invention is a compound or a composition according to the invention, as described herein, for detecting GFRα1 in a sample. In one embodiment, GFRα1 is human GFRα1, preferably with SEQ ID NO: 1. In one embodiment, the compound according to the invention may be fused to a detectable label, such as, e.g., a fluorophore or any other moiety that can re-emit light upon light excitation, a radiolabel, a contrast agent and the like. Manufacturing process Synthesis of the compound

[0122] The compound according to the invention, as described herein, may be manufactured by means of synthetic methods well-known in the art.

[0123] Another object of the present invention is a process for manufacturing a compound of the invention, as described herein. According to one embodiment, the process is a Buchwald-Hartwig amination.

[0124] According to one aspect of the present invention, the compound according to the invention is manufactured starting from a compound of formula (II)wherein A1-A5and R10are as defined under formula (I) herein and X represents halide or -CF3SO3.

[0125] The compound of formula (II) herein may be manufactured by means of synthetic methods well-known in the art.

[0126] According to one embodiment, the process comprises a step of reaction of: a compound of formula (II)wherein A1-A5and R10are as defined under formula (I) herein and X represents halide or -CF3SO3, with a compound of formula (III)wherein W, RA-RDand R1-R4are as defined under formula (I) herein, in presence of a base and a metal catalyst; thereby obtaining the compound of the invention.

[0127] The base may be any suitable base known in the art. In one embodiment, the base is cesium carbonate (Cs2CO3), sodium carbonate (Na2CO3) or potassium carbonate (K2CO3). In one particular embodiment, the base is cesium carbonate (Cs2CO3). In one embodiment, the base is sodium tert-butanoate (t-BuONa), potassium tert-butanoate (t- BuOK) or potassium phosphate. In one particular embodiment, the base is sodium tert-butanoate (t-BuONa). The catalyst may be any suitable catalyst known in the art. In one embodiment, the catalyst is a palladium catalyst. In one particular embodiment, the catalyst is a Pd(OAc)2 and rac-BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphtyle) system. In one particular embodiment, the catalyst is XPhos-Pd-G3. In one embodiment, X represents halide. In one particular embodiment, X represents Br. In one embodiment, the reaction is carried out in a solvent. The solvent may be any suitable solvent known in the art. In one particular embodiment, the solvent is toluene. In one embodiment, the reaction is carried out at reflux.

[0128] According to another embodiment, the process comprises: (a’-1) a step of reaction of a compound of formula (II)wherein A1-A5and R10are as defined under formula (I) herein and X represents halide or -CF3SO3, with a mono-protected piperazine (i.e., a piperazine wherein only one of the NH groups is protected by means of a protecting group RP) of the following formula (MPP),wherein R1-R4are as defined under formula (I) herein; in presence of a base and a metal catalyst; thereby obtaining a compound of formula (IV)wherein R1-R4, A1-A5and R10are as defined under formula (I) herein and RPis the protecting group; then (a’-2) a step of deprotection of the compound of formula (IV); thereby obtaining a compound of formula (V)wherein R1-R4, A1-A5and R10are as defined under formula (I) herein; and (a’-3) a step of reaction of the compound of formula (V) with a compound of formula (VI)wherein W and RA-RDare as defined under formula (I) herein, in presence of a peptide coupling agent and a base; thereby obtaining the compound of the invention.

[0129] In one embodiment, the base and / or the catalyst at step (a’-1) are as described hereinabove under step (a-1). In one embodiment, X represents halide. In one particular embodiment, X represents Br. The protecting group (RP) may be any suitable protecting group known in the art such as, for example, tert-butyloxycarbonyl (Boc). The protective group may be removed at step (a’-2) by any method known in the art appropriate to the nature of the protective group, such as, for example, addition of a strong Bronsted acid (e.g., hydrochloric acid [HCl]). The peptide coupling agent at step (a’-3) may be any suitable peptide coupling agent known in the art such as, for example, 2-(1H- benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU). The base at step (a’-3) may be any suitable base known in the art such as, for example, an amine base. According to one embodiment, the amine is triethylamine (Et3N) or diisopropylethylamine (iPr2NEt). In one embodiment, the reaction at step (a’-3) is carried out in a solvent. The solvent may be any suitable solvent known in the art. In one particular embodiment, the solvent is dimethylformamide (DMF) and / or tetrahydrofuran (THF). In one particular embodiment, the solvent is dichloroethane (DCE) and / or acetonitrile (MeCN). In one embodiment, the reaction is carried out at room temperature (RT).

[0130] In one embodiment, the process further comprises a work-up step (b). In one embodiment, the work-up step (b) comprises a step of extraction by a solvent. In one particular embodiment, the solvent is ethyl acetate (EtOAc). In one particular embodiment, the solvent is water or a 1N HCl solution. In one particular embodiment, the solvent is dichloromethane (DCM). In one embodiment, the work-up step (b) comprises a step of filtration. In one particular embodiment, the filtration is over Celite® In one embodiment, the work-up step (b) comprises a step of concentration under reduced pressure. In one embodiment, the process further comprises a purification step (c). The purification may be any suitable purification method known in the art. In one embodiment, the purification step (c) comprises a purification by chromatography. In one particular embodiment, the chromatography is flash chromatography (FC) (e.g., cHex / EtOAc gradient), preparative thin-layer chromatography (PTLC) or semi-preparative high-performance liquid chromatography (HPLC).

[0131] According to another aspect of the present invention, the compound according to the invention is manufactured starting from a compound of formula (VII)wherein W, RA-RD, R1-R4, R10and R12are as defined under formula (I) herein.

[0132] This aspect is especially relevant to the manufacture of a compound according to the invention wherein A1represents N, A2represents C, A3represents CH, A4represents N, A4represents CR12.

[0133] According to one embodiment, the process comprises a step of reaction of a compound of formula (VII)wherein W, RA-RD, R1-R4, R10and R12are as defined under formula (I) herein; in presence of a dehydrating agent; thereby obtaining the compound of the invention.

[0134] The dehydrating agent may be any suitable dehydrating agent known in the art such as, for example, acetic anhydride (Ac2O) or phosphorous oxychloride (POCl3). In one embodiment, the dehydrating agent is phosphorous oxychloride (POCl3).

[0135] The compound of formula (VII) herein may be manufactured by means of synthetic methods well-known in the art.

[0136] According to one embodiment, the compound of formula (VII) herein is manufactured by reaction of a compound of formula (VIII)wherein W, RA-RD, R1-R4and R10are as defined under formula (I) herein,with a compound of formula R12-C(=O)-LG, wherein R12is as defined under formula (I) herein and LG (which is a “Leaving Group”) is as defined hereinafter, in one of the following conditions: (i) LG represents ethoxy (-OCH2CH3) and R12represents hydrogen (preferably, at a temperature of at least about 60°C); (ii) LG represents Cl, in presence of a base; or (iii) LG represents OH in presence of a peptide coupling agent.

[0137] The base may be any suitable base known in the art such as, for example, N,N-diisopropylethylamine (DIPEA) or triethylamine (Et3N). The peptide coupling agent (or “amide bond formation reagent”) may be any suitable peptide coupling agent known in the art such as, for example, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) or 2-(2-Pyridon-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU).

[0138] The compound of formula (VIII) herein may be manufactured by means of synthetic methods well-known in the art.

[0139] According to one embodiment, the compound of formula (VIII) herein is manufactured by a process comprising the following steps: (a) reaction of a compound of formula (IX)wherein W, RA-RD, R1-R4and R10are as defined under formula (I) herein,with a compound of formula RPHN-CH2-BF3K, wherein RPrepresents a protecting group, in presence of a palladium complex and a base; then (b) a deprotection step.

[0140] The palladium complex may be any suitable palladium complex known in the art such as, for example, di(1-adamantyl)-n-butylphosphine (CatacXium-Pd-G3). The base may be any suitable base known in the art such as, for example, cesium carbonate (Cs2CO3). The protecting group (RP) may be any suitable protecting group known in the art such as, for example, tert-butyloxycarbonyl (Boc). The deprotection step may, for example, be carried out by chlorohydric acid (HCl) in dioxane.

[0141] The compound of formula (IX) herein may be manufactured by means of synthetic methods well-known in the art.

[0142] According to one embodiment, the compound of formula (IX) herein is manufactured by reaction of a compound of formula (X)wherein R10is as defined under formula (I) herein, with a compound of formula (III)wherein W, RA-RDand R1-R4are as defined under formula (I) herein, in presence of a base.

[0143] The base may be any suitable base known in the art such as, for example, N,N-diisopropylethylamine (DIPEA). Synthetic intermediates

[0144] Another object of the present invention is a compound of formula (II)wherein A1-A5and R10are as defined under formula (I) herein and X represents halide or -CF3SO3.

[0145] Another object of the present invention is a compound of formula (III)wherein W, RA-RDand R1-R4are as defined under formula (I) herein.

[0146] Another object of the present invention is a compound of formula (IV)wherein R1-R4, A1-A5and R10are as defined under formula (I) herein and RPrepresents a protecting group (e.g., Boc).

[0147] Another object of the present invention is a compound of formula (V)wherein R1-R4, A1-A5and R10are as defined under formula (I) herein.

[0148] Another object of the present invention is a compound of formula (VII)wherein W, RA-RD, R1-R4, R10and R12are as defined under formula (I) herein.

[0149] Another object of the present invention is a compound of formula (VIII)wherein W, RA-RD, R1-R4and R10are as defined under formula (I) herein.

[0150] Another object of the present invention is a compound of formula (IX)wherein W, RA-RD, R1-R4and R10are as defined under formula (I) herein. EXAMPLES

[0151] The present invention is further illustrated by the following examples. Example 1: Synthesis of the compounds General material and methods Abbreviations

[0152] List of abbreviations: Ac: acetyl Ar: argon BINAP: (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) cataCXium: di(1-adamantyl)-n-butylphosphine cPr: cyclopropane cHex: cyclohexane dba: (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one DCM: dichloromethane DCE: 1,2-dichloroethane DMAP: 4-dimethylaminopyridine DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DMF: dimethylformamide Et: ethylFC: flash chromatography m-CPBA: meta-chloroperbenzoic acid PTLC: preparative thin-layer chromatography RP-FC: reverse phase flash chromatography RT: room temperature TBAF: tetrabutylammonium fluoride TBTU: 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate TFA: trifluoroacetic acid THF: tetrahydrofuran XantPhos : 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos: dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′-biphenyl]-2-yl]phosphane Analytical methods

[0153] 1H NMR spectra (400 MHz) and19F NMR spectra (376 MHz) were recorded with a Bruker ULTRASHIELD 400 spectrometer. Processing and analyses of the spectra were performed with MestReNova. Data appear in the following order: chemical shifts in ppm which were referenced to the internal solvent signal, multiplicity, coupling constant J in Hertz and number of protons.

[0154] Reversed-phase HPLC / MS analyses were carried out with a Waters Alliance 2795 HPLC equipped with an autosampler, an inline membrane degasser, a column oven 10 (T° = 45 °C), a UV detector, and a ZQ quadrupole mass detector working in ionization electrospray mode. Analyzed compounds (0.1 to 0.3 mg) were solubilized in a minimum amount of DMSO completed with acetonitrile (total volume: 1 mL). Standard analytical parameters: flow rate: 1 mL / min, Vinj.: 5μL. Acidic conditions: Waters XSelect CSH C18 column (3.5μm, 2.1x 1550 mm). Gradient: (H2O + 0.04% v / v HCO2H (10mM)) / ACN from 95 / 5 to 0 / 100 in 2.5 min. Alkaline conditions: Waters Xbridge C18 column (3.5μm, 2.1x 50 mm). Gradient: (H2O + 0.06% v / v NH3 (aq.) (10mM)) / ACN from 95 / 5 to 0 / 100 in 2.5 min.General synthetic methods General protocol 1 (GP-1): Palladium-catalyzed coupling of thiol and aryl halide

[0155] A MW was charged with the required aryl halide and XantPhos-Pd-G3. The vial was flushed with Ar and the required degassed solvent was added. iPr2NEt and the required thiol were added. The vial was sealed and the mixture was stirred at 100°C for the required time. After cooling down to RT, the RM was concentrated under reduced pressure and the residue. The residue was purified by FC (cHex / EtOAc gradient) to afford the required thioether. General protocol 2 (GP-2): Thioether oxidation

[0156] To a solution of thioether in DCM at 0°C, was added m-CPBA. The mixture was stirred at RT for the required time. Aq. Sat. Na2S2O3, aq. sat. NaHCO3 and EtOAc were added. The mixture was vigorously stirred for 10 min. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was optionally purified by FC (cHex / EtOAc gradient) to afford the required sulfone. General protocol 3 (GP-3): Hartwig-Buchwald coupling using Pd(OAc)2 / rac-BINAP or palladium precomplex

[0157] A microwave reaction vial was charged with the required arylbromide; the required piperazine; Cs2CO3, NaOt-Bu or LiHMDS (1M solution in THF); Pd(OAc)2and rac-BINAP or the required palladium precomplex. The vial was flushed with argon and the degassed solvent was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating-block for the required time. After cooling down to RT, EtOAc was added and the suspension was filtered over Celite® (EtOAc rinses). The filtrate was concentrated under reduced pressure. The residue was purified by FC or PTLC to afford the required product. General protocol 4 (GP-4): Sulfonamide formation

[0158] To a solution of the required amine and Et3N or iPr2NEt in the required solvent, was added a solution of the required sulfonyl chloride in the same solvent at RT. The reaction mixture was stirred at RT for the required time. The reaction mixture waspartitioned between EtOAc and aq. sat. NH4Cl. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (aq. sat. NH4Cl, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc gradient) or PTLC to afford the required product. Synthesis of intermediate compounds

[0159] tert-butyl 4-(2-chloro-4-fluoro-benzoyl)piperazine-1-carboxylate (Boc-I-001)Formula Weight: 342,79 Molecular Formula: C16H20ClFN2O3To a solution of 2-chloro-4-fluorobenzoic acid (5.00g, 28.6mmol, 1 equiv.) in THF (89mL) at RT, was added TBTU (9.20g, 28.6mmol, 1 equiv.). The mixture was stirred 15min at RT, and a solution of tert-butyl piperazine-1-carboxylate (6.40g, 34.4mmol, 1.2 equiv.) and Et3N (6.0mL, 43mmol, 1.5 equiv.) in THF (30mL) was added dropwise. The mixture was stirred at RT for 60h. The reaction mixture was concentrated under reduced pressure. The reaction mixture was partitioned between 1N HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc(2*). The combined organic extracts were washed (aq. 1N HCl, aq. sat. NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 10.2g of Boc-I-001 (100%) as an orange oil.1H NMR (400 MHz, Chloroform-d) δ 7.32-7.29 (m, 1H), 7.18 (dd, J = 8.5, 2.5 Hz, 1H), 7.07 (td, J = 8.3, 2.5 Hz, 1H), 3.92-3.79 (m, 1H), 3.73 (dt, J = 13.2, 5.7 Hz, 1H), 3.63-3.50 (m, 2H), 3.48-3.34 (m, 2H), 3.34-3.10 (m, 2H), 1.48 (s, 9H). MS (ESI+): [M+H]+343.1 / 345.1.

[0160] (2-chloro-4-fluoro-phenyl)-piperazin-1-yl-methanone (I-001)Formula Weight: 242,68 Molecular Formula: C11H12ClFN2O To a solution of crude Boc-I-001 (10.2g, 28.6mmol, 1 equiv.) in dioxane (37 mL) at RT, was added HCl (4M solution in dioxane, 37mL, 148 mmol, 5 equiv.). The mixture was stirred at RT for 16h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM. K2CO3(s) was added portionwise until pH >11. The layers were separated and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (80g column, dry load, DCM / MeOH = 98 / 2 to 80 / 20) to afford 5.24g of I-001 (72%) as an orange solid.1H NMR (400 MHz, Chloroform-d) δ 7.41 (dd, J = 8.8, 2.4 Hz, 1H), 7.32 (qd, J = 8.4, 5.6 Hz, 2H), 3.87-3.69 (m, 2H), 3.15 (t, J = 5.1 Hz, 2H), 2.94 (t, J = 5.2 Hz, 2H), 2.80 – 2.70 (m, 2H). MS (ESI+): [M+H]+243.1 / 245.1.

[0161] tert-butyl 3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Boc-I-002)Formula Weight: 368,83 Molecular Formula: C18H22ClFN2O3To a solution of 2-chloro-4-fluorobenzoic acid (9.87g, 56.5mmol, 1.2 equiv.) in DMF (118mL) at RT, was added TBTU (18.1g, 56.5mmol, 1.2 equiv.). The mixture was stirred 15min at RT, and a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10.0g, 47.1mmol, 1 equiv.) and Et3N (9.8mL, 71mmol, 1.5 equiv.) in THF (118mL) was added dropwise. The mixture was stirred at RT for 16h. The reaction mixture was concentrated under reduced pressure. The reaction mixture was partitioned between aq. sat. NH4Cl and EtOAc. The layers were separated and the aqueous phase was extractedwith EtOAc(2*). The combined organic extracts were washed (aq. sat. NH4Cl, aq. sat. NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 21.3g of Boc-I-002 (76% purity, 93%) as an orange oil.1H NMR (400 MHz, Chloroform-d) δ 7.33 (dd, J = 8.5, 5.9 Hz, 0.5H), 7.23-7.09 (m, 1.5H), 7.09-6.97 (m, 1H), 4.54-4.40 (m, 1H), 4.33 (s, 1H), 4.23-4.01 (m, 1H), 3.56-3.17 (m, 1H), 3.17-2.93 (m, 2H), 2.11-1.70 (m, 4H), 1.47 (s, 9H). MS (ESI+): [M+H]+369.1 / 371.1.

[0162] (2-chloro-4-fluoro-phenyl)-(3,8-diazabicyclo[3.2.1]octan-3-yl)methanone (I-002)Formula Weight: 268,71 Molecular Formula: C13H14ClFN2O To a solution Boc-I-002 (21.3g, 76% pure, 43.9mmol, 1 equiv.) in dioxane (55 mL) at RT, was added HCl (4M solution in dioxane, 55mL, 220 mmol, 5 equiv.). The mixture was stirred at RT for 60h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM. K2CO3(s) was added portionwise until pH >11. The layers were separated and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (220g column, dry load, DCM / MeOH (7N NH3) = 99 / 1 to 95 / 5) to afford 10.3g of I-002 (88%) as a white solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.32 (dd, J = 8.5, 5.9 Hz, 0.5H), 7.20-7.15 (m, 0.5H), 7.15-7.10 (m, 1H), 7.09-6.98 (m, 1H), 4.47-4.37 (m, 1H), 3.69-3.56 (m, 1H), 3.44-3.34 (m, 1.5H), 3.22 (d, J = 11.9 Hz, 0.5H), 3.10-2.98 (m, 2H), 1.95-1.48 (m, 4H). MS (ESI+): [M+H]+269.1 / 271.0.

[0163] tert-butyl (2S)-4-(2-chloro-4-fluoro-benzoyl)-2-methyl-piperazine-1- carboxylate (Boc-I-003)Formula Weight: 356,82 Molecular Formula: C17H22ClFN2O3To a solution of 2-chloro-4-fluorobenzoic acid (2.09g, 12.0mmol, 1.2 equiv.) in THF (20mL) at RT, was added TBTU (3.85g, 12.0mmol, 1 equiv.). The mixture was stirred 15min at RT, and a solution of tert-butyl (S)-2-methylpiperazine-1-carboxylate (2.00g, 99.9mmol, 1 equiv.) and Et3N (2.1mL, 15mmol, 1.5 equiv.) in DMF (20mL) was added dropwise. The mixture was stirred at RT for 16h. The reaction mixture was concentrated under reduced pressure. The reaction mixture was partitioned between aq. 1N HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc(2*). The combined organic extracts were washed (aq.1N HCl, aq. sat. NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (80g column, dry load, cHex / EtOAc = 90 / 10 to 50 / 50) to afford 3.56g of Boc-I-003 (98%) as a colorless oil.1H NMR (400 MHz, Chloroform-d, multiple sets of rotamers) δ 7.36-7.21 (m, 1H), 7.20-7.09 (m, 1H), 7.08-6.97 (m, 1H), 4.67-4.13 (m, 2H), 3.99-3.74 (m, 1H), 3.41-3.23 (m, 1H), 3.23-2.83 (m, 3H), 1.44 (s, 9H), 1.29-0.97 (m, 3H). MS (ESI+): [M+H]+357.0 / 359.0.

[0164] (2-chloro-4-fluoro-phenyl)-[(3S)-3-methylpiperazin-1-yl]methanone (I-003)Formula Weight: 256,7 Molecular Formula: C12H14ClFN2O To a solution of Boc-I-003 (3.50g, 9.79mmol, 1 equiv.) in DCM (49mL) at 0°C, was added HCl (4N solution in dioxane, 24mL, 98mmol, 10 equiv.). The mixture was stirredat RT for 16h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM at 0°C. K2CO3(s) was added portionwise until pH >11. The layers were separated and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na2SO4), filtered and concentrated underequiv.) and Et3N (0.86mL, 6.2mmol, 1.5 equiv.). The mixture was stirred at RT for 16h. The reaction mixture was partitioned between EtOAc and aq. sat. NH4Cl. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washes (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, cHex / DCM (50 / 50) / EtOAc = 97 / 3 to 70 / 30) to afford 1.60g of I-004 (92% purity, 86%) as a beige solid.1H NMR (400 MHz, Chloroform-d) δ 8.73 (d, J = 2.1 Hz, 1H), 8.31 (d, J = 2.2 Hz, 1H), 7.38 – 7.30 (m, 2H), 7.28 – 7.22 (m, 1H), 7.22 – 7.14 (m, 2H), 4.04 – 3.97 (m, 2H), 2.57 – 2.47 (m, 3H), 2.04 – 1.82 (m, 4H). MS (ESI+): [M+H]+415.0 / 417.0 / 419.0.

[0166] 3-bromo-5-[(4-phenyl-1-piperidyl)sulfonyl]pyridin-2-amine (I-005)Formula Weight: 396,3 Molecular Formula: C16H18BrN3O2S To a suspension of I-004 (500mg, 1.11mmol, 1 equiv.) in THF (2.5mL) at RT, was added 28% aq. NH4OH (1mL). The mixture was stirred at 100°C under MW irradiation for 3h. The reaction mixture was concentrated under reduced pressure to afford 0.51g of I-005 (85% purity, 99%) as a yellow solid.1H NMR (400 MHz, Chloroform-d) δ 8.41 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.35 – 7.25 (m, 2H), 7.22 (t, J = 7.2 Hz, 1H), 7.19 – 7.13 (m, 2H), 5.48 (s, 2H), 3.97 – 3.85 (m, 2H), 2.55 – 2.32 (m, 3H), 2.55 – 2.35 (m, 4H). MS (ESI+): [M+H]+395.9 / 397.9.

[0167] 8-bromo-6-[(4-phenyl-1-piperidyl)sulfonyl]imidazo[1,2-a]pyridine (I-006)Formula Weight: 420,32 Molecular Formula: C18H18BrN3O2S To a solution of I-005 (256mg, 85% purity, 549µmol, 1 equiv.) in EtOH (2.5mL) at RT, were added Na2CO3 (116mg, 1.10mmol, 2 equiv.) and chloroacetaldehyde (50% in water, 349µL, 2.74mmol, 5 equiv.) and the mixture was stirred at 80°C for 16h. More Na2CO3 (116mg, 1.10mmol, 2 equiv.) and chloroacetaldehyde (50% in water, 349µL, 2.74mmol, 5 equiv.) were added and the mixture was stirred a further 24h at 80°C. The reaction mixture was filtered over fritted glass and the filtrate was concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 95 / 5 to 50 / 50) to afford 52mg of I-006 (23%) as a white solid.1H NMR (400 MHz, Chloroform- d) δ 8.64 (d, J = 1.6 Hz, 1H), 7.78 (d, J = 1.3 Hz, 1H), 7.75 (d, J = 1.3 Hz, 1H), 7.64 (d,J = 1.5 Hz, 1H), 7.27 – 7.20 (m, 2H), 7.18 – 7.12 (m, 1H), 7.12 – 7.07 (m, 2H), 3.98 – 3.88 (m, 2H), 2.59 – 2.37 (m, 3H), 1.94 – 1.73 (m, 4H). MS (ESI+): [M+H]+420.0 / 422.0.

[0168] 8-bromo-6-[(4-phenyl-1-piperidyl)sulfonyl]-[1,2,4]triazolo[1,5-a]pyridine (I-007)Formula Weight: 421,31 Molecular Formula: C17H17BrN4O2S To a solution of I-005 (256mg, 85% purity, 549µmol, 1 equiv.) in dry DMF (1mL) at RT, was added N,N-dimethylformamide dimethyl acetal (272µL, 2.05mmol, 3.7 equiv.). The mixture was stirred at 130°C for 15min and then concentrated under reduced pressure. The residue was dissolved in MeOH (1.4mL) and pyridine (103µL, 1.28mmol, 2.3 equiv.) at 0°C. Hydroxylamine-O-sulfonic acid (101mg, 0.897mmol, 1.6 equiv.) was added. After stirring at RT for 16h, sat. aq. NaHCO3(5mL) and water (5mL) were added and the mixture was stirred at RT for 1h. The suspension was filtered over fritted glass and the filter cake was washed (1mL water), collected and azeotroped with toluene. The residue was dissolved in THF (3.2mL) at 0°C, and trifluoroacetic anhydride (0.27mL, 1.9mmol, 3.4 equiv.) was added dropwise. The mixture was stirred at RT for 16h. The reaction mixture was partitioned between EtOAc and aq. sat. NaHCO3. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washes (aq. sat. NaHCO3,brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 95 / 5 to 50 / 50) and then FC (24g column, dry load, DCM / EtOAc = 98 / 2 to 80 / 20) to afford 132mg of I-007 (49%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 9.03 (d, J = 1.5 Hz, 1H), 8.47 (s, 1H), 7.97 (d, J = 1.5 Hz, 1H), 7.29 – 7.21 (m, 2H), 7.18 – 7.13 (m, 1H), 7.12 – 7.05 (m, 2H), 4.03 – 3.91 (m, 2H), 2.53 (td, J = 11.9, 2.8 Hz, 2H), 2.45 (tt, J = 12.0, 3.9 Hz, 1H), 1.98 – 1.73 (m, 4H). MS (ESI+): [M+H]+421.0 / 422.9.

[0169] 3-bromo-2-chloro-5-(2,2-dimethylpropylsulfanyl)pyridine (I-008)Formula Weight: 294,64 Molecular Formula: C10H13BrClNS Using GP-1, I-008 was obtained as a light yellow oil in 94% yield using 3-bromo-2-chloro-5-iodopyridine (600mg, 1.88mmol, 1 equiv.), XantPhos-Pd-G3 (36mg, 38µmol, 0.02 equiv.), iPr2NEt (0.49mL, 2.8mmol, 1.5 equiv.) and 2,2- dimethylpropane-1-thiol (236µL, 1.88mmol, 1 equiv.) in dioxane (7.5mL) at 100°C for 1h. Purification by FC (cHex / EtOAc = 99 / 1 to 90 / 10).1H NMR (400 MHz, Chloroform- d) δ 8.24 (d, J = 2.2 Hz, 1H), 7.84 (d, J = 2.3 Hz, 1H), 2.87 (s, 2H), 1.04 (s, 9H). MS (ESI+): [M+H]+294.0 / 296.0 / 298.0.

[0170] 3-bromo-2-chloro-5-(2,2-dimethylpropylsulfonyl)pyridine (I-009)Formula Weight: 326,64 Molecular Formula: C10H13BrClNO2S Using GP-2, I-009 was obtained as a colorless oil in 100% yield using I-008 (522mg, 1.77mmol, 1 equiv.) and m-CPBA (70% wet, 961mg, 3.90mmol, 2.2 equiv.) in DCM (9mL) at RT for 2h.1H NMR (400 MHz, Chloroform-d) δ 8.80 (s, 1H), 8.38 (s, 1H), 3.05 (s, 2H), 1.21 (s, 9H). MS (ESI+): [M+H]+326.0 / 327.9 / 330.0.

[0171] 3-bromo-5-(2,2-dimethylpropylsulfonyl)pyridin-2-amine (I-010)Formula Weight: 307,21 Molecular Formula: C10H15BrN2O2S To a suspension of I-009 (350mg, 1.07mmol, 1 equiv.) in dioxane (2.1mL) at RT, was added 28% aq. NH4OH (1.1mL). The mixture was stirred at 100°C under MW irradiationfor 1.5h. The reaction mixture was concentrated under reduced pressure to afford 324mg of I-010 (99%) as a yellow solid.1H NMR (400 MHz, Chloroform-d) δ 8.48 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 5.50 (s, 2H), 3.01 (s, 2H), 1.19 (s, 9H). MS (ESI+): [M+H]+307.1 / 309.0.

[0172] [8-[2-amino-5-(2,2-dimethylpropylsulfonyl)-3-pyridyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-011)Formula Weight: 495,01 Molecular Formula: C23H28ClFN4O3S According to GP-3, I-011 was obtained in 22% yield using aryl bromide I-010 (274mg, 892µmol, 1 equiv.), piperazine I-002 (360mg, 1.34mmol, 1.5 equiv.), LiHMDS (2.23mL, 2.23mmol, 2.5 equiv.) and RuPhos-Pd-G2 (66mg, 89µmol, 0.10 equiv.) in THF (8.9mL) at reflux for 3h. Purification by FC (cHex / EtOAc = 95 / 5 to 0 / 100) and then FC (DCM / MeOH = 99 / 1 to 95 / 5).1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 8.30 (s, 1H), 7.45 – 7.30 (m, 1.5H), 7.27 – 7.03 (m, 2.5H), 5.48 (s, 2H), 4.70 – 4.60 (m, 1H), 3.96 (s, 1H), 3.72 (s, 1H), 3.65 – 3.40 (m, 1H), 3.35 – 3.20 (m, 2H), 3.03 (s, 2H), 2.15 – 1.90 (m, 4H), 1.20 (s, 9H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.71, -108.84. MS (ESI+): [M+H]+495.1 / 497.1.

[0173] 1-[5-[(4-phenyl-1-piperidyl)sulfonyl]indolin-1-yl]ethanone (I-012)Formula Weight: 384,49 Molecular Formula: C21H24N2O3S According to GP-4, I-012 was obtained as a white solid in 90% yield using 1-Acetyl-2,3- dihydro-1H-indole-5-sulfonyl chloride (300mg, 1.15mmol, 1 equiv.), 4-phenylpiperidine(223mg, 1.39mmol, 1.2 equiv.) and Et3N (480µL, 3.46mmol, 3 equiv.) in DCM (5.8mL) at RT for 16h. Purification by FC (DCM / EtOAc = 100 / 0 to 40 / 60).1H NMR (400 MHz, Chloroform-d) δ 8.34 (d, J = 8.5 Hz, 1H), 7.64 (dd, J = 8.6, 1.9 Hz, 1H), 7.59 (d, J = 1.9 Hz, 1H), 7.29 (dd, J = 8.2, 6.7 Hz, 2H), 7.24 – 7.17 (m, 1H), 7.17 – 7.11 (m, 2H), 4.16 (t, J = 8.6 Hz, 2H), 3.95 – 3.85 (m, 2H), 3.28 (t, J = 8.6 Hz, 2H), 2.46 – 2.30 (m, 3H), 2.27 (s, 3H), 1.94 – 1.73 (m, 4H). MS (ESI+): [M+H]+385.0.

[0174] 5-[(4-phenyl-1-piperidyl)sulfonyl]indoline (I-013)Formula Weight: 342,46 Molecular Formula: C19H22N2O2S To a solution of I-012 (400mg, 1.04mmol, 1 equiv.) in THF / MeOH / H2O (4 / 2 / 1, 5mL) at RT, was added NaOH 32% (0.35mL, 5.2mmol, 5 equiv.). The mixture was stirred at reflux for 16h. The volatiles were removed under reduced pressure. The residue was partitioned between water and DCM. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to afford 315mg of I-013 (88%) as a light brown solid.1H NMR (400 MHz, Chloroform-d) δ 7.49 – 7.43 (m, 2H), 7.29 (dd, J = 8.1, 6.7 Hz, 2H), 7.24 – 7.11 (m, 3H), 6.66 – 6.60 (m, 1H), 3.93 – 3.85 (m, 2H), 3.71 (t, J = 8.6 Hz, 2H), 3.11 (t, J = 8.6 Hz, 2H), 2.48 – 2.30 (m, 3H), 1.98 – 1.75 (m, 4H). MS (ESI+): [M+H]+343.1.

[0175] 7-bromo-5-[(4-phenyl-1-piperidyl)sulfonyl]indoline (I-014)Formula Weight: 421,35 Molecular Formula: C19H21BrN2O2STo a solution of I-013 (315mg, 0.92mmol, 1 equiv.) in acetic acid (630µL) at 0°C, was added dropwise a solution of N-bromosuccinimide (246mg, 1.38mmol, 1.5 equiv.) in dioxane (4.6mL). The mixture was stirred at RT for 2h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between 2N NaOH and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, cHex / EtOAc = 95 / 5 to 50 / 50) to afford 303mg of I-014 (78%) as a white solid. MS (ESI+): [M+H]+421.0 / 423.0.

[0176] 7-bromo-5-[(4-phenyl-1-piperidyl)sulfonyl]-1H-indole (I-015)Formula Weight: 419,34 Molecular Formula: C19H19BrN2O2S To a solution of I-014 (303mg, 720µmol, 1 equiv.) in DCM (3.6mL) at RT, was added DDQ (0.21g, 0.93mmol, 1.3 equiv.). The mixture was stirred at RT for 16h and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, cHex / EtOAc = 100 / 0 to 0 / 100) to afford 215mg of I-015 (71%) as an offwhite solid.1H NMR (400 MHz, Chloroform-d) δ 8.67 (s, 1H), 8.12 (s, 1H), 7.82 (d, J = 1.5 Hz, 1H), 7.45 (t, J = 2.8 Hz, 1H), 7.37 – 7.29 (m, 2H), 7.25 – 7.12 (m, 3H), 6.82 (dd, J = 3.3, 2.1 Hz, 1H), 4.05 – 3.95 (m, 2H), 2.45 – 2.30 (m, 3H), 2.00 – 1.80 (m, 4H). MS (ESI+): [M+H]+419.0 / 421.0.

[0177] 2-[[7-bromo-5-[(4-phenyl-1-piperidyl)sulfonyl]indol-1-yl]methoxy]ethyl- trimethyl-silane (I-016)Formula Weight: 549,6 Molecular Formula: C25H33BrN2O3SSi To a solution of I-015 (114mg, 271µmol, 1 equiv.) in dry DMF (1.4mL) at 0°C, was added NaH (60% in mineral oil, 29mg, 0.73mmol, 2.7 equiv.). The mixture was stirred at 0°C for 1h and then 2-(trimethylsilyl)ethoxymethyl chloride (72µL, 0.41mmol, 1.5 equiv.) was added. The mixture was stirred at RT for 2h. The residue was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 95 / 5 to 50 / 50) to afford 149mg of I-016 (100%) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 1.7 Hz, 1H), 7.82 (d, J = 3.3 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.26 (t, J = 7.5 Hz, 2H), 7.21 – 7.11 (m, 3H), 6.82 (d, J = 3.3 Hz, 1H), 5.88 (s, 2H), 3.83 – 3.75 (m, 2H), 3.51 (t, J = 7.9 Hz, 2H), 2.50 – 2.40 (m, 1H), 2.35 – 2.22 (m, 2H), 1.90 – 1.75 (m, 2H), 1.75 – 1.60 (m, 2H), 0.82 (t, J = 7.8 Hz, 2H), -0.10 (s, 9H). MS (ESI+): [M+H]+549.0 / 551.0.

[0178] 1-acetyl-N-tert-butyl-indoline-5-sulfonamide (I-017)Formula Weight: 296,39 Molecular Formula: C14H20N2O3S According to GP-4, I-017 was obtained as a white solid in 93% yield using 1-Acetyl-2,3- dihydro-1H-indole-5-sulfonyl chloride (3.00g, 11.5mmol, 1 equiv.) and tert-butylamine (3.03mL, 28.9mmol, 2.5 equiv.) in DCM (23mL) at RT for 16h.1H NMR (400 MHz,Chloroform-d) δ 8.26 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 4.51 (s, 1H), 4.14 (t, J = 8.6 Hz, 2H), 3.25 (t, J = 8.6 Hz, 2H), 2.25 (s, 3H), 1.22 (s, 9H). MS (ESI+): [M+H]+297.2.

[0179] N-tert-butylindoline-5-sulfonamide (I-018)Formula Weight: 254,35 Molecular Formula: C12H18N2O2S To a solution of I-017 (3.70g, 12.5mmol, 1 equiv.) in THF / MeOH / H2O (1 / 3 / 1, 60mL) at RT, was added NaOH 32% (14.0mL, 151mmol, 12 equiv.). The mixture was stirred at reflux for 2h. The volatiles were removed under reduced pressure. The residue was partitioned between water and DCM. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, cHex / EtOAc = 50 / 50) to afford 2.20g of I-018 (69%) as a light brown solid.1H NMR (400 MHz, Chloroform-d) δ 7.56 – 7.51 (m, 2H), 6.55 (d, J = 7.9 Hz, 1H), 4.38 (s, 1H), 3.66 (t, J = 8.6 Hz, 2H), 3.07 (t, J = 8.6 Hz, 2H), 1.22 (s, 9H). MS (ESI+): [M+H]+254.1.

[0180] 7-bromo-N-tert-butyl-indoline-5-sulfonamide (I-019)Formula Weight: 333,24 Molecular Formula: C12H17BrN2O2S To a solution of I-018 (2.20g, 8.04mmol, 1 equiv.) and acetic acid (2.3mL, 40mmol, 5 equiv.) in dioxane (20mL) at 0°C, was added dropwise a solution of N-bromosuccinimide (1.43g, 8.04mmol, 1 equiv.) in dioxane (20mL). The mixture was stirred at 0°C for 1h.The reaction mixture was concentrated under reduced pressure. The residue was partitioned between 2N NaOH and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue wasTo a solution of I-019 (2.17g, 6.51mmol, 1 equiv.) in DCE (33mL) at RT, was added activated MnO2(2.8g, 33mmol, 5 equiv.). The mixture was stirred at reflux for 16h. More activated MnO2(2.8g, 33mmol, 5 equiv.) was added and the mixture was stirred at reflux a further 24h. The resulting suspension was filtered over Celite (DCM rinses). The filtrateMolecular Formula: C20H23BrN2O3STo a solution of I-020 (200mg, 0.604mol, 1 equiv.) in dry THF (3mL) at 0°C, was added NaH (60% in mineral oil, 48mg, 1.2mmol, 2 equiv.). The mixture was stirred at 0°C for 15min and benzyloxymethyl chloride (84µL, 0.61mmol, 1 equiv.). The mixture was stirred at RT for 16h. The residue was partitioned between water and DCM. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 95 / 5 to 50 / 50) to afford 149mg of I-021 (67%) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.88 (s, 1H), 7.35 – 7.18 (m, 6H), 6.60 (d, J = 3.4 Hz, 1H),Molecular Formula: C33H36ClFN4O4S According to GP-3, I-022 was obtained in 60% yield using aryl bromide I-021 (183mg, 405µmol, 1 equiv.), piperazine I-002 (218mg, 811µmol, 2 equiv.), Cs2CO3(396mg, 1.22mmol, 3 equiv.), Pd(OAc)2 (9.1mg, 41µmol, 0.10 equiv.) and rac-BINAP (30mg, 49µmol, 0.12 equiv.) in toluene (2mL) at reflux for 3h. Purification by FC (cHex / EtOAc = 95 / 5 to 0 / 100).1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.93 (s, 1H), 7.45 – 7.15 (m, 8H), 7.15 – 7.00 (m, 2H), 6.68 (d, J = 3.3 Hz, 1H), 6.25 – 5.95 (m, 2H), 4.60 – 4.46 (m, 3H), 4.38 (s, 1H), 4.06 (s, 1H), 3.81 (s, 1H), 3.70 – 3.40 (m, 1H), 3.33 – 3.25 (m, 1H), 3.20 – 3.05 (m, 1H), 2.20 – 1.85 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 1.24 (s, 9H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.14, -109.29. MS (ESI+): [M+H]+639.4 / 641.3.

[0184] 1-(benzyloxymethyl)-N-tert-butyl-7-[3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-N-(trideuteriomethyl)indole-5-sulfonamide (I-023)To a solution of I-022 (90mg, 141µmol, 1 equiv.) in dry DMF (1.4mL) at 0°C, was added NaH (60% in mineral oil, 11mg, 0.28mmol, 2 equiv.). The mixture was stirred at RT for 30min and then iodomethane-d3 (19µL, 0.28mmol, 2 equiv.) was added. The mixture was stirred at RT for 30min. The residue was partitioned between sat. aq. NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 95 / 5 to 50 / 50) to afford 89mg of I-023 (96%) as a white solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.85 (s, 1H), 7.45 – 7.15 (m, 9H), 7.15 – 7.05 (m, 1H), 6.67 (d, J = 3.3 Hz, 1H), 6.25 – 5.95 (m, 2H), 4.60 – 4.40 (m, 3H), 4.05 (s, 1H), 3.80 (s, 1H), 3.68 – 3.40 (m, 1H), 3.32 & 3.28 (s, 1H), 3.20 – 3.05 (m, 1H), 2.15 – 1.85 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 1.36 (s, 9H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.17, -109.33. MS (ESI+): [M+H]+656.4 / 658.4.

[0185] 7-bromo-N-tert-butyl-1-cyclopropyl-indole-5-sulfonamide (I-024)Formula Weight: 371,29 Molecular Formula: C15H19BrN2O2S Under air, a MW vial was charged with I-020 (150mg, 0.45mmol, 1 equiv.), Cu(OAc)2(82mg, 0.45mmol, 1 equiv.), 2,2'-bipyridyl (71mg, 0.45mmol, 1 equiv.),cyclopropylboronic acid (78mg, 0.91mmol, 2 equiv.) and Na2CO3 (96mg, 0.91mmol, 2 equiv.). DCE (1.1mL) was added, the vial was sealed and the reaction mixture was stirred at 70°C for 16h. The mixture was partitioned between sat. aq. NH4Cl and DCM. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 95 / 5 to 50 / 50) to afford 22mg of I-024 (13%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.08 (s, 1H), 7.87 (s, 1H), 7.23 (d, J = 3.3 Hz, 1H), 6.51 (d, J = 3.5 Hz, 1H), 4.45 (s, 1H), 3.85 – 3.75 (m, 1H), 1.24 (s, 9H), 1.24 – 1.14 (m, 4H). MS (ESI+): [M+H]+371.0 / 373.1.

[0186] 1-acetyl-N-tert-butyl-N-methyl-indoline-5-sulfonamide (I-025)Formula Weight: 310,41 Molecular Formula: C15H22N2O3S According to GP-4, I-025 was obtained as a white solid in 76% yield using 1-Acetyl-2,3- dihydro-1H-indole-5-sulfonyl chloride (1.00g, 3.85mmol, 1 equiv.), N-methyl-tert- butylamine (0.58mL, 4.6mmol, 1.2 equiv.) and Et3N (0.80mL, 5.8mmol, 1.5 equiv.) in DCM (7.7mL) at RT for 2h.1H NMR (400 MHz, Chloroform-d) δ 8.29 (d, J = 8.5 Hz, 1H), 7.71 – 7.62 (m, 2H), 4.16 (t, J = 8.6 Hz, 2H), 3.27 (t, J = 8.6 Hz, 2H), 2.96 (s, 3H), 2.28 (s, 3H), 1.37 (s, 9H). MS (ESI+): [M+H]+311.1.

[0187] N-tert-butyl-N-methyl-indoline-5-sulfonamide (I-026)Formula Weight: 268,38 Molecular Formula: C13H20N2O2STo a solution of I-025 (1.00g, 3.22mmol, 1 equiv.) in THF / MeOH / H2O (1 / 1 / 1, 18mL) at RT, was added NaOH(s) (580mg, 14.5mmol, 4.5 equiv.). The mixture was stirred at reflux for 5h. The volatiles were removed under reduced pressure. The residue was partitioned between water and DCM. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 90 / 10 to 0 / 100) to afford 525mg of I-026 (67%) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 7.62 – 7.43 (m, 2H), 6.57 (d, J = 8.8 Hz, 1H), 4.11 (s, 1H), 3.68 (td, J = 8.6, 1.7 Hz, 2H), 3.09 (t, J = 8.5 Hz, 2H), 2.90 (s, 3H), 1.38 (s, 9H).Formula Weight: 347,27 Molecular Formula: C13H19BrN2O2S To a solution of I-026 (520mg, 1.94mmol, 1 equiv.) and acetic acid (0.55mL, 9.7mmol, 5 equiv.) in dioxane (4mL) at 0°C, was added dropwise a solution of N-bromosuccinimide (379mg, 2.13mmol, 1.1 equiv.) in dioxane (4mL). The mixture was stirred at RT for 1h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between 2N NaOH and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 90 / 10 to 0 / 100 to afford 630mg of I-027 (94%) as a yellow solid.1H NMR (400 MHz, Chloroform-d) δ 7.68 – 7.64 (m, 1H), 7.43 – 7.40 (m, 1H), 4.36 (s, 1H), 3.75 (t, J = 8.7 Hz, 2H), 3.21 (t, J = 8.7 Hz, 2H), 2.90 (s, 3H), 1.38 (s, 9H). MS (ESI+): [M+H]+347.0 / 349.0.

[0189] 7-bromo-N-tert-butyl-N-methyl-1H-indole-5-sulfonamide (I-028)Formula Weight: 345,26 Molecular Formula: C13H17BrN2O2S To a solution of I-027 (630mg, 1.81mmol, 1 equiv.) in DCM (9.1mL) at RT, was added DDQ (0.62g, 2.7mmol, 1.5 equiv.). The mixture was stirred at RT for 16h and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 96 / 4 to 60 / 40) to afford 483mg of I-028 (73%) as a beige solid.1H NMR (400 MHz, Chloroform-d) δ 8.62 (s, 1H), 8.14 (s, 1H), 7.82 (d, J = 1.5 Hz, 1H), 7.41 (t, J = 2.8 Hz, 1H), 6.76 (dd, J = 3.2, 2.1 Hz, 1H), 2.99 (s, 3H), 1.40 (s, 9H). MS (ESI+): [M+H]+345.0 / 347.0.

[0190] 7-bromo-N-tert-butyl-N,1-dimethyl-indole-5-sulfonamide (I-029)Formula Weight: 359,28 Molecular Formula: C14H19BrN2O2S To a solution of I-028 (100mg, 275µmol, 1 equiv.) in dry DMF (1.1mL) at 0°C, was added NaH (60% in mineral oil, 17mg, 0.41mmol, 1.5 equiv.). The mixture was stirred at RT for 30min and iodomethane (43µL, 0.69mmol, 2.5 equiv.). The mixture was stirred at RT for 30min. The residue was partitioned between sat. aq. NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 98 / 2 to 80 / 20) to afford 103mg of I-029 (95%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.06 (d, J = 1.7 Hz, 1H), 7.78 (d, J = 1.7 Hz, 1H), 7.12 (d, J = 3.2 Hz, 1H), 6.59 (d, J = 3.2 Hz, 1H), 4.21 (s, 3H), 2.98 (s, 3H), 1.39 (s, 9H). MS (ESI+): [M+H]+359.1 / 361.1.

[0191] 7-bromo-N-tert-butyl-N-methyl-1-(2-trimethylsilylethoxymethyl)indole-5- sulfonamide (I-030)Formula Weight: 475,52 Molecular Formula: C19H31BrN2O3SSi To a solution of I-028 (150mg, 413µmol, 1 equiv.) in dry DMF (2.1mL) at 0°C, was added NaH (60% in mineral oil, 25mg, 0.62mmol, 1.5 equiv.). The mixture was stirred at RT for 30min and then 2-(trimethylsilyl)ethoxymethyl chloride (183µL, 1.03mmol, 2.5 equiv.) was added. The mixture was stirred at RT for 1h. The mixture was partitioned between sat. aq. NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 98 / 2 to 80 / 20) to afford 190mg of I-030 (94%) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 8.12 (d, J = 1.7 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.36 (d, J = 3.3 Hz, 1H), 6.70 (d, J = 3.3 Hz, 1H), 5.93 (s, 2H), 3.68 – 3.48 (m, 2H), 3.03 (s, 3H), 1.43 (s, 9H), 1.01 – 0.90 (m, 2H), 0.00 (s, 9H). MS (ESI+): [M+H]+475.1 / 477.1.

[0192] N-tert-butyl-7-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8- yl]-N-methyl-1-(2-trimethylsilylethoxymethyl)indole-5-sulfonamide (I-031)Formula Weight: 663,32 Molecular Formula: C32H44ClFN4O4SSi According to GP-3, I-031 was obtained in 13% yield using aryl bromide I-030 (183mg, 366µmol, 1 equiv.), piperazine I-002 (118mg, 439µmol, 1.2 equiv.), t-BuONa (105mg,1.10mmol, 3 equiv.) and XPhos-Pd-G3 (31mg, 37µmol, 0.10 equiv.) in toluene (1.8mL) at reflux for 3h. Purification by FC (cHex / EtOAc = 95 / 5 to 0 / 100).1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.90 – 7.84 (m, 1H), 7.47 – 7.40 (m, 0.5H), 7.31 – 7.05 (m, 4.5H), 6.67 (d, J = 3.3 Hz, 1H), 6.15 – 5.89 (m, 2H), 4.66 – 4.56 (m, 1H), 4.11 (s, 1H), 3.89 (s, 1H), 3.81 – 3.54 (m, 3H), 3.47 – 3.39 (m, 1H), 3.32 – 3.19 (m, 1H), 3.00 & 2.99 (s, 3H), 2.25 – 1.90 (m, 3.5H), 1.78 – 1.68 (m, 0.5H), 1.39 (s, 9H), 0.99 – 0.85 (m, 2H), 0.00 & -0.02 (s, 9H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ - 109.17, -109.35. MS (ESI+): [M+H]+663.3 / 665.3.

[0193] 1-(5-sulfanylindolin-1-yl)ethanone (I-032)Formula Weight: 193,27 Molecular Formula: C10H11NOS To a solution of 1-acetyl-2,3-dihydro-1H-indole-5-sulfonyl chloride (1.02g, 3.95mmol, 1 equiv.) in THF (40mL) at RT, were added water (1.3mL) and PPh3 (3.62g, 13.8mmol, 3.5 equiv.) portionwise. The mixture was stirred at 50°C for 4h. After cooling down to RT, water and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, cHex / EtOAc = 98 / 2 to 20 / 80) to afford 550mg of I-032 (72%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 8.3 Hz, 1H), 7.16 (d, J = 1.9 Hz, 1H), 7.06 (dd, J = 8.4, 1.9 Hz, 1H), 5.19 (s, 1H), 4.06 (t, J = 8.5 Hz, 2H), 3.09 (t, J = 8.5 Hz, 2H), 2.13 (s, 3H). MS (ESI+): [M+H]+194.1.

[0194] 1-[5-(2,2-dimethylpropylsulfanyl)indolin-1-yl]ethanone (I-033)Formula Weight: 263,4 Molecular Formula: C15H21NOS To a solution of I-032 (550mg, 2.84mmol, 1 equiv.) in dry DMF (2.8mL) at RT, was added NaH (60% in mineral oil, 137mg, 3.42mmol, 1.2 equiv.). The mixture was stirred at RT for 30min and 1-bromo-2,2-dimethylpropane (0.43mL, 3.42mmol, 1.2 equiv.) was added dropwise. The mixture was stirred at 80°C for 1.5h. After cooling down to RT, the mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 90 / 10 to 0 / 100) to afford 642mg of I-033 (86%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.13 (d, J = 8.3 Hz, 1H), 7.27 – 7.17 (m, 2H), 4.07 (t, J = 8.5 Hz, 2H), 3.19 (t, J = 8.5 Hz, 2H), 2.87 (s, 2H), 2.24 (s, 3H), 1.04 (s, 9H). MS (ESI+): [M+H]+263.1.

[0195] 1-[5-(2,2-dimethylpropylsulfonyl)indolin-1-yl]ethanone (I-034)Formula Weight: 295,4 Molecular Formula: C15H21NO3S Using GP-2, I-034 was obtained as a colorless oil in 100% yield using I-033 (640mg, 2.43mmol, 1 equiv.) and m-CPBA (70% wet, 1.32g, 5.34mmol, 2.2 equiv.) in DCM (12mL) at RT for 1h.1H NMR (400 MHz, Chloroform-d) δ 8.34 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 8.5, 1.9 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 4.17 (t, J = 8.6 Hz, 2H), 3.28 (t, J = 8.6 Hz, 2H), 3.03 (s, 2H), 2.28 (s, 3H), 1.19 (s, 9H). MS (ESI+): [M+H]+296.2.

[0196] 5-(2,2-dimethylpropylsulfonyl)indoline (I-035)Formula Weight: 253,36 Molecular Formula: C13H19NO2S To a solution of I-034 (720mg, 2.44mmol, 1 equiv.) in THF / MeOH / H2O (1 / 1 / 1, 15mL) at RT, was added NaOH(s) (487mg, 12.2mmol, 5 equiv.). The mixture was stirred at reflux for 2.5h. The volatiles were removed under reduced pressure. The residue was partitioned between water and DCM. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to afford 620mg of I-035 (100%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 7.68 – 7.47 (m, 2H), 6.60 (d, J = 8.7 Hz, 1H), 4.23 (s, 1H), 3.71 (td, J = 8.6, 1.4 Hz, 2H), 3.11 (t, J = 8.6 Hz, 2H), 3.01 (s, 2H), 1.18 (s, 9H). MS (ESI+): [M+H]+254.1.

[0197] 7-bromo-5-(2,2-dimethylpropylsulfonyl)indoline (I-036)Formula Weight: 332,26 Molecular Formula: C13H18BrNO2S To a solution of I-035 (620mg, 2.45mmol, 1 equiv.) and acetic acid (0.700mL, 12.2mmol, 5 equiv.) in dioxane (5mL) at 0°C, was added dropwise a solution of N-bromosuccinimide (479mg, 2.69mmol, 1.1 equiv.) in dioxane (5mL). The mixture was stirred at RT for 1h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between 2N NaOH and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 90 / 10 to 0 / 100 to afford 751mg of I-036 (88%) as a yellow solid.1H NMR (400 MHz, Chloroform-d) δ 7.73 (d, J = 2.0 Hz,1H), 7.48 (d, J = 2.0 Hz, 1H), 4.49 (s, 1H), 3.78 (t, J = 8.7 Hz, 2H), 3.23 (t, J = 8.7 Hz, 2H), 3.00 (s, 2H), 1.19 (s, 9H). MS (ESI+): [M+H]+332.0 / 334.0.

[0198] 7-bromo-5-(2,2-dimethylpropylsulfonyl)-1H-indole (I-037)Formula Weight: 330,24 Molecular Formula: C13H16BrNO2S To a solution of I-036 (745mg, 2.13mmol, 1 equiv.) in DCM (11mL) at RT, was added DDQ (0.73g, 3.2mmol, 1.5 equiv.). The mixture was stirred at RT for 16h and at reflux for 2h. After cooling down to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 96 / 4 to 60 / 40) to afford 640mg of I-037 (86%) as a beige solid.1H NMR (400 MHz, Chloroform- d) δ 1H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 8.22 (s, 1H), 7.90 (s, 1H), 7.44 (s, 1H), 6.80 (s, 1H), 3.10 (s, 2H), 1.22 (s, 9H). MS (ESI+): [M+H]+330.0 / 332.0.

[0199] 2-[[7-bromo-5-(2,2-dimethylpropylsulfonyl)indol-1-yl]methoxy]ethyl-trimethyl- silane (I-038)Formula Weight: 460,5 Molecular Formula: C19H30BrNO3SSi To a solution of I-037 (230mg, 662µmol, 1 equiv.) in dry DMF (3.3mL) at 0°C, was added NaH (60% in mineral oil, 40mg, 0.99mmol, 1.5 equiv.). The mixture was stirred at RT for 30min and then 2-(trimethylsilyl)ethoxymethyl chloride (293µL, 1.65mmol, 2.5 equiv.) was added dropwise. The mixture was stirred at RT for 1h. The mixture was partitioned between sat. aq. NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. Theresidue was purified by FC (12g column, dry load, cHex / EtOAc = 97 / 3 to 70 / 30) to afford 297mg of I-038 (97%) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 8.21 (d, J = 1.7 Hz, 1H), 7.97 (d, J = 1.7 Hz, 1H), 7.39 (d, J = 3.3 Hz, 1H), 6.73 (d, J = 3.4 Hz, 1H), 5.94 (s, 2H), 3.63 – 3.53 (m, 2H), 3.13 (s, 2H), 1.25 (s, 9H), 0.96 (dd, J = 8.6, 7.6 Hz, 2H), 0.00 (s, 9H). MS (ESI+): [M+H]+460.1 / 462.1.

[0200] (2-chloro-4-fluoro-phenyl)-[8-[5-(2,2-dimethylpropylsulfonyl)-1-(2- trimethylsilylethoxymethyl)indol-7-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-039)Formula Weight: 648,3 Molecular Formula: C32H43ClFN3O4SSi According to GP-3, I-039 was obtained in 13% yield using aryl bromide I-038 (271mg, 592µmol, 1 equiv.), piperazine I-002 (191mg, 711µmol, 1.2 equiv.), t-BuONa (171mg, 1.78mmol, 3 equiv.) and XPhos-Pd-G3 (50mg, 59µmol, 0.10 equiv.) in toluene (1.8mL) at reflux for 4h. Purification by FC (cHex / EtOAc = 95 / 5 to 50 / 50).1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.95 (s, 1H), 7.48 – 7.41 (m, 0.5H), 7.35 – 7.04 (m, 4.5H), 6.71 & 6.70 (s, 1H), 6.17 – 5.88 (m, 2H), 4.65 & 4.62 (s, 1H), 4.15 (s, 1H), 3.92 (s, 1H), 3.83 – 3.51 (m, 3H), 3.51 – 3.34 (m, 1H), 3.32 – 3.20 (m, 1H), 3.08 (s, 2H), 2.28 – 1.91 (m, 3.5H), 1.80 – 1.65 (m, 0.5H), 1.20 (s, 9H), 0.96 – 0.84 (m, 2H), 0.00 & -0.02 (s, 9H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.11, -109.29. MS (ESI+): [M+H]+648.3 / 650.2.

[0201] 7-bromo-5-(2,2-dimethylpropylsulfonyl)-1-methyl-indole (I-040)Formula Weight: 344,27 Molecular Formula: C14H18BrNO2S To a solution of I-037 (190mg, 575µmol, 1 equiv.) in dry DMF (2.3mL) at 0°C, was added NaH (60% in mineral oil, 35mg, 0.86mmol, 1.5 equiv.). The mixture was stirred at RT for 30min and iodomethane (90µL, 1.44mmol, 2.5 equiv.) was added dropwise. The mixture was stirred at RT for 30min. The residue was partitioned between sat. aq. NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 97 / 3 to 70 / 30) to afford 198mg of I-040 (100%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.14 (d, J = 1.6 Hz, 1H), 7.87 (d, J = 1.7 Hz, 1H), 7.16 (d, J = 3.2 Hz, 1H), 6.63 (d, J = 3.1 Hz, 1H), 4.23 (s, 3H), 3.08 (s, 2H), 1.21 (s, 9H). MS (ESI+): [M+H]+344.1 / 346.1.

[0202] 7-bromo-1-cyclopropyl-5-(2,2-dimethylpropylsulfonyl)indole (I-041)Formula Weight: 370,3 Molecular Formula: C16H20BrNO2S Under air, a MW vial was charged with I-037 (200mg, 606µmol, 1 equiv.), Cu(OAc)2monohydrate (121mg, 606µmol, 1 equiv.), 2,2'-bipyridyl (95mg, 606µmol, 1 equiv.), cyclopropylboronic acid (104mg, 1.21mmol, 2 equiv.) and Na2CO3 (128mg, 1.21mmol, 2 equiv.). DCE (2mL) was added, the vial was sealed and the reaction mixture was stirred at 70°C for 16h. The mixture was partitioned between sat. aq. NH4Cl and DCM. The layers were separated and the aqueous phase was extracted with DCM. The combinedorganic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 98 / 2 to 70 / 30) to afford 114mg of I-041 (51%) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 8.09 (d, J = 1.7 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.26 (d, J = 3.3 Hz,Exotherm & gas release]. The resulting green solution was stirred at RT for 1h. In another 500mL flask: to a solution of 7-bromo-1H-indazol-5-amine (2.00 g, 9.43 mmol, 1 equiv.) in water (80mL) and 37% HCl (35mL) at 0°C, was added dropwise a solution of NaNO2 (716mg, 10.4mmol, 1.1 equiv.) in water (30mL). The mixture was stirred at 0°C for 30min at which point, the first solution was added dropwise. The resulting mixture was stirred at RT for 2h. The dark suspension was filtered over fritted glass and the filter cake was washed with water (30mL). The filter cake was dissolved in EtOAc and the organic solution was dried (Na2SO4), filtered and concentrated under reduced pressure to afford 1.1g of I-042 (41%) as a brown solid, which was promptly used in the next step.1H NMR (400 MHz, Chloroform-d) δ 8.52 (s, 1H), 8.40 (s, 1H), 8.20 (s, 1H).

[0204] 7-bromo-5-[(4-phenyl-1-piperidyl)sulfonyl]-1H-indazole (I-043)Formula Weight: 420,32 Molecular Formula: C18H18BrN3O2S According to GP-4, I-043 was obtained as a white solid in 50% yield using I-042 (130mg, 220µmol, 1 equiv.), 4-phenylpiperidine (71mg, 0.44mmol, 2 equiv.) and Et3N (0.15mL, 1.1mmol, 5 equiv.) in DCM (3mL) at RT for 16h.1H NMR (400 MHz, Chloroform-d) δ 10.46 (s, 1H), 8.33 (s, 1H), 8.25 (d, J = 1.4 Hz, 1H), 7.97 (d, J = 1.4 Hz, 1H), 7.33 – 7.27 (m, 2H), 7.24 – 7.18 (m, 1H), 7.17 – 7.10 (m, 2H), 4.03 – 3.95 (m, 2H), 2.48 – 2.33 (m, 3H), 1.96 – 1.82 (m, 4H). MS (ESI+): [M+H]+420.0 / 422.0.

[0205] Mixture of 2-[[7-bromo-5-[(4-phenyl-1-piperidyl)sulfonyl]indazol-1- yl]methoxy]ethyl-trimethyl-silane and 2-[[7-bromo-5-[(4-phenyl-1- piperidyl)sulfonyl]indazol-2-yl]methoxy]ethyl-trimethyl-silane (I-044)Formula Weight: 550,58 Molecular Formula: C24H32BrN3O3SSi To a solution of I-043 (50.0mg, 111µmol, 1 equiv.) in dry THF (1.7mL) at 0°C, was added NaH (60% in mineral oil, 10mg, 0.25mmol, 2.3 equiv.). The mixture was stirred at 0°C for 30min and then 2-(trimethylsilyl)ethoxymethyl chloride (44µL, 0.25mmol, 2.3 equiv.) was added dropwise. The mixture was stirred at RT for 16h. The mixture was partitioned between sat. aq. NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 98 / 2 to 60 / 40) to afford 30mg of I-044 (59%, inconsequential 3 / 1 mixture of isomers) as a colorless oil.1H NMR(400 MHz, Chloroform-d) of major isomer δ 8.44 (s, 1H), 8.26 (d, J = 1.4 Hz, 1H), 7.86 (d, J = 1.5 Hz, 1H), 7.29 (t, J = 7.3 Hz, 2H), 7.25 – 7.18 (m, 1H), 7.17 – 7.07 (m, 2H), 5.82 (s, 2H), 4.09 – 3.89 (m, 2H), 3.77 – 3.69 (m, 2H), 2.64 – 2.28 (m, 3H), 2.05 – 1.77 (m, 4H), 1.04 – 0.94 (m, 2H), 0.00 (s, 9H).1H NMR (400 MHz, Chloroform-d) of minor isomer δ 8.23 – 8.14 (m, 2H), 8.01 (d, J = 1.5 Hz, 1H), 7.29 (t, J = 7.3 Hz, 2H), 7.25 – 7.18 (m, 1H), 7.17 – 7.07 (m, 2H), 6.11 (s, 2H), 4.09 – 3.89 (m, 2H), 3.67 – 3.57 (m, 2H), 2.64 – 2.28 (m, 3H), 2.05 – 1.77 (m, 4H), 0.94 – 0.85 (m, 2H), -0.05 (s, 9H). MS (ESI+): [M+H]+550.1 / 550.2.

[0206] 7-bromo-N-tert-butyl-1H-indazole-5-sulfonamide (I-045)Formula Weight: 332,22 Molecular Formula: C11H14BrN3O2S According to GP-4, I-045 was obtained as a white solid in 49% yield using I-042 (525mg, 1.78mmol, 1 equiv.) and t-BuNH2(1.9mL, 18mmol, 10 equiv.) in DCM (9mL) at RT for 16h.1H NMR (400 MHz, DMSO-d6) δ 13.92 (s, 1H), 8.42 (s, 1H), 8.31 (d, J = 1.5 Hz, 1H), 7.98 (t, J = 1.4 Hz, 1H), 7.53 (s, 1H), 1.09 (s, 9H). MS (ESI+): [M+H]+332.0 / 334.0.

[0207] 7-bromo-N-tert-butyl-1-(2-trimethylsilylethoxymethyl)indazole-5-sulfonamide (I-046)Formula Weight: 462,48 Molecular Formula: C17H28BrN3O3SSi To a solution of I-045 (185mg, 557µmol, 1 equiv.) in dry DMF (2.8mL) at 0°C, was added NaH (60% in mineral oil, 67mg, 1.7mmol, 3 equiv.). The mixture was stirred at RT for 30min and then 2-(trimethylsilyl)ethoxymethyl chloride (98µL, 0.56mmol, 1equiv.) was added dropwise. The mixture was stirred at RT for 16h. The mixture was partitioned between sat. aq. NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, DCM / MeOH = 99 / 1 to 80 / 20) to afford 53mg of I-046 (21%) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.34 (s, 1H), 8.08 (s, 1H), 7.61 (s, 1H), 6.01 (s, 2H), 3.55 (t, J = 7.7 Hz, 2H), 1.08 (s, 9H), 0.77 (t, J = 7.7 Hz, 2H), -0.16 (s, 9H). MS (ESI+): [M+H]+462.0 / 464.0.

[0208] 7-bromo-N-tert-butyl-1-cyclopropyl-indazole-5-sulfonamide (I-047)Formula Weight: 372,28 Molecular Formula: C14H18BrN3O2S Under air, a MW vial was charged with I-045 (100mg, 301µmol, 1 equiv.), Cu(OAc)2 (55mg, 0.30mmol, 1 equiv.), 2,2'-bipyridyl (47mg, 0.30mmol, 1 equiv.), cyclopropylboronic acid (52mg, 0.60mmol, 2 equiv.) and Na2CO3(64mg, 0.60mmol, 2 equiv.). DCE (2mL) was added, the vial was sealed and the reaction mixture was stirred at 70°C for 3h. The mixture was partitioned between sat. aq. NH4Cl and DCM. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 95 / 5 to 50 / 50) to afford 42mg of I-047 (37%) as a white solid.1H NMR (400 MHz, Chloroform- d) δ 8.17 (d, J = 1.7 Hz, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.94 (s, 1H), 4.87 (s, 1H), 4.03 (tt, J = 7.3, 3.7 Hz, 1H), 1.42 – 1.32 (m, 2H), 1.22 – 1.12 (s, 11H). MS (ESI+): [M+H]+372.0 / 374.0.

[0209] 7-bromo-5-(3,3-difluoropyrrolidin-1-yl)sulfonyl-1H-indazole (I-048)Formula Weight: 366,18 Molecular Formula: C11H10BrF2N3O2S According to GP-4, I-048 was obtained as a white solid in 18% yield using I-042 (300mg, 1.02mmol, 1 equiv.), 3,3-difluoropyrrolidine hydrochloride (175mg, 1.22mmol, 1.2 equiv.) and Et3N (0.35mL, 2.0mmol, 2 equiv.) in THF (5mL) at RT for 16h.1H NMR (400 MHz, Chloroform-d) δ 8.33 (s, 1H), 8.27 (s, 1H), 7.97 (s, 1H), 3.59 (t, J = 12.8 Hz, 2H), 3.47 (d, J = 7.6 Hz, 2H), 2.37 – 2.22 (m, 2H). MS (ESI+): [M+H]+366.0 / 368.0.

[0210] Mixture of 2-[[7-bromo-5-(3,3-difluoropyrrolidin-1-yl)sulfonyl-indazol-1- yl]methoxy]ethyl-trimethyl-silane and 2-[[7-bromo-5-(3,3-difluoropyrrolidin-1- yl)sulfonyl-indazol-2-yl]methoxy]ethyl-trimethyl-silane (I-049)Formula Weight: 496,44 Molecular Formula: C17H24BrF2N3O3SSi To a solution of I-048 (66mg, 0.18mmol, 1 equiv.) in dry THF (1.8mL) at 0°C, was added NaH (60% in mineral oil, 8.8mg, 0.22mmol, 1.2 equiv.). The mixture was stirred at 0°C for 30min and then 2-(trimethylsilyl)ethoxymethyl chloride (39µL, 0.22mmol, 1.2 equiv.) was added dropwise. The mixture was stirred at RT for 16h. More NaH (60% in mineral oil, 7.3mg, 0.18mmol, 1 equiv.) and 2-(trimethylsilyl)ethoxymethyl chloride (32µL, 0.18mmol, 1 equiv.) were added and the reaction mixture was stirred a further 3h at RT. The mixture was partitioned between sat. aq. NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc =95 / 5 to 50 / 50) to afford 64mg of I-049 (69%, inconsequential 2 / 1 mixture of isomers) as a colorless oil.1H NMR (400 MHz, Chloroform-d) of major isomer δ 8.22 (d, J = 1.5 Hz, 1H), 8.19 (s, 1H), 8.01 (d, J = 1.5 Hz, 1H), 6.09 (s, 2H), 3.74 – 3.42 (m, 6H), 2.41 – 2.19 (m, 2H), 0.92 – 0.85 (m, 2H), -0.08 (s, 9H).1H NMR (400 MHz, Chloroform-d) of minor isomer δ 8.45 (s, 1H), 8.28 (d, J = 1.5 Hz, 1H), 7.86 (d, J = 1.5 Hz, 1H), 5.81 (s, 2H), 3.74 – 3.42 (m, 6H), 2.41 – 2.19 (m, 2H), 1.00 – 0.94 (m, 2H), -0.02 (s, 9H). MS (ESI+): [M+H]+496.0 / 497.9.

[0211] 7-bromo-5-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-1H-indazole (I-050)483,81 Molecular Formula: C19H20BrClN4O2S According to GP-4, I-050 was obtained as a white solid in 37% yield using I-042 (1.25g, 4.23mmol, 1 equiv.), 1-[2-(4-chlorophenyl)ethyl]piperazine (952mg, 4.23mmol, 1 equiv.) and Et3N (0.71mL, 5.1mmol, 1.2 equiv.) in THF / DCM (40mL) at RT for 16h.1H NMR (400 MHz, Chloroform-d) δ 10.64 (s, 1H), 8.29 (s, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 7.20 (d, J = 7.8 Hz, 2H), 7.06 (d, J = 7.8 Hz, 2H), 3.09 (s, 4H), 2.75 – 2.50 (m, 8H).MS (ESI+): [M+H]+483.0 / 485.0 / 487.0.

[0212] Mixture of 2-[[7-bromo-5-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl- indazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[7-bromo-5-[4-[2-(4- chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-indazol-2-yl]methoxy]ethyl-trimethyl-silane (I-051)Formula Weight: 614,07 Molecular Formula: C25H34BrClN4O3SSiTo a solution of I-050 (210mg, 434µmol, 1 equiv.) in dry DMF (2.2mL) at 0°C, was added NaH (60% in mineral oil, 35mg, 0.87mmol, 2 equiv.). The mixture was stirred at 0°C for 30min and 2-(trimethylsilyl)ethoxymethyl chloride (0.15mL, 0.87mmol, 2 equiv.) was added dropwise. The mixture was stirred at RT for 16h. The mixture was partitioned between sat. aq. NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 98 / 2 to 50 / 50) to afford 220mg of I-051 (83%, inconsequential 2 / 1 mixture of isomers) as an orange oil.1H NMR (400 MHz, Chloroform-d) of major isomer δ 8.19 – 8.12 (m, 2H), 7.96 (s, 1H), 7.22 (d, J = 7.6 Hz, 2H), 7.08 (d, J = 7.6 Hz, 2H), 6.10 (s, 2H), 3.61 (t, J = 8.2 Hz, 2H), 3.20 – 2.85 (m, 4H), 2.75 – 2.45 (m, 8H), 0.93 (t, J = 8.2 Hz, 2H), -0.05 (s, 9H).1H NMR (400 MHz, Chloroform-d) of minor isomer δ 8.43 (s, 1H), 8.21 (s, 1H), 7.82 (s, 1H), 7.22 (d, J = 7.6 Hz, 2H), 7.08 (d, J = 7.6 Hz, 2H), 5.82 (s, 2H), 3.70 (t, J = 8.3 Hz, 2H), 3.20 – 3.00 (s, 4H), 2.75 – 2.50 (m, 8H), 1.04 – 0.95 (m, 2H), 0.02 (s, 9H). MS (ESI+): [M+H]+613.2 / 615.2 / 617.2.

[0213] 7-bromo-5-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-1-cyclopropyl- indazole (I-052)Formula Weight: 523,87 Molecular Formula: C22H24BrClN4O2S Under air, a MW vial was charged with I-050 (250mg, 517µmol, 1 equiv.), Cu(OAc)2(94mg, 0.52mmol, 1 equiv.), 2,2'-bipyridyl (81mg, 0.52mmol, 1 equiv.), cyclopropylboronic acid (88.7mg, 1.03mmol, 2 equiv.) and Na2CO3(110mg, 1.04mmol, 2 equiv.). DCE (2mL) was added, the vial was sealed and the reaction mixture was stirred at 75°C for 16h. The mixture was partitioned between sat. aq. NH4Cl and DCM. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated underreduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 95 / 5 to 30 / 70) to afford 130mg of I-052 (48%) as a brown solid.1H NMR (400 MHz, Chloroform-d) δ 8.13 (d, J = 1.6 Hz, 1H), 8.07 (s, 1H), 7.94 (s, 1H), 7.24 (d, J = 7.9 Hz, 2H), 7.09 (d, J = 7.9 Hz, 2H), 4.14 (tt, J = 7.5, 3.8 Hz, 1H), 3.10 (br s, 4H), 2.80 – 2.50 (m, 8H), 1.52 – 1.42 (m, 2H), 1.32 – 1.22 (m, 2H). MS (ESI+): [M+H]+523.1 / 525.1 / 527.1.

[0214] 7-bromo-5-iodo-1H-indazole (I-053)Formula Weight: 322,93 Molecular Formula: C7H4BrIN2To a solution of 7-bromo-1H-indazol-5-amine (3.20 g, 15.1 mmol, 1 equiv.) in 6N HCl (30mL) at 0°C, was added dropwise a solution of NaNO2 (1.15g, 16.6mmol, 1.1 equiv.) in water (17mL). The mixture was stirred at 0°C for 30min at which point it was added dropwise to a solution of KI (12.5g, 75.5mmol, 5 equiv.) in water (26mL) at 0°C. The resulting thick suspension was stirred at RT for 1.5h and then at 90°C for 1h. After cooling down to RT, EtOAc was added and the biphasic suspension was filtered over Celite (EtOAc rinses). The layers of the filtrate were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, 3*1N Na2S2O3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (80g column, dry load, cHex / EtOAc = 97 / 3 to 70 / 30) to afford 3.63g of I-053 (74%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 10.39 (s, 1H), 8.15 – 8.05 (m, 2H), 7.87 – 7.78 (m, 1H). MS (ESI+): [M+H]+322.9 / 324.9.

[0215] Mixture of 2-[(7-bromo-5-iodo-indazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(7-bromo-5-iodo-indazol-2-yl)methoxy]ethyl-trimethyl-silane (I-054)Formula Weight: 453,19 Molecular Formula: C13H18BrIN2OSiTo a solution of I-053 (1.17g, 3.62mol, 1 equiv.) in dry THF (18mL) at 0°C, was added NaH (60% in mineral oil, 290mg, 7.24mmol, 2 equiv.). The mixture was stirred at RT for 30min and 2-(trimethylsilyl)ethoxymethyl chloride (0.96mL, 5.43mmol, 1.5 equiv.) was added dropwise. The mixture was stirred at RT for 2h. The mixture was partitioned between water and DCM. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, DCM / MeOH = 98 / 2 to 80 / 20) to afford 1.64g of I-054 (98%, inconsequential 2 / 1 mixture of isomers) as an orange oil.1H NMR (400 MHz, Chloroform-d) of major isomer δ 8.03 (d, J = 1.4 Hz, 1H), 7.94 (s, 1H), 7.86 (d, J = 1.4 Hz, 1H), 6.03 (s, 2H), 3.59 – 3.53 (m, 2H), 0.91 – 0.85 (m, 2H), -0.07 (s, 9H).1H NMR (400 MHz, Chloroform-d) of minor isomer δ 8.14 (s, 1H), 8.04 (d, J = 1.3 Hz, 1H), 7.76 (d, J = 1.3 Hz, 1H), 5.75 (s, 2H), 3.68 – 3.62 (m, 2H), 0.98 – 0.92 (m, 2H), -0.02 (s, 9H). MS (ESI+): [M+H]+452.9 / 454.9.

[0216] Mixture of 2-[[7-bromo-5-(2,2-dimethylpropylsulfanyl)indazol-1- yl]methoxy]ethyl-trimethyl-silane and 2-[[7-bromo-5-(2,2- dimethylpropylsulfanyl)indazol-2-yl]methoxy]ethyl-trimethyl-silane (I-055)Molecular Formula: C18H29BrN2OSSi Using GP-1, I-055 was obtained as a light yellow oil in 95% yield using I-054 (500mg, 1.10mmol, 1 equiv.), XantPhos-Pd-G3 (105mg, 110µmol, 0.10 equiv.), iPr2NEt (0.38mL, 2.2mmol, 2 equiv.) and 2,2-dimethylpropane-1-thiol (139µL, 1.10mmol, 1 equiv.) in toluene (5.5mL) at 100°C for 2h. Purification by FC (cHex / EtOAc = 99 / 1 to 90 / 10). MS (ESI+): [M+H]+429.1 / 431.1.

[0217] Mixture of 2-[[7-bromo-5-(2,2-dimethylpropylsulfonyl)indazol-1- yl]methoxy]ethyl-trimethyl-silane and 2-[[7-bromo-5-(2,2- dimethylpropylsulfonyl)indazol-2-yl]methoxy]ethyl-trimethyl-silane (I-056)Formula Weight: 461,49 Molecular Formula: C18H29BrN2O3SSi Using GP-2, I-056 was obtained as a white solid in 71% yield (inconsequential 2 / 1 mixture of isomers) using I-055 (449mg, 1.05mmol, 1 equiv.) and m-CPBA (70% wet, 569mg, 2.31mmol, 2.2 equiv.) in DCM (5.2mL) at RT for 16h. Purification by FC (cHex / EtOAc = 95 / 5 to 50 / 50).1H NMR (400 MHz, Chloroform-d) of major isomer δ 8.32 (d, J = 1.6 Hz, 1H), 8.18 (s, 1H), 8.10 (d, J = 1.5 Hz, 1H), 6.10 (s, 2H), 3.64 – 3.55 (m, 2H), 3.08 (s, 2H), 1.21 (s, 9H), 0.92 – 0.86 (m, 2H), -0.07 (s, 9H).1H NMR (400 MHz, Chloroform-d) of minor isomer δ 8.45 (s, 1H), 8.37 (d, J = 1.5 Hz, 1H), 7.95 (d, J = 1.5 Hz, 1H), 5.82 (s, 2H), 3.72 – 3.65 (m, 2H), 3.08 (s, 2H), 1.21 (s, 9H), 1.01 – 0.93 (m, 2H), -0.01 (s, 9H). MS (ESI+): [M+H]+461.0 / 463.0.

[0218] 7-bromo-5-iodo-1-methyl-indazole (I-057)Formula Weight: 336,96 Molecular Formula: C8H6BrIN2 To a solution of I-053 (237mg, 0.734mmol, 1 equiv.) in dry THF (3.7mL) at 0°C, was added NaH (60% in mineral oil, 44mg, 1.10mmol, 1.5 equiv.). The mixture was stirred at RT for 30min and iodomethane (0.11mL, 1.8mmol, 2.5 equiv.) was added dropwise. The mixture was stirred at RT for 1h. The mixture was partitioned between water and DCM. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load,cHex / EtOAc = 98 / 2 to 80 / 20) to afford 70mg of I-057 (28%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 7.99 (d, J = 1.5 Hz, 1H), 7.87 (s, 1H), 7.78 (d, J = 1.4 Hz, 1H), 4.39 (s, 3H). MS (ESI+): [M+H]+336.8 / 338.8.

[0219] 7-bromo-5-(2,2-dimethylpropylsulfanyl)-1-methyl-indazole (I-058)Formula Weight: 313,26 Molecular Formula: C13H17BrN2S Using GP-1, I-058 was obtained as a light yellow oil in 69% yield using I-057 (70mg, 0.21mmol, 1 equiv.), XantPhos-Pd-G3 (5.9mg, 6.2µmol, 0.03 equiv.), iPr2NEt (70µL, 0.42mmol, 2 equiv.) and 2,2-dimethylpropane-1-thiol (26µL, 0.21mmol, 1 equiv.) in toluene (1mL) at 100°C for 2h. Purification by FC (DCM / EtOAc = 99 / 1 to 80 / 20).1H NMR (400 MHz, Chloroform-d) δ 7.87 (s, 1H), 7.67 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 4.38 (s, 3H), 2.89 (s, 2H), 1.03 (s, 9H). MS (ESI+): [M+H]+313.1 / 315.1.

[0220] 7-bromo-5-(2,2-dimethylpropylsulfonyl)-1-methyl-indazole (I-059)Formula Weight: 345,26 Molecular Formula: C13H17BrN2O2S Using GP-2, I-059 was obtained as a white solid in 81% yield using I-058 (45mg, 0.14mmol, 1 equiv.) and m-CPBA (77% wet, 71mg, 0.32mmol, 2.2 equiv.) in DCM (0.7mL) at RT for 1h. Purification by FC (cHex / EtOAc = 95 / 5 to 50 / 50).1H NMR (400 MHz, Chloroform-d) δ 8.29 (d, J = 1.5 Hz, 1H), 8.13 (s, 1H), 8.03 (d, J = 1.5 Hz, 1H), 4.47 (s, 3H), 3.06 (s, 2H), 1.20 (s, 9H). MS (ESI+): [M+H]+345.0 / 347.0.

[0221] 7-bromo-5-(2,2-dimethylpropylsulfanyl)-1H-indazole (I-060)Formula Weight: 299,23 Molecular Formula: C12H15BrN2S Using GP-1, I-060 was obtained as a white solid in 83% yield using I-053 (630mg, 1.95mmol, 1 equiv.), XantPhos (56mg, 0.70mmol, 0.05 equiv.), Pd2(dba)3 (36mg, 39µmol, 0.05 equiv.), iPr2NEt (0.68mL, 3.9mmol, 2 equiv.) and 2,2- dimethylpropane-1-thiol (245µL, 1.95mmol, 1 equiv.) in toluene (10mL) at 100°C for 2h. Purification by FC (DCM / EtOAc = 99 / 1 to 90 / 10).1H NMR (400 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.77 (d, J = 1.4 Hz, 1H), 7.65 (d, J = 1.4 Hz, 1H), 5.63 (br s, 1H), 2.93 (s, 2H), 1.07 (s, 9H). MS (ESI+): [M+H]+299.1 / 301.1.

[0222] 7-bromo-5-(2,2-dimethylpropylsulfonyl)-1H-indazole (I-061)Formula Weight: 331,23 Molecular Formula: C12H15BrN2O2S Using GP-2, I-061 was obtained as a white solid in 100% yield using I-060 (485mg, 1.62mmol, 1 equiv.) and m-CPBA (77% wet, 875mg, 3.56mmol, 2.2 equiv.) in DCM (8mL) at RT for 16h. Purification by FC (cHex / EtOAc = 95 / 5 to 50 / 50).1H NMR (400 MHz, Chloroform-d) δ 8.40 (d, J = 1.4 Hz, 1H), 8.35 (s, 1H), 8.09 (d, J = 1.4 Hz, 1H), 3.11 (s, 2H), 1.24 (s, 9H). MS (ESI+): [M+H]+331.0 / 333.0.

[0223] 7-bromo-1-cyclopropyl-5-(2,2-dimethylpropylsulfonyl)indazole (I-062)Formula Weight: 371,29 Molecular Formula: C15H19BrN2O2S Under air, a MW vial was charged with I-061 (250mg, 755µmol, 1 equiv.), Cu(OAc)2(137mg, 0.75mmol, 1 equiv.), 2,2'-bipyridyl (118mg, 0.75mmol, 1 equiv.), cyclopropylboronic acid (130mg, 1.51mmol, 2 equiv.) and Na2CO3 (160mg, 1.51mmol, 2 equiv.). DCE (3.8mL) was added and the reaction mixture was stirred at 70°C for 3h. The mixture was partitioned between sat. aq. NH4Cl and DCM. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 95 / 5 to 50 / 50) to afford 118mg of I-062 (42%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.28 – 8.24 (m, 1H), 8.08 – 8.04 (m, 2H), 4.16 – 4.08 (m, 1H), 3.06 (s, 2H), 1.48 – 1.40 (m, 2H), 1.30 – 1.24 (m, 2H), 1.21 (s, 9H). MS (ESI+): [M+H]+371.1 / 373.1.

[0224] 2-[7-bromo-5-(2,2-dimethylpropylsulfonyl)indazol-1-yl]ethoxy-tert-butyl- dimethyl-silane (I-063)To a solution of I-061 (310mg, 0.936mmol, 1 equiv.) in dry DMF (4.7mL) at 0°C, was added NaH (60% in mineral oil, 45mg, 1.12mmol, 1.2 equiv.). The mixture was stirred at RT for 30min and (2-bromoethoxy)-tert-butyldimethylsilane (0.30mL, 1.4mmol, 1.5 equiv.) was added dropwise. The mixture was stirred at RT for 16h. The mixture waspartitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 96 / 4 to 60 / 40) to afford 133mg of I-063 (29%) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J = 1.7 Hz, 1H), 8.34 (s, 1H), 8.19 (d, J = 1.7 Hz, 1H), 5.16 (t, J = 5.8 Hz, 2H), 4.20 (t, J = 5.8 Hz, 2H), 3.22 (s, 2H), 1.35 (s, 9H), 0.88 (s, 9H), 0.00 (s, 6H). MS (ESI+): [M+H]+489.2 / 491.1.

[0225] [8-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-(2,2- dimethylpropylsulfonyl)indazol-7-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4- fluoro-phenyl)methanone (I-064)Molecular Formula: C33H46ClFN4O4SSi According to GP-3, I-064 was obtained in 56% yield using aryl bromide I-063 (133mg, 272µmol, 1 equiv.), piperazine I-002 (102mg, 380µmol, 1.4 equiv.), Cs2CO3 (266mg, 0.815mmol, 3 equiv.), Pd(OAc)2(6.1mg, 27µmol, 0.10 equiv.) and BINAP (20mg, 33µmol, 0.12 equiv.) in toluene (1.4mL) at reflux for 4h. Purification by FC (cHex / EtOAc = 95 / 5 to 0 / 100).1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 8.29 (s, 1H), 8.15 (s, 1H), 7.57 – 7.47 (m, 0.5H), 7.40 – 7.15 (m, 3.5H), 5.15 – 4.90 (m, 2H), 4.77 & 4.74 (s, 1H), 4.40 – 4.22 (m, 3H), 4.07 & 4.02 (s, 1H), 3.95 – 3.70 (m, 1H), 3.57 & 3.54 (s, 1H), 3.43 – 3.32 (m, 1H), 3.15 (s, 2H), 2.42 – 1.98 (m, 3.5H), 1.85 – 1.75 (m, 0.5H), 1.29 (s, 9H), 0.83 (s, 9H), 0.00 (s, 6H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.96, -109.10. MS (ESI+): [M+H]+677.4 / 679.4.

[0226] 2-bromo-6-nitro-4-[(4-phenyl-1-piperidyl)sulfonyl]aniline (I-065)Formula Weight: 440,31 Molecular Formula: C17H18BrN3O4S According to GP-4, I-065 was obtained as a white solid in 95% yield using 4-amino-3- bromo-5-nitro-benzenesulfonyl chloride (811mg, 2.57mmol, 1 equiv.), 4- phenylpiperidine (828mg, 5.13mmol, 2 equiv.) and Et3N (1.8mL, 13mmol, 5 equiv.) in DCM (27mL) at RT for 16h. Purification by FC (DCM / EtOAc = 98 / 2 to 60 / 40).1H NMR (400 MHz, Chloroform-d) δ 8.60 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.37 – 7.29 (m, 2H), 7.27 – 7.22 (m, 1H), 7.21 – 7.15 (m, 2H), 4.01 – 3.94 (m, 2H), 2.55 – 2.40 (m, 3H), 2.00 – 1.79 (m, 4H). MS (ESI+): [M+H]+440.0 / 442.0.

[0227] 3-bromo-5-[(4-phenyl-1-piperidyl)sulfonyl]benzene-1,2-diamine (I-066)Formula Weight: 410,33 Molecular Formula: C17H20BrN3O2S To a solution of I-065 (810mg, 1.84mmol, 1 equiv.) in MeOH (9.2mL) at 0°C, were added iron powder (325 mesh, 411mg, 7.36mmol, 4 equiv.) and AcOH (0.64mL, 11.0mmol, 6 equiv.). The mixture was stirred at 60°C for 16h. After cooling down to RT, EtOAc was added and the suspension was filtered over Celite (EtOAc / MeOH rinses). The filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc and sat. aq. NaHCO3. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, cHex / EtOAc = 98 / 2 to 50 / 50) to afford 377mg of I-066 (50%) as a grey solid.1H NMR(400 MHz, DMSO-d6) δ 7.30 – 7.24 (m, 2H), 7.22 – 7.14 (m, 3H), 7.00 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 2.1 Hz, 1H), 5.48 (s, 2H), 5.34 (s, 2H), 3.74 – 3.59 (m, 2H), 2.50 – 2.44 (m, 1H), 2.29 (td, J = 11.9, 2.4 Hz, 2H), 1.86 – 1.76 (m, 2H), 1.72 – 1.56 (m, 2H). MS (ESI+): [M+H]+410.0 / 412.0.

[0228] 7-bromo-5-[(4-phenyl-1-piperidyl)sulfonyl]-1H-benzotriazole (I-067)Formula Weight: 421,31 Molecular Formula: C17H17BrN4O2S To a solution of I-066 (192mg, 468µmol, 1 equiv.) in AcOH (1.5mL) at 0°C, was added a solution of NaNO2 (48mg, 0.70mmol, 1.5 equiv.) in water (0.4mL). the reaction mixture was stirred at RT for 16h. Water and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (sat. aq. NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, cHex / EtOAc = 98 / 2 to 50 / 50) to afford 190mg of I-067 (96%) as a grey solid.1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 1.4 Hz, 1H), 7.82 (d, J = 1.2 Hz, 1H), 7.35 – 7.09 (m, 5H), 3.90 – 3.75 (m, 2H), 2.53 – 2.42 (m, 1H), 2.37 (td, J = 12.1, 2.6 Hz, 2H), 1.87 – 1.75 (m, 2H), 1.75 – 1.62 (m, 2H). MS (ESI+): [M+H]+420.9 / 422.9.

[0229] Mixture of 2-[[7-bromo-5-[(4-phenyl-1-piperidyl)sulfonyl]benzotriazol-1- yl]methoxy]ethyl-trimethyl-silane, 2-[[4-bromo-6-[(4-phenyl-1- piperidyl)sulfonyl]benzotriazol-2-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-bromo-6- [(4-phenyl-1-piperidyl)sulfonyl]benzotriazol-1-yl]methoxy]ethyl-trimethyl-silane (I- 068)To a solution of I-067 (217mg, 494µmol, 1 equiv.) in dry DMF (2.5mL) at 0°C, was added NaH (60% in mineral oil, 36mg, 0.89mmol, 1.8 equiv.). The mixture was stirred at 0°C for 30min and 2-(trimethylsilyl)ethoxymethyl chloride (0.11mL, 0.59mmol, 1.2 equiv.). The mixture was stirred at RT for 16h at which point more 2- (trimethylsilyl)ethoxymethyl chloride (0.11mL, 0.59mmol, 1.2 equiv.) was added. After a further 1h at RT, the mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 98 / 2 to 50 / 50) to afford 210mg of I-068 (77%, inconsequential 3 / 2 / 1 mixture of isomers) as a colorless oil. MS (ESI+): [M+H]+551.0 / 553.0.

[0230] 7-bromo-5-[(4-phenyl-1-piperidyl)sulfonyl]-1H-benzimidazole (I-069)Formula Weight: 420,32 Molecular Formula: C18H18BrN3O2S To a solution of I-065 (310mg, 704µmol, 1 equiv.) in iPrOH (3.5mL) and formic acid (3.5mL) at RT, were added NH4Cl (377mg, 7.04mmol, 10 equiv.) and iron powder (325mesh, 393mg, 7.04mmol, 10 equiv.). The mixture was stirred at 80°C for 2.5h. After cooling down to RT, iPrOH was added and the suspension was filtered over Celite (iPrOH rinses). The filtrate was concentrated under reduced pressure. The residue was partitioned between DCM and sat. aq. NaHCO3. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 98 / 2 to 0 / 100) to afford 140mg of I-069 (47%) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 8.59 (s, 1H), 7.99 (s, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.32 – 7.23 (m, 2H), 7.23 – 7.11 (m, 3H), 3.85 – 3.77 (m, 2H), 2.50 – 2.40 (m, 1H), 2.33 (td, J = 11.9, 2.5 Hz, 2H), 1.87 – 1.75 (m, 2H), 1.75 – 1.60 (m, 2H). MS (ESI+): [M+H]+420.1 / 422.0.

[0231] Mixture of 2-[[7-bromo-5-[(4-phenyl-1-piperidyl)sulfonyl]benzimidazol-1- yl]methoxy]ethyl-trimethyl-silane and 2-[[4-bromo-6-[(4-phenyl-1- piperidyl)sulfonyl]benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (I-070)To a solution of I-069 (200mg, 476µmol, 1 equiv.) in dry DMF (2.4mL) at 0°C, was added NaH (60% in mineral oil, 29mg, 0.71mmol, 1.5 equiv.). The mixture was stirred at 0°C for 30min and 2-(trimethylsilyl)ethoxymethyl chloride (84µL, 0.48mmol, 1 equiv.) was added dropwise. The mixture was stirred at RT for 24h at which point more NaH (60% in mineral oil, 15mg, 0.62mmol, 1.3 equiv.) and 2-(trimethylsilyl)ethoxymethyl chloride (84µL, 0.48mmol, 1 equiv.) were added. After a further 4h at RT, the mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 98 / 2 to 50 / 50) to afford 150mg of I-070 (57%, inconsequential 3 / 2 mixture of isomers) as a yellow solid. MS (ESI+): [M+H]+550.2 / 552.2

[0232] 7-bromo-1-methyl-5-[(4-phenyl-1-piperidyl)sulfonyl]benzimidazole (I-071)Formula Weight: 434,35 Molecular Formula: C19H20BrN3O2S To a solution of I-069 (140mg, 0.333mmol, 1 equiv.) in dry DMF (0.7mL) at RT, were added K2CO3 (115mg, 0.833mmol, 2.5 equiv.) and iodomethane (30µL, 0.50mmol, 1.5 equiv.). The mixture was stirred at 80°C for 2h. After cooling down to RT, the mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 90 / 10 to 20 / 80) to afford 32mg of I-071 (22%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.18 (s, 1H), 7.97 (s, 1H), 7.87 (s, 1H), 7.32 – 7.24 (m, 2H), 7.24 – 7.17 (m, 1H), 7.16 – 7.09 (m, 2H), 4.20 (s, 3H), 4.02 – 3.93 (m, 2H), 2.45 – 2.30 (m, 3H), 1.98 – 1.76 (m, 4H). MS (ESI+): [M+H]+434.1 / 436.1.

[0233] 4-amino-3-bromo-N-tert-butyl-5-nitro-benzenesulfonamide (I-072)Formula Weight: 352,2 Molecular Formula: C10H14BrN3O4S A solution of 2-bromo-6-nitroaniline (590mg, 2.72mmol, 1 equiv.) in HSO3Cl (3mL) was stirred at 100°C for 1.5h. After cooling down to RT, the RM was carefully poured [caution: exotherm, gas release] on ice. Upon the melting of the ice, DCM was added and the layers were separated. The aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting arylsulfonyl chloride was dissolved in DCM (5mL) and the solution wasadded dropwise to a solution of t-BuNH2 (1.4mL, 14mmol, 5 equiv.) in DCM (5mL) at RT. The mixture was stirred at RT for 16h. It was partitioned between 1N HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1N HCl, brine), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 795mg of I-072 (83%) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 2.2 Hz, 1H), 8.13 (d, J = 2.2 Hz, 1H), 7.70 (s, 2H), 7.56 (s, 1H), 1.12 (s, 9H). MS (ESI+): [M+H]+352.0 / 354.0.

[0234] 7-bromo-N-tert-butyl-1H-benzimidazole-5-sulfonamide (I-073)Formula Weight: 332,22 Molecular Formula: C11H14BrN3O2S To a solution of I-072 (350mg, 994µmol, 1 equiv.) in iPrOH (5mL) and formic acid (5mL) at RT, were added NH4Cl (532mg, 9.93mmol, 10 equiv.) and iron powder (325 mesh, 555mg, 9.93mmol, 10 equiv.). The mixture was stirred at 80°C for 2.5h. After cooling down to RT, iPrOH was added and the suspension was filtered over Celite (iPrOH rinses). The filtrate was concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 98 / 2 to 0 / 100) to afford 309mg of I-073 (80% purity, 75%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.51 (s, 1H), 8.02 (s, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.57 (s, 1H), 1.09 (s, 9H). MS (ESI+): [M+H]+331.9 / 334.0.

[0235] 7-bromo-N-tert-butyl-3-(2-trimethylsilylethoxymethyl)benzimidazole-5- sulfonamide (I-074)Molecular Formula: C17H28BrN3O3SSi To a solution of I-073 (200mg, 772µmol, 1 equiv.) in DCM (7.7mL) at RT, were added iPr2NEt (222µL, 1.28mmol, 1.6 equiv.) and 2-(trimethylsilyl)ethoxymethyl chloride (246µL, 1.39mmol, 1.8 equiv.). The mixture was stirred at RT for 24h before being partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 98 / 2 to 50 / 50) to afford 220mg of I-074 (62%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.17 (d, J = 1.5 Hz, 1H), 7.94 (d, J = 1.6 Hz, 1H), 7.62 (s, 1H), 5.75 (s, 2H), 3.52 – 3.45 (m, 2H), 1.09 (s, 9H), 0.85 – 0.78 (m, 2H), -0.10 (s, 9H). MS (ESI+): [M+H]+462.0 / 463.9.

[0236] 7-bromo-N-tert-butyl-1-cyclopropyl-benzimidazole-5-sulfonamide (I-075)Formula Weight: 372,28 Molecular Formula: C14H18BrN3O2S Under air, a MW vial was charged with I-073 (351mg, 1.06mmol, 1 equiv.), Cu(OAc)2(211mg, 1.06mmol, 1 equiv.), 2,2'-bipyridyl (165mg, 1.06mmol, 1 equiv.), cyclopropylboronic acid (100mg, 1.16mmol, 1.1 equiv.) and Na2CO3 (224mg, 2.11mmol, 2 equiv.). DCE (1.1mL) was added and the reaction mixture was stirred at 70°C for 16h.The mixture was partitioned between sat. aq. NH4Cl and DCM. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 95 / 5 to 50 / 50) and then by PTLC (2 plates, 2 migrations in DCM / MeOH = 98 / 2) to afford 19mg of I-075 (5%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.28 (s, 1H), 8.06 (s, 1H), 8.02 (s, 1H), 4.58 (s, 1H), 3.80 – 3.70 (m, 1H), 1.35 – 1.10 (m, 13H). MS (ESI+): [M+H]+372.1 / 374.0.

[0237] 4-amino-3-bromo-N-tert-butyl-N-methyl-5-nitro-benzenesulfonamide (I-076)Formula Weight: 366,23 Molecular Formula: C11H16BrN3O4S A solution of 2-bromo-6-nitroaniline (610mg, 2.81mmol, 1 equiv.) in HSO3Cl (3mL) was stirred at 100°C for 1.5h. After cooling down to RT, the RM was carefully poured [caution: exotherm, gas release] on ice. Upon the melting of the ice, DCM was added and the layers were separated. The aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting arylsulfonyl chloride was dissolved in DCM (5mL) and the solution was added dropwise to a solution of N-methyl-tert-butylamine (0.51mL, 4.2mmol, 1.5 equiv.) and Et3N (0.59mL, 4.2mmol, 1.5 equiv.) in DCM (5mL). The mixture was stirred at RT for 16h. It was partitioned between 1N HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1N HCl, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 98 / 2 to 75 / 25) to afford 433mg of I-076 (42%) as a yellow solid.1H NMR (400 MHz, Chloroform-d) δ 8.59 (d, J = 2.2 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 2.95 (s, 3H), 1.39 (s, 9H). MS (ESI+): [M+H]+366.1 / 368.2.

[0238] 7-bromo-N-tert-butyl-N-methyl-1H-benzimidazole-5-sulfonamide (I-077)Formula Weight: 346,24 Molecular Formula: C12H16BrN3O2S To a solution of I-076 (433mg, 1.18mmol, 1 equiv.) in iPrOH (6mL) and formic acid (6mL) at RT, were added NH4Cl (632mg, 11.8mmol, 10 equiv.) and iron powder (325 mesh, 660mg, 11.8mmol, 10 equiv.). The mixture was stirred at 80°C for 3h. After cooling down to RT, iPrOH was added and the suspension was filtered over Celite (iPrOH rinses). The filtrate was concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 80 / 20 to 0 / 100) to afford 117mg of I-077 (29%) as a yellow solid.1H NMR (400 MHz, Chloroform-d) δ 8.45 (s, 1H), 8.20 (d, J = 1.5 Hz, 1H), 7.94 (d, J = 1.4 Hz, 1H), 2.99 (s, 3H), 1.37 (s, 9H). MS (ESI+): [M+H]+346.0 / 348.0.

[0239] Mixture of 7-bromo-N-tert-butyl-N-methyl-1-(2- trimethylsilylethoxymethyl)benzimidazole-5-sulfonamide and 7-bromo-N-tert-butyl-N- methyl-3-(2-trimethylsilylethoxymethyl)benzimidazole-5-sulfonamide (I-078)To a solution of I-077 (117mg, 338µmol, 1 equiv.) and iPr2NEt (65µL, 0.37mmol, 1.1 equiv.) in dry DCM (3.4mL) at RT, was added 2-(trimethylsilyl)ethoxymethyl chloride (72µL, 0.41mmol, 1.2 equiv.). The mixture was stirred at RT for 16h before being partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 98 / 2 to 50 / 50) to afford 118mg ofI-078 (73%, inconsequential 55 / 45 mixture of isomers) as a yellow oil. MS (ESI+): [M+H]+476.0 / 478.0.

[0240] 2-bromo-4-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-6-nitro-aniline (I-079)A solution of 2-bromo-6-nitroaniline (1.00g, 4.61mmol, 1 equiv.) in HSO3Cl (3.1mL) was stirred at 100°C for 1.5h. After cooling down to RT, the RM was carefully poured [caution: exotherm, gas release] on ice. Upon the melting of the ice, DCM was added and the layers were separated. The aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting arylsulfonyl chloride was dissolved in DCM (10mL) and the solution was added dropwise to a solution of 1-[2-(4-chlorophenyl)ethyl]piperazine (1.24g, 5.53mmol, 1.2 equiv.) and Et3N (0.96mL, 6.9mmol, 1.5 equiv.) in DCM (10mL). The mixture was stirred at RT for 16h. It was partitioned between 1N HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1N HCl, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, cHex / EtOAc = 94 / 6 to 40 / 60) to afford 1.60g of I-079 (69%) as a yellow solid.1H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J = 2.1 Hz, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.25 – 7.00 (m, 4H), 3.08 (s, 4H), 2.75 – 2.50 (m, 8H). MS (ESI+): [M+H]+503.0 / 505.0 / 507.0.

[0241] 7-bromo-5-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-1H- benzimidazole (I-080)Molecular Formula: C19H20BrClN4O2S To a solution of I-079 (1.60g, 3.18mmol, 1 equiv.) in iPrOH (15mL) and formic acid (15mL) at RT, were added NH4Cl (1.7g, 32mmol, 10 equiv.) and iron powder (325 mesh, 1.8g, 32mmol, 10 equiv.). The mixture was stirred at 80°C for 6h. After cooling down to RT, the volatiles were removed under reduced pressure. The residue was partitioned between water and EtOAc. K2CO3(s) was added until pH > 11. The suspension was filtered over Celite (DCM / MeOH 95 / 5 rinses). The layers of the filtrate were separated and the organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, DCM / MeOH = 98 / 2 to 90 / 10) to afford 605mg of I-080 (39%) as a yellow solid.1H NMR (400 MHz, DMSO- d6) δ 13.29 (br s, 1H), 8.57 (s, 1H), 7.95 (s, 1H), 7.70 (s, 1H), 7.31 – 7.11 (m, 4H), 2.90 (s, 4H), 2.63 (t, J = 7.5 Hz, 2H), 2.55 – 2.40 (m, 6H). MS (ESI+): [M+H]+483.0 / 485.0 / 487.0.

[0242] Mixture of 2-[[7-bromo-5-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl- benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-bromo-6-[4-[2-(4- chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl- silane (I-081)To a solution of I-080 (200mg, 413µmol, 1 equiv.) and iPr2NEt (0.11mL, 0.62mmol, 1.5 equiv.) in dry DCM (4.1mL) at RT, was added 2-(trimethylsilyl)ethoxymethyl chloride(88µL, 0.50mmol, 1.2 equiv.). The mixture was stirred at RT for 16h before being partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, DCM / MeOH = 100 / 0 to 96 / 4) to afford 177mg of I-081 (70%, inconsequential 2 / 1 mixture of isomers) as an orange oil. MS (ESI+): [M+H]+613.2 / 615.2 / 617.2.

[0243] 7-bromo-5-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-1-cyclopropyl- benzimidazole (I-082)Formula Weight: 523,87 Molecular Formula: C22H24BrClN4O2S Under air, a MW vial was charged with I-080 (245mg, 0.51mmol, 1 equiv.), Cu(OAc)2 (92mg, 0.51mmol, 1 equiv.), 2,2'-bipyridyl (79mg, 0.51mmol, 1 equiv.), cyclopropylboronic acid (87mg, 1.0mmol, 2 equiv.) and Na2CO3(107mg, 1.0mmol, 2 equiv.). DCE (5.1mL) was added and the reaction mixture was stirred at 70°C for 16h. The mixture was partitioned between sat. aq. NH4Cl and DCM. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 90 / 10 to 0 / 100) and then by PTLC (3 plates, 3 migrations in cHex / EtOAc / EtOH = 70 / 23 / 7) to afford 27mg of I-082 (10%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 8.07 (s, 1H), 7.87 (s, 1H), 7.22 (d, J = 7.9 Hz, 2H), 7.08 (d, J = 7.9 Hz, 2H), 3.82 – 3.72 (m, 1H), 3.15 – 3.00 (m, 4H), 2.75 – 2.50 (m, 8H), 1.42 – 1.19 (m, 4H). MS (ESI+): [M+H]+523.0 / 525.0 / 527.0.

[0244] 4-(2,2-dimethylpropylsulfanyl)-2-nitro-aniline (I-083)Formula Weight: 240,32 Molecular Formula: C11H16N2O2S Using GP-1, I-083 was obtained as an orange oil in 83% yield using 4-bromo-2-nitroaniline (800mg, 3.69mmol, 1 equiv.), XantPhos-Pd-G3 (70mg, 74µmol, 0.02 equiv.), iPr2NEt (0.96mL, 5.5mmol, 1.5 equiv.) and 2,2-dimethylpropane-1-thiol (469µL, 3.87mmol, 1.05 equiv.) in toluene (15mL) at 100°C for 1h. Purification by FC (cHex / EtOAc = 97 / 3 to 70 / 30).1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 2.2 Hz, 1H), 7.40 (dd, J = 8.7, 2.2 Hz, 1H), 6.74 (d, J = 8.7 Hz, 1H), 6.05 (s, 2H), 2.82 (s, 2H), 1.02 (s, 9H). MS (ESI+): [M+H]+241.1.

[0245] 4-(2,2-dimethylpropylsulfonyl)-2-nitro-aniline (I-084)Formula Weight: 272,32 Molecular Formula: C11H16N2O4S Using GP-2, I-084 was obtained as a white solid in 97% yield using I-083 (390mg, 1.62mmol, 1 equiv.) and m-CPBA (70% wet, 880mg, 3.57mmol, 2.2 equiv.) in DCM (16mL) at RT for 1h.1H NMR (400 MHz, Chloroform-d) δ 8.71 (d, J = 2.1 Hz, 1H), 7.82 (dd, J = 8.8, 2.2 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.54 (s, 2H), 3.03 (s, 2H), 1.21 (s, 9H). MS (ESI+): [M+H]+273.2.

[0246] 2-bromo-4-(2,2-dimethylpropylsulfonyl)-6-nitro-aniline (I-085)Formula Weight: 351,22 Molecular Formula: C11H15BrN2O4S To a solution of I-084 (429mg, 1.57mmol, 1 equiv.) in DMF (7.9mL) at RT, was added N-bromosuccinimide (308mg, 1.73mmol, 1.1 equiv.). The mixture was stirred at RT for 16h. The mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 97 / 3 to 70 / 30) to afford 419mg of I-085 (76%) as a yellow solid.1H NMR (400 MHz, Chloroform-d) δ 8.72 (d, J = 2.2 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.25 (br s, 2H), 3.05 (s, 2H), 1.24 (s, 9H). MS (ESI+): [M+H]+351.0 / 353.0.

[0247] 7-bromo-5-(2,2-dimethylpropylsulfonyl)-1H-benzimidazole (I-086)Formula Weight: 331,23 Molecular Formula: C12H15BrN2O2S To a solution of I-085 (419mg, 1.19mmol, 1 equiv.) in iPrOH (6mL) and formic acid (6mL) at RT, were added NH4Cl (638mg, 11.9mmol, 10 equiv.) and iron powder (325 mesh, 666mg, 11.9mmol, 10 equiv.). The mixture was stirred at 80°C for 3h. After cooling down to RT, iPrOH was added and the suspension was filtered over Celite (iPrOH rinses). The filtrate was concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, DCM / MeOH = 98 / 2 to 80 / 20) to afford 356mg of I-086 (88%) as a beige solid.1H NMR (400 MHz, DMSO-d6) δ 13.28 (s, 1H), 8.58 (s, 1H), 8.11(d, J = 1.6 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H), 3.36 (s, 2H), 1.09 (s, 9H). MS (ESI+): [M+H]+331.0 / 333.0.

[0248] Mixture of 2-[[7-bromo-5-(2,2-dimethylpropylsulfonyl)benzimidazol-1- yl]methoxy]ethyl-trimethyl-silane and 2-[[4-bromo-6-(2,2- dimethylpropylsulfonyl)benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (I-087)To a solution of I-086 (150mg, 430µmol, 1 equiv.) and iPr2NEt (150µL, 0.860mmol, 2 equiv.) in dry DCM (2.2mL) at RT, was added 2-(trimethylsilyl)ethoxymethyl chloride (114µL, 0.645mmol, 1.5 equiv.). The mixture was stirred at RT for 16h before being partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 93 / 7 to 30 / 70) to afford 138mg of I-087 (70%, inconsequential 2 / 1 mixture of isomers) as a yellow oil.1H NMR (400 MHz, Chloroform-d) of major isomer δ 8.25 (s, 1H), 8.14 (d, J = 1.5 Hz, 1H), 8.06 (d, J = 1.6 Hz, 1H), 5.60 (s, 2H), 3.58 – 3.52 (m, 2H), 3.10 (s, 2H), 1.23 (s, 9H), 1.05 – 0.78 (m, 2H), -0.03 (s, 9H).1H NMR (400 MHz, Chloroform-d) of minor isomer δ 8.35 (d, J = 1.6 Hz, 1H), 8.19 (s, 1H), 8.06 (d, J = 1.6 Hz, 1H), 5.89 (s, 2H), 3.65 – 3.58 (m, 2H), 3.10 (s, 2H), 1.21 (s, 9H), 1.05 – 0.78 (m, 2H), -0.02 (s, 9H). MS (ESI+): [M+H]+461.0 / 463.0.

[0249] 7-bromo-5-(2,2-dimethylpropylsulfonyl)-1-methyl-benzimidazole (I-088)Formula Weight: 345,26 Molecular Formula: C13H17BrN2O2STo a suspension of I-086 (200mg, 592µmol, 1 equiv.) and K2CO3 (245mg, 1.8mmol, 3 equiv.) in dry DMF (3mL) at RT, was added iodomethane (0.11mL, 1.8mmol, 3 equiv.). The mixture was stirred at RT for 1.5h before being partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by PTLC (3 plates, 2 migrations in cHex / EtOAc = 25 / 75) to afford 67mg of I-088 (33%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J = 1.6 Hz, 1H), 8.00 (s, 1H), 7.98 (d, J = 1.5 Hz, 1H), 4.21 (s, 3H), 3.09 (s, 2H), 1.20 (s, 9H). MS (ESI+): [M+H]+345.0 / 347.1.

[0250] 7-bromo-1-cyclopropyl-5-(2,2-dimethylpropylsulfonyl)benzimidazole (I-089)Formula Weight: 371,29 Molecular Formula: C15H19BrN2O2S Under air, a MW vial was charged with I-086 (270mg, 0.815mmol, 1 equiv.), Cu(OAc)2(148mg, 0.815mmol, 1 equiv.), 2,2'-bipyridyl (127mg, 0.815mmol, 1 equiv.), cyclopropylboronic acid (140mg, 1.63mmol, 2 equiv.) and Na2CO3 (173mg, 1.63mmol, 2 equiv.). DCE (4.1mL) was added and the reaction mixture was stirred at 70°C for 16h. The mixture was partitioned between sat. aq. NH4Cl and DCM. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 95 / 5 to 70 / 30) to afford 20mg of I-089 (7%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.27 (s, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 3.76 (tt, J = 7.3, 3.8 Hz, 1H), 3.08 (s, 2H), 1.38 – 1.14 (m, 13H). MS (ESI+): [M+H]+371.1 / 373.1.

[0251] 2-bromo-N-ethyl-6-nitro-aniline (I-090)Formula Weight: 245,07 Molecular Formula: C8H9BrN2O2A mixture of 1-bromo-2-fluoro-3-nitrobenzene (1.00 g, 4.55 mmol, 1 equiv.) and ethylamine (2M in THF, 11 mL, 23 mmol, 5equiv.) was stirred at RT for 1h. The mixture was concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, cHex / EtOAc = 95 / 5 to 50 / 50) to afford 869mg of I-090 (78%) as a yellow oil.1H NMR (400 MHz, Chloroform-d) δ 7.81 (dd, J = 8.4, 1.6 Hz, 1H), 7.61 (dd, J = 7.7, 1.6 Hz, 1H), 6.63 (t, J = 8.1 Hz, 1H), 5.90 (br s, 1H), 3.26 (q, J = 7.2 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H). MS (ESI+): [M+H]+245.0 / 247.1.

[0252] 2-bromo-N-ethyl-4-iodo-6-nitro-aniline (I-091)Formula Weight: 370,97 Molecular Formula: C8H8BrIN2O2To a solution of I-090 (494mg, 2.02mmol, 1 equiv.) in AcOH (3.1mL) at RT, was added N-iodosuccinimide (544mg, 2.42mmol, 1.2 equiv.). The mixture was stirred at 50°C for 16h (in the dark). The volatiles were removed under reduced pressure. The residue was dissolved in EtOAc and the resulting solution was washed (1N Na2S2O3, sat. aq. NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, cHex / EtOAc = 99 / 1 to 90 / 10) to afford 713mg of I-091 (93%) as an orange oil.1H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J = 2.1 Hz, 1H), 7.95 (d, J = 2.1 Hz, 1H), 6.05 (s, 1H), 3.34 (qd, J = 7.2, 5.4 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H). MS (ESI+): [M+H]+370.9 / 372.9.

[0253] 7-bromo-1-ethyl-5-iodo-benzimidazole (I-092)Formula Weight: 350,98 Molecular Formula: C9H8BrIN2To a solution of I-091 (713mg, 1.88mmol, 1 equiv.) in iPrOH (9.5mL) and formic acid (9.5mL) at RT, were added NH4Cl (1.01g, 18.8mmol, 10 equiv.) and iron powder (325 mesh, 1.05g, 18.8mmol, 10 equiv.). The mixture was stirred at 80°C for 4h. After cooling down to RT, EtOAc was added and the suspension was filtered over Celite (EtOAc rinses). The filtrate was concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, DCM / MeOH = 98 / 2 to 90 / 10) to afford 446mg of I-092 (67%) as a beige solid.1H NMR (400 MHz, Chloroform-d) 8.09 (d, J = 1.5 Hz, 1H), 7.98 (s, 1H), 7.75 (d, J = 1.3 Hz, 1H), 4.56 (q, J = 7.2 Hz, 2H), 1.55 (t, J = 7.2 Hz, 3H). MS (ESI+): [M+H]+350.9 / 352.9.

[0254] 7-bromo-5-(2,2-dimethylpropylsulfanyl)-1-ethyl-benzimidazole (I-093)Formula Weight: 327,28 Molecular Formula: C14H19BrN2S Using GP-1, I-093 was obtained as a yellow oil in 58% yield using I-092 (150mg, 0.42mmol, 1 equiv.), XantPhos-Pd-G3 (20mg, 21µmol, 0.05 equiv.), iPr2NEt (0.15mL, 0.85mmol, 2 equiv.) and 2,2-dimethylpropane-1-thiol (52µL, 0.43mmol, 1 equiv.) in toluene (2.1mL) at 110°C for 1.5h. Purification by FC (DCM / MeOH = 99 / 1 to 95 / 5).1H NMR (400 MHz, Chloroform-d) δ 7.87 (s, 1H), 7.76 (d, J = 1.5 Hz, 1H), 7.49 (d, J = 1.5 Hz, 1H), 4.53 (q, J = 7.2 Hz, 2H), 2.92 (s, 2H), 1.54 (t, J = 7.2 Hz, 3H), 1.04 (s, 9H). MS (ESI+): [M+H]+327.1 / 329.1.

[0255] 7-bromo-5-(2,2-dimethylpropylsulfonyl)-1-ethyl-benzimidazole (I-094)Formula Weight: 359,28 Molecular Formula: C14H19BrN2O2S Using GP-2, I-094 was obtained as a white solid in 81% yield using I-093 (81mg, 0.25mmol, 1 equiv.) and m-CPBA (70% wet, 134mg, 0.54mmol, 2.2 equiv.) in DCM 1.2mL) at RT for 16h. Purification by FC (DCM / MeOH = 99 / 1 to 95 / 5).1H NMR (400 MHz, Chloroform-d) δ 8.24 (d, J = 1.6 Hz, 1H), 8.01 (s, 1H), 7.93 (d, J = 1.6 Hz, 1H), 4.56 (q, J = 7.2 Hz, 2H), 3.01 (s, 2H), 1.51 (t, J = 7.2 Hz, 3H), 1.13 (s, 9H). MS (ESI+): [M+H]+359.0 / 361.0.

[0256] 2,6-dichloropyridine-4-sulfonyl chloride (I-095)Formula Weight: 246,5 Molecular Formula: C5H2Cl3NO2S In a first 250mL flask: to water (37mL) at 0°C, was added dropwise SOCl2(6.0mL, 83mmol, 4.5 equiv.) [Caution: Exotherm & gas release]. The resulting solution was stirred at RT for 1h and CuCl (91mg, 0.92mmol, 0.05 equiv.) was added. The resulting green solution was stirred at 0°C for 10min. In another 250mL flask: to a solution of 4- amino-2,6-dichloropyridine (3.00 g, 18.4 mmol, 1 equiv.) in 37% HCl (31mL) at 0°C, was added dropwise a solution of NaNO2 (1.42g, 20.6mmol, 1.12 equiv.) in water (15mL). The mixture was stirred at 0°C for 45min at which point, the resulting mixture was added dropwise to the first solution, maintaining the temperature at 0°C. The mixture was stirred at RT for 2h. The suspension was filtered over fritted glass and the filter cake was washed with water (20mL). The filter cake was dissolved in EtOAc and the organic solution was dried (Na2SO4), filtered and concentrated under reduced pressure to afford3.50g of I-095 (78%) as a brown solid, which was promptly used in the next step.1H NMR (400 MHz, Chloroform-d) δ 7.78 (s, 2H).

[0257] 2,6-dichloro-4-[(4-phenyl-1-piperidyl)sulfonyl]pyridine (I-096)Formula Weight: 371,28 Molecular Formula: C16H16Cl2N2O2S According to GP-4, I-096 was obtained as an orange solid in 80% yield using I-095 (333mg, 1.35mmol, 1 equiv.), 4-phenylpiperidine (261mg, 1.62mmol, 1.2 equiv.) and Et3N (0.28mL, 2.0mmol, 1.5 equiv.) in DCM (6.8mL) at RT for 16h. Purification by FC (cHex / EtOAc = 100 / 0 to 80 / 20).1H NMR (400 MHz, Chloroform-d) δ 7.59 (s, 2H), 7.39 – 7.29 (m, 2H), 7.26 – 7.06 (m, 3H), 4.07 – 3.91 (m, 2H), 2.63 – 2.45 (m, 3H), 2.13 – 1.74 (m, 4H). MS (ESI+): [M+H]+371.1 / 373.1.

[0258] (2-chloro-4-fluoro-phenyl)-[8-[6-chloro-4-[(4-phenyl-1-piperidyl)sulfonyl]-2- pyridyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-097)Formula Weight: 603,53 Molecular Formula:A solution of I-096 (400mg, 1.08mmol, 1 equiv.), I-002 (318mg, 1.19mmol, 1.1 equiv.) and iPr2NEt (0.28mL, 1.6mmol, 1.5 equiv.) in NMP (4mL) was stirred at 100°C for 16h. After cooling down to RT, the mixture was partitioned between 1N HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1N HCl, water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dryload, cHex / EtOAc = 100 / 0 to 50 / 50) to afford 406mg of I-097 (62%) as a white solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.43 – 7.29 (m, 2.5H), 7.26 – 7.21 (m, 1.5H), 7.20 – 6.98 (m, 4H), 6.92 – 6.85 (m, 1H), 6.74 (d, J = 1.1 Hz, 1H), 4.74 – 4.50 (m, 3H), 4.00 – 3.90 (m, 2H), 3.60 – 3.38 (m, 1H), 3.23 – 3.10 (m, 2H), 2.65 – 2.45 (m, 3H), 2.20 – 1.80 (m, 7.5H), 1.80 – 1.65 (m, 0.5H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.76, -108.90. MS (ESI+): [M+H]+603.1 / 605.1.

[0259] (2-chloro-4-fluoro-phenyl)-[8-[6-hydrazino-4-[(4-phenyl-1-piperidyl)sulfonyl]- 2-pyridyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-098)Formula Weight: 599,12 Molecular Formula: C29H32ClFN6O3S A solution of I-097 (200mg, 0.331mmol, 1 equiv.), hydrazine hydrate (83mg, 1.7mmol, 5 equiv.) in n-butanol (1.6mL) was stirred at 130°C for 72h. The reaction mixture was concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, DCM / MeOH = 99 / 1 to 90 / 10) to afford 50mg of I-098 (25%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.57 – 7.28 (m, 2.5H), 7.26 – 6.95 (m, 5.5H), 6.39 (s, 1H), 6.24 (s, 1H), 4.65 (s, 1H), 4.58 – 4.41 (m, 2H), 4.00 – 3.85 (m, 2H), 3.63 – 3.40 (m, 1H), 3.32 – 3.03 (m, 2H), 2.64 – 2.42 (m, 3H), 2.10 – 1.65 (m, 8H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.03, -109.17. MS (ESI+): [M+H]+599.2 / 601.1.

[0260] [8-[6-amino-4-[(4-phenyl-1-piperidyl)sulfonyl]-2-pyridyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-099)Formula Weight: 584,1 Molecular Formula: C29H31ClFN5O3S A MW vial was charged with I-097 (161mg, 0.267mmol, 1 equiv.), benzophenone imine (91mg, 0.40mmol, 1.5 equiv.), NaOt-Bu (43mg, 0.48mmol, 1.8 equiv.), Pd2(dba)3(12mg, 13µmol, 0.05 equiv.) and rac-BINAP (17mg, 27µmol, 0.1 equiv.). The vial was flushed with Ar and degassed toluene (1.3mL) was added. The reaction mixture was stirred at 140°C under microwave irradiation for 1h. After cooling down to RT, MeOH (0.4mL) and 1N HCl (0.4mL) was added and the mixture vigorously stirred for 0.5h. EtOAc and water were added and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 90 / 10 to 0 / 100) to afford 106mg of I-099 (68%) as a white solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.43 – 7.28 (m, 2.5H), 7.25 – 7.00 (m, 5.5H), 6.22 (s, 1H), 6.14 (s, 1H), 4.63 (s, 1H), 4.57 – 4.39 (m, 4H), 3.95 – 3.85 (m, 2H), 3.65 – 3.38 (m, 1H), 3.23 & 3.20 (d, J = 5.1 Hz, 1H), 3.15 – 3.00 (m, 1H), 2.65 – 2.42 (m, 3H), 2.05 – 1.61 (m, 8H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ - 109.11, -109.25. MS (ESI+): [M+H]+584.2 / 586.1.

[0261] [8-[6-(aminomethyl)-4-[(4-phenyl-1-piperidyl)sulfonyl]-2-pyridyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-100)Formula Weight: 598,13 Molecular Formula: C30H33ClFN5O3S A MW vial was charged with I-097 (300mg, 0.497mmol, 1 equiv.), potassium N-Boc- aminomethyltrifluoroborate (306mg, 1.29mmol, 2.6 equiv.), Cs2CO3 (810mg, 2.49mmol, 5 equiv.) and cataCXium-Pd-G3 (11mg, 15µmol, 0.03 equiv.). The vial was flushed with Ar and a degassed dioxane / water (1 / 1, 4mL) was added. The vial was sealed and the mixture was stirred at 100°C for 22h. After cooling down to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 95 / 5 to 50 / 50) to afford an inseparable mixture of starting material and intermediate Boc-protected desired product. It was dissolved in DCM (1.7mL) at RT and HCl (4N in dioxane, 0.85mL, 3.4 mmol, 7 equiv.) was added. The mixture was stirred at RT for 5h before being concentrated under reduced pressure. The residue was partitioned between water and DCM, and Na2CO3(s) was added portionwise until pH > 11. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, DCM / MeOH = 98 / 2 to 80 / 20) to afford 92mg of I-100 (31%) as a white solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.48 – 7.27 (m, 2.5H), 7.26 – 6.97 (m, 5.5H), 6.89 (s, 1H), 6.77 (s, 1H), 4.77 & 4.75 (s, 1H), 4.62 – 4.40 (m, 2H), 4.11 – 3.83 (m, 4H), 3.63 – 3.38 (m, 1H), 3.28 – 3.06 (m, 2H), 2.62 – 2.41 (m, 3H), 2.23 – 1.64 (m, 10H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.93, -109.06. MS (ESI+): [M+H]+598.1 / 600.1.

[0262] 2,6-dichloro-N,N-diethyl-pyridine-4-sulfonamide (I-101)Formula Weight: 283,17 Molecular Formula: C9H12Cl2N2O2S According to GP-4, I-101 was obtained as a yellow solid in 79% yield using I-095 (1.00g, 4.06mmol, 1 equiv.), diethylamine (0.50mL, 4.9mmol, 1.2 equiv.) and Et3N (0.85mL, 6.1mmol, 1.5 equiv.) in DCM (20mL) at RT for 16h. Purification by FC (cHex / EtOAc = 100 / 0 to 80 / 20).1H NMR (400 MHz, Chloroform-d) δ 7.60 (s, 2H), 3.30 (q, J = 7.1 Hz, 4H), 1.20 (t, J = 7.1 Hz, 6H). MS (ESI+): [M+H]+283.0 / 285.1.

[0263] 2-chloro-6-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]- N,N-diethyl-pyridine-4-sulfonamide (I-102)Formula Weight: 515,43 Molecular Formula: C22H25Cl2FN4O3S A solution of I-101 (910mg, 3.22mmol, 1 equiv.), I-002 (1.04g, 3.86mmol, 1.2 equiv.) and iPr2NEt (0.84mL, 4.8mmol, 1.5 equiv.) in NMP (8mL) was stirred at 120°C for 16h. After cooling down to RT, the mixture was partitioned between 1N HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1N HCl, water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, cHex / EtOAc = 90 / 10 to 0 / 100) to afford 1.42g of I-102 (86%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.42 – 7.32 (m, 0.5H), 7.24 – 6.96 (m, 2.5H), 6.87 (s, 1H), 6.78 (s, 1H), 4.73 – 4.43 (m, 3H), 3.59 – 3.34 (m, 1H), 3.28 (q, J= 7.2 Hz, 4H), 3.20 – 3.05 (m, 2H), 2.22 – 1.93 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 1.19 (t, J = 7.2 Hz, 6H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.83, - 108.97. MS (ESI+): [M+H]+515.1 / 517.1.

[0264] 2-(aminomethyl)-6-[3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-N,N-diethyl-pyridine-4-sulfonamide (I-103)Formula Weight: 510,02 Molecular Formula: C23H29ClFN5O3S A MW vial was charged with I-102 (1.42g, 2.75mmol, 1 equiv.), potassium N-Boc- aminomethyltrifluoroborate (1.96g, 8.26mmol, 3 equiv.), Cs2CO3 (5.39g, 16.5mmol, 5 equiv.) and cataCXium-Pd-G3 (60mg, 83µmol, 0.03 equiv.). The vial was flushed with Ar and a degassed dioxane / water (1 / 1, 14mL) was added. The vial was sealed and the mixture was stirred at 100°C for 20h. After cooling down to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, cHex / EtOAc = 90 / 10 to 0 / 100) to afford an inseparable mixture of starting material and intermediate Boc-protected desired product. It was dissolved in DCM (14mL) at RT and HCl (4N in dioxane, 6.9mL, 28 mmol, 10 equiv.) was added. The mixture was stirred at RT for 16h before being concentrated under reduced pressure. The residue was partitioned between water and DCM, and K2CO3(s) was added portionwise until pH > 11. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, DCM / MeOH = 98 / 2 to 80 / 20) to afford 805mg of I-103 (57%) as a white solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.42 – 7.32 (m, 0.5H), 7.25 – 6.95 (m, 2.5H), 6.88 (s,1H), 6.80 (s, 1H), 4.73 (d, 1H), 4.60 – 4.44 (m, 2H), 3.90 (s, 2H), 3.60 – 3.34 (m, 1H), 3.33 – 3.01 (m, 6H), 2.38 – 1.92 (m, 5.5H), 1.76 – 1.64 (m, 0.5H), 1.17 (t, J = 7.1 Hz, 6H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.02, -109.15. MS (ESI+): [M+H]+510.2 / 512.2.

[0265] N-tert-butyl-2,6-dichloro-pyridine-4-sulfonamide (I-104)Formula Weight: 283,17 Molecular Formula: C9H12Cl2N2O2S According to GP-4, I-104 was obtained as a yellow solid in 78% yield using I-095 (2.00g, 8.11mmol, 1 equiv.), t-BuNH2 (1.0mL, 10mmol, 1.2 equiv.) and Et3N (1.7mL, 12mmol, 1.5 equiv.) in DCM (41mL) at RT for 16h. Purification by FC (cHex / EtOAc = 97 / 3 to 70 / 30).1H NMR (400 MHz, Chloroform-d) δ 7.68 (s, 2H), 4.85 (s, 1H), 1.30 (s, 9H). MS (ESI+): [M+H]+283.0 / 285.1.

[0266] N-tert-butyl-2-chloro-6-[3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]pyridine-4-sulfonamide (I-105)Formula Weight: 515,43 Molecular Formula: C22H25Cl2FN4O3S A solution of I-104 (1.78g, 6.30mmol, 1 equiv.), I-002 (2.03g, 7.56mmol, 1.2 equiv.) and iPr2NEt (1.65mL, 9.5mmol, 1.5 equiv.) in NMP (16mL) was stirred at 120°C for 16h. After cooling down to RT, the mixture was partitioned between sat. aq. NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered andconcentrated under reduced pressure. The residue was purified by FC (80g column, dry load, cHex / EtOAc = 90 / 10 to 0 / 100) to afford 2.77g of I-105 (85%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.42 – 7.33 (m, 0.5H), 7.24 – 6.98 (m, 2.5H), 6.96 (s, 1H), 6.89 (s, 1H), 4.81 (s, 1H), 4.68 – 4.59 (m, 1H), 4.59 – 4.46 (m, 2H), 3.57 – 3.35 (m, 1H), 3.18 – 3.05 (m, 2H), 2.17 – 1.94 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 1.29 (s, 9H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.83, - 108.97. MS (ESI+): [M+H]+515.1 / 517.1.

[0267] 2-(aminomethyl)-N-tert-butyl-6-[3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]pyridine-4-sulfonamide (I-106)Formula Weight: 510,02 Molecular Formula: C23H29ClFN5O3S A sealable flask was charged with I-105 (2.67g, 5.17mmol, 1 equiv.), potassium N-Boc- aminomethyltrifluoroborate (1.47g, 6.21mmol, 1.2 equiv.), Cs2CO3(8.43g, 25.9mmol, 5 equiv.) and cataCXium-Pd-G3 (113mg, 155µmol, 0.03 equiv.). The flask was flushed with Ar and a degassed dioxane / water (1 / 1, 26mL) was added. The flask was sealed and the mixture was stirred at 100°C for 1h. After cooling down to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (80g column, dry load, cHex / EtOAc = 90 / 10 to 0 / 100) to afford an inseparable mixture of starting material and intermediate Boc-protected desired product. It was dissolved in DCM (26mL) at RT and HCl (4N in dioxane, 13mL, 52 mmol, 10 equiv.) was added. The mixture was stirred at RT for 16h before being concentrated under reduced pressure. The residue was partitioned between water and DCM, and K2CO3(s) was added portionwise until pH > 11. The layers were separated and the aqueous phase was extracted with DCM.The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, DCM / MeOH = 98 / 2 to 80 / 20) to afford 1.09g of I-106 (41%) as a white solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.42 – 7.30 (m, 0.5H), 7.25 – 6.95 (m, 3.5H), 6.91 (s, 1H), 4.90 (br s, 1H), 4.72 (s, 1H), 4.62 – 4.37 (m, 2H), 3.92 (s, 2H), 3.57 – 3.35 (m, 1H), 3.23 – 3.02 (m, 2H), 2.44 (br s, 2H), 2.15 – 1.90 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 1.27 (s, 9H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.02, -109.17. MS (ESI+): [M+H]+510.2 / 512.2.

[0268] 2,6-dichloro-4-(3,3-difluoropyrrolidin-1-yl)sulfonyl-pyridine (I-107)Formula Weight: 317,14 Molecular Formula: C9H8Cl2F2N2O2S According to GP-4, I-107 was obtained as a yellow solid in 45% yield using I-095 (1.24g, 4.53mmol, 1 equiv.), 3,3-difluoropyrrolidine hydrochloride (975mg, 6.79mmol, 1.5 equiv.) and Et3N (1.9mL, 14mmol, 3 equiv.) in DCM (18mL) at RT for 2h. Purification by FC (cHex / EtOAc = 97 / 3 to 70 / 30).1H NMR (400 MHz, Chloroform-d) δ 7.63 (s, 2H), 3.68 (t, J = 12.5 Hz, 2H), 3.58 (t, J = 7.3 Hz, 2H), 2.42 (tt, J = 13.6, 7.3 Hz, 2H).19F NMR (376 MHz, Chloroform-d) δ -100.1. MS (ESI+): [M+H]+317.0 / 319.0.

[0269] [8-[6-chloro-4-(3,3-difluoropyrrolidin-1-yl)sulfonyl-2-pyridyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-108)Formula Weight: 549,39 Molecular Formula: C22H21Cl2F3N4O3SA solution of I-107 (635mg, 2.00mmol, 1 equiv.), I-002 (646mg, 2.40mmol, 1.2 equiv.) and iPr2NEt (0.52mL, 3.0mmol, 1.5 equiv.) in NMP (8mL) was stirred at 100°C for 16h. After cooling down to RT, the mixture was partitioned between 1N HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combinedA sealable flask was charged with I-108 (4.48g, 8.15mmol, 1 equiv.), potassium N-Boc- aminomethyltrifluoroborate (2.51g, 10.6mmol, 1.3 equiv.), Cs2CO3 (6.64g, 20.4mmol, 2.5 equiv.) and cataCXium-Pd-G3 (178mg, 245µmol, 0.03 equiv.). The flask was flushed with Ar and a degassed dioxane / water mixture (1 / 1, 82mL) was added. The flask was sealed and the mixture was stirred at 100°C for 1h. After cooling down to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (80g column, dry load, cHex / EtOAc = 90 / 10 to 0 / 100) to afford an inseparablemixture of starting material and intermediate Boc-protected desired product. It was dissolved in DCM (35mL) at RT and HCl (4N in dioxane, 17mL, 69 mmol, 8.5 equiv.) was added. The mixture was stirred at RT for 16h before being concentrated under reduced pressure. The residue was partitioned between water and DCM, and K2CO3(s)Formula Weight: 287,14 Molecular Formula: C8H9Cl2FN2O2S According to GP-4, I-110 was obtained as a yellow solid in 72% yield using I-095 (1.50g, 6.09mmol, 1 equiv.), 3-fluoropropan-1-amine hydrochloride (829mg, 7.30mmol, 1.2 equiv.) and Et3N (2.5mL, 18mmol, 3 equiv.) in DCM (30mL) at RT for 16h. Purification by FC (cHex / EtOAc = 94 / 6 to 40 / 60).1H NMR (400 MHz, Chloroform-d) δ 7.66 (s, 2H), 4.92 (t, J = 5.9 Hz, 1H), 4.55 (dt, J = 47.1, 5.4 Hz, 2H), 3.26 (q, J = 6.3 Hz, 2H), 1.96 (dp, J = 27.8, 5.9 Hz, 2H). MS (ESI+): [M+H]+287.0 / 289.0.

[0272] 2-chloro-6-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]- N-(3-fluoropropyl)pyridine-4-sulfonamide (I-111)Formula Weight: 519,39 Molecular Formula:A solution of I-110 (1.26g, 4.39mmol, 1 equiv.), I-002 (1.42g, 5.27mmol, 1.2 equiv.) and iPr2NEt (1.2mL, 6.6mmol, 1.5 equiv.) in NMP (20mL) was stirred at 120°C for 16h. After cooling down to RT, the mixture was partitioned between sat. aq. NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (80g column, dry load, cHex / EtOAc = 90 / 10 to 0 / 100) to afford 1.99g of I-111 (87%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.42 – 4.32 (m, 0.5H), 7.25 – 6.96 (m, 2.5H), 6.93 (s, 1H), 6.83 (s, 1H), 4.93 (s, 1H), 4.65 (s, 1H), 4.61 – 4.41 (m, 4H), 3.62 – 3.35 (m, 1H), 3.29 – 3.01 (m, 4H), 2.20 – 1.85 (m, 5.5H), 1.75 – 1.65 (m, 0.5H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.73, -108.87, -221.10, -221.13. MS (ESI+): [M+H]+519.1 / 521.1.

[0273] 2-(aminomethyl)-6-[3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-N-(3-fluoropropyl)pyridine-4-sulfonamide (I-112)Formula Weight: 513,99 Molecular Formula: C22H26ClF2N5O3S A sealable flask was charged with I-109 (1.99g, 3.84mmol, 1 equiv.), potassium N-Boc- aminomethyltrifluoroborate (1.18g, 4.99mmol, 1.3 equiv.), Cs2CO3(3.12g, 9.59mmol,2.5 equiv.) and cataCXium-Pd-G3 (83.8mg, 115µmol, 0.03 equiv.). The flask was flushed with Ar and degassed dioxane / water (1 / 1, 20mL) was added. The flask was sealed and the mixture was stirred at 100°C for 2h. After cooling down to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, cHex / EtOAc = 90 / 10 to 0 / 100) to afford an inseparable mixture of starting material and intermediate Boc-protected desired product. It was dissolved in DCM (20mL) at RT and HCl (4N in dioxane, 9.6mL, 38 mmol, 10 equiv.) was added. The mixture was stirred at RT for 16h before being concentrated under reduced pressure. The residue was partitioned between water and DCM, and K2CO3(s) was added portionwise until pH > 11. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (80g column, dry load, DCM / MeOH) = 98 / 2 to 80 / 20) to afford 1.39g of I-112 (63%) as a white solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.43 – 7.33 (m, 0.5H), 7.23 – 6.96 (m, 2.5H), 6.94 (s, 1H), 6.85 (s, 1H), 4.70 (s, 1H), 4.61 – 4.34 (m, 4H), 3.86 (s, 2H), 3.60 – 3.35 (m, 1H), 3.24 – 3.00 (m, 4H), 2.41 (br s, 2H), 2.15 – 1.80 (m, 5.5H), 1.75 – 1.65 (m, 0.5H). MS (ESI+): [M+H]+514.2 / 516.2.

[0274] 2,6-dichloro-N-(3,3-difluorocyclobutyl)pyridine-4-sulfonamide (I-113)Formula Weight: 317,14 Molecular Formula: C9H8Cl2F2N2O2S According to GP-4, I-113 was obtained as a white solid in 49% yield using I-095 (3.27g, 13.3mmol, 1 equiv.), 3,3-difluorocyclobutanamine hydrochloride (2.00g, 13.9mmol, 1.05 equiv.) and Et3N (4.6mL, 33mmol, 2.5 equiv.) in DCM (66mL) at RT for 16h. Purification by FC (cHex / EtOAc = 95 / 5 to 50 / 50).1H NMR (400 MHz, Chloroform-d) δ 7.67 (s, 2H), 5.22 (d, J = 7.4 Hz, 1H), 3.90 – 3.80 (m, 1H), 3.10 – 2.90 (m, 2H), 2.64 – 2.43 (m, 2H).19F NMR (376 MHz, Chloroform-d) δ -84.80 (d, JF-F = 201.6 Hz), -97.86 (d, JF-F = 201.6 Hz). MS (ESI+): [M+H]+317.1 / 319.0.

[0275] 2-chloro-6-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]- N-(3,3-difluorocyclobutyl)pyridine-4-sulfonamide (I-114)Formula Weight: 549,39 Molecular Formula: C22H21Cl2F3N4O3S A solution of I-113 (2.08g, 6.56mmol, 1 equiv.), I-002 (1.94g, 7.21mmol, 1.1 equiv.) and iPr2NEt (1.7mL, 9.8mmol, 1.5 equiv.) in NMP (24mL) was stirred at 120°C for 16h. After cooling down to RT, the mixture was partitioned between sat. aq. NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (80g column, dry load, cHex / EtOAc = 95 / 5 to 50 / 50) to afford 3.1g of I-114 (86%) as a white solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.47 – 7.37 (m, 0.5H), 7.28 – 7.02 (m, 2.5H), 6.92 (s, 1H), 6.85 (s, 1H), 5.75 – 5.60 (m, 1H), 4.76 – 4.45 (m, 3H), 3.78 (s, 1H), 3.60 – 3.38 (m, 1H), 3.25 – 3.10 (m, 2H), 3.00 – 2.80 (m, 2H), 2.62 – 2.42 (m, 2H), 2.20 – 1.95 (m, 3.5H), 1.80 – 1.65 (m, 0.5H). MS (ESI+): [M+H]+549.2 / 551.2.

[0276] 2-(aminomethyl)-6-[3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-N-(3,3-difluorocyclobutyl)pyridine-4-sulfonamide (I-115)Formula Weight: 543,99 Molecular Formula: C23H25ClF3N5O3S A sealable flask was charged with I-114 (3.10g, 5.64mmol, 1 equiv.), potassium N-Boc- aminomethyltrifluoroborate (1.61g, 6.77mmol, 1.2 equiv.), Cs2CO3(4.6g, 14mmol, 2.5 equiv.) and cataCXium-Pd-G3 (123mg, 169µmol, 0.03 equiv.). The flask was flushed with Ar and degassed dioxane / water (1 / 1, 56mL) was added. The flask was sealed and the mixture was stirred at 100°C for 1h. After cooling down to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (80g column, dry load, cHex / EtOAc = 95 / 5 to 50 / 50) to afford an inseparable mixture of starting material and intermediate Boc-protected desired product. It was dissolved in DCM (14mL) at RT and HCl (4N in dioxane, 14mL, 56 mmol, 10 equiv.) was added. The mixture was stirred at RT for 4h before being concentrated under reduced pressure. The residue was partitioned between water and DCM, and K2CO3(s) was added portionwise until pH > 11. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, DCM / MeOH) = 98 / 2 to 80 / 20) to afford 900mg of I-115 (29%) as a white solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.45 – 7.30 (m, 0.5H), 7.24 – 6.97 (m, 2.5H), 6.90 (s, 1H), 6.84 (s, 1H), 5.80 (s, 1H), 4.67 (s, 1H), 4.61 – 4.40 (m, 2H), 4.30 (s, 2H), 3.74 (s, 1H), 3.57 – 3.37 (m, 1H), 3.20 – 3.05 (m, 2H), 2.92 – 2.75 (m, 2H), 2.57 – 2.38 (m, 2H), 2.15 – 1.90 (m, 3.5H), 1.85 – 1.65 (m, 2.5H).19F NMR (376 MHz, Chloroform-d, 2 setsof rotamers) δ -84.36 (d, JF-F = 200.3 Hz), -98.55 & -98.53 (d, JF-F = 200.6 Hz), -108.79, -108.94. MS (ESI+): [M+H]+544.1 / 546.2.

[0277] 1-[2-(4-chlorophenyl)ethyl]-4-[(2,6-dichloro-4-pyridyl)sulfonyl]piperazine (I-116)434,77 Molecular Formula: C17H18Cl3N3O2S According to GP-4, I-116 was obtained as a white solid in 54% yield using I-095 (1.64g, 6.65mmol, 1 equiv.), 1-[2-(4-chlorophenyl)ethyl]piperazine (1.64g, 7.32mmol, 1.1 equiv.) and Et3N (1.4mL, 10mmol, 1.5 equiv.) in DCM (33mL) at RT for 16h. Purification by FC (cHex / EtOAc = 95 / 5 to 50 / 50).1H NMR (400 MHz, Chloroform-d) δ 7.56 (s, 2H), 7.26 (d, J = 7.9 Hz, 2H), 7.11 (d, J = 7.9 Hz, 2H), 3.17 (s, 4H), 2.72 (s, 2H), 2.63 (s, 6H). MS (ESI+): [M+H]+434.1 / 436.0 / 438.0.

[0278] [8-[6-chloro-4-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-2-pyridyl]- 3,8-diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-117)A solution of I-116 (1.56g, 3.59mmol, 1 equiv.), I-002 (1.06g, 3.95mmol, 1.1 equiv.) and iPr2NEt (0.94mL, 5.4mmol, 1.5 equiv.) in NMP (13mL) was stirred at 120°C for 16h. After cooling down to RT, the mixture was partitioned between sat. aq. NaHCO3and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered andconcentrated under reduced pressure. The residue was purified by FC (80g column, dry load, cHex / EtOAc = 95 / 5 to 50 / 50) to afford 1.6g of I-117 (66%) as a white solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.45 – 7.35 (m, 0.5H), 7.30 – 7.20 (m, 2.5H), 7.21 – 7.00 (m, 4H), 6.85 (s, 1H), 6.70 (s, 1H), 4.70 – 4.50 (m, 3H), 3.62 – 3.38 (m, 1H), 3.25 – 3.05 (m, 6H), 2.80 – 2.70 (m, 2H), 2.70 – 2.55 (m, 6H), 2.20 – 1.95 (m, 3.5H), 1.80 – 1.70 (s, 0.5H). MS (ESI+): [M+H]+666.3 / 668.4 / 670.4.

[0279] [8-[6-(aminomethyl)-4-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-2- pyridyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-118)Formula Weight: 661,62 Molecular Formula: C31H35Cl2FN6O3S A sealable flask was charged with I-117 (1.57g, 2.35mmol, 1 equiv.), potassium N-Boc- aminomethyltrifluoroborate (670mg, 2.82mmol, 1.2 equiv.), Cs2CO3(1.92g, 5.88mmol, 2.5 equiv.) and cataCXium-Pd-G3 (51mg, 71µmol, 0.03 equiv.). The flask was flushed with Ar and degassed dioxane / water (1 / 1, 18mL) was added. The flask was sealed and the mixture was stirred at 100°C for 1h. After cooling down to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (80g column, dry load, cHex / EtOAc = 98 / 2 to 50 / 50) to afford an inseparable mixture of starting material and intermediate Boc-protected desired product. It was dissolved in Dioxane (11mL) at RT and HCl (4N in dioxane, 2.7mL, 11mmol, 4.6 equiv.) was added. The mixture was stirred at RT for 4h before being concentrated under reduced pressure. The residue was partitioned between water and DCM, and K2CO3(s) was added portionwise until pH > 11. The layers were separated and the aqueous phase was extractedwith DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, DCM / MeOH) = 99 / 1 to 90 / 10) to afford 1.1g of I-118 (63%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.42 – 7.32 (m, 0.5H), 7.28 – 7.17 (m, 2.5H), 7.16 – 6.95 (m, 4H), 6.88 (s, 1H), 6.71 (s, 1H), 4.74 (s, 1H), 4.60 – 4.40 (m, 2H), 4.07 – 3.90 (m, 2H), 3.60 – 3.30 (m, 1H), 3.28 – 3.00 (m, 6H), 2.75 – 2.65 (m, 2H), 2.65 – 2.52 (m, 6H), 2.20 – 1.90 (m, 3.5H), 1.75 – 1.60 (m, 0.5H), 1.24 – 1.15 (m, 2H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.95, -109.07. MS (ESI+): [M+H]+661.3 / 663.3.

[0280] 2,6-dichloro-4-(2,2-dimethylpropylsulfanyl)pyridine (I-119)Formula Weight: 250,19 Molecular Formula: C10H13Cl2NS Using GP-1, I-119 was obtained as a light yellow oil in 95% yield using 2,6-dichloro-4-iodo-pyridine (1.50g, 5.48mmol, 1 equiv.), XantPhos-Pd-G3 (104mg, 110µmol, 0.02 equiv.), iPr2NEt (1.43mL, 8.2mmol, 1.5 equiv.) and 2,2-dimethylpropane- 1-thiol (722µL, 5.75mmol, 1.05 equiv.) in dioxane (22mL) at 100°C for 1.5h. Purification by FC (cHex / EtOAc = 100 / 0 to 80 / 20).1H NMR (400 MHz, Chloroform-d) δ 7.08 (s, 2H), 2.92 (s, 2H), 1.11 (s, 9H).

[0281] 2,6-dichloro-4-(2,2-dimethylpropylsulfonyl)pyridine (I-120)Formula Weight: 282,19 Molecular Formula: C10H13Cl2NO2S Using GP-2, I-120 was obtained as a colorless oil in 100% yield using I-119 (1.30g, 5.20mmol, 1 equiv.) and m-CPBA (70% wet, 2.82g, 11.4mmol, 2.2 equiv.) in DCM(26mL) at RT for 16h.1H NMR (400 MHz, Chloroform-d) δ 7.75 (s, 2H), 3.07 (s, 2H), 1.27 (s, 9H). MS (ESI+): [M+H]+282.1 / 284.1.

[0282] [8-[6-chloro-4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-121)Formula Weight: 514,44 Molecular Formula: C23H26Cl2FN3O3S A solution of I-120 (1.07g, 3.79mmol, 1 equiv.), I-002 (1.22g, 4.55mmol, 1.2 equiv.) and iPr2NEt (0.99mL, 5.7mmol, 1.5 equiv.) in NMP (7.6mL) was stirred at 100°C for 16h. After cooling down to RT, the mixture was partitioned between 1N HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1N HCl, water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, cHex / EtOAc = 92 / 8 to 20 / 80) to afford 1.68g of I-121 (86%) as a white solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.40 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.24 (dd, J = 8.5, 2.4 Hz, 0.5H), 7.20 – 6.98 (m, 3H), 6.90 – 6.86 (m, 1H), 4.82 – 4.45 (m, 3H), 3.60 – 3.35 (m, 1H), 3.23 – 3.11 (m, 2H), 3.05 & 3.04 (s, 2H), 2.20 – 1.95 (m, 3.5H), 1.78 – 1.65 (m, 0.5H), 1.25 (s, 9H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.77, -108.91. MS (ESI+): [M+H]+514.1 / 516.2.

[0283] [8-[6-amino-4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-122)(20mg, 22µmol, 0.05 equiv.) and rac-BINAP (28mg, 45µmol, 0.1 equiv.). The vial was flushed with Ar and degassed toluene (2.2mL) was added. The reaction mixture was stirred at 140°C under microwave irradiation for 1h. After cooling down to RT, MeOH (1mL) and 1N HCl (1mL) was added and the mixture vigorously stirred for 0.5h. EtOAc and water were added and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 90 / 10 to 0 / 100) to afford 174mg of I-122 (50% purity, 39%) as a yellow solid. MS (ESI+): [M+H]+495.1 / 497.1.

[0284] [8-[6-(aminomethyl)-4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-123)Formula Weight: 509,04 Molecular Formula: C24H30ClFN4O3SA sealable flask was charged with I-121 (1.68g, 3.27mmol, 1 equiv.), potassium N-Boc- aminomethyltrifluoroborate (929mg, 3.92mmol, 1.2 equiv.), Cs2CO3(2.66g, 8.16mmol, 2.5 equiv.) and cataCXium-Pd-G3 (71mg, 98µmol, 0.03 equiv.). The flask was flushed with Ar and degassed dioxane / water (1 / 1, 25mL) was added. The flask was sealed and the mixture was stirred at 100°C for 1h. After cooling down to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (80g column, dry load, cHex / EtOAc = 98 / 2 to 50 / 50) to afford an inseparable mixture of starting material and intermediate Boc-protected desired product. It was dissolved in Dioxane (14mL) at RT and HCl (4N in dioxane, 7.1mL, 29mmol, 8.7 equiv.) was added. The mixture was stirred at RT for 4h before being concentrated under reduced pressure. The residue was partitioned between water and DCM, and K2CO3(s) was added portionwise until pH > 11. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, DCM / MeOH) = 99 / 1 to 90 / 10) to afford 1.15g of I-123 (69%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.37 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.20 (dd, J = 8.5, 2.4 Hz, 0.5H), 7.16 – 6.95 (m, 3H), 6.87 (s, 1H), 4.74 & 4.72 (s, 1H), 4.60 – 4.40 (m, 2H), 3.90 (s, 2H), 3.57 – 3.34 (m, 1H), 3.26 – 3.04 (m, 2H), 3.01 & 3.00 (s, 2H), 2.20 – 1.90 (m, 5.5H), 1.75 – 1.65 (m, 0.5H), 1.21 (s, 9H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.84, -108.96. MS (ESI+): [M+H]+509.2 / 511.2.

[0285] 2-[tert-butyl(diphenyl)silyl]oxy-N-[[6-[3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-4-(2,2-dimethylpropylsulfonyl)-2- pyridyl]methyl]acetamide (I-124)Formula Weight: 805,47 Molecular Formula: C42H50ClFN4O5SSi To a solution of 2-[tert-butyl(diphenyl)silyl]oxyacetic acid (56mg, 0.18mmol, 1.2 equiv.) in DMF (0.5mL) was added TBTU (54mg, 0.18mmol, 1.2 equiv.). The mixture was stirred at RT for 10min and a solution of I-123 (75mg, 0.15mmol, 1 equiv.) and Et3N (51µL, 0.37mmol, 2.5 equiv.) in THF (0.5mL) was added. The mixture was stirred at RT for 3h. The reaction mixture was partitioned between EtOAc and water. The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (water, sat. aq. NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 98 / 2 to 50 / 50) to afford 69mg of I-124 (48%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.90 – 7.80 (m, 0.5H), 7.65 – 7.55 (m, 3.5H), 7.48 – 7.29 (m, 6H), 7.25 – 6.90 (m, 5H), 4.95 – 4.30 (m, 5H), 4.19 (s, 2H), 3.55 – 3.25 (m, 1H), 3.15 – 2.95 (m, 4H), 2.10 – 1.85 (m, 3.5H), 1.70 – 1.60 (m, 0.5H), 1.23 (s, 9H), 1.08 (s, 9H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ - 108.73, -108.85. MS (ESI+): [M+H]+805.5 / 807.5.

[0286] [8-[3-[[tert-butyl(diphenyl)silyl]oxymethyl]-7-(2,2- dimethylpropylsulfonyl)imidazo[1,5-a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]- (2-chloro-4-fluoro-phenyl)methanone (I-125)Formula Weight: 787,46 Molecular Formula: C42H48ClFN4O4SSi To a solution of I-124 (69mg, 86µmol, 1 equiv.) and Et3N (0.16mL, 1.1mmol, 13 equiv.) in DCE (1.1mL) at RT, was added POCl3(53µL, 0.57mmol, 6.6 equiv.). The mixture was stirred at 80°C for 16h. After cooling down to RT, the reaction mixture was carefully poured in sat. aq. NaHCO3 and the mixture was vigorously stirred for 15min. EtOAc was added and the layers were separated. The aqueous phase was extracted twice with EtOAc and the combined organic extracts were washed (sat. aq. NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 98 / 2 to 40 / 60) to afford 54mg of I-125 (60%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.87 – 7.75 (m, 1.5H), 7.67 – 7.55 (m, 3.5H), 7.45 – 7.37 (m, 7H), 7.20 – 6.80 (m, 3H), 6.32 (s, 1H), 5.75 – 5.50 (m, 2H), 4.50 – 4.37 (m, 1H), 3.91 (s, 1H), 3.80 – 3.60 (m, 1H), 3.57 – 3.17 (m, 1H), 3.10 – 2.85 (m, 4H), 2.20 – 1.85 (m, 3.5H), 1.70 – 1.60 (m, 0.5H), 1.21 (s, 9H), 1.05 & 1.03 (s, 9H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.60, -108.73. MS (ESI+): [M+H]+787.5 / 789.5.

[0287] ethyl 2-[[6-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]- 4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]methylamino]-2-oxo-acetate (I-126)Formula Weight: 609,11 Molecular Formula: C28H34ClFN4O6S To a solution of I-123 (436mg, 0.856mmol, 1 equiv.) and Et3N (0.18L, 1.3mmol, 1.5 equiv.) in DCM (4.3mL) at RT, was added ethyl oxalyl chloride (0.14mL, 1.3mmol, 1.5 equiv.). The mixture was stirred at RT for 2h. The reaction mixture was partitioned between 1N HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (sat. aq. NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 471mg of I-126 (90%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 8.08 (s, 1H), 7.41 – 7.35 (m, 0.5H), 7.24 – 7.18 (m, 0.5H), 7.16 – 6.98 (m, 2H), 6.95 – 6.90 (m, 2H), 4.72 (s, 1H), 4.63 – 4.50 (m, 4H), 4.42 – 4.32 (m, 2H), 3.57 – 3.35 (m, 1H), 3.20 – 3.10 (m, 2H), 3.01 & 3.00 (s, 2H), 2.20 – 1.95 (m, 3.5H), 1.78 – 1.68 (m, 0.5H), 1.42 – 1.35 (m, 3H), 1.22 (s, 9H). MS (ESI+): [M+H]+609.2 / 611.2.

[0288] 3-[tert-butyl(diphenyl)silyl]oxy-N-[[6-[3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-4-(2,2-dimethylpropylsulfonyl)-2- pyridyl]methyl]propanamide (I-127)Formula Weight: 819,5 Molecular Formula: C43H52ClFN4O5SSi To a solution of I-123 (200mg, 0.393mmol, 1 equiv.) in DCE (2mL) at RT, was added β- propiolactone (32µL, 0.51mmol, 1.3 equiv.). The mixture was stirred at RT for 16h. Imidazole (134mg, 1.96mmol, 5 equiv.) DMAP (4.8mg, 36µmol, 0.1 equiv.) and tert- butyldiphenylchlorosilane (0.2mL, 0.8mmol, 2 equiv.) were added and the mixture was stirred a further 24h. The reaction mixture was partitioned between EtOAc and sat. aq. NH4Cl. The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (sat. aq. NH4Cl, sat. aq. NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 90 / 10 to 0 / 100) to afford 176mg of I-127 (55%) as a white foam.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.70 – 7.60 (m, 3.5H), 7.50 – 7.32 (m, 6.5H), 7.27 – 6.95 (m, 4H), 6.92 (s, 1H), 4.70 (s, 1H), 4.62 – 4.45 (m, 4H), 4.00 (t, J = 5.8 Hz, 2H), 3.57 – 3.31 (m, 1H), 3.25 – 3.03 (m, 2H), 3.01 (s, 2H), 2.52 (t, J = 5.7 Hz, 2H), 2.15 – 1.90 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 1.24 (s, 9H), 1.02 (s, 9H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ - 108.91, -109.05. MS (ESI+): [M+H]+819.5 / 821.5.

[0289] [8-[3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-7-(2,2- dimethylpropylsulfonyl)imidazo[1,5-a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]- (2-chloro-4-fluoro-phenyl)methanone (I-128)To a solution of I-127 (170mg, 207µmol, 1 equiv.) and Et3N (0.29mL, 2.1mmol, 10 equiv.) in DCE (2.1mL) at RT, was added POCl3(97µL, 1.0mmol, 5 equiv.). The mixture was stirred at 80°C for 3h. After cooling down to RT, the reaction mixture was carefully poured in sat. aq. NaHCO3 and the mixture was vigorously stirred for 15min. EtOAc was added and the layers were separated. The aqueous phase was extracted twice with EtOAc and the combined organic extracts were washed (sat. aq. NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 93 / 7 to 30 / 70) to afford 144mg of I-128 (87%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.80 (s, 1H), 7.69 (s, 1H), 7.61 – 7.50 (m, 4H), 7.50 – 7.30 (m, 6H), 7.26 – 6.94 (m, 3H), 6.28 & 6.25 (s, 1H), 4.70 – 4.55 (m, 1H), 4.30 – 4.15 (m, 2H), 4.00 (s, 1H), 3.90 – 3.60 (m, 4H), 3.50 – 3.10 (m, 2H), 2.97 (s, 2H), 2.10 – 1.90 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 1.20 (s, 9H), 1.01 – 0.97 (m, 9H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.58, - 108.76. MS (ESI+): [M+H]+801.5 / 803.5.

[0290] 2,6-dichloro-4-cyclopentylsulfanyl-pyridine (I-129)Formula Weight: 248,17 Molecular Formula: C10H11Cl2NSUsing GP-1, I-129 was obtained as a light yellow oil in 54% yield using 2,6-dichloro-4-iodo-pyridine (500mg, 1.83mmol, 1 equiv.), XantPhos-Pd-G3 (35mg, 37µmol, 0.02 equiv.), iPr2NEt (0.48mL, 2.7mmol, 1.5 equiv.) and cyclopentylmercaptan (205µL, 1.92mmol, 1.05 equiv.) in dioxane (7.3mL) at 100°C for 1h. Purification by FC (cHex / EtOAc = 100 / 0 to 70 / 30).1H NMR (400 MHz, Chloroform-d) δ 7.04 (s, 2H), 3.75 – 3.60 (m, 1H), 2.30 – 2.05 (m, 2H), 1.90 – 1.55 (m, 6H). MS (ESI+): [M+H]+248.1 / 250.1.

[0291] 2,6-dichloro-4-cyclopentylsulfonyl-pyridine (I-130)Formula Weight: 280,17 Molecular Formula: C10H11Cl2NO2S Using GP-2, I-130 was obtained as a colorless oil in 82% yield using I-129 (243mg, 0.979mmol, 1 equiv.) and m-CPBA (70% wet, 0.99g, 4.00mmol, 4.1 equiv.) in DCM (5mL) at RT for 4h. Purification by FC (cHex / EtOAc = 100 / 0 to 95 / 5).1H NMR (400 MHz, Chloroform-d) δ 7.71 (s, 2H), 3.60 – 3.45 (m, 1H), 2.15 – 2.00 (m, 2H), 2.00 – 1.75 (m, 4H), 1.75 – 1.65 (m, 2H). MS (ESI+): [M+H]+280.1 / 282.1.

[0292] [8-(6-chloro-4-cyclopentylsulfonyl-2-pyridyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]-(2-chloro-4-fluoro-phenyl)methanone (I-131)Formula Weight: 512,42 Molecular Formula: C23H24Cl2FN3O3S A solution of I-130 (226mg, 0.807mmol, 1 equiv.), I-002 (260mg, 0.968mmol, 1.2 equiv.) and iPr2NEt (0.28mL, 1.6mmol, 2 equiv.) in NMP (4mL) was stirred at 100°C for 16h. After cooling down to RT, the mixture was partitioned between 1N HCl and EtOAc.The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1N HCl, water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 95 / 5 to 50 / 50) to afford 0.33g of I-131 (86%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.42 – 7.33 (m, 0.5H), 7.26 – 7.18 (m, 0.5H), 7.18 – 6.92 (m, 3H), 6.85 (s, 1H), 4.66 (s, 1H), 4.62 – 4.48 (m, 2H), 3.61 – 3.34 (m, 2H), 3.20 – 3.08 (m, 2H), 2.20 – 1.75 (m, 9.5H), 1.75 – 1.60 (m, 2.5H). MS (ESI+): [M+H]+512.1 / 514.1.

[0293] [8-[6-(aminomethyl)-4-cyclopentylsulfonyl-2-pyridyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-132)Formula Weight: 507,02 Molecular Formula: C24H28ClFN4O3S A sealable flask was charged with I-131 (330mg, 0.644mmol, 1 equiv.), potassium N- Boc-aminomethyltrifluoroborate (229mg, 0.966mmol, 1.5 equiv.), Cs2CO3(0.52g, 1.6mmol, 2.5 equiv.) and cataCXium-Pd-G3 (14mg, 19µmol, 0.03 equiv.). The flask was flushed with Ar and degassed dioxane / water (1 / 1, 3.2mL) was added. The flask was sealed and the mixture was stirred at 100°C for 16h. After cooling down to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in DCM (3.2mL) at RT and HCl (4N in dioxane, 1.6mL, 6.4mmol, 10 equiv.) was added. The mixture was stirred at RT for 16h before being concentrated under reduced pressure. The residue was partitioned between water and DCM, and K2CO3(s) was added portionwise until pH > 11. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filteredand concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, DCM / MeOH) = 99 / 1 to 90 / 10) to afford 120mg of I-132 (37%) as a yellow solid. MS (ESI+): [M+H]+507.2 / 509.2.

[0294] 2,6-dichloro-4-[(4-methoxyphenyl)methylsulfanyl]pyridine (I-133)Formula Weight: 300,2 Molecular Formula: C13H11Cl2NOS Using GP-1, I-133 was obtained as a light yellow oil in 99% yield using 2,6-dichloro-4-iodo-pyridine (2.02g, 7.37mmol, 1 equiv.), XantPhos-Pd-G3 (70mg, 74µmol, 0.01 equiv.), iPr2NEt (2.6mL, 15mmol, 2 equiv.) and 4-methoxybenzyl mercaptan (1.07mL, 7.68mmol, 1.05 equiv.) in dioxane (30mL) at 100°C for 1.5h. Purification by FC (cHex / EtOAc = 99 / 1 to 80 / 20).1H NMR (400 MHz, Chloroform-d) δ 7.39 – 7.27 (m, 2H), 7.05 (s, 2H), 6.95 – 6.81 (m, 2H), 4.18 (s, 2H), 3.81 (s, 3H). MS (ESI+): [M+H]+300.1 / 302.1.

[0295] 2,6-dichloro-4-[(2,6-dichloro-4-pyridyl)disulfanyl]pyridine (I-134)Formula Weight: 358,09 Molecular Formula: C10H4Cl4N2S2To a solution of I-133 (2.40g, 7.28mmol, 1 equiv.) in anisole (6.5mL) was added TFA (28mL). The mixture was stirred at reflux for 16h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between water and EtOAc and NaHCO3(s) was added portionwise until neutralization of the residual acid. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The basicaqueous phase was acidified to pH =2 using 2N HCl and the aqueous phase was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The combined organic residues were purified by FC (80g column, dry load, cHex / EtOAc = 98 / 2 to 80 / 20) to afford 900mg of I-134 (69%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.47 (s, 4H). MS (ESI+): [M+H]+356.9 / 359.0 / 360.9.

[0296] 2,6-dichloropyridine-4-thiol (I-135)Formula Weight: 180,06 Molecular Formula: C5H3Cl2NS To a solution of I-134 (798mg, 2.29mmol, 1 equiv.) in THF / EtOH (1 / 1, 22mL) at 0°C, was added portionwise NaBH4 (421mg, 11.1mmol, 5 equiv.). the reaction mixture was stirred at RT for 3h. Sat. aq. NH4Cl was added dropwise, followed by EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 707mg of I-135 (86%) as a white solid.1H NMR (400 MHz, DMSO- d6) δ 7.27 (s, 2H). MS (ESI+): [M+H]+180.1 / 182.1.

[0297] 2,6-dichloro-4-(1-ethylpropylsulfanyl)pyridine (I-136)Formula Weight: 250,19 Molecular Formula: C10H13Cl2NS To a solution of I-135 (340mg, 1.89mmol, 1 equiv.) in DMF (9mL) at RT, were successively added 3-bromopentane (0.47mL, 3.8mmol, 2 equiv.) and K2CO3 (522mg, 3.78mmol, 2 equiv.). The mixture was stirred at RT for 16h before being partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 99 / 1) to afford 300mg of I-136 (64%) as acolorless oil.1H NMR (400 MHz, Chloroform-d) δ 7.05 (s, 2H), 3.24 (p, J = 6.3 Hz, 1H), 1.85 – 1.60 (m, 4H), 1.03 (t, J = 7.4 Hz, 6H). MS (ESI+): [M+H]+250.1 / 252.1.

[0298] 2,6-dichloro-4-(1-ethylpropylsulfonyl)pyridine (I-137)Formula Weight: 514,44 Molecular Formula: C23H26Cl2FN3O3S A solution of I-137 (323mg, 1.12mmol, 1 equiv.), I-002 (392mg, 1.46mmol, 1.3 equiv.) and iPr2NEt (0.39mL, 2.2mmol, 2 equiv.) in NMP (5.6mL) was stirred at 120°C for 3h. After cooling down to RT, the mixture was partitioned between 1N HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1N HCl, water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 95 / 5 to 50 / 50) to afford 0.47g of I-138 (80%) as a white solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.38 (dd, J = 8.5, 5.6 Hz, 0.5H), 7.22 (dd, J = 8.3, 2.5 Hz, 0.5H), 7.18 – 6.98 (m, 2H), 6.96 & 6.95 (s, 1H), 6.83 (s, 1H),4.66 (s, 1H), 4.61 – 4.49 (m, 2H), 3.60 – 3.34 (m, 1H), 3.22 – 3.08 (m, 2H), 2.90 – 2.78 (m, 1H), 2.20 – 1.94 (m, 3.5H), 1.94 – 1.66 (m, 4.5H), 1.05 (t, J = 7.4 Hz, 6H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.78, -108.92. MS (ESI+): [M+H]+514.1 / 516.1.

[0300] [8-[6-(aminomethyl)-4-(1-ethylpropylsulfonyl)-2-pyridyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-139)Formula Weight: 509,04 Molecular Formula: C24H30ClFN4O3S A sealable flask was charged with I-138 (473mg, 0.901mmol, 1 equiv.), potassium N- Boc-aminomethyltrifluoroborate (320mg, 1.35mmol, 1.5 equiv.), Cs2CO3(0.73g, 2.25mmol, 2.5 equiv.) and cataCXium-Pd-G3 (20mg, 27µmol, 0.03 equiv.). The flask was flushed with Ar and degassed dioxane / water (1 / 1, 7mL) was added. The flask was sealed and the mixture was stirred at 100°C for 16h at which point more potassium N- Boc-aminomethyltrifluoroborate (160mg, 0.675mmol, 0.75 equiv.), Cs2CO3(0.36g, 1.12mmol, 1.25 equiv.) and cataCXium-Pd-G3 (10mg, 13µmol, 0.015 equiv.) were added. The reaction was stirred a further 2h at 100°C. After cooling down to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in Dioxane (3.3mL) at RT and HCl (4N in dioxane, 1.7mL, 6.7mmol, 7.5 equiv.) was added. The mixture was stirred at RT for 16h before being concentrated under reduced pressure. The residue was partitioned between water and DCM, and K2CO3(s) was added portionwise until pH > 11. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column,dry load, DCM / MeOH) = 99 / 1 to 90 / 10) to afford 283mg of I-139 (61%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.42 – 7.32 (m, 0.5H), 7.24 – 7.17 (m, 0.5H), 7.16 – 6.91 (m, 3H), 6.86 (s, 1H), 4.78 (s, 1H), 4.63 – 4.40 (m, 2H), 3.97 & 3.96 (s, 2H), 3.60 – 3.35 (m, 1H), 3.27 – 3.02 (m, 2H), 3.00 – 2.40 (br s, 2H), 2.90 – 2.80 (m, 1H), 2.20 – 1.94 (m, 3.5H), 1.94 – 1.65 (m, 4.5H), 1.03 (t, J = 7.3 Hz, 6H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.96, -109.09. MS (ESI+): [M+H]+509.2 / 511.2.

[0301] 2,6-dichloro-4-[rac-(1R)-1-methylpropyl]sulfanyl-pyridine (I-140)Formula Weight: 236,16 Molecular Formula: C9H11Cl2NS To a solution of I-135 (350mg, 1.94mmol, 1 equiv.) in DMF (9mL) at RT, were successively added rac-2-bromobutane (0.42mL, 3.9mmol, 1 equiv.) and K2CO3(537mg, 3.89mmol, 2 equiv.). The mixture was stirred at RT for 16h before being partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 99 / 1) to afford 291mg of I-140 (63%) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 7.04 (s, 2H), 3.45 – 3.33 (m, 1H), 1.80 – 1.60 (m, 2H), 1.39 (d, J = 6.7 Hz, 3H), 1.05 (t, J = 7.4 Hz, 3H). MS (ESI+): [M+H]+236.1 / 238.1.

[0302] 2,6-dichloro-4-[rac-(1R)-1-methylpropyl]sulfonyl-pyridine (I-141)Formula Weight: 268,16 Molecular Formula: C9H11Cl2NO2S Using GP-2, I-141 was obtained as a colorless in 100% yield using I-140 (291mg, 1.23mmol, 1 equiv.) and m-CPBA (70% wet, 0.67g, 2.7mmol, 2.2 equiv.) in DCM (6mL)at RT for 2h.1H NMR (400 MHz, Chloroform-d) δ 7.69 (s, 2H), 3.08 – 2.96 (m, 1H), 2.06 – 1.94 (m, 1H), 1.58 – 1.44 (m, 1H), 1.32 (d, J = 6.9 Hz, 3H), 1.04 (t, J = 7.5 Hz, 3H). MS (ESI+): [M+H]+268.0 / 270.0.

[0303] (2-chloro-4-fluoro-phenyl)-[8-[6-chloro-4-[rac-(1R)-1-methylpropyl]sulfonyl- 2-pyridyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-142)Formula Weight: 500,41 Molecular Formula:A solution of I-141(347mg, 1.23mmol, 1 equiv.), I-002 (429mg, 1.60mmol, 1.3 equiv.) and iPr2NEt (0.43mL, 2.5mmol, 2 equiv.) in NMP (6.1mL) was stirred at 120°C for 3h. After cooling down to RT, the mixture was partitioned between 1N HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1N HCl, water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 95 / 5 to 40 / 60) to afford 0.52g of I-142 (80%) as a white solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.42 – 7.33 (m, 0.5H), 7.25 – 7.18 (m, 0.5H), 7.17 – 6.98 (m, 2H), 6.95 (s, 1H), 6.83 (s, 1H), 4.72 – 4.46 (m, 3H), 3.60 – 3.35 (m, 1H), 3.22 – 3.08 (m, 2H), 3.05 – 2.90 (m, 1H), 2.20 – 1.95 (m, 4.5H), 1.75 – 1.65 (m, 0.5H), 1.58 – 1.42 (m, 1H), 1.31 (d, J = 6.8 Hz, 3H), 1.03 (t, J = 7.4 Hz, 3H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.77, -108.91. MS (ESI+): [M+H]+500.1 / 502.1.

[0304] [8-[6-(aminomethyl)-4-[rac-(1R)-1-methylpropyl]sulfonyl-2-pyridyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-143)Formula Weight: 495,01 Molecular Formula: C23H28ClFN4O3S A sealable flask was charged with I-142 (518mg, 0.983mmol, 1 equiv.), potassium N- Boc-aminomethyltrifluoroborate (350mg, 1.48mmol, 1.5 equiv.), Cs2CO3 (0.80g, 2.46mmol, 2.5 equiv.) and cataCXium-Pd-G3 (21mg, 30µmol, 0.03 equiv.). The flask was flushed with Ar and degassed dioxane / water (1 / 1, 8mL) was added. The flask was sealed and the mixture was stirred at 100°C for 2h at which point more potassium N-Boc- aminomethyltrifluoroborate (175mg, 0.737mmol, 0.75 equiv.), Cs2CO3(0.400g, 1.23mmol, 1.25 equiv.) and cataCXium-Pd-G3 (10mg, 15µmol, 0.015 equiv.) were added. The reaction was stirred a further 1h at 100°C. After cooling down to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in Dioxane (3.6mL) at RT and HCl (4N in dioxane, 1.8mL, 7.2mmol, 7.3 equiv.) was added. The mixture was stirred at RT for 16h before being concentrated under reduced pressure. The residue was partitioned between water and DCM, and K2CO3(s) was added portionwise until pH > 11. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, DCM / MeOH) = 99 / 1 to 90 / 10) to afford 314mg of I-143 (63%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.42 – 7.32 (m, 0.5H), 7.25 – 7.18 (m, 0.5H), 7.17 – 6.90 (m, 3H), 6.86 (s, 1H), 4.79 (s, 1H), 4.62 – 4.40 (m, 2H), 4.00 & 3.98 (s, 2H), 3.58 – 3.35 (m, 1H), 3.27 – 3.05 (m, 2H), 3.05 – 2.90 (m, 1H), 3.00 – 2.20 (br s, 2H), 2.20 – 1.90 (m, 4.5H), 1.75 – 1.65 (m, 0.5H), 1.55 – 1.40 (m, 1H),1.35 – 1.20 (m, 3H), 1.01 (t, J = 8.1 Hz, 3H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.95, -109.06. MS (ESI+): [M+H]+495.2 / 497.2.

[0305] [4-[6-chloro-4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]piperazin-1-yl]-(2- chloro-4-fluoro-phenyl)methanone (I-144)Formula Weight: 488,4 Molecular Formula: C21H24Cl2FN3O3S A solution of I-120 (200mg, 0.709mmol, 1 equiv.), I-001 (206mg, 0.851mmol, 1.2 equiv.) and iPr2NEt (0.19mL, 1.1mmol, 1.5 equiv.) in NMP (2.6mL) was stirred at 100°C for 18h. After cooling down to RT, the mixture was partitioned between 1N HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1N HCl, water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 92 / 8 to 20 / 80) to afford 291mg of I-144 (84%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 7.34 (dd, J = 8.5, 5.8 Hz, 1H), 7.22 (dd, J = 8.4, 2.4 Hz, 1H), 7.11 (td, J = 8.2, 2.5 Hz, 1H), 7.04 (d, J = 1.0 Hz, 1H), 6.96 (d, J = 1.1 Hz, 1H), 4.10 – 3.60 (m, 6H), 3.50 – 3.25 (m, 2H), 3.03 (s, 2H), 1.25 (s, 9H).19F NMR (376 MHz, Chloroform-d) δ -108.64. MS (ESI+): [M+H]+488.1 / 490.2.

[0306] [4-[6-(aminomethyl)-4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]piperazin-1-yl]- (2-chloro-4-fluoro-phenyl)methanone (I-145)Formula Weight: 483 Molecular Formula: C22H28ClFN4O3S A sealable flask was charged with I-144 (280mg, 0.573mmol, 1 equiv.), potassium N- Boc-aminomethyltrifluoroborate (163mg, 0.688mmol, 1.2 equiv.), Cs2CO3(467mg, 1.43mmol, 2.5 equiv.) and cataCXium-Pd-G3 (13mg, 17µmol, 0.03 equiv.). The flask was flushed with Ar and degassed dioxane / water (1 / 1, 4.5mL) was added. The flask was sealed and the mixture was stirred at 100°C for 1h. After cooling down to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 93 / 7 to 30 / 70) to afford an inseparable mixture of starting material and intermediate Boc-protected desired product. It was dissolved in dioxane (3.1mL) at RT and HCl (4N in dioxane, 1.2mL, 4.6mmol, 8.1 equiv.) was added. The mixture was stirred at RT for 16h before being concentrated under reduced pressure. The residue was partitioned between water and DCM, and K2CO3(s) was added portionwise until pH > 11. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, DCM / MeOH (7N NH3)) = 98 / 2 to 80 / 20) to afford 200mg of I-145 (71%) as a light yellow solid.1H NMR (400 MHz, Chloroform-d) δ 7.25 (dd, J = 8.5, 5.8 Hz, 1H), 7.12 (dd, J = 8.4, 2.4 Hz, 1H), 7.01 (td, J = 8.2, 2.5 Hz, 1H), 6.96 (d, J = 1.2 Hz, 1H), 6.88 (d, J = 1.2 Hz, 1H), 4.00 – 3.98 (m, 1H), 3.83 (s, 2H), 3.83 – 3.50 (m, 5H), 3.40 – 3.20 (m, 2H), 2.94 (s, 2H), 1.15 (s, 9H).19F NMR (376 MHz, Chloroform-d) δ -108.86. MS (ESI+): [M+H]+483.2 / 485.2.

[0307] [(3S)-4-[6-chloro-4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]-3-methyl- piperazin-1-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-146)Formula Weight: 502,43 Molecular Formula: C22H26Cl2FN3O3S A solution of I-120 (200mg, 0.709mmol, 1 equiv.), I-003 (200mg, 0.780mmol, 1.1 equiv.) and iPr2NEt (0.19mL, 1.1mmol, 1.5 equiv.) in NMP (2.6mL) was stirred at 120°C for 18h. After cooling down to RT, the mixture was partitioned between 1N HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1N HCl, water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 95 / 5 to 50 / 50) to afford 217mg of I-146 (61%) as a white solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.42 – 7.27 (m, 1H), 7.25 – 7.15 (m, 1H), 7.12 – 7.04 (m, 1H), 7.00 (s, 1H), 6.90 & 6.88 (s, 1H), 4.80 – 4.40 (m, 2H), 4.25 – 4.05 (m, 1H), 3.57 – 3.00 (m, 4H), 3.00 (s, 2H), 1.40 – 1.05 (m, 3H), 1.23 (s, 9H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.45, -108.66. MS (ESI+): [M+H]+502.1 / 504.1.

[0308] [(3S)-4-[6-(aminomethyl)-4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]-3-methyl- piperazin-1-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-147)Formula Weight: 497,03 Molecular Formula: C23H30ClFN4O3SA sealable flask was charged with I-146 (217mg, 0.432mmol, 1 equiv.), potassium N- Boc-aminomethyltrifluoroborate (123mg, 0.518mmol, 1.2 equiv.), Cs2CO3(352mg, 1.08mmol, 2.5 equiv.) and cataCXium-Pd-G3 (9.4mg, 13µmol, 0.03 equiv.). The flask was flushed with Ar and degassed dioxane / water (1 / 1, 3.5mL) was added. The flask was sealed and the mixture was stirred at 100°C for 2h. After cooling down to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 90 / 10 to 0 / 100) to afford an inseparable mixture of starting material and intermediate Boc-protected desired product. It was dissolved in DCM (1.6mL) at RT and HCl (4N in dioxane, 0.82mL, 3.3mmol, 7.6 equiv.) was added. The mixture was stirred at RT for 16h before being concentrated under reduced pressure. The residue was partitioned between water and DCM, and K2CO3(s) was added portionwise until pH > 11. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, DCM / MeOH) = 98 / 2 to 80 / 20) to afford 84mg of I-147 (39%) as a light yellow solid.1H NMR (500 MHz, Chloroform-d, multiple sets of rotamers) δ 7.50 – 7.25 (m, 1H), 7.24 – 6.95 (m, 3H), 6.95 – 6.85 (m, 1H), 4.80 – 4.40 (m, 2H), 4.25 – 4.05 (m, 1H), 3.94 (s, 2H), 3.57 – 3.40 (m, 1H), 3.37 – 3.05 (m, 3H), 3.01 (s, 2H), 2.28 (br s, 2H), 1.35 – 1.05 (m, 3H), 1.21 (s, 9H).19F NMR (470 MHz, Chloroform-d, multiple sets of rotamers) δ -108.73, -108.75, -108.79, -108.97. MS (ESI+): [M+H]+497.1 / 499.2.

[0309] 1-(7-bromo-5-iodo-indazol-1-yl)-2-methyl-propan-2-ol (I-148)Formula Weight: 395.03 Molecular Formula: C11H12BrIN2O To a solution of I-053 (900mg, 2.79mmol, 1 equiv.) in dry DMF (11mL) at 0°C, was added 2,2-dimethyloxirane (497µL, 5.57mmol, 2 equiv.). The mixture was stirred at100°C for 16h. The mixture was partitioned between water and DCM. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (80g column, dry load, cHex / EtOAc = 100 / 0 to 0 / 100) to afford 240mg of I-148 (22%) as a white solid.1H NMR (400 MHz, Chloroform- d) δ 7.99 (d, J = 1.4 Hz, 1H), 7.92 (s, 1H), 7.77 (d, J = 1.3 Hz, 1H), 4.79 (s, 2H), 1.10 (s, 6H). MS (ESI+): [M+H]+394.9 / 396.9.

[0310] [2-(7-bromo-5-iodo-indazol-1-yl)-1,1-dimethyl-ethoxy]-tert-butyl-dimethyl- silane (I-149)Formula Weight: 509.3 Molecular Formula: C17H26BrIN2OSi To a solution of I-148 (240mg, 0.608mmol, 1 equiv.) in dry DCM (1.2mL) at 0°C, were added 2,6-dimethylpyridine (142µL, 1.22mmol, 2 equiv.) and tert- butyldimethylsilyltrifluoromethanesulfonate (209uL, 0.911mmol, 1 equiv.). The mixture was stirred at 0°C for 2h. Water was added and the layers were separated. The aqueous phase was extracted with DCM. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 100 / 0 to 80 / 20) to afford 260mg of I-149 (84%) as a yellow oil.1H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J = 1.4 Hz, 1H), 7.92 (s, 1H), 7.79 (d, J = 1.4 Hz, 1H), 4.79 (s, 2H), 1.31 (s, 6H), 0.67 (s, 9H), 0.00 (s, 6H).

[0311] Methyl 3-[7-bromo-1-[2-[tert-butyl(dimethyl)silyl]oxy-2-methyl- propyl]indazol-5-yl]sulfanylpropanoate (I-150)Formula Weight: 501.55 Molecular Formula: C21H33BrN2O3SSi A MW vial was charged with I-149 (260mg, 0.511mmol, 1 equiv.) and XPhos-Pd-G3 (48mg, 51µmol, 0.1 equiv.). The vial was flashed with Ar and degassed dioxane (2.5mL) was added. DIPEA (0.18mL, 1.0mmol, 2 equiv.) and methyl 3-mercaptopropionate (61 mg, 0.51 mmol, 1.00 eq.) were added. The vial was sealed and the mixture was stirred at 100°C for 1.5h. The mixture was concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 100 / 0 to 80 / 20) to afford 186mg of I-150 (83%) as a colourless oil.1H NMR (400 MHz, Chloroform-d) δ 7.98 (s, 1H), 7.78 (d, J = 1.5 Hz, 1H), 7.66 (d, J = 1.5 Hz, 1H), 4.83 (s, 2H), 3.70 (s, 3H), 3.14 (t, J = 7.4 Hz, 2H), 2.62 (t, J = 7.3 Hz, 2H), 1.35 (s, 6H), 0.66 (s, 9H), 0.02 (s, 6H). MS (ESI+): [M+H]+501.3 / 503.3.

[0312] 7-bromo-1-[2-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propyl]indazole-5-thiol (I-151)Formula Weight: 415.46 Molecular Formula: C17H27BrN2OSSi To a solution of I-150 (286mg, 0.371mmol, 1 equiv.) in THF (3.7mL) at -78°C, was added t-BuOK (1M solution in THF, 742µL, 0.742mmol, 2 equiv.). The mixture was allowed to warm-up to RT over 3h. Aq. sat. NH4Cl and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reducedpressure. The residue was purified by FC (24g column, dry load, cHex / EtOAc = 100 / 0 to 80 / 20) to afford 124mg of I-151 (80%) as a colourless oil.1H NMR (400 MHz, Chloroform-d) δ 7.90 (s, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 4.79 (s, 2H), 3.52 (s, 1H), 1.30 (s, 6H), 0.67 (s, 9H), 0.00 (s, 6H). MS (ESI+): [M+H]+415.1 / 417.1.

[0313] [2-[7-bromo-5-(2,2-dimethylpropylsulfonyl)indazol-1-yl]-1,1-dimethyl-ethoxy]- tert-butyl-dimethyl-silane (I-152)Formula Weight: 517.6 Molecular Formula: C22H37BrN2O3SSi To a solution of I-151 (124mg, 0.298mmol, 1 equiv.) in DMF (0.6mL) at -0°C, was added NaH (60% in mineral oil, 14.3mg, 0.358mmol, 1.2 equiv.). The mixture was stirred at 0°C for 0.5h.1-bromo-2,2-dimethylpropane (54 mg, 0.36 mmol, 1.20 eq.) was added and the mixture was stirred at 80°C for 1h. After cooling to RT, the mixture was partitioned between MTBE and water. The layers were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in DCM (1.5mL) and m-CPBA (70% wet, 184mg, 0.746mmol, 2.5 equiv.) was added. The mixture was stirred at RT for 1h. Aq Na2S2O3and aq. sat. NaHCO3were added and the mixture was vigorously stirred at RT for 0.5h. EtOAc was added and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 100 / 0 to 50 / 50) to afford 106mg of I-152 (69%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J = 1.6 Hz, 1H), 8.18 (s, 1H), 8.04 (d, J = 1.6 Hz, 1H), 4.88 (s, 2H), 3.06 (s, 2H), 1.36 (s, 6H), 1.22 (s, 9H), 0.61 (s, 9H), 0.00 (s, 6H). MS (ESI+): [M+H]+517.1 / 519.1.

[0314] [8-[1-[2-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propyl]-5-(2,2- dimethylpropylsulfonyl)indazol-7-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4- fluoro-phenyl)methanone (I-153)To a solution of I-053 (1.00g, 3.10mmol, 1 equiv.) in dry DMF (15.5mL) at 0°C, was added NaH (60% in mineral oil, 149mg, 3.72mmol, 1.2 equiv.). The mixture was stirred at RT for 0.5h and 2-bromoethyl methyl ether (0.58mL, 6.2mmol, 2 equiv.) was added dropwise. The mixture was stirred at RT for 2h. Aq. sat. NH4Cl and EtOAc were added.The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (40g column, dry load, cHex / EtOAc = 100 / 0 to 85 / 15) to afford 437mg of I-154 (37%) as a colourless oil.1H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J = 1.4 Hz, 1H), 7.93 (s, 1H), 7.80 (d, J = 1.4 Hz, 1H), 4.97 (t, J = 6.0 Hz, 2H), 3.83 (t, J = 6.0 Hz, 2H), 3.33 (s, 3H). MS (ESI+): [M+H]+380.9 / 382.9.

[0316] 7-bromo-5-(2,2-dimethylpropylsulfanyl)-1-(2-methoxyethyl)indazole (I-155)Formula Weight: 357.31 Molecular Formula: C15H21BrN2OS Using GP-1, I-155 was obtained as a light yellow oil in 95% yield using I-154 (890mg, 2.54mmol, 1 equiv.), XantPhos-Pd-G3 (44.3mg, 46.7µmol, 0.03 equiv.), iPr2NEt (0.76mL, 3.5mmol, 1.5 equiv.) and 2,2-dimethylpropane-1-thiol (0.83mL, 2.3mmol, 1 equiv.) in dioxane (12mL) at 100°C for 1.5h. Purification by FC (cHex / EtOAc = 99 / 1 to 90 / 10).1H NMR (400 MHz, Chloroform-d) δ 7.93 (s, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 1.5 Hz, 1H), 4.96 (t, J = 6.1 Hz, 2H), 3.84 (t, J = 6.1 Hz, 2H), 3.34 (s, 3H), 2.89 (s, 2H), 1.04 (s, 9H). MS (ESI+): [M+H]+357.0 / 359.0.

[0317] 7-bromo-5-(2,2-dimethylpropylsulfonyl)-1-(2-methoxyethyl)indazole (I-156)Formula Weight: 389.31 Molecular Formula: C15H21BrN2O3S Using GP-2, I-156 was obtained as a white solid in 100% yield using I-155 (790mg, 2.21mmol, 1 equiv.) and m-CPBA (77% wet, 1.09g, 4.86mmol, 2.2 equiv.) in DCM(11mL) at RT for 1h. Purification by FC (cHex / EtOAc = 97 / 3 to 70 / 30).1H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J = 1.5 Hz, 1H), 8.18 (s, 1H), 8.04 (d, J = 1.6 Hz, 1H), 5.05 (t, J = 5.8 Hz, 2H), 3.87 (t, J = 5.9 Hz, 2H), 3.33 (s, 3H), 3.06 (s, 2H), 1.21 (s, 9H). MS (ESI+): [M+H]+389.0 / 391.0.

[0318] tert-butyl 8-[5-(2,2-dimethylpropylsulfonyl)-1-(2-methoxyethyl)indazol-7-yl]- 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (I-157)Formula Weight: 520.68 Molecular Formula: C26H40N4O5S According to GP-3, I-157 was obtained in 91% yield using aryl bromide I-156 (500mg, 1.28mmol, 1 equiv.), 3-boc-3,8-diazabicyclo[3.2.1]octane (327mg, 1.54mmol, 1.2 equiv.), Cs2CO3 (1.26g, 3.85mmol, 3 equiv.), Pd(OAc)2 (28.8mg, 128µmol, 0.10 equiv.) and rac-BINAP (96.0mg, 154µmol, 0.12 equiv.) in toluene (6.4mL) at reflux for 4h. Purification by FC (cHex / EtOAc = 100 / 0 to 50 / 50).1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 8.15 (s, 1H), 7.99 (d, J = 1.4 Hz, 1H), 7.28 (d, J = 1.5 Hz, 1H), 5.15 – 4.80 (m, 2H), 4.03 – 3.78 (m, 6H), 3.45 – 3.25 (m, 2H), 3.31 (s, 3H), 3.02 (s, 2H), 2.10 – 1.75 (m, 4H), 1.50 (s, 9H), 1.16 (s, 9H). MS (ESI+): [M+H]+521.3.

[0319] 7-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2,2-dimethylpropylsulfonyl)-1-(2- methoxyethyl)indazole (I-158)Formula Weight: 420.57 Molecular Formula: C21H32N4O3STo a solution of I-157 (609 mg, 1.17 mmol, 1 equiv.) in DCM (5.8mL) at RT, was added HCl (4M solution in dioxane, 2.92mL, 11.7 mmol, 10 equiv.). The mixture was stirred at RT for 16h before being concentrated under reduced pressure. The residue was partitioned between DCM and water and K2CO3(s) was added until pH > 11. The layersFormula Weight: 609.15 Molecular Formula: C29H38ClFN4O5S To a solution of hydroxyisovaleric acid (89µL, 0.71mmol, 1.2 equiv.) in DMF (3mL) were added DIPEA (0.21mL, 1.2mmol, 2 equiv.) and HATU (269mg, 0.707mmol, 1.2 equiv.). The mixture was stirred at RT for 30min and I-123 (300mg, 0.589mmol, 1 equiv.) was added. The mixture was stirred at RT for 16h. The reaction mixture was partitioned between EtOAc and water. The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (20g column, dry load, cHex / EtOAc = 50 / 50) to afford 250mg of I-159 (70%) as a white solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.42 – 7.18 (m, 1H), 7.18 – 6.98 (m, 2H), 6.97 (s, 1H), 6.92 – 6.85 (m, 2H), 4.74 (s, 1H), 4.61 –4.48 (m, 4H), 3.57 – 3.35 (m, 1H), 3.20 – 3.07 (m, 2H), 3.01 & 3.00 (s, 2H), 2.43 (s, 2H), 2.15 – 1.95 (m, 4H), 1.30 (s, 6H), 1.21 (s, 9H). MS (ESI+): [M+H]+609.3 / 611.3.

[0321] 3-[tert-butyl(dimethyl)silyl]oxy-N-[[6-[3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]methyl]-3- methyl-butanamide (I-160)Formula Weight: 723.41 Molecular Formula: C35H52ClFN4O5SSi To a solution of I-159 (250mg, 0.410mmol, 1 equiv.) in DCM (0.8mL) at RT, were added 2,6-dimethylpyridine (100µL, 0.821mmol, 2 equiv.) and tert-butyldimethylsilyl- trifluoromethanesulfonate (0.11mL, 0.49mmol, 1.2 equiv.). The mixture was stirred at RT for 2.5h at which point more 2,6-dimethylpyridine (100µL, 0.821mmol, 2 equiv.) and tert-butyldimethylsilyltrifluoromethanesulfonate (0.11mL, 0.49mmol, 1.2 equiv.) were added and the mixture was stirred at RT for 16h. Water was added. The layers were separated and the aqueous phase was extracted twice with DCM. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 100 / 0 to 50 / 50) to afford 140mg of I-160 (47%) as a white solid.1H NMR (400 MHz, Chloroform- d, 2 sets of rotamers) δ 7.50 – 7.20 (m, 1H), 7.20 – 6.95 (m, 4H), 6.88 (s, 1H), 4.72 (s, 1H), 4.60 – 4.40 (m, 4H), 3.60 – 3.30 (m, 1H), 3.22 – 3.06 (m, 2H), 3.00 & 2.99 (s, 2H), 2.44 (s, 2H), 2.15 – 1.95 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 1.37 (s, 6H), 1.22 (m, 9H), 0.81 & 0.79 (s, 9H), 0.11 (m, 6H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.97, -109.10. MS (ESI+): [M+H]+723.4 / 725.4.

[0322] [8-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propyl]-7-(2,2- dimethylpropylsulfonyl)imidazo[1,5-a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]- (2-chloro-4-fluoro-phenyl)methanone (I-161)Formula Weight: 705.4 Molecular Formula: C35H50ClFN4O4SSi To a solution of I-160 (140mg, 193µmol, 1 equiv.) and Et3N (0.27mL, 1.9mmol, 10 equiv.) in DCE (1mL) at RT, was added POCl3(240µL, 976µmol, 5 equiv.). The mixture was stirred at 80°C for 2h. After cooling down to RT, the reaction mixture was carefully poured in sat. aq. NaHCO3 and the mixture was vigorously stirred for 15min. EtOAc was added and the layers were separated. The aqueous phase was extracted twice with EtOAc and the combined organic extracts were washed (sat. aq. NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 98 / 2 to 60 / 40) to afford 121mg of I-161 (89%) as a yellow solid. MS (ESI+): [M+H]+705.5 / 707.4.

[0323] N-[[6-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4- (2,2-dimethylpropylsulfonyl)-2-pyridyl]methyl]propanamide (I-162)Formula Weight: 565.1 Molecular Formula: C27H34ClFN4O4STo a solution of I-123 (100mg, 0.196mmol, 1 equiv.) in DCM (2mL) at RT, were added Et3N (55µL, 0.39mmol, 2 equiv.) and propionyl chloride (33µL, 0.39mmol, 2 equiv.). The mixture was stirred at RT for 2h. 1N HCl and EtOAc were added. The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (1N HCl, brine), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 90mg of I-162 (81%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.45 – 7.20 (m, 1H), 7.19 – 6.99 (m, 2H), 6.95 (s, 1H), 6.93 (s, 1H), 6.40 (br s, 1H), 4.81 – 4.42 (m, 5H), 3.60 – 3.35 (m, 1H), 3.20 – 3.10 (m, 2H), 3.02 & 3.01 (s, 2H), 2.30 (q, J = 7.7 Hz, 2H), 2.20 – 1.95 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 1.32 – 1.08 (m, 12H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.75, -108.88. MS (ESI+): [M+H]+565.2 / 567.3.

[0324] N-[[6-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4- (2,2-dimethylpropylsulfonyl)-2-pyridyl]methyl]-3-methyl-butanamide (I-163)Formula Weight: 593.15 Molecular Formula: C29H38ClFN4O4S To a solution of I-123 (100mg, 0.196mmol, 1 equiv.) in DCM (2mL) at RT, were added Et3N (55µL, 0.39mmol, 2 equiv.) and isovaleryl chloride (31µL, 0.25mmol, 1.3 equiv.). The mixture was stirred at RT for 1h. 1N HCl and EtOAc were added. The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (1N HCl, brine), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 110mg of I-163 (94%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.45 – 7.20 (m, 1H), 7.18 – 6.97 (m, 2H), 6.97 (s, 1H), 6.95 (s, 1H), 6.45 (br s, 1H), 4.79 – 4.42 (m, 5H), 3.60 – 3.38 (m, 1H), 3.22 – 3.10 (m, 2H), 3.01 (s, 2H), 2.20 – 1.90 (m, 6.5H), 1.80 – 1.70 (m, 0.5H), 1.22 (s, 9H), 0.99 –0.95 (m, 6H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.71, -108.84. MS (ESI+): [M+H]+593.3 / 595.3.

[0325] N-[[6-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4- (2,2-dimethylpropylsulfonyl)-2-pyridyl]methyl]cyclobutanecarboxamide (I-164)Formula Weight: 591.14 Molecular Formula: C29H36ClFN4O4S To a solution of I-123 (100mg, 0.196mmol, 1 equiv.) in DCM (2mL) at RT, were added Et3N (55µL, 0.39mmol, 2 equiv.) and cyclobutylcarbonyl chloride (29µL, 0.25mmol, 1.3 equiv.). The mixture was stirred at RT for 1h.1N HCl and EtOAc were added. The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (1N HCl, brine), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 100mg of I-164 (86%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.45 – 7.20 (m, 1H), 7.20 – 7.00 (m, 2H), 6.96 (s, 1H), 6.94 (s, 1H), 6.41 (br s, 1H), 4.81 – 4.40 (m, 5H), 3.60 – 3.38 (m, 1H), 3.23 – 3.13 (m, 2H), 3.13 – 3.04 (m, 1H), 3.02 & 3.01 (s, 2H), 2.37 – 1.82 (m, 9.5H), 1.78 – 1.68 (m, 0.5H), 1.23 (s, 9H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.68, -108.81. MS (ESI+): [M+H]+591.3 / 593.2.

[0326] N-[[6-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4- (3,3-difluoropyrrolidin-1-yl)sulfonyl-2-pyridyl]methyl]acetamide (I-165)Formula Weight: 586.03 Molecular Formula: C25H27ClF3N5O4S To a solution of I-109 (100mg, 0.184mmol, 1 equiv.) in DCM (1mL) at RT, were added Et3N (51µL, 0.37mmol, 2 equiv.) and acetyl chloride (16µL, 0.22mmol, 1.2 equiv.). The mixture was stirred at RT for 1h. 1N HCl and EtOAc were added. The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (1N HCl, brine), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 109mg of I-165 (100%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.45 – 7.20 (m, 1H), 7.20 – 7.00 (m, 2H), 6.86 (br s, 1H), 6.79 (s, 1H), 6.36 (s, 1H), 4.80 – 4.40 (m, 5H), 3.61 (t, J = 12.8 Hz, 2H), 3.55 – 3.35 (m, 3H), 3.25 – 3.05 (m, 2H), 2.36 (tt, J = 13.7, 7.3 Hz, 2H), 2.15 – 2.00 (m, 6.5H), 1.78 – 1.68 (m, 0.5H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -99.13, -99.15, -108.74, -108.86. MS (ESI+): [M+H]+586.2 / 588.2.

[0327] N-[[6-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4- (3,3-difluoropyrrolidin-1-yl)sulfonyl-2-pyridyl]methyl]propanamide (I-166)Formula Weight: 600.05 Molecular Formula: C26H29ClF3N5O4STo a solution of I-109 (100mg, 0.184mmol, 1 equiv.) in DCM (1mL) at RT, were added Et3N (51µL, 0.37mmol, 2 equiv.) and propionyl chloride (19µL, 0.22mmol, 1.2 equiv.). The mixture was stirred at RT for 1h. 1N HCl and EtOAc were added. The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (1N HCl, brine), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 110mg of I-166 (100%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.42 – 7.20 (m, 1H), 7.17 – 6.95 (m, 2H), 6.88 (s, 1H), 6.82 (s, 1H), 6.49 (br s, 1H), 4.81 – 4.45 (m, 5H), 3.65 – 3.35 (m, 5H), 3.25 – 3.10 (m, 2H), 2.45 – 2.25 (m, 4H), 2.15 – 2.00 (m, 3.5H), 1.80 – 1.70 (m, 0.5H), 1.30 – 1.22 (m, 3H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -99.20, -108.66, - 108.79. MS (ESI+): [M+H]+600.2 / 602.2.

[0328] N-[[6-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4- (3,3-difluoropyrrolidin-1-yl)sulfonyl-2-pyridyl]methyl]-3-methyl-butanamide (I-167)Formula Weight: 628.11 Molecular Formula: C28H33ClF3N5O4S To a solution of I-109 (100mg, 0.184mmol, 1 equiv.) in DCM (1mL) at RT, were added Et3N (51µL, 0.37mmol, 2 equiv.) and isovaleryl chloride (27µL, 0.22mmol, 1.2 equiv.). The mixture was stirred at RT for 1h. 1N HCl and EtOAc were added. The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (1N HCl, brine), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 115mg of I-167 (100%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.45 – 7.20 (m, 1H), 7.20 – 6.99 (m, 2H), 6.90 (s, 1H), 6.82 (s, 1H), 6.46 (br s, 1H), 4.80 – 4.40 (m, 5H), 3.65 – 3.35 (m, 5H), 3.25 – 3.10 (m, 2H), 2.50 – 2.30 (m, 3H), 2.20 – 2.00 (m, 5.5H), 1.80 – 1.70 (m, 0.5H), 1.00 – 0.90(m, 6H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -99.17, -108.64, - 108.77. MS (ESI+): [M+H]+628.3 / 630.3.

[0329] 3-[tert-butyl(diphenyl)silyl]oxy-N-[[6-[3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-4-(3,3-difluoropyrrolidin-1-yl)sulfonyl-2-Formula Weight: 854.45 Molecular Formula: C42H47ClF3N5O5SSi To a solution of 3-[tert-butyl(diphenyl)silyl]oxypropanoic acid (121mg, 0.368mmol, 1 equiv.) and DIPEA (128µL, 0.735mmol, 2 equiv.) in DMF (1.8mL) at RT, was added HATU (168mg, 0.441mmol, 1.2 equiv.). The mixture was stirred at RT for 0.5h and I- 109 (200mg, 0.368mmol, 1 equiv.) was added. The mixture was stirred at RT for 16h. Aq. sat. NH4Cl and EtOAc were added. The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (1N NaOH, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (20g column, dry load, DCM / MeOH = 99 / 1 to 90 / 10) to afford 135mg of I-168 (43%) as a white solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.70 – 7.60 (m, 4H), 7.50 – 7.35 (m, 6.5H), 7.25 – 7.20 (m, 0.5H), 7.15 - 6.95 (m, 3H), 6.90 (s, 1H), 6.79 (s, 1H), 4.76 – 4.42 (m, 5H), 4.00 – 3.90 (m, 2H), 3.65 – 3.30 (m, 5H), 3.20 – 3.05 (m, 2H), 2.48 (t, J = 5.7 Hz, 2H), 2.33 (tt, J = 13.7, 7.2 Hz, 2H), 2.10 – 1.90 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 1.00 (s, 9H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -99.04, -108.84, -108.92. MS (ESI+): [M+H]+854.4 / 856.4.

[0330] [8-[3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-7-(3,3-difluoropyrrolidin-1- yl)sulfonyl-imidazo[1,5-a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4- fluoro-phenyl)methanone (I-169)Formula Weight: 836.44 Molecular Formula: C42H45ClF3N5O4SSi To a solution of I-168 (135mg, 158µmol, 1 equiv.) and Et3N (0.22mL, 1.6mmol, 10 equiv.) in DCE (1mL) at RT, was added POCl3(198µL, 790µmol, 5 equiv.). The mixture was stirred at 80°C for 3h. After cooling down to RT, the reaction mixture was carefully poured in sat. aq. NaHCO3 and the mixture was vigorously stirred for 15min. EtOAc was added and the layers were separated. The aqueous phase was extracted twice with EtOAc and the combined organic extracts were washed (sat. aq. NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (12g column, dry load, cHex / EtOAc = 100 / 0 to 60 / 40) to afford 102mg of I-169 (77%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.80 – 7.65 (m, 2H), 7.60 – 7.48 (m, 4H), 7.45 – 7.30 (m, 6H), 7.25 – 6.90 (m, 3H), 6.21 & 6.17 (s, 1H), 4.59 (s, 1H), 4.35 – 4.20 (m, 2H), 4.00 – 3.05 (m, 4H), 3.65 – 3.55 (m, 3H), 3.53 – 3.42 (m, 2H), 3.43 – 3.10 (m, 2H), 2.44 – 2.27 (m, 2H), 2.20 – 1.90 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 0.97 & 0.95 (s, 9H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ - 99.10, -99.17, -108.45, -108.63. MS (ESI+): [M+H]+836.4 / 838.4.

[0331] N-[[6-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4- (3,3-difluoropyrrolidin-1-yl)sulfonyl-2-pyridyl]methyl]cyclobutanecarboxamide (I-170)Formula Weight: 626.09 Molecular Formula: C28H31ClF3N5O4S To a solution of I-109 (100mg, 0.184mmol, 1 equiv.) in DCM (1mL) at RT, were added Et3N (51µL, 0.37mmol, 2 equiv.) and cyclobutylcarbonyl chloride (25µL, 0.22mmol, 1.2 equiv.). The mixture was stirred at RT for 1h.1N HCl and EtOAc were added. The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (1N HCl, brine), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 115mg of I-170 (100%) as a yellow solid.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.45 – 7.20 (m, 1H), 7.20 – 6.95 (m, 2H), 6.86 (s, 1H), 6.79 (s, 1H), 6.32 (br s, 1H), 4.75 – 4.45 (m, 5H), 3.65 – 3.35 (m, 5H), 3.30 – 3.00 (m, 4H), 2.50 – 1.90 (m, 10.5H), 1.80 – 1.70 (m, 0.5H).19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -99.12, -108.72, -108.85. MS (ESI+): [M+H]+626.3 / 628.2. Synthesis of final compounds Synthetic methods for final compounds

[0332] The synthetic protocols for the final compounds are presented on the following Table 2.Table 2 Cpd Synthetic protocols Purity According to GP-3, 001 was obtained in 3% yield using aryl bromide I-006 (52mg, 0.12mmol, 1 equiv.), piperazine I-002 (50mg, 0.19mmol, 1.5 equiv.), t-BuONa (36mg, 0.37mmol, 3 001 >95% equiv.), and XantPhos-Pd-G3 (12mg, 12µmol, 0.1 equiv.) in dioxane (0.6mL) at reflux for 24h. Purification by FC (cHex / EtOAc = 95 / 5 to 0 / 100) and PTLC (cHex / EtOAc = 50 / 50). According to GP-3, 002 was obtained in 2% yield using aryl bromide I-007 (130mg, 0.309mmol, 1 equiv.), piperazine I-002 (124mg, 0.462mmol, 1.5 equiv.), t-BuONa (89mg, 0.93mmol, 3 002 >95% equiv.), and XantPhos-Pd-G3 (30mg, 31µmol, 0.1 equiv.) in dioxane (1.5mL) at reflux for 24h. Purification by FC (cHex / EtOAc = 95 / 5 to 0 / 100) and PTLC (cHex / EtOAc = 50 / 50). To a suspension of I-011 (55mg, 0.11mmol, 1 equiv.) and Na2CO3 (24mg, 0.22mmol, 2 equiv.) in EtOH (0.6mL) at RT, was added chloroacetaldehyde (50% in water, 39µL, 0.28mmol, 2.5 equiv.). 003 The mixture was stirred at 80°C for 16h. It was concentrated under >95% reduced pressure. The residue was purified by FC (cHex / EtOAc = 95 / 5 to 50 / 50) and PTLC (cHex / EtOAc / EtOH = 50 / 37 / 13) affording 003 in 29% yield. To a solution of I-011 (30mg, 61µmol, 1 equiv.) in dry DMF (0.5mL) at RT, was added N,N-dimethylformamide dimethyl acetal (26µL, 0.19mmol, 2.5 equiv.). The mixture was stirred at 130°C for 2h and then concentrated under reduced pressure. The residue was dissolved in MeOH (0.2mL) and pyridine (10µL, 0.12mmol, 2 equiv.) at 0°C. Hydroxylamine-O-sulfonic acid (10mg, 85µmol, 1.4 equiv.) was added. After stirring at RT for 16h, sat. aq. NaHCO3(5mL) and water (5mL) were added and the mixture was stirred at RT for 1h. The suspension was filtered over fritted glass and the filter cake was washed (1mL water), collected 004 >95% and azeotroped with toluene. The residue was dissolved in THF (0.3mL) at 0°C, and trifluoroacetic anhydride (25µL, 0.18mmol, 3 equiv.) was added dropwise. The mixture was stirred at RT for 16h. The reaction mixture was partitioned between EtOAc and aq. sat. NaHCO3. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washes (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc = 95 / 5 to 50 / 50) and PTLC (DCM / MeOH = 95 / 5) affording 004 in 8% yield. A MW vial was charged with aryl bromide I-016 (150mg, 224µmol, 1 equiv.), piperazine I-002 (90mg, 0.34mmol, 1.5 005 equiv.), t-BuONa (65mg, 0.67mmol, 3 equiv.), and XPhos-Pd-G3 >95% (19mg, 22µmol, 0.10 equiv.) in Toluene (1.1mL) at reflux for 16h. EtOAc was added and the suspension was filtered over CeliteCpd Synthetic protocols Purity (EtOAc rinses). The filtrate was concentrated under reduced pressure. The residue was dissolved in THF (1.1mL) and TBAF (1M solution in THF, 0.67mL, 0.67mmol, 3 equiv.). The mixture was stirred at 60°C of 16h. The solution was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (DCM / EtOAc = 100 / 0 to 80 / 20) and PTLC (cHex / EtOAc / EtOH = 50 / 37 / 13) affording 005 in 11% yield. A suspension of I-023 (462mg, 0.704mmol, 1 equiv.) and Pd(OH)2 (20% on C, 50% wet, 87mg, 0.07mmol, 0.1 equiv.) in THF / EtOH (1 / 2, 14mL) at RT was stirred under an H2atmosphere for 16h. After switching to an Ar atmosphere, the suspension as 006 >95% filtered over Celite (THF rinses). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc = 94 / 6 to 40 / 60) and FC (cHex / EtOAc / EtOH = 50 / 37 / 13) affording 006 in 60% yield. According to GP-3, 007 was obtained in 21% yield using aryl bromide I-024 (22mg, 59µmol, 1 equiv.), piperazine I-002 (24mg, 89µmol, 1.5 equiv.), Cs2CO3(58mg, 0.18mmol, 3 equiv.), 007 Pd(OAc)2(1.3mg, 5.9µmol, 0.1 equiv.) and rac-BINAP (4.4mg, >95% 7.1µmol, 0.12 equiv.) in Toluene (0.3mL) at reflux for 3h. Purification by PTLC (cHex / EtOAc = 50 / 50). A suspension of I-022 (80mg, 0.13mmol, 1 equiv.) and Pd(OH)2(20% on C, 50% wet, 8.0mg, 32µmol, 0.25 equiv.) in EtOH (1.3mL) at RT was stirred under an H2 atmosphere for 48h. After switching to an Ar atmosphere, the suspension as filtered over Celite (THF rinses). The filtrate was concentrated under reduced 008 pressure. The residue was dissolved in THF (1.2mL) and 3N >95% NaOH (400µL). The mixture was stirred at RT for 2h. EtOAc was added and the layers were separated. The organic phase was dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was purified by PTLC (DCM / MeOH = 98 / 2) affording 008 in 43% yield. According to GP-3, 009 was obtained in 62% yield using aryl bromide I-029 (97mg, 0.27mmol, 1 equiv.), piperazine I-002 009 (87mg, 0.32mmol, 1.2 equiv.), t-BuONa (78mg, 0.81mmol, 3 >95% equiv.) and XPhos-Pd-G3 (23mg, 27µmol, 0.1 equiv.) in Toluene (1.3mL) at reflux for 7h. Purification by FC (cHex / EtOAc = 95 / 5 to 50 / 50). A mixture of I-031 (50mg, 75µmol, 1 equiv.) and TBAF (1M solution in THF, 0.75mL, 0.75mmol, 10 equiv.) in THF (0.8mL) 010 was stirred at reflux for 5h. The reaction mixture was partitioned >95% between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organicCpd Synthetic protocols Purity extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by PTLC (cHex / EtOAc = 50 / 50) affording 010 in 35% yield. A mixture of I-039 (33mg, 51µmol, 1 equiv.) and TBAF (1M solution in THF, 0.51mL, 0.51mmol, 10 equiv.) in THF (0.5mL) was stirred at reflux for 5h. The reaction mixture was partitioned between water and EtOAc. The layers were separated and the 011 aqueous phase was extracted with EtOAc. The combined organic >95% extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by PTLC (cHex / EtOAc = 50 / 50) affording 011 in 76% yield. According to GP-3, 012 was obtained in 62% yield using aryl bromide I-040 (110mg, 288µmol, 1 equiv.), piperazine I-002 012 (116mg, 431µmol, 1.5 equiv.), t-BuONa (83mg, 0.86mmol, 3 >95% equiv.) and XPhos-Pd-G3 (24mg, 29µmol, 0.1 equiv.) in Toluene (1.4mL) at reflux for 5h. Purification by FC (cHex / EtOAc = 95 / 5 to 50 / 50). According to GP-3, 013 was obtained in 25% yield using aryl bromide I-041 (115mg, 311µmol, 1 equiv.), piperazine I-002 (100mg, 373µmol, 1.2 equiv.), t-BuONa (90mg, 0.93mmol, 3 equiv.) and XPhos-Pd-G3 (26mg, 31µmol, 0.1 equiv.) in Toluene 013 >95% (1.6mL) at reflux for 5h. More t-BuONa (90mg, 0.93mmol, 3 equiv.) and XPhos-Pd-G3 (26mg, 31µmol, 0.1 equiv.) were added and the mixture was stirred a further 1h. Purification by FC (cHex / EtOAc = 95 / 5 to 50 / 50) and PTLC (cHex / EtOAc = 50 / 50). A MW vial was charged with aryl bromide I-044 (30mg, 55µmol, 1 equiv.), piperazine I-002 (22mg, 82µmol, 1.5 equiv.), Cs2CO3(58mg, 0.18mmol, 3.3 equiv.), Pd(OAc)2 (3.3mg, 15µmol, 0.27 equiv.) and rac-BINAP (14mg, 22µmol, 0.4 equiv.). The vial was flushed with Ar and degassed toluene (0.6mL) was added. The vial was sealed and the mixture was stirred at 110°C for 2.5h. After cooling down to RT, EtOAc was added and the suspension was filtered over Celite (EtOAc rinses). The filtrate was concentrated 014 >95% under reduced pressure. The residue was dissolved in DCM (1mL) and TFA (0.15mL, 1.9mmol, 20 equiv.) was added. The mixture was stirred at RT for 3h. Sat. aq. NaHCO3was added and the layers were separated. The aqueous phase was extracted with DCM and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by PTLC (DCM / MeOH = 95 / 5 and cHex / EtOAc / EtOH = 60 / 30 / 10) affording 014 in 19% yield. A MW vial was charged with aryl bromide I-046 (120mg, 260µmol, 1 equiv.), piperazine I-002 (84mg, 0.31mmol, 1.2 015 equiv.), Cs2CO3(254mg, 778µmol, 3 equiv.), Pd(OAc)2(5.8mg, >95% 26µmol, 0.1 equiv.) and rac-BINAP (19mg, 31µmol, 0.12 equiv.). The vial was flushed with Ar and degassed toluene (1.3mL) wasCpd Synthetic protocols Purity added. The vial was sealed and the mixture was stirred at 110°C for 16h. After cooling down to RT, EtOAc was added and the suspension was filtered over Celite (EtOAc rinses). The filtrate was concentrated under reduced pressure. The residue was dissolved in THF (1mL) and TBAF (1M solution in THF, 1.2mL, 1.2mmol, 4.6 equiv.) was added. The mixture was stirred at 60°C for 16h. The reaction mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (DCM / EtOAc = 80 / 20) and PTLC (DCM / MeOH (7N NH3) = 95 / 5) affording 015 in 31% yield. According to GP-3, 016 was obtained in 59% yield using aryl bromide I-047 (42mg, 0.11mmol, 1 equiv.), piperazine I-002 (36mg, 0.13mmol, 1.2 equiv.), Cs2CO3 (110mg, 339µmol, 3 016 >95% equiv.), Pd(OAc)2 (2.5mg, 11µmol, 0.1 equiv.) and rac-BINAP (8.4mg, 14µmol, 0.12 equiv.) in Toluene (0.6mL) at reflux for 16h. Purification by FC (cHex / EtOAc = 95 / 5 to 50 / 50). A MW vial was charged with aryl bromide I-049 (68mg, 0.13mmol, 1 equiv.), piperazine I-002 (51mg, 0.19mmol, 1.5 equiv.), Cs2CO3(135mg, 416µmol, 3 equiv.), Pd(OAc)2(8.5mg, 38µmol, 0.3 equiv.) and rac-BINAP (31mg, 50µmol, 0.4 equiv.). The vial was flushed with Ar and degassed toluene (1.3mL) was added. The vial was sealed and the mixture was stirred at 110°C for 2h. After cooling down to RT, EtOAc was added and the 017 >95% suspension was filtered over Celite (EtOAc rinses). The filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (0.4mL) and TFA (24µL, 0.30mmol, 4 equiv.) was added. The mixture was stirred at RT for 16h before being concentrated under reduced pressure. The residue was purified by PTLC (DCM / MeOH = 95 / 5 and cHex / EtOAc / EtOH = 50 / 37 / 13) affording 017 in 4% yield. A MW vial was charged with aryl bromide I-051 (220mg, 358µmol, 1 equiv.), piperazine I-002 (96mg, 0.36mmol, 1 equiv.), Cs2CO3 (350mg, 1.07mmol, 3 equiv.), Pd(OAc)2 (8.0mg, 36µmol, 0.1 equiv.) and rac-BINAP (27mg, 43µmol, 0.12 equiv.). The vial was flushed with Ar and degassed toluene (1.8mL) was added. The vial was sealed and the mixture was stirred at 110°C for 16h. 018 After cooling down to RT, EtOAc was added and the suspension >95% was filtered over Celite (EtOAc rinses). The filtrate was concentrated under reduced pressure. Purification by FC (cHex / EtOAc = 98 / 2 to 30 / 70) afforded 170mg as a mixture of isomers which were dissolved in THF (2.1mL). TBAF (1M solution in...

Claims

CLAIMS 1. Compound of formula (I)or a pharmaceutically acceptable salt and / or solvate thereof; wherein W represents CH or N; RA, RB, RCand RDeach independently represents hydrogen, F, Cl, CH3, CF3, CHF2or CH2F, provided that at least one among RA, RB, RCand RDdoes not represent hydrogen; R1represents hydrogen or (C1-C8) alkyl, wherein the alkyl is optionally substituted by at least one OH, (C1-C3) alkoxy or F; and R2, R3and R4represents hydrogen; or R1and R4form together -CH2-O-CH2- or -CH2-CH2-, wherein the -CH2-CH2- is optionally substituted by at least one F, OH or OCH3; and R2and R3each represents hydrogen; A1and A2each independently represents N or C; and A3, A4and A5each independently represents N, NR11, C or CR12; provided that at least one among A1, A2, A3, A4and A5represents N or NR11;wherein each R11represents independently hydrogen, (C1-C8) alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1-C8) alkyl-, heterocycloalkyl-(C1-C8) alkyl-, aryl-(C1-C8) alkyl- or heteroaryl-(C1-C8) alkyl-; and each R12represents independently hydrogen, (C1-C8) alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1-C8) alkyl-, heterocycloalkyl-(C1-C8) alkyl-, aryl-(C1-C8) alkyl- or heteroaryl-(C1-C8) alkyl-; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl in R11or R12is optionally substituted by at least one F, Cl, OH, =O, (C1-C8) alkyl, (C1-C8) alkyl-O- or NR13R14; wherein R13and R14each independently represents hydrogen or (C1-C8) alkyl; and R10represents NR5R6or C(R5)(R6)(R9); wherein R5represents hydrogen, (C1-C8) alkyl, CH3 substituted by one to three (C1-C8) alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl-(C1-C8) alkyl; wherein the alkyl or cycloalkyl in R5is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, NR17R18, CO2H, R17R18N-C(O)-, R17O-NR18-, heterocycloalkyl, aryl or heteroaryl; wherein R17and R18each independently represents hydrogen or (C1-C8) alkyl; wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR19R20, CO2H, R19R20N-C(O)-, R19O-NR20-, (C1-C8) alkyl-CO2-, R19R20N-(C1-C8) alkyl-, R19O2C-(C1-C8) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl-(C1-C8) alkyl-; wherein R19and R20each independently represents hydrogen or (C1-C8) alkyl;R6represents hydrogen, (C1-C8) alkyl, CH3 substituted by one to three (C1-C8) alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl- (C1-C8) alkyl; wherein the alkyl or cycloalkyl in R6is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, NR21R22, CO2H, R21R22N-C(O)-, R21O-NR22-, heterocycloalkyl, aryl or heteroaryl; wherein R21and R22each independently represents hydrogen or (C1-C8) alkyl; wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR23R24, CO2H, R23R24N-C(O)-, R23O-NR24-, (C1-C8) alkyl-CO2-, R23R24N-(C1-C8) alkyl-, R23O2C-(C1-C8) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl-(C1-C8) alkyl-; wherein R23and R24each independently represents hydrogen or (C1-C8) alkyl; or R5and R6form together with the carbon atom or nitrogen atom to which they are bound a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR25R26, CO2H, (C1-C8) alkyl-CO2-, R25R26N-C(O)-, R25O-NR26-, R25R26N-(C1-C8) alkyl-, R25O2C-(C1-C8) alkyl-, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1-C8) alkyl-, heterocycloalkyl-(C1-C8) alkyl-, aryl-(C1-C8) alkyl-, heteroaryl-(C1-C8) alkyl-, aryl-cycloalkyl-, cycloalkyl-O-, heterocycloalkyl-O-, aryl-O-, heteroaryl-O-, cycloalkyl-(C1-C8) alkyl-O-, heterocycloalkyl-(C1-C8) alkyl-O-, aryl-(C1-C8) alkyl-O-, heteroaryl-(C1-C8) alkyl-O-, cycloalkyl-NR25-, heterocycloalkyl-NR25-, aryl-NR25-, heteroaryl-NR25-, cycloalkyl-(C1-C8) alkyl-NR25-, heterocycloalkyl-(C1-C8) alkyl-NR25-, aryl-(C1-C8) alkyl-NR25-, heteroaryl-(C1-C8) alkyl-NR25-, benzylidene, heteroarylidene,aryl-(C1-C8) alkyl-ylidene- or heteroaryl-(C1-C8) alkyl-ylidene-; wherein R25and R26each independently represents hydrogen or (C1-C8) alkyl; wherein the heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylidene is optionally substituted at least one F, Cl, (C1-C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR27R28, CO2H, R27R28N-C(O)-, R27O-NR28-, (C1-C8) alkyl-CO2-, R27R28N-(C1-C8) alkyl-, R27O2C-(C1-C8) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl-(C1-C8) alkyl-; wherein R27and R28each independently represents hydrogen or (C1-C8) alkyl; and R9represents hydrogen, (C1-C8) alkyl, CH3 substituted by one to three (C1-C8) alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl-(C1-C8) alkyl; wherein the alkyl or cycloalkyl in R9is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, NR29R30, CO2H, R29R30N-C(O)-, R29O-NR30-, heterocycloalkyl, aryl or heteroaryl; wherein R29and R30each independently represents hydrogen or (C1-C8) alkyl; wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR31R32, CO2H, R31R32N-C(O)-, R31O-NR32-, (C1-C8) alkyl-CO2-, R31R32N-(C1-C8) alkyl-, R31O2C-(C1-C8) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl-(C1-C8) alkyl-; wherein R31and R32each independently represents hydrogen or (C1-C8) alkyl.

2. The compound according to claim 1, wherein at least one among RA, RB, RCand RDrepresents hydrogen, preferably at least one among RAand RCrepresents hydrogen, more preferably RCrepresents hydrogen.

3. The compound according to claim 1 or claim 2, wherein at least one among RA, RBand RDrepresents F or Cl, preferably at least one among RBand RDrepresents F or Cl; more preferably RBand RDeach independently represents F or Cl; more preferably RBrepresents F and RDrepresents Cl.

4. The compound according to any one of claims 1 to 3, wherein R1represents hydrogen or (C1-C8) alkyl; preferably R1represents hydrogen or methyl.

5. The compound according to any one of claims 1 to 3, wherein R1and R4form together -CH2-CH2-; wherein the -CH2-CH2- is optionally substituted by at least one F, OH or OCH3; preferably R1and R4form together -CH2-CH2-.

6. The compound according to any one of claims 1 to 5, wherein A1, A2, A3, A4and A5form together a five-membered heteroaryl selected from the following formulaewherein R11and R12are each independently as defined in claim 1; and wherein the dotted lines represent the points of fusion of the five-membered heteroaryl to the six-membered ring to which it is fused.

7. The compound according to claim 6, wherein A1, A2, A3, A4and A5form together a five-membered heteroaryl selected from the following formulaewherein R11and R12are each independently as defined in claim 1; and wherein the dotted lines represent the points of fusion of the five-membered heteroaryl to the six-membered ring to which it is fused.

8. The compound according to any one of claims 1 to 7, wherein A5represents NR11or CR12, wherein R11and R12are as defined in claim 1, provided that R11and R12do not represent hydrogen; preferably R11and R12each independently represents methyl, ethyl, isobutyl, hydroxymethyl, hydroxyethyl, hydroxybutyl, methoxyethyl, ethyl-O-C(O)-, cyclobutyl or cyclopropyl.

9. The compound according to any one of claims 1 to 8, wherein R10represents NR5R6, wherein: R5represents hydrogen or (C1-C8) alkyl; preferably R5represents hydrogen, methyl, trideuteriomethyl (CD3) or ethyl; and / or R6represents (C1-C8) alkyl or cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by at least one F; preferably R6represents ethyl, propyl, 3-fluoropropyl, butyl or difluorocyclobutyl; orR5and R6form together with the nitrogen atom to which they are bound an heterocycloalkyl; preferably R5and R6form together with the nitrogen atom to which they are bound a difluoropyrrolidine, phenyl-piperidine or (chlorophenyl)ethyl-piperazine.

10. The compound according to any one of claims 1 to 8, wherein R10represents C(R5)(R6)(R9), wherein: R5represents hydrogen or (C1-C8) alkyl; preferably R5represents hydrogen, methyl or ethyl; and / or R6represents (C1-C8) alkyl; preferably R6represents ethyl or butyl; or R5and R6form together with the carbon atom to which they are bound a cycloalkyl; preferably cyclopentyl; and / or R9represents hydrogen.

11. The compound according to any one of claims 1 to 10, wherein said compound is selected from: (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[6-[(4-phenyl-1- 001 piperidyl)sulfonyl]imidazo[1,2-a]pyridin-8-yl]-3,8-diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[6-[(4-phenyl-1-piperidyl)sulfonyl]- 002 [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[6-(2,2- 003 dimethylpropylsulfonyl)imidazo[1,2-a]pyridin-8-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[6-(2,2-dimethylpropylsulfonyl)- 004 [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-[(4-phenyl-1-piperidyl)sulfonyl]- 005 1H-indol-7-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanoneN-tert-butyl-7-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-N-(trideuteriomethyl)-1H-indole-5- sulfonamide N-tert-butyl-7-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-1-cyclopropyl-indole-5-sulfonamide N-tert-butyl-7-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-1H-indole-5-sulfonamide N-tert-butyl-7-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-N,1-dimethyl-indole-5-sulfonamide N-tert-butyl-7-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-N-methyl-1H-indole-5-sulfonamide (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-(2,2-dimethylpropylsulfonyl)-1H- indol-7-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-(2,2-dimethylpropylsulfonyl)-1- methyl-indol-7-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[1-cyclopropyl-5-(2,2- dimethylpropylsulfonyl)indol-7-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-[(4-phenyl-1-piperidyl)sulfonyl]- 1H-indazol-7-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone N-tert-butyl-7-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-1H-indazole-5-sulfonamide N-tert-butyl-7-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-1-cyclopropyl-indazole-5-sulfonamide (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-(3,3-difluoropyrrolidin-1- yl)sulfonyl-1H-indazol-7-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-[4-[2-(4- chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-1H-indazol-7-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone;hydrochloride (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-[4-[2-(4- chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-1-cyclopropyl-indazol-7-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone;hydrochloride (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-(2,2-dimethylpropylsulfonyl)-1H- indazol-7-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-(2,2-dimethylpropylsulfonyl)-1- methyl-indazol-7-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[1-cyclopropyl-5-(2,2- dimethylpropylsulfonyl)indazol-7-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl]methanone(2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-(2,2-dimethylpropylsulfonyl)-1-(2- hydroxyethyl)indazol-7-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-(2,2-dimethylpropylsulfonyl)-1-(2- methoxyethyl)indazol-7-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1R,5S)-8-[6-[(4-phenyl-1-piperidyl)sulfonyl]- 3H-benzotriazol-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[6-[(4-phenyl-1-piperidyl)sulfonyl]- 1H-benzimidazol-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[3-methyl-6-[(4-phenyl-1- piperidyl)sulfonyl]benzimidazol-4-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl]methanone N-tert-butyl-7-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-1H-benzimidazole-5-sulfonamide N-tert-butyl-7-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-1-cyclopropyl-benzimidazole-5-sulfonamide N-tert-butyl-7-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-N-methyl-1H-benzimidazole-5-sulfonamide (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[6-[4-[2-(4- chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-1H-benzimidazol-4-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone;hydrochloride (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[6-[4-[2-(4- chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-3-cyclopropyl-benzimidazol-4- yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone;hydrochloride (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[6-(2,2-dimethylpropylsulfonyl)-3H- benzimidazol-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[6-(2,2-dimethylpropylsulfonyl)-3- methyl-benzimidazol-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[3-cyclopropyl-6-(2,2- dimethylpropylsulfonyl)benzimidazol-4-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[6-(2,2-dimethylpropylsulfonyl)-3- ethyl-benzimidazol-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-[(4-phenyl-1-piperidyl)sulfonyl]- [1,2,4]triazolo[4,3-a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-[(4-phenyl-1- piperidyl)sulfonyl]imidazo[1,2-a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octan- 3-yl]methanone(2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-[(4-phenyl-1- piperidyl)sulfonyl]imidazo[1,5-a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octan- 3-yl]methanone 5-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]- N,N-diethyl-imidazo[1,5-a]pyridine-7-sulfonamide 5-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]- 3-cyclopropyl-N,N-diethyl-imidazo[1,5-a]pyridine-7-sulfonamide N-tert-butyl-5-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]imidazo[1,5-a]pyridine-7-sulfonamide N-tert-butyl-5-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-N-(trideuteriomethyl)imidazo[1,5-a]pyridine- 7-sulfonamide N-tert-butyl-5-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-3-methyl-imidazo[1,5-a]pyridine-7- sulfonamide N-tert-butyl-5-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-3-cyclopropyl-imidazo[1,5-a]pyridine-7- sulfonamide N-tert-butyl-5-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-3-cyclopropyl-N-methyl-imidazo[1,5- a]pyridine-7-sulfonamide N-tert-butyl-5-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-3-cyclopropyl-N- (trideuteriomethyl)imidazo[1,5-a]pyridine-7-sulfonamide (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-(3,3-difluoropyrrolidin-1- yl)sulfonylimidazo[1,5-a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[3-cyclopropyl-7-(3,3- difluoropyrrolidin-1-yl)sulfonyl-imidazo[1,5-a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 5-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]- N-(3-fluoropropyl)imidazo[1,5-a]pyridine-7-sulfonamide 5-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]- N-(3-fluoropropyl)-N-methyl-imidazo[1,5-a]pyridine-7-sulfonamide 5-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]- 3-cyclopropyl-N-(3-fluoropropyl)imidazo[1,5-a]pyridine-7-sulfonamide 5-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]- 3-cyclopropyl-N-(3-fluoropropyl)-N-methyl-imidazo[1,5-a]pyridine-7- sulfonamide5-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]- N-(3,3-difluorocyclobutyl)imidazo[1,5-a]pyridine-7-sulfonamide 5-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]- N-(3,3-difluorocyclobutyl)-N-methyl-imidazo[1,5-a]pyridine-7-sulfonamide 5-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]- 3-cyclopropyl-N-(3,3-difluorocyclobutyl)imidazo[1,5-a]pyridine-7- sulfonamide 5-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]- 3-cyclopropyl-N-(3,3-difluorocyclobutyl)-N-methyl-imidazo[1,5-a]pyridine- 7-sulfonamide (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-[4-[2-(4- chlorophenyl)ethyl]piperazin-1-yl]sulfonylimidazo[1,5-a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone;hydrochloride (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-[4-[2-(4- chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-3-cyclopropyl-imidazo[1,5- a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone;hydrochloride (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-(2,2- dimethylpropylsulfonyl)imidazo[1,2-a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-(2,2- dimethylpropylsulfonyl)imidazo[1,5-a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-(2,2-dimethylpropylsulfonyl)-3- methyl-imidazo[1,5-a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[3-cyclopropyl-7-(2,2- dimethylpropylsulfonyl)imidazo[1,5-a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-(2,2-dimethylpropylsulfonyl)-3- (hydroxymethyl)imidazo[1,5-a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl]methanone ethyl 5-[(1S,5R)-3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan- 8-yl]-7-(2,2-dimethylpropylsulfonyl)imidazo[1,5-a]pyridine-3-carboxylate (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-(2,2-dimethylpropylsulfonyl)-3-(2- hydroxyethyl)imidazo[1,5-a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-(2,2-dimethylpropylsulfonyl)-3-(2- methoxyethyl)imidazo[1,5-a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl]methanone(2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-(7-cyclopentylsulfonylimidazo[1,5- a]pyridin-5-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-(1-ethylpropylsulfonyl)imidazo[1,5- a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-[(1SR)-1- methylpropyl]sulfonylimidazo[1,5-a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[4-[3-cyclopropyl-7-(2,2- dimethylpropylsulfonyl)imidazo[1,5-a]pyridin-5-yl]piperazin-1-yl]methanone (2-chloro-4-fluoro-phenyl)-[4-[7-(2,2-dimethylpropylsulfonyl)-3-methyl- imidazo[1,5-a]pyridin-5-yl]piperazin-1-yl]methanone (2-chloro-4-fluoro-phenyl)-[(3S)-4-[7-(2,2-dimethylpropylsulfonyl)-3-methyl- imidazo[1,5-a]pyridin-5-yl]-3-methyl-piperazin-1-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-(2,2-dimethylpropylsulfonyl)-1-(2- hydroxy-2-methyl-propyl)indazol-7-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl]methanone [(1S,5R)-8-[5-(2,2-dimethylpropylsulfonyl)-1-(2-methoxyethyl)indazol-7-yl]- 3,8-diazabicyclo[3.2.1]octan-3-yl]-(4-fluorophenyl)methanone (2-chlorophenyl)-[(1S,5R)-8-[5-(2,2-dimethylpropylsulfonyl)-1-(2- methoxyethyl)indazol-7-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4,5-difluoro-phenyl)-[(1S,5R)-8-[5-(2,2-dimethylpropylsulfonyl)-1- (2-methoxyethyl)indazol-7-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone [(1S,5R)-8-[5-(2,2-dimethylpropylsulfonyl)-1-(2-methoxyethyl)indazol-7-yl]- 3,8-diazabicyclo[3.2.1]octan-3-yl]-(4-fluoro-2-methyl-phenyl)methanone (3-chloro-5-fluoro-2-pyridyl)-[(1S,5R)-8-[5-(2,2-dimethylpropylsulfonyl)-1- (2-methoxyethyl)indazol-7-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-(2,2-dimethylpropylsulfonyl)-3-(2- hydroxy-2-methyl-propyl)imidazo[1,5-a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-(2,2-dimethylpropylsulfonyl)-3- ethyl-imidazo[1,5-a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-(2,2-dimethylpropylsulfonyl)-3- isobutyl-imidazo[1,5-a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[3-cyclobutyl-7-(2,2- dimethylpropylsulfonyl)imidazo[1,5-a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone(2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-(3,3-difluoropyrrolidin-1- 084 yl)sulfonyl-3-methyl-imidazo[1,5-a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-(3,3-difluoropyrrolidin-1- 085 yl)sulfonyl-3-ethyl-imidazo[1,5-a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octan- 3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-(3,3-difluoropyrrolidin-1- 086 yl)sulfonyl-3-isobutyl-imidazo[1,5-a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[7-(3,3-difluoropyrrolidin-1- 087 yl)sulfonyl-3-(2-hydroxyethyl)imidazo[1,5-a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[3-cyclobutyl-7-(3,3- 088 difluoropyrrolidin-1-yl)sulfonyl-imidazo[1,5-a]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone and pharmaceutically acceptable salts and / or solvates thereof.

12. Pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and at least one pharmaceutically acceptable carrier.

13. The compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12 for use as a medicament.

14. The compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12 for use in the treatment of a neurological disorder.

15. Process for manufacturing a compound according to any one of claims 1 to 11, wherein said process comprises either: - a step of reaction of a compound of formula (II)wherein A1-A5and R10are as defined in claim 1, and X represents halide or -CF3SO3, with a compound of formula (III)wherein W, RA-RDand R1-R4are as defined in claim 1, in presence of a base and a metal catalyst; thereby obtaining the compound of formula (I) or the pharmaceutically acceptable salt and / or solvate thereof; or - a step of reaction of a compound of formula (VII)wherein W, RA-RD, R1-R4, R10and R12are as defined in claim 1, in presence of a dehydrating agent, preferably, wherein said dehydrating agent is phosphorous oxychloride (POCl3); thereby obtaining the compound of formula (I) or the pharmaceutically acceptable salt and / or solvate thereof.

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