NOVEL SULFONAMIDES AND THEIR USE AS NEUROPROTECTIVE

AND/OR NEURORESTORATIVE AGENTS

FIELD OF INVENTION

[0001] The present invention relates to novel polycyclic sulfonamides comprising at least one substituted and/or bridged piperazine. 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 21 ^st century, 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 symptoms that 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/intemal 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 Elkl through the activation of the GFRal-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 it does 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] WO 2011/070177 A2 (BALTIC TECHNOLOGY DEV LTD) discloses polycyclic compounds for treating neurological disorders. Although these compounds represented a significant improvement at this time, they still have limitations in terms of activity on GFRal-RET target, solubility, membrane permeability (PAMPA and CaCO2), intrinsic clearance microsomes and hepatocytes, plasma protein binding, and pharmacokinetic profile. In particular, these compounds are limited in terms of activity on GFRal-RET target (as evidenced, for example, in luciferase assays).

[0009] It was surprisingly found out by the Applicants that novel polycyclic sulfonamides of formula (I) showed potent GFRal-RET activity in a luciferase assay, thereby opening the way to overcoming the limitations of available therapeutic solutions.

SUMMARY

[0010] An object of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof; wherein W, R ^A -R ^D , R ^x -R ⁴ , Z, R ⁵ -R ⁷ and R ^E are as defined hereinafter and/or as defined in the claims. [0011] According to one embodiment, the compound is selected from the compounds of Table 1 herein, and pharmaceutically acceptable salts and/or solvates thereof. [0012] Another object of the present invention is a pharmaceutical composition comprising a compound according to the invention and at least one pharmaceutically acceptable carrier. [0013] 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. According to one embodiment, the compound or the pharmaceutical composition is for use in the treatment of a neurological disorder. [0014] Another object of the present invention is a process for manufacturing a compound according to the invention. DEFINITIONS [0015] In the present invention, the following terms have the following meanings: Chemical definitions [0016] 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-”. [0017] Unless otherwise indicated, the compounds were named using BIOVIA Draw 2021 (Dassault, France). [0018] 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, “R ^x represents hydrogen, (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) 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 R ^x may optionally substituted by at least one F, including said (C ₁ -C ₈ ) alkyl as such (e.g., CF ₃ ), 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-). [0019] “Alkoxy” refers to an alkyl-O- group. [0020] “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). [0021] “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 -NH ₂ group. [0022] “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), (C ₁ -C ₈ ) 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. [0023] “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. [0024] “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 (C ₁ -C ₈ ) alkyl (preferably, (C ₁ -C ₄ ) 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. [0025] “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. [0026] “Halogen” refers to a fluorine, chlorine, bromine or iodine atom. [0027] “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 =0 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 molecule through 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 poly thioethers, and combinations thereof.

[0028] “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 (=0) for sulfur atom or (— >0) 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. [0029] “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. [0030] “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 (=0) for sulfur atom or (— >0) 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 heterocyclo alkyl 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 otherwise specified. Heterocycloalkyls may optionally be substituted by at least one group such as, for example, halogen (e.g., F or Cl), (Ci-Cs) alkyl (preferably, (C1-C4) alkyl, e.g., methyl), nitrile (CN) or =0. Non-limiting examples of heterocycloalkyl include aziridine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, azepane, azocane, octahydro- ///-isoindolc, 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.

[0031] “Isobutyronitrile” refers to a (NC)(CH3hC- group of the following formula.

[0032] “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.

[0033] “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).

[0034] “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

[0035] “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%.

[0036] “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.

[0037] “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.

[0038] “GDNF family receptor alpha-1”, “GFRal”, or “GDNFRal”, 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, GFRal is encoded by the GFRA1 gene. An exemplary amino acid sequence of human GFRal 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.

[0039] “Human” refers to a male or female human subject at any stage of development, including neonate, infant, juvenile, adolescent and adult.

[0040] “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.

[0041] “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.

[0042] “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.

[0043] “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.

[0044] “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, poly acrylates, waxes, polyethylene- polyoxypropylene- block polymers, polyethylene glycol and wool fat.

[0045] “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.

[0046] “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., GFRal, GFRa2, GFRa3 or GFRa4), 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.

[0047] “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.

[0048] “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.

[0049] “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.

[0050] “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 prior to 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.

[0051] “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

Compound

[0052] 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;

R ^A , R ^B , R ^c and R ^D each independently represents hydrogen, F, Cl, CH3, CF3, CHF ₂ or CH ₂ F, provided that at least one among R ^A , R ^B , R ^c and R ^D does not represent hydrogen;

R ¹ represents (Ci-Cs) alkyl, wherein the alkyl is optionally substituted by at least one OH, (C1-C3) alkoxy or F; and R ² , R ³ and R ⁴ represents hydrogen; or R ¹ and R ⁴ form together -CH2-O-CH2- or -CH2-CH2-, wherein the -CH ₂ -CH ₂ - is optionally substituted by at least one F, OH or OCH ₃ ; and R ² and R ³ each represents hydrogen; R ⁷ represents hydrogen, OH, halogen, (C1-C8) alkyl, cycloalkyl, (C1-C8) alkyl- O-, cycloalkyl-O-, cycloalkyl-(C ₁ -C ₈ ) alkyl-O-, heterocycloalkyl-O-, R ¹¹ O-(C1-C8) alkyl-O-, R ¹¹ R ¹² N-(C1-C8) alkyl-O-, (R ¹¹ O)(R ¹² )N-(C1-C8) alkyl- O-, R ¹¹ R ¹² N-(C1-C8) alkyl-, R ¹¹ O-(C1-C8) alkyl-, NR ¹¹ R ¹² , CN, CO2H, CO2R ¹¹ , CONH ₂ , CON(R ¹¹ )H, heterocycloalkyl, or heteroaryl; wherein R ¹¹ and R ¹² each independently represents hydrogen or (C ₁ -C ₈ ) alkyl; wherein the alkyl or cycloalkyl in R ⁷ is optionally substituted by at least one F, Cl, OH, =O, (C1-C8) alkyl, (C1-C8) alkyl-O-, heterocycloalkyl, aryl or heteroaryl; 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, (C ₁ -C ₈ ) alkoxy, NR ¹³ R ¹⁴ , R ¹³ R ¹⁴ N-(C ₁ -C ₈ ) alkyl-, R ¹³ O ₂ C- (C1-C8) alkyl-, CO2H, R ¹³ R ¹⁴ N-C(O)-, R ¹³ O-NR ¹⁴ -, or (C1-C8) alkyl-CO2- ; wherein R ¹³ and R ¹⁴ each independently represents hydrogen or (C ₁ -C ₈ ) alkyl; Z represents C-H, C-R ⁸ or N; wherein R ⁸ represents (C1-C4) alkyl, F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH or (C1-C4) alkoxy; or Z represents C-R ⁸ and R ⁷ and R ⁸ form together with the carbon atoms to which they are bound a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by at least one F, OH, =O, →O, (C ₁ -C ₈ ) alkyl, CF ₃ , HO ₂ C-CH ₂ -, (C ₁ -C ₄ ) alkyl- CO2-CH2-, R ¹⁵ R ¹⁶ N-CH2-, aryl, or aryl-(C1-C8) alkyl-, wherein R ¹⁵ and R ¹⁶ each independently represents hydrogen or (C1-C8) alkyl; R ⁵ represents hydrogen, (C1-C8) alkyl, CH3 substituted by one to three (C ₁ -C ₈ ) alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl- (C1-C8) alkyl; wherein the alkyl or cycloalkyl in R ⁵ is optionally substituted by at least one F, Cl, (C ₁ -C ₈ ) alkyl, CF ₃ , OCF ₃ , CN, OH, =O, (C ₁ -C ₈ ) alkoxy, NR ¹⁷ R ¹⁸ , CO2H, R ¹⁷ R ¹⁸ N-C(O)-, R ¹⁷ O-NR ¹⁸ -, heterocycloalkyl, aryl or heteroaryl; wherein R ¹⁷ and R ¹⁸ each independently represents hydrogen or (C ₁ -C ₈ ) alkyl; wherein the heterocycloalkyl, aryl or heteroaryl (i.e., any heterocycloalkyl, aryl or heteroaryl that is represented by R ⁵ or that is part of any substituent thereof) is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, CHF ₂ , CH ₂ F, OCF ₃ , CN, OH, =O, →O, (C ₁ -C ₈ ) alkoxy, NR ¹⁹ R ²⁰ , CO ₂ H, R ¹⁹ R ²⁰ N-C(O)-, R ¹⁹ O-NR ²⁰ -, (C1-C8) alkyl-CO2-, R ¹⁹ R ²⁰ N-(C1-C8) alkyl-, R ¹⁹ O2C-(C1-C8) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl- (C ₁ -C ₈ ) alkyl-; wherein R ¹⁹ and R ²⁰ each independently represents hydrogen or (C1-C8) alkyl; R ⁶ represents (C1-C8) alkyl, CH3 substituted by one to three (C1-C8) alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl-(C ₁ -C ₈ ) alkyl; wherein the alkyl or cycloalkyl in R ⁶ is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, NR ²¹ R ²² , CO2H, R ²¹ R ²² N-C(O)-, R ²¹ O-NR ²² -, heterocycloalkyl, aryl or heteroaryl; wherein R ²¹ and R ²² each independently represents hydrogen or (C1-C8) alkyl; wherein the heterocycloalkyl, aryl or heteroaryl (i.e., any heterocycloalkyl, aryl or heteroaryl that is represented by R ⁶ or 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, NR ²³ R ²⁴ , CO2H, R ²³ R ²⁴ N-C(O)-, R ²³ O-NR ²⁴ -, (C ₁ -C ₈ ) alkyl-CO ₂ -, R ²³ R ²⁴ N-(C ₁ -C ₈ ) alkyl-, R ²³ O ₂ C-(C ₁ -C ₈ ) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl- (C1-C8) alkyl-; wherein R ²³ and R ²⁴ each independently represents hydrogen or (C ₁ -C ₈ ) alkyl; or R ⁵ and R ⁶ form together with the nitrogen atom to which they are bound an heterocycloalkyl, wherein the heterocycloalkyl (i.e., the heterocycloalkyl that is formed by R ⁵ , R ⁶ and the nitrogen atom to which they are bound) is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, →O, (C ₁ -C ₈ ) alkoxy, NR ²⁵ R ²⁶ , CO ₂ H, (C ₁ -C ₈ ) alkyl-CO ₂ -, R ²⁵ R ²⁶ N-C(O)- , R ²⁵ O-NR ²⁶ -, R ²⁵ R ²⁶ N-(C ₁ -C ₈ ) alkyl-, R ²⁵ O ₂ C-(C ₁ -C ₈ ) alkyl-, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1-C8) alkyl-, heterocycloalkyl-(C1-C8) alkyl-, aryl-(C1-C8) alkyl-, heteroaryl- (C ₁ -C ₈ ) 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-NR ²⁵ -, heterocycloalkyl-NR ²⁵ -, aryl-NR ²⁵ -, heteroaryl-NR ²⁵ -, cycloalkyl-(C1-C8) alkyl-NR ²⁵ -, heterocycloalkyl-(C1-C8) alkyl-NR ²⁵ -, aryl-(C1-C8) alkyl-NR ²⁵ -, heteroaryl-(C1-C8) alkyl-NR ²⁵ -, benzylidene, heteroarylidene, aryl-(C ₁ -C ₈ ) alkyl-ylidene- or heteroaryl-(C ₁ -C ₈ ) alkyl- ylidene-; wherein R ²⁵ and R ²⁶ each 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 R ⁵ , R ⁶ and the nitrogen atom to which they are bound) is optionally substituted at least one F, Cl, (C1-C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR ²⁷ R ²⁸ , CO ₂ H, R ²⁷ R ²⁸ N-C(O)-, R ²⁷ O-NR ²⁸ -, (C ₁ -C ₈ ) alkyl-CO ₂ -, R ²⁷ R ²⁸ N-(C ₁ - C ₈ ) alkyl-, R ²⁷ O ₂ C-(C ₁ -C ₈ ) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl-(C1-C8) alkyl-; wherein R ²⁷ and R ²⁸ each independently represents hydrogen or (C ₁ -C ₈ ) alkyl; R ^E represents hydrogen, (C1-C3) alkyl or halogen. [0053] 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. [0054] According to one preferred embodiment, the compound of formula (I) is a compound of formula (I’) or a pharmaceutically acceptable salt and/or solvate thereof; wherein W represents CH or N; R ^A , R ^B , R ^C and R ^D each independently represents hydrogen, F, Cl, CH ₃ , CF ₃ , CHF2 or CH2F, provided that at least one among R ^A , R ^B , R ^C and R ^D does not represent hydrogen; R ¹ represents (C ₁ -C ₈ ) alkyl, wherein the alkyl is optionally substituted by at least one OH, (C1-C3) alkoxy or F; and R ² , R ³ and R ⁴ represents hydrogen; or R ¹ and R ⁴ form together -CH ₂ -O-CH ₂ - or -CH ₂ -CH ₂ -, wherein the -CH ₂ -CH ₂ - is optionally substituted by at least one F, OH or OCH ₃ ; and R ² and R ³ each represents hydrogen; R ⁷ represents hydrogen, OH, halogen, (C1-C8) alkyl, cycloalkyl, (C1-C8) alkyl- O-, cycloalkyl-O-, cycloalkyl-(C ₁ -C ₈ ) alkyl-O-, heterocycloalkyl-O-, R ¹¹ O-(C1-C8) alkyl-O-, R ¹¹ R ¹² N-(C1-C8) alkyl-O- or (R ¹¹ O)(R ¹² )N- (C1-C8) alkyl-O-; wherein R ¹¹ and R ¹² each independently represents hydrogen or (C ₁ -C ₈ ) alkyl; wherein the alkyl or cycloalkyl is optionally substituted by at least one F, Cl, heterocycloalkyl, aryl or heteroaryl; wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , CN, OH, (C ₁ -C ₈ ) alkoxy, NR ¹³ R ¹⁴ , CO2H, R ¹³ R ¹⁴ N-C(O)-, or R ¹³ O-NR ¹⁴ -; wherein R ¹³ and R ¹⁴ each independently represents hydrogen or (C1-C8) alkyl; Z represents C-H or N; or Z represents C-R ⁸ and R ⁷ and R ⁸ form together with the carbon atoms to which they are bound a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by at least one F, OH, CF3, HO2C-CH2-, (C1-C4) alkyl-CO2-CH2-, or R ¹⁵ R ¹⁶ N-CH2-, wherein R ¹⁵ and R ¹⁶ each independently represents hydrogen or (C ₁ -C ₈ ) alkyl; R ⁵ represents hydrogen, (C ₁ -C ₈ ) alkyl, CH ₃ substituted by one to three (C1-C8) alkyl groups, cycloalkyl or cycloalkyl-(C1-C8) alkyl; wherein the alkyl or cycloalkyl is optionally substituted by at least one F, Cl, CF ₃ , OCF ₃ , CN, OH, (C ₁ -C ₈ ) alkoxy, NR ¹⁷ R ¹⁸ , CO ₂ H, R ¹⁷ R ¹⁸ N-C(O)-, R ¹⁷ O-NR ¹⁸ -, heterocycloalkyl, aryl or heteroaryl; wherein R ¹⁷ and R ¹⁸ each independently represents hydrogen or (C1-C8) alkyl; wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH, (C1-C8) alkoxy, NR ¹⁹ R ²⁰ , CO2H, R ¹⁹ R ²⁰ N-C(O)-, or R ¹⁹ O-NR ²⁰ -; wherein R ¹⁹ and R ²⁰ each independently represents hydrogen or (C ₁ -C ₈ ) alkyl; R ⁶ represents (C1-C8) alkyl, CH3 substituted by one to three (C1-C8) alkyl groups, cycloalkyl or cycloalkyl-(C ₁ -C ₈ ) alkyl; wherein the alkyl or cycloalkyl is optionally substituted by at least one F, Cl, CF3, OCF3, CN, OH, (C1-C8) alkoxy, NR ²¹ R ²² , CO2H, R ²¹ R ²² N-C(O)-, R ²¹ O-NR ²² -, heterocycloalkyl, aryl or heteroaryl; wherein R ²¹ and R ²² each independently represents hydrogen or (C1-C8) alkyl; wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , CN, OH, (C ₁ -C ₈ ) alkoxy, NR ²³ R ²⁴ , CO ₂ H, R ²³ R ²⁴ N-C(O)-, or R ²³ O-NR ²⁴ -; wherein R ²³ and R ²⁴ each independently represents hydrogen or (C1-C8) alkyl; or R ⁵ and R ⁶ form together with the nitrogen atom to which they are bound an heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by at least one F, Cl, CF3, OCF3, CN, OH, (C1-C8) alkoxy, NR ²⁵ R ²⁶ , CO2H, R ²⁵ R ²⁶ N-C(O)-, R ²⁵ O-NR ²⁶ -, heterocycloalkyl, aryl, heteroaryl, heterocycloalkyl- (C1-C8) alkyl-, aryl-(C1-C8) alkyl-, heteroaryl-(C1-C8) alkyl-, cycloalkyl- (C1-C8) alkyl-O-, aryl-(C1-C8) alkyl-O-, heteroaryl-(C1-C8) alkyl-O-, cycloalkyl-(C ₁ -C ₈ ) alkyl-NR ²⁵ -, aryl-(C ₁ -C ₈ ) alkyl-NR ²⁵ -, heteroaryl- (C ₁ -C ₈ ) alkyl-NR ²⁵ -, benzylidene, heteroarylidene, aryl-(C ₁ -C ₈ ) alkyl- ylidene- or heteroaryl-(C1-C8) alkyl-ylidene-; wherein R ²⁵ and R ²⁶ each independently represents hydrogen or (C ₁ -C ₈ ) alkyl; wherein the heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylidene is optionally substituted at least one F, Cl, CF3, CHF2, CH ₂ F, OCF ₃ , CN, OH, (C ₁ -C ₈ ) alkoxy, NR ²⁷ R ²⁸ , CO ₂ H, R ²⁷ R ²⁸ N- C(O)-, or R ²⁷ O-NR ²⁸ -; wherein R ²⁷ and R ²⁸ each independently represents hydrogen or (C1-C8) alkyl. [0055] According to one embodiment, W represents CH. [0056] According to one embodiment, at least one among R ^A , R ^B , R ^C and R ^D represents hydrogen. In one embodiment, exactly one among R ^A , R ^B , R ^C and R ^D represents hydrogen. In one embodiment, exactly two among R ^A , R ^B , R ^C and R ^D represents hydrogen. In one embodiment, exactly three among R ^A , R ^B , R ^C and R ^D represents hydrogen. [0057] In one embodiment, at least one among R ^A and R ^C represents hydrogen. In one particular embodiment, R ^A represents hydrogen. In one particular embodiment, R ^C represents hydrogen. [0058] According to one embodiment, at least one among R ^A , R ^B and R ^D represents F or Cl. In one embodiment, at least one among R ^B and R ^D represents F or Cl. In one particular embodiment, R ^B and R ^D each independently represents F or Cl. In one particular embodiment, R ^B represents F. In one particular embodiment, R ^B represents Cl. In one particular embodiment, R ^D represents F. In one particular embodiment, R ^D represents Cl. In one preferred embodiment, R ^B represents F. In one preferred embodiment, R ^D represents Cl. In one further preferred embodiment, R ^B represents F and R ^D represents Cl. [0059] As defined under formula (I) hereinabove, R ¹ may represents (C1-C8) alkyl, wherein the alkyl is optionally substituted by at least one OH, (C ₁ -C ₃ ) alkoxy or F, i.e., the (C ₁ -C ₈ ) alkyl in R ¹ is optionally substituted by at least one group, and the group may be OH, (C1-C3) alkoxy or F. According to one embodiment, R ¹ represents (C1-C8) alkyl, wherein the alkyl is optionally substituted by at least one group selected from OH, (C ₁ -C ₃ ) alkoxy and F. [0060] According to one embodiment, R ¹ and R ⁴ form together -CH2-O- CH2- or -CH2-CH2. In one embodiment, R ¹ and R ⁴ form together -CH2-CH2-. In one embodiment, the -CH ₂ -CH ₂ - is optionally substituted by at least one F, OH or OCH ₃ . In one embodiment, the -CH2-CH2- is not substituted. [0061] According to one embodiment, R ¹ represents methyl, ethyl, CF3 or methoxymethyl (CH ₃ OCH ₂ -). In one embodiment, R ¹ represents methyl, ethyl or CF ₃ . In one embodiment, R ¹ represents methoxymethyl (CH ₃ OCH ₂ -). [0062] According to one embodiment, R ⁷ represents hydrogen, OH, halogen, (C ₁ -C ₈ ) alkyl, cycloalkyl, (C ₁ -C ₈ ) alkyl-O-, cycloalkyl-O-, cycloalkyl-(C ₁ -C ₈ ) alkyl-O-, heterocycloalkyl-O-, R ¹¹ O-(C1-C8) alkyl-O-, R ¹¹ R ¹² N-(C1-C8) alkyl-O- or (R ¹¹ O)(R ¹² )N- (C1-C8) alkyl-O-; wherein R ¹¹ and R ¹² each independently represents hydrogen or (C ₁ -C ₈ ) alkyl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted as defined under formula (I) hereinabove. [0063] According to one embodiment, R ⁷ represents hydrogen, OH or halogen. In one embodiment, R ⁷ represents hydrogen. In one preferred embodiment, R ⁷ represents hydroxyl (OH). In one embodiment, R ⁷ represents halogen. In one particular preferred embodiment, R ⁷ represents F or Cl. In one particular embodiment, R ⁷ represents F. In one particular embodiment, R ⁷ represents Cl. [0064] In one preferred embodiment, R ⁷ does not represent hydrogen. [0065] According to one embodiment, R ⁷ represents (C1-C8) alkyl-O- (i.e., (C1-C8) alkoxy), or cycloalkyl-O-. In one embodiment, the alkyl or cycloalkyl is optionally substituted by at least one F, Cl, OH, (C ₁ -C ₈ ) alkoxy or aryl. In one particular embodiment, R ⁷ represents OCH3 (methoxy), OCH2CH3, OCF3, cyclobutyl-O-, HO-CH2- CH2-O-, CH3O-CH2-CH2-O- or phenyl-CH2-O-. [0066] According to one embodiment, R ⁷ represents (C ₁ -C ₈ ) alkyl-O- (i.e., (C ₁ -C ₈ ) alkoxy). In one embodiment, the alkyl is optionally substituted by at least one F or Cl. In one particular embodiment, the halogen is F. In one embodiment, R ⁷ represents OCH3 (methoxy), OCH2CH3 or OCF3. [0067] According to one embodiment, R ⁷ represents cycloalkyl-O-. In one embodiment, R ⁷ represents cyclobutyl-O-. [0068] According to one embodiment, R ⁷ represents (C1-C8) alkyl-O- (i.e., (C ₁ -C ₈ ) alkoxy), wherein the alkyl is optionally substituted by at least one OH or (C1-C8) alkoxy, i.e., RO-(C1-C8) alkyl-O- wherein R represents H or (C1-C8) alkyl. In one embodiment, R ⁷ represents HO-CH2-CH2-O- or CH3O-CH2-CH2-O-. [0069] According to one embodiment, R ⁷ represents (C1-C8) alkyl-O- (i.e., (C ₁ -C ₈ ) alkoxy), wherein the alkyl is optionally substituted by at least one aryl. In one embodiment, the aryl is not substituted. In one embodiment, R ⁷ represents phenyl- CH2-O-. [0070] According to one embodiment, R ⁷ represents (C ₁ -C ₈ ) alkyl-O- (i.e., (C1-C8) alkoxy), wherein the alkyl is optionally substituted by at least one heteroaryl. In one embodiment, the heteroaryl is not substituted. In one embodiment, R ⁷ represents heteroaryl -CH ₂ -O-. [0071] According to one embodiment, R ⁷ represents (C ₁ -C ₈ ) alkyl-O- (i.e., (C1-C8) alkoxy), wherein the alkyl is optionally substituted by at least one heterocycloalkyl. In one embodiment, R ⁷ represents heterocycloalkyl-(C1-C8) alkyl-O-, i.e., the alkyl is substituted by exactly one heterocycloalkyl. In one embodiment, the heterocycloalkyl is not substituted. [0072] In one preferred embodiment, R ⁷ represents F, Cl, OCH3 (methoxy), OCH2CH3, OCF ₃ , cyclobutyl-O-, HO-CH ₂ -CH ₂ -O-, CH ₃ O-CH ₂ -CH ₂ -O-, phenyl-CH ₂ -O-, 1H- imidazole-4-yl-, 1-methyl-imidazole-4-yl-, CH3, CN, CO2H, Cl, F, CH2OH, C(CH3)2OH, CH2N(CH3)2, cyclopropyl, cyclobutyl-O-, (4-pyridine)-CH2-O-, (3-pyridine)-CH2-O- or benzyl-O-. In one particular preferred embodiment, R ⁷ represents 1H-imidazole-4-yl-, 1- methyl-imidazole-4-yl-, CH ₃ , CN, CO ₂ H, CH ₂ OH, C(CH ₃ ) ₂ OH, CH ₂ N(CH ₃ ) ₂ , cyclopropyl, cyclobutyl-O-, (4-pyridine)-CH2-O-, (3-pyridine)-CH2-O- or benzyl-O-. [0073] According to one embodiment, Z represents C-H or N; or Z represents C-R ⁸ and R ⁷ and R ⁸ form together with the carbon atoms to which they are bound a cycloalkyl or heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted as defined under formula (I) hereinabove. In other words, in this embodiment, R ⁸ represent hydrogen, except where R ⁷ and R ⁸ form together with the carbon atoms to which they are bound a cycloalkyl or heterocycloalkyl. [0074] According to one embodiment, Z represents C-H or N. In one embodiment, Z represents C-H. In one embodiment, Z represents N. [0075] According to one preferred embodiment, Z represents C-R ⁸ ; wherein R ⁸ represents (C ₁ -C ₄ ) alkyl, F, Cl, CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , CN, OH or (C ₁ -C ₄ ) alkoxy. In one preferred embodiment, R ⁸ represents methyl, ethyl, F, Cl, CF3, CN or OH. [0076] According to another embodiment, Z represents C-R ⁸ and R ⁷ and R ⁸ form together with the carbon atoms to which they are bound a cycloalkyl or heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted as defined under formula (I) herein. [0077] In one preferred embodiment, Z represents C-R ⁸ and R ⁷ and R ⁸ form together with the carbon atoms to which they are bound an heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted as defined under formula (I) herein. In one particular embodiment, the heterocycloalkyl comprises at least one oxygen atom, i.e., the heterocycloalkyl is a cyclic ether. In one particular embodiment, the heterocycloalkyl comprises at least one nitrogen atom, i.e., the heterocycloalkyl is a cyclic amine. In one particular embodiment, the heterocycloalkyl is six-membered or five-membered. In one particular embodiment, the heterocycloalkyl comprises exactly one oxygen atom, two oxygen atoms, or one nitrogen atom. [0078] According to one embodiment, R ⁵ represents hydrogen or (C1-C8) alkyl. In one embodiment, R ⁵ represents hydrogen. In one embodiment, R ⁵ represents (C ₁ -C ₈ ) alkyl. In one preferred embodiment, R ⁵ represents hydrogen, methyl or ethyl. In one particular embodiment, R ⁵ represents hydrogen. In one particular embodiment, R ⁵ represents methyl or ethyl. [0079] According to one embodiment, R ⁶ represents (C ₁ -C ₈ ) alkyl, cycloalkyl or cycloalkyl-(C1-C8) alkyl-. In one embodiment, the alkyl or cycloalkyl is optionally substituted by at least one F. In one preferred embodiment, the alkyl or cycloalkyl is not substituted. In one embodiment, R ⁶ represents methyl, ethyl, n-propyl, 1-fluoro-n- propane, tert-butyl, cyclopropyl, cyclobutyl or cyclopropyl-CH2-. [0080] According to one embodiment, R ⁶ represents (C1-C8) alkyl, cycloalkyl or cycloalkyl-(C ₁ -C ₈ ) alkyl- or heterocycloalkyl. In one embodiment, the alkyl or cycloalkyl is optionally substituted by at least one F, CN or CF ₃ . In one preferred embodiment, the alkyl or cycloalkyl is not substituted. In one embodiment, R ⁶ represents methyl, ethyl, i-propyl, isobutyronitrile, n-propyl, 3-fluoro-n-propane, tert-butyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, 1-methylcyclobutyl, cyclopropyl-CH2-, (F3C)C(Me)2-, 3-methyloxetane-3-yl or oxetane-3-yl. [0081] According to one embodiment, R ⁶ represents (C ₁ -C ₈ ) alkyl. In one embodiment, the alkyl is optionally substituted by at least one F. In one embodiment, the alkyl is not substituted. In one particular embodiment, R ⁵ represents methyl, ethyl, n-propyl, 1-fluoro-n-propane or tert-butyl. [0082] According to one embodiment, R ⁶ represents cycloalkyl. In one embodiment, R ⁶ represents cyclopropyl or cyclobutyl. [0083] According to one embodiment, R ⁶ represents cycloalkyl-(C1-C8) alkyl. In one particular embodiment, R ⁶ represents cyclopropylmethyl (cyclopropyl-CH ₂ -). [0084] According to one embodiment, R ⁵ and R ⁶ form together with the nitrogen atom to which they are bound an heterocycloalkyl. In one embodiment, the heterocycloalkyl is optionally substituted by at least one F. In one preferred embodiment, R ⁵ and R ⁶ form together with the nitrogen atom to which they are bound a pyrrolidine, piperidine, 4- fluoropiperidine, 3-fluoropyrrolidine, 4-trifluoromethylpiperidine, 4-benzyl-piperidine, 3-benzylpyrrolidine, 3-benzyl-piperidine, 4-phenylpiperidine, 4-benzylidenepiperidine, octahydro-1H-isoindole, 2-benzyloctahydropyrrolo[3,4-c]pyrrole, 3-(benzyloxy)pyrrole, 3-(methoxymethyl)azetidine, 2-azabicyclo[2.2.1]heptane, 5-(4-methylpiperazin-1- yl)pyrimidine and 4-phenethylpiperidine. In one particular embodiment, R ⁵ and R ⁶ form together with the nitrogen atom to which they are bound a pyrrolidine, 4-fluoropiperidine, 3-fluoropyrrolidine, 4-trifluoromethylpiperidine, 4-benzyl-piperidine, 3-benzylpyrrolidine, 3-benzyl-piperidine, 4-phenylpiperidine, 4-benzylidenepiperidine, octahydro-1H-isoindole, 3-(benzyloxy)pyrrole, 2-azabicyclo[2.2.1]heptane, 5-(4- methylpiperazin-1-yl)pyrimidine or 4-phenethylpiperidine. [0085] In one preferred embodiment, R ⁵ and R ⁶ form together with the nitrogen atom to which they are bound a pyrrolidine, 3,3-dimethylmorpholine, 4-fluoropiperidine, 3-fluoropyrrolidine, 4-trifluoromethylpiperidine, 4-benzyl-piperidine, 3-benzylpyrrolidine, 3-benzyl-piperidine, 4-phenylpiperidine, 4-(4- fluorophenyl)piperidine, 4-benzylidenepiperidine, octahydro-1H-isoindole, 3- (benzyloxy)pyrrolidine, 3-phenoxypyrrolidine, N-methyl-N-phenyl-pyrrolidin-3-amine, 2-azabicyclo[2.2.1]heptane, 5-(4-methylpiperazin-1-yl)pyrimidine, 4-phenethylpiperidine, phenylpiperazine, 4-benzyl-piperazine, 3-(4- piperidyl)benzonitrile, methyl 3-(4-piperidyl)benzoate, methyl 4-(4-piperidyl)benzoate, 4-(3-pyrazol-1-ylphenyl)piperidine, 1-[(1R,2S)-2-(4- fluorophenyl)cyclopropyl]piperazine, 1-[2-(4-fluorophenyl)propyl]piperazine, 1-[2-(4- fluorophenyl)ethyl]piperazine 1-[2-(4-chlorophenyl)ethyl]piperazine, 1-(2- phenylpropyl)piperazine, or 1-(4-fluorophenyl)-2-piperazin-1-yl-ethanol. [0086] 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. [0087] According to one embodiment, R ^E represents hydrogen or halogen. In one preferred embodiment, R ^E represents hydrogen or F. In one further preferred embodiment, R ^E represents hydrogen. According to one embodiment, R ^E represents (C ₁ -C ₃ ) alkyl. According to one embodiment, R ^E represents halogen. [0088] 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, R ^B , R ^D , Z, R ¹ -R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^E are as defined under formula (I) herein. [0089] In one embodiment, W in formula (I-a) represents CH.

[0090] In one embodiment, R ^B and R ^D in formula (I-a) each independently represents F or Cl. In one particular embodiment, R ^B represents F, R ^D represents Cl.

[0091] In one embodiment, R ^E in formula (I-a) represents hydrogen. [0092] 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

[0093] 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. [0094] 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.

[0095] 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, hemisulphate 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.

[0096] 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 ringopening 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.

[0097] 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.

[0098] 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 each distinct 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

[0099] 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.

[0100] 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. [0101] Another object of the present invention is a medicament comprising a compound according to the invention, as described herein.

Kit

[0102] 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.

[0103] According to one embodiment, the kit comprises: a pharmaceutical composition comprising the compound according to the invention, and another separate pharmaceutical 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

[0104] Another object of the present invention is a compound or a composition according to the invention, as described herein, for use as a medicament.

[0105] 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.

[0106] 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. [0107] 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.

[0108] 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, Frontotemporal 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 system performance, 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 by motor 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-Barre 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 (S AH), 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-oncological disease 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.

[0109] 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.

[0110] 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).

[0111] 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.

[0112] 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. [0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] Another object of the present invention is a method of binding or modulating GFRal 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 GFRal . According to one preferred embodiment, the compound or a composition is for activating GFRal. In one embodiment, GFRal is human GFRal, preferably with SEQ ID NO: 1.

[0118] Another object of the present invention is a method of activating the GFRa 1/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 GFRal/RET signaling pathway. [0119] Another object of the present invention is a method of detecting GFRal 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 GFRal in a sample. In one embodiment, GFRal is human GFRal, 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

[0120] The compound according to the invention, as described herein, may be manufactured by means of synthetic methods well-known in the art.

[0121] 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.

[0122] According to one embodiment, the process comprises a step of reaction of: a compound of formula (II) wherein Z, R ⁵ , R ⁶ , R ⁷ and R ^E are as defined under formula (I) herein and X represents halide or -CF3SO3, with a compound of formula (III)

wherein W, R ^A -R ^D and R ^x -R ⁴ are as defined under formula (I) herein, in presence of a base and a metal catalyst; thereby obtaining the compound of the invention.

[0123] In one embodiment, the base is cesium carbonate (CS2CO3), sodium carbonate (Na2COa) 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).

[0124] 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)- l,l’-binaphtyle) system. In one particular embodiment, the catalyst is Xphos-Pd-G3.

[0125] In one embodiment, X represents halide. In one particular embodiment, X represents Br.

[0126] In one embodiment, the reaction is carried out in a solvent. In one particular embodiment, the solvent is toluene. In one embodiment, the reaction is carried out at reflux.

[0127] According to another embodiment, the process comprises:

(a’-l) a step of reaction of wherein Z, R ⁵ , R ⁶ , R ⁷ and R ^E are as defined under formula (I) herein and X represents halide or -CF3SO3, with a mono-protected piperazine (z.e., a piperazine wherein only one of the NH groups is protected by means of a protecting group R ^p ) of the following formula (MPP), wherein R'-R ⁴ are as defined under formula (I) herein; in presence of a base and a metal catalyst; thereby obtaining a compound of formula (IV) wherein Z, R' R ⁴ . R ⁵ , R ⁶ , R ⁷ and R ^E are as defined under formula (I) herein and R ^p is the protecting group; then

(a’ -2) a step of deprotection of the compound of formula (IV); thereby obtaining a compound of formula (V) wherein Z, R' R ⁴ . R ⁵ , R ⁶ , R ⁷ and R ^E are 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 R ^A -R ^D are as defined under formula (I) herein, in presence of a peptide coupling agent and a base; thereby obtaining the compound of the invention.

[0128] In one embodiment, the base and/or the catalyst at step (a’-l) are as described hereinabove under step (a-1). In one embodiment, X represents halide. In one particular embodiment, X represents Br.

[0129] The protecting group may be any 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 [HC1]).

[0130] The peptide coupling agent at step (a’ -3) may be any peptide coupling agent known in the art such as, for example, 2-(J//-benzotriazole-l-yl)-l,l,3,3- tetramethylaminium tetrafluoroborate (TBTU).

[0131] The base at step (a’-3) may be any base known in the art such as, for example, an amine base. According to one embodiment, the amine is triethylamine (EtsN) or diisopropylethylamine (i Pro Net).

[0132] In one embodiment, the reaction at step (a’ -3) is carried out in a solvent. 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). [0133] According to another embodiment, the process comprises:

(a”-l) a step of reaction of: a compound of formula (III) wherein W, R'-R ⁴ , and R ^A -R ^D are as defined under formula (I) herein, with a compound of formula (VII) wherein Z, R ⁷ and R ^E are as defined under formula (I) herein, except that Z does not represent N, and X represents halide or -CF3SO3, in presence of a base and a metal catalyst; thereby obtaining a compound of formula (VIII) wherein W, R ^A -R ^D , R' R ⁴ . R ⁷ and R ^E are as defined under formula (I) herein and Z is as defined under formula (VII) herein; (a” -2) a step of reaction of the compound of formula (VIII) with chlorosulfonic acid (HSO3CI); thereby obtaining a compound of formula (IX);

wherein W, R ^A -R ^D , R' R ⁴ . R ⁷ and R ^E are as defined under formula (I) herein and Z is as defined under formula (VII) herein;

(a” -3) a step of reaction of the compound of formula (IX) with a primary or secondary amine of formula (X)

NHR ⁵ R ⁶ (X) wherein R ⁵ and R ⁶ are as defined under formula (I) herein, in presence of a base; thereby obtaining the compound of the invention.

[0134] According to an alternative embodiment, the process comprises a step (a”-l) of reaction of a compound of formula (III) with a compound of formula (VII) as described hereinabove, thereby obtaining a compound of formula (VIII); but no step (a” -2) of reaction of the compound of formula (VIII) with chlorosulfonic acid (HSO3CI); and Z may represent N.

[0135] In one embodiment, the base and/or the catalyst at step (a”-l) are as described hereinabove under step (a-1). In one embodiment, X represents halide. In one particular embodiment, X represents Br.

[0136] The base at step (a”-3) may be any base known in the art such as, for example, an amine base. According to one embodiment, the amine is triethylamine (EtsN) or diisopropylethylamine (i Pro Net).

[0137] In one embodiment, the reaction at step (a” -3) is carried out in a solvent. In one particular embodiment, the solvent is dichloromethane (DCM). [0138] 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 IN HC1 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.

[0139] In one embodiment, the process further comprises a purificationstep (c). 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).

Synthetic intermediates

[0140] Another object of the present invention is a compound of formula (II) wherein Z, R ⁵ , R ⁶ , R ⁷ and R ^E are as defined under formula (I) herein and X represents halide or -CF3SO3.

[0141] Another object of the present invention is a compound of formula (III) wherein W, R ^A -R ^D and RkR ⁴ are as defined under formula (I) herein. [0142] Another object of the present invention is a compound of formula (IV) wherein Z, R' R ⁴ . R ⁵ , R ⁶ , R ⁷ and R ^E are as defined under formula (I) herein and R ^p is a protecting group (e.g., Boc). [0143] Another object of the present invention is a compound of formula (V) wherein Z, R' R ⁴ . R ⁵ , R ⁶ , R ⁷ and R ^E are as defined under formula (I) herein.

[0144] Another object of the present invention is a compound of formula (VIII) wherein W, Z, R ^A -R ^D , R'-R ⁴ , R ⁷ and R ^E are as defined under formula (I) herein.

[0145] According to one preferred embodiment, in formula (VIII) hereinabove, Z does not represent N. [0146] Another object of the present invention is a compound of formula (IX) wherein W, Z, R ^A -R ^D , R'-R ⁴ , R ⁷ and R ^E are as defined under formula (I) herein.

[0147] According to one preferred embodiment, in formula (IX) hereinabove, Z does not represent N.

EXAMPLES

[0148] The present invention is further illustrated by the following examples.

Example 1: Synthesis of the compounds

General material and methods

Abbreviations

[0149] List of abbreviations:

Ac: acetyl

Ar: argon

BINAP: (2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl) t-Bu: tert-butyl cHex: cyclohexane dba: dibenzylideneacetone

DCM: dichloromethane

DCE: dichloroethane

DMF: dimethylformamide

Et: ethyl FC: flash chromatography

JohnPhos: 2-(di-tert-butylphosphino)biphenyl MTBE: tert-butyl methyl ether

PTLC: preparative thin-layer chromatography

RT: room temperature

TBTU: 2-(777-benzotriazole-l-yl)-l,l,3,3-tetramethylaminium tetrafluoroborate

TPTU: O-(2-oxo-l(2H)pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate

TFA: trifluoroacetic acid

THF: tetrahydrofuran

XPhos: dicyclohexyl[2',4',6'-tris(propan-2-yl)[l,l'-biphenyl]-2-yl] phosphane XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Analytical methods

[0150] ^! H NMR spectra (400 MHz) and ¹⁹ F 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.

[0151] 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.: 5pL. Acidic conditions: Waters XSelect CSH C18 column (3.5pm, 2. lx 15 50 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 (3.5pm, 2. lx 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 ): Peptide coupling using TBTU

[0152] To a solution of the required carboxylic acid in DMF at RT, was added TBTU. The mixture was stirred for 15min at RT and a solution of the required piperazine and EhN in THF was added dropwise. The mixture was stirred at RT for the required time. The volatiles were removed under reduced pressure and the residue was partitioned between IN HC1 and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (IN HC1, aq. sat. NaHCO3, 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.

General protocol 2 (GP-2): Peptide coupling using TPTU (small scale)

[0153] To a solution of the required carboxylic acid in DCE/MeCN (1/1) at RT, were added iPnNEt and TPTU. After stirring for 5min at RT, the required piperazine was added and the mixture was stirred at RT for the required time. 2 drops of ethylene diamine were added and the reaction mixture was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc gradient) or PTLC to afford the required product.

General protocol 3 (GP-3): Chlorosulfonylation

[0154] To chloro sulfonic acid at 0°C, was added drop wise a solution of the required arene in DCM. The mixture was allowed to warm-up to the required temperature and allowed to stir at required temperature for the required time. The reaction mixture was poured drop wise on crushed ice while stirring (very exothermic quench). At the end of the addition, the residual ice was allowed to melt, DCM was 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 to afford the desired sulfonyl chloride. General protocol 4 (GP-4): Sulfonamide formation

[0155] To a solution of the required amine and EhN or iPnNEt in DCM, was added a solution of the required sulfonyl chloride in DCM at RT. The reaction mixture was stirred at RT for the required time. The reaction mixture was partitioned between EtOAc and aq. sat. NH4CI. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (aq. sat. NH4CI, 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.

General protocol 5 (GP-5): Buchwald coupling using Pd(OAc)2 or Pd2(dba)3/rac-BINAP

[0156] A micro wave reaction vial was charged with the required arylbromide, the required piperazine, CS2CO3, Pd(OAc)2 or Pd2(dba)3 and rac-BINAP. The vial was flushed with argon and degassed toluene 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 as filtered over Celite® (EtOAc rinses). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc gradient) or PTLC to afford the required product.

General protocol 6 (GP-6): Buchwald coupling using XantPhos-Pd-G3

[0157] A microwave reaction vial was charged with the required arylbromide, the required piperazine, t-BuONa and XantPhos-Pd-G3. The vial was flushed with argon and degassed toluene 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 as filtered over Celite® (EtOAc rinses). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc gradient) or PTLC to afford the required product.

General protocol 7 (GP-7): Buchwald coupling using XPhos-Pd-G3

[0158] A microwave reaction vial was charged with the required arylbromide, the required piperazine, t-BuoNa and XPhos-Pd-G3. The vial was flushed with argon and degassed toluene 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 as filtered over Celite® (EtOAc rinses). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc gradient) or PTLC to afford the required product. Synthesis of intermediate compounds Synthesis of common intermediate piperazines [0159] tert-butyl 3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octane- 8- carboxylate (Boc-I-001) Formula Weight: 368,83 Molecular Formula: C ₁₈ H ₂₂ ClFN ₂ O ₃ To 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 extracted with EtOAc(2*). The combined organic extracts were washed (aq. sat. NH4Cl, aq. sat. NaHCO ₃ , brine), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to afford 21.3g (76% pure, 93%) of tert-butyl 3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Boc-I-001) as an orange oil. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 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. [0160] (2-chloro-4-fluoro-phenyl)-(3,8-diazabicyclo[3.2.1]octan-3-y l)methanone (I-001) Formula Weight: 268,71 Molecular Formula: C ₁₃ H ₁₄ ClFN ₂ O To a solution of crude tert-butyl 3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate Boc-I-001 (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 (Na ₂ SO ₄ ), 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 (88%) of (2-chloro-4-fluoro-phenyl)-(3,8-diazabicyclo[3.2.1]octan-3-y l)methanone I-001 as a white solid. ¹ H 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. [0161] tert-butyl 3-[4-fluoro-2-(trifluoromethyl)benzoyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Boc-I-002) Formula Weight: 402.38 Molecular Formula: C ₁₉ H ₂₂ F ₄ N ₂ O ₃ To a solution of commercial 4-fluoro-2-(trifluoromethyl)benzoic acid (784mg, 3.77mmol, 2 equiv.In DCE/ACN (1:1, 9mL) at RT, was added iPr2NEt (656µL, 3.77mmol, 2 equiv.) and TPTU (1.12g, 3.77mmol, 2 equiv.). The mixture was stirred for 15min at RT and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400mg, 1.88mmol, 1 equiv.) was added. The mixture was stirred at RT for 16h. The volatiles were removed under reduced pressure and the residue 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, aq. sat. NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc 95/5 to 40/60) affording 724mg (95%) of tert-butyl 3-[4- fluoro-2-(trifluoromethyl)benzoyl]-3,8-diazabicyclo[3.2.1]oc tane-8-carboxylate (Boc-I-002) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d6, multiple sets of rotamers) δ 7.83-7.70 (m, 1H), 7.69-7.55 (m, 2H), 4.31-4.14 (m, 2H), 4.08-3.95 (m, 1H), 3.37-2.82 (m, 3H), 1.95-1.47 (m, 4H), 1.42 (d, J = 7.8 Hz, 9H). MS (ESI ⁺ ): [M+H] ⁺ 403.2. [0162] 3,8-diazabicyclo[3.2.1]octan-3-yl-[4-fluoro-2- (trifluoromethyl)phenyl]methanone (I-002) Formula Weight: 302.27 Molecular Formula: C ₁₄ H ₁₄ F ₄ N ₂ O To a solution of tert-butyl 3-[4-fluoro-2-(trifluoromethyl)benzoyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate Boc-I-002 (724mg, 1.80mmol, 1 equiv.) was treated with HCl (4M solution in dioxane, 4.5mL, 18mmol, 10 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 (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure, affording 607 mg (quantitative yield) of I-002 as a colorless oil. ¹ H NMR (400 MHz, DMSO-d6, 2 sets of rotamers) δ 7.75 (ddd, J = 9.3, 4.4, 2.6 Hz, 1H), 7.69-7.49 (m, 2H), 4.14 (ddd, J = 19.8, 12.4, 2.3 Hz, 1H), 3.62-3.58 (m, 1H), 3.57 (s, 1H), 3.39-3.33 (m, 1H), 3.33-3.26 (m, 0.5H), 3.12-2.96 (m, 1H), 2.95-2.92 (m, 1.5H), 1.82- 1.57 (m, 3H), 1.57-1.39 (m, 1H). MS (ESI ⁺ ): [M+H] ⁺ 303.0. [0163] tert-butyl 4-(2-chloro-4-fluoro-benzoyl)-2-methyl-piperazine-1-carboxyl ate (Boc-I-003) To a solution of 2-chloro-4-fluorobenzoic acid (10.5g, 59.9mmol, 1.2 equiv.) in THF (120mL) at RT, was added TBTU (19.2g, 59.9mmol, 1 equiv.). The mixture was stirred 15min at RT, and a solution of tert-butyl 2-methylpiperazine-1-carboxylate (10.0g, 49.9mmol, 1 equiv.) and Et3N (6.5mL, 37mmol, 0.75 equiv.) in THF (120mL) 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 aq. sat. NH ₄ Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (2*). The combined organic extracts were Washed (aq. sat. NH4Cl, aq. sat. NaHCO3, brine), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by FC (220g column, dry load, cHex/EtOAc = 90/10 to 50/50) to afford 16.8g (94%) of tert-butyl 4-(2-chloro-4-fluoro-benzoyl)-2-methyl-piperazine-1-carboxyl ate (Boc-I-003) as a white solid. ¹ H 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)-(3-methylpiperazin-1-yl)methanone (I-003) To a solution of crude tert-butyl 4-(2-chloro-4-fluoro-benzoyl)-2-methyl-piperazine-1- carboxylate Boc-I-003 (16.8g, 47.1mmol, 1 equiv.) in DCM (235mL) at 0°C, was added TFA (72mL, 941mmol, 20 equiv.). The mixture was stirred at RT for 2h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM at 0°C. K ₂ CO ₃ (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 (7N NH ₃ ) = 99/1 to 90/10) to afford 9.8g (81%) of (2-chloro-4-fluoro-phenyl)-(3-methylpiperazin-1- yl)methanone I-003 as a white solid. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.32 (ddd, J = 8.6, 5.9, 1.3 Hz, 0.5H), 7.25 (ddd, J = 8.5, 5.9, 1.4 Hz, 0.5H), 7.21-7.13 (m, 1H), 7.09-7.01 (m, 1H), 4.69-4.56 (m, 1H), 3.31-2.75 (m, 5H), 2.51 (m, 1H), 1.15 (dd, J = 6.3, 2.4 Hz, 1.5H), 0.98 (dd, J = 6.3, 4.5 Hz, 1.5H). MS (ESI+): [M+H]+ 257.1/259.1. (2-chloro-4-fluoro-phenyl)-[(3S)-3-methylpiperazin-1-yl]meth anone ((S)-I-003) & (2- chloro-4-fluoro-phenyl)-[(3R)-3-methylpiperazin-1-yl]methano ne ((R)-I-003). (S)-I-003 and (R)-I-003 were obtained using the same synthetic sequence than the one used for I- 003 starting respectively, from tert-butyl (2S)-2-methylpiperazine-1-carboxylate and tert- butyl (2R)-2-methylpiperazine-1-carboxylate. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.32 (ddd, J = 8.6, 5.9, 1.3 Hz, 0.5H), 7.25 (ddd, J = 8.5, 5.9, 1.4 Hz, 0.5H), 7.21-7.13 (m, 1H), 7.09-7.01 (m, 1H), 4.69-4.56 (m, 1H), 3.31-2.75 (m, 5H), 2.51 (m, 1H), 1.15 (dd, J = 6.3, 2.4 Hz, 1.5H), 0.98 (dd, J = 6.3, 4.5 Hz, 1.5H). MS (ESI+): [M+H]+ 257.1/259.1. [0165] tert-butyl 3-(2-chloro-4,5-difluoro-benzoyl)-3,8-diazabicyclo[3.2.1]oct ane-8- carboxylate (Boc-I-033) Formula Weight: 386,82 Molecular Formula: C ₁₈ H ₂₁ ClF ₂ N ₂ O ₃ To a solution of 2-chloro-4,5-difluorobenzoic acid (2.72g, 14.1mmol, 1.2 equiv.) in DMF (29mL) at RT, was added TBTU (4.54g, 14.1mmol, 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 (2.50g, 11.8mmol, 1 equiv.) and Et3N (2.5mL, 17mmol, 1.5 equiv.) in THF (29mL) 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 extracted with EtOAc(2*). The combined organic extracts were washed (aq. sat. NH ₄ Cl, aq. sat. NaHCO ₃ , brine), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to afford 6.76g (88% pure) of tert-butyl 3-(2-chloro-4,5-difluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Boc-I-033) as an orange oil. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.32 – 6.94 (m, 2H), 4.47 – 4.36 (m, 1H), 4.38 – 4.00 (m, 2H), 3.55 – 3.20 (m, 1H), 3.11 – 3.01 (m, 2H), 2.07 – 1.64 (m, 3.5H), 1.60 – 1.50 (m, 0.5H), 1.46 (s, 9H). MS (ESI ⁺ ): [M+H] ⁺ 387.1/389.1. [0166] (2-chloro-4,5-difluoro-phenyl)-(3,8-diazabicyclo[3.2.1]octan -3-yl)methanone (I-033) To a solution of crude tert-butyl 3-(2-chloro-4,5-difluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate Boc-I-033 (6.76g, 88% pure, 15.3mmol, 1 equiv.) in dioxane (77 mL) at RT, was added HCl (4M solution in dioxane, 19mL, 77mmol, 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 (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by FC (24g column, dry load, DCM/MeOH (7N NH3) = 99/1 to 95/5) to afford 3.15g (70%) of (2-chloro-4,5-difluoro-phenyl)-(3,8-diazabicyclo[3.2.1]octan -3-yl)methanone I-033 as a white solid. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.32 – 7.22 (m, 1H), 7.21 – 6.96 (m, 1H), 4.45 – 4.30 (m, 1H), 3.62 (s, 1H), 3.44 – 3.20 (m, 2H), 3.10 – 2.98 (m, 2H), 1.94 – 1.71 (m, 3.5H), 1.62 – 1.53 (m, 0.5H). MS (ESI ⁺ ): [M+H] ⁺ 287.0/289.0. Synthesis of required amines [0167] tert-butyl 4-(3-pyrazol-1-ylphenyl)piperidine-1-carboxylate (Boc-I-034) A MW vial was charged with tert-butyl 4-(3-bromophenyl)piperidine-1-carboxylate (100mg, 294µmol, 1 equiv.), pyrazole (40mg, 0.59mmol, 2 equiv.), Cs2CO3 (239mg, 735µmol, 2.5 equiv.), CuI (11mg, 59µmol, 0.2 equ’v.) and trans-N,N'- dimethylcyclohexane-1,2-diamine (0.012mL, 0.074mmol, 0.25 equiv.). The vial was purged and degassed NMP (1.5mL) was added. The vial was sealed and the mixture was stirred at 150°C for 18h. 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 (12g column, dry load, cHex/EtOAc = 95/5 to 50/50) to afford 49mg (51%) of tert-butyl 4-(3-pyrazol-1-ylphenyl)piperidine-1- carboxylate Boc-I-034 as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.85 (dd, J = 2.5, 0.6 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.53 (t, J = 2.0 Hz, 1H), 7.42 (ddd, J = 8.1, 2.2, 1.1 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.12 – 7.00 (m, 1H), 6.39 (dd, J = 2.5, 1.8 Hz, 1H), 4.19 (s, 2H), 2.83 – 2.48 (m, 3H), 1.80 (d, J = 13.1 Hz, 2H), 1.61 (qd, J = 12.6, 4.4 Hz, 2H), 1.42 (s, 9H). MS (ESI ⁺ ): [M+H] ⁺ 328.1. [0168] 4-(3-pyrazol-1-ylphenyl)piperidine;hydrochloride (I-034)

To a solution of crude tert-butyl 4-(3-pyrazol-1-ylphenyl)piperidine-1-carboxylate Boc- I-034 (49mg, 0.15mmol, 1 equiv.) in dioxane (71mL) at RT, was added HCl (4M solution in dioxane, 0.37mL, 1.5mmol, 10 equiv.). The mixture was stirred at RT for 3h. The reaction mixture was concentrated under reduced pressure to afford 344mg (98%) 4-(3- pyrazol-1-ylphenyl)piperidine;hydrochloride I-034 as a white solid. ¹ H NMR (400 MHz, D2O) δ 8.14 (d, J = 2.6 Hz, 1H), 7.78 (d, J = 1.9 Hz, 1H), 7.61 – 7.41 (m, 3H), 7.29 (dt, J = 7.2, 1.7 Hz, 1H), 6.56 (t, J = 2.3 Hz, 1H), 3.59 – 3.44 (m, 2H), 3.23 – 3.07 (m, 2H), 2.98 (ddt, J = 12.1, 7.3, 3.6 Hz, 1H), 2.21 – 2.03 (m, 2H), 2.01 – 1.80 (m, 2H). [0169] 2-(4-fluorophenyl)cyclopropanol (I-035) M A solution of 4-fluorophenylethyl magnesium bromide [prepared by slowly adding a solution of 1-(2-Bromoethyl)-4-fluorobenzene (3.0g, 15mmol, 3 equiv.) in dry THF (10mL) to Mg (547mg, 22.5mmol, 4.5equiv.) in dry THF (5mL) and refluxing the resulting suspension for 1h only the supernatant was used] was added dropwise over 2h on a solution of ClTi(Oi-Pr)3 (1.95g, 7.49mmol, 1.5 equiv.) and methyl formate (0.30g, 5.0mmol, 1 equiv.) in dry THF (35mL) at RT. Ice-cold 10% H2SO4 was added dropwise, followed by Et ₂ O. The layers were separated and the aqueous phase was extracted with Et2O. The combined organic extracts were washed (sat. aq. NaHCO3, 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 231mg (27%, 90% purity) of 2-(4-fluorophenyl)cyclopropanol I-035 as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.03 – 6.92 (m, 4H), 3.63 – 3.56 (m, 1H), 2.29 – 2.08 (m, 2H), 1.28 (ddd, J = 10.0, 6.1, 3.5 Hz, 1H), 1.02 (q, J = 6.4 Hz, 1H). [0170] trans tert-butyl 4-[rac-(1R,2S)-2-(4-fluorophenyl)cyclopropyl]piperazine-1- carboxylate (Boc-I-036) A MW vial was charged with ZnCl2 (372mg, 2.73mmol, 2 equiv.) Na2CO3 (290mg, 2.73mmol, 2 equiv.) and tert-butyl-1-piperazine carboxylate (254mg, 1.37mmol, 1 equiv.). The vial was purged with Ar and a solution of 2-(4-fluorophenyl)cyclopropanol I-035 (90% purity, 231mg, 1.37mmol, 1 equiv.). The vial was sealed and the mixture was stirred at 110°C for 16h. After cooling down to RT, the reaction mixture was partitioned between sat. aq. NaHCO ₃ 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 = 95/5 to 50/50) to afford 60mg (14%) of trans tert-butyl 4-[rac-(1R,2S)-2-(4-fluorophenyl)cyclopropyl]piperazine-1-ca rboxylate Boc- I-036 as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.02 – 6.98 (m, 2H), 6.96 – 6.91 (m, 2H), 3.49 – 3.31 (m, 4H), 2.58 (t, J = 5.1 Hz, 4H), 1.98 (ddd, J = 9.3, 5.8, 3.2 Hz, 1H), 1.80 (dt, J = 7.3, 3.8 Hz, 1H), 1.46 (s, 9H), 1.10 (dt, J = 9.5, 4.7 Hz, 1H), 0.91 (dt, J = 6.9, 5.5 Hz, 1H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -117.6. MS (ESI ⁺ ): [M+H] ⁺ 321.2. [0171] trans 1-[rac-(1R,2S)-2-(4-fluorophenyl)cyclopropyl]piperazine (I-036) To a solution of trans tert-butyl 4-[rac-(1R,2S)-2-(4- fluorophenyl)cyclopropyl]piperazine-1-carboxylate Boc-I-036 (60mg, 0.19mmol, 1 equiv.) in dioxane (0.9 mL) at RT, was added HCl (4M solution in dioxane, 0.94mL, 3.7mmol, 20 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. K ₂ CO ₃ (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 PTLC (DCM/MeOH (7N NH3) = 90/10) to afford 26mg (63%) trans 1-[rac-(1R,2S)-2- (4-fluorophenyl)cyclopropyl]piperazine I-036 as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.05 – 6.96 (m, 2H), 6.96 – 6.86 (m, 2H), 2.97 – 2.76 (m, 4H), 2.62 (s, 4H), 2.05 (s, 1H), 1.96 (ddd, J = 9.3, 5.8, 3.2 Hz, 1H), 1.80 (dt, J = 7.3, 3.8 Hz, 1H), 1.09 (dt, J = 9.5, 4.7 Hz, 1H), 0.93 – 0.85 (m, 1H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ - 117.8. MS (ESI ⁺ ): [M+H] ⁺ 221.2. Synthesis of intermediates required for final product 001 [0172] 1-(2-methoxyphenyl)-2-methyl-piperazine (I-004) A microwave reaction vial was charged with 2-bromoanisole (471µL, 3.74mmol, 1.5 equiv.), tert-butyl 3-methylpiperazine-1-carboxylate (500mg, 2.50mmol, 1 equiv.), t-BuONa (360mg, 3.74mmol, 1.5 equiv.), Pd(OAc)2 (56mg, 0.25mmol, 0.1 equiv.) and XPhos (143mg, 300µmol, 0.12 equiv.). The vial was flushed with argon and degassed toluene (12.5mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating-block for 72h. 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 (cHex/EtOAc gradient = 95/5 to 50/50). The residue was directly treated with TFA (1.33mL, 17.4mmol, 20 equiv.). The mixture was stirred at RT for 5h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM. K2CO3(s) was added dropwise 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 (DCM/MeOH (7N NH3) = 99/1 to 95/5) affording 92 mg (18% over two steps) of I-004 as a yellow oil. ¹ H NMR (400 MHz, Chloroform-d, two sets of rotamers) δ 7.08-6.98 (m, 2H), 6.95-6.83 (m, 2H), 3.85 (s, 3H), 3.44 (pd, J = 6.3, 3.0 Hz, 1H), 3.21 (ddd, J = 11.5, 5.3, 3.1 Hz, 1H), 3.15-2.94 (m, 3H), 2.78-2.68 (m, 2H), 1.78 (s, 1H), 0.92 (s, 1.5H), 0.90 (s, 1.5H). MS (ESI ⁺ ): [M+H] ⁺ 207.4. [0173] (2-chloro-4-fluoro-phenyl)-[4-(2-methoxyphenyl)-3-methyl-pip erazin-1- yl]methanone (I-005) According to GP-1, I-005 was obtained as a white solid in 68% yield using 2-chloro-4- fluorobenzoic acid (338mg, 1.93mmol, 1.5 equiv.) and TBTU (414mg, 1.29mmol, 1 equiv.) in DMF (3.3mL), followed by piperazine I-004 (266mg, 1.29mmol, 1 equiv.) and Et3N (270µL, 1.93mmol, 1.5 equiv.) in THF (3.3mL) at RT for 16h. Purification by FC (cHex/EtOAc = 95/5 to 20/80). ¹ H NMR (400 MHz, Chloroform-d, multiple sets of rotamers) δ 7.36-7.29 (m, 1H), 7.21-7.14 (m, 1H), 7.11-7.01 (m, 2H), 7.01-6.84 (m, 3H), 3.85 (dd, J = 5.7, 2.9 Hz, 3H), 3.76-3.20 (m, 5H), 3.19-3.04 (m, 1H), 3.01-2.71 (m, 1H), 1.04-0.96 (m, 1.5H), 0.82-0.79 (m, 1.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, multiple sets of rotamers) δ -109.59, -109.61, -109.63, -109.67. MS (ESI ⁺ ): [M+H] ⁺ 363.1. [0174] 3-[4-(2-chloro-4-fluoro-benzoyl)-2-methyl-piperazin-1-yl]-4- methoxy- benzenesulfonyl chloride (I-006) Formula Weight: 461.33 Molecular Formula: C ₁₉ H ₁₉ Cl ₂ FN ₂ O ₄ S According to GP-3, I-006 was obtained as an orange oil in 91% yield using I-005 (370mg, 877µmol, 1 equiv.) and HSO3Cl (1.17mL, 17.5mmol, 20 equiv.) in DCM (4.4mL) at RT for 1h30. ¹ H NMR (400 MHz, Chloroform-d, multiple sets of rotamers) δ 7.83-7.72 (m, 1H), 7.51-7.45 (m, 1H), 7.37-7.28 (m, 1H), 7.24-7.15 (m, 1H), 7.13-7.04 (m, 1H), 7.04- 6.96 (m, 1H), 4.27-2.81 (m, 10H), 1.10-0.78 (m, 3H). ¹⁹ F NMR (376 MHz, Chloroform- d, multiple sets of rotamers) δ -109.13, -109.15, -109.21. MS (ESI ⁺ ): [M+H] ⁺ 461.0/463.0. Synthesis of intermediates required for final products 002 to 015 and 039 to 048 [0175] (2-chloro-4-fluoro-phenyl)-[8-(2-methoxyphenyl)-3,8-diazabic yclo[3.2.1]octan- 3-yl]methanone (I-007)

Formula Weight: 374.84 Molecular Formula: C ₂₀ H ₂₀ ClFN ₂ O ₂ According to GP-5, I-007 was obtained as an orange solid in 40% yield using 2-bromoanisole (1.28mL, 10.3mmol, 1.2 equiv.), piperazine I-001 (2.30g, 8.56mmol, 1 equiv.), Cs ₂ CO ₃ (5.58g, 17.2mmol, 2 equiv.), Pd(OAc) ₂ (192mg, 856µmol, 0.1 equiv.) and rac-BINAP (800mg, 1.28mmol, 0.15 equiv.) in toluene (43mL) at reflux for 16h. Purification by FC (DCM/MeOH 99:1 to 90:10) and FC (cHex/EtOAc = 95/5 to 60/40). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.36 (dd, J = 8.5, 5.9 Hz, 0.5H), 7.20 (dd, J = 8.5, 2.5 Hz, 0.5H), 7.18-7.10 (m, 1H), 7.07-7.00 (m, 1H), 6.97-6.90 (m, 1H), 6.90-6.82 (m, 2H), 6.82-6.75 (m, 1H), 4.55-4.42 (m, 1H), 4.23 (d, J = 6.5 Hz, 1H), 4.07- 4.00 (m, 1H), 3.86 (s, 1.5H), 3.85 (s, 1.5H), 3.69 (dd, J = 12.9, 1.9 Hz, 0.5H), 3.52 (dd, J = 12.2, 2.2 Hz, 0.5H), 3.35 (dt, J = 12.9, 1.5 Hz, 1H), 3.22-3.04 (m, 1H), 2.12-1.80 (m, 4H). MS (ESI ⁺ ): [M+H] ⁺ 375.1/377.1. [0176] 3-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octa n-8-yl]-4- methoxy-benzenesulfonyl chloride (I-008) Formula Weight: 473.35 Molecular Formula: C ₂₀ H ₁₉ Cl ₂ FN ₂ O ₄ S According to GP-3, I-008 was obtained as a yellow solid in 85% yield using I-007 (1.25g, 3.35mmol, 1 equiv.) and HSO ₃ Cl (4.5mL, 67mmol, 20 equiv.) in DCM (17mL) at RT for 2.5h. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.62 (dt, J = 8.7, 2.1 Hz, 1H), 7.37 (dd, J = 8.5, 5.9 Hz, 0.5H), 7.33 (t, J = 2.6 Hz, 1H), 7.22 (dd, J = 8.6, 2.5 Hz, 0.5H), 7.24-7.12 (m, 1H), 7.12-7.01 (m, 1H), 6.97 (d, J = 8.7 Hz, 1H), 4.52 (td, J = 10.1, 9.3, 4.6 Hz, 1H), 4.33 (dd, J = 12.4, 6.3 Hz, 1H), 4.16-4.06 (m, 1H), 3.97 (s, 1.5H), 3.96 (s, 1.5H), 3.66 (d, J = 12.5 Hz, 0.5H), 3.65 (d, J = 12.5 Hz, 0.5H), 3.33-3.25 (m, 1H), 3.20-3.10 (m, 1H), 2.23-1.69 (m, 4H). MS (ESI ⁺ ): [M+H] ⁺ 473.0/474.9. Synthesis of intermediates required for final products 049 to 054 [0177] (2-chloro-4,5-difluoro-phenyl)-[8-(2-methoxyphenyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone (I-038) Formula Weight: 392,83 Molecular Formula: C ₂₀ H ₁₉ ClF ₂ N ₂ O ₂ According to GP-5, I-038 was obtained as an orange solid in 90% yield using 2-bromoanisole (1.08mL, 8.66mmol, 1.2 equiv.), piperazine I-033 (2.07g, 7.22mmol, 1 equiv.), Cs2CO3 (2.00g, 14.4mmol, 2 equiv.), Pd(OAc)2 (162mg, 722µmol, 0.1 equiv.) and rac-BINAP (670mg, 1.08mmol, 0.15 equiv.) in toluene (34mL) at reflux for 16h. Purification by FC (cHex/EtOAc = 95/5 to 40/60) and FC (DCM/MeOH 99:1 to 95:5). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.37 – 7.20 (m, 1.5H), 7.10 – 6.8 (m, 4.5H), 4.55 – 4.40 (m, 1H), 4.30 – 4.22 (m, 1H), 4.08 (s, 1H), 3.89 & 3.88 (s, 3H), 3.76 – 3.52 (m, 1H), 3.42 – 3.34 (m, 1H), 3.13 (t, J = 12.2 Hz, 1H), 2.15 – 1.84 (m, 3.5H), 1.65 – 1.55 (m, 0.5H). MS (ESI ⁺ ): [M+H] ⁺ 393.1/395.1. [0178] 3-[3-(2-chloro-4,5-difluoro-benzoyl)-3,8-diazabicyclo[3.2.1] octan-8-yl]-4- methoxy-benzenesulfonyl chloride (I-039)

Formula Weight: 491,34 Molecular Formula: C ₂₀ H ₁₈ Cl ₂ F ₂ N ₂ O ₄ S According to GP-3, I-039 was obtained as a yellow solid in 91% yield using I-038 (845mg, 2.15mmol, 1 equiv.) and HSO3Cl (2.9mL, 43mmol, 20 equiv.) in DCM (11mL) at RT for 2.5h. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.64 & 7.62 (s, 1H), 7.40 – 7.15 (m, 2H), 7.10 – 6.95 (m, 2H), 4.49 (t, J = 11.9 Hz, 1H), 4.32 (s, 1H), 4.11 (s, 1H), 3.97 & 3.96 (s, 3H), 3.72 – 3.48 (m, 1H), 3.35 – 3.25 (m, 1H), 3.20 – 3.08 (m, 1H), 2.15 – 1.90 (m, 3.5H), 1.70 – 1.60 (m, 0.5H). Synthesis of intermediates required for final products 055 to 060 [0179] (2-chloro-4-fluoro-phenyl)-[8-(2,3-dihydrobenzofuran-7-yl)-3 ,8- diazabicyclo[3.2.1]octan-3-yl]methanone (I-040) Formula Weight: 386,85 Molecular Formula: C ₂₁ H ₂₀ ClFN ₂ O ₂ According to GP-5, I-040 was obtained as a white foam in 36% yield using 7-bromo-2,3- dihydrobenzofuran (500mg, 2.51mmol, 1 equiv.), piperazine I-001 (877mg, 3.27mmol, 1.3 equiv.), Cs2CO3 (1.64g, 5.02mmol, 2 equiv.), Pd(OAc)2 (56.4mg, 251µmol, 0.1 equiv.) and rac-BINAP (188mg, 301µmol, 0.12 equiv.) in toluene (13mL) at reflux for 4h. Purification by FC (cHex/EtOAc = 96/4 to 60/40). ¹ H NMR (400 MHz, Chloroform- d, 2 sets of rotamers) δ 7.36 – 7.15 (m, 1H), 7.16 – 6.95 (m, 2H), 6.88 – 6.72 (m, 2H), 6.71 – 6.54 (m, 1H), 4.55 & 4.54 (t, J = 8.8 Hz, 2H), 4.49 – 4.36 (m, 2H), 4.25 (s, 1H), 3.70 – 3.40 (m, 1H), 3.39 – 3.26 (m, 1H), 3.19 (t, J = 8.8 Hz, 2H), 3.03 (t, J = 11.9 Hz, 1H), 2.14 – 1.82 (m, 3.5H), 1.65 – 1 .55 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.6, -109.7. MS (ESI ⁺ ): [M+H] ⁺ 387.1/389.1. [0180] 7-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octa n-8-yl]-2,3- dihydrobenzofuran-5-sulfonyl chloride (I-041) Formula Weight: 485,36 Molecular Formula: C ₂₁ H ₁₉ Cl ₂ FN ₂ O ₄ S According to GP-3, I-041 was obtained as a yellow solid in 93% yield using I-040 (370mg, 959µmol, 1 equiv.) and HSO ₃ Cl (1.3mL, 19mmol, 20 equiv.) in DCM (5.6mL) at RT for 2h. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.43 (s, 1H), 7.37 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.24 – 7.17 (m, 1.5H), 7.16 – 6.96 (m, 2H), 4.73 & 4.72 (t, J = 9.0 Hz, 2H), 4.60 – 4.40 (m, 2H), 4.28 (s, 1H), 3.60 (d, J = 12.7 Hz, 0.5H), 3.44 (d, J = 12.7 Hz, 0.5H), 3.30 (t, J = 8.9 Hz, 2H), 3.24 & 3.21 (s, 1H), 3.09 (t, J = 11.3 Hz, 1H), 2.15 – 1.88 (m, 3.5H), 1.75 – 1.65 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.1, -109.2. Synthesis of intermediates required for final product 061 [0181] (2-chloro-4,5-difluoro-phenyl)-[8-(2,3-dihydrobenzofuran-7-y l)-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone (I-042) Formula Weight: 404,84 Molecular Formula: C ₂₁ H ₁₉ ClF ₂ N ₂ O ₂ According to GP-5, I-042 was obtained as a white solid in 33% yield using 7-bromo-2,3- dihydrobenzofuran (162mg, 816µmol, 1.2 equiv.), piperazine I-033 (200mg, 680µmol, 1.2 equiv.), Cs2CO3 (0.44g, 1.4mmol, 2 equiv.), Pd(OAc)2 (15mg, 68µmol, 0.1 equiv.) and rac-BINAP (51mg, 82µmol, 0.12 equiv.) in toluene (3.4mL) at reflux for 16h. Purification by FC (cHex/EtOAc = 96/4 to 60/40). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.35 – 7.17 (m, 1.5H), 7.01 – 6.93 (m, 0.5H), 6.82 – 6.75 (m, 2H), 6.60 (s, 1H), 4.55 & 4.54 (t, J = 8.8 Hz, 2H), 4.44 – 4.31 (m, 2H), 4.27 (s, 1H), 3.70 – 3.45 (m, 1H), 3.36 – 3.27 (m, 1H), 3.19 (t, J = 8.8 Hz, 2H), 3.02 (t, J = 13.6 Hz, 1H), 2.12 – 1.82 (m, 3.5H), 1.65 – 1.55 (m, 0.5H). MS (ESI ⁺ ): [M+H] ⁺ 405.1/407.1. [0182] 7-[3-(2-chloro-4,5-difluoro-benzoyl)-3,8-diazabicyclo[3.2.1] octan-8-yl]-2,3- dihydrobenzofuran-5-sulfonyl chloride (I-043) Formula Weight: 503,35 Molecular Formula: C ₂₁ H ₁₈ Cl ₂ F ₂ N ₂ O ₄ S According to GP-3, I-043 was obtained as a yellow solid in 63% yield using I-042 (90.0mg, 222µmol, 1 equiv.) and HSO ₃ Cl (0.3mL, 4mmol, 20 equiv.) in DCM (1.1mL) at RT for 2h. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.44 (s, 1H), 7.32 (dd, J = 9.6, 6.8 Hz, 0.5H), 7.27 – 7.18 (m, 2H), 7.03 – 6.95 (m, 0.5H), 4.74 & 4.73 (t, J = 9.0 Hz, 2H), 4.52 (s, 1H), 4.48 – 4.38 (m, 1H), 4.34 – 4.28 (m, 1H), 3.66 – 3.42 (m, 1H), 3.30 (t, J = 8.9 Hz, 2H), 3.25 & 3.21 (s, 1H), 3.08 (t, J = 11.6 Hz, 1H), 2.16 – 1.87 (m, 3.5H), 1.70 – 1.60 (m, 0.5H) . Synthesis of intermediates required for final product 016 [0183] 3-bromo-4-methoxy-N-methyl-N-propyl-benzenesulfonamide (I-009) Formula Weight: 322.22 Molecular Formula: C ₁₁ H ₁₆ BrNO ₃ S According to GP-4, I-009 was obtained in 97% yield using commercial 3-bromo-4- methoxy-benzenesulfonyl chloride (5.00g, 17.5mmol, 1 equiv.), methyl-N-propylamine (2.7mL, 27mmol, 1.5 equiv.) and Et3N (3.7mL, 27mmol, 1.5 equiv.) in DCM (101mL) at RT for 4h. Purification by FC (cHex/EtOAc = 95/5 to 50/50). ¹ H NMR (400 MHz, Chloroform-d) δ 7.99 (d, J = 2.2 Hz, 1H), 7.74 (dd, J = 8.7, 2.2 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 3.99 (s, 3H), 2.99 (dd, J = 8.0, 6.5 Hz, 2H), 2.75 (s, 3H), 1.71-1.51 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). MS (ESI ⁺ ): [M+H] ⁺ 322.0/324.0. [0184] 4-methoxy-N-methyl-N-propyl-3-[2-(trifluoromethyl)piperazin- 1- yl]benzenesulfonamide (I-010) Formula Weight: 395.44 Molecular Formula: C ₁₆ H ₂₄ F ₃ N ₃ O ₃ S A microwave reaction vial was charged with the aryl bromide I-009 (100mg, 310µmol, 1 equiv.), commercial tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate (118mg, 466µmol, 1.5 equiv.), t-BuONa (89.5mg, 931µmol, 3 equiv.), Pd ₂ (dba) ₃ (29mg, 31µmol, 0.1 equiv.) and JohnPhos (19mg, 62µmol, 0.2 equiv.). The vial was flushed with argon and degassed toluene (3.1mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating-block 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 purified by FC (cHex/EtOAc = 95/5 to 50/50). The residue was directly treated with TFA (678µL, 8.80mmol, 10 equiv.). The mixture was stirred at RT for 1h. 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 (DCM/MeOH (7N NH3) = 99/1 to 90/10) to afford 61mg (50% over two steps) of I-010 as an orange oil. MS (ESI ⁺ ): [M+H] ⁺ 396.1. Synthesis of intermediates required for final product 017 [0185] 3-(2-ethylpiperazin-1-yl)-4-methoxy-N-methyl-N-propyl-benzen esulfonamide (I-011) A microwave reaction vial was charged with the aryl bromide I-009 (600mg, 1.86mmol, 1 equiv.), commercial tert-butyl 3-ethylpiperazine-1-carboxylate (400mg, 1.86mmol, 1 equiv.), Cs ₂ CO ₃ (1.21g, 3.72mmol, 2 equiv.), Pd(OAc) ₂ (42mg, 0.19mmol, 0.1 equiv.) and rac-BINAP (139mg, 223µmol, 0.12 equiv.). The vial was flushed with argon and degassed toluene (9.5mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating-block for 20h. After cooling down to RT, EtOAc was added and the suspension was filtered over Celite® (EtOAc rinses). The filtrate was concentrated under reduced pressure and purified by FC (cHex/EtOAc = 93/7 to 30/70). The residue was directly treated with HCl (4M solution in dioxane, 1.11mL, 4.46mmol, 20 equiv.). The mixture was stirred at RT for 2h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM. NaOH 2M was added dropwise until pH >11. The layers were separated and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by FC (DCM/MeOH = 99/1 to 80/20) to afford 74mg (11% over two steps) of I-011 as an orange oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.51 (dd, J = 8.5, 2.3 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 3.94 (s, 3H), 3.58-3.42 (m, 1H), 3.42-3.22 (m, 2H), 3.15 (dt, J = 6.7, 3.5 Hz, 2H), 3.08-2.88 (m, 4H), 2.72 (s, 3H), 1.73-1.46 (m, 3H), 1.44- 1.34 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H), 0.80 (t, J = 7.5 Hz, 3H). MS (ESI ⁺ ): [M+H] ⁺ 356.2. Synthesis of intermediates required for final products 018 and 019 [0186] 4-benzyl-1-(3-bromo-4-methoxy-phenyl)sulfonyl-piperidine (I-012) Formula Weight: 424.35 Molecular Formula: C ₁₉ H ₂₂ BrNO ₃ S According to GP-4, I-012 was obtained in 95% yield using commercial 3-bromo-4- methoxy-benzenesulfonyl chloride (3.00g, 10.5mmol, 1 equiv.), 4-benzylpiperidine (2.40g, 13.7mmol, 1.3 equiv.) and Et3N (2.2mL, 16mmol, 1.5 equiv.) in DCM (20mL) at RT for 16h. Purification by FC (cHex/EtOAc = 97/3 to 70/30). ¹ H NMR (400 MHz, Chloroform-d) δ 7.94 (d, J = 2.2 Hz, 1H), 7.69 (dd, J = 8.7, 2.2 Hz, 1H), 7.39-7.24 (m, 2H), 7.24-7.15 (m, 1H), 7.14-7.06 (m, 2H), 6.98 (d, J = 8.6 Hz, 1H), 3.98 (s, 3H), 3.84- 3.67 (m, 2H), 2.54 (d, J = 6.9 Hz, 2H), 2.23 (td, J = 11.8, 2.5 Hz, 2H), 1.80-1.65 (m, 2H), 1.54-1.22 (m, 3H). MS (ESI ⁺ ): [M+H] ⁺ 424.0/426.0. [0187] 1-[5-[(4-benzyl-1-piperidyl)sulfonyl]-2-methoxy-phenyl]-2-me thyl-piperazine (I-013) Formula Weight: 443.6 Molecular Formula: C ₂₄ H ₃₃ N ₃ O ₃ S A microwave reaction vial was charged with the aryl bromide I-012 (1.24g, 2.92mmol, 1 equiv.), commercial tert-butyl 3-methylpiperazine-1-carboxylate (702mg, 3.51mmol, 1.2 equiv.), Cs2CO3 (1.90g, 5.84mmol, 2 equiv.), Pd(OAc)2 (33mg, 0.15mmol, 0.05 equiv.) and rac-BINAP (110mg, 175µmol, 0.06 equiv.). The vial was flushed with argon and degassed toluene (15mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating-block for 24h. After cooling down to RT, EtOAc was added and the suspension was filtered over Celite® (EtOAc rinses). The filtrate was concentrated under reduced pressure and purified by FC (cHex/EtOAc = 96/4 to 60/40). The residue was directly treated with HCl (4M solution in dioxane, 1.56mL, 6.25mmol, 10 equiv.). The mixture was stirred at RT for 2h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM. NaOH 2M was added dropwise 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 (DCM/MeOH = 98/2 to 80/20) to afford 140mg (10% over two steps) of I-013 as an orange oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.47 (dd, J = 8.6, 2.2 Hz, 1H), 7.34 (d, J = 2.3 Hz, 1H), 7.32-7.24 (m, 2H), 7.24-7.17 (m, 1H), 7.15-7.06 (m, 2H), 6.94 (d, J = 8.6 Hz, 1H), 3.93 (s, 3H), 3.77 (d, J = 11.5 Hz, 2H), 3.70-3.60 (m, 1H), 3.33-3.18 (m, 2H), 3.18-3.06 (m, 2H), 2.89-2.83 (m, 1H), 2.83-2.76 (m, 1H), 2.53 (d, J = 6.6 Hz, 2H), 2.19 (td, J = 11.8, 2.6 Hz, 2H), 1.70 (d, J = 11.2 Hz, 2H), 1.55-1.31 (m, 3H), 0.96 (d, J = 6.4 Hz, 3H). MS (ESI ⁺ ): [M+H] ⁺ 444.0. Synthesis of intermediates required for final product 020 [0188] 3-bromo-N-tert-butyl-4-methoxy-benzenesulfonamide (I-014) Formula Weight: 322.22 Molecular Formula: C ₁₁ H ₁₆ BrNO ₃ S According to GP-4, I-014 was obtained in 90% yield using commercial 3-bromo-4- methoxybenzenesulfonyl chloride (2.02g, 7.07mmol, 1 equiv.), tert-butylamine (1.5mL, 14mmol, 2 equiv.) and Et3N (2.0mL, 14mmol, 2 equiv.) in DCM (28mL) at RT for 16h. Purification by FC (cHex/EtOAc = 100/0 to 20/80). ¹ H NMR (400 MHz, Chloroform-d) δ 8.06 (d, J = 2.3 Hz, 1H), 7.82 (dd, J = 8.7, 2.3 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 4.48 (s, 1H), 3.96 (s, 3H), 1.24 (s, 9H). MS (ESI ⁺ ): [M+H] ⁺ 322.0/324.0. [0189] N-tert-butyl-4-methoxy-3-(2-methylpiperazin-1-yl)benzenesulf onamide (I-015) A microwave reaction vial was charged with the aryl bromide I-014 (844mg, 2.54mmol, 1 equiv.), commercial tert-butyl 3-methylpiperazine-1-carboxylate (763mg, 3.81mmol, 1.5 equiv.), Cs2CO3 (1.7g, 5.2mmol, 2 equiv.), Pd(OAc)2 (57mg, 0.25mmol, 0.1 equiv.) and rac-BINAP (237mg, 381µmol, 0.15 equiv.). The vial was flushed with argon and degassed toluene (12mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating-block for 24h. After cooling down to RT, EtOAc was added and the suspension was filtered over Celite® (EtOAc rinses). The filtrate was concentrated under reduced pressure and purified by FC (cHex/EtOAc = 100/0 to 50/50). The residue was directly treated with HCl (aq. 37%, 50µL, 1.6mmol, 10 equiv.). The mixture was stirred at RT for 2h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM. NaOH 2M was added dropwise 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 PTLC (DCM/MeOH = 85/15) to afford 45mg (5% over two steps) of I-015 as a yellow oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.52 (dd, J = 8.6, 2.3 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 4.68 (s, 1H), 3.84 (s, 3H), 3.49 (td, J = 6.4, 3.3 Hz, 1H), 3.16 (ddd, J = 11.5, 6.2, 3.2 Hz, 1H), 3.07 (dd, J = 12.2, 3.4 Hz, 1H), 2.97 (qdd, J = 12.2, 6.6, 3.2 Hz, 2H), 2.77- 2.59 (m, 2H), 1.14 (s, 9H), 0.85 (d, J = 6.4 Hz, 3H). MS (ESI ⁺ ): [M+H] ⁺ 342.1. Synthesis of intermediate required for final product 021 [0190] 4-methoxy-N-methyl-3-(2-methylpiperazin-1-yl)-N-propyl-benze nesulfonamide (I-016) Formula Weight: 341.47 Molecular Formula: C ₁₆ H ₂₇ N ₃ O ₃ S A microwave reaction vial was charged with the aryl bromide I-009 (1.0g, 3.1mmol, 1 equiv.), commercial tert-butyl 3-methylpiperazine-1-carboxylate (932mg, 4.66mmol, 1.5 equiv.), t-BuONa (895mg, 9.31mmol, 3 equiv.), Pd(OAc) ₂ (70mg, 0.31mmol, 0.1 equiv.) and rac-BINAP (290mg, 466µmol, 0.15 equiv.). The vial was flushed with argon and degassed toluene (16mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating-block 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 and purified by FC (cHex/EtOAc = 95/5 to 40/60). The residue was directly treated with HCl (aq. 37%, 800µL, 793µmol, 10 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. NaOH 2M was added dropwise until pH >11. The layers were separated and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under Reduced pressure. residue was purified by FC (DCM/MeOH (7N NH3) = 99/1 to 90/10) to afford 96mg (9% over two steps) of I-016 as an orange oil. NMR (400 MHz, DMSO-d ₆ ) δ 7.41 (dd, J = 8.5, 2.3 Hz, 1H), 7.23-7.07 (m, 2H), 3.87 (s, 3H), 3.51 (dt, J = 6.4, 3.2 Hz, 1H), 3.11 (td, J = 7.1, 3.3 Hz, 1H), 2.99 (dd, J = 12.0, 3.3 Hz, 1H), 2.92-2.76 (m, 4H), 2.65 – 2.55 (m, 5H), 1.46 (q, J = 7.2 Hz, 2H), 0.85-0.82 (m, 6H). MS (ESI ⁺ ): [M+H] ⁺ 342.2. Synthesis of intermediate required for final product 022 [0191] 4-methoxy-3-[2-(methoxymethyl)piperazin-1-yl]-N-methyl-N-pro pyl- benzenesulfonamide (I-017) Formula Weight: 371.49 Molecular Formula: C ₁₇ H ₂₉ N ₃ O ₄ S A microwave reaction vial was charged with the aryl bromide I-009 (600mg, 1.86mmol, 1 equiv.), tert-butyl 3-(methoxymethyl) piperazine-1-carboxylate (429mg, 1.86mmol, 1 equiv.), Cs2CO3 (1.82g, 5.59mmol, 3 equiv.), Pd(OAc)2 (42mg, 0.19mmol, 0.1 equiv.) and rac-BINAP (174mg, 279µmol, 0.15 equiv.). The vial was flushed with argon and degassed toluene (9.5mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating-block for 3h. After cooling down to RT, EtOAc was added and the suspension was filtered over Celite® (EtOAc rinses). The filtrate was concentrated under reduced pressure and purified by FC (DCM/EtOAc = 95/5 to 40/60). The residue was directly treated with HCl (4M solution in dioxane, 1.03mL, 4.14mmol, 10 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. residue was purified by FC (DCM/MeOH (7N NH3) = 99/1 to 90/10) to afford 78mg (8% over two steps) of I-017 as an orange oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.46 (dd, J = 8.6, 2.0 Hz, 1H), 7.36 (d, J = 2.1 Hz, 1H), 6.94 (dd, J = 8.5, 1.6 Hz, 1H), 3.93 (d, J = 1.7 Hz, 3H), 3.80 (dt, J = 7.6, 3.7 Hz, 1H), 3.65-3.58 (m, 1H), 3.40-3.26 (m, 2H), 3.22 (d, J = 1.7 Hz, 3H), 3.19- 2.99 (m, 4H), 2.99-2.87 (m, 3H), 2.72 (d, J = 1.6 Hz, 3H), 1.56 (q, J = 7.4 Hz, 2H), 0.94 (td, J = 7.4, 1.6 Hz, 3H). MS (ESI ⁺ ): [M+H] ⁺ 372.2. Synthesis of intermediate required for final product 023 [0192] 4-methoxy-N-methyl-3-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-y l)-N-propyl- benzenesulfonamide (I-018) Formula Weight: 369.48 Molecular Formula: C ₁₇ H ₂₇ N ₃ O ₄ S A microwave reaction vial was charged with the aryl bromide I-009 (100mg, 310µmol, 1 equiv.), tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (71mg, 0.31mmol, 1 equiv.), Cs2CO3 (304g, 931µmol, 3 equiv.), Pd(OAc)2 (7.0mg, 31µmol, 0.1 equiv.) and rac-BINAP (29mg, 47µmol, 0.15 equiv.). The vial was flushed with argon and degassed toluene (1.6mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating-block 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 and purified by FC (cHex/EtOAc = 93/7 to 30/70). The residue was directly treated with HCl (4M solution in dioxane, 650µL, 2.60mmol, 10 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 (DCM/MeOH (7N NH ₃ ) = 99/1 to 90/10) to afford 90mg (79% over two steps) of I-018 as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.39-7.25 (m, 2H), 6.93 (d, J = 8.8 Hz, 1H), 4.24-4.04 (m, 4H), 3.92 (s, 3H), 3.90-3.78 (m, 1H), 3.63 (s, 1H), 3.53-3.41 (m, 2H), 3.37-3.35 (m, 2H), 3.14-2.93 (m, 3H), 2.72 (d, J = 6.4 Hz, 3H), 1.58 (q, J = 7.3 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H). MS (ESI ⁺ ): [M+H] ⁺ 370.2. Synthesis of intermediate required for final product 026 [0193] 3-bromo-4-fluoro-N-methyl-N-propyl-benzenesulfonamide (I-019) Formula Weight: 310.18 Molecular Formula: C ₁₀ H ₁₃ BrFNO ₂ S According to GP-4, I-019 was obtained as a white solid in 95% yield using commercial 3-bromo-4-fluorobenzenesulfonyl chloride (388mg, 1.35mmol, 1 equiv.), methyl-N- propylamine (145µL, 1.41mmol, 1.05 equiv.) and Et ₃ N (281µL, 2.02mmol, 1.5 equiv.) in DCM (7mL) at RT for 1h. ¹ H NMR (400 MHz, Chloroform-d) δ 8.01 (dd, J = 6.3, 2.3 Hz, 1H), 7.73 (ddd, J = 8.6, 4.5, 2.2 Hz, 1H), 7.26 (dd, J = 8.6, 8.0 Hz, 1H), 3.08-2.90 (m, 2H), 2.75 (s, 3H), 1.58 (q, J = 7.3 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -99.95. MS (ESI ⁺ ): [M+H] ⁺ 310.0/312.0. Synthesis of intermediate required for final product 027 [0194] 3-bromo-N-methyl-N-propyl-4-(trifluoromethoxy)benzenesulfona mide (I-020) Formula Weight: 376.19 Molecular Formula: C ₁₁ H ₁₃ BrF ₃ NO ₃ S According to GP-4, I-020 was obtained as a white solid in 77% yield using commercial 3-bromo-4-(trifluoromethoxy)benzene-1-sulfonyl chloride (500mg, 1.47mmol, 1 equiv.), methyl-N-propylamine (159µL, 1.55mmol, 1.05 equiv.) and Et3N (308µL, 2.21mmol, 1.5 equiv.) in DCM (7.5mL) at RT for 1h. ¹ H NMR (400 MHz, Chloroform-d) δ 8.07 (d, J = 2.2 Hz, 1H), 7.76 (dd, J = 8.6, 2.2 Hz, 1H), 7.48-7.39 (m, 1H), 3.07-2.98 (m, 2H), 2.78 (s, 3H), 1.59 (q, J = 7.3 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -57.36. MS (ESI ⁺ ): [M+H] ⁺ 376.5/378.3. Synthesis of intermediate required for final product 028 [0195] 3-bromo-N-methyl-N-propyl-benzenesulfonamide (I-021) Formula Weight: 292.19 Molecular Formula: C ₁₀ H ₁₄ BrNO ₂ S According to GP-4, I-021 was obtained as a white solid in 100% yield using commercial 3-bromobenzenesulfonyl chloride (500mg, 1.96mmol, 1 equiv.), methyl-N-propylamine (301µL, 2.94mmol, 1.5 equiv.) and Et3N (408µL, 2.94mmol, 1.5 equiv.) in DCM (4mL) at RT for 2h. ¹ H NMR (400 MHz, Chloroform-d) δ 7.95 (t, J = 1.8 Hz, 1H), 7.73 (dddd, J = 6.4, 4.9, 2.4, 1.1 Hz, 2H), 7.42 (t, J = 7.9 Hz, 1H), 3.06-2.94 (m, 2H), 2.77 (s, 3H), 1.69-1.48 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). MS (ESI ⁺ ): [M+H] ⁺ 292.2/294.2. Synthesis of intermediates required for final product 029 [0196] 3-bromo-4-hydroxy-N-methyl-N-propyl-benzenesulfonamide (I-022) Formula Weight: 308.19 Molecular Formula: C ₁₀ H ₁₄ BrNO ₃ S To a solution of I-009 (2.37g, 7.34mmol, 1.00 eq) in DCM (90mL) at 0°C under argon atmosphere, was added boron tribromide (1M in DCM, 11mL, 11mmol, 1.5 equiv.). The reaction mixture was stirred at RT for 48h. More boron tribromide (1M in DCM, 11 mL, 11 mmol, 1.50 eq.) was added at 0°C and the reaction was stirred at RT for 72h. Water was added at 0°C 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 residue was purified by FC (cHex/EtOAc = 99/1 to 70/30) affording 2.1g (86%) of I-022 as a grey oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.93 (d, J = 2.1 Hz, 1H), 7.64 (dd, J = 8.6, 2.2 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.08 (s, 1H), 3.00-2.93 (m, 2H), 2.72 (s, 3H), 1.57 (h, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H). MS (ESI ⁺ ): [M+H] ⁺ 308.0/310.0. [0197] 3-bromo-4-ethoxy-N-methyl-N-propyl-benzenesulfonamide (I-023) To a solution of I-022 (100mg, 325µmol , 1 equiv.) in dry DMF (1.7mL) under argon atmosphere were added K ₂ CO ₃ (90mg, 0.65mmol, 2 equiv.) and bromoethane (53mg, 0.49mmol, 1.5 equiv.). The solution was stirred at RT for 16h. Water was added and the product was extracted with EtOAc. The combined organic extracts were washed (brine), dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc = 95/5 to 70/30) to afford 97mg (88%) of I-023 as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J = 2.3 Hz, 1H), 7.68 (dd, J = 8.6, 2.3 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 4.17 (q, J = 7.0 Hz, 2H), 3.02-2.88 (m, 2H), 2.71 (s, 3H), 1.60 – 1.45 (m, 5H), 0.93 (t, J = 7.4 Hz, 3H). MS (ESI ⁺ ): [M+H] ⁺ 336.0/338.0. Synthesis of intermediate required for final product 030 [0198] 3-bromo-4-(cyclobutoxy)-N-methyl-N-propyl-benzenesulfonamide (I-024) To a solution of I-022 (100mg, 325µmol, 1 equiv.) in dry DMF (1.6mL) under argon atmosphere were added K ₂ CO ₃ (90mg, 0.65mmol, 2 equiv.) and bromocyclobutane (46µL, 0.49mmol, 1.5 equiv.). The solution was stirred at RT for 16h. Water was added and the product was extracted with EtOAc. The combined organic extracts were washed (brine), dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc = 100/0 to 50/50) to afford 53mg (43%) of I-024 as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J = 1.9 Hz, 1H), 7.65 (dd, J = 8.6, 2.2 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 4.81-4.68 (m, 1H), 2.96 (t, J = 7.3 Hz, 2H), 2.72 (s, 3H), 2.56-2.45 (m, 2H), 2.28 (ddd, J = 12.7, 6.3, 2.4 Hz, 2H), 1.93 (q, J = 10.6 Hz, 1H), 1.81-1.66 (m, 1H), 1.56 (dd, J = 14.4, 6.9 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H). MS (ESI ⁺ ): [M+H] ⁺ 362.0/364.0. Synthesis of intermediate required for final product 031 [0199] 3-bromo-4-(cyclobutoxy)-N-methyl-N-propyl-benzenesulfonamid3 -bromo-4- (methoxymethoxy)-N-methyl-N-propyl-benzenesulfonamide (I-025) Formula Weight: 352.24 Molecular Formula: C ₁₂ H ₁₈ BrNO ₄ S To a solution of I-022 (265mg, 860µmol, 1 equiv.) in dry DMF (3.5mL) under argon atmosphere were added iPr2NEt (450µL, 2.58 mmol, 3 equiv.) and chloromethyl methyl ether (131µL, 1.72mmol, 2 equiv.). The solution was stirred at RT for 1h. The reaction mixture was partitioned between MTBE and HCl. The layers were separated and the aqueous phase was extracted with MTBE. the combined organic extracts were washed (HCl, brine), dried (Na2SO4), filtered and concentrated under reduced pressure affording 300mg (96%) of I-025 as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J = 2.2 Hz, 1H), 7.70 (dd, J = 8.7, 2.3 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 5.34 (s, 2H), 3.55 (s, 3H), 3.00 (dd, J = 8.0, 6.5 Hz, 2H), 2.75 (s, 3H), 1.67-1.45 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). MS (ESI ⁺ ): [M+H] ⁺ 352.0/354.0. Synthesis of intermediate required for final product 032 [0200] 5-bromo-6-chloro-N,N-diethyl-pyridine-3-sulfonamide (I-026) Formula Weight: 327.63 Molecular Formula: C ₉ H ₁₂ BrClN ₂ O ₂ S According to GP-4, I-026 was obtained as a white solid in 100% yield using commercial 5-bromo-6-chloro-pyridine-3-sulfonyl chloride (438mg, 1.50mmol, 1 equiv.), diethylamine (100mg, 1.37mmol, 1 equiv.) and Et ₃ N (229µL, 1.64mmol, 1.2 equiv.) in DCM (6.9mL) at RT for 1h. ¹ H NMR (400 MHz, Chloroform-d) δ 8.74 (d, J = 2.2 Hz, 1H), 8.32 (d, J = 2.2 Hz, 1H), 3.31 (q, J = 7.2 Hz, 4H), 1.21 (t, J = 7.1 Hz, 6H). MS (ESI ⁺ ): [M+H] ⁺ 326.8/328.9. Synthesis of intermediate required for final product 033 [0201] 5-bromo-N,N-diethyl-6-methoxy-pyridine-3-sulfonamide (I-027) Formula Weight: 323.21 Molecular Formula: C ₁₀ H ₁₅ BrN ₂ O ₃ S To a solution of I-026 (150 mg, 458 µmol, 1.00 equiv.) in dry MeOH (1.83mL) at RT, was added MeONa (124mg, 2.29mmol, 5 equiv.). The mixture was stirred at RT overnight. The RM was partitioned between aq. sat. NH ₄ Cl 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 to afford 138mg (95%) of I-027 as a light-yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.52 (d, J = 2.2 Hz, 1H), 8.16 (d, J = 2.2 Hz, 1H), 4.08 (s, 3H), 3.25 (q, J = 7.2 Hz, 4H), 1.17 (t, J = 7.1 Hz, 6H). MS (ESI ⁺ ): [M+H] ⁺ 323.0/324.9. Synthesis of intermediate required for final product 034 [0202] 6-benzyloxy-5-bromo-N,N-diethyl-pyridine-3-sulfonamide (I-028) Formula Weight: 399.3 Molecular Formula: C ₁₆ H ₁₉ BrN ₂ O ₃ S To a solution of commercial benzyl alcohol (77µL, 0.73mmol, 1.2 equiv.) in dry toluene (1.22mL) at 0°C, was added NaH (60% in mineral oil, 29mg, 0.73mmol, 1.2 equiv.) and the mixture was stirred at 0°C for 40min before the addition of I-026 (200mg, 610µmol, 1.00 equiv.). The solution 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 (brine), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 239mg (98%) of I-028 as a yellow oil. ¹ H NMR (400 MHz, Chloroform-d) δ 8.52 (d, J = 2.2 Hz, 1H), 8.18 (d, J = 2.2 Hz, 1H), 7.54- 7.43 (m, 2H), 7.42-7.31 (m, 3H), 5.52 (s, 2H), 3.25 (q, J = 7.1 Hz, 4H), 1.18 (t, J = 7.1 Hz, 6H). MS (ESI ⁺ ): [M+H] ⁺ 398.9/401.0. Synthesis of intermediate required for final product 036 [0203] 4-benzyloxy-3-bromo-N-methyl-N-propyl-benzenesulfonamide (I-029) Formula Weight: 398.31 Molecular Formula: C ₁₇ H ₂₀ BrNO ₃ S To a solution of I-022 (2.09g, 6.30mmol , 1 equiv.) in dry DMF (68mL) under argon atmosphere were added K2CO3 (1.74g, 12.6mmol, 2 equiv.) and benzyl bromide (750µL, 6.30mmol, 1 equiv.). The solution was stirred at RT for 16h. Water was added and the product was extracted with EtOAc. The combined organic extracts were washed (brine), dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc = 95/5 to 70/30) to afford 2.37g (91%) of I-029 as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.99 (d, J = 2.2 Hz, 1H), 7.67 (dd, J = 8.6, 2.3 Hz, 1H), 7.50-7.44 (m, 2H), 7.44-7.38 (m, 2H), 7.38-7.31 (m, 1H), 7.01 (d, J = 8.7 Hz, 1H), 5.23 (s, 2H), 2.97 (dd, J = 7.9, 6.6 Hz, 2H), 2.72 (s, 3H), 1.66-1.50 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). MS (ESI ⁺ ): [M+H] ⁺ 399.0/401.0. [0204] 4-benzyloxy-3-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicycl o[3.2.1]octan-8- yl]-N-methyl-N-propyl-benzenesulfonamide (I-030) According to GP-5, I-030 was obtained as a white foam in 72% yield using aryl bromide I-029 (1.13g, 2.84mmol, 1 equiv.), piperazine I-001 (915mg, 3.40mmol, 1.2 equiv.), Cs ₂ CO ₃ (2.31g, 7.09mmol, 2.5 equiv.), Pd(OAc) ₂ (64mg, 0.28mmol, 0.1 equiv.) and rac-BINAP (212mg, 340µmol, 0.12 equiv.) in toluene (12mL) at reflux for 16h. Purification by FC (cHex/EtOAc = 100/0 to 50/50) and PTLC (DCM/MeOH = 99/1). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.52-7.31 (m, 6H), 7.24-6.95 (m, 4H), 5.21-5.10 (m, 2H), 4.47 (d, J = 13.1 Hz, 1H), 4.35 (d, J = 13.5 Hz, 1H), 4.09 (d, J = 10.5 Hz, 1H), 3.70-3.50 (m, 1H), 3.40-3.23 (m, 1H), 3.14-3.06 (m, 1H), 3.00-2.88 (m, 2H), 2.69 (s, 3H), 2.09-1.84 (m, 4H), 1.67-1.43 (m, 3H), 0.91 (t, J = 7.3 Hz, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.21, -109.23. MS (ESI ⁺ ): [M+H] ⁺ 586.6/588.6. Synthesis of intermediates required for final product 037 [0205] (2-chloro-4-fluoro-phenyl)-[8-[5-(3-hydroxypyrrolidin-1-yl)s ulfonyl-2- methoxy-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-031) According to GP-4, I-031 was obtained as a white solid in 83% yield using I-008 (400mg, 845µmol, 1 equiv.), 3-Pyrrolidinol (103µL, 1.27mmol, 1.5 equiv.) and iPr2NEt (295µL, 1.69mmol, 2 equiv.) in DCM (5mL) at RT for 4h. Purification by FC (cHex/EtOAc = 70/30 to 0/100). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.42 (dd, J = 8.5, 2.1 Hz, 1H), 7.36 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.24-7.19 (m, 1.5H), 7.15 (dd, J = 8.4, 2.5 Hz, 1H), 7.11-6.98 (m, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.57-4.45 (m, 1H), 4.37 (s, 1H), 4.34-4.26 (m, 1H), 4.07 (s, 1H), 3.92 & 3.91 (s, 3H), 3.70-3.45 (m, 1H), 3.44-3.25 (m, 4H), 3.20 (d, J = 11.3 Hz, 1H), 3.12 (t, J = 11.0 Hz, 1H), 2.06-1.78 (m, 5.5H), 1.65-1.55 (m, 0.5H). MS (ESI ⁺ ): [M+H] ⁺ 524.1/526.1. Synthesis of intermediates required for final product 038 [0206] 3-[4-(2-chloro-4-fluoro-benzoyl)-2-methyl-piperazin-1-yl]-N- (3-fluoropropyl)- 4-methoxy-benzenesulfonamide (I-032) According to GP-4, I-032 was obtained as a white solid in 32% yield using I-006 (175mg, 379µmol, 1 equiv.), 3-Fluoropropan-1-amine hydrochloride (87mg, 0.80mmol, 2 equiv.) and Et3N (212µL, 1.52mmol, 4 equiv.) in DCM (1.9mL) at RT for 16h. Purification by FC (DCM/MeOH = 99/1 to 90/10). ¹ H NMR (400 MHz, Chloroform-d, multiple sets of rotamers) δ 7.65-7.55 (m, 1H), 7.45-7.28 (m, 2H), 7.23-7.15 (m, 1H), 7.11-7.03 (m, 1H), 6.96-6.90 (m, 1H), 4.59-4.37 (m, 3H), 3.98-3.70 (m, 5H), 3.60-3.27 (m, 3H), 3.20-2.73 (m, 4H), 1.91 (p, J = 5.9 Hz, 1H), 1.82 (p, J = 6.0 Hz, 1H), 1.06-0.78 (m, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d, multiple sets of rotamers) δ -109.28, -109.33, -109.35, -221.18, -221.20. MS (ESI ⁺ ): [M+H] ⁺ 502.1/504.1. Synthesis of intermediates required for final products 046 to 048 [0207] tert-butyl 4-[3-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]o ctan-8- yl]-4-methoxy-phenyl]sulfonylpiperazine-1-carboxylate (Boc-I-037) Formula Weight: 623,14 Molecular Formula: C ₂₉ H ₃₆ ClFN ₄ O ₆ S According to GP-4, Boc-I-037 was obtained as a white solid in 74% yield using I-008 (2.14g, 4.24mmol, 1 equiv.), tert-butyl piperazine-1-carboxylate (1.2g, 6.4mmol, 1.5 equiv.) and iPr2NEt (2.22mL, 12.7mmol, 3 equiv.) in DCM (21mL) at RT for 16h. Purification by FC (cHex/EtOAc = 95/5 to 0/100). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.40 – 7.28 (m, 1.5H), 7.24 – 7.00 (m, 3.5H), 6.94 (dd, J = 8.5, 1.3 Hz, 1H), 4.51 (dd, J = 13.0, 4.8 Hz, 1H), 4.28 (s, 1H), 4.05 (s, 1H), 3.93 & 3.92 (s, 3H), 3.70 – 3.45 (m, 5H), 3.33 – 3.09 (m, 2H), 2.93 (t, J = 5.1 Hz, 4H), 2.04 – 1.85 (m, 3.5H), 1.70 – 1.60 (m, 0.5H), 1.41 (s, 9H). MS (ESI ⁺ ): [M+H] ⁺ 623.3/625.3. [0208] (2-chloro-4-fluoro-phenyl)-[8-(2-methoxy-5-piperazin-1-ylsul fonyl-phenyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone (I-037) Formula Weight: 523,02 Molecular Formula: C ₂₄ H ₂₈ ClFN ₄ O ₄ S To a solution of tert-butyl 4-[3-[3-(2-chloro-4-fluoro-benzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-4-methoxy-phenyl]sulfonylpipe razine-1-carboxylate Boc-I-037 (2.02g, 3.14mmol, 1 equiv.) in DCM (4 mL) at RT, was added HCl (4M solution in dioxane, 3.9mL, 16mmol, 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. 2N NaOH was added dropwise until pH >11. The layers were separated and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to afford 1.54g (94%) of (2-chloro-4-fluoro-phenyl)-[8-(2-methoxy-5-piperazin- 1-ylsulfonyl-phenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]metha none I-037 as a white solid. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.41 – 7.29 (m, 1.5H), 7.23 – 7.18 (m, 0.5H), 7.19 – 7.12 (m, 1H), 7.12 – 7.00 (m, 2H), 6.93 (dd, J = 8.5, 1.3 Hz, 1H), 4.56 – 4.46 (m, 1H), 4.28 & 4.27 (s, 1H), 4.05 (s, 1H), 3.92 & 3.91 (s, 3H), 3.70 – 3.46 (m, 1H), 3.37 – 3.24 (m, 1H), 3.13 (t, J = 10.6 Hz, 1H), 2.99 – 2.88 (m, 8H), 2.09 – 1.85 (m, 3.5H), 1.70 – 1.60(m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.3, -109.4. MS (ESI ⁺ ): [M+H] ⁺ 523.1/525.1. Synthesis of intermediates required for final product 062 [0209] 1-(3-bromo-4-methoxy-phenyl)sulfonyl-4-(2-phenylethyl)piperi dine (I-044) Molecular Formula: C ₂₀ H ₂₄ BrNO ₃ S According to GP-4, I-044 was obtained as a white solid in 93% yield using 3-bromo-4- methoxybenzenesulfonyl chloride (1.50g, 5.25mmol, 1 equiv.), 4-phenethyl-piperidine (1.12g, 6.30mmol, 1.2 equiv.) and Et3N (1.1mL, 7.9mmol, 1.5 equiv.) in DCM (10mL) at RT for 2h. ¹ H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J = 2.2 Hz, 1H), 7.71 (dd, J = 8.6, 2.2 Hz, 1H), 7.34 – 7.24 (m, 2H), 7.24 – 7.06 (m, 3H), 7.00 (d, J = 8.6 Hz, 1H), 3.99 (s, 3H), 3.78 (dt, J = 11.2, 2.7 Hz, 2H), 2.66 – 2.55 (m, 2H), 2.26 (td, J = 11.8, 2.5 Hz, 2H), 1.89 – 1.71 (m, 2H), 1.64 – 1.50 (m, 2H), 1.45 – 1.15 (m, 3H). MS (ESI ⁺ ): [M+H] ⁺ 438.0/440.0 [0210] 1-[3-bromo-4-(methoxymethoxy)phenyl]sulfonyl-4-(2-phenylethy l)piperidine (I- 045) , Molecular Formula: C ₂₁ H ₂₆ BrNO ₄ S To a solution of I-044 (2.15g, 4.90 mmol, 1 equiv.) in DCM (10mL) at 0°C, was added BBr3 (1M solution in DCM, 9.8mL, 9.8mmol, 2 equiv.). The mixture was stirred at RT for 60h. Water was carefully added and the layers were separated. The aqueous phase was extracted with DCM and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was dissolved in DCM (20ml) at RT and iPr2NEt (3.4mL, 20mmoL, 4 equiv) and chloromethyl methyl ether (0.74mL, 9.8mmol, 2 equiv.) were added dropwise. The mixture was stirred at RT for 1h. It was partitioned between EtOAc and 1N HCl. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1N HCl, brine), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc = 97/3 to 70/30) to afford 1.38g of I-045 (61% over two steps) as a white solid. ¹ H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J = 2.2 Hz, 1H), 7.66 (dd, J = 8.7, 2.3 Hz, 1H), 7.32 – 7.23 (m, 3H), 7.25 – 7.12 (m, 3H), 5.34 (s, 2H), 3.89 – 3.66 (m, 2H), 3.55 (s, 3H), 2.65 – 2.60 (m, 2H), 2.30 – 2.20 (m, 2H), 1.86 – 1.72 (m, 2H), 1.66 – 1.53 (m, 2H), 1.45 – 1.15 (m, 3H). MS (ESI ⁺ ): [M+H] ⁺ 468.0/470.0 [0211] (2-chloro-4-fluoro-phenyl)-[8-[2-(methoxymethoxy)-5-[[4-(2-p henylethyl)-1- piperidyl]sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl ]methanone (I-046) According to GP-5, I-046 was obtained as a white foam in 21% yield using aryl bromide I-045 (1.38g, 2.96mmol, 1 equiv.), piperazine I-001 (1.12g, 4.15mmol, 1.4 equiv.), Cs2CO3 (1.93g, 5.93mmol, 2 equiv.), Pd(OAc)2 (67mg, 0.30mmol, 0.1 equiv.) and rac-BINAP (222mg, 356µmol, 0.12 equiv.) in toluene (15mL) at reflux for 2h. Purification by FC (cHex/EtOAc = 95/5 to 0/100). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.40 – 7.33 (m, 1H), 7.30 – 7.20 (m, 2H), 7.20 – 7.10 (m, 6H), 7.10 – 6.98 (m, 2H), 5.30 – 5.20 (m, 2H), 4.53 & 4.50 (s, 1H), 4.31 & 4.29 (s, 1H), 4.06 (s, 1H), 3.80 – 3.65 (m, 2.5H), 3.55 – 3.45 (m 3.5H), 3.30 & 3.27 (s, 1H), 3.30 – 3.10 (m, 1H), 2.65 – 2.60 (m, 2H), 2.30 – 2.15 (m, 2H), 3.10 – 1.85 (m, 3.5H), 1.85 – 1.60 (m, 2.5H), 1.60 – 1.45 (m, 3H), 1.40 – 1.25 (m, 2H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.2, -109.3. MS (ESI ⁺ ): [M+H] ⁺ 656.2/658.2. Synthesis of intermediates required for final product 063 [0212] 1-(3-bromo-4-methoxy-phenyl)sulfonyl-4-phenyl-piperidine (I-047) Formula Weight: 410,33 Molecular Formula: C ₁₈ H ₂₀ BrNO ₃ S According to GP-4, I-047 was obtained as a white solid in 99% yield using 3-bromo-4- methoxybenzenesulfonyl chloride (1.50g, 5.25mmol, 1 equiv.), 4-phenylpiperidine (1.02g, 6.30mmol, 1.2 equiv.) and Et3N (1.1mL, 7.9mmol, 1.5 equiv.) in DCM (10mL) at RT for 2h. ¹ H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 8.6, 2.2 Hz, 1H), 7.40 – 7.27 (m, 2H), 7.27 – 7.19 (m, 1H), 7.19 – 7.14 (m, 2H), 7.03 (d, J = 8.7 Hz, 1H), 4.01 (s, 3H), 3.98 – 3.89 (m, 2H), 2.62 – 2.32 (m, 3H), 2.01 – 1.73 (m, 4H). MS (ESI ⁺ ): [M+H] ⁺ 410.0/412.0. [0213] 1-[3-bromo-4-(methoxymethoxy)phenyl]sulfonyl-4-phenyl-piperi dine (I-048) Formula Weight: 440,35 Molecular Formula: C ₁₉ H ₂₂ BrNO ₄ S To a solution of I-047 (2.25g, 5.21mmol, 1 equiv.) in DCM (10mL) at 0°C, was added BBr3 (1M solution in DCM, 10.4mL, 10.4mmol, 2 equiv.). The mixture was stirred at RT for 60h. Water was carefully added and the layers were separated. The aqueous phase was extracted with DCM and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was dissolved in DCM (20ml) at RT and iPr2NEt (3.6mL, 21mmol, 4 equiv) and chloromethyl methyl ether (0.79mL, 10.4mmol, 2 equiv.) were added dropwise. The mixture was stirred at RT for 1h. It was partitioned between EtOAc and 1N HCl. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1N HCl, brine), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc = 97/3 to 70/30) to afford 1.74g of I-048 (74% over two steps) as a white solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J = 2.2 Hz, 1H), 7.71 (dd, J = 8.7, 2.2 Hz, 1H), 7.36 – 7.28 (m, 3H), 7.27 – 7.20 (m, 1H), 7.20 – 7.13 (m, 2H), 5.36 (s, 2H), 3.96 (d, J = 11.7 Hz, 2H), 3.57 (s, 3H), 2.57 – 2.32 (m, 3H), 1.99 – 1.77 (m, 4H). MS (ESI ⁺ ): [M+H] ⁺ 440.0/442.0 [0214] (2-chloro-4-fluoro-phenyl)-[8-[2-(methoxymethoxy)-5-[(4-phen yl-1- piperidyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl ]methanone (I-049)

According to GP-5, I-049 was obtained as a white foam in 87% yield using aryl bromide I-048 (1.20g, 2.72mmol, 1 equiv.), piperazine I-001 (0.88g, 3.3mmol, 1.2 equiv.), Cs2CO3 (1.77g, 5.45mmol, 2 equiv.), Pd(OAc)2 (61mg, 0.27mmol, 0.1 equiv.) and rac-BINAP (204mg, 327µmol, 0.12 equiv.) in toluene (14mL) at reflux for 3.5h. Purification by FC (cHex/EtOAc = 94/6 to 40/60). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.43 – 7.27 (m, 3.5H), 7.26 – 7.14 (m, 6.5H), 7.16 – 7.05 (m, 1H), 5.39 – 5.19 (m, 2H), 4.57 & 4.53 (s, 1H), 4.36 & 4.35 (s, 1H), 4.10 (s, 1H), 3.95 – 3.87 (m, 2H), 3.75 – 3.50 (m, 4H), 3.33 & 3.30 (s, 1H), 3.24 – 3.13 (m, 1H), 2.51 – 2.25 (m, 3H), 2.17 – 1.76 (m, 7.5H), 1.72 – 1.62 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.1, -109.3. MS (ESI ⁺ ): [M+H] ⁺ 628.2/630.2. Synthesis of intermediates required for final product 064 [0215] 2-bromo-4-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfony l-phenol (I-050) Formula Weight: 459,78 Molecular Formula: C ₁₈ H ₂₀ BrClN ₂ O ₃ S To a solution of 1-[2-(4-chlorophenyl)ethyl]piperazine dihydrochloride (1.08g, 3.64mmol, 1.3 equiv.) and Et ₃ N (3.9mL, 28mmol, 10 equiv.) in DCM (14mL) at RT, was added dropwise a solution of 3-bromo-4-hydroxy-benzenesulfonyl chloride (800mg, 2.80mmol, 1 equiv.) in DCM (10mL). The mixture was stirred at RT for 4h. Sat. aq. NH ₄ Cl and EtOAc were added. 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 (DCM/MeOH = 99/1 to 90/10) to afford 623mg of I-050 (44%) as a beige solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 8.6, 2.3 Hz, 1H), 7.36 – 7.25 (m, 2H), 7.25 – 7.19 (m, 2H), 7.15 (d, J = 8.6 Hz, 1H), 2.88 (s, 4H), 2.75 – 2.50 (m, 8H). MS (ESI ⁺ ): [M+H] ⁺ 459.1/461.1/463.0. [0216] 1-[3-bromo-4-(methoxymethoxy)phenyl]sulfonyl-4-[2-(4- chlorophenyl)ethyl]piperazine (I-051) Formula Weight: 503,84 Molecular Formula: C ₂₀ H ₂₄ BrClN ₂ O ₄ S To a solution of I-050 (623mg, 1.22mmol, 1 equiv.) and iPr ₂ NEt (0.64mL, 3.7mmol, 3 equiv.) in DCM (6mL) at RT, was added chloromethyl methyl ether (0.19mL, 2.4mmol, 2 equiv.). The mixture was stirred at RT for 16h. It 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 (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc = 95/5 to 50/50) to afford 0.51g of I-051 (83%) as a white solid. ¹ H NMR (400 MHz, Chloroform-d) δ 7.94 (d, J = 2.3 Hz, 1H), 7.64 (dd, J = 8.7, 2.2 Hz, 1H), 7.25 – 7.21 (m, 3H), 7.10 – 7.05 (m, 2H), 5.32 (s, 2H), 3.53 (s, 3H), 3.11 – 2.99 (m, 4H), 2.74 – 2.66 (m, 2H), 2.62 – 2.52 (m, 6H) .MS (ESI ⁺ ): [M+H] ⁺ 503.1/505.1/507.1. [0217] (2-chloro-4-fluoro-phenyl)-[8-[5-[4-[2-(4-chlorophenyl)ethyl ]piperazin-1- yl]sulfonyl-2-(methoxymethoxy)phenyl]-3,8-diazabicyclo[3.2.1 ]octan-3-yl]methanone (I-052)

According to GP-5, I-052 was obtained as a white foam in 51% yield using aryl bromide I-051 (0.51g, 1.0mmol, 1 equiv.), piperazine I-001 (0.33g, 1.2mmol, 1.2 equiv.), K2CO3 (0.28g, 2.0mmol, 2 equiv.), Pd(OAc) ₂ (23mg, 0.10mmol, 0.1 equiv.) and rac-BINAP (75.6mg, 121µmol, 0.12 equiv.) in toluene (5mL) at reflux for 16h. Purification by FC (cHex/EtOAc = 90/10 to 10/90). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.40 – 7.00 (m, 10H), 5.26 & 5.25 (s, 2H), 4.57 – 4.47 (m, 1H), 4.30 & 4.28 (s, 1H), 4.08 (s, 1H), 3.70 – 3.45 (m, 4H), 3.34 – 3.11 (m, 2H), 3.10 – 2.90 (m, 4H), 2.75 – 2.65 (m, 2H), 2.65 – 2.45 (m, 6H), 2.05 – 1.80 (m, 3.5H), 1.70 – 1.60 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.2, -109.3. MS (ESI ⁺ ): [M+H] ⁺ 691.4/693.4/695.4. Synthesis of intermediates required for final product 065 [0218] 1-(3-bromo-4-methoxy-phenyl)sulfonyl-4-(4-fluorophenyl)piper idine (I-053) According to GP-4, I-053 was obtained as a white solid in 90% yield using 3-bromo-4- methoxybenzenesulfonyl chloride (637mg, 2.23mmol, 1 equiv.), 4-(4- fluorophenyl)piperidine (400g, 2.23mmol, 1 equiv.) and iPr ₂ NEt (0.78mL, 4.5mmol, 2 equiv.) in DCM (11mL) at RT for 16h. ¹ H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J = 2.2 Hz, 1H), 7.73 (dd, J = 8.7, 2.2 Hz, 1H), 7.15 – 7.07 (m, 2H), 7.04 – 6.93 (m, 3H), 3.99 (s, 3H), 3.94 – 3.84 (m, 2H), 2.47 – 2.26 (m, 3H), 2.00 – 1.71 (m, 4H). MS (ESI ⁺ ): [M+H] ⁺ 428.0/430.0. [0219] 2-bromo-4-[[4-(4-fluorophenyl)-1-piperidyl]sulfonyl]phenol (I-054) To a solution of I-053 (0.86g, 2.0mmol, 1 equiv.) in DCM (4mL) at 0°C, was added BBr ₃ (1M solution in DCM, 4.0mL, 4.0mmol, 2 equiv.). The mixture was stirred at RT for 60h. Water was carefully added and the layers were separated. The aqueous phase was extracted with DCM and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by FC (DCM 100%) to afford 285mg of I-054 (34%) as a white solid. ¹ H NMR (400 MHz, Chloroform-d) δ 7.94 (d, J = 2.2 Hz, 1H), 7.66 (dd, J = 8.6, 2.1 Hz, 1H), 7.19 – 7.06 (m, 3H), 7.03 – 6.94 (m, 2H), 5.99 (s, 1H), 3.98 – 3.82 (m, 2H), 2.48 – 2.31 (m, 3H), 1.97 – 1.71 (m, 4H). MS (ESI ⁺ ): [M+H] ⁺ 414.0/416.0. [0220] 1-[3-bromo-4-(methoxymethoxy)phenyl]sulfonyl-4-(4-fluorophen yl)piperidine (I-055) To a solution of I-054 (285mg, 674µmol, 1 equiv.) and iPr ₂ NEt (0.35mL, 2.0mmol, 3 equiv.) in DCM (3mL) at RT, was added chloromethyl methyl ether (0.10mL, 1.3mmol, 2 equiv.). The mixture was stirred at RT for 16h. It was partitioned between MTBE and 1N HCl. The layers were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were washed (1N HCl, brine), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to afford 0.31g of I-055 (81%) as a yellow oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J = 2.2 Hz, 1H), 7.66 (dd, J = 8.7, 2.3 Hz, 1H), 7.27 – 7.20 (m, 1H), 7.12 – 7.04 (m, 2H), 6.99 – 6.92 (m, 2H), 5.31 (s, 2H), 3.94 – 3.86 (m, 2H), 3.52 (s, 3H), 2.49 – 2.31 (m, 3H), 1.90 – 1.72 (m, 4H). MS (ESI ⁺ ): [M+H] ⁺ 458.0/460.0. [0221] (2-chloro-4-fluoro-phenyl)-[8-[5-[[4-(4-fluorophenyl)-1-pipe ridyl]sulfonyl]-2- (methoxymethoxy)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]me thanone (I-056) According to GP-5, I-056 was obtained as a white foam in 66% yield using aryl bromide I-055 (309mg, 613µmol, 1 equiv.), piperazine I-001 (0.20g, 0.73mmol, 1.2 equiv.), Cs ₂ CO ₃ (600mg, 1.84mmol, 3 equiv.), Pd(OAc) ₂ (14mg, 61µmol, 0.1 equiv.) and rac-BINAP (46mg, 74µmol, 0.12 equiv.) in toluene (3.1mL) at reflux for 16h. Purification by FC (cHex/EtOAc = 95/5 to 50/50). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.43 – 7.27 (m, 1.5H), 7.25 – 7.01 (m, 6.5H), 7.01 – 6.91 (m, 2H), 5.35 – 5.23 (m, 2H), 4.54 & 4.51 (s, 1H), 4.33 & 4.32 (s, 1H), 4.08 (s, 1H), 3.91 & 3.88 (s, 2H), 3.75 – 3.47 (m, 4H), 3.31 & 3.27 (s, 1H), 3.17 & 3.14 (d, J = 6.7 Hz, 1H), 2.50 – 2.28 (m, 3H), 2.03 – 1.60 (m, 8H). MS (ESI ⁺ ): [M+H] ⁺ 646.2/648.2. Synthesis of intermediate required for final product 066 [0222] 1-(3-bromo-4-chloro-phenyl)sulfonyl-4-phenyl-piperidine (I-057)

According to GP-4, I-057 was obtained as a white solid in 58% yield using commercial 3-bromo-4-chlorobenzenesulfonyl chloride (200mg, 690µmol, 1 equiv.), 4- phenylpiperidine (122mg, 759µmol, 1.1 equiv.) and Et3N (144µL, 1.03mmol, 1.5 equiv.) in DCM (3.4mL) at RT for 16h. Purification by FC (cHex/EtOAc = 97/3 to 70/30). ¹ H NMR (400 MHz, Chloroform-d) δ 8.07 (d, J = 2.0 Hz, 1H), 7.73 – 7.61 (m, 2H), 7.38 – 7.30 (m, 2H), 7.27 – 7.21 (m, 1H), 7.21 – 7.14 (m, 2H), 4.06 – 3.89 (m, 2H), 2.59 – 2.34 (m, 3H), 2.03 – 1.77 (m, 4H). MS (ESI ⁺ ): [M+H] ⁺ 414.0/416.0/418.0. Synthesis of intermediate required for final product 067 [0223] 1-(3-bromo-4-methyl-phenyl)sulfonyl-4-phenyl-piperidine (I-058) According to GP-4, I-058 was obtained as a white solid in 72% yield using commercial 3-bromo-4-methylbenzenesulfonyl chloride (200mg, 741µmol, 1 equiv.), 4- phenylpiperidine (132mg, 816µmol, 1.1 equiv.) and Et3N (144µL, 1.03mmol, 1.5 equiv.) in DCM (3.4mL) at RT for 16h. ¹ H NMR (400 MHz, Chloroform-d) δ 7.89 (d, J = 1.8 Hz, 1H), 7.55 (dd, J = 7.9, 1.9 Hz, 1H), 7.37 – 7.30 (m, 1H), 7.27 – 7.20 (m, 2H), 7.17 – 7.11 (m, 1H), 7.11 – 7.03 (m, 2H), 3.92 – 3.81 (m, 2H), 2.42 (s, 3H), 2.40 – 2.24 (m, 3H), 1.89 – 1.70 (m, 4H). MS (ESI ⁺ ): [M+H] ⁺ 394.0/396.0. Synthesis of intermediate required for final product 068 [0224] 3-bromo-N,4-dimethyl-N-propyl-benzenesulfonamide (I-059)

According to GP-4, I-059 was obtained as a white solid in 88% yield using commercial 3-bromo-4-methylbenzenesulfonyl chloride (60.0mg, 223µmol, 1 equiv.), methyl-N- propylamine (30µL, 0.29mmol, 1.3 equiv.) and Et ₃ N (93µL, 0.67mmol, 3 equiv.) in DCM (1.1mL) at RT for 1h. ¹ H NMR (400 MHz, Chloroform-d) δ 7.94 (d, J = 1.9 Hz, 1H), 7.61 (dd, J = 7.9, 1.9 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 3.00 – 2.94 (m, 2H), 2.73 (s, 3H), 2.47 (s, 3H), 1.63 – 1.56 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). MS (ESI ⁺ ): [M+H] ⁺ 306.0/308.0. Synthesis of intermediate required for final product 069 [0225] methyl 2-bromo-4-[(4-phenyl-1-piperidyl)sulfonyl]benzoate (I-060) According to GP-4, I-060 was obtained as a white solid in 48% yield using 3-bromo-4- methyl 2-bromo-4-chlorosulfonyl benzoate (1.36g, 4.34mmol, 1 equiv.), 4- phenylpiperidine (769mg, 4.77mmol, 1.1 equiv.) and iPr ₂ NEt (1.14mL, 6.50mmol, 1.5 equiv.) in DCM (43mL) at RT for 16h. Purification by FC (cHex/EtOAc = 93/7 to 30/70). ¹ H NMR (400 MHz, Chloroform-d) δ 8.10 (d, J = 1.7 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.79 (dd, J = 8.1, 1.7 Hz, 1H), 7.37 – 7.30 (m, 2H), 7.27 – 7.22 (m, 1H), 7.20 – 7.15 (m, 2H), 4.01 (s, 3H), 4.01 – 3.96 (m, 2H), 2.54 – 2.36 (m, 3H), 2.01 – 1.79 (m, 4H). MS (ESI ⁺ ): [M+H] ⁺ 438.0/440.0. Synthesis of intermediate required for final product 074 [0226] 3-bromo-5-chloro-4-methyl-aniline (I-061)

To a solution of 1-bromo-3-chloro-2-methyl-5-nitro-benzene (1.39g, 5.53mmol, 1 equiv.) in AcOH (31mL) at RT, was added Zn (3.62g, 55.3mmol, 10 equiv.). The mixture was stirred at RT for 4h. The suspension was filtered over Celite (EtOAc rinses) and the combined filtrates were concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc = 98/2 to 80/20) to afford 967mg (79%) of I-061 as a brown solid. ¹ H NMR (400 MHz, Chloroform-d) δ 6.83 (d, J = 2.4 Hz, 1H), 6.68 (d, J = 2.3 Hz, 1H), 3.52 (s, 2H), 2.38 (s, 3H). MS (ESI ⁺ ): [M+H] ⁺ 220.0/222.0/224.0. [0227] 3-bromo-5-chloro-4-methyl-benzenesulfonyl chloride (I-062) To a solution of CuCl (27mg, 0.27mmol, 0.12 equiv.) in water (7mL) at 0°C, was added dropwise thionyl chloride (1.3mL, 18mmol, 8 equiv.). The mixture was stirred at RT for 1.5h. In the meantime, to a solution of aniline I-061 (500mg, 2.27mmol, 1 equiv.) in water (30mL) at 0°C, were added 37% HCl (16mL) and a solution of NaNO ₂ (172mg, 2.49mmol, 1.1 equiv.) in water (7mL). The mixture was stirred at 0°C for 30min. The first solution was then added dropwise and the resulting mixture was vigorously stirred at RT for 2h. It was filtered over fritted glass and the filter cake was washed with water. The filter cake was dissolved using DCM and the resulting wet organic solution was dried (Na2SO4), filtered and concentrated under reduced pressure to afford 157mg (23%) of I- 062 as a brown solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.12 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 2.65 (s, 3H). [0228] 3-bromo-N-tert-butyl-5-chloro-4-methyl-benzenesulfonamide (I-063) According to GP-4, I-063 was obtained as a beige solid in 68% yield using I-062 (157mg, 0.516mmol, 1 equiv.) and t-butylamine (0.54mL, 5.17mmol, 10 equiv.) in DCM (2mL) at RT for 16h. Purification by FC (cHex/EtOAc = 98/2 to 80/20). ¹ H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J = 1.9 Hz, 1H), 7.83 (d, J = 1.9 Hz, 1H), 4.51 (s, 1H), 2.58 (s, 3H), 1.28 (s, 9H). MS (ESI ⁺ ): [M+H] ⁺ 338.1/340.1/342.1. Synthesis of intermediate required for final product 075 [0229] 3-bromo-4,5-dichloro-benzenesulfonyl chloride (I-064) To a solution of CuCl (25mg, 0.25mmol, 0.12 equiv.) in water (30mL) at 0°C, was added dropwise thionyl chloride (1.2mL, 17mmol, 8 equiv.). The mixture was stirred at RT for 1.5h. In the meantime, to a solution of 3-bromo-4,5-dichloroaniline (500mg, 2.08mmol, 1 equiv.) in water (30mL) at 0°C, were added 37% HCl (16mL) and a solution of NaNO2 (158mg, 2.28mmol, 1.1 equiv.) in water (7mL). The mixture was stirred at 0°C for 30min. The first solution was then added dropwise and the resulting mixture was vigorously stirred at RT for 2h. It was filtered over fritted glass and the filter cake was washed with water. The filter cake was dissolved using DCM and the resulting wet organic solution was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to afford 673mg (100%) of I-064 as a brown solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J = 2.2 Hz, 1H), 8.09 (d, J = 2.2 Hz, 1H). [0230] 3-bromo-N-tert-butyl-4,5-dichloro-benzenesulfonamide (I-065) According to GP-4, I-065 was obtained as an orange solid in 14% yield using I-064 (673mg, 2.07mmol, 1 equiv.), t-butylamine (0.26mL, 2.49mmol, 1.2 equiv.) and Et3N (0.43mL, 3.1mmol, 1.5 equiv.) in DCM (4mL) at RT for 16h. Purification by FC (cHex/EtOAc = 98/2 to 80/20). ¹ H NMR (400 MHz, Chloroform-d) δ 8.04 (d, J = 2.1 Hz, 1H), 7.93 (d, J = 2.1 Hz, 1H), 4.54 (s, 1H), 1.30 (s, 9H). MS (ESI ⁺ ): [M+H] ⁺ 358.0/360.0/362.0. Synthesis of intermediate required for final product 079 [0231] [2-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]oct an-8-yl]-4- [methyl(propyl)sulfamoyl]phenyl] trifluoromethanesulfonate (I-066) To a solution of 036 (70% pure, 410mg, 579µmol, 1 equiv.) dry DCM (5.8mL) at 0°C, were added Et3N (0.16mL, 1.2mmol, 2 equiv.) and Tf2O (0.19mL, 1.2mmol, 2 equiv.). The mixture was stirred at RT for 2h. Sat. aq. NaHCO3 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 (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc = 95/5 to 50/50) to afford 359mg (99%) of I-066 as a white foam. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.46 – 7.30 (m, 3.5H), 7.25 – 6.97 (m, 2.5H), 4.61 & 4.58 (s, 1H), 4.16 (s, 1H), 4.00 – 3.83 (m, 1H), 3.81 – 3.57 (m, 1H), 3.38 & 3.34 (s, 1H), 3.25 – 3.15 (m, 1H), 3.05 – 2.97 (m, 2H), 2.78 (s, 3H), 2.15 – 1.85 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 1.62 – 1.51 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -73.82, -73.84, -109.0, -109.1. MS (ESI ⁺ ): [M+H] ⁺ 628.1/630.1. Synthesis of intermediate required for final products 080 & 81 [0232] [2-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]oct an-8-yl]-4-[(4- phenyl-1-piperidyl)sulfonyl]phenyl] trifluoromethanesulfonate (I-067) To a solution of 063 (100mg, 171µmol, 1 equiv.) dry DCM (1.7mL) at 0°C, were added Et3N (0.12mL, 0.86mmol, 5 equiv.) and Tf2O (0.060mL, 0.34mmol, 2 equiv.). The mixture was stirred at RT for 2h. Sat. aq. NH ₄ Cl 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), filtereda and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc = 96/4 to 60/40) to afford 115mg (94%) of I-067 as a yellow foam. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.46 – 7.33 (m, 3.5H), 7.33 – 7.27 (m, 2H), 7.24 – 7.18 (m, 2H), 7.18 – 7.11 (m, 2.5H), 7.12 – 7.02 (m, 1H), 4.60 & 4.56 (s, 1H), 4.23 – 4.12 (m, 1H), 3.98 – 3.85 (m, 3H), 3.77 & 3.61(d, J = 12.5 Hz, 1H), 3.36 & 3.33 (s, 1H), 3.18 (d, J = 12.5 Hz, 1H), 2.52 – 2.37 (m, 3H), 2.10 – 1.74 (m, 7.5H), 1.73 – 1.62 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -73.78, -73.81, -108.9, -109.1. MS (ESI ⁺ ): [M+H] ⁺ 716.2/718.2. Synthesis of intermediates required for final product 083 [0233] 3-bromo-5-fluoro-4-hydroxy-benzenesulfonyl chloride (I-068) According to GP-3, I-068 was obtained as a yellow solid in 82% yield using 2-bromo-6- fluoro-phenol (1.02g, 5.35mmol, 1 equiv.) in HSO ₃ Cl (8.36mL, 107mmol, 20 equiv.) at RT for 2h. ¹ H NMR (400 MHz, Chloroform-d) 8.02 (t, J = 2.0 Hz, 1H), 7.77 (dd, J = 8.8, 2.3 Hz, 1H), 5.75 (s, 1H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -128.4. [0234] 2-bromo-6-fluoro-4-[(4-phenyl-1-piperidyl)sulfonyl]phenol (I-069) According to GP-4, I-069 was obtained as a white solid in 88% yield using I-068 (1.27g, 4.39mmol, 1 equiv.) 4-phenylpiperidine (1.06g, 6.58mmol, 1.5 equiv.) and iPr2NEt (2.29mL, 13.1mmol, 3 equiv.) in DCM (22mL) at RT for 1h. Purification by FC (cHex/EtOAc = 95/5 to 50/50). ¹ H NMR (400 MHz, DMSO-d6) δ 7.58 (s, 1H), 7.43 (dd, J = 10.3, 2.2 Hz, 1H), 7.32 – 7.24 (m, 2H), 7.23 – 7.15 (m, 3H), 3.79 – 3.67 (m, 2H), 3.62 (p, J = 6.6 Hz, 1H), 3.40 (br s, 1H), 2.34 (td, J = 12.0, 2.5 Hz, 2H), 1.87 – 1.77 (m, 2H), 1.66 (qd, J = 12.6, 4.0 Hz, 2H). ¹⁹ F NMR (376 MHz, DMSO-d6) δ -130.4. MS (ESI ⁺ ): [M+H] ⁺ 414.0/416.0/418.0. [0235] 1-[3-bromo-5-fluoro-4-(methoxymethoxy)phenyl]sulfonyl-4-phen yl-piperidine (I-070) ₉ To a solution of I-069 (1.60g, 3.86mmol, 1 equiv.) and iPr2NEt (2.02mL, 11.6mmol, 3 equiv.) in DCM (3mL) at RT, was added chloromethyl methyl ether (0.59mL, 7.7mmol, 2 equiv.). The mixture was stirred at RT for 1h. Sat. aq. NaHCO ₃ was added. 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 (cHex/EtOAc = 95/5 to 50/50) to afford 1.85g of I-070 (100%) as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.80 (s, 1H), 7.51 (dd, J = 10.0, 2.0 Hz, 1H), 7.31 (t, J = 7.4 Hz, 2H), 7.25 – 7.20 (m, 1H), 7.19 – 7.13 (m, 2H), 5.32 (s, 2H), 3.94 (d, J = 11.6 Hz, 2H), 3.65 (s, 3H), 2.55 – 2.40 (m, 3H), 1.99 – 1.77 (m, 4H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -122.5. MS (ESI ⁺ ): [M+H] ⁺ 458.0/460.0. [0236] (2-chloro-4-fluoro-phenyl)-[8-[3-fluoro-2-(methoxymethoxy)-5 -[(4-phenyl-1- piperidyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl ]methanone (I-071) According to GP-5, I-071 was obtained as a white foam in 14% yield using aryl bromide I-070 (300mg, 622µmol, 1 equiv.), piperazine I-001 (0.20g, 0.75mmol, 1.2 equiv.), Cs2CO3 (608mg, 1.86mmol, 3 equiv.), Pd(OAc)2 (14mg, 62µmol, 0.1 equiv.) and rac-BINAP (58mg, 93µmol, 0.15 equiv.) in toluene (3.1mL) at reflux for 16h. Purification by FC (cHex/EtOAc = 95/5 to 50/50) and PTLC (DCM/EtOAc = 95/5). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.39 – 7.28 (m, 2.5H), 7.24 – 6.98 (m, 7.5H), 5.22 & 5.21 (s, 2H), 4.55 & 4.52 (s, 1H), 4.39 (s, 1H), 4.16 (s, 1H), 3.91 (d, J = 11.5 Hz, 2H), 3.64 – 3.40 (m, 4H), 3.27 – 3.10 (m, 2H), 2.55 – 2.40 (m, 3H), 2.02 – 1.77 (m, 7.5H), -1.70 – 1.60 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.9, -109.1, -125.2, -125.3. MS (ESI ⁺ ): [M+H] ⁺ 646.2/648.1. Synthesis of intermediates required for final products 084 to 86 [0237] 1-bromo-3-fluoro-2-(methoxymethoxy)benzene (I-072) To a solution of 2-bromo-6-fluoro-phenol (1.00g, 5.24mmol, 1 equiv.) and iPr2NEt (2.74mL, 15.7mmol, 3 equiv.) in DCM (26mL) at RT, was added chloromethyl methyl ether (0.60mL, 7.8mmol, 2 equiv.). The mixture was stirred at RT for 1h. 1N HCl was added. 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 (cHex/EtOAc = 95/5 to 50/50) to afford 920mg of I-072 (75%) as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.34 (dt, J = 8.1, 1.6 Hz, 1H), 7.06 (ddd, J = 10.6, 8.3, 1.5 Hz, 1H), 6.94 (td, J = 8.2, 5.3 Hz, 1H), 5.20 (s, 2H), 3.65 (s, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -126.0. [0238] (2-chloro-4-fluoro-phenyl)-[8-[3-fluoro-2-(methoxymethoxy)ph enyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone (I-073) According to GP-5, I-073 was obtained as a white foam in 73% yield using aryl bromide I-072 (920mg, 3.91mmol, 1 equiv.), piperazine I-001 (1.16g, 4.31mmol, 1.1 equiv.), Cs2CO3 (3.82g, 11.7mmol, 3 equiv.), Pd(OAc)2 (87.9mg, 391µmol, 0.1 equiv.) and rac-BINAP (292mg, 470µmol, 0.12 equiv.) in toluene (20mL) at reflux for 16h. Purification by FC (cHex/EtOAc = 92/8 to 20/80). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.36 (dd, J = 8.5, 5.9 Hz, 0.5H), 7.24 – 6.99 (m, 2.5H), 6.97 – 6.88 (m, 1H), 6.74 – 6.66 (m, 1H), 6.58 (dd, J = 8.2, 4.0 Hz, 1H), 5.17 – 5.10 (m, 2H), 4.55 – 4.45 (m, 1H), 4.28 (d, J = 6.4 Hz, 1H), 4.15 – 4.08 (m, 1H), 3.65 – 3.40 (m, 4H), 3.27 & 3.24 (m, 1H), 3.16 – 3.06 (m, 1H), 2.06 – 1.82 (m, 3.5H), 1.65 – 1.55 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.3, -109.4, -129.2, -129.3. MS (ESI ⁺ ): [M+H] ⁺ 423.1/425.1. [0239] (2-chloro-4-fluoro-phenyl)-[8-(3-fluoro-2-hydroxy-phenyl)-3, 8- diazabicyclo[3.2.1]octan-3-yl]methanone (I-074) To a solution of I-073 (1.20g, 2.84mmol, 1 equiv.) in DCM (14mL) at RT, was added CF ₃ CO ₂ H (4.4mL, 57mmol, 20 equiv.). The mixture was stirred at RT for 2h. It was concentrated under reduced pressure and the residue was azeotroped with toluene. The residue was purified by FC (cHex/EtOAc = 94/6 to 40/60) to afford 833mg of I-074 (78%) as a white foam. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.37 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.23 – 7.13 (m, 1.5H), 7.12 – 7.00 (m, 1H), 6.84 – 6.70 (m, 2H), 6.63 (t, J = 8.9 Hz, 1H), 4.87 (s, 1H), 4.57 & 4.55 (s, 1H), 4.06 (s, 1H), 3.84 (s, 1H), 3.71 – 3.50 (m, 1H), 3.35 &3.31 (d, J = 5.9 Hz, 1H), 3.18 (d, J = 12.5 Hz, 1H), 2.04 – 1.88 (m, 3.5H), 1.70 – 1.60 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ - 109.13, -109.14, -137.5, -137.7. MS (ESI ⁺ ): [M+H] ⁺ 379.1/381.1. [0240] 3-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octa n-8-yl]-5-fluoro- 4-hydroxy-benzenesulfonyl chloride (I-075) According to GP-3, I-075 was obtained as a white foam in 83% yield using I-074 (510mg, 1.34mmol, 1 equiv.) and HSO3Cl (1.8mL, 27mmol, 20 equiv.) in DCM (7mL) at reflux for 5h. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.47 (dt, J = 8.4, 1.9 Hz, 1H), 7.38 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.25 – 7.01 (m, 3.5H), 4.65 – 4.55 (m, 1H), 4.35 (br s, 1H), 4.35 – 4.20 (m, 1H), 4.03 (s, 1H), 3.70 – 3.50 (m, 1H), 3.36 – 3.27 (m, 1H), 3.21 (d, J = 12.6 Hz, 1H), 2.17 – 1.94 (m, 3.5H), 1.75 – 1.65 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.65, -108.72, -133.2, -133.4. Synthesis of intermediates required for final products 087 to 89 [0241] 1-bromo-2-(methoxymethoxy)-3-(trifluoromethyl)benzene (I-076) To a solution of 2-bromo-6-(trifluoromethyl)phenol (675mg, 2.80mmol, 1 equiv.) and iPr2NEt (0.73mL, 4.2mmol, 1.5 equiv.) in DCM (6mL) at RT, was added chloromethyl methyl ether (0.26mL, 3.4mmol, 1.2 equiv.). The mixture was stirred at RT for 1h. 1N HCl was added. 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 (cHex/EtOAc = 98/2 to 90/10) to afford 700mg of I-076 (88%) as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.79 (dd, J = 8.0, 1.5 Hz, 1H), 7.61 (dd, J = 7.9, 1.5 Hz, 1H), 7.19 – 7.04 (m, 1H), 5.22 (s, 2H), 3.70 (s, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -60.6. [0242] (2-chloro-4-fluoro-phenyl)-[8-[2-(methoxymethoxy)-3-(trifluo romethyl)phenyl]- 3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-077) According to GP-5, I-077 was obtained as a white foam in 71% yield using aryl bromide I-076 (690mg, 2.42mmol, 1 equiv.), piperazine I-001 (780mg, 2.90mmol, 1.2 equiv.), Cs ₂ CO ₃ (2.37g, 7.26mmol, 3 equiv.), Pd(OAc) ₂ (54.3mg, 242µmol, 0.1 equiv.) and rac-BINAP (181mg, 291µmol, 0.12 equiv.) in toluene (12mL) at reflux for 5h. Purification by FC (cHex/EtOAc = 95/5 to 50/50). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.39 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.25 – 7.15 (m, 2.5H), 7.14 – 6.99 (m, 3H), 5.30 – 5.10 (m, 2H), 4.58 – 4.50 (m, 1H), 4.35 – 4.25 (m, 1H), 4.20 – 4.12 (m, 1H), 3.67 – 3.45 (m, 4H), 3.35 – 3.26 (m, 1H), 3.20 – 3.10 (m, 1H), 2.10 – 1.85 (m, 3.5H), 1.70 – 1.60 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -60.36, -60.40, -109.3, -109.4. MS (ESI ⁺ ): [M+H] ⁺ 473.1/475.0. [0243] (2-chloro-4-fluoro-phenyl)-[8-[2-hydroxy-3-(trifluoromethyl) phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone (I-078) To a solution of I-077 (810mg, 1.71mmol, 1 equiv.) in DCM (8.6mL) at RT, was added CF ₃ CO ₂ H (2.64mL, 34mmol, 20 equiv.). The mixture was stirred at RT for 1h. It was concentrated under reduced pressure and the residue was azeotroped with toluene. The residue was purified by FC (cHex/EtOAc = 95/5 to 50/50) to afford 713mg of I-078 (97%) as a white foam. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.40 – 7.15 (m, 4H), 7.15 – 7.03 (m, 2H), 6.95 – 6.81 (m, 1H), 4.78 – 4.58 (m, 1H), 3.79 – 3.39 (m, 3H), 3.39 – 3.14 (m, 2H), 2.28 – 1.90 (m, 3.5H), 1.82 – 1.69 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -62.31, -62.33, -108.9, -109.0. MS (ESI ⁺ ): [M+H] ⁺ 429.0/431.0. [0244] 3-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octa n-8-yl]-4- hydroxy-5-(trifluoromethyl)benzenesulfonyl chloride (I-079) According to GP-3, I-079 was obtained as a white foam in 100% yield using I-078 (710mg, 1.66mmol, 1 equiv.) and HSO ₃ Cl (2.2mL, 33mmol, 20 equiv.) in DCM (2mL) at reflux for 16h. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 8.05 (d, J = 2.1 Hz, 1H), 7.67 & 7.64 (d, J = 2.2 Hz, 1H), 7.39 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.25 – 7.04 (m, 2.5H), 4.80 (br s, 1H), 4.70 & 4.67 (s, 1H), 3.82 (s, 1H), 3.71 – 3.48 (m, 2H), 3.36 – 3.26 (m, 2H), 2.26 – 2.03 (m, 3.5H), 1.80 – 1.70 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -62.94, -62.96, -108.3, -108.4. Synthesis of intermediates required for final product 090 [0245] 3-bromo-4-hydroxy-5-methyl-benzenesulfonyl chloride (I-080)

According to GP-3, I-080 was obtained as a brown solid in 68% yield using 2-bromo-6- methyl-phenol (1.00g, 5.35mmol, 1 equiv.) in HSO3Cl (8.36mL, 107mmol, 20 equiv.) at RT for 2h. ¹ H NMR (400 MHz, Chloroform-d) δ 8.03 (d, J = 2.4 Hz, 1H), 7.78 (dd, J = 2.4, 0.9 Hz, 1H), 6.28 (s, 1H), 2.40 (d, J = 0.7 Hz, 3H). [0246] 2-bromo-6-methyl-4-[(4-phenyl-1-piperidyl)sulfonyl]phenol (I-081) According to GP-4, I-081 was obtained as a white solid in 60% yield using I-080 (1.04g, 3.64mmol, 1 equiv.) 4-phenylpiperidine (881mg, 5.46mmol, 1.5 equiv.) and iPr ₂ NEt (1.90mL, 10.9mmol, 3 equiv.) in DCM (18mL) at RT for 1h. Purification by FC (cHex/EtOAc = 95/5 to 50/50). ¹ H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.33 – 7.24 (m, 2H), 7.23 – 7.16 (m, 3H), 3.81 – 3.67 (m, 2H), 2.58 – 2.46 (m, 1H), 2.37 – 2.26 (m, 5H), 1.89 – 1.76 (m, 2H), 1.75 – 1.55 (m, 2H). MS (ESI ⁺ ): [M+H] ⁺ 410.0/412.0. [0247] 1-[3-bromo-4-(methoxymethoxy)-5-methyl-phenyl]sulfonyl-4-phe nyl-piperidine (I-082) To a solution of I-081 (900mg, 2.19mmol, 1 equiv.) and iPr2NEt (1.15mL, 6.58mmol, 3 equiv.) in DCM (11mL) at RT, was added chloromethyl methyl ether (0.33mL, 4.4mmol, 2 equiv.). The mixture was stirred at RT for 1h. Sat. aq. NaHCO3 was added. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc = 95/5 to 50/50) to afford 880mg of I-082 (89%) as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.84 (d, J = 2.2 Hz, 1H), 7.58 – 7.54 (m, 1H), 7.34 – 7.27 (m, 2H), 7.25 – 7.18 (m, 1H), 7.18 – 7.13 (m, 2H), 5.16 (s, 2H), 3.97 – 3.88 (m, 2H), 3.67 (s, 3H), 2.53 – 2.38 (m, 6H), 1.97 – 1.79 (m, 4H). MS (ESI ⁺ ): [M+H] ⁺ 454.0/456.0. [0248] (2-chloro-4-fluoro-phenyl)-[8-[2-(methoxymethoxy)-3-methyl-5 -[(4-phenyl-1- piperidyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl ]methanone (I-083) According to GP-5, I-083 was obtained as a white foam in 44% yield using aryl bromide I-082 (230mg, 460µmol, 1 equiv.), piperazine I-001 (0.15g, 0.55mmol, 1.2 equiv.), Cs ₂ CO ₃ (450mg, 1.38mmol, 3 equiv.), Pd(OAc) ₂ (10mg, 46µmol, 0.1 equiv.) and rac-BINAP (43mg, 69µmol, 0.15 equiv.) in toluene (2.3mL) at reflux for 16h. Purification by FC (cHex/EtOAc = 90/10 to 10/90). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.40 – 7.27 (m, 2.5H), 7.24 – 7.00 (m, 7.5H), 5.21 – 5.14 (m, 2H), 4.55 & 4.52 (m, 1H), 4.29 (s, 1H), 4.06 (s, 1H), 3.95 – 3.85 (m, 2H), 3.65 – 3.40 (m, 4H), 3.36 – 3.12 (m, 2H), 2.50 – 2.32 (m, 6H), 2.03 – 1.76 (m, 7.5H), 1.70 – 1.60 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.1, -109.2. MS (ESI ⁺ ): [M+H] ⁺ 642.2/644.1. Synthesis of intermediates required for final products 091 to 93 [0249] 1-bromo-2-(methoxymethoxy)-3-methyl-benzene (I-084) To a solution of 2-bromo-6-methyl-phenol (1.00g, 5.35mmol, 1 equiv.) and iPr ₂ NEt (1.4mL, 8.1mmol, 1.5 equiv.) in DCM (21mL) at RT, was added chloromethyl methyl ether (0.49mL, 6.4mmol, 1.2 equiv.). The mixture was stirred at RT for 60h. 1N HCl was added. 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 1.22g of I-084 (99%) as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.42 (ddd, J = 8.0, 1.6, 0.7 Hz, 1H), 7.15 (ddd, J = 7.6, 1.6, 0.8 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 5.11 (s, 2H), 3.68 (s, 3H), 2.39 (s, 3H). [0250] (2-chloro-4-fluoro-phenyl)-[8-[2-(methoxymethoxy)-3-methyl-p henyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone (I-085) According to GP-7, I-085 was obtained as a white foam in 24% yield using aryl bromide I-084 (811mg, 3.51mmol, 1 equiv.), piperazine I-001 (1.22g, 4.56mmol, 1.3 equiv.), t- BuONa (1.01g, 10.5mmol, 3 equiv.) and XPhos-Pd-G3 (148mg, 175µmol, 0.05 equiv.) in toluene (14mL) at reflux for 4h. Purification by FC (cHex/EtOAc = 95/5 to 50/50). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.42 – 7.35 (m, 0.5H), 7.26 – 7.14 (m, 1.5H), 7.13 – 7.00 (m, 1H), 6.97 – 6.89 (m, 1H), 6.87 – 6.76 (m, 1H), 6.68 (t, J = 6.7 Hz, 1H), 5.27 – 4.98 (m, 2H), 4.54 & 4.50 (d, J = 6.1 Hz, 1H), 4.24 (s, 1H), 4.06 (s, 1H), 3.64 – 3.42 (m, 4H), 3.31 – 3.24 (m, 1H), 3.14 (t, J = 11.1 Hz, 1H), 2.33 (s, 3H), 2.05 – 1.83 (m, 3.5H), 1.64 – 1.56 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.5, -109.6. MS (ESI ⁺ ): [M+H] ⁺ 419.1/421.0. [0251] (2-chloro-4-fluoro-phenyl)-[8-(2-hydroxy-3-methyl-phenyl)-3, 8- diazabicyclo[3.2.1]octan-3-yl]methanone (I-086) To a solution of I-085 (350mg, 0.835mmol, 1 equiv.) in DCM (4.2mL) at RT, was added CF3CO2H (1.3mL, 17mmol, 20 equiv.). The mixture was stirred at RT for 24h. It was concentrated under reduced pressure and the residue was azeotroped with toluene to afford 330mg of I-086 (100%) as a white foam. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.40 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.26 – 7.15 (m, 1.5H), 7.15 – 7.05 (m, 1H), 7.01 – 6.88 (m, 1H), 6.88 – 6.60 (m, 2H), 4.65 & 4.62 (dd, J = 2.7, 1.4 Hz, 1H), 3.84 – 3.61 (m, 2H), 3.56 – 3.48 (m, 2H), 3.40 – 3.17 (m, 2H), 2.29 (s, 3H), 2.24 – 1.90 (m, 3.5H), 1.73 – 1.65 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ - 109.07, -109.11. MS (ESI ⁺ ): [M+H] ⁺ 375.1/377.1. [0252] 3-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octa n-8-yl]-4- hydroxy-5-methyl-benzenesulfonyl chloride (I-087) According to GP-3, I-087 was obtained as a beige foam in 100% yield using I-086 (330mg, 0.863mmol, 1 equiv.) and HSO ₃ Cl (1.4mL, 22mmol, 20 equiv.) in DCM (3.5mL) at RT for 1h. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.70 – 7.68 (m, 1H), 7.44 – 7.38 (m, 1.5H), 7.27 – 7.16 (m, 1.5H), 7.17 – 7.05 (m, 1H), 4.69 & 4.66 (s, 1H), 3.83 – 3.73 (m, 1H), 3.72 – 3.45 (m, 2H), 3.35 – 3.25 (m, 2H), 2.37 (s, 3H), 2.26 – 2.00 (m, 3.5H), 1.82 – 1.72 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.6, -108.8. Synthesis of intermediates required for final product 094 [0253] 1-bromo-3-ethyl-2-(methoxymethoxy)benzene (I-088) To a solution of 2-bromo-6-ethyl-phenol (500mg, 2.49mmol, 1 equiv.) and iPr ₂ NEt (0.65mL, 3.7mmol, 1.5 equiv.) in DCM (12mL) at RT, was added chloromethyl methyl ether (0.23mL, 3.0mmol, 1.2 equiv.). The mixture was stirred at RT for 16h. Sat. aq. NH ₄ Cl and MTBE were added. 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 to afford 647mg of I-088 (100%) as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.32 (dd, J = 7.9, 1.6 Hz, 1H), 7.13 – 6.99 (m, 1H), 6.87 (t, J = 7.8 Hz, 1H), 5.01 (s, 2H), 3.57 (s, 3H), 2.68 (q, J = 7.5 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H). [0254] (2-chloro-4-fluoro-phenyl)-[8-[3-ethyl-2-(methoxymethoxy)phe nyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone (I-089)

According to GP-5, I-089 was obtained as a white foam in 68% yield using aryl bromide I-088 (640mg, 2.61mmol, 1 equiv.), piperazine I-001 (842mg, 3.13mmol, 1.2 equiv.), Cs ₂ CO ₃ (2.55g, 7.83mmol, 3 equiv.), Pd(OAc) ₂ (58.6mg, 261µmol, 0.1 equiv.) and rac-BINAP (195mg, 313µmol, 0.12 equiv.) in toluene (13mL) at reflux for 3h. Purification by FC (cHex/EtOAc = 90/10 to 10/90). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.38 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.25 – 7.14 (m, 1.5H), 7.14 – 7.01 (m, 1H), 7.01 – 6.93 (m, 1H), 6.91 – 6.80 (m, 1H), 6.76 – 6.61 (m, 1H), 5.23 – 5.03 (m, 2H), 4.62 – 4.45 (m, 1H), 4.30 – 4.19 (m, 1H), 4.09 – 4.00 (m, 1H), 3.67 – 3.40 (m, 4H), 3.36 – 3.21 (m, 1H), 3.21 – 3.03 (m, 1H), 2.79 – 2.64 (m, 2H), 2.04 – 1.82 (m, 3.5H), 1.65 – 1.55 (m, 0.5H), 1.25 (t, J = 7.4 Hz, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.5, -109.6. MS (ESI ⁺ ): [M+H] ⁺ 433.1/435.0. [0255] (2-chloro-4-fluoro-phenyl)-[8-(3-ethyl-2-hydroxy-phenyl)-3,8 - diazabicyclo[3.2.1]octan-3-yl]methanone (I-090) To a solution of I-089 (750mg, 1.73mmol, 1 equiv.) in DCM (8.7mL) at RT, was added CF3CO2H (2.7mL, 34mmol, 20 equiv.). The mixture was stirred at RT for 24h. It was concentrated under reduced pressure and the residue was azeotroped with toluene. The residue was purified by FC (cHex/EtOAc = 95/5 to 50/50) to afford 618mg of I-090 (92%) as a white foam. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.40 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.26 – 7.15 (m, 1.5H), 7.15 – 7.02 (m, 1H), 7.02 – 6.90 (m, 1H), 6.90 – 6.66 (m, 3H), 4.68 – 4.54 (m, 1H), 3.78 –3.41 (m, 3H), 3.36 – 3.14 (m, 2H), 2.70 (q, J = 7.5 Hz, 2H), 2.32 – 1.86 (m, 3.5H), 1.77 – 1.65 (m, 0.5H), 1.25 (t, J = 7.6 Hz, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.2, -109.3. MS (ESI ⁺ ): [M+H] ⁺ 389.0/391.0. [0256] 3-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octa n-8-yl]-5-ethyl-4- hydroxy-benzenesulfonyl chloride (I-091) Fo rmua eg t: 8 ,3 Molecular Formula: C ₂₁ H ₂₁ Cl ₂ FN ₂ O ₄ S According to GP-3, I-091 was obtained as a beige foam in 80% yield using I-090 (150mg, 0.386mmol, 1 equiv.) and HSO3Cl (0.51mL, 7.7mmol, 20 equiv.) in DCM (1mL) at RT for 1h. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.74 – 7.67 (m, 1H), 7.48 – 7.36 (m, 1.5H), 7.24 – 7.03 (m, 2.5H), 4.72 – 4.63 (m, 1H), 3.92 – 3.54 (m, 3H), 3.43 – 3.26 (m, 2H), 2.75 (q, J = 7.5 Hz, 2H), 2.22 – 1.99 (m, 3.5H), 1.80 – 1.70 (m, 0.5H), 1.28 (t, J = 7.5 Hz, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -108.5. Synthesis of intermediates required for final products 095 to 109 [0257] 1-bromo-3-chloro-2-(methoxymethoxy)benzene (I-092) Formula Weight: 251,5 Molecular Formula: C ₈ H ₈ BrClO ₂ To a solution of 2-bromo-6-chlorophenol (3.17g, 10.5mmol, 1 equiv.) and iPr ₂ NEt (3.73mL, 15.7mmol, 1.5 equiv.) in DCM (21mL) at RT, was added chloromethyl methyl ether (0.95mL, 13mmol, 1.2 equiv.). The mixture was stirred at RT for 16h. The volatiles were removed under reduced pressure. EtOAc was added and the organic solution was washed washed (1N HCl, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc = 95/5) to afford 2.59g of I-092 (98%) as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.50 (dd, J = 8.0, 1.6 Hz, 1H), 7.37 (dd, J = 8.1, 1.5 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 5.21 (s, 2H), 3.74 (s, 3H). [0258] (2-chloro-4-fluoro-phenyl)-[8-[3-chloro-2-(methoxymethoxy)ph enyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone (I-093) Molecular Formula: C ₂₁ H ₂₁ Cl ₂ FN ₂ O ₃ According to GP-5, I-093 was obtained as a white foam in 79% yield using aryl bromide I-092 (1.20g, 4.77mmol, 1 equiv.), piperazine I-001 (1.54g, 5.73mmol, 1.2 equiv.), Cs2CO3 (4.66g, 14.3mmol, 3 equiv.), Pd(OAc)2 (107mg, 477µmol, 0.1 equiv.) and rac-BINAP (357mg, 573µmol, 0.12 equiv.) in toluene (14mL) at reflux for 5h. Purification by FC (cHex/EtOAc = 95/5 to 50/50). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.38 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.26 – 7.14 (m, 1.5H), 7.14 – 7.02 (m, 1H), 7.02 – 6.92 (m, 2H), 6.80 – 6.69 (m, 1H), 5.24 – 5.11 (m, 2H), 4.54 & 4.50 (dd, J = 5.4, 2.3 Hz, 1H), 4.32 – 4.21 (m, 1H), 4.14 – 4.10 (m, 1H), 3.70 – 3.40 (m, 4H), 3.29 & 3.26 (d, J = 2.0 Hz, 1H), 3.20 – 3.08 (m, 1H), 2.10 – 1.80 (m, 3.5H), 1.67 – 1.57 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.3, -109.4. MS (ESI ⁺ ): [M+H] ⁺ 439.1/441.1/443.1. [0259] (2-chloro-4-fluoro-phenyl)-[8-(3-chloro-2-hydroxy-phenyl)-3, 8- diazabicyclo[3.2.1]octan-3-yl]methanone (I-094)

To a solution of I-093 (1.60g, 3.64mmol, 1 equiv.) in DCM (18mL) at RT, was added CF3CO2H (5.6mL, 73mmol, 20 equiv.). The mixture was stirred at RT for 3h. It was concentrated under reduced pressure and the residue was azeotroped with toluene. The residue was purified by FC (cHex/EtOAc = 95/5 to 50/50) to afford 1.47g of I-094 (99%) as a white foam. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.39 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.27 – 7.14 (m, 1.5H), 7.14 – 7.00 (m, 2H), 6.85 – 6.75 (m, 2H), 5.63 (br s, 1H), 4.66 – 4.54 (m, 1H), 4.07 – 4.00 (m, 1H), 3.88 – 3.74 (m, 1H), 3.73 – 3.48 (m, 1H), 3.35 & 3.32 (s, 1H), 3.26 – 3.15 (m, 1H), 2.20 – 1.90 (m, 3.5H), 1.75 – 1.65 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.1, -109.2. MS (ESI ⁺ ): [M+H] ⁺ 395.0/397.0/399.0. [0260] 3-chloro-5-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3 .2.1]octan-8-yl]- 4-hydroxy-benzenesulfonyl chloride (I-095) According to GP-3, I-095 was obtained as a beige solid in 97% yield using I-094 (735mg, 1.77mmol, 1 equiv.) and HSO ₃ Cl (2.9mL, 44mmol, 20 equiv.) in DCM (7mL) at reflux for 4h. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.75 (d, J = 2.1 Hz, 1H), 7.40 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.38 – 7.32 (m, 1H), 7.27 – 7.16 (m, 1.5H), 7.16 – 7.03 (m, 1H), 4.70 – 4.53 (m, 1H), 4.33 – 4.15 (m, 1H), 3.97 (s, 1H), 3.71 – 3.48 (m, 1H), 3.41 – 3.17 (m, 2H), 2.30 – 1.89 (m, 3.5H), 1.80 – 1.70 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.7, -108.8. Synthesis of intermediates required for final product 110 [0261] (2-chloro-4-fluoro-phenyl)-[(3S)-4-[3-chloro-2-(methoxymetho xy)phenyl]-3- methyl-piperazin-1-yl]methanone ((S)-I-096) According to GP-5, (S)-I-096 was obtained as a white foam in 4% yield using aryl bromide I-092 (0.41g, 1.63mmol, 1 equiv.), piperazine (S)-I-003 (502mg, 1.96mmol, 1.2 equiv.), Cs ₂ CO ₃ (4.66g, 4.89mmol, 3 equiv.), Pd(OAc) ₂ (36.6mg, 163µmol, 0.1 equiv.) and rac-BINAP (122mg, 196µmol, 0.12 equiv.) in toluene (8.2mL) at reflux for 6h. Purification by FC (cHex/EtOAc = 94/6 to 40/60) and PTLC (cHex/EtOAc = 70/30). ¹ H NMR (400 MHz, Chloroform-d, multiple sets of rotamers) δ 7.27 – 7.20 (m, 1H), 7.16 – 6.88 (m, 4H), 6.88 – 6.73 (m, 1H), 5.26 – 5.18 (m, 2H), 5.17 – 5.10 (m, 1H), 4.17 – 3.81 (m, 1H), 3.80 – 3.50 (m, 4H), 3.48 – 2.95 (m, 3H), 2.87 – 2.50 (m, 1H), 1.02 – 0.70 (m, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d, multiple sets of rotamers) δ -109.17, -109.20, - 109.24, -109.27. MS (ESI ⁺ ): [M+H] ⁺ 427.0/429.0/431.0. [0262] (2-chloro-4-fluoro-phenyl)-[(3S)-4-(3-chloro-2-hydroxy-pheny l)-3-methyl- piperazin-1-yl]methanone ((S)-I-097) To a solution of (S)-I-096 (26mg, 61µmol, 1 equiv.) in DCM (0.3mL) at RT, was added CF ₃ CO ₂ H (90µL, 1.2mol, 20 equiv.). The mixture was stirred at RT for 2h. It was concentrated under reduced pressure and the residue was azeotroped with toluene. The residue was purified by FC (cHex/EtOAc = 95/5 to 50/50) to afford 22mg of (S)-I-097 (94%) as a white foam. ¹ H NMR (400 MHz, Chloroform-d, multiple sets of rotamers) δ 7.56 – 7.19 (m, 2H), 7.15 – 7.07 (m, 2H), 7.05 – 6.90 (m, 2H), 6.80 – 6.72 (m, 1H), 4.83 – 4.54 (m, 1H), 3.45 – 2.50 (m, 6H), 0.90 – 0.60 (m, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d, multiple sets of rotamers) δ -108.87, -108.88, -108.93, -108.96. MS (ESI ⁺ ): [M+H] ⁺ 383.0/385.0/387.0. [0263] 3-chloro-5-[(2S)-4-(2-chloro-4-fluoro-benzoyl)-2-methyl-pipe razin-1-yl]-4- hydroxy-benzenesulfonyl chloride ((S)-I-098) According to GP-3, (S)-I-098 was obtained as a beige solid in 90% yield using (S)-I-097 (22mg, 57µmol, 1 equiv.) and HSO3Cl (0.10mL, 1.4mmol, 20 equiv.) in DCM (0.3mL) at reflux for 4h. ¹ H NMR (400 MHz, Chloroform-d, multiple sets of rotamers) δ 7.90 – 7.86 (m, 1H), 7.66 – 7.62 (m, 1H), 7.36 – 7.08 (m, 3H), 7.08 – 6.98 (m, 1H), 4.82 – 4.54 (m, 1H), 3.50 – 2.72 (m, 6H), 0.95 – 0.65 (m, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d, multiple sets of rotamers) δ -108.40, -108.46, -108.49, -108.53. Synthesis of intermediates required for final product 111 [0264] 3-chloro-5-[(2R)-4-(2-chloro-4-fluoro-benzoyl)-2-methyl-pipe razin-1-yl]-4- hydroxy-benzenesulfonyl chloride ((R)-I-098) (R)-I-098 was obtained using the same synthetic sequence than the one used for (S)-I- 098 starting from (R)-I-003. ¹ H NMR (400 MHz, Chloroform-d, multiple sets of rotamers) δ 7.90 – 7.86 (m, 1H), 7.66 – 7.62 (m, 1H), 7.36 – 7.08 (m, 3H), 7.08 – 6.98 (m, 1H), 4.82 – 4.54 (m, 1H), 3.50 – 2.72 (m, 6H), 0.95 – 0.65 (m, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d, multiple sets of rotamers) δ -108.40, -108.46, -108.49, -108.53. Synthesis of intermediate required for final product 115 [0265] 3-bromo-4-chloro-N-methyl-N-propyl-benzenesulfonamide (I-099) According to GP-4, I-099 was obtained as a white solid in 89% yield using commercial 3-bromo-4-chlorobenzenesulfonyl chloride (300mg, 1.03mmol, 1 equiv.), methyl-N- propylamine (120µL, 1.14mmol, 1.1 equiv.) and Et ₃ N (216µL, 2.55mmol, 1.5 equiv.) in DCM (5mL) at RT for 16h. ¹ H NMR (400 MHz, Chloroform-d) δ 8.04 (d, J = 2.0 Hz, 1H), 7.66 (dd, J = 8.4, 2.0 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 3.00 (dd, J = 7.9, 6.6 Hz, 2H), 2.76 (s, 3H), 1.59 (h, J = 7.3 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). MS (ESI ⁺ ): [M+H] ⁺ 326.0/328.0/329.9. Synthesis of intermediate required for final product 116 [0266] 1-(3-bromo-4-methyl-phenyl)sulfonyl-4-[2-(4-fluorophenyl)eth yl]piperazine (I- 100) According to GP-4, I-100 was obtained as a white solid in 88% yield using commercial 3-bromo-4-methylbenzenesulfonyl chloride (200mg, 742µmol, 1 equiv.), 1-[2-(4- fluorophenyl)ethyl]piperazine dihydrochloride (229mg, 0.816mmol, 1.1 equiv.) and Et3N (0.52mL, 3.7mmol, 5 equiv.) in DCM (4mL) at RT for 16h. Purification by FC (cHex/EtOAc = 97/3 to 70/30). ¹ H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J = 1.8 Hz, 1H), 7.59 (dd, J = 8.0, 1.9 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.16 – 7.06 (m, 2H), 7.02 – 6.90 (m, 2H), 3.06 (t, J = 4.8 Hz, 4H), 2.75 – 2.68 (m, 2H), 2.66 – 2.52 (m, 6H), 2.48 (s, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -117.0. MS (ESI ⁺ ): [M+H] ⁺ 440.9/442.9. Synthesis of intermediates required for final products 117 [0267] [8-(1,3-benzodioxol-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl] -(2-chloro-4- fluoro-phenyl)methanone (I-101) According to GP-7, I-101 was obtained as a white solid in 90% yield using 4-bromo-1,3- benzodioxole (400mg, 1.99mmol, 1 equiv.), piperazine I-001 (642mg, 2.39mmol, 1.2 equiv.), t-BuONa (574mg, 5.97mmol, 3 equiv.) and XPhos-Pd-G3 (168mg, 199µmol, 0.1 equiv.) in toluene (10mL) at reflux for 2h. Purification by FC (cHex/EtOAc = 95/5 to 0/100). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.36 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.23 – 6.95 (m, 2.5H), 6.77 (t, J = 8.1 Hz, 1H), 6.46 – 6.33 (m, 2H), 5.90 – 5.84 (m, 2H), 4.46 – 4.35 (m, 2H), 4.26 – 4.20 (m, 1H), 3.66 – 3.43 (m, 1H), 3.33 – 3.25 (m, 1H), 3.06 – 2.95 (m, 1H), 2.12 – 1.87 (m, 3.5H), 1.66 – 1.58 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.4, -109.5. MS (ESI ⁺ ): [M+H] ⁺ 389.1/391.1. [0268] 7-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octa n-8-yl]-1,3- benzodioxole-5-sulfonyl chloride (I-102)

According to GP-3, I-102 was obtained as a beige solid in 50% yield using I-101 (100mg, 0.257mmol, 1 equiv.) and HSO ₃ Cl (0.34mL, 5.1mmol, 20 equiv.) in DCM (1.3mL) at RT for 1h. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.40 – 7.33 (m, 0.5H), 7.27 – 7.08 (m, 2.5H), 7.06 – 7.00 (m, 2H), 6.11 – 6.05 (m, 2H), 4.55 – 4.41 (m, 2H), 4.26 (s, 1H), 3.63 – 3.38 (m, 1H), 3.26 – 3.03 (m, 2H), 2.15 – 1.90 (m, 3.5H), 1.80 – 1.60 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.9, -109.0. Synthesis of intermediate required for final product 118 [0269] 1-[(5-bromo-2,3-dihydro-1,4-benzodioxin-7-yl)sulfonyl]-4-phe nyl-piperidine (I- 103) According to GP-4, I-103 was obtained as a white solid in 93% yield using 8-bromo-2,3- dihydro-1,4-benzodioxine-6-sulfonyl chloride (75mg, 0.27mmol, 1 equiv.), 4- phenylpiperidine (46mg, 0.29mmol, 1.2 equiv.) and Et3N (100µL, 0.718mmol, 3 equiv.) in DCM (1.2mL) at RT for 1h. ¹ H NMR (400 MHz, Chloroform-d) δ 7.56 (d, J = 2.1 Hz, 1H), 7.33 – 7.27 (m, 3H), 7.24 – 7.19 (m, 1H), 7.17 – 7.13 (m, 2H), 4.48 – 4.30 (m, 4H), 3.91 (dp, J = 11.3, 1.8 Hz, 2H), 2.51 – 2.32 (m, 3H), 1.96 – 1.79 (m, 4H). MS (ESI ⁺ ): [M+H] ⁺ 438.0/439.9. Synthesis of intermediates required for final product 119 & 120 [0270] 1-[5-[(4-phenyl-1-piperidyl)sulfonyl]indolin-1-yl]ethanone (I-104) According to GP-4, I-104 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). ¹ H 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. [0271] 5-[(4-phenyl-1-piperidyl)sulfonyl]indoline (I-105) To a solution of I-104 (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 (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to afford 315mg of I-105 (88%) as a light brown solid. ¹ H 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. [0272] 1-methyl-5-[(4-phenyl-1-piperidyl)sulfonyl]indoline (I-106) To a solution of I-105 (530mg, 1.39mmol, 1 equiv.) in DMF (5.6mL) at 0°C, was added NaH (60% in mineral oil, 84mg, 2.1mmol, 1.5 equiv.). The mixture was stirred at RT for 30min and iodomethane (0.13mL, 2.09mmol, 1.5 equiv.) was added. The resulting mixture was stirred at RT for 16h. Sat. aq. NH4Cl and EtOAc were added. The layers were added and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/DCM (70/30)/EtOAc = 98/2 to 80/20) to afford 333mg of I-106 (67%) as a white solid. ¹ H NMR (400 MHz, Chloroform- d) δ 7.54 (dd, J = 8.3, 1.9 Hz, 1H), 7.44 – 7.40 (m, 1H), 7.37 – 7.28 (m, 2H), 7.26 – 7.11 (m, 3H), 6.43 (d, J = 8.3 Hz, 1H), 3.95 – 3.86 (m, 2H), 3.54 (t, J = 8.5 Hz, 2H), 3.06 (t, J = 8.4 Hz, 2H), 2.88 (s, 3H), 2.50 – 2.30 (m, 3H), 1.99 – 1.76 (m, 4H). MS (ESI ⁺ ): [M+H] ⁺ 357.1. [0273] 7-bromo-1-methyl-5-[(4-phenyl-1-piperidyl)sulfonyl]indoline (I-107) To a solution of I-106 (333mg, 0.831mmol, 1 equiv.) in DMF (8.3mL) at 0°C, was added N-bromosuccinimide (237mg, 1.33mmol, 1.6 equiv.). The mixture was stirred at RT for 2h. Water 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 (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc = 97/3 to 70/30) to afford 341mg of I-107 (90%) as a white solid. ¹ H NMR (400 MHz, Benzene-d6) δ 7.95 (d, J = 1.8 Hz, 1H), 7.33 – 7.28 (m, 1H), 7.14 – 7.08 (m, 2H), 7.08 – 7.00 (m, 1H), 6.91 – 6.86 (m, 2H), 3.80 (dq, J = 11.4, 2.1 Hz, 2H), 2.77 – 2.70 (m, 5H), 2.32 (t, J = 8.8 Hz, 2H), 1.99 (td, J = 11.9, 2.6 Hz, 2H), 1.90 – 1.80 (m, 1H), 1.62 – 1.43 (m, 2H), 1.42 – 1.31 (m, 2H). MS (ESI ⁺ ): [M+H] ⁺ 433.0/435.0. Synthesis of intermediate required for final product 121 [0274] 1-(3-bromo-4-fluoro-phenyl)sulfonyl-4-phenyl-piperidine (I-108) According to GP-4, I-108 was obtained as a white solid in 100% yield using commercial 3-bromo-4-fluorobenzenesulfonyl chloride (500mg, 1.83mmol, 1 equiv.), 4- phenylpiperidine (442mg, 2.74mmol, 1.5 equiv.) and Et ₃ N (510µL, 3.66mmol, 2 equiv.) in DCM (7.3mL) at RT for 2h. ¹ H NMR (400 MHz, Chloroform-d) δ 8.05 (dd, J = 6.3, 2.2 Hz, 1H), 7.77 (ddd, J = 8.6, 4.5, 2.2 Hz, 1H), 7.37 – 7.29 (m, 3H), 7.27 – 7.21 (m, 1H), 7.21 – 7.13 (m, 2H), 4.06 – 3.89 (m, 2H), 2.58 – 2.35 (m, 3H), 2.01 – 1.81 (m, 4H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -99.4. MS (ESI ⁺ ): [M+H] ⁺ 398.0/399.9. [0275] 2-bromo-N,N-dimethyl-4-[(4-phenyl-1-piperidyl)sulfonyl]anili ne (I-109)

A mixture of I-108 (725mg, 1.82mmol, 1 equiv) and dimethylamine (2M solution in THF, 4.55mL, 9.10mmol, 5 equiv.) was stirred at 50°C for 18h. 1N NaOH 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 to afford 685mg of I-109 (89%) as a beige solid. ¹ H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J = 2.2 Hz, 1H), 7.68 (dd, J = 8.5, 2.2 Hz, 1H), 7.36 – 7.29 (m, 2H), 7.27 – 7.20 (m, 1H), 7.20 – 7.08 (m, 3H), 4.00 – 3.90 (m, 2H), 2.95 (s, 6H), 2.54 – 2.33 (m, 3H), 1.98 – 1.78 (m, 4H). MS (ESI ⁺ ): [M+H] ⁺ 423.1/425.0. Synthesis of intermediates required for final product 122 [0276] benzyl 8-[2-fluoro-5-[(4-phenyl-1-piperidyl)sulfonyl]phenyl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (I-110) According to GP-5, I-110 was obtained as a white foam in 64% yield using aryl bromide I-108 (0.40g, 1.0mmol, 1.2 equiv.), benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (205mg, 0.832mmol, 1 equiv.), Cs2CO3 (542mg, 1.66mmol, 2 equiv.), Pd(OAc)2 (19mg, 83µmol, 0.1 equiv.) and rac-BINAP (77.7mg, 125µmol, 0.15 equiv.) in toluene (4.2mL) at reflux for 16h. Purification by FC (cHex/EtOAc = 90/10 to 50/50). ¹ H NMR (400 MHz, Chloroform-d, multiple sets of rotamers) δ 7.39 – 7.27 (m, 7H), 7.25 – 7.12 (m, 6H), 5.15 (s, 2H), 4.30 – 4.17 (m, 2H), 3.96 – 3.87 (m, 3H), 3.86 – 3.80 (m, 1H), 3.38 – 3.23 (m, 2H), 2.50 – 2.33 (m, 3H), 2.06 – 1.76 (m, 8H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -115.9. MS (ESI ⁺ ): [M+H] ⁺ 564.2. [0277] benzyl 8-[2-(dimethylamino)-5-[(4-phenyl-1-piperidyl)sulfonyl]pheny l]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (I-111) g , Molecular Formula: C ₃₃ H ₄₀ N ₄ O ₄ S To a solution of I-110 (136mg, 0.241mmol, 1 equiv.) in NMP (4.8mL) at RT, were added dimethylamine hydrochloride (393mg, 4.82mmol, 20 equiv.) and iPr2NEt (840µL, 1.82mmol, 20 equiv.). The mixture was stirred at 150°C under MW irradiation for 40h. 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 (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was dissolved in DCM (1mL) and Et3N (67µL, 0.48mmol, 2 equiv.) and CbzCl (34µL, 0.24mmol, 1 equiv.) were added. The mixture was stirred at RT for 16h. The mixture was concentrated under reduced pressure and the residue was purified by FC (cHex/EtOAc = 95/5 to 50/50) to afford 127mg of I-111 (89%) as a white solid. ¹ H NMR (400 MHz, Chloroform-d) δ 7.42 – 7.27 (m, 8H), 7.25 – 7.11 (m, 4H), 6.98 (d, J = 8.4 Hz, 1H), 5.15 (s, 2H), 4.36 – 4.22 (m, 2H), 3.98 – 3.80 (m, 4H), 3.38 – 3.22 (m, 2H), 2.85 (s, 6H), 2.49 – 2.33 (m, 3H), 1.99 – 1.76 (m, 8H). MS (ESI ⁺ ): [M+H] ⁺ 589.4. Synthesis of intermediates required for final product 123 [0278] tert-butyl N-[1-[2-bromo-4-[(4-phenyl-1-piperidyl)sulfonyl]phenyl]azeti din-3- yl]-N-methyl-carbamate (I-112) A mixture of I-108 (200mg, 0.502mmol, 1 equiv), tert-butyl azetidin-3- yl(methyl)carbamate hydrochloride (335mg, 1.50mmol, 3 equiv.) and K2CO3 (386mg, 3.12mmol, 6 equiv.) in dry DMF (2mL) was stirred at 80°C for 48h. 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 (cHex/EtOAc = 100/0 to 0/100 to afford 166mg of I-112 (59%) as a yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 7.81 (d, J = 2.1 Hz, 1H), 7.56 (dd, J = 8.6, 2.1 Hz, 1H), 7.33 – 7.27 (m, 2H), 7.24 – 7.13 (m, 3H), 6.50 (d, J = 8.6 Hz, 1H), 5.08 – 4.77 (br s, 1H), 4.48 (t, J = 8.3 Hz, 2H), 4.17 (dd, J = 8.7, 6.0 Hz, 2H), 3.98 – 3.86 (m, 2H), 2.96 (s, 3H), 2.48 – 2.32 (m, 3H), 1.96 – 1.78 (m, 4H), 1.48 (s, 9H). MS (ESI ⁺ ): [M+H] ⁺ 564.2/566.0. [0279] tert-butyl N-[1-[2-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2. 1]octan- 8-yl]-4-[(4-phenyl-1-piperidyl)sulfonyl]phenyl]azetidin-3-yl ]-N-methyl-carbamate (I- 113) Molecular Formula: C ₃₉ H ₄₇ ClFN ₅ O ₅ S According to GP-5, I-113 was obtained as a white foam in 50% yield using aryl bromide I-112 (73.0mg, 129µmol, 1 equiv.), piperazine I-001 (52.1mg, 194µmol, 1.5 equiv.), Cs2CO3 (126mg, 0.388mmol, 3 equiv.), Pd(OAc)2 (2.9mg, 13µmol, 0.1 equiv.) and rac-BINAP (9.7mg, 15µmol, 0.12 equiv.) in toluene (0.7mL) at reflux for 16h. Purification by FC (cHex/EtOAc = 95/5 to 50/50). ¹ H NMR (400 MHz, Chloroform-d, multiple sets of rotamers) δ 7.40 – 7.27 (m, 3.5H), 7.23 – 7.02 (m, 6.5H), 6.61 (d, J = 8.4 Hz, 1H), 4.90 (br s, 1H), 4.60 – 4.40 (m, 1H), 4.26 – 4.18 (m, 2H), 3.95 – 3.80 (m, 5H), 3.70 – 3.45 (m, 2H), 3.36 – 3.10 (m, 2H), 3.00 – 2.89 (m, 3H), 2.50 – 2.25 (m, 3H), 2.01 – 1.75 (m, 7.5H), 1.65 – 1.58 (m, 0.5H), 1.48 (s, 9H). MS (ESI ⁺ ): [M+H] ⁺ 752.0/754.0. Synthesis of intermediates required for final product 124 [0280] 3,5-dibromo-4-methyl-benzenesulfonyl chloride (I-114) To a solution of CuCl (45mg, 0.45mmol, 0.12 equiv.) in water (13mL) at 0°C, was added dropwise thionyl chloride (2.2mL, 30mmol, 8 equiv.). The mixture was stirred at RT for 16h. In the meantime, to a solution of 3,5-dibromo-4-methylaniline (1.00g, 3.77mmol, 1 equiv.) in water (50mL) at 0°C, were added 37% HCl (14mL) and a solution of NaNO2 (286mg, 4.15mmol, 1.1 equiv.) in water (13mL). The mixture was stirred at 0°C for 30min. The first solution was then added dropwise and the resulting mixture was vigorously stirred at RT for 2h. It was filtered over fritted glass and the filter cake was washed with water. The filter cake was dissolved using DCM and the resulting wet organic solution was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to afford 1.09g (82%) of I-114 as an orange solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.16 (s, 2H), 2.69 (s, 3H). [0281] 1-(3,5-dibromo-4-methyl-phenyl)sulfonyl-4-phenyl-piperidine (I-115)

According to GP-4, I-115 was obtained as a beige solid in 62% yield using I-114 (1.08g, 3.10mmol, 1 equiv.), 4-phenylpiperidine (600mg, 3.72mmol, 1.2 equiv.) and iPr ₂ NEt (0.81mL, 4.7mmol, 1.5 equiv.) in DCM (15mL) at RT for 1h. Purification by FC (cHex/EtOAc = 95/5 to 50/50). ¹ H NMR (400 MHz, Chloroform-d) δ 7.94 (s, 2H), 7.37 – 7.30 (m, 2H), 7.27 – 7.21 (m, 1H), 7.20 – 7.14 (m, 2H), 4.05 – 3.89 (m, 2H), 2.68 (s, 3H), 2.57 – 2.41 (m, 3H), 2.00 – 1.79 (m, 4H). MS (ESI ⁺ ): [M+H] ⁺ 471.9/473.8/475.8. [0282] 3-bromo-2-methyl-5-[(4-phenyl-1-piperidyl)sulfonyl]phenol (I-116) A MW was charged with I-115 (573mg, 1.21mmol, 1 equiv.), KOAc (356mg, 3.63mmol, 3 equiv.), PdCl2(dppf).CH2Cl2 complex (99mg, 0.12mmol, 0.1 equiv.) and B2pin2 (277mg, 1.09mmol, 0.9 equiv.). The vial was purged with Ar and degassed 1,4-dioxane (6.1mL) was added. The mixture was stirred at 80°C for 16h. The mixture was partitioned between EtOAc and water. The organic phase was washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in acetone (6mL) at RT and a solution of oxone (968mg, 1.57mmol, 1.3 equiv.) in water (4mL) was added. The mixture was stirred at RT for 20min. Aq. Na ₂ S ₂ O ₅ and EtOAc were added. 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 (cHex/EtOAc = 97/3 to 70/30) to afford 100mg of I-116 (20% over two steps) as an orange solid. ¹ H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J = 1.7 Hz, 1H), 7.34 – 7.27 (m, 2H), 7.24 – 7.12 (m, 4H), 5.77 (s, 1H), 3.90 (d, J = 11.6 Hz, 2H), 2.53 – 2.34 (m, 3H), 1.96 – 1.76 (m, 4H), 1.43 (s, 3H). MS (ESI ⁺ ): [M+H] ⁺ 410.0/412.0. [0283] 1-[3-bromo-5-(methoxymethoxy)-4-methyl-phenyl]sulfonyl-4-phe nyl-piperidine (I-117) To a solution of phenol I-116 (100mg, 0.243mmol, 1 equiv.) and iPr ₂ NEt (64µL, 0.37mmol, 1.5 equiv.) in DCM (1.2mL) at RT, was added chloromethyl methyl ether (22µL, 0.29mmol, 1.2 equiv.). The mixture was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc = 97/3 to 70/30) to afford 72mg of I-117 (65%) as a white solid. ¹ H NMR (400 MHz, Chloroform-d) δ 7.64 (d, J = 1.6 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.33 – 7.27 (m, 2H), 7.24 – 7.18 (m, 1H), 7.17 – 7.11 (m, 2H), 5.26 (s, 2H), 3.99 – 3.89 (m, 2H), 3.49 (s, 3H), 2.51 – 2.38 (m, 6H), 1.96 – 1.77 (m, 4H). MS (ESI ⁺ ): [M+H] ⁺ 454.0.0/455.9. [0284] (2-chloro-4-fluoro-phenyl)-[8-[3-(methoxymethoxy)-2-methyl-5 -[(4-phenyl-1- piperidyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl ]methanone (I-118) According to GP-7, I-118 was obtained as a white solid in 59% yield using aryl bromide I-117 (72mg, 0.16mmol, 1 equiv.), piperazine I-001 (47mg, 0.17mmol, 1.1 equiv.), t- BuONa (46mg, 0.48mmol, 3 equiv.), XPhos-Pd-G3 (13mg, 16µmol, 0.1 equiv.) in toluene (0.8mL) at reflux for 4h. Purification by PTLC (cHex/EtOAc = 70/30). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.45 – 7.27 (m, 2.5H), 7.27 – 7.03 (m, 6.5H), 6.96 (d, J = 7.2 Hz, 1H), 5.27 (s, 2H), 4.65 – 4.55 (m, 1H), 3.98 – 3.88 (m, 3H), 3.75 – 3.48 (m, 5H), 3.40 – 3.29 (m, 1H), 3.30 – 3.20 (m, 1H), 2.51 – 2.28 (m, 6H), 2.04 – 1.77 (m, 7.5H), 1.70 – 1.60 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.2, -109.3. MS (ESI ⁺ ): [M+H] ⁺ 642.2/644.1. Synthesis of intermediates required for final product 125 [0285] 3-bromo-4-cyano-benzenesulfonyl chloride (I-119) Formula Weight: 280,53 Molecular Formula: C ₇ H ₃ BrClNO ₂ S To a solution of CuCl (121mg, 1.22mmol, 0.12 equiv.) in water (34mL) at 0°C, was added dropwise thionyl chloride (5.9mL, 81mmol, 8 equiv.). The mixture was stirred at RT for 14h. In the meantime, to a solution of 4-amino-2-bromobenzonitrile (2.00g, 10.1mmol, 1 equiv.) in water (130mL) at 0°C, were added 37% HCl (37mL) and a solution of NaNO2 (770mg, 11.2mmol, 1.1 equiv.) in water (34mL). The mixture was stirred at 0°C for 30min. The first solution was then added dropwise and the resulting mixture was vigorously stirred at RT for 1h. It was filtered over fritted glass and the filter cake was washed with water. The filter cake was dissolved using DCM and the resulting wet organic solution was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to afford 2.5g (88%) of I-119 as an orange solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.16 δ 7.67 (d, J = 1.8 Hz, 1H), 7.42 (dd, J = 8.3, 1.9 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H). [0286] 2-bromo-4-[(4-phenyl-1-piperidyl)sulfonyl]benzonitrile (I-120) Formula Weight: 405,31 Molecular Formula: C ₁₈ H ₁₇ BrN ₂ O ₂ S According to GP-4, I-120 was obtained as a beige solid in 47% yield using I-119 (2.5g, 8.91mmol, 1 equiv.), 4-phenylpiperidine (2.16g, 13.4mmol, 1.5 equiv.) and Et3N (1.86mL, 13.4mmol, 1.5 equiv.) in DCM (45mL) at RT for 1h. Purification by FC (DCM/EtOAc = 96/4 to 60/40). ¹ H NMR (400 MHz, Chloroform-d) δ 8.11 (dd, J = 1.4, 0.7 Hz, 1H), 7.86 – 7.80 (m, 2H), 7.35 – 7.28 (m, 2H), 7.25 – 7.21 (m, 1H), 7.18 – 7.12 (m, 2H), 4.03 – 3.94 (m, 2H), 2.54 – 2.42 (m, 3H), 1.98 – 1.91 (m, 2H), 1.91 – 1.79 (m, 2H). MS (ESI ⁺ ): [M+H] ⁺ 404.9/406.9. Synthesis of intermediates required for final product 139 [0287] 3-bromo-1-chloro-4-fluoro-2-(methoxymethoxy)benzene (I-121) Formula Weight: 269,5 Molecular Formula: C ₈ H ₇ BrClFO ₂ To a solution of 2-bromo-6-chloro-3-fluorophenol (1.11g, 4.44mmol, 1 equiv.) and iPr2NEt (0.933mL, 5.33mmol, 1.2 equiv.) in DCM (22mL) at RT, was added chloromethyl methyl ether (0.37mL, 4.9mmol, 1.1 equiv.). The mixture was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc = 95/5 to 50/50) to afford 756mg of I-121 (55%) as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ 7.26 (dd, J = 9.0, 5.7 Hz, 1H), 6.83 (dd, J = 9.0, 7.5 Hz, 1H), 5.14 (s, 2H), 3.64 (s, 3H). ¹⁹ F NMR (376 MHz, Chloroform-d) δ -104.5. [0288] [8-[3-chloro-6-fluoro-2-(methoxymethoxy)phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro-phenyl)met hanone (I-122)

According to GP-5, I-122 was obtained as a yello sticky oil in 26% yield using aryl bromide I-121 (756mg, 2.81mmol, 1 equiv.), piperazine I-001 (905mg, 3.37mmol, 1.2 equiv.), Cs ₂ CO ₃ (2.74g, 8.41mmol, 3 equiv.), Pd(OAc) ₂ (63mg, 0.28mmol, 0.1 equiv.) and rac-BINAP (210mg, 337µmol, 0.12 equiv.) in toluene (14mL) at reflux for 16h. Purification by FC (cHex/EtOAc = 97/3 to 70/30). ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 1H NMR (400 MHz, Chloroform-d) δ 7.29 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.16 – 7.06 (m, 1.5H), 7.03 – 6.93 (m, 1H), 6.85 – 6.80 (m, 1H), 6.72 – 6.63 (m, 1H), 5.13 – 5.02 (m, 2H), 4.47 – 4.36 (m, 1H), 4.23 (s, 1H), 4.05 – 3.95 (m, 1H), 3.59 (s, 3H), 3.56 – 3.34 (m, 1H), 3.21 – 3.12 (m, 1H), 3.10 – 3.00 (m, 1H), 2.05 – 1.75 (m, 3.5H), 1.57 (s, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.4, -109.5, - 126.8, 126.9. MS (ESI ⁺ ): [M+H] ⁺ 457.0/459.0. [0289] [8-(3-chloro-6-fluoro-2-hydroxy-phenyl)-3,8-diazabicyclo[3.2 .1]octan-3-yl]-(2- chloro-4-fluoro-phenyl)methanone (I-123) To a solution of I-122 (336mg, 0.735mmol, 1 equiv.) in DCM (3.7mL) at RT, was added HCl (4M solution in dioxane, 3.67mL, 14.7mmol, 20 equiv.). The mixture was stirred at RT for 16h. It was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc = 95/5 to 50/50) to afford 222mg of I-123 (73%) as a white foam. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.30 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.16 – 7.06 (m, 1.5H), 7.05 – 6.95 (m, 1H), 6.95 – 6.87 (m, 1H), 6.68 (br s, 1H), 6.53 – 6.43 (m, 1H), 4.56 – 4.44 (m, 1H), 3.92 – 3.83 (m, 1H), 3.66 – 3.35 (m, 2H), 3.25 – 3.09 (m, 2H), 2.24 – 1.80 (m, 3.5H), 1.65 – 1.55 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -109.2, -109.3, -124.3, -124.5. MS (ESI ⁺ ): [M+H] ⁺ 413.1/415.1. [0290] 5-chloro-3-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3 .2.1]octan-8-yl]- 2-fluoro-4-hydroxy-benzenesulfonyl chloride (I-124) Formula Weight: 511,75 Molecular Formula: C ₁₉ H ₁₅ Cl ₃ F ₂ N ₂ O ₄ S According to GP-3, I-124 was obtained as a beige solid in 89% yield using I-123 (110mg, 0.215mmol, 1 equiv.) in HSO3Cl (0.32mL, 4.8mmol, 20 equiv.) at 50°C for 16h and then at 80°C for 4h. ¹ H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) δ 7.62 & 7.60 (s, 1H), 7.35 – 7.38 (m, 0.5H), 7.18 – 7.07 (m, 1.5H), 7.06 – 6.95 (m, 1H), 4.63 – 4.45 (m, 1H), 4.07 – 3.95 (m, 1H), 3.77 (s, 1H), 3.65 – 3.40 (m, 1H), 3.27 – 3.13 (m, 2H), 2.20 – 1.85 (m, 3.5H), 1.70 – 1.60 (m, 0.5H). ¹⁹ F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) δ -108.6, -108.7, -120.3, -120.5.

Synthesis of final compounds

Synthetic methods for final compounds

[0291] The synthetic protocols for the final compounds are presented on the following Table 2. Table 2

Analytical data for the final compounds

[0292] The analytical data for the final compounds are presented on the following

Table 3.

Table 3

Example 2: Biological activity of the compounds

[0293] The purpose of this experiment was to evaluate the GFRal-RET activity of the compounds 001-139 according to the invention.

Materials and methods [0294] The compounds were tested for their activating activity of Elkl signaling using the previously developed reporter-gene -based system in cells expressing GFRal-RET (MG87 murine fibroblast stably transfected with PathDetect Elk-1, GFRal, and RET) disclosed in Sidorova, Y. A. et al.: “Persephin signaling through GFRal: The potential for the treatment of Parkinson’s disease.” Molecular and Cellular Neuroscience, July 2010, Vol. 44, pp. 223-232. DOI: 10.1016/j. men.2010.03.009. For EC50 determination, a dose-response test was performed using 6 concentrations of each tested compound. Dose-response curves were fitted using the sigmoidal dose-response (variable slope) analysis in GraphPad Prism program (Graph Pad Inc) and EC50 of agonist / activator activity was calculated. Dose-response experiments were all performed in duplicate, two times independently.

Results

[0295] The results are presented on Table 4 below (* means “50 uM > EC50 > lOpM”, ** means “IpM < EC50 < lOpM”, *** means “EC50 < IpM”).

Table 4 [0296] The above results clearly evidence that the tested compounds 001-139 have significant GFRal-RET activity. Thus, the compounds of the invention are useful as neuroprotective and neurorestorative agents. The tested compounds 001-139are well-representing the class of the compounds of formula (I).