Novel sulfonamides and their use as neuroprotective and / or neurorepair agents

Abstract

The present invention relates to compounds of general formula (I) or pharmaceutically acceptable salts and / or solvates thereof. The invention also relates to the use of the compounds according to the invention as neuroprotective and / or neural repair agents, in particular for the treatment of neurological disorders. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to novel polycyclic sulfonamides comprising at least one substituted piperazine and / or bridged piperazine. The compounds of the present invention are useful as neuroprotective and / or neurorestorative agents, in particular for the treatment of neurological disorders. Background Art

[0002] Neurological disorders (NDs) are heterogeneous diseases that affect the autonomic, peripheral, and central nervous systems of the body. Among 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 tumors, pain, and epilepsy have been the most challenging diseases to be addressed. The activity of compounds used to treat the CNS may also be associated with other diseases, such as those of the peripheral nervous system, eyes, spinal cord, and intestinal system.

[0003] It is expected that the incidence of ND will increase dramatically in the 21st century, especially due to the increase in life expectancy and demographic changes. Some of these diseases are characterized by the age-related gradual decline of neurological function. Medically, neurological disorders are an important and common cause of disability-adjusted life years or healthy life years lost due to death or disability in the world. CNS diseases represent the largest and fastest growing therapeutic area of ​​unmet medical needs, which is considered a challenge to global public health and has become a major priority for global health. Adequate neurological diagnosis represents a huge challenge, and patients are more concerned about the development of new and effective treatments to treat pathophysiology or symptoms. Neurological disorders affect millions of people worldwide and cause permanent damage. They are progressive diseases in which symptoms may worsen over time. Although there is usually no definite cure, there is supportive treatment. The purpose of these treatments is mainly to alleviate symptoms and maintain the patient's quality of life for as long as possible.

[0004] Neurons are post-mitotic cells that cannot regenerate. While young neurons have self-healing protective mechanisms that function normally, aging or external or internal insults disrupt them, ultimately leading to neurodegeneration. These external / internal hazards include traumatic injury or excitotoxic compounds, reactive oxygen species (ROS), protein aggregates, and other toxic molecules. Fortunately, cells have intrinsic mechanisms to prevent death by activating recovery mechanisms or promoting regenerative pathways. Dysfunction or insufficiency of these self-healing mechanisms is also seen in neurodegenerative diseases.

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

[0006] The fields of application of these proteins are vast. Preclinical and clinical trials have been conducted to evaluate the role of neurotrophic factors of the GDNF family in the prevention, treatment or management of Parkinson's disease, chronic pain, Alzheimer's disease, amyotrophic lateral sclerosis, neuropathy, depression, stroke, and these proteins have even been proposed as male contraceptives. However, the clinical application of GDNF is hampered by its poor pharmacokinetic properties, its inability to cross the blood-brain barrier and the resulting need for intracranial delivery via stereotactic surgery, its variable biological activity, and its high price.

[0007] Blood-brain barrier penetrating small molecule compounds that target the GDNF receptor complex and mimic the biological effects of GDNF in neurons may be a way to overcome these problems and translate into more effective results in the clinic. The greater tissue penetration of these compounds may promote the survival of all affected neuronal pathways.

[0008] WO 2011 / 070177 A2 (BALTIC TECHNOLOGY DEV LTD) discloses polycyclic compounds for the treatment of neurological disorders. Although these compounds represent a significant improvement at the time, they still have limitations in terms of activity on the GFRα1-RET target, solubility, membrane permeability (PAMPA and CaCO2), intrinsic clearance of microsomes and hepatocytes, plasma protein binding and pharmacokinetic profiles. In particular, these compounds have limitations in terms of activity on the GFRα1-RET target (as demonstrated, for example, in luciferase assays).

[0009] Applicants have surprisingly discovered that the novel polycyclic sulfonamides of formula (I) exhibit potent GFRα1-RET activity in a luciferase assay, thus opening a way to overcome the limitations of existing therapeutic options. Summary of the invention

[0010] The present invention is directed to compounds of formula (I)

[0011]

[0012] or a pharmaceutically acceptable salt and / or solvate thereof;

[0013] Among them, W, R A To R D , R 1 To R 4 , Z, R 5 To R 7 and R E As defined below and / or in the claims.

[0014] According to one embodiment, the compound is selected from the compounds of Table 1 herein and pharmaceutically acceptable salts and / or solvates thereof.

[0015] Another object of the invention is a pharmaceutical composition comprising a compound according to the invention and at least one pharmaceutically acceptable carrier.

[0016] Another object of the 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.

[0017] Another object of the present invention is a process for preparing the compounds according to the invention.

[0018] definition

[0019] In the present invention, the following terms have the following meanings:

[0020] Chemical Definition

[0021] When a chemical substituent is a combination of chemical groups, the point of attachment of the substituent to the molecule is at the last chemical group to the right of the substituent name. For example, an arylalkyl substituent is attached to the rest of the molecule through the alkyl portion and can be represented as follows: "aryl-alkyl-".

[0022] Unless otherwise stated, the compounds are named using BIOVIA Draw 2021 (Dassault, France).

[0023] Definitions herein relating to optional or mandatory substitution of a particular group apply to the group considered as such substituted and to the same group contained in another chemical moiety, which may be substituted as described herein. For example, "R xrepresents hydrogen, (C1 to C8)alkyl, (C1 to C8)alkyl-O- or cycloalkyl-(C1 to C8)alkyl-NH-; wherein the alkyl group is optionally substituted with at least one F" refers to the presence of x Any alkyl group in the structure may be optionally substituted with at least one F, including the (C1 to C8)alkyl itself (e.g., CF3), the alkyl group contained in the (C1 to C8)alkyl-O- (e.g., OCF3), and the alkyl group contained in the cycloalkyl-(C1 to C8)alkyl-NH- (e.g., cyclopropyl-CH2-CHF-CH2-NH-).

[0024] "Alkoxy" refers to an alkyl-O- group.

[0025] "Alkyl" refers to a saturated straight or branched hydrocarbon chain, which generally contains 1 to 16 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, and even more preferably 1 to 6 carbon atoms. Alkyl can be monovalent or polyvalent (i.e., "alkyl" includes "alkylene" groups in the definition, which are divalent alkyl groups). Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl and isomers thereof (e.g., n-pentyl, isopentyl) and hexyl and isomers thereof (e.g., n-hexyl, isohexyl). Special examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl (including methylene, ethylene, n-propylene, n-butylene and n-butylene).

[0026] "Amine" refers to a derivative of ammonia (NH3) in which one or more hydrogen atoms have been replaced with a substituent such as an alkyl or aryl group. "Amino" refers to a -NH2 group.

[0027] "Aryl" refers to a cyclic polyunsaturated aromatic hydrocarbon group, which includes at least one aromatic ring and includes 5 to 12 carbon atoms, preferably 6 to 10 carbon atoms. Aryl can be monovalent or polyvalent (e.g., divalent). Aryl can have a monocyclic ring (e.g., phenyl) or multiple aromatic rings fused together (e.g., naphthyl) or multiple aromatic rings covalently linked. The aromatic ring may optionally include one to two other rings fused thereto (cycloalkyl, heterocycloalkyl, or heteroaryl). This definition of "aryl" includes partially hydrogenated derivatives of the carbocyclic ring systems listed herein, as long as at least one ring is an aromatic ring. Aryl may optionally be substituted with at least one group, such as halogen (e.g., F or Cl), (C1 to C8) alkyl (e.g., methyl) or nitrile (CN). Non-limiting examples of aryl groups include phenyl, biphenyl, biphenylenyl, 5-tetrahydronaphthyl or 6-tetrahydronaphthyl, naphth-1-yl or naphth-2-yl, 4-indenyl, 5-indenyl, 6-indenyl or 7-indenyl, 1-acenaphthyl, 2-acenaphthyl, 3-acenaphthyl, 4-acenaphthyl or 5-acenaphthyl, 3-acenaphthyl, 4-acenaphthyl or 5-acenaphthyl. 5-acenaphthenyl, 1-pentalenyl or 2-pentalenyl, 4-indanyl or 5-indanyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 7-tetrahydronaphthyl or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and 1-, 2-, 3-, 4- or 5-pyrenyl. A particular example of aryl is phenyl.

[0028] "Benzal" refers to a phenyl group attached to a moiety via an exo-carbon-carbon double bond, ie, =CH-Ph, bonded to a carbon atom. The moiety is typically cyclic, such as a heterocycloalkyl group.

[0029] "Cycloalkyl" refers to a cyclic alkyl group, which generally contains 3 to 15 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and even more preferably 3 to 6 carbon atoms. Cycloalkyl groups can be monovalent or polyvalent (e.g., divalent). This definition of "cycloalkyl" includes polycyclic cycloalkyl groups (e.g., bicyclic) and bridged cycloalkyl structures, including rings bonded together by one atom ("spirocycle") or by two atoms. This definition of "cycloalkyl" includes cycloalkyl groups, which contain cyclic alkyl groups substituted with at least one non-cyclic alkyl group, such as (C1 to C8) alkyl (preferably (C1 to C4) alkyl, such as methyl). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, adamantyl, bicyclo[2.2.2]octyl, bicyclo[4.4.0]decyl, bicyclo[3.2.1]octyl, bicyclo[3.3.1]nonyl, bicyclo[2.1.1]hexane, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthyl, decahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and octahydropentalenyl.

[0030] According to common terminology in the chemical field, the “C x To C y " or "(C x To C y )" means that the group contains x to y carbon atoms.

[0031] The "halogen" refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0032] "Heteroalkyl" refers to an alkyl group as defined herein, in which one or more carbon atoms are substituted by heteroatoms selected from oxygen, nitrogen and sulfur, and wherein the resulting heteroalkyl group comprises at least one carbon atom. In heteroalkyl groups, heteroatoms along the alkyl chain are bonded only to carbon atoms, i.e., each heteroatom is separated from any other heteroatom by at least one carbon atom, typically at least two carbon atoms. Heteroalkyl groups may be monovalent or polyvalent (e.g., divalent). Nitrogen heteroatoms and sulfur heteroatoms may optionally be oxidized and nitrogen heteroatoms may optionally be quaternized (e.g., sulfur may be oxidized to SO or SO2). Heteroalkyl groups may also comprise one or more than one =O group and / or =S group. In one embodiment, at least two carbon atoms are substituted by heteroatoms. In one embodiment, heteroalkyl groups are bonded to another group or molecule by carbon atoms, i.e., the bonding atom is not selected from the heteroatoms contained therein. In one embodiment, heteroalkyl groups are bonded to another group or molecule by one heteroatom contained therein. Unless otherwise specified, when substituted by one or more than one other group, heteroalkyl groups may be substituted by carbon atoms or by heteroatoms (e.g., nitrogen). Non-limiting examples of heteroalkyl groups include alkoxy groups, ethers and polyethers (eg, polyethylene glycol), secondary and tertiary amines and polyamines, thioethers and polythioethers, and combinations thereof.

[0033] "Heteroaryl" refers to an aromatic ring or aromatic ring system containing 5 to 15 carbon atoms, preferably 4 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, with one or two rings fused together or covalently linked, wherein at least one ring is aromatic, and one or more carbon atoms in one or more rings are substituted with oxygen atoms, nitrogen atoms and / or sulfur atoms. Heteroaryl groups can be monovalent or polyvalent (e.g., divalent). Nitrogen heteroatoms and sulfur heteroatoms can be optionally oxidized and nitrogen heteroatoms can be optionally quaternized (e.g., for sulfur atoms, heteroatoms are substituted with oxo (=O), or for nitrogen atoms, heteroatoms are substituted with oxo (→O)). This definition of "heteroaryl" includes partially hydrogenated derivatives of the carbocyclic ring systems listed herein as well as ring systems containing one or more fused non-aromatic cycloalkyl and / or one or more heterocycloalkyl rings, as long as at least one ring is aromatic. In one embodiment, heteroaryl is bonded to another group or molecule through a carbon atom, i.e., the bonding atom is not selected from the heteroaryl atom contained therein. In one embodiment, heteroaryl is bonded to another group or molecule through a heteroatom contained therein. Unless otherwise indicated, when substituted by one or more than one other group, heteroaryl can be substituted by carbon atom or by heteroatom (e.g., nitrogen). Heteroaryl can be optionally substituted by at least one group, such as halogen (e.g., F or Cl), (C1 to C8) alkyl (preferably (C1 to C4) alkyl, such as methyl) or nitrile (CN).Non-limiting examples of heteroaryl groups include pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, tetrazinyl, imidazo[2,1-b][ 1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thienyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indazolyl , benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazole oxazolyl, thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolyl, isoquinolyl, 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, indolyl, 2,3-dihydrobenzo[b][1,4]dioxolyl, 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]oxathiin.

[0034] "Heteroarylene" refers to a heteroaryl group bonded to a moiety through an exo carbon-carbon double bond, ie, a =CH-heteroaryl bond, to a carbon atom. The moiety is typically cyclic, such as a heterocycloalkyl group.

[0035] "Heterocycloalkyl" refers to a cyclic heteroalkyl group, which generally contains 2 to 15 carbon atoms, preferably 2 to 11 carbon atoms, more preferably 2 to 7 carbon atoms, and even more preferably 2 to 6 carbon atoms. Heterocycloalkyl can be monovalent or polyvalent (e.g., divalent). Heterocycloalkyl is generally 3 to 7 members, preferably 5 or 6 members. Heterocycloalkyl is generally monocyclic or bicyclic, preferably monocyclic. This definition includes polycyclic heterocycloalkyl (e.g., bicyclic) and bridged heterocycloalkyl structures, including rings bonded together by one atom ("spiro") or by two atoms. Nitrogen heteroatoms and sulfur heteroatoms may be optionally oxidized and nitrogen heteroatoms may be optionally quaternized (e.g., for sulfur atoms, heteroatoms are substituted by oxo (=O), or for nitrogen atoms, heteroatoms are substituted by oxo (→O)). In one embodiment, heterocycloalkyl is bonded to another group or molecule through a carbon atom, i.e., the bonding atom is not selected from the heteroaryl atom contained therein. In one embodiment, the heterocycloalkyl is bonded to another group or molecule through a heteroatom contained therein. Unless otherwise indicated, when substituted by one or more than one other group, the heterocycloalkyl may be substituted by a carbon atom or by a heteroatom (e.g., nitrogen). The heterocycloalkyl may optionally be substituted by at least one group, such as halogen (e.g., F or Cl), (C1 to C8) alkyl (preferably (C1 to C4) alkyl, such as methyl), nitrile (CN) or =O. Non-limiting examples of heterocycloalkyl groups include aziridine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, azepane, azacyclooctane, octahydro-1H-isoindole, decahydroisoquinoline, tetrahydrofuran, tetrahydropyran, tetrahydroisoquinoline (e.g., 1,2,3,4-tetrahydroisoquinoline), hexahydropyridazine, hexahydropyrazine, hexahydropyrimidine, decahydroquinoline, octahydropyrrolo[3,4-c]pyrrole, isoindoline, 1,2,3,4-tetrahydroquinoline, and oxetane.

[0036] "Isobutyronitrile" refers to a radical of the formula (NC)(CH3)2C-.

[0037]

[0038] "Prodrug" refers to a pharmaceutically acceptable derivative of a therapeutic agent (e.g., a compound according to the invention), the biotransformation product of which in vivo is a therapeutic agent (active drug). Typically, a prodrug is characterized by increased bioavailability and is easily metabolized to an active compound in vivo. Non-limiting examples of prodrugs include amide prodrugs and carboxylate prodrugs.

[0039] "Solvate" refers to a molecular complex comprising a compound and stoichiometric or substoichiometric amounts of one or more than one molecule of one or more than one solvent, typically a pharmaceutically acceptable solvent such as ethanol. The term "hydrate" refers to a solvate when the solvent is water (H2O).

[0040] "Subunit" refers to a CH group that participates in an exo-carbon-carbon double bond to another moiety. The moiety is typically cyclic, such as a heterocycloalkyl.

[0041] General Definition

[0042] As used herein, "about" means approximately, roughly, about or roughly, or within the above range. The term "about" before a number means the numerical value ± 10%. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the numerical value by 10%.

[0043] "Administering" or variations thereof refers to providing a therapeutic agent, either alone or as part of a pharmaceutically acceptable composition, to a patient whose condition, symptom or disease is to be treated.

[0044] "Includes" or its variants are used herein according to common patent application drafting terms. Therefore, "includes" is preceded by an object and followed by a component, which means that the component is required to be present in the object (usually as a component of a composition), but does not exclude the presence of any other components in the object. In addition, unless otherwise specified, any occurrence of "includes" or its variants herein also includes the narrow expression "essentially consisting of...", the narrower expression "consisting of..." and any variants thereof, and may be replaced by them.

[0045] "GDNF family receptor alpha-1", "GFRα1" or "GDNFRα1", also known as "RET ligand 1" or "neurotrophin receptor associated with TGF-β 1", is a protein in the GDNFR family that is a receptor for GDNF. It mediates GDNF-induced autophosphorylation and activation of the RET receptor. In humans, GFRα1 is encoded by the GFRA1 gene. An exemplary amino acid sequence of human GFRα1 is given in SEQ ID NO: 1, wherein amino acid residue 1 to amino acid residue 24 correspond to the signal peptide and amino acid residue 430 to amino acid residue 465 correspond to the propeptide that is removed in the mature form.

[0046]

[0047] "Human" refers to a male or female human subject at any stage of development, including neonates, infants, adolescents, teenagers, and adults.

[0048] "Neuroprotection" refers to protecting neuronal cells from damage, events or conditions that would normally result in loss of neuronal cell function and ultimately neuronal cell death. These damages, events or conditions include, but are not limited to, neuronal stress, such as neuronal stress caused by hypoxia or ischemia; traumatic injury; and exposure to toxic molecules, such as abnormally misfolded proteins, protein aggregates, excitotoxins, reactive oxygen species, endoplasmic reticulum stressors, mitochondrial stressors, Golgi antagonists, and the like. The term is also characterized by a detectable biological activity of the compound in reducing the amount or level of neuronal cell function loss and / or neuronal cell death.

[0049] "Neural repair" refers to the restoration or rescue of neuronal cells, particularly their function, from insults, events or conditions that would normally result in loss of neuronal cell function or even neuronal cell death.

[0050] A "patient" is a subject who is awaiting or receiving medical treatment, or who has been / is / will be the subject of a medical procedure, or who is being monitored for the development of a target disease or target condition, such as a neurological disorder.

[0051] "Pharmaceutically acceptable" means that the ingredients of the composition are compatible with each other and not deleterious to the subject to which it is administered.

[0052] "Pharmaceutically acceptable carrier" refers to an excipient that does not produce harmful reactions, allergic reactions or other adverse reactions when applied to animals, preferably humans. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents, etc. For application to humans, the preparation should meet the sterility, pyrogenicity, general safety and purity standards required by regulatory agencies such as the FDA office or EMA. Examples of pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum oxide, aluminum 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 silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (such as sodium carboxymethyl cellulose), polyethylene glycol, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0053] A "pharmaceutical composition" refers to a composition comprising at least one therapeutic agent (eg, a compound according to the present invention) and at least one pharmaceutically acceptable carrier.

[0054] "Proto-oncogene tyrosine-protein kinase receptor Ret", or "RET" for short, also known as "cadherin family member 12", is a receptor tyrosine kinase that is involved in a variety of cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation. RET is activated under the following conditions: (i) binding of a neurotrophic factor of the GDNF family (e.g., GDNF, neurturin, artemin, or persephin) to a receptor of the GDNFR family (e.g., GFRα1, GFRα2, GFRα3, or GFRα4), followed by (ii) formation of a complex between RET and a GDNFR family receptor, (iii) dimerization, and (iv) trans-autophosphorylation. An exemplary amino acid sequence of human RET is given in SEQ ID NO: 2, wherein amino acid residues 1 to 28 correspond to a signal peptide.

[0055]

[0056] "Selected from" herein is used according to common patent application drafting terms to introduce a list of elements, wherein one or more items are selected from the list of elements. Any appearance of "selected from" in this specification can be replaced with "selected from a group comprising or consisting of ...", and can be replaced with each other without changing its meaning.

[0057] "Subject" refers to an animal, typically a warm-blooded animal, preferably a mammal, more preferably a primate, and even more preferably a human. In one embodiment, the subject is a "patient" as defined herein. In one embodiment, the subject is affected by a disease, preferably diagnosed with a disease. In one embodiment, the subject is at risk of the disease. Examples of risk factors include, but are not limited to, a genetic predisposition or a family history of a disease.

[0058] "Therapeutic agent," "active pharmaceutical ingredient," and "active ingredient" refer to compounds that are used for therapeutic purposes and are relevant to health. In particular, therapeutic agents (e.g., compounds according to the present invention) may be useful for treating diseases (e.g., neurological disorders). Active ingredients may also be useful for improving the therapeutic activity of another therapeutic agent.

[0059] "Therapeutically effective amount" ("effective amount" for short) refers to an amount of a therapeutic agent (e.g., a compound according to the present invention) sufficient to achieve the desired therapeutic effect, prophylactic effect, or preventive effect in a patient to which it is administered without causing significant negative or harmful side effects to the patient. A therapeutically effective amount may be administered before the onset of a disease to implement preventive or prophylactic actions. Alternatively or additionally, a therapeutically effective amount may be administered after the onset of a disease to implement a therapeutic action.

[0060] "Treatment" or "alleviation" refers to therapeutic treatment as well as prophylactic or preventative measures, wherein the goal is to prevent or slow down (alleviate) a target pathological condition or target disorder (herein, a "disease") (e.g., a neurological disorder). Those in need of treatment include those already suffering from the disease as well as those susceptible to the disease or those in need of prevention of symptoms or disease. 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 invention), the patient shows an observable and / or measurable reduction or absence in one or more of the following aspects: a reduction in the number of pathogens; a reduction in the percentage of pathogenic cells to total cells; and / or a relief to some extent of one or more symptoms associated with a particular disease; a reduction in morbidity and mortality and an improvement in quality of life issues. The above parameters for assessing successful treatment and improvement of the disease can be readily measured by conventional methods familiar to physicians. DETAILED DESCRIPTION

[0061] Compound

[0062] The present invention is directed to compounds of formula (I)

[0063]

[0064] or a pharmaceutically acceptable salt and / or solvate thereof;

[0065] in

[0066] W represents CH or N;

[0067] R A , R B , R C and R D each independently represents hydrogen, F, Cl, CH3, CF3, CHF2 or CH2F, provided that R A , R B , R C and R D At least one of them does not represent hydrogen;

[0068] R 1 represents a (C1 to C8)alkyl group, wherein the alkyl group is optionally substituted with at least one OH, (C1 to C3)alkoxy group or F; and R 2 , R 3 and R 4 represents hydrogen;

[0069] or R 1 and R 4 Together they form -CH2-O-CH2- or -CH2-CH2-, wherein -CH2-CH2- is optionally substituted with at least one F, OH or OCH3; and R 2and R 3 each independently represents hydrogen;

[0070] R 7 represents hydrogen, OH, halogen, (C1 to C8) alkyl, cycloalkyl, (C1 to C8) alkyl-O-, cycloalkyl-O-, cycloalkyl-(C1 to C8) alkyl-O-, heterocycloalkyl-O-, R 11 O-(C1 to C8)alkyl-O-, R 11 R 12 N-(C1 to C8)alkyl-O-, (R 11 O)(R 12 )N-(C1 to C8)alkyl-O-, R 11 R 12 N-(C1 to C8)alkyl-, R 11 O-(C1 to C8)alkyl-, NR 11 R 12 、CN、CO2H、CO2R 11 、CONH2、CON(R 11 )H, heterocycloalkyl or heteroaryl; wherein R 11 and R 12 each independently represents hydrogen or (C1 to C8) alkyl;

[0071] Where R 7 The alkyl or cycloalkyl in is optionally substituted with at least one F, Cl, OH, =O, (C1 to C8)alkyl, (C1 to C8)alkyl-O-, heterocycloalkyl, aryl or heteroaryl;

[0072] wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, (C1 to C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1 to C8) alkoxy, NR 13 R 14 , R 13 R 14 N-(C1 to C8)alkyl-, R 13 O2C-(C1 to C8)alkyl-, CO2H, R 13 R 14 NC(O)-、R 13 O-NR 14 - or (C1 to C8) alkyl-CO2-substituted; wherein R 13 and R 14 each independently represents hydrogen or (C1 to C8) alkyl;

[0073] Z stands for CH, CR 8 or N;

[0074] Where R8 represents (C1 to C4) alkyl, F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH or (C1 to C4) alkoxy;

[0075] or Z for CR 8 And R 7 and R 8 together with the carbon atoms to which they are bound, form a cycloalkyl or heterocycloalkyl group,

[0076] wherein the cycloalkyl or heterocycloalkyl group is optionally substituted by at least one of F, OH, =O, →O, (C1 to C8)alkyl, CF3, HO2C-CH2-, (C1 to C4)alkyl-CO2-CH2-, R 15 R 16 N-CH2-, aryl or aryl-(C1 to C8)alkyl-substituted, wherein R 15 and R 16 each independently represents hydrogen or (C1 to C8) alkyl;

[0077] R 5 represents hydrogen, (C1 to C8)alkyl, CH3 substituted by one to three (C1 to C8)alkyl, cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C1 to C8)alkyl;

[0078] Where R 5 The alkyl or cycloalkyl in the alkyl group is optionally substituted with at least one F, Cl, (C1 to C8) alkyl, CF3, OCF3, CN, OH, =O, (C1 to C8) alkoxy, NR 17 R 18 ,CO2H,R 17 R 18 NC(O)-、R 17 O-NR 18 -, heterocycloalkyl, aryl or heteroaryl; wherein R 17 and R 18 each independently represents hydrogen or (C1 to C8) alkyl;

[0079] Wherein heterocycloalkyl, aryl or heteroaryl (i.e. R 5 any heterocycloalkyl, aryl or heteroaryl represented by or as part of any substituent thereof) is optionally substituted by at least one F, Cl, (C1 to C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1 to C8) alkoxy, NR 19 R 20 ,CO2H,R 19 R 20 NC(O)-、R 19 O-NR 20-, (C1 to C8) alkyl-CO2-, R 19 R 20 N-(C1 to C8)alkyl-, R 19 O2C-(C1 to C8)alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C1 to C8)alkyl-substituted; wherein R 19 and R 20 each independently represents hydrogen or (C1 to C8) alkyl;

[0080] R 6 represents (C1 to C8)alkyl, CH3 substituted by one to three (C1 to C8)alkyl, cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C1 to C8)alkyl;

[0081] Where R 6 The alkyl or cycloalkyl in the alkyl group is optionally substituted with at least one F, Cl, (C1 to C8) alkyl, CF3, OCF3, CN, OH, =O, (C1 to C8) alkoxy, NR 21 R 22 ,CO2H,R 21 R 22 NC(O)-、R 21 O-NR 22 -, heterocycloalkyl, aryl or heteroaryl; wherein R 21 and R 22 each independently represents hydrogen or (C1 to C8) alkyl;

[0082] Wherein heterocycloalkyl, aryl or heteroaryl (i.e. R 6 any heterocycloalkyl, aryl or heteroaryl represented by or as part of any substituent thereof) is optionally substituted by at least one F, Cl, (C1 to C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1 to C8) alkoxy, NR 23 R 24 ,CO2H,R 23 R 24 NC(O)-、R 23 O-NR 24 -, (C1 to C8) alkyl-CO2-, R 23 R 24 N-(C1 to C8)alkyl-, R 23 O2C-(C1 to C8)alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C1 to C8)alkyl-substituted; wherein R 23 and R 24 each independently represents hydrogen or (C1 to C8) alkyl;

[0083] or R 5 and R6 together with the nitrogen atom to which they are bound, form a heterocycloalkyl group,

[0084] Wherein the heterocycloalkyl group (i.e., R 5 , R 6 and the nitrogen atom to which it is bonded) are optionally substituted with at least one F, Cl, (C1 to C8) alkyl, CF3, OCF3, CN, OH, =O, →O, (C1 to C8) alkoxy, NR 25 R 26 、CO2H、(C1 to C8)alkyl-CO2-、R 25 R 26 NC(O)-、R 25 O-NR 26 -、R 25 R 26 N-(C1 to C8)alkyl-, R 25 O2C-(C1 to C8)alkyl-, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1 to C8)alkyl-, heterocycloalkyl-(C1 to C8)alkyl-, aryl-(C1 to C8)alkyl-, heteroaryl-(C1 to C8)alkyl-, aryl-cycloalkyl-, cycloalkyl-O-, heterocycloalkyl-O-, aryl-O-, heteroaryl-O-, cycloalkyl-(C1 to C8)alkyl-O-, heterocycloalkyl-(C1 to C8)alkyl-O-, aryl-(C1 to C8)alkyl-O-, heteroaryl-(C1 to C8)alkyl-O-, cycloalkyl-NR 25 -, heterocycloalkyl-NR 25 -, aryl-NR 25 -, heteroaryl-NR 25 -, cycloalkyl-(C1 to C8)alkyl-NR 25 -, heterocycloalkyl-(C1 to C8)alkyl-NR 25 -, aryl-(C1 to C8)alkyl-NR 25 -, heteroaryl-(C1 to C8)alkyl-NR 25 -, benzylidene, heteroarylene, aryl-(C1 to C8)alkyl-ylidene- or heteroaryl-(C1 to C8)alkyl-ylidene-;

[0085] Where R 25 and R 26 each independently represents hydrogen or (C1 to C8) alkyl;

[0086] wherein heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylene (i.e., R 5 , R 6any heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylene group that is part of any heterocycloalkyl substituent formed by the nitrogen atom to which it is bonded) is optionally substituted by at least one F, Cl, (C1 to C8)alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1 to C8)alkoxy, NR 27 R 28 ,CO2H,R 27 R 28 NC(O)-、R 27 O-NR 28 -, (C1 to C8) alkyl-CO2-, R 27 R 28 N-(C1 to C8)alkyl-, R 27 O2C-(C1 to C8)alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C1 to C8)alkyl-substituted; wherein R 27 and R 28 each independently represents hydrogen or (C1 to C8) alkyl;

[0087] R E represents hydrogen, (C1 to C3) alkyl or halogen.

[0088] Unless otherwise stated, in any of the following embodiments involving specific limitations on the structure of compounds of Formula (I), any alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylene group may independently be optionally substituted as shown herein for Formula (I).

[0089] According to a preferred embodiment, the compound of formula (I) is a compound of formula (I').

[0090]

[0091] or a pharmaceutically acceptable salt and / or solvate thereof;

[0092] in

[0093] W represents CH or N;

[0094] R A , R B , R C and R D each independently represents hydrogen, F, Cl, CH3, CF3, CHF2 or CH2F, provided that R A , R B , R C and R D At least one of them does not represent hydrogen;

[0095] R 1represents a (C1 to C8)alkyl group, wherein the alkyl group is optionally substituted with at least one OH, (C1 to C3)alkoxy group or F; and R 2 , R 3 and R 4 represents hydrogen;

[0096] or R 1 and R 4 Together they form -CH2-O-CH2- or -CH2-CH2-, wherein -CH2-CH2- is optionally substituted with at least one F, OH or OCH3; and R 2 and R 3 each independently represents hydrogen;

[0097] R 7 represents hydrogen, OH, halogen, (C1 to C8) alkyl, cycloalkyl, (C1 to C8) alkyl-O-, cycloalkyl-O-, cycloalkyl-(C1 to C8) alkyl-O-, heterocycloalkyl-O-, R 11 O-(C1 to C8)alkyl-O-, R 11 R 12 N-(C1 to C8)alkyl-O- or (R 11 O)(R 12 )N-(C1 to C8)alkyl-O-; wherein R 11 and R 12 each independently represents hydrogen or (C1 to C8) alkyl;

[0098] wherein the alkyl or cycloalkyl is optionally substituted with at least one F, Cl, heterocycloalkyl, aryl or heteroaryl;

[0099] wherein the heterocycloalkyl, aryl or heteroaryl group is optionally substituted by at least one F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH, (C1 to C8) alkoxy, NR 13 R 14 ,CO2H,R 13 R 14 NC(O)- or R 13 O-NR 14 -substituted; wherein R 13 and R 14 each independently represents hydrogen or (C1 to C8) alkyl;

[0100] Z represents CH or N;

[0101] or Z for CR 8 And R 7 and R 8 together with the carbon atoms to which they are bound, form a cycloalkyl or heterocycloalkyl group,

[0102] wherein the cycloalkyl or heterocycloalkyl group is optionally substituted by at least one of F, OH, CF3, HO2C-CH2-, (C1 to C4)alkyl-CO2-CH2- or R 15 R 16 N-CH2-substituted, where R 15 and R 16 each independently represents hydrogen or (C1 to C8) alkyl;

[0103] R 5 represents hydrogen, (C1 to C8)alkyl, CH3 substituted by one to three (C1 to C8)alkyl, cycloalkyl or cycloalkyl-(C1 to C8)alkyl;

[0104] wherein the alkyl or cycloalkyl group is optionally substituted with at least one F, Cl, CF3, OCF3, CN, OH, (C1 to C8) alkoxy, NR 17 R 18 ,CO2H,R 17 R 18 NC(O)-、R 17 O-NR 18 -, heterocycloalkyl, aryl or heteroaryl; wherein R 17 and R 18 each independently represents hydrogen or (C1 to C8) alkyl;

[0105] wherein the heterocycloalkyl, aryl or heteroaryl group is optionally substituted by at least one F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH, (C1 to C8) alkoxy, NR 19 R 20 ,CO2H,R 19 R 20 NC(O)- or R 19 O-NR 20 -substituted; wherein R 19 and R 20 each independently represents hydrogen or (C1 to C8) alkyl;

[0106] R 6 represents (C1 to C8)alkyl, CH3 substituted by one to three (C1 to C8)alkyl, cycloalkyl or cycloalkyl-(C1 to C8)alkyl;

[0107] wherein the alkyl or cycloalkyl group is optionally substituted with at least one F, Cl, CF3, OCF3, CN, OH, (C1 to C8) alkoxy, NR 21 R 22 ,CO2H,R 21 R 22 NC(O)-、R 21 O-NR 22-, heterocycloalkyl, aryl or heteroaryl; wherein R 21 and R 22 each independently represents hydrogen or (C1 to C8) alkyl;

[0108] wherein the heterocycloalkyl, aryl or heteroaryl group is optionally substituted by at least one F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH, (C1 to C8) alkoxy, NR 23 R 24 ,CO2H,R 23 R 24 NC(O)- or R 23 O-NR 24 -substituted; wherein R 23 and R 24 each independently represents hydrogen or (C1 to C8) alkyl;

[0109] or R 5 and R 6 together with the nitrogen atom to which they are bound, form a heterocycloalkyl group,

[0110] wherein the heterocycloalkyl group is optionally substituted with at least one F, Cl, CF3, OCF3, CN, OH, (C1 to C8) alkoxy, NR 25 R 26 ,CO2H,R 25 R 26 NC(O)-、R 25 O-NR 26 -, heterocycloalkyl, aryl, heteroaryl, heterocycloalkyl-(C1 to C8)alkyl-, aryl-(C1 to C8)alkyl-, heteroaryl-(C1 to C8)alkyl-, cycloalkyl-(C1 to C8)alkyl-O-, aryl-(C1 to C8)alkyl-O-, heteroaryl-(C1 to C8)alkyl-O-, cycloalkyl-(C1 to C8)alkyl-NR 25 -, aryl-(C1 to C8)alkyl-NR 25 -, heteroaryl-(C1 to C8)alkyl-NR 25 -, benzylidene, heteroarylene, aryl-(C1 to C8)alkyl-ylidene- or heteroaryl-(C1 to C8)alkyl-ylidene-;

[0111] Where R 25 and R 26 each independently represents hydrogen or (C1 to C8) alkyl;

[0112] wherein the heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylene group is optionally substituted by at least one F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH, (C1 to C8) alkoxy, NR 27 R28 ,CO2H,R 27 R 28 NC(O)- or R 27 O-NR 28 -substituted; wherein R 27 and R 28 Each independently represents hydrogen or (C1 to C8) alkyl.

[0113] According to one embodiment, W represents CH.

[0114] According to one embodiment, R A , R B , R C and R D In one embodiment, at least one of R A , R B , R C and R D Exactly one of them represents hydrogen. In one embodiment, R A , R B , R C and R D In one embodiment, R A , R B , R C and R D Exactly three of them represent hydrogen.

[0115] In one embodiment, R A and R C In a particular embodiment, at least one of R A In a particular embodiment, R C Represents hydrogen.

[0116] According to one embodiment, R A , R B and R D At least one of them represents F or Cl. In one embodiment, R B and R D In one particular embodiment, at least one of R B and R D Each independently represents F or Cl. In a particular embodiment, R B In a particular embodiment, R B In a particular embodiment, R D In a particular embodiment, R D In a preferred embodiment, R BIn a preferred embodiment, R D In a further preferred embodiment, R B Indicates F and R D Indicates Cl.

[0117] As defined in formula (I) above, R 1 may represent a (C1 to C8)alkyl group, wherein the alkyl group is optionally substituted with at least one OH, (C1 to C3)alkoxy group or F, that is, R 1 The (C1 to C8) alkyl in is optionally substituted by at least one group and the group may be OH, (C1 to C3) alkoxy or F. According to one embodiment, R 1 represents a (C1 to C8)alkyl group, wherein the alkyl group is optionally substituted with at least one group selected from OH, (C1 to C3)alkoxy and F.

[0118] According to one embodiment, R 1 and R 4 Together they form -CH2-O-CH2- or -CH2-CH2. In one embodiment, R 1 and R 4 Together they form -CH2-CH2-. In one embodiment, -CH2-CH2- is optionally substituted with at least one F, OH or OCH3. In one embodiment, -CH2-CH2- is not substituted.

[0119] According to one embodiment, R 1 represents methyl, ethyl, CF3 or methoxymethyl (CH3OCH2-). In one embodiment, R 1 represents methyl, ethyl or CF3. In one embodiment, R 1 It represents methoxymethyl (CH3OCH2-).

[0120] According to one embodiment, R 7 represents hydrogen, OH, halogen, (C1 to C8) alkyl, cycloalkyl, (C1 to C8) alkyl-O-, cycloalkyl-O-, cycloalkyl-(C1 to C8) alkyl-O-, heterocycloalkyl-O-, R 11 O-(C1 to C8)alkyl-O-, R 11 R 12 N-(C1 to C8)alkyl-O- or (R 11 O)(R 12 )N-(C1 to C8)alkyl-O-; wherein R 11 and R 12 Each independently represents hydrogen or (C1 to C8)alkyl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted as defined above for formula (I).

[0121] According to one embodiment, R 7 represents hydrogen, OH or halogen. In one embodiment, R 7 In a preferred embodiment, R 7 In one embodiment, R 7 In a particularly preferred embodiment, R 7 In a particular embodiment, R 7 In a particular embodiment, R 7 Indicates Cl.

[0122] In one embodiment, R 7 Does not represent hydrogen.

[0123] According to one embodiment, R 7 represents (C1 to C8) alkyl-O- (i.e. (C1 to C8) alkoxy) or cycloalkyl-O-. In one embodiment, the alkyl or cycloalkyl is optionally substituted with at least one F, Cl, OH, C1 to C8) alkoxy or aryl. In a particular embodiment, R 7 It represents OCH3(methoxy), OCH2CH3, OCF3, cyclobutyl-O-, HO-CH2-CH2-O-, CH3O-CH2-CH2-O- or phenyl-CH2-O-.

[0124] According to one embodiment, R 7 represents (C1 to C8)alkyl-O- (i.e. (C1 to C8)alkoxy). In one embodiment, the alkyl group is optionally substituted with at least one F or Cl. In a particular embodiment, the halogen group is F. In one embodiment, R 7 It represents OCH3(methoxy), OCH2CH3, and OCF3.

[0125] According to one embodiment, R 7 In one embodiment, R 7 It represents cyclobutyl-O-.

[0126] According to one embodiment, R 7 represents (C1 to C8)alkyl-O- (i.e. (C1 to C8)alkoxy), wherein the alkyl group is optionally substituted with at least one OH or (C1 to C8)alkoxy group, i.e. RO-(C1 to C8)alkyl-O-, wherein R represents H or (C1 to C8)alkyl. In one embodiment, R 7 It represents HO-CH2-CH2-O- or CH3O-CH2-CH2-O-.

[0127] According to one embodiment, R 7 represents (C1 to C8) alkyl-O- (i.e. (C1 to C8) alkoxy), wherein the alkyl group is optionally substituted with at least one aryl group. In one embodiment, the aryl group is not substituted. In one embodiment, R 7 It represents phenyl-CH2-O-.

[0128] According to one embodiment, R 7 represents (C1 to C8) alkyl-O- (i.e. (C1 to C8) alkoxy), wherein the alkyl group is optionally substituted with at least one heteroaryl group. In one embodiment, the heteroaryl group is not substituted. In one embodiment, R 7 It represents heteroaryl-CH2-O-.

[0129] According to one embodiment, R 7 represents (C1 to C8) alkyl-O- (i.e. (C1 to C8) alkoxy), wherein the alkyl group is optionally substituted with at least one heterocycloalkyl group. 7 represents heterocycloalkyl-(C1 to C8)alkyl-O-, i.e., the alkyl group is substituted by exactly one heterocycloalkyl group. In one embodiment, the heterocycloalkyl group is not substituted.

[0130] In a preferred embodiment, R 7 represents F, Cl, OCH3 (methoxy), OCH2CH3, OCF3, cyclobutyl-O-, HO-CH2-CH2-O-, CH3O-CH2-CH2-O-, phenyl-CH2-O-, 1H-imidazol-4-yl-, 1-methyl-imidazol-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 a particularly preferred embodiment, R 7 It represents 1H-imidazol-4-yl-, 1-methyl-imidazol-4-yl-, CH3, CN, CO2H, CH2OH, C(CH3)2OH, CH2N(CH3)2, cyclopropyl, cyclobutyl-O-, (4-pyridine)-CH2-O-, (3-pyridine)-CH2-O- or benzyl-O-.

[0131] According to one embodiment, Z represents CH or N; or Z represents CR 8 And R 7 and R 8 and the carbon atom to which they are bound together form a cycloalkyl or heterocycloalkyl group; wherein the cycloalkyl or heterocycloalkyl group is optionally substituted as defined above for formula (I). In other words, in this embodiment, except for R 7 and R8 Except when R is taken together with the carbon atom to which it is bonded to form a cycloalkyl group or a heterocycloalkyl group, 8 Represents hydrogen.

[0132] According to one embodiment, Z represents CH or N. In one embodiment, Z represents CH. In one embodiment, Z represents N.

[0133] According to a preferred embodiment, Z represents CR 8 ; where R 8 represents (C1 to C4) alkyl, F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH or (C1 to C4) alkoxy. In a preferred embodiment, R 8 represents methyl, ethyl, F, Cl, CF3, CN or OH.

[0134] According to another embodiment, Z represents CR 8 And R 7 and R 8 Together with the carbon atom to which they are bound, they form a cycloalkyl or heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted as defined herein for formula (I).

[0135] In a preferred embodiment, Z represents CR 8 And R 7 and R 8 and the carbon atoms to which they are bound form a heterocycloalkyl group; wherein the heterocycloalkyl group is optionally substituted as defined herein in formula (I). In a particular embodiment, the heterocycloalkyl group comprises at least one oxygen atom, i.e. the heterocycloalkyl group is a cyclic ether. In a particular embodiment, the heterocycloalkyl group comprises at least one nitrogen atom, i.e. the heterocycloalkyl group is a cyclic amine. In a particular embodiment, the heterocycloalkyl group is six-membered or five-membered. In a particular embodiment, the heterocycloalkyl group comprises exactly one oxygen atom, two oxygen atoms or one nitrogen atom.

[0136] According to one embodiment, R 5 represents hydrogen or (C1 to C8)alkyl. 5 According to one embodiment, R 5 In a preferred embodiment, R 5 represents hydrogen, methyl or ethyl. In a particular embodiment, R 5 In a particular embodiment, R 5 It represents a methyl or ethyl group.

[0137] According to one embodiment, R 6represents (C1 to C8)alkyl, cycloalkyl or cycloalkyl-(C1 to C8)alkyl-. In one embodiment, the alkyl or cycloalkyl is optionally substituted with at least one F. In a preferred embodiment, the alkyl or cycloalkyl is unsubstituted. In one embodiment, R 6 represents methyl, ethyl, n-propyl, 1-fluoro-n-propane, tert-butyl, cyclopropyl, cyclobutyl or cyclopropyl-CH2-.

[0138] According to one embodiment, R 6 represents (C1 to C8)alkyl, cycloalkyl or cycloalkyl-(C1 to C8)alkyl- or heterocycloalkyl. In one embodiment, the alkyl or cycloalkyl is optionally substituted with at least one F, CN or CF3. In a preferred embodiment, the alkyl or cycloalkyl is not substituted. In one embodiment, R 6 It represents methyl, ethyl, isopropyl, isobutyronitrile, n-propyl, 3-fluoro-n-propane, tert-butyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, 1-methylcyclobutyl, cyclopropyl-CH2-, (F3C)C(Me)2-, 3-methyloxetan-3-yl or oxetan-3-yl.

[0139] According to one embodiment, R 6 represents (C1 to C8)alkyl. In one embodiment, the alkyl group is optionally substituted with at least one F. In a preferred embodiment, the alkyl group is unsubstituted. In a particular embodiment, R 5 represents methyl, ethyl, n-propyl, 1-fluoro-n-propane or tert-butyl.

[0140] According to one embodiment, R 6 In one embodiment, R 6 represents cyclopropyl or cyclobutyl.

[0141] According to one embodiment, R 6 In a particular embodiment, R 6 It represents cyclopropylmethyl (cyclopropyl-CH2-).

[0142] According to one embodiment, R 5 and R 6 Together with the nitrogen atom to which they are bound, form a heterocycloalkyl group. In one embodiment, the heterocycloalkyl group is optionally substituted with at least one F. In a preferred embodiment, R 5 and R 6Together with the nitrogen atom to which they are bound, they form 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-phenylethylpiperidine. In a particular embodiment, R 5 and R 6 Together with the nitrogen atom to which they are bound, they form 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.

[0143] In a preferred embodiment, R 5 and R 6 Together with the nitrogen atom to which they are bound, they form 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-piperidinyl)benzonitrile, 3-(4-piperidinyl)benzoic acid methyl ester, 4-(4-piperidinyl)benzoic acid methyl ester, 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.

[0144] According to one embodiment, at least one heterocycloalkyl group present in the compound of formula (I) is a water-soluble group, ie the presence of this group in the molecule increases its solubility in water compared to the same molecule not comprising said heterocycloalkyl group.

[0145] According to one embodiment, R E In a preferred embodiment, R Erepresents hydrogen or F. In a further preferred embodiment, R E According to one embodiment, R E represents a (C1 to C3)alkyl group. According to one embodiment, R E Represents halogen.

[0146] According to one embodiment, the compound of formula (I) is a compound of formula (Ia)

[0147]

[0148] or a pharmaceutically acceptable salt and / or solvate thereof;

[0149] Among them, W, R B , R D , Z, R 1 To R 4 , R 5 , R 6 , R 7 and R E As defined herein in formula (I).

[0150] In one embodiment, W in formula (Ia) represents CH.

[0151] In one embodiment, R in Formula (Ia) B and R D Each independently represents F or Cl. In a particular embodiment, R B Indicates F, R D Indicates Cl.

[0152] In one embodiment, R in Formula (Ia) E Represents hydrogen.

[0153] 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.

[0154] Table 1

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181] All references herein to compounds of the invention (e.g., "compounds of formula (I)") include references to their salts, solvates, multicomponent complexes, and liquid crystals. All references herein to compounds of the invention include references to polymorphs and their crystal habits. All references herein to compounds of the invention include references to isotopically labeled compounds thereof, including deuterated compounds thereof. All references herein to compounds of the invention include references to their stereoisomers. All references herein to compounds of the invention include references to their pharmaceutically acceptable prodrugs.

[0182] In particular, the compounds of the invention may be in the form of a pharmaceutically acceptable salt. According to one embodiment, the compounds of the invention are in the form of a pharmaceutically acceptable salt.

[0183] Pharmaceutically acceptable salts include acid addition salts and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, and xinafoate. Suitable alkali salts are formed by the alkali that forms non-toxic salts.Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, 2-(diethylamino)ethanol salts, diethanolamine salts, aminoethanol salts, glycine salts, 4-(2-hydroxyethyl)-morpholine salts, lysine salts, magnesium salts, meglumine salts, morpholine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts and zinc salts.Also can form the half salt of acid and base, for example hemisulfate and hemicalcium salt.When compound contains acidic group and basic group, described compound also can form inner salt, and these compounds are within the scope of the present invention.When compound contains hydrogen heteroatom (for example NH), the present invention also includes the salt and / or isomer formed by transferring described hydrogen atom to the basic group or basic atom in molecule.

[0184] The pharmaceutically acceptable salts of the compounds of the present invention may be prepared by one or more of the following methods: (i) by reacting the compound with a desired acid; (ii) by reacting the compound with a desired base; (iii) by removing an acid-labile or base-labile protecting group from a suitable precursor of the compound, or by ring-opening a suitable cyclic precursor, such as a lactone or lactam, with a desired acid; and / or (iv) by converting one salt of the compound into another salt by reacting with a suitable acid or by passing through a suitable ion exchange column. All of these reactions are typically carried out in solution. The salt may be precipitated from the solution and collected by filtration, or may be recovered by evaporating the solvent. The degree of ionization of the salt may vary from completely ionized to almost non-ionized.

[0185] In particular, the compounds of the present invention may be in the form of pharmaceutically acceptable solvates. According to one embodiment, the compounds of the present invention are pharmaceutically acceptable solvates. According to one embodiment, the compounds of the present invention are pharmaceutically acceptable salts and solvates.

[0186] In particular, the compounds of the present invention may include at least one asymmetric center and therefore may exist as different stereoisomeric forms. Therefore, all references to the compounds of the present invention herein include references to all possible stereoisomers thereof, including not only racemic compounds, but also single enantiomers and non-racemic mixtures thereof. Non-racemic mixtures may include any amount of each different stereoisomer, for example, a stereoisomer may be dominant (e.g., 90 / 10 mixture or 80 / 20 mixture), or enantiomer ratios may be close to racemic mixtures (e.g., 40 / 60 mixtures). When the desired single enantiomer compound, this single enantiomer may be synthesized by stereospecificity, by resolving the final product or any convenient intermediate, or by obtaining chiral chromatography methods known in the art. The resolution of the final product, intermediate or raw material may be carried out by any suitable method known in the art.

[0187] Pharmaceutical composition

[0188] Another object of the 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, making the composition a "pharmaceutical composition" as defined herein.

[0189] In a first embodiment, the pharmaceutical composition comprises a compound of the invention as the sole therapeutic agent. In a second embodiment, the pharmaceutical composition further comprises at least one other therapeutic agent, such as a therapeutic agent suitable for treating a neurological disorder.

[0190] As described herein, another object of the present invention is a medicament comprising a compound according to the invention.

[0191] Reagent test kit

[0192] As described herein, another object of the present invention is a kit of parts (hereinafter referred to as "kit") comprising a compound or composition according to the present invention. According to one embodiment, the kit includes an article such as a package or container. According to one embodiment, the kit includes instructions for use. The kit can be promoted, distributed or sold as a unit for performing the method of the present invention.

[0193] According to one embodiment, the kit comprises: a pharmaceutical composition comprising a compound according to the invention, and another separate pharmaceutical composition comprising at least another therapeutic agent, eg, a therapeutic agent suitable for the treatment of a neurological disorder.

[0194] Medical uses of compounds

[0195] As described herein, another object of the present invention is a compound or composition according to the invention for use as a medicament.

[0196] Another object of the present invention is a compound or composition according to the invention for use in the treatment of a neurological disorder, as described herein.

[0197] 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 composition according to the present invention in the preparation of a medicament for treating a neurological disorder, as described herein. Another object of the present invention is the use of a compound or composition according to the present invention in the treatment of a neurological disorder, as described herein.

[0198] According to one embodiment, the method or use comprises the step of administering to a subject a therapeutically effective amount of a compound, composition or medicament according to the present invention, as described herein.

[0199] According to one embodiment, the neurological disorder treated by the method or use of the invention is:

[0200] - Diseases or disorders associated with defective neurogenesis, such as Hirschsprung's disease, schizophrenia, ataxia-telangiectasia, age-related decline in nervous system performance, or neurodevelopmental disorders;

[0201] - a neurodegenerative disease or disorder, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, frontotemporal dementia, a retinal neurodegenerative disease, a neuro-ophthalmological disease, neurotrophic keratitis, Charcot-Marie-Tooth disease, spinal muscular atrophy, epilepsy (e.g., epilepsy, or seizure disorder, or a chronic neurological disorder manifesting as epilepsy), dementia, age-related decline in nervous system performance, prion disease, Creutzfeldt-Jakob disease, multiple system atrophy (Shay-Dreyfuss syndrome), multiple sclerosis, or Guillain-Barré syndrome;

[0202] - Diseases or disorders related to nerve damage or neurotoxicity, such as head injury, brain injury, traumatic brain injury, peripheral nerve injury, traumatic peripheral nerve injury, peripheral neuropathy, complications of nerve transplantation, spinal cord injury, traumatic spinal cord injury, neurectomy or nerve injury, cerebrospinal nerve rupture, brain cell or nerve cell damage, syringomyelia, optic neuropathy, trauma, stroke, ischemia, stroke, ischemic stroke, neurotoxicity caused by alcohol abuse or substance abuse (e.g., ecstasy, methamphetamine, etc.), or aphasia;

[0203] - neurodevelopmental disorders, such as Rett syndrome, X-linked mental retardation, fragile X syndrome, Down syndrome, autism spectrum disorder, Hirschsprung's disease, Tourette syndrome, childhood learning disabilities, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Angelman syndrome, extremely low birth weight infants (micropreemie), schizophrenia, language disorders, prematurity, perinatal arterial ischemic stroke, spina bifida, mental retardation, non-syndromic X-linked mental retardation, Ondine syndrome or WAGR syndrome;

[0204] - neuropsychiatric disorders, such as depression, major depressive disorder, schizophrenia, schizoaffective disorder, delusional disorder, anxiety disorder, anxiety disorder, panic disorder, phobia, obsessive-compulsive disorder, post-traumatic stress disorder, bipolar disorder, anorexia nervosa, bulimia nervosa, anhedonia, apathy, dementia, substance-induced dementia, movement disorders characterized by motor tics and / or verbal tics (e.g. Tourette syndrome), substance use disorders, addiction disorders, mood disorders, suicidal tendencies, cancer-related psychiatric symptoms, Alzheimer's disease, Huntington's disease, frontotemporal dementia, or reward deficiency syndrome (RDS);

[0205] - Movement disorders, such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, movement disorders characterized by motor tics and / or speech tics and / or tic disorders (e.g. Tourette's disease), ataxia, ataxic muscle rigidity (spasticity), Charcot-Marie-Tooth disease, spinal muscular atrophy, Werdnig-Hoffmann syndrome, or chronic proximal spinal muscular atrophy;

[0206] - pain disorders such as neuralgia, trigeminal neuralgia, chronic pain, inflammatory pain, arthritis-related pain, fibromyalgia, back pain, cancer-related pain, digestive disease-related pain, Crohn's disease-related pain, autoimmune disease-related pain, endocrine disease-related pain, diabetic neuropathy-related pain, phantom limb pain, spontaneous pain, chronic postoperative pain, chronic temporomandibular pain, causalgia, postherpetic neuralgia, AIDS-related pain, complex regional pain syndrome type I and II, trigeminal neuralgia, chronic back pain, spinal cord injury-related pain, pain associated with medication ingestion and recurrent acute pain, neuropathic pain or neuroesthesia caused by inappropriate neuronal activity in diseases such as diabetes, multiple sclerosis and motor neuron disease;

[0207] - Ophthalmic disease or eye disease, such as retinal disease, retinal neurodegenerative disease, retinitis pigmentosa, non-arteritic anterior ischemic optic neuropathy (NAION), macular degeneration, age-related macular degeneration, glaucoma, diabetic retinopathy, optic neuropathy and retinitis pigmentosa, neuro-ophthalmologic disease, 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 paraopia;

[0208] - Intestinal system disorders or gastrointestinal disorders, such as intestinal motility disorders, constipation, Hirschsprung's disease, inflammatory bowel disease, enteric neuronal dysplasia, ulcerative colitis, achalasia, esophageal spasm, duodenal ulcer, Zollinger-Ellison syndrome, excessive gastric acid secretion, malabsorption disorders or intestinal inflammation;

[0209] - progressive muscular dystrophy, such as Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreyfus muscular dystrophy, Landowy-Dejerine muscular dystrophy, scapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, von Graefe-Fuchs muscular dystrophy, oculopharyngeal muscular dystrophy, myotonic muscular dystrophy and congenital muscular dystrophy, congenital or acquired myopathy, Charcot-Marie-Tooth disease, Werdnig-Hoffmann disease or chronic proximal spinal muscular atrophy;

[0210] - Diseases or disorders related to long-term or short-term memory deficits, such as memory loss, benign amnesia, or Alzheimer's disease;

[0211] - Autoimmune disorders, such as multiple sclerosis, autoimmune encephalomyelitis, autoimmune encephalitis, autoimmune hemolytic anemia, chronic lymphocytic leukemia, Zag-Strauss syndrome, anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, thyroid-related eye disease, autoimmune thyroiditis, Guillain-Barré syndrome, or autoimmune thrombocytopenic purpura;

[0212] - Neurological diseases or disorders, such as damage to cochlear sensory cells, auditory perception defects, hearing loss, or tinnitus;

[0213] - Sleep disorders such as narcolepsy, restless legs syndrome, obstructive sleep apnea, chronic insomnia disorder, paradoxical sleep deprivation, or REM sleep deprivation;

[0214] - Cerebrovascular disease or neurovascular disease, such as early brain injury (EBI) after subarachnoid hemorrhage (SAH), cerebral ischemia, stroke, hypoxic-ischemic brain injury, perinatal arterial ischemic stroke, or neovascular age-related macular degeneration (nvAMD);

[0215] - Substance abuse disorders, such as substance dependence, sequelae of substance abuse and dependence, substance-induced psychological disorders, dementia or amnestic disorders caused by substance withdrawal, and substance-induced dementia or amnestic disorders;

[0216] - Neuronal response to viral infection, trypanosome infection, AIDS-related neurological deficit, obesity, temporomandibular joint dysfunction, aphasia, Bell's palsy, encephalitis, renal disease or disorder, pheochromocytoma, metabolic syndrome, cancer, eczema, thrombocytopenia; dysplasia; disseminated vascular coagulation (DIC); myelodysplasia; immune thrombocytopenic purpura (ITP), HIV-induced ITP, neuroneoplastic disease or disorder, neuroimmune disease or disorder, multiple endocrine neoplasia type 2, Von Hippel-Lindau disease (VHL), neurofibromatosis type I, scleroderma, epidermal and interstitial wound healing disorders and / or scarring disorders; or

[0217] - Diseases or disorders related to age and / or aging.

[0218] According to one embodiment, the neurological disorder is epilepsy, such as Dravet syndrome, benign Rolandic epilepsy, frontal lobe epilepsy, infantile spasms, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy, childhood absence epilepsy (e.g., seizure-like seizures), febrile seizures, Lafora progressive myoclonic epilepsy, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, generalized epilepsy with febrile seizures plus (GEFS+), severe myoclonic epilepsy of infancy (SMEI), benign familial neonatal convulsions (BFNC), West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, wandering Partial epilepsy, infantile epileptic encephalopathy, tuberous sclerosis complex (TSC), focal cortical dysplasia, lissencephaly type I, Miller-Dickel syndrome, Angelman syndrome, fragile X syndrome, epilepsy in autism spectrum disorder, epilepsy in subcortical band heterotopia, epilepsy in Walker-Warburg syndrome, epilepsy in Alzheimer's disease, post-traumatic epilepsy, progressive myoclonic epilepsy, reflex epilepsy, Rasmussen syndrome, temporal lobe epilepsy, limbic epilepsy, status epilepticus, abdominal epilepsy, massive bilateral myoclonus, catamenial epilepsy, Jackson epilepsy disorder, myoclonic epilepsy of the Mediterranean type (Unverricht-Lundborg disease), or photosensitive epilepsy.

[0219] According to one embodiment, as described herein, the composition or medicine according to the present invention is administered to a subject, and it can be prepared using methods generally known in the art. Non-limiting examples of forms suitable for administration include solutions (e.g., sterile aqueous solutions), gels, dispersants, emulsions, suspensions, and solid forms (e.g., powder forms or liposomal forms) suitable for adding liquids to prepare solutions or suspensions prior to use.

[0220] As described herein, the compositions or medicaments according to the present invention may be administered using routes of administration generally known in the art, such as parenteral, oral, by inhalation, spray, rectal, nasal or via an implanted reservoir.

[0221] However, it should be understood that the total daily usage of the compound, composition or drug will be determined by the attending physician within the scope of reasonable medical judgment. The specific therapeutically effective dosage level for any particular patient will depend on a variety of factors, including the disease being treated and the severity of the disease; the activity of the compound used; the age, weight, general health, sex and diet of the subject; the time of administration, route of administration and the excretion rate of the specific therapeutic agent used; the duration of treatment; the drugs used in combination with the specific therapeutic agent used or always used; and factors well known in the medical field. For example, those skilled in the art can start the dosage of the compound at a level lower than the dosage required to obtain the desired therapeutic effect and gradually increase the dosage until the desired effect is obtained. The total dose required for each treatment can be administered by multiple doses or in a single dose.

[0222] In one embodiment, the dosage of the compound is about 0.01 mg to 500 mg per kg of patient body weight per day, which can be administered in a single dose or multiple doses. Preferably, the dosage level will be about 0.1 mg / kg to about 250 mg / kg per day; more preferably about 0.5 mg / kg to about 100 mg / kg per day. Suitable dosage levels may be about 0.01 mg / kg to about 250 mg / kg per day, about 0.05 mg / kg to about 100 mg / kg per day, or about 0.1 mg / kg to about 50 mg / kg per day. Within this range, the dosage may be about 0.05 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 5 mg / kg, or about 5 mg / kg to about 50 mg / kg per day. For oral administration, the composition is preferably provided in the form of a tablet containing from about 1.0 mg to about 1000 mg of active ingredient, particularly containing about 1.0 mg, about 5.0 mg, about 10.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 50.0 mg, about 75.0 mg, about 100.0 mg, about 150.0 mg, about 200.0 mg, about 250.0 mg, about 300.0 mg, about 400.0 mg, about 500.0 mg, about 600.0 mg, about 750.0 mg, about 800.0 mg, about 900.0 mg and about 1000.0 mg of active ingredient for symptomatic adjustment of the dosage to be treated. The compound can be administered in a regimen of 1 to 4 times daily, preferably once or twice daily. It should be understood, however, that the specific dosage level and dosage frequency for any particular patient may vary and depend on a variety of factors, including the activity of the specific compound employed, the metabolic stability and duration of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, severity of the particular condition and the subject being treated.

[0223] According to a first embodiment, the composition or medicament according to the invention is administered as the sole therapeutic agent, as described herein. According to a second embodiment, the composition or medicament according to the invention is administered before at least one other therapeutic agent, simultaneously with at least one other therapeutic agent, and / or after at least one other therapeutic agent, as described herein. In one embodiment, the other therapeutic agent is suitable for treating a neurological disorder.

[0224] Another object of the present invention is a method for promoting neuronal cell survival and / or neuronal cell function. As described herein, another object of the present invention is a compound or composition according to the present invention for promoting neuronal cell survival and / or neuronal cell function. According to one embodiment, as described herein, the method or use includes a step of contacting a therapeutically effective amount of a compound, composition or drug according to the present invention with a neuronal cell. The method or use may be in vitro, ex vivo or in vivo.

[0225] Another object of the present invention is a method for rescuing neuronal cell function after neuronal cells are subjected to damage, events or conditions that are harmful to neuronal cell function. As described herein, another object of the present invention is a compound or composition according to the present invention, which is used to rescue neuronal cell function after neuronal cells are subjected to damage, events or conditions that are harmful to neuronal cell function. These injuries, events or conditions include but are not limited to neuronal stress, such as neuronal stress caused by hypoxia or ischemia; traumatic injury; and exposure to toxic molecules, such as abnormal misfolded proteins, protein aggregates, excitotoxins, reactive oxygen species, endoplasmic reticulum stressors, mitochondrial stressors, Golgi antagonists, etc. According to one embodiment, as described herein, the method or use includes a step of contacting a therapeutically effective amount of a compound, composition or drug according to the present invention with a neuronal cell. The method or use may be in vitro, ex vivo or in vivo.

[0226] Another object of the invention is a method of using a compound or composition according to the invention to bind to GFRα1 or modulate GFRα1 as described herein. Another object of the invention is a compound or composition according to the invention for binding to GFRα1 or modulating GFRα1 as described herein. According to a preferred embodiment, the compound or composition is used to activate GFRα1. In one embodiment, GFRα1 is human GFRα1, which preferably has SEQ ID NO:1.

[0227] Another object of the invention is a method of activating the GFRα1 / RET signaling pathway using a compound or composition according to the invention as described herein. Another object of the invention is a compound or composition according to the invention for activating the GFRα1 / RET signaling pathway as described herein.

[0228] As described herein, another object of the present invention is a method for detecting GFRα1 in a sample using a compound or composition according to the present invention. As described herein, another object of the present invention is a compound or composition according to the present invention for detecting GFRα1 in a sample. In one embodiment, GFRα1 is human GFRα1, which preferably has SEQ ID NO: 1. In one embodiment, the compound according to the present invention may be fused to a detectable label, such as a fluorophore or any other part that can re-emit light under light excitation, a radioactive label, a contrast agent, etc.

[0229] Preparation method

[0230] Synthesis of compounds

[0231] As described herein, compounds according to the present invention can be prepared by synthetic methods well known in the art.

[0232] Another object of the present invention is a process for preparing the compounds of the present invention, as described herein. According to one embodiment, the process is a Buchwald-Hartwig amination.

[0233] According to one embodiment, the method comprises the step of reacting the following compounds in the presence of a base and a metal catalyst:

[0234] Compound of formula (II)

[0235]

[0236] Among them, Z, R 5 , R 6 , R 7 and R E As defined herein in formula (I) and X represents halogen or -CF3SO3, and a compound of formula (III)

[0237]

[0238] Among them, W, R A To R D and R 1 To R 4 As defined herein in formula (I);

[0239] Thus, the compound of the present invention is obtained.

[0240] In one embodiment, the base is cesium carbonate (Cs2CO3), sodium carbonate (Na2CO3) or potassium carbonate (K2CO3). In a particular embodiment, the base is cesium carbonate (Cs2CO3). In one embodiment, the base is sodium tert-butoxide (t-BuONa), potassium tert-butoxide (t-BuOK) or potassium phosphate. In a particular embodiment, the base is sodium tert-butoxide (t-BuONa).

[0241] In one embodiment, the catalyst is a palladium catalyst. In a particular embodiment, the catalyst is a Pd(Oac)2 and racemic-BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) system. In a particular embodiment, the catalyst is Xphos-Pd-G3.

[0242] In one embodiment, X represents halogen. In a particular embodiment, X represents Br.

[0243] In one embodiment, the reaction is carried out in a solvent. In a particular embodiment, the solvent is toluene. In one embodiment, the reaction is carried out under reflux.

[0244] According to another embodiment, the method comprises:

[0245] (a'-1) In the presence of a base and a metal catalyst, the following steps of reacting the compounds

[0246] Compound of formula (II)

[0247]

[0248] Among them, Z, R 5 , R 6 , R 7 and R E As defined herein in formula (I) and X represents halogen or -CF3SO3,

[0249] With a monoprotected piperazine (i.e., one in which only one NH group is protected by a protecting group R) having the formula (MPP) P protected piperazine),

[0250]

[0251] Where R 1 To R 4 As defined herein in formula (I);

[0252] Thus, a compound of formula (IV) is obtained

[0253]

[0254] Among them, Z, R1 To R 4 , R 5 , R 6 , R 7 and R E As defined herein in formula (I) and R P is a protecting group; subsequently

[0255] (a'-2) deprotection step of the compound of formula (IV);

[0256] Thus, a compound of formula (V) is obtained

[0257]

[0258] Among them, Z, R 1 To R 4 , R 5 , R 6 , R 7 and R E As defined herein in formula (I); and

[0259] (a'-3) a step of reacting a compound of formula (V) with a compound of formula (VI) in the presence of a peptide coupling agent and a base

[0260]

[0261] Among them, W, R A To R D and as defined herein in formula (I),

[0262] Thus, the compound of the present invention is obtained.

[0263] In one embodiment, the base and / or catalyst in step (a'-1) is as described above for step (a-1). In one embodiment, X represents halogen. In a particular embodiment, X represents Br.

[0264] The protecting group may be any protecting group known in the art, such as tert-butoxycarbonyl (Boc). The protecting group may be removed in step (a'-2) by any method known in the art suitable for the nature of the protecting group, such as the addition of a strong Bronsted acid (eg hydrochloric acid [HCl]).

[0265] The peptide coupling agent in step (a'-3) can be any peptide coupling agent known in the art, such as 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU).

[0266] The base in step (a'-3) can be any base known in the art, such as an amine base. According to one embodiment, the amine is triethylamine (Et3N) or diisopropylethylamine (iPr2Net).

[0267] In one embodiment, the reaction in step (a'-3) is carried out in a solvent. In a particular embodiment, the solvent is dimethylformamide (DMF) and / or tetrahydrofuran (THF). In a particular embodiment, the solvent is dichloroethane (DCE) and / or acetonitrile (MeCN). In one embodiment, the reaction is carried out at room temperature (RT).

[0268] According to another embodiment, the method comprises:

[0269] (a"-1) A step of reacting the following compounds in the presence of a base and a metal catalyst:

[0270] Compound of formula (III)

[0271]

[0272] Among them, W, R 1 To R 4 and R A To R D As defined in formula (I) herein,

[0273] and a compound of formula (VII)

[0274]

[0275] Among them, except that Z does not represent N, Z, R 7 and R E As defined in formula (I) herein, and X represents halogen or -CF3SO3,

[0276] Thus, a compound of formula (VIII) is obtained

[0277]

[0278] Among them, Z, R A To R D , R 1 To R 4 , R 7 and R E as defined herein in formula (I) and Z is as defined herein in formula (VII);

[0279] (a"-2) a step of reacting a compound of formula (VIII) with chlorosulfonic acid (HSO3Cl);

[0280] Thus obtaining a compound of formula (IX);

[0281]

[0282] Among them, W, R ATo R D , R 1 To R 4 , R 7 and R E as defined herein in formula (I) and Z is as defined herein in formula (VII);

[0283] (a"-3) a step of reacting a compound of formula (IX) with a primary or secondary amine of formula (X) in the presence of a base

[0284] NHR 5 R 6 (X)

[0285] Where R 5 and R 6 As defined herein in formula (I);

[0286] Thus, the compound of the present invention is obtained.

[0287] According to an alternative embodiment, the method includes step (a"-1) of reacting a compound of formula (III) as described above with a compound of formula (VII) to obtain a compound of formula (VIII); but without step (a"-2) of reacting the compound of formula (VIII) with chlorosulfonic acid (HSO3Cl); and Z may represent N.

[0288] In one embodiment, the base and / or catalyst in step (a"-1) is as described above for step (a-1). In one embodiment, X represents halogen. In a particular embodiment, X represents Br.

[0289] The base in step (a"-3) can be any base known in the art, such as an amine base. According to one embodiment, the amine is triethylamine (Et3N) or diisopropylethylamine (iPr2Net).

[0290] In one embodiment, the reaction in step (a"-3) is carried out in a solvent. In a particular embodiment, the solvent is dichloromethane (DCM).

[0291] In one embodiment, the method further comprises a post-processing step (b). In one embodiment, the post-processing step (b) comprises a step of extraction by solvent. In a particular embodiment, the solvent is ethyl acetate (EtOAc). In a particular embodiment, the solvent is water or 1N HCl solution. In a particular embodiment, the solvent is dichloromethane (DCM). In one embodiment, the post-processing step (b) comprises a step of filtration. In a particular embodiment, the silicon In one embodiment, the post-treatment step (b) comprises a step of concentrating under reduced pressure.

[0292] In one embodiment, the method further comprises a purification step (c). In one embodiment, the purification step (c) comprises purification by chromatography. In a particular embodiment, the chromatography is fast liquid chromatography (FC) (e.g., cHex / EtOAc gradient), preparative thin layer chromatography (PTLC) or semi-preparative high performance liquid chromatography (HPLC).

[0293] Synthetic intermediates

[0294] Another object of the present invention is a compound of formula (II)

[0295]

[0296] Among them, Z, R 5 , R 6 , R 7 and R E As defined herein in formula (I) and X represents halogen or -CF3SO3.

[0297] Another object of the present invention is a compound of formula (III)

[0298]

[0299] Among them, W, R A To R D and R 1 To R 4 As defined herein in formula (I).

[0300] Another object of the present invention is a compound of formula (IV)

[0301]

[0302] Among them, Z, R 1 To R 4 , R 5 , R 6 , R 7 and R E As defined herein in formula (I) and R P is a protecting group (eg Boc).

[0303] Another object of the present invention is a compound of formula (V)

[0304]

[0305] Among them, Z, R 1 To R 4 , R 5 , R 6 , R 7 and R EAs defined herein in formula (I).

[0306] Another object of the present invention is a compound of formula (VIII)

[0307]

[0308] Among them, W, Z, R A To R D , R 1 To R 4 , R 7 and R E As defined herein in formula (I).

[0309] According to a preferred embodiment, in formula (VIII) above, Z does not represent N.

[0310] Another object of the present invention is a compound of formula (IX)

[0311]

[0312] Among them, W, Z, R A To R D , R 1 To R 4 , R 7 and R E As defined herein in formula (I).

[0313] According to a preferred embodiment, in formula (IX) above, Z does not represent N.

[0314] Example

[0315] The present invention is further illustrated by the following examples.

[0316] Example 1: Synthesis of compounds

[0317] Common Materials and Common Methods

[0318] abbreviation

[0319] List of abbreviations:

[0320] Ac:Acetyl

[0321] Ar: Argon

[0322] BINAP: (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)

[0323] t-Bu: tert-butyl

[0324] cHex: Cyclohexane

[0325] dba: dibenzylideneacetone

[0326] DCM: dichloromethane

[0327] DCE: dichloroethane

[0328] DMF: dimethylformamide

[0329] Et: Ethyl

[0330] FC: fast liquid chromatography

[0331] JohnPhos: 2-(di-tert-butylphosphino)biphenyl

[0332] MTBE: tert-butyl methyl ether

[0333] PTLC: Preparative Thin Layer Chromatography

[0334] RT: Room temperature

[0335] TBTU: 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate

[0336] TPTU: O-(2-oxo-1(2H)pyridinyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate

[0337] TFA: trifluoroacetic acid

[0338] THF: Tetrahydrofuran

[0339] XPhos: dicyclohexyl[2′,4′,6′-tri(propan-2-yl)[1,1′-biphenyl]-2-yl]phosphane

[0340] XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0341] Analytical methods

[0342] Recorded with a Bruker ULTRASHIELD 400 spectrometer 1 H NMR spectroscopy (400 MHz) and 19 F NMR spectra (376 MHz). Spectral processing and analysis were performed using MestReNova. The data appear in the following order: chemical shift in ppm referenced to the internal solvent signal, multiplicity, coupling constant J in Hertz, and number of protons.

[0343] Reverse phase HPLC / MS analysis was performed using a Waters Alliance 2795 HPLC equipped with an autosampler, an online membrane degasser, a column oven 10 (T = 45°C), a UV detector and a ZQ quadrupole mass detector operating in electrospray ionization mode. The compounds to be analyzed (0.1 mg to 0.3 mg) were dissolved in a minimum amount of DMSO and made up with acetonitrile (total volume: 1 mL). Standard analytical parameters: Flow rate: 1 mL / min, V 进样 : 5 μL. Acidic conditions: Waters XSelect CSH C18 column (3.5 μm, 2.1×15 50 mm). Gradient: (H2O+0.04 vol / vol % HCO2H (10 mM)) / ACN from 95 / 5 to 0 / 100 in 2.5 minutes. Basic conditions: Waters Xbridge C18 column (3.5 μm, 2.1×50 mm). Gradient: (H2O+0.06 vol / vol % NH3 (aq.) (10 mM)) / ACN from 95 / 5 to 0 / 100 in 2.5 minutes.

[0344] General synthetic method

[0345] General Protocol 1 (GP-1): Peptide Coupling Using TBTU

[0346] Under RT, TBTU is added to the DMF solution of the required carboxylic acid. The mixture was stirred at RT for 15 minutes, and required piperazine and Et were added dropwise The THF solution of N. The mixture was stirred for the required time at RT. Volatiles were removed under reduced pressure, and the residue was distributed between 1N HCl and EtOAc. Each layer was separated and the aqueous phase was extracted with EtOAc. The organic extracts merged were washed (1N HCl, saturated NaHCO The aqueous solution, saline), dried (Na SO ), filtered and concentrated under reduced pressure. By FC (cHex / EtOAc gradient) or PTLC purification of the residue to obtain the required product.

[0347] General Protocol 2 (GP-2): Peptide Coupling Using TPTU (Small Scale)

[0348] At RT, iPr2NEt and TPTU are added to a DCE / MeCN (1 / 1) solution of the desired carboxylic acid. After stirring for 5 minutes at RT, the desired piperazine is added and the mixture is stirred for the required time at RT. 2 drops of ethylenediamine are added and the mixture is concentrated under reduced pressure. The residue is purified by FC (cHex / EtOAc gradient) or PTLC to obtain the desired product.

[0349] General Scheme 3 (GP-3): Chlorosulfonylation

[0350] At 0 ℃, a DCM solution of the desired aromatics is added dropwise to chlorosulfonic acid. The mixture is warmed to the desired temperature and stirred at the desired temperature for the required time. The reaction mixture is poured dropwise onto crushed ice (very exothermic quenching) while stirring. At the end of the addition, the remaining ice is melted, DCM is added and the layers are separated. The aqueous phase is extracted with DCM, and the combined organic extracts are dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the desired sulfonyl chloride.

[0351] General Scheme 4 (GP-4): Formation of sulfonamide

[0352] Under RT, the DCM solution of required sulfonyl chloride is joined to required amine and Et3N or iPr2NEt in the DCM solution.Reaction mixture is stirred for required time under RT.Reaction mixture is distributed between EtOAc and NH4Cl saturated aqueous solution.Separate each layer and extract aqueous phase with EtOAc.By the organic extract washing (NH4Cl saturated aqueous solution, salt solution) merged, dry (Na2SO4), filter and concentrate under reduced pressure.By FC (cHex / EtOAc gradient) or PTLC purification of residue to obtain required product.

[0353] General Scheme 5 (GP-5): Buchwald coupling using Pd(OAc)2 or Pd2(dba)3 / rac-BINAP

[0354] The desired aryl bromide, the desired piperazine, Cs2cO3, Pd(OAc)2 or Pd2(dba)3 and racemic-BINAP were charged to a microwave reaction vial. 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 desired time. After cooling to RT, EtOAc was added and the suspension was stirred at 40 °C for 1 h. The product was filtered over 4% paraformaldehyde (EtOAc rinse). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc gradient) or PTLC to give the desired product.

[0355] General Protocol 6 (GP-6): Buchwald coupling using XantPhos-Pd-G3

[0356] The desired aryl bromide, the desired piperazine, t-BuONa and XantPhos-Pd-G3 were charged to a microwave reaction vial. 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 desired time. After cooling to RT, EtOAc was added and the suspension was stirred at 40 °C for 1 h. The product was filtered over 4% paraformaldehyde (EtOAc rinse). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc gradient) or PTLC to give the desired product.

[0357] General Scheme 7 (GP-7): Buchwald coupling using XPhos-Pd-G3

[0358] The desired aryl bromide, the desired piperazine, t-BuONa and XPhos-Pd-G3 were charged to a microwave reaction vial. 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 desired time. After cooling to RT, EtOAc was added and the suspension was stirred at 4 °C for 1 h. The product was filtered over 4% paraformaldehyde (EtOAc rinse). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc gradient) or PTLC to give the desired product.

[0359] Synthesis of intermediate compounds

[0360] Synthesis of Common Intermediate Piperazine

[0361] Tert-butyl 3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Boc-I-001)

[0362]

[0363] At RT, TBTU (18.1g, 56.5 mmoles, 1.2 equivalents) is added to DMF (118mL) solution of 2-chloro-4-fluorobenzoic acid (9.87g, 56.5 mmoles, 1.2 equivalents). The mixture is stirred at RT for 15 minutes, and tert-butyl 3,8-diazabicyclo [3.2.1] octane-8-carboxylate (10.0g, 47.1 mmoles, 1 equivalent) and Et are added dropwise THF (118mL) solution of N (9.8mL, 71 mmoles, 1.5 equivalents). The mixture is stirred at RT for 16h. The reaction mixture is concentrated under reduced pressure. The reaction mixture is distributed between NH4Cl saturated aqueous solution and EtOAc. Separate each layer and extract the aqueous phase with EtOAc (2*). The combined organic extracts were washed (saturated aqueous NH4Cl, saturated aqueous NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure to give 21.3 g (purity 76%, 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.

[0364] 1H NMR (400 MHz, chloroform-d, 2 groups of rotamers) δ7.33 (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.

[0365] (2-Chloro-4-fluoro-phenyl)-(3,8-diazabicyclo[3.2.1]octan-3-yl)methanone (I-001)

[0366]

[0367] HCl (4M solution in dioxane, 55 mL, 220 mmol, 5 eq) was added 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 (21.3 g, 76% pure, 43.9 mmol, 1 eq) in dioxane (55 mL) at RT. The mixture was stirred for 60 h at RT. The reaction mixture was concentrated under reduced pressure and the residue was distributed between water and DCM. K2CO3 was added in batches 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 (220 g column, dry loading, DCM / MeOH (7N NH3) = 99 / 1 to 95 / 5) to give 10.3 g (88%) of (2-chloro-4-fluoro-phenyl)-(3,8-diazabicyclo[3.2.1]octan-3-yl)methanone I-001 as a white solid.

[0368] 1 H NMR (400 MHz, chloroform-d, 2 groups 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.

[0369] Tert-butyl 3-[4-fluoro-2-(trifluoromethyl)benzoyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Boc-I-002)

[0370]

[0371] At RT, iPr2NEt (656 μL, 3.77 mmol, 2 equivalents) and TPTU (1.12 g, 3.77 mmol, 2 equivalents) were added to a DCE / ACN (1:1, 9 mL) solution of commercially available 4-fluoro-2-(trifluoromethyl)benzoic acid (784 mg, 3.77 mmol, 2 equivalents). The mixture was stirred at RT for 15 minutes and tert-butyl (1R, 5S)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate (400 mg, 1.88 mmol, 1 equivalent) was added. The mixture was stirred at RT for 16 h. Volatiles were removed under reduced pressure, and the residue was distributed 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, NaHCO3 saturated aqueous solution, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=95 / 5 to 40 / 60) to give 724 mg (95%) of tert-butyl 3-[4-fluoro-2-(trifluoromethyl)benzoyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Boc-I-002) as a colorless oil.

[0372] 1 H NMR (400 MHz, DMSO-d6, multiple groups of rotational isomers) 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.

[0373] 3,8-Diazabicyclo[3.2.1]octan-3-yl-[4-fluoro-2-(trifluoromethyl)phenyl]methanone (I-002)

[0374]

[0375] A solution of tert-butyl 3-[4-fluoro-2-(trifluoromethyl)benzoyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Boc-I-002 (724 mg, 1.80 mmol, 1 eq) was treated with HCl (4M solution in dioxane, 4.5 mL, 18 mmol, 10 eq). The mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was distributed between water and DCM. K2CO3 was added in batches 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 to obtain 607 mg (quantitative yield) of I-002 as a colorless oil.

[0376] 1 H NMR (400 MHz, DMSO-d6, 2 groups 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.

[0377] Tert-butyl 4-(2-chloro-4-fluoro-benzoyl)-2-methyl-piperazine-1-carboxylate (Boc-I-003)

[0378]

[0379] Under RT, TBTU (19.2g, 59.9 mmol, 1 equivalent) is added to THF (120mL) solution of 2-chloro-4-fluorobenzoic acid (10.5g, 59.9 mmol, 1.2 equivalent). The mixture is stirred at RT for 15 minutes, and THF (120mL) solution of tert-butyl 2-methylpiperazine-1-carboxylate (10.0g, 49.9 mmol, 1 equivalent) and Et is added dropwise. The mixture is stirred for 60h at RT. The reaction mixture is concentrated under reduced pressure. The reaction mixture is distributed between the saturated EtOAc of NH4Cl. Separate each layer and extract the aqueous phase with EtOAc (2*). The organic extracts merged are washed (NH4Cl saturated aqueous solution, NaHCO3 saturated aqueous solution, saline), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (220 g column, dry loading, cHex / EtOAc = 90 / 10 to 50 / 50) to give 16.8 g (94%) of tert-butyl 4-(2-chloro-4-fluoro-benzoyl)-2-methyl-piperazine-1-carboxylate (Boc-I-003) as a white solid.

[0380] 1 H NMR (400 MHz, chloroform-d, multiple groups of rotational isomers) δ7.36-7.21 (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.

[0381] (2-Chloro-4-fluoro-phenyl)-(3-methylpiperazine-1-yl)methanone (I-003)

[0382]

[0383] TFA (72 mL, 941 mmol, 20 eq) was added to a solution of crude tert-butyl 4-(2-chloro-4-fluoro-benzoyl)-2-methyl-piperazine-1-carboxylate Boc-I-003 (16.8 g, 47.1 mmol, 1 eq) in DCM (235 mL) at 0 °C. The mixture was stirred for 2 h at RT. The reaction mixture was concentrated under reduced pressure and the residue was distributed between water and DCM at 0 °C. K2CO3 was added in batches 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 (80 g column, dry loading, DCM / MeOH (7N NH3) = 99 / 1 to 90 / 10) to give 9.8 g (81%) of (2-chloro-4-fluoro-phenyl)-(3-methylpiperazin-1-yl)methanone I-003 as a white solid.

[0384] 1 H NMR (400 MHz, chloroform-d, multiple groups of rotational isomers) δ 7.32 (ddd, J = 8.6, 5.9, 1.3 Hz, 0.5 H), 7.25 (ddd, J = 8.5, 5.9, 1.4 Hz, 0.5 H), 7.21-7.13 (m, 1 H), 7.09-7.01 (m, 1 H), 4.69-4.56 (m, 1 H), 3.31-2.75 (m, 5 H), 2.51 (m, 1 H), 1.15 (dd, J = 6.3, 2.4 Hz, 1.5 H), 0.98 (dd, J = 6.3, 4.5 Hz, 1.5 H). MS (ESI+): [M+H]+ 257.1 / 259.1.

[0385] (2-Chloro-4-fluoro-phenyl)-[(3S)-3-methylpiperazine-1-yl]methanone ((S)-I-003) and (2-chloro-4-fluoro-phenyl)-[(3R)-3-methylpiperazine-1-yl]methanone ((R)-I-003). (S)-I-003 and (R)-I-003 were obtained using the same synthetic sequence as I-003 starting from tert-butyl (2S)-2-methylpiperazine-1-carboxylate and tert-butyl (2R)-2-methylpiperazine-1-carboxylate, respectively.

[0386] 1H NMR (400 MHz, chloroform-d, 2 groups of rotamers) δ 7.32 (ddd, J = 8.6, 5.9, 1.3 Hz, 0.5 H), 7.25 (ddd, J = 8.5, 5.9, 1.4 Hz, 0.5 H), 7.21-7.13 (m, 1 H), 7.09-7.01 (m, 1 H), 4.69-4.56 (m, 1 H), 3.31-2.75 (m, 5 H), 2.51 (m, 1 H), 1.15 (dd, J = 6.3, 2.4 Hz, 1.5 H), 0.98 (dd, J = 6.3, 4.5 Hz, 1.5 H). MS (ESI+): [M+H]+ 257.1 / 259.1.

[0387] Tert-butyl 3-(2-chloro-4,5-difluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Boc-I-033)

[0388]

[0389] Under RT, TBTU (4.54g, 14.1 mmoles, 1.2 equivalents) is added to 2-chloro-4,5-difluorobenzoic acid (2.72g, 14.1 mmoles, 1.2 equivalents) in DMF (29mL) solution. The mixture is stirred at RT for 15 minutes, and tert-butyl 3,8-diazabicyclo [3.2.1] octane-8-carboxylate (2.50g, 11.8 mmoles, 1 equivalent) and Et are added dropwise THF (29mL) solution of N (2.5mL, 17 mmoles, 1.5 equivalents). The mixture is stirred at RT for 16h. The reaction mixture is concentrated under reduced pressure. The reaction mixture is distributed between NH4Cl saturated aqueous solution and EtOAc. Separate each layer and extract aqueous phase with EtOAc (2*). The combined organic extracts were washed (saturated aqueous NH4Cl, saturated aqueous NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure to give 6.76 g (88% purity) 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.

[0390] 1 H NMR (400 MHz, chloroform-d, 2 groups of rotamers) δ7.32-6.94 (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.

[0391] (2-Chloro-4,5-difluoro-phenyl)-(3,8-diazabicyclo[3.2.1]octan-3-yl)methanone (I-033)

[0392]

[0393] HCl (4M solution in dioxane, 19 mL, 77 mmol, 5 eq) was added 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 (6.76 g, 88% purity, 15.3 mmol, 1 eq) in dioxane (77 mL) at RT. The mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was distributed between water and DCM. K2CO3 was added in batches 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 (24 g column, dry loading, DCM / MeOH (7N NH3) = 99 / 1 to 95 / 5) to give 3.15 g (70%) of (2-chloro-4,5-difluoro-phenyl)-(3,8-diazabicyclo[3.2.1]octan-3-yl)methanone (I-033) as a white solid.

[0394] 1 H NMR (400 MHz, chloroform-d, 2 groups of rotamers) δ7.32-7.22 (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.

[0395] Synthesis of the desired amines

[0396] Tert-butyl 4-(3-pyrazol-1-ylphenyl)piperidine-1-carboxylate (Boc-I-034)

[0397]

[0398] Tert-butyl 4-(3-bromophenyl)piperidine-1-carboxylate (100 mg, 294 μmol, 1 eq), pyrazole (40 mg, 0.59 mmol, 2 eq), Cs2CO3 (239 mg, 735 μmol, 2.5 eq), CuI (11 mg, 59 μmol, 0.2 eq) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.012 mL, 0.074 mmol, 0.25 eq) were loaded into a MW bottle. The bottle was purged and degassed NMP (1.5 mL) was added. The bottle was sealed and the mixture was stirred at 150 °C for 18 h. After cooling to RT, EtOAc was added and the suspension was filtered on diatomaceous earth (EtOAc rinse). The filtrate was concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50) to give 49 mg (51%) of tert-butyl 4-(3-pyrazol-1-ylphenyl)piperidine-1-carboxylate (Boc-I-034) as a colorless oil.

[0399] 1 H NMR (400MHz, chloroform-d) δ7.85 (dd, J=2.5, 0.6Hz, 1H), 7.65 (d, J=1.7Hz, 1H), 7.53 (t,J=2.0Hz,1H),7.42(ddd,J=8.1,2.2,1.1Hz,1H),7.31(t,J=7.8Hz,1H),7 .12-7.00(m,1H),6.39(dd,J=2.5,1.8Hz,1H),4.19(s,2H),2.83-2.48(m,3H ),1.80(d,J=13.1Hz,2H),1.61(qd,J=12.6,4.4Hz,2H),1.42(s,9H).MS(ESI + ):[M+H] + 328.1.

[0400] 4-(3-Pyrazol-1-ylphenyl)piperidine; hydrochloride (I-034)

[0401]

[0402] HCl (4M solution in dioxane, 0.37 mL, 1.5 mmol, 10 eq) was added to a solution of crude tert-butyl 4-(3-pyrazol-1-ylphenyl)piperidine-1-carboxylate Boc-I-034 (49 mg, 0.15 mmol, 1 eq) in dioxane (71 mL) at RT. The mixture was stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure to give 344 mg (98%) of 4-(3-pyrazol-1-ylphenyl)piperidine; hydrochloride salt I-034 as a white solid.

[0403] 1 H NMR (400MHz, D2O) δ8.14(d,J=2.6Hz,1H),7.78(d,J=1.9Hz,1H),7.61-7.41(m,3H),7.29(dt,J=7.2,1.7Hz,1H),6.56(t,J= 2.3Hz,1H),3.59-3.44(m,2H),3.23-3.07(m,2H),2.98(ddt,J=12.1,7.3,3.6Hz,1H),2.21-2.03(m,2H),2.01-1.80(m,2H).

[0404] 2-(4-Fluorophenyl)cyclopropanol (I-035)

[0405]

[0406] 4-Fluorophenethylmagnesium bromide solution [prepared by slowly adding a solution of 1-(2-bromoethyl)-4-fluorobenzene (3.0 g, 15 mmol, 3 eq) in dry THF (10 mL) to Mg (547 mg, 22.5 mmol, 4.5 eq) in dry THF (5 mL) and refluxing the resulting suspension for 1 h, using only the supernatant] was added dropwise over 2 h to a solution of ClTi(Oi-Pr)3 (1.95 g, 7.49 mmol, 1.5 eq) and methyl formate (0.30 g, 5.0 mmol, 1 eq) in dry THF (35 mL). Ice-cold 10% H2SO4 was added dropwise, followed by Et2O. The layers were separated and the aqueous phase was extracted with Et2O. The combined organic extracts were washed (saturated aqueous NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 96 / 4 to 60 / 40) to give 231 mg (27%, 90% purity) of 2-(4-fluorophenyl)cyclopropanol I-035 as a colorless oil.

[0407] 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).

[0408] Trans-tert-butyl 4-[rac-(1R,2S)-2-(4-fluorophenyl)cyclopropyl]piperazine-1-carboxylate (Boc-I-036)

[0409]

[0410] By ZnCl2 (372mg, 2.73 mmoles, 2 equivalents), Na2CO3 (290mg, 2.73 mmoles, 2 equivalents) and tert-butyl-1-piperazinecarboxylate (254mg, 1.37 mmoles, 1 equivalent) are loaded into MW bottle.Purge bottle with Ar and 2-(4-fluorophenyl) cyclopropanol I-035 (90% purity, 231mg, 1.37 mmoles, 1 equivalent).Sealed bottle and mixture is stirred at 110 ℃ for 16h.After being cooled to RT, reaction mixture is distributed between NaHCO3 saturated aqueous solution and EtOAc.Separate each layer and extract aqueous phase with EtOAc.By the organic extract washing (salt water), drying (Na2SO4), filtering and concentrating under reduced pressure that merge. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc=95 / 5 to 50 / 50) to give 60 mg (14%) of trans-tert-butyl 4-[rac-(1R,2S)-2-(4-fluorophenyl)cyclopropyl]piperazine-1-carboxylate Boc-I-036 as a colorless oil.

[0411] 1 H NMR (400MHz, chloroform-d) δ7.02-6.98(m,2H),6.96-6.91(m,2H),3.49-3.31(m,4H),2.58(t,J=5.1Hz,4H),1.98(ddd,J=9.3 ,5.8,3.2Hz,1H),1.80(dt,J=7.3,3.8Hz,1H),1.46(s,9H),1.10(dt,J=9.5,4.7Hz,1H),0.91(dt,J=6.9,5.5Hz,1H). 19 F NMR (376MHz, chloroform-d) δ-117.6.MS (ESI + ):[M+H] + 321.2.

[0412] Trans-1-[rac-(1R,2S)-2-(4-fluorophenyl)cyclopropyl]piperazine (I-036)

[0413]

[0414] At RT, HCl (4M solution in dioxane, 0.94 mL, 3.7 mmol, 20 eq) was added to a dioxane (0.9 mL) solution of trans-tert-butyl 4-[racemic-(1R, 2S)-2-(4-fluorophenyl) cyclopropyl] piperazine-1-carboxylate Boc-I-036 (60 mg, 0.19 mmol, 1 eq). The mixture was stirred for 16 h at RT. The reaction mixture was concentrated under reduced pressure and the residue was distributed between water and DCM. K2CO3 was added in batches 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 NH 3 )=90 / 10) to give 26 mg (63%) of trans 1-[rac-(1R,2S)-2-(4-fluorophenyl)cyclopropyl]piperazine I-036 as a colorless oil.

[0415] 1 H NMR (400MHz, chloroform-d) δ7.05-6.96(m,2H),6.96-6.86(m,2H),2.97-2.76(m,4H),2.62(s,4H),2.05(s,1H),1.9 6(ddd,J=9.3,5.8,3.2Hz,1H),1.80(dt,J=7.3,3.8Hz,1H),1.09(dt,J=9.5,4.7Hz,1H),0.93-0.85(m,1H). 19 F NMR (376MHz, chloroform-d) δ-117.8.MS (ESI + ):[M+H] + 221.2.

[0416] Synthesis of intermediates required for final product 001

[0417] 1-(2-Methoxyphenyl)-2-methyl-piperazine (I-004)

[0418]

[0419] 2-Bromoanisole (471 μL, 3.74 mmol, 1.5 eq), tert-butyl 3-methylpiperazine-1-carboxylate (500 mg, 2.50 mmol, 1 eq), t-BuONa (360 mg, 3.74 mmol, 1.5 eq), Pd(OAc)2 (56 mg, 0.25 mmol, 0.1 eq) and XPhos (143 mg, 300 micromoles, 0.12 eq) were loaded into a microwave reaction bottle. The bottle was flushed with argon and degassed toluene (12.5 mL) was added. The bottle was sealed and the reaction was stirred at reflux for 72 h in a preheated heating block. After cooling to RT, EtOAc was added and the suspension was heated to 40 °C. The mixture was stirred for 5 h at RT. The reaction mixture was concentrated under reduced pressure and the residue was distributed between water and DCM. K2CO3 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) to obtain 92 mg (18% for two steps) of I-004 as a yellow oil.

[0420] 1 H NMR (400 MHz, chloroform-d, 2 groups 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.

[0421] (2-Chloro-4-fluoro-phenyl)-[4-(2-methoxyphenyl)-3-methyl-piperazine-1-yl]methanone (I-005)

[0422]

[0423] According to GP-1, 2-chloro-4-fluorobenzoic acid (338 mg, 1.93 mmol, 1.5 eq) and TBTU (414 mg, 1.29 mmol, 1 eq) in DMF (3.3 mL) were used, followed by piperazine I-004 (266 mg, 1.29 mmol, 1 eq) and Et3N (270 μL, 1.93 mmol, 1.5 eq) in THF (3.3 mL) at RT for 16 h to obtain I-005 as a white solid in 68% yield. Purification by FC (cHex / EtOAc=95 / 5 to 20 / 80).

[0424] 1 H NMR (400 MHz, chloroform-d, multiple groups of rotational isomers) 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 groups of rotational isomers) δ -109.59, -109.61, -109.63, -109.67. MS (ESI + ):[M+H] + 363.1.

[0425] 3-[4-(2-Chloro-4-fluoro-benzoyl)-2-methyl-piperazin-1-yl]-4-methoxy-benzenesulfonyl chloride (I-006)

[0426]

[0427] According to GP-3, I-006 was obtained as an orange oil in 91% yield using I-005 (370 mg, 877 μmol, 1 eq) and HSO 3 Cl (1.17 mL, 17.5 mmol, 20 eq) in DCM (4.4 mL) at RT for 1 h30.

[0428] 1H NMR (400 MHz, chloroform-d, multiple groups of rotational isomers) δ7.83-7.72 (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). 9F NMR (376 MHz, chloroform-d, multiple groups of rotational isomers) δ-109.13, -109.15, -109.21. MS (ESI + ):[M+H] + 461.0 / 463.0.

[0429] Synthesis of intermediates required for final products 002 to 015 and 039 to 048

[0430] (2-Chloro-4-fluoro-phenyl)-[8-(2-methoxyphenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-007)

[0431]

[0432] According to GP-5, 2-bromoanisole (1.28 mL, 10.3 mmol, 1.2 eq), piperazine I-001 (2.30 g, 8.56 mmol, 1 eq), Cs2CO3 (5.58 g, 17.2 mmol, 2 eq), Pd(OAc)2 (192 mg, 856 μmol, 0.1 eq) and racemic-BINAP (800 mg, 1.28 mmol, 0.15 eq) were used in toluene (43 mL) under reflux for 16 h to obtain I-007 as an orange solid in 40% yield. Purification was performed by FC (DCM / MeOH=99:1 to 90:10) and FC (cHex / EtOAc=95 / 5 to 60 / 40).

[0433] 1H NMR (400 MHz, chloroform-d, 2 groups of rotamers) δ7.36 (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=6.5Hz,1H),4.07-4.00(m,1H),3.86(s,1.5H),3.85(s,1.5H),3.69(dd,J=12.9,1.9Hz,0.5H),3. 52(dd,J=12.2,2.2Hz,0.5H),3.35(dt,J=12.9,1.5Hz,1H),3.22-3.04(m,1H),2.12-1.80(m,4H).MS(ESI + ):[M+H] + 375.1 / 377.1.

[0434] 3-[3-(2-Chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-methoxy-benzenesulfonyl chloride (I-008)

[0435]

[0436] According to GP-3, I-008 was obtained as a yellow solid in 85% yield using I-007 (1.25 g, 3.35 mmol, 1 eq) and HSO 3 Cl (4.5 mL, 67 mmol, 20 eq) in DCM (17 mL) at RT for 2.5 h.

[0437] 1H NMR (400 MHz, chloroform-d, 2 groups of rotamers) δ7.62 (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 = 1 0.1,9.3,4.6Hz,1H),4.33(dd,J=12.4,6.3Hz,1H),4.16-4.06(m,1H),3.97(s,1.5H),3.96(s,1.5H),3.66(d ,J=12.5Hz,0.5H),3.65(d,J=12.5Hz,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.

[0438] Synthesis of intermediates required for final products 049 to 054

[0439] (2-Chloro-4,5-difluoro-phenyl)-[8-(2-methoxyphenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-038)

[0440]

[0441] According to GP-5, 2-bromoanisole (1.08 mL, 8.66 mmol, 1.2 eq), piperazine I-033 (2.07 g, 7.22 mmol, 1 eq), Cs2CO3 (2.00 g, 14.4 mmol, 2 eq), Pd(OAc)2 (162 mg, 722 μmol, 0.1 eq) and racemic-BINAP (670 mg, 1.08 mmol, 0.15 eq) were used in toluene (34 mL) under reflux for 16 h to obtain I-038 as an orange solid in 90% yield. Purification was performed by FC (cHex / EtOAc=95 / 5 to 40 / 60) and FC (DCM / MeOH=99:1 to 95:5).

[0442] 1H NMR (400 MHz, chloroform-d, 2 groups 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.

[0443] 3-[3-(2-Chloro-4,5-difluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-methoxy-benzenesulfonyl chloride (I-039)

[0444]

[0445] According to GP-3, I-039 was obtained as a yellow solid in 91% yield using I-038 (845 mg, 2.15 mmol, 1 eq) and HSO 3 Cl (2.9 mL, 43 mmol, 20 eq) in DCM (11 mL) at RT for 2.5 h.

[0446] 1 H NMR (400 MHz, chloroform-d, 2 groups 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).

[0447] Synthesis of intermediates required for final products 055 to 060

[0448] (2-Chloro-4-fluoro-phenyl)-[8-(2,3-dihydrobenzofuran-7-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-040)

[0449]

[0450] According to GP-5, 7-bromo-2,3-dihydrobenzofuran (500 mg, 2.51 mmol, 1 eq), piperazine I-001 (877 mg, 3.27 mmol, 1.3 eq), Cs2CO3 (1.64 g, 5.02 mmol, 2 eq), Pd(OAc)2 (56.4 mg, 251 μmol, 0.1 eq) and racemic-BINAP (188 mg, 301 μmol, 0.12 eq) were used in toluene (13 mL) under reflux for 4 h to obtain I-040 as a white foam in 36% yield. Purification by FC (cHex / EtOAc=96 / 4 to 60 / 40).

[0451] 1 H NMR (400 MHz, chloroform-d, 2 groups 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 (376MHz, chloroform-d, 2 groups of rotational isomers) δ-109.6, -109.7. MS (ESI + ):[M+H] + 387.1 / 389.1.

[0452] 7-[3-(2-Chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,3-dihydrobenzofuran-5-sulfonyl chloride (I-041)

[0453]

[0454] According to GP-3, I-041 was obtained as a yellow solid in 93% yield using I-040 (370 mg, 959 μmol, 1 eq) and HSO 3 Cl (1.3 mL, 19 mmol, 20 eq) in DCM (5.6 mL) at RT for 2 h.

[0455] 1H NMR (400 MHz, chloroform-d, 2 groups of rotamers) δ7.43 (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=12.7Hz,0.5H),3.44(d,J=12.7Hz,0.5H),3.30(t,J=8.9Hz,2H),3 .24&3.21(s,1H),3.09(t,J=11.3Hz,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 rotational isomers) δ -109.1, -109.2.

[0456] Synthesis of intermediates required for final product 061

[0457] (2-Chloro-4,5-difluoro-phenyl)-[8-(2,3-dihydrobenzofuran-7-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-042)

[0458]

[0459] According to GP-5, 7-bromo-2,3-dihydrobenzofuran (162 mg, 816 micromol, 1.2 eq.), piperazine I-033 (200 mg, 680 micromol, 1.2 eq.), Cs2CO3 (0.44 g, 1.4 mmol, 2 eq.), Pd(OAc)2 (15 mg, 68 micromol, 0.1 eq.) and racemic-BINAP (51 mg, 82 micromol, 0.12 eq.) were used in toluene (3.4 mL) under reflux for 16 h to obtain I-042 as a white solid in 33% yield. Purification by FC (cHex / EtOAc=96 / 4 to 60 / 40).

[0460] 1H NMR (400 MHz, chloroform-d, 2 groups 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.

[0461] 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)

[0462]

[0463] According to GP-3, I-042 (90.0 mg, 222 μmol, 1 eq) and HSO 3 Cl (0.3 mL, 4 mmol, 20 eq) in DCM (1.1 mL) were used at RT for 2 h to obtain I-043 as a yellow solid in 63% yield.

[0464] 1 H NMR (400 MHz, chloroform-d, 2 groups of rotamers) δ7.44 (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=8.9Hz,2H),3.25 &3.21(s,1H),3.08(t,J=11.6Hz,1H),2.16-1.87(m,3.5H),1.70-1.60(m,0.5H).

[0465] Synthesis of intermediates required for final product 016

[0466] 3-Bromo-4-methoxy-N-methyl-N-propyl-benzenesulfonamide (I-009)

[0467]

[0468] According to GP-4, I-009 was obtained with a yield of 97% using commercially available 3-bromo-4-methoxy-benzenesulfonyl chloride (5.00 g, 17.5 mmol, 1 eq), methyl-N-propylamine (2.7 mL, 27 mmol, 1.5 eq) and Et3N (3.7 mL, 27 mmol, 1.5 eq) in DCM (101 mL) at RT for 4 h. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0469] 1 H NMR (400 MHz, CHLOROFORM-d) δ7.99 (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.

[0470] 4-Methoxy-N-methyl-N-propyl-3-[2-(trifluoromethyl)piperazin-1-yl]benzenesulfonamide (I-010)

[0471]

[0472] Aryl bromide I-009 (100 mg, 310 micromoles, 1 equiv), commercially available tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate (118 mg, 466 micromoles, 1.5 equiv), t-BuONa (89.5 mg, 931 micromoles, 3 equiv), Pd2(dba)3 (29 mg, 31 micromoles, 0.1 equiv) and JohnPhos (19 mg, 62 micromoles, 0.2 equiv) were charged into a microwave reaction vial. The vial was flushed with argon and degassed toluene (3.1 mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating block for 16 h. After cooling to RT, EtOAc was added and the suspension was stirred at 40 °C for 1 h. (EtOAc rinse). 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, 8.80 mmol, 10 eq). The mixture was stirred for 1h at RT. The reaction mixture was concentrated under reduced pressure and the residue was distributed between water and DCM. K2CO3 was added in batches 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 obtain 61mg (50% for two steps) of I-010 as an orange oil. MS (ESI + ): [M+H] + 396.1.

[0473] Synthesis of intermediates required for final product 017

[0474] 3-(2-Ethylpiperazin-1-yl)-4-methoxy-N-methyl-N-propyl-benzenesulfonamide (I-011)

[0475]

[0476] Aryl bromide I-009 (600 mg, 1.86 mmol, 1 eq), commercially available tert-butyl 3-ethylpiperazine-1-carboxylate (400 mg, 1.86 mmol, 1 eq), Cs2CO3 (1.21 g, 3.72 mmol, 2 eq), Pd(OAc)2 (42 mg, 0.19 mmol, 0.1 eq) and rac-BINAP (139 mg, 223 μmol, 0.12 eq) were charged into a microwave reaction vial. The vial was flushed with argon and degassed toluene (9.5 mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating block for 20 h. After cooling to RT, EtOAc was added and the suspension was stirred at 40 °C for 1 hr. (EtOAc rinse). 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 equivalents). The mixture was stirred for 2h at RT. The reaction mixture was concentrated under reduced pressure and the residue was distributed 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=99 / 1 to 80 / 20) to obtain 74mg (11% for two steps) of I-011 as an orange oil.

[0477] 1 H NMR (400MHz, chloroform-d) δ7.51 (dd, J=8.5, 2.3Hz, 1H), 7.36 (d, J=2.3Hz, 1H), 6. 96(d,J=8.6Hz,1H),3.94(s,3H),3.58-3.42(m,1H),3.42-3.22(m,2H),3. 15(dt,J=6.7,3.5Hz,2H),3.08-2.88(m,4H),2.72(s,3H),1.73-1.46(m,3 H),1.44-1.34(m,1H),0.94(t,J=7.4Hz,3H),0.80(t,J=7.5Hz,3H).MS(ESI + ):[M+H] + 356.2.

[0478] Synthesis of intermediates required for final products 018 and 019

[0479] 4-Benzyl-1-(3-bromo-4-methoxy-phenyl)sulfonyl-piperidine (I-012)

[0480]

[0481] According to GP-4, I-012 was obtained with 95% yield using commercially available 3-bromo-4-methoxy-benzenesulfonyl chloride (3.00 g, 10.5 mmol, 1 eq), 4-benzylpiperidine (2.40 g, 13.7 mmol, 1.3 eq) and Et3N (2.2 mL, 16 mmol, 1.5 eq) in DCM (20 mL) at RT for 16 h. Purification by FC (cHex / EtOAc=97 / 3 to 70 / 30).

[0482] 1 H NMR (400MHz, chloroform-d) δ7.94(d,J=2.2Hz,1H),7.69(dd,J=8.7,2.2Hz,1H),7.39-7.24(m,2H),7.24-7.15(m,1H),7.14-7.06(m,2H),6.98(d,J=8 .6Hz,1H),3.98(s,3H),3.84-3.67(m,2H),2.54(d,J=6.9Hz,2H),2.23(td,J=11.8,2.5Hz,2H),1.80-1.65(m,2H),1.54-1.22(m,3H).MS(ESI + ):[M+H] + 424.0 / 426.0.

[0483] 1-[5-[(4-Benzyl-1-piperidinyl)sulfonyl]-2-methoxy-phenyl]-2-methyl-piperazine (I-013)

[0484]

[0485] Aryl bromide I-012 (1.24 g, 2.92 mmol, 1 eq), commercially available tert-butyl 3-methylpiperazine-1-carboxylate (702 mg, 3.51 mmol, 1.2 eq), Cs2CO3 (1.90 g, 5.84 mmol, 2 eq), Pd(OAc)2 (33 mg, 0.15 mmol, 0.05 eq) and racemic-BINAP (110 mg, 175 micromol, 0.06 eq) were charged into a microwave reaction bottle. The bottle was flushed with argon and degassed toluene (15 mL) was added. The bottle was sealed and the reaction was stirred at reflux in a preheated heating block for 24 h. After cooling to RT, EtOAc was added and the suspension was stirred at 40 °C for 1 h. (EtOAc rinse). 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, 6.25 mmol, 10 equivalents). The mixture was stirred for 2h at RT. The reaction mixture was concentrated under reduced pressure and the residue was distributed 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 obtain 140mg (10% for two steps) of I-013 as an orange oil.

[0486] 1 H NMR (400 MHz, chloroform-d) δ7.47 (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, 1 H),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=6.6Hz,2H), 2.19(td,J=11.8,2.6Hz,2H),1.70(d,J=11.2Hz,2H),1.55-1.31(m,3H),0.96(d,J=6.4Hz,3H).MS(ESI+ ):[M+H] + 444.0.

[0487] Synthesis of intermediates required for final product 020

[0488] 3-Bromo-N-tert-butyl-4-methoxy-benzenesulfonamide (I-014)

[0489]

[0490] According to GP-4, commercially available 3-bromo-4-methoxy-benzenesulfonyl chloride (2.02 g, 7.07 mmol, 1 eq), tert-butylamine (1.5 mL, 14 mmol, 2 eq) and Et3N (2.0 mL, 14 mmol, 2 eq) were used in DCM (28 mL) at RT for 16 h to obtain I-014 in 90% yield. Purification was performed by FC (cHex / EtOAc=100 / 0 to 20 / 80).

[0491] 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.

[0492] N-tert-Butyl-4-methoxy-3-(2-methylpiperazin-1-yl)benzenesulfonamide (I-015)

[0493]

[0494] Aryl bromide I-014 (844 mg, 2.54 mmol, 1 eq), commercially available tert-butyl 3-methylpiperazine-1-carboxylate (763 mg, 3.81 mmol, 1.5 eq), Cs2CO3 (1.7 g, 5.2 mmol, 2 eq), Pd(OAc)2 (57 mg, 0.25 mmol, 0.1 eq) and racemic-BINAP (237 mg, 381 micromol, 0.15 eq) were charged into a microwave reaction bottle. The bottle was flushed with argon and degassed toluene (12 mL) was added. The bottle was sealed and the reaction was stirred at reflux in a preheated heating block for 24 h. After cooling to RT, EtOAc was added and the suspension was stirred at 40 °C for 1 h. The product was concentrated under reduced pressure and purified by FC (cHex / EtOAc=100 / 0 to 50 / 50). The residue was directly treated with HCl (37% aqueous solution, 50 μL, 1.6 mmol, 10 equivalents). The mixture was stirred for 2h at RT. The reaction mixture was concentrated under reduced pressure and the residue was distributed 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 obtain 45mg (5% for two steps) of I-015 as a yellow oil.

[0495] 1 H NMR (400MHz, chloroform-d) 87.52 (dd, J=8.6, 2.3Hz, 1H), 7.41 (d, J=2.3Hz, 1H), 6.83 ( d,J=8.6Hz,1H),4.68(s,1H),3.84(s,3H),3.49(td,J=6.4,3.3Hz,1H),3.16(d dd,J=11.5,6.2,3.2Hz,1H),3.07(dd,J=12.2,3.4Hz,1H),2.97(qdd,J=12.2, 6.6,3.2Hz,2H),2.77-2.59(m,2H),1.14(s,9H),0.85(d,J=6.4Hz,3H).MS(ESI + ):[M+H] + 342.1.

[0496] Synthesis of intermediates required for final product 021

[0497] 4-Methoxy-N-methyl-3-(2-methylpiperazin-1-yl)-N-propyl-benzenesulfonamide (I-016)

[0498]

[0499] Aryl bromide I-009 (1.0 g, 3.1 mmol, 1 eq), commercially available tert-butyl 3-methylpiperazine-1-carboxylate (932 mg, 4.66 mmol, 1.5 eq), t-BuONa (895 mg, 9.31 mmol, 3 eq), Pd(OAc)2 (70 mg, 0.31 mmol, 0.1 eq) and racemic-BINAP (290 mg, 466 micromol, 0.15 eq) were charged into a microwave reaction bottle. The bottle was flushed with argon and degassed toluene (16 mL) was added. The bottle was sealed and the reaction was stirred at reflux in a preheated heating block for 16 h. After cooling to RT, EtOAc was added and the suspension was stirred at 40 °C for 1 h. The mixture was stirred for 16 h at RT. The reaction mixture was concentrated under reduced pressure and the residue was distributed 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 (7N NH3) = 99 / 1 to 90 / 10) to obtain 96 mg (9% for two steps) of I-016 as an orange oil.

[0500] 1 H NMR (400MHz, DMSO-d6) δ7.41(dd,J=8.5,2.3Hz,1H),7.23-7.07(m,2H),3.87(s,3H),3.51(dt,J=6.4,3.2Hz,1H),3.11(td,J=7.1 ,3.3Hz,1H),2.99(dd,J=12.0,3.3Hz,1H),2.92-2.76(m,4H),2.65-2.55(m,5H),1.46(q,J=7.2Hz,2H),0.85-0.82(m,6H).MS(ESI + ):[M+H] + 342.2.

[0501] Synthesis of intermediates required for final product 022

[0502] 4-Methoxy-3-[2-(methoxymethyl)piperazin-1-yl]-N-methyl-N-propyl-benzenesulfonamide (I-017)

[0503]

[0504] Aryl bromide I-009 (600 mg, 1.86 mmol, 1 eq), tert-butyl 3-(methoxymethyl)piperazine-1-carboxylate (429 mg, 1.86 mmol, 1 eq), Cs2CO3 (1.82 g, 5.59 mmol, 3 eq), Pd(OAc)2 (42 mg, 0.19 mmol, 0.1 eq) and rac-BINAP (174 mg, 279 micromol, 0.15 eq) were charged to a microwave reaction vial. The vial was flushed with argon and degassed toluene (9.5 mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating block for 3 h. After cooling to RT, EtOAc was added and the suspension was stirred at 40 °C for 1 h. (EtOAc rinse). 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, 4.14 mmol, 10 equivalents). The mixture was stirred for 16h at RT. The reaction mixture was concentrated under reduced pressure and the residue was distributed between water and DCM. K2CO3 was added in batches 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 obtain 78mg (8% for two steps) of I-017 as an orange oil.

[0505] 1 H NMR (400 MHz, chloroform-d) δ7.46 (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=1.7Hz,3H),3.19-2.99(m,4H),2.99-2.87(m,3H ),2.72(d,J=1.6Hz,3H),1.56(q,J=7.4Hz,2H),0.94(td,J=7.4,1.6Hz,3H).MS(ESI + ):[M+H] + 372.2.

[0506] Synthesis of intermediates required for final product 023

[0507] 4-Methoxy-N-methyl-3-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-N-propyl-benzenesulfonamide (I-018)

[0508]

[0509] Aryl bromide I-009 (100 mg, 310 μmol, 1 eq), tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (71 mg, 0.31 mmol, 1 eq), Cs2CO3 (304 mg, 931 μmol, 3 eq), Pd(OAc)2 (7.0 mg, 31 μmol, 0.1 eq) and rac-BINAP (29 mg, 47 μmol, 0.15 eq) were charged into a microwave reaction vial. The vial was flushed with argon and degassed toluene (1.6 mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating block for 16 h. After cooling to RT, EtOAc was added and the suspension was stirred at 40 °C for 1 h. (EtOAc rinse). 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, 650 μL, 2.60 mmol, 10 equivalents). The mixture was stirred at RT for 16h. The reaction mixture was concentrated under reduced pressure and the residue was distributed between water and DCM. K2CO3 was added in batches 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 obtain 90mg (79% for two steps) of I-018 as a colorless oil.

[0510] 1 H NMR (400 MHz, chloroform-d, 2 groups 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.

[0511] Synthesis of intermediates required for final product 026

[0512] 3-Bromo-4-fluoro-N-methyl-N-propyl-benzenesulfonamide (I-019)

[0513]

[0514] According to GP-4, I-019 was obtained as a white solid in 95% yield using commercially available 3-bromo-4-fluorobenzenesulfonyl chloride (388 mg, 1.35 mmol, 1 eq), methyl-N-propylamine (145 μL, 1.41 mmol, 1.05 eq) and Et3N (281 μL, 2.02 mmol, 1.5 eq) in DCM (7 mL) at RT for 1 h.

[0515] 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 (376MHz, chloroform-d) δ-99.95.MS (ESI + ):[M+H] + 310.0 / 312.0.

[0516] Synthesis of intermediates required for final product 027

[0517] 3-Bromo-N-methyl-N-propyl-4-(trifluoromethoxy)benzenesulfonamide (I-020)

[0518]

[0519] According to GP-4, I-020 was obtained as a white solid in 77% yield using commercially available 3-bromo-4-(trifluoromethoxy)benzene-1-sulfonyl chloride (500 mg, 1.47 mmol, 1 eq), methyl-N-propylamine (159 μL, 1.55 mmol, 1.05 eq) and Et3N (308 μL, 2.21 mmol, 1.5 eq) in DCM (7.5 mL) at RT for 1 h.

[0520] 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 (376MHz, chloroform-d) δ-57.36.MS (ESI + ):[M+H] +376.5 / 378.3.

[0521] Synthesis of intermediates required for final product 028

[0522] 3-Bromo-N-methyl-N-propyl-benzenesulfonamide (I-021)

[0523]

[0524] According to GP-4, I-021 was obtained as a white solid in 100% yield using commercially available 3-bromobenzenesulfonyl chloride (500 mg, 1.96 mmol, 1 eq), methyl-N-propylamine (301 μL, 2.94 mmol, 1.5 eq) and Et3N (408 μL, 2.94 mmol, 1.5 eq) in DCM (4 mL) at RT for 2 h.

[0525] 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.

[0526] Synthesis of intermediates required for final product 029

[0527] 3-Bromo-4-hydroxy-N-methyl-N-propyl-benzenesulfonamide (I-022)

[0528]

[0529] Boron tribromide (1 M in DCM, 11 mL, 11 mmol, 1.5 eq) was added to a solution of I-009 (2.37 g, 7.34 mmol, 1.00 eq) in DCM (90 mL) at 0°C under argon atmosphere. The reaction mixture was stirred at RT for 48 h. More boron tribromide (1 M in DCM, 11 mL, 11 mmol, 1.50 eq) was added at 0°C and the reaction was stirred at RT for 72 h. Water was added at 0°C and the layers 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) to give 2.1 g (86%) of I-022 as a grey oil.

[0530] 1H NMR (400 MHz, CHLOROFORM-d) δ7.93 (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.

[0531] 3-Bromo-4-ethoxy-N-methyl-N-propyl-benzenesulfonamide (I-023)

[0532]

[0533] K2CO3 (90 mg, 0.65 mmol, 2 eq) and bromoethane (53 mg, 0.49 mmol, 1.5 eq) were added to a dry DMF (1.7 mL) solution of I-022 (100 mg, 325 μmol, 1 eq) under argon. The solution was stirred for 16 h at RT. Water was added and the product was extracted with EtOAc. The combined organic extracts were washed (brine), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=95 / 5 to 70 / 30) to give 97 mg (88%) of I-023 as a colorless oil.

[0534] 1 H NMR (400 MHz, CHLOROFORM-d) δ7.95 (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.

[0535] Synthesis of intermediates required for final product 030

[0536] 3-Bromo-4-(cyclobutyloxy)-N-methyl-N-propyl-benzenesulfonamide (I-024)

[0537]

[0538] K2CO3 (90 mg, 0.65 mmol, 2 eq.) and bromocyclobutane (46 μL, 0.49 mmol, 1.5 eq.) were added to a dry DMF (1.6 mL) solution of I-022 (100 mg, 325 micromol, 1 eq.) under an argon atmosphere. The solution was stirred for 16 h at RT. Water was added and the product was extracted with EtOAc. The combined organic extracts were washed (brine), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=100 / 0 to 50 / 50) to give 53 mg (43%) of I-024 as a colorless oil.

[0539] 1 H NMR (400MHz, chloroform-d) δ7.95 (d, J=1.9Hz, 1H), 7.65 (dd, J=8.6, 2.2Hz, 1H), 6.79 (d,J=8.6Hz,1H),4.81-4.68(m,1H),2.96(t,J=7.3Hz,2H),2.72(s,3H),2.5 6-2.45(m,2H),2.28(ddd,J=12.7,6.3,2.4Hz,2H),1.93(q,J=10.6Hz,1H),1 .81-1.66(m,1H),1.56(dd,J=14.4,6.9Hz,2H),0.93(t,J=7.4Hz,3H).MS(ESI + ):[M+H] + 362.0 / 364.0.

[0540] Synthesis of intermediates required for final product 031

[0541] 3-Bromo-4-(cyclobutyloxy)-N-methyl-N-propyl-benzenesulfonamide 3-Bromo-4-(methoxymethoxy)-N-methyl-N-propyl-benzenesulfonamide (I-025)

[0542]

[0543] iPr2NEt (450 μL, 2.58 mmol, 3 eq.) and chloromethyl methyl ether (131 μL, 1.72 mmol, 2 eq.) were added to a dry DMF (3.5 mL) solution of I-022 (265 mg, 860 micromol, 1 eq.) under argon atmosphere. The solution was stirred for 1 h at RT. The reaction mixture was distributed 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 to give 300 mg (96%) of I-025 as a colorless oil.

[0544] 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.

[0545] Synthesis of intermediates required for final product 032

[0546] 5-Bromo-6-chloro-N,N-diethyl-pyridine-3-sulfonamide (I-026)

[0547]

[0548] According to GP-4, I-026 was obtained as a white solid in 100% yield using commercially available 5-bromo-6-chloro-pyridine-3-sulfonyl chloride (438 mg, 1.50 mmol, 1 eq), diethylamine (100 mg, 1.37 mmol, 1 eq) and Et3N (229 μL, 1.64 mmol, 1.2 eq) in DCM (6.9 mL) at RT for 1 h.

[0549] 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.

[0550] Synthesis of intermediates required for final product 033

[0551] 5-Bromo-N,N-diethyl-6-methoxy-pyridine-3-sulfonamide (I-027)

[0552]

[0553] MeONa (124 mg, 2.29 mmol, 5 eq) was added to a dry MeOH (1.83 mL) solution of I-026 (150 mg, 458 μmol, 1.00 eq) at RT. The mixture was stirred overnight at RT. The RM was partitioned between saturated aqueous NH4Cl 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 give 138 mg (95%) of I-027 as a light yellow solid.

[0554] 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.

[0555] Synthesis of intermediates required for final product 034

[0556] 6-Benzyloxy-5-bromo-N,N-diethyl-pyridine-3-sulfonamide (I-028)

[0557]

[0558] NaH (60% in mineral oil, 29 mg, 0.73 mmol, 1.2 eq) was added to a solution of commercially available benzyl alcohol (77 μL, 0.73 mmol, 1.2 eq) in dry toluene (1.22 mL) at 0°C and the mixture was stirred for 40 minutes at 0°C before adding I-026 (200 mg, 610 micromoles, 1.00 eq). The solution was stirred at RT for 16 h. 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 give 239 mg (98%) of I-028 as a yellow oil.

[0559] 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.

[0560] Synthesis of intermediates required for final product 036

[0561] 4-Benzyloxy-3-bromo-N-methyl-N-propyl-benzenesulfonamide (I-029)

[0562]

[0563] K2CO3 (1.74 g, 12.6 mmol, 2 eq) and benzyl bromide (750 μL, 6.30 mmol, 1 eq) were added to a dry DMF (68 mL) solution of I-022 (2.09 g, 6.30 mmol, 1 eq) under argon atmosphere. The solution was stirred for 16 h at RT. Water was added and the product was extracted with EtOAc. The combined organic extracts were washed (brine), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=95 / 5 to 70 / 30) to give 2.37 g (91%) of I-029 as a colorless oil.

[0564] 1 H NMR (400 MHz, CHLOROFORM-d) δ7.99 (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.

[0565] 4-Benzyloxy-3-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-N-methyl-N-propyl-benzenesulfonamide (I-030)

[0566]

[0567] According to GP-5, aryl bromide I-029 (1.13 g, 2.84 mmol, 1 eq), piperazine I-001 (915 mg, 3.40 mmol, 1.2 eq), Cs2CO3 (2.31 g, 7.09 mmol, 2.5 eq), Pd(OAc)2 (64 mg, 0.28 mmol, 0.1 eq) and racemic-BINAP (212 mg, 340 μmol, 0.12 eq) were used in toluene (12 mL) under reflux for 16 h to obtain I-030 as a white foam in 72% yield. Purification was performed by FC (cHex / EtOAc=100 / 0 to 50 / 50) and PTLC (DCM / MeOH=99 / 1).

[0568] 1 H NMR (400 MHz, chloroform-d, 2 groups 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 groups of rotational isomers) δ -109.21, -109.23. MS (ESI + ):[M+H] + 586.6 / 588.6.

[0569] Synthesis of intermediates required for final product 037

[0570] (2-Chloro-4-fluoro-phenyl)-[8-[5-(3-hydroxypyrrolidin-1-yl)sulfonyl-2-methoxy-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-031)

[0571]

[0572] According to GP-4, I-008 (400 mg, 845 micromol, 1 eq.), 3-pyrrolidinol (103 μL, 1.27 mmol, 1.5 eq.) and iPr2NEt (295 μL, 1.69 mmol, 2 eq.) were used in DCM (5 mL) at RT for 4 h to obtain I-031 as a white solid in 83% yield. Purification was performed by FC (cHex / EtOAc=70 / 30 to 0 / 100).

[0573] 1 H NMR (400 MHz, chloroform-d, 2 groups of rotational isomers) δ7.42 (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=11.3Hz,1H),3.12(t,J=11.0Hz,1H),2.06-1.78(m,5.5H),1.65-1.55(m,0.5H).MS(ESI + ):[M+H] + 524.1 / 526.1.

[0574] Synthesis of intermediates required for final product 038

[0575] 3-[4-(2-Chloro-4-fluoro-benzoyl)-2-methyl-piperazin-1-yl]-N-(3-fluoropropyl)-4-methoxy-benzenesulfonyl chloride (I-032)

[0576]

[0577] According to GP-4, I-006 (175 mg, 379 μmol, 1 eq.), 3-fluoropropane-1-amine hydrochloride (87 mg, 0.80 mmol, 2 eq.) and Et3N (212 μL, 1.52 mmol, 4 eq.) were used in DCM (1.9 mL) at RT for 16 h to obtain I-032 as a white solid in 32% yield. Purification was performed by FC (DCM / MeOH=99 / 1 to 90 / 10).

[0578] 1H NMR (400 MHz, chloroform-d, multiple groups of rotational isomers) 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 groups of rotational isomers) δ -109.28, -109.33, -109.35, -221.18, -221.20. MS (ESI + ):[M+H] + 502.1 / 504.1.

[0579] Synthesis of intermediates required for final products 046 to 048

[0580] Tert-butyl 4-[3-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-methoxy-phenyl]sulfonylpiperazine-1-carboxylate (Boc-I-037)

[0581]

[0582] According to GP-4, Boc-I-037 as a white solid was obtained with a yield of 74% using I-008 (2.14 g, 4.24 mmol, 1 eq), tert-butylpiperazine-1-carboxylate (1.2 g, 6.4 mmol, 1.5 eq) and iPr2NEt (2.22 mL, 12.7 mmol, 3 eq) in DCM (21 mL) at RT for 16 h. Purification was performed by FC (cHex / EtOAc=95 / 5 to 0 / 100).

[0583] 1H NMR (400 MHz, chloroform-d, 2 groups 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.

[0584] (2-Chloro-4-fluoro-phenyl)-[8-(2-methoxy-5-piperazin-1-ylsulfonyl-phenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-037)

[0585]

[0586] HCl (4M in dioxane, 3.9 mL, 16 mmol, 5 eq) was added to a solution of tert-butyl 4-[3-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octane-8-yl]-4-methoxy-phenyl]sulfonylpiperazine-1-carboxylate Boc-I-037 (2.02 g, 3.14 mmol, 1 eq) in DCM (4 mL) at RT. The mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was distributed 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 (Na2SO4), filtered and concentrated under reduced pressure to afford 1.54 g (94%) of (2-chloro-4-fluoro-phenyl)-[8-(2-methoxy-5-piperazin-1-ylsulfonyl-phenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone I-037 as a white solid.

[0587] 1H NMR (400 MHz, chloroform-d, 2 groups of rotamers) δ7.41-7.29 (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=10.6Hz,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 rotational isomers) δ -109.3, -109.4. MS (ESI + ):[M+H] + 523.1 / 525.1.

[0588] Synthesis of intermediates required for final product 062

[0589] 1-(3-Bromo-4-methoxy-phenyl)sulfonyl-4-(2-phenylethyl)piperidine (I-044)

[0590]

[0591] According to GP-4, I-044 was obtained as a white solid in 93% yield using 3-bromo-4-methoxybenzenesulfonyl chloride (1.50 g, 5.25 mmol, 1 eq), 4-phenethyl-piperidine (1.12 g, 6.30 mmol, 1.2 eq) and Et3N (1.1 mL, 7.9 mmol, 1.5 eq) in DCM (10 mL) at RT for 2 h.

[0592] 1 H NMR (400 MHz, CHLOROFORM-d) δ7.95 (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

[0593] 1-[3-Bromo-4-(methoxymethoxy)phenyl]sulfonyl-4-(2-phenylethyl)piperidine (I-045)

[0594]

[0595] BBr3 (1M solution in DCM, 9.8mL, 9.8mmol, 2 equivalents) was added to a DCM (10mL) solution of I-044 (2.15g, 4.90mmol, 1 equivalent) at 0°C. The mixture was stirred for 60h at RT. Water was carefully added and the layers were separated. The phase was extracted with DCM water, and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in DCM (20ml) at RT, and iPr2NEt (3.4mL, 20mmol, 4 equivalents) and chloromethyl methyl ether (0.74mL, 9.8mmol, 2 equivalents) were added dropwise. The mixture was stirred for 1h at RT. It was distributed 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 (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=97 / 3 to 70 / 30) to give 1.38 g of I-045 as a white solid (61% for two steps).

[0596] 1 H NMR (400 MHz, CHLOROFORM-d) δ7.96 (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

[0597] (2-Chloro-4-fluoro-phenyl)-[8-[2-(methoxymethoxy)-5-[[4-(2-phenylethyl)-1-piperidinyl]sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-046)

[0598]

[0599] According to GP-5, aryl bromide I-045 (1.38 g, 2.96 mmol, 1 eq), piperazine I-001 (1.12 g, 4.15 mmol, 1.4 eq), Cs2CO3 (1.93 g, 5.93 mmol, 2 eq), Pd(OAc)2 (67 mg, 0.30 mmol, 0.1 eq) and racemic-BINAP (222 mg, 356 μmol, 0.12 eq) were used in toluene (15 mL) under reflux for 2 h to obtain I-046 as a white foam in 21% yield. Purification by FC (cHex / EtOAc=95 / 5 to 0 / 100).

[0600] 1 H NMR (400 MHz, chloroform-d, 2 groups of rotamers) δ7.40-7.33 (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(m3.5H),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 groups of rotational isomers) δ -109.2, -109.3. MS (ESI + ):[M+H] + 656.2 / 658.2.

[0601] Synthesis of intermediates required for final product 063

[0602] 1-(3-Bromo-4-methoxy-phenyl)sulfonyl-4-phenyl-piperidine (I-047)

[0603]

[0604] According to GP-4, I-047 was obtained as a white solid in 99% yield using 3-bromo-4-methoxybenzenesulfonyl chloride (1.50 g, 5.25 mmol, 1 eq), 4-phenylpiperidine (1.02 g, 6.30 mmol, 1.2 eq) and Et3N (1.1 mL, 7.9 mmol, 1.5 eq) in DCM (10 mL) at RT for 2 h.

[0605] 1 H NMR (400 MHz, CHLOROFORM-d) 88.00 (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.

[0606] 1-[3-Bromo-4-(methoxymethoxy)phenyl]sulfonyl-4-phenyl-piperidine (I-048)

[0607]

[0608] BBr3 (1M solution in DCM, 10.4 mL, 10.4 mmol, 2 equivalents) was added to a DCM (10 mL) solution of I-047 (2.25 g, 5.21 mmol, 1 equivalent) at 0°C. The mixture was stirred for 60 h at RT. Water was added carefully and the layers were separated. The phase was extracted with DCM water, and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in DCM (20 ml) at RT, and iPr2NEt (3.6 mL, 21 mmol, 4 equivalents) and chloromethyl methyl ether (0.79 mL, 10.4 mmol, 2 equivalents) were added dropwise. The mixture was stirred for 1 h at RT. It was distributed 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 (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=97 / 3 to 70 / 30) to give 1.74 g of I-048 as a white solid (74% for two steps).

[0609] 1H NMR (400 MHz, CHLOROFORM-d) δ8.01 (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

[0610] (2-Chloro-4-fluoro-phenyl)-[8-[2-(methoxymethoxy)-5-[(4-phenyl-1-piperidinyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-049)

[0611]

[0612] According to GP-5, aryl bromide I-048 (1.20 g, 2.72 mmol, 1 eq), piperazine I-001 (0.88 g, 3.3 mmol, 1.2 eq), Cs2CO3 (1.77 g, 5.45 mmol, 2 eq), Pd(OAc)2 (61 mg, 0.27 mmol, 0.1 eq) and racemic-BINAP (204 mg, 327 μmol, 0.12 eq) were used in toluene (14 mL) under reflux for 3.5 h to obtain I-049 as a white foam in 87% yield. Purification by FC (cHex / EtOAc=94 / 6 to 40 / 60).

[0613] 1 H NMR (400 MHz, chloroform-d, 2 groups 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 groups of rotational isomers) δ -109.1, -109.3. MS (ESI +):[M+H] + 628.2 / 630.2.

[0614] Synthesis of intermediates required for final product 064

[0615] 2-Bromo-4-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-phenol (I-050)

[0616]

[0617] A solution of 3-bromo-4-hydroxy-benzenesulfonyl chloride (800 mg, 2.80 mmol, 1 eq) in DCM (10 mL) was added dropwise to a solution of 1-[2-(4-chlorophenyl)ethyl]piperazine dihydrochloride (1.08 g, 3.64 mmol, 1.3 eq) and EtN (3.9 mL, 28 mmol, 10 eq) in DCM (14 mL) at RT. The mixture was stirred for 4 h at RT. A saturated aqueous solution of NHCl and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (NaSO), filtered and concentrated under reduced pressure. The residue was purified by FC (DCM / MeOH=99 / 1 to 90 / 10) to give 623 mg of I-050 (44%) as a beige solid.

[0618] 1 H NMR (400 MHz, DMSO-d s )δ11.48(s,1H),7.78(d,J=2.2Hz,1H),7.58(dd,J=8.6,2.3Hz,1H),7.36-7.25(m,2 H),7.25-7.19(m,2H),7.15(d,J=8.6Hz,1H),2.88(s,4H),2.75-2.50(m,8H).MS(ESI + ):[M+H] + 459.1 / 461.1 / 463.0.

[0619] 1-[3-Bromo-4-(methoxymethoxy)phenyl]sulfonyl-4-[2-(4-chlorophenyl)ethyl]piperazine (I-051)

[0620]

[0621] Chloromethyl methyl ether (0.19 mL, 2.4 mmol, 2 eq) was added to a solution of I-050 (623 mg, 1.22 mmol, 1 eq) and iPr2NEt (0.64 mL, 3.7 mmol, 3 eq) in DCM (6 mL) at RT. The mixture was stirred for 16 h at RT. It was distributed between EtOAc and a saturated aqueous solution of NaHCO3. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=95 / 5 to 50 / 50) to give 0.51 g of I-051 (83%) as a white solid.

[0622] 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.

[0623] (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)

[0624]

[0625] According to GP-5, aryl bromide I-051 (0.51 g, 1.0 mmol, 1 eq), piperazine I-001 (0.33 g, 1.2 mmol, 1.2 eq), K2CO3 (0.28 g, 2.0 mmol, 2 eq), Pd(OAc)2 (23 mg, 0.10 mmol, 0.1 eq) and racemic-BINAP (75.6 mg, 121 μmol, 0.12 eq) were used in toluene (5 mL) under reflux for 16 h to obtain I-052 as a white foam in 51% yield. Purification by FC (cHex / EtOAc=90 / 10 to 10 / 90).

[0626] 1H NMR (400 MHz, chloroform-d, 2 groups 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 groups of rotational isomers) δ -109.2, -109.3. MS (ESI + ):[M+H] + 691.4 / 693.4 / 695.4.

[0627] Synthesis of intermediates required for final product 065

[0628] 1-(3-Bromo-4-methoxy-phenyl)sulfonyl-4-(4-fluorophenyl)piperidine (I-053)

[0629]

[0630] According to GP-4, I-053 was obtained as a white solid in 90% yield using 3-bromo-4-methoxybenzenesulfonyl chloride (637 mg, 2.23 mmol, 1 eq), 4-(fluorophenyl)piperidine (400 mg, 2.23 mmol, 1 eq) and iPr2NEt (0.78 mL, 4.5 mmol, 2 eq) in DCM (11 mL) at RT for 16 h.

[0631] 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.

[0632] 2-Bromo-4-[[4-(4-fluorophenyl)-1-piperidinyl]sulfonyl-phenol (I-054)

[0633]

[0634] BBr3 (1M solution in DCM, 4.0 mmol, 2 eq) was added to a solution of I-053 (0.86 g, 2.0 mmol, 1 eq) in DCM (4 mL) at 0°C. The mixture was stirred for 60 h at RT. Water was carefully added and the layers were separated. The phases were extracted with DCM water and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (DCM 100%) to give 285 mg of I-054 (34%) as a white solid.

[0635] 1 H NMR (400 MHz, chloroform-d) δ7.94 (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.

[0636] 1-[3-Bromo-4-(methoxymethoxy)phenyl]sulfonyl-4-(4-fluorophenyl)piperidine (I-055)

[0637]

[0638] Chloromethyl methyl ether (0.10 mL, 1.3 mmol, 2 eq) was added to a solution of I-054 (285 mg, 674 micromol, 1 eq) and iPr2NEt (0.35 mL, 2.0 mmol, 3 eq) in DCM (3 mL) at RT. The mixture was stirred for 16 h at RT. 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 (Na2SO4), filtered and concentrated under reduced pressure to give 0.31 g of I-055 (81%) as a yellow oil.

[0639] 1 H NMR (400 MHz, chloroform-d) δ7.96 (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.

[0640] (2-Chloro-4-fluoro-phenyl)-[8-[5-[[4-(4-fluorophenyl)-1-piperidinyl]sulfonyl]-2-(methoxymethoxy)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-056)

[0641]

[0642] According to GP-5, aryl bromide I-055 (309 mg, 613 μmol, 1 eq.), piperazine I-001 (0.20 g, 0.73 mmol, 1.2 eq.), Cs2CO3 (600 mg, 1.84 mmol, 3 eq.), Pd(OAc)2 (14 mg, 61 μmol, 0.1 eq.) and racemic-BINAP (46 mg, 74 μmol, 0.12 eq.) were used in toluene (3.1 mL) under reflux for 16 h to obtain I-056 as a white foam in 66% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0643] 1 H NMR (400 MHz, chloroform-d, 2 groups 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.

[0644] Synthesis of intermediates required for final product 066

[0645] 1-(3-Bromo-4-chloro-phenyl)sulfonyl-4-phenyl-piperidine (I-057)

[0646]

[0647] According to GP-4, commercially available 3-bromo-4-chlorobenzenesulfonyl chloride (200 mg, 690 micromol, 1 eq.), 4-phenylpiperidine (122 mg, 759 micromol, 1.1 eq.) and Et3N (144 μL, 1.03 mmol, 1.5 eq.) were used in DCM (3.4 mL) at RT for 16 h to obtain I-057 as a white solid in 58% yield. Purification by FC (cHex / EtOAc=97 / 3 to 70 / 30).

[0648] 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.

[0649] Synthesis of intermediates required for final product 067

[0650] 1-(3-Bromo-4-methyl-phenyl)sulfonyl-4-phenyl-piperidine (I-058)

[0651]

[0652] According to GP-4, I-058 was obtained as a white solid in 72% yield using commercially available 3-bromo-4-methylbenzenesulfonyl chloride (200 mg, 741 μmol, 1 eq), 4-phenylpiperidine (132 mg, 816 μmol, 1.1 eq) and Et3N (144 μL, 1.03 mmol, 1.5 eq) in DCM (3.4 mL) at RT for 16 h.

[0653] 1 H NMR (400 MHz, CHLOROFORM-d) δ7.89 (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.

[0654] Synthesis of intermediates required for final product 068

[0655] 3-Bromo-N,4-dimethyl-N-propyl-benzenesulfonamide (I-059)

[0656]

[0657] According to GP-4, I-059 was obtained as a white solid in 88% yield using commercially available 3-bromo-4-methylbenzenesulfonyl chloride (60.0 mg, 223 μmol, 1 eq), methyl-N-propylamine (30 μL, 0.29 mmol, 1.3 eq) and Et3N (93 μL, 0.67 mmol, 3 eq) in DCM (1.1 mL) at RT for 1 h.

[0658] 1 H NMR (400 MHz, CHLOROFORM-d) δ7.94 (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.

[0659] Synthesis of intermediates required for final product 069

[0660] Methyl 2-bromo-4-[(4-phenyl-1-piperidinyl)sulfonyl]benzoate (I-060)

[0661]

[0662] According to GP-4, 3-bromo-4-methyl-2-bromo-4-chlorosulfonylbenzoate (1.36 g, 4.34 mmol, 1 eq), 4-phenylpiperidine (769 mg, 4.77 mmol, 1.1 eq) and iPrNEt (1.14 mL, 6.50 mmol, 1.5 eq) were used in DCM (43 mL) at RT for 16 h to obtain I-060 as a white solid in 48% yield. Purification was performed by FC (cHex / EtOAc=93 / 7 to 30 / 70).

[0663] 1H 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.

[0664] Synthesis of intermediates required for final product 074

[0665] 3-Bromo-5-chloro-4-methyl-aniline (I-061)

[0666]

[0667] Zn (3.62 g, 55.3 mmol, 10 eq) was added to a solution of 1-bromo-3-chloro-2-methyl-5-nitro-benzene (1.39 g, 5.53 mmol, 1 eq) in AcOH (31 mL) at RT. The mixture was stirred for 4 h at RT. The suspension was filtered with diatomaceous earth (EtOAc rinse) and the combined filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=98 / 2 to 80 / 20) to give 967 mg (79%) of I-061 as a brown solid.

[0668] 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.

[0669] 3-Bromo-5-chloro-4-methyl-benzenesulfonyl chloride (I-062)

[0670]

[0671] Sulfuryl chloride (1.3mL, 18 mmoles, 8 equivalents) was added dropwise to a solution of CuCl (27mg, 0.27 mmoles, 0.12 equivalents) in water (7mL) at 0°C. The mixture was stirred at RT for 1.5h. Meanwhile, a solution of 37% HCl (16mL) and NaNO2 (172mg, 2.49 mmoles, 1.1 equivalents) in water (7mL) was added to a solution of aniline I-061 (500mg, 2.27 mmoles, 1 equivalent) in water (30mL) at 0°C. The mixture was stirred at 0°C for 30 minutes. The first solution was then added dropwise and the resulting mixture was vigorously stirred at RT for 2h. It was filtered with sintered 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 obtain 157mg (23%) of I-062 as a brown solid.

[0672] 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).

[0673] 3-Bromo-N-tert-butyl-5-chloro-4-methyl-benzenesulfonamide (I-063)

[0674]

[0675] According to GP-4, I-062 (157 mg, 0.516 mmol, 1 eq) and tert-butylamine (0.54 mL, 5.17 mmol, 10 eq) were used in DCM (2 mL) at RT for 16 h to obtain I-063 as a beige solid in 68% yield. Purification by FC (cHex / EtOAc=98 / 2 to 80 / 20).

[0676] 1 H NMR (400 MHz, chloroform-d) δ7.97 (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.

[0677] Synthesis of intermediates required for final product 075

[0678] 3-Bromo-4,5-dichloro-benzenesulfonyl chloride (I-064)

[0679]

[0680] Sulfuryl chloride (1.2mL, 17 mmoles, 8 equivalents) was added dropwise to a water (30mL) solution of CuCl (25mg, 0.25 mmoles, 0.12 equivalents) at 0°C. The mixture was stirred at RT for 1.5h. Meanwhile, a water (7mL) solution of 37% HCl (16mL) and NaNO2 (158mg, 2.28 mmoles, 1.1 equivalents) was added to a water (30mL) solution of 3-bromo-4,5-dichloroaniline (500mg, 2.08 mmoles, 1 equivalent) at 0°C. The mixture was stirred at 0°C for 30 minutes. The first solution was then added dropwise and the resulting mixture was vigorously stirred at RT for 2h. It was filtered with sintered 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 obtain 673mg (100%) of I-064 as a brown solid.

[0681] 1 H NMR (400 MHz, chloroform-d) δ 8.20 (d, J = 2.2 Hz, 1H), 8.09 (d, J = 2.2 Hz, 1H).

[0682] 3-Bromo-N-tert-butyl-4,5-dichloro-benzenesulfonamide (I-065)

[0683]

[0684] According to GP-4, I-064 (673 mg, 2.07 mmol, 1 eq.), tert-butylamine (0.26 mL, 2.49 mmol, 1.2 eq.) and Et3N (0.43 mL, 3.1 mmol, 1.5 eq.) were used in DCM (4 mL) at RT for 16 h to obtain I-065 as an orange solid in 14% yield. Purification by FC (cHex / EtOAc=98 / 2 to 80 / 20).

[0685] 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.

[0686] Synthesis of intermediates required for final product 079

[0687] [2-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-4-[methyl(propyl)sulfamoyl]phenyl]trifluoromethanesulfonate (I-066)

[0688]

[0689] Et3N (0.16 mL, 1.2 mmol, 2 eq) and Tf2O (0.19 mL, 1.2 mmol, 2 eq) were added to a solution of 036 (70% purity, 410 mg, 579 micromol, 1 eq) in dry DCM (5.8 mL) at 0°C. The mixture was stirred for 2 h at RT. NaHCO3 saturated aqueous solution and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=95 / 5 to 50 / 50) to give 359 mg (99%) of I-066 as a white foam.

[0690] 1 H NMR (400 MHz, chloroform-d, 2 groups 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 rotational isomers) δ -73.82, -73.84, -109.0, -109.1. MS (ESI + ):[M+H] + 628.1 / 630.1.

[0691] Synthesis of intermediates required for final products 080 and 081

[0692] [2-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-[(4-phenyl-1-piperidinyl)sulfonyl]phenyl]trifluoromethanesulfonate (I-067)

[0693]

[0694] Et3N (0.12 mL, 0.86 mmol, 5 eq) and Tf2O (0.060 mL, 0.34 mmol, 2 eq) were added to a solution of 063 (100 mg, 171 micromol, 1 eq) in dry DCM (1.7 mL) at 0°C. The mixture was stirred for 2 h at RT. A saturated aqueous solution of NH4Cl and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=96 / 4 to 60 / 40) to give 115 mg (94%) of I-067 as a yellow foam.

[0695] 1 H NMR (400 MHz, chloroform-d, 2 groups of rotamers) δ7.46-7.33 (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=12.5Hz,1H),3.36&3.33(s,1H),3.18 (d,J=12.5Hz,1H),2.52-2.37(m,3H),2.10-1.74(m,7.5H),1.73-1.62(m,0.5H). 19 F NMR (376MHz,

[0696] Chloroform-d, 2 groups of rotational isomers)δ-73.78,-73.81,-108.9,-109.1.MS(ESI + ):[M+H] + 716.2 / 718.2.

[0697] Synthesis of intermediates required for final product 083

[0698] 3-Bromo-5-chloro-4-hydroxy-benzenesulfonyl chloride (I-068)

[0699]

[0700] According to GP-3, I-068 was obtained as a yellow solid in 82% yield using 2-bromo-6-fluoro-phenol (1.02 g, 5.35 mmol, 1 eq) in HSO 3 Cl (8.36 mL, 107 mmol, 20 eq) at RT for 2 h.

[0701] 1H 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.

[0702] 2-Bromo-6-fluoro-4-[(4-phenyl-1-piperidinyl)sulfonyl]phenol (I-069)

[0703]

[0704] According to, I-068 (1.27 g, 4.39 mmol, 1 eq), 4-phenylpiperidine (1.06 g, 6.58 mmol, 1.5 eq) and iPr2NEt (2.29 mL, 13.1 mmol, 3 eq) were used in DCM (22 mL) at RT for 1 h to obtain I-069 as a white solid in 88% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0705] 1 H NMR(400MHz, DMSO-d6)δ7.58(s,1H),7.43(dd,J=10.3,2.2Hz,1H),7.32-7.24(m,2H),7.23-7.15(m,3H),3.79-3.67(m,2 H),3.62(p,J=6.6Hz,1H),3.40(brs,1H),2.34(td,J=12.0,2.5Hz,2H),1.87-1.77(m,2H),1.66(qd,J=12.6,4.0Hz,2H). 19 F NMR(376MHz,DMSO-d6)δ-130.4.MS(ESI + ):[M+H] + 414.0 / 416.0 / 418.0.

[0706] 1-[3-Bromo-5-fluoro-4-(methoxymethoxy)phenyl]sulfonyl-4-phenyl-piperidine (I-070)

[0707]

[0708] Chloromethyl methyl ether (0.59 mL, 7.7 mmol, 2 eq) was added to a solution of I-069 (1.60 g, 3.86 mmol, 1 eq) and iPr2NEt (2.02 mL, 11.6 mmol, 3 eq) in DCM (3 mL) at RT. The mixture was stirred for 1 h at RT. A saturated aqueous solution of NaHCO3 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 give 1.85 g of I-070 (100%) as a colorless oil.

[0709] 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.

[0710] (2-Chloro-4-fluoro-phenyl)-[8-[3-fluoro-2-(methoxymethoxy)-5-[(4-phenyl-1-piperidinyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-071)

[0711]

[0712] According to GP-5, aryl bromide I-070 (300 mg, 622 μmol, 1 eq.), piperazine I-001 (0.20 g, 0.75 mmol, 1.2 eq.), Cs2CO3 (608 mg, 1.86 mmol, 3 eq.), Pd(OAc)2 (14 mg, 62 μmol, 0.1 eq.) and racemic-BINAP (58 mg, 93 μmol, 0.15 eq.) were used in toluene (3.1 mL) under reflux for 16 h to obtain I-071 as a white foam in 14% yield. Purification was performed by FC (cHex / EtOAc=95 / 5 to 50 / 50) and PTLC (DCM / EtOAc=95 / 5).

[0713] 1H NMR (400 MHz, chloroform-d, 2 groups 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 rotational isomers) δ -108.9, -109.1, -125.2, -125.3. MS (ESI + ):[M+H] + 646.2 / 648.1.

[0714] Synthesis of intermediates required for final products 084 to 086

[0715] 1-Bromo-3-chloro-2-(methoxymethoxy)benzene (I-072)

[0716]

[0717] Chloromethyl methyl ether (0.60 mL, 7.8 mmol, 2 eq) was added to a solution of 2-bromo-6-fluoro-phenol (1.00 g, 5.24 mmol, 1 eq) and iPr2NEt (2.74 mL, 15.7 mmol, 3 eq) in DCM (26 mL) at RT. The mixture was stirred for 1 h at RT. 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 give 920 mg of I-072 (75%) as a colorless oil.

[0718] 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.

[0719] (2-Chloro-4-fluoro-phenyl)-[8-[3-fluoro-2-(methoxymethoxy)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-073)

[0720]

[0721] According to GP-5, aryl bromide I-072 (920 mg, 3.91 mmol, 1 eq), piperazine I-001 (1.16 g, 4.31 mmol, 1.1 eq), Cs2CO3 (3.82 g, 11.7 mmol, 3 eq), Pd(OAc)2 (87.9 mg, 391 μmol, 0.1 eq) and racemic-BINAP (292 mg, 470 μmol, 0.12 eq) were used in toluene (20 mL) under reflux for 16 h to obtain I-073 as a white foam in 73% yield. Purification by FC (cHex / EtOAc=92 / 8 to 20 / 80).

[0722] 1 H NMR (400 MHz, chloroform-d2 group rotamer) δ7.36 (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, 2 H),4.55-4.45(m,1H),4.28(d,J=6.4Hz,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 FNMR (376MHz, chloroform-d, 2 groups of rotational isomers) δ-109.3, -109.4, -129.2, -129.3. MS (ESI + ):[M+H] + 423.1 / 425.1.

[0723] (2-Chloro-4-fluoro-phenyl)-[8-(3-fluoro-2-hydroxy-phenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-074)

[0724]

[0725] CFCOH (4.4 mL, 57 mmol, 20 eq) was added to a solution of I-073 (1.20 g, 2.84 mmol, 1 eq) in DCM (14 mL) at RT. The mixture was stirred for 2 h at RT. 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 give 833 mg of I-074 (78%) as a white foam.

[0726] 1 H NMR (400 MHz, chloroform-d, 2 groups of rotamers) δ 7.37 (dd, J = 8.5, 5.8 Hz, 0.5 H), 7.23-7.13 (m, 1.5 H), 7.12-7.00 (m, 1 H), 6.84-6.70 (m, 2 H), 6.63 (t, J = 8.9 Hz, 1 H), 4.87 (s, 1 H), 4.57 & 4.55 (s, 1 H), 4.06 (s, 1 H), 3.84 (s, 1 H), 3.71-3.50 (m, 1 H), 3.35 & 3.31 (d, J = 5.9 Hz, 1 H), 3.18 (d, J = 12.5 Hz, 1 H), 2.04-1.88 (m, 3.5 H), 1.70-1.60 (m, 0.5 H). 19 F NMR (376 MHz, chloroform-d, 2 sets of rotational isomers) δ -109.13, -109.14, -137.5, -137.7. MS (ESI + ):[M+H] + 379.1 / 381.1.

[0727] 3-[3-(2-Chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-5-fluoro-4-hydroxy-benzenesulfonyl chloride (I-075)

[0728]

[0729] According to GP-3, I-074 (510 mg, 1.34 mmol, 1 eq) and HSO 3 Cl (1.8 mL, 27 mmol, 20 eq) in DCM (7 mL) were used at RT for 5 h to obtain I-075 as a white foam in 83% yield.

[0730] 1H NMR (400 MHz, chloroform-d, 2 groups of rotamers) 87.47 (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 (brs, 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.

[0731] Synthesis of intermediates required for final products 087 to 089

[0732] 1-Bromo-2-(methoxymethoxy)-3-(trifluoromethyl)benzene (I-076)

[0733]

[0734] Chloromethyl methyl ether (0.26 mL, 3.4 mmol, 2 eq) was added to a solution of 2-bromo-6-(trifluoromethyl)phenol (675 mg, 2.80 mmol, 1 eq) and iPr2NEt (0.73 mL, 4.2 mmol, 1.5 eq) in DCM (6 mL) at RT. The mixture was stirred for 1 h at RT. 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 give 700 mg of I-076 (88%) as a colorless oil.

[0735] 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.

[0736] (2-Chloro-4-fluoro-phenyl)-[8-[2-(methoxymethoxy)-3-(trifluoromethyl)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-077)

[0737]

[0738] According to GP-5, aryl bromide I-076 (690 mg, 2.42 mmol, 1 eq), piperazine I-001 (780 mg, 2.90 mmol, 1.2 eq), Cs2CO3 (2.37 g, 7.26 mmol, 3 eq), Pd(OAc)2 (54.3 mg, 242 μmol, 0.1 eq) and racemic-BINAP (181 mg, 291 μmol, 0.12 eq) were used in toluene (12 mL) under reflux for 5 h to obtain I-077 as a white foam in 71% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0739] 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 rotational isomers) δ -60.36, -60.40, -109.3, -109.4. MS (ESI + ):[M+H] + 473.1 / 475.0.

[0740] (2-Chloro-4-fluoro-phenyl)-[8-[2-hydroxy-3-(trifluoromethyl)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-078)

[0741]

[0742] CFCOH (2.64 mL, 34 mmol, 20 eq) was added to a solution of I-077 (810 mg, 1.71 mmol, 1 eq) in DCM (8.6 mL) at RT. The mixture was stirred for 1 h at RT. 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 give 713 mg of I-078 (97%) as a white foam.

[0743] 1 H NMR (400 MHz, chloroform-d, 2 groups 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 rotational isomers) δ -62.31, -62.33, -108.9, -109.0. MS (ESI + ):[M+H] + 429.0 / 431.0.

[0744] 3-[3-(2-Chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-4-hydroxy-5-(trifluoromethyl)benzenesulfonyl chloride (I-079)

[0745]

[0746] According to GP-3, I-079 was obtained as a white foam in 100% yield using I-078 (710 mg, 1.66 mmol, 1 eq) and HSO 3 Cl (2.2 mL, 33 mmol, 20 eq) in DCM (2 mL) at RT for 16 h.

[0747] 1 H NMR (400 MHz, chloroform-d, 2 groups 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 (brs, 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 rotational isomers) δ -62.94, -62.96, -108.3, -108.4.

[0748] Synthesis of intermediates required for final product 090

[0749] 3-Bromo-4-hydroxy-5-methyl-benzenesulfonyl chloride (I-080)

[0750]

[0751] According to GP-3, I-080 was obtained as a brown solid in 68% yield using 2-bromo-6-methyl-phenol (1.00 g, 5.35 mmol, 1 eq) in HSO 3 Cl (8.36 mL, 107 mmol, 20 eq) at RT for 2 h.

[0752] 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).

[0753] 2-Bromo-6-methyl-4-[(4-phenyl-1-piperidinyl)sulfonyl]phenol (I-081)

[0754]

[0755] According to, I-080 (1.04 g, 3.64 mmol, 1 eq), 4-phenylpiperidine (881 mg, 5.46 mmol, 1.5 eq) and iPr2NEt (1.90 mL, 10.9 mmol, 3 eq) were used in DCM (18 mL) at RT for 1 h to obtain I-081 as a white solid in 60% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0756] 1 H NMR (400MHz, DMSO-d6) δ10.23(s,1H),7.68(d,J=2.3Hz,1H),7.53(d,J=2.2Hz,1H),7.33-7.24(m,2H),7.23-7.1 6(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.

[0757] 1-[3-Bromo-4-(methoxymethoxy)-5-methyl-phenyl]sulfonyl-4-phenyl-piperidine (I-082)

[0758]

[0759] Chloromethyl methyl ether (0.33 mL, 4.4 mmol, 2 eq) was added to a solution of I-081 (900 mg, 2.19 mmol, 1 eq) and iPr2NEt (1.15 mL, 6.58 mmol, 3 eq) in DCM (11 mL) at RT. The mixture was stirred for 1 h at RT. A saturated aqueous solution of NaHCO3 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 give 880 mg of I-082 (89%) as a colorless oil.

[0760] 1 H NMR (400 MHz, chloroform-d) δ7.84 (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.

[0761] (2-Chloro-4-fluoro-phenyl)-[8-[2-(methoxymethoxy)-3-methyl-5-[(4-phenyl-1-piperidinyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-083)

[0762]

[0763] According to GP-5, aryl bromide I-082 (230 mg, 460 μmol, 1 eq.), piperazine I-001 (0.15 g, 0.55 mmol, 1.2 eq.), Cs2CO3 (450 mg, 1.38 mmol, 3 eq.), Pd(OAc)2 (10 mg, 46 μmol, 0.1 eq.) and racemic-BINAP (43 mg, 69 μmol, 0.15 eq.) were used in toluene (2.3 mL) under reflux for 16 h to obtain I-083 as a white foam in 44% yield. Purification by FC (cHex / EtOAc=90 / 10 to 10 / 90).

[0764] 1H NMR (400 MHz, chloroform-d, 2 groups 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 rotational isomers) δ -109.1, -109.2. MS (ESI + ):[M+H] + 642.2 / 644.1.

[0765] Synthesis of intermediates required for final products 091 to 093

[0766] 1-Bromo-2-(methoxymethoxy)-3-methyl-benzene (I-084)

[0767]

[0768] Chloromethyl methyl ether (0.49 mL, 6.4 mmol, 1.2 eq) was added to a solution of 2-bromo-6-methyl-phenol (1.00 g, 5.35 mmol, 1 eq) and iPr2NEt (1.4 mL, 8.1 mmol, 1.5 eq) in DCM (21 mL) at RT. The mixture was stirred for 60 h at RT. 1 N 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 give 1.22 g of I-084 (99%) as a colorless oil.

[0769] 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).

[0770] (2-Chloro-4-fluoro-phenyl)-[8-[2-(methoxymethoxy)-3-methyl-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-085)

[0771]

[0772] According to GP-7, aryl bromide I-084 (811 mg, 3.51 mmol, 1 eq), piperazine I-001 (1.22 g, 4.56 mmol, 1.3 eq), t-BuONa (1.01 g, 10.5 mmol, 3 eq) and XPhos-Pd-G3 (148 mg, 175 μmol, 0.05 eq) were used in toluene (14 mL) under reflux for 4 h to obtain I-085 as a white foam in 24% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0773] 1 H NMR (400MHz, chloroform-d, 2 groups of rotational isomers) δ7.42-7.35 (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=6.1Hz,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=11.1Hz,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 groups of rotational isomers) δ -109.5, -109.6. MS (ESI + ):[M+H] + 419.1 / 421.0.

[0774] (2-Chloro-4-fluoro-phenyl)-[8-(2-hydroxy-3-methyl-phenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-086)

[0775]

[0776] CF3CO2H (1.3 mL, 17 mmol, 20 eq) was added to a solution of I-085 (350 mg, 0.835 mmol, 1 eq) in DCM (4.2 mL) at RT. The mixture was stirred at RT for 24 h. It was concentrated under reduced pressure and the residue was azeotroped with toluene to give 330 mg of I-086 (100%) as a white foam.

[0777] 1H NMR (400 MHz, chloroform-d, 2 groups of rotamers) 67.40 (dd, J = 8.5, 5.8 Hz, 0.5 H), 7.26-7.15 (m, 1.5 H), 7.15-7.05 (m, 1 H), 7.01-6.88 (m, 1 H), 6.88-6.60 (m, 2 H), 4.65 & 4.62 (dd, J = 2.7, 1.4 Hz, 1 H), 3.84-3.61 (m, 2 H), 3.56-3.48 (m, 2 H), 3.40-3.17 (m, 2 H), 2.29 (s, 3 H), 2.24-1.90 (m, 3.5 H), 1.73-1.65 (m, 0.5 H). 19 F NMR (376MHz, chloroform-d, 2 groups of rotational isomers) δ -109.07, -109.11.MS (ESI + ):[M+H] + 375.1 / 377.1.

[0778] 3-[3-(2-Chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-4-hydroxy-5-methyl-benzenesulfonyl chloride (I-087)

[0779]

[0780] According to GP-3, I-087 was obtained as a beige foam in 100% yield using I-086 (330 mg, 0.863 mmol, 1 eq) and HSO 3 Cl (1.4 mL, 22 mmol, 20 eq) in DCM (3.5 mL) at RT for 1 h.

[0781] 1 H NMR (400 MHz, chloroform-d, 2 groups 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 FNMR (376 MHz, chloroform-d, 2 sets of rotational isomers) δ -108.6, -108.8.

[0782] Synthesis of intermediates required for final product 094

[0783] 1-Bromo-3-ethyl-2-(methoxymethoxy)benzene (I-088)

[0784]

[0785] Chloromethyl methyl ether (0.23 mL, 3.0 mmol, 1.2 eq) was added to a solution of 2-bromo-6-ethyl-phenol (500 mg, 2.49 mmol, 1 eq) and iPr2NEt (0.65 mL, 3.7 mmol, 1.5 eq) in DCM (12 mL) at RT. The mixture was stirred for 16 h at RT. A saturated aqueous solution of NH4Cl 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 give 647 mg of I-088 (100%) as a colorless oil.

[0786] 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).

[0787] (2-Chloro-4-fluoro-phenyl)-[8-[3-ethyl-2-(methoxymethoxy)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-089)

[0788]

[0789] According to GP-5, aryl bromide I-088 (640 mg, 2.61 mmol, 1 eq), piperazine I-001 (842 mg, 3.13 mmol, 1.2 eq), Cs2CO3 (2.55 g, 7.83 mmol, 3 eq), Pd(OAc)2 (58.6 mg, 261 μmol, 0.1 eq) and racemic-BINAP (195 mg, 313 μmol, 0.12 eq) were used in toluene (13 mL) under reflux for 3 h to obtain I-089 as a white foam in 68% yield. Purification by FC (cHex / EtOAc=90 / 10 to 10 / 90).

[0790] 1 H NMR (400 MHz, chloroform-d, 2 sets of rotational isomers) 1HNMR (400 MHz, chloroform-d, 2 groups of rotational isomers) δ7.38 (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), 4.62-4.4 5(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=7.4Hz,3H). 19 F NMR (376 MHz, chloroform-d, 2 groups of rotational isomers) δ -109.5, -109.6. MS (ESI + ):[M+H] + 433.1 / 435.0.

[0791] (2-Chloro-4-fluoro-phenyl)-[8-(3-ethyl-2-hydroxy-phenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-090)

[0792]

[0793] CFCOH (2.7 mL, 34 mmol, 20 eq) was added to a solution of I-089 (750 mg, 1.73 mmol, 1 eq) in DCM (8.7 mL) at RT. The mixture was stirred for 24 h at RT. 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 give 618 mg of I-090 (92%) as a white foam.

[0794] 1H NMR (400 MHz, chloroform-d, 2 sets of rotamers) δ 7.40 (dd, J = 8.5, 5.8 Hz, 0.5 H), 7.26-7.15 (m, 1.5 H), 7.15-7.02 (m, 1 H), 7.02-6.90 (m, 1 H), 6.90-6.66 (m, 3 H), 4.68-4.54 (m, 1 H), 3.78-3.41 (m, 3 H), 3.36-3.14 (m, 2 H), 2.70 (q, J = 7.5 Hz, 2 H), 2.32-1.86 (m, 3.5 H), 1.77-1.65 (m, 0.5 H), 1.25 (t, J = 7.6 Hz, 3 H). 19 F NMR (376 MHz, chloroform-d, 2 groups of rotational isomers) δ -109.2, -109.3. MS (ESI + ):[M+H] + 389.0 / 391.0.

[0795] 3-[3-(2-Chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-5-ethyl-4-hydroxy-benzenesulfonyl chloride (I-091)

[0796]

[0797] According to GP-3, I-091 was obtained as a beige foam in 80% yield using I-090 (150 mg, 0.386 mmol, 1 eq) and HSO 3 Cl (0.51 mL, 7.7 mmol, 20 eq) in DCM (1 mL) at RT for 1 h.

[0798] 1 H NMR (400 MHz, chloroform-d, 2 groups 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 FNMR (376MHz, chloroform-d)δ-108.5.

[0799] Synthesis of intermediates required for final products 095 to 109

[0800] 1-Bromo-3-chloro-2-(methoxymethoxy)benzene (I-092)

[0801]

[0802] Chloromethyl methyl ether (0.95 mL, 13 mmol, 2 eq) was added to a solution of 2-bromo-6-chlorophenol (3.17 g, 10.5 mmol, 1 eq) and iPr2NEt (3.73 mL, 15.7 mmol, 1.5 eq) in DCM (21 mL) at RT. The mixture was stirred for 16 h at RT. Volatiles were removed under reduced pressure. EtOAc was added and the organic extract was washed (1N HCl, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=95 / 5) to give 2.59 g of I-092 (98%) as a colorless oil.

[0803] 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).

[0804] (2-Chloro-4-fluoro-phenyl)-[8-[3-chloro-2-(methoxymethoxy)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-093)

[0805]

[0806] According to GP-5, aryl bromide I-092 (1.20 g, 4.77 mmol, 1 eq), piperazine I-001 (1.54 g, 5.73 mmol, 1.2 eq), Cs2CO3 (4.66 g, 14.3 mmol, 3 eq), Pd(OAc)2 (107 mg, 477 μmol, 0.1 eq) and racemic-BINAP (357 mg, 573 μmol, 0.12 eq) were used in toluene (14 mL) under reflux for 5 h to obtain I-093 as a white foam in 79% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0807] 1H NMR (400 MHz, chloroform-d, 2 groups of rotamers) δ7.38 (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=5.4,2.3Hz,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=2.0Hz,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 rotational isomers) δ -109.3, -109.4. MS (ESI + ):[M+H] + 439.1 / 441.1 / 443.1.

[0808] (2-Chloro-4-fluoro-phenyl)-[8-(3-chloro-2-hydroxy-phenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-094)

[0809]

[0810] CF3CO2H (5.6 mL, 73 mmol, 20 eq) was added to a solution of I-093 (1.60 g, 3.64 mmol, 1 eq) in DCM (18 mL) at RT. The mixture was stirred for 3 h at RT. 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 give 1.47 g of I-094 (99%) as a white foam.

[0811] 1 H NMR (400 MHz, chloroform-d, 2 groups 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 (brs, 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 rotational isomers) δ -109.1, -109.2. MS (ESI + ):[M+H] + 395.0 / 397.O / 399.0.

[0812] 3-Chloro-5-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-4-hydroxy-benzenesulfonyl chloride (I-095)

[0813]

[0814] According to GP-3, I-094 (735 mg, 1.77 mmol, 1 eq) and HSO 3 Cl (2.9 mL, 44 mmol, 20 eq) were used in DCM (7 mL) at RT for 4 h to obtain I-095 as a beige solid in 97% yield.

[0815] 1 H NMR (400 MHz, chloroform-d, 2 groups 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 rotational isomers) δ -108.7, -108.8.

[0816] Synthesis of intermediates required for final product 110

[0817] (2-Chloro-4-fluoro-phenyl)-[(3S)-4-[3-chloro-2-(methoxymethoxy)phenyl]-3-methyl-piperazin-1-yl]methanone ((S)-I-096)

[0818]

[0819] According to GP-5, aryl bromide I-092 (0.41 g, 1.63 mmol, 1 eq), piperazine (S)-I-003 (502 mg, 1.96 mmol, 1.2 eq), Cs2CO3 (4.66 g, 4.89 mmol, 3 eq), Pd(OAc)2 (36.6 mg, 163 μmol, 0.1 eq) and racemic-BINAP (122 mg, 196 μmol, 0.12 eq) were used in toluene (8.2 mL) under reflux for 6 h to obtain (S)-I-096 as a white foam in 4% yield. Purification was performed by FC (cHex / EtOAc=94 / 6 to 40 / 60) and PTLC (cHex / EtOAc=70 / 30).

[0820] 1 H NMR (400 MHz, chloroform-d, multiple groups of rotational isomers) 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 groups of rotational isomers) δ -109.17, -109.20, -109.24, -109.27. MS (ESI + ):[M+H] + 427.0 / 429.0 / 431.0.

[0821] (2-Chloro-4-fluoro-phenyl)-[(3S)-4-(3-chloro-2-hydroxy-phenyl)-3-methyl-piperazin-1-yl]methanone ((S)-I-097)

[0822]

[0823] CFCOH (90 μL, 1.2 mmol, 20 eq) was added to a solution of (S)-I-096 (26 mg, 61 μmol, 1 eq) in DCM (0.3 mL) at RT. The mixture was stirred for 2 h at RT. 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 give 22 mg of (S)-I-097 (94%) as a white foam.

[0824] 1H NMR (400 MHz, chloroform-d, multiple groups 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 groups of rotational isomers) δ -108.87, -108.88, -108.93, -108.96. MS (ESI + ):[M+H] + 383.0 / 385.0 / 387.O.

[0825] 3-Chloro-5-[(2S)-4-(2-chloro-4-fluoro-benzoyl)-2-methyl-piperazin-1-yl]-4-hydroxy-benzenesulfonyl chloride ((S)-I-098)

[0826]

[0827] According to GP-3, (S)-I-097 (22 mg, 57 μmol, 1 eq) and HSO 3 Cl (0.10 mL, 1.4 mmol, 20 eq) were used in DCM (0.3 mL) and refluxed for 4 h to obtain (S)-I-098 as a beige solid in 90% yield.

[0828] 1 H NMR (400 MHz, chloroform-d, multiple groups of rotational isomers) 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 groups of rotational isomers) δ -108.40, -108.46, -108.49, -108.53.

[0829] Synthesis of intermediates required for final product 111

[0830] 3-Chloro-5-[(2R)-4-(2-chloro-4-fluoro-benzoyl)-2-methyl-piperazin-1-yl]-4-hydroxy-benzenesulfonyl chloride ((R)-I-098)

[0831] (R)-I-098 was obtained using the same synthetic sequence as (S)-I-098 starting from (R)-I-003.

[0832] 1 H NMR (400 MHz, chloroform-d, multiple 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 groups of rotational isomers) δ -108.40, -108.46, -108.49, -108.53.

[0833] Synthesis of intermediates required for final product 115

[0834] 3-Bromo-4-chloro-N-methyl-N-propyl-benzenesulfonamide (I-099)

[0835]

[0836] According to GP-4, I-099 was obtained as a white solid in 89% yield using commercially available 3-bromo-4-chlorobenzenesulfonyl chloride (300 mg, 1.03 mmol, 1 eq), methyl-N-propylamine (120 μL, 1.14 mmol, 1.1 eq) and Et3N (216 μL, 2.55 mmol, 1.5 eq) in DCM (5 mL) at RT for 16 h.

[0837] 1 H NMR (400 MHz, CHLOROFORM-d) δ8.04 (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.

[0838] Synthesis of intermediates required for final product 116

[0839] 1-(3-Bromo-4-methyl-phenyl)sulfonyl-4-[2-(4-fluorophenyl)ethyl]piperazine (I-100)

[0840]

[0841] According to GP-4, commercially available 3-bromo-4-methylbenzenesulfonyl chloride (200 mg, 742 μmol, 1 eq), 1-[2-(4-fluorophenyl)ethyl]piperazine dihydrochloride (229 mg, 0.816 mmol, 1.1 eq) and Et3N (0.52 mL, 3.7 mmol, 5 eq) were used in DCM (4 mL) at RT for 16 h to obtain I-100 as a white solid in 88% yield. Purification by FC (cHex / EtOAc=97 / 3 to 70 / 30).

[0842] 1 H NMR (400MHz, chloroform-d) δ7.92 (d, J=1.8Hz, 1H), 7.59 (dd, J=8.0, 1.9Hz, 1H), 7.40 (d, J=8.0Hz, 1H), 7.16-7. 06(m,2H),7.02-6.90(m,2H),3.06(t,J=4.8Hz,4H),2.75-2.68(m,2H),2.66-2.52(m,6H),2.48(s,3H). 19 F NMR (376MHz, chloroform-d) δ-117.0.MS (ESI + ):[M+H] + 440.9 / 442.9.

[0843] Synthesis of intermediates required for final product 117

[0844] [8-(1,3-Benzodioxin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-101)

[0845]

[0846] According to GP-7, 4-bromo-1,3-benzodioxole-(400 mg, 1.99 mmol, 1 eq), piperazine I-001 (642 mg, 2.39 mmol, 1.2 eq), t-BuONa (574 mg, 5.97 mmol, 3 eq) and XPhos-Pd-G3 (168 mg, 199 μmol, 0.1 eq) were used in toluene (10 mL) under reflux for 2 h to obtain I-101 as a white solid in 90% yield. Purification by FC (cHex / EtOAc=95 / 5 to 0 / 100).

[0847] 1H NMR (400 MHz, chloroform-d, 2 groups of rotamers) δ 7.36 (dd, J = 8.5, 5.8 Hz, 0.5 H), 7.23-6.95 (m, 2.5 H), 6.77 (t, J = 8.1 Hz, 1 H), 6.46-6.33 (m, 2 H), 5.90-5.84 (m, 2 H), 4.46-4.35 (m, 2 H), 4.26-4.20 (m, 1 H), 3.66-3.43 (m, 1 H), 3.33-3.25 (m, 1 H), 3.06-2.95 (m, 1 H), 2.12-1.87 (m, 3.5 H), 1.66-1.58 (m, 0.5 H). 19 F NMR (376 MHz, chloroform-d, 2 groups of rotational isomers) δ -109.4, -109.5. MS (ESI + ):[M+H] + 389.1 / 391.1.

[0848] 7-[3-(2-Chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-1,3-benzodioxole-5-sulfonyl chloride (I-102)

[0849]

[0850] According to GP-3, I-102 was obtained as a beige solid in 50% yield using I-101 (100 mg, 0.257 mmol, 1 eq) and HSO 3 Cl (0.34 mL, 5.1 mmol, 20 eq) in DCM (1.3 mL) at RT for 1 h.

[0851] 1 H NMR (400 MHz, chloroform-d, 2 groups 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 rotational isomers) δ -108.9, -109.0.

[0852] Synthesis of intermediates required for final product 118

[0853] 1-[(5-bromo-2,3-dihydro-1,4-benzodioxin-7-yl)sulfonyl]-4-phenyl-piperidine (I-103)

[0854]

[0855] According to GP-4, 1-103 was obtained as a white solid in 93% yield using 8-bromo-2,3-dihydro-1,4-benzodioxin-6-sulfonyl chloride (75 mg, 0.27 mmol, 1 eq), 4-phenylpiperidine (46 mg, 0.29 mmol, 1.2 eq) and Et3N (100 μL, 0.718 mmol, 3 eq) in DCM (1.2 mL) at RT for 1 h.

[0856] 1 H NMR (400 MHz, chloroform-d) δ7.56 (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.

[0857] Synthesis of intermediates required for final products 119 and 120

[0858] 1-[5-[(4-phenyl-1-piperidinyl)sulfonyl]indolin-1-yl]ethanone (I-104)

[0859]

[0860] According to GP-4, 1-acetyl-2,3-dihydro-1H-indole-5-sulfonyl chloride (300 mg, 1.15 mmol, 1 eq), 4-phenylpiperidine (223 mg, 1.39 mmol, 1.2 eq) and Et3N (480 μL, 3.46 mmol, 3 eq) were used in DCM (5.8 mL) at RT for 16 h to obtain I-104 as a white solid in 90% yield. Purification by FC (DCM / EtOAc=100 / 0 to 40 / 60).

[0861] 1H NMR (400MHz, chloroform-d) δ8.34(d,J=8.5Hz,1H),7.64(dd,J=8.6,1.9Hz,1H),7.59(d,J=1.9Hz,1H),7.29(dd,J=8.2,6.7Hz,2H),7.24-7.17(m,1H), 7.17-7.11(m,2H),4.16(t,J=8.6Hz,2H),3.95-3.85(m,2H),3.28(t,J=8.6Hz,2H),2.46-2.30(m,3H),2.27(s,3H),1.94-1.73(m,4H).MS(ESI + ):[M+H] + 385.0.

[0862] 5-[(4-phenyl-1-piperidinyl)sulfonyl]indoline (I-105)

[0863]

[0864] NaOH 32% (0.35 mL, 5.2 mmol, 5 eq) was added to a solution of I-104 (400 mg, 1.04 mmol, 1 eq) in THF / MeOH / H2O (4 / 2 / 1, 5 mL) at RT. The mixture was stirred at reflux for 16 h. The volatiles were removed under reduced pressure. The mixture was partitioned between water and DCM. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give 315 mg of I-105 (88%) as a light brown solid.

[0865] 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.

[0866] 1-Methyl-5-[(4-phenyl-1-piperidinyl)sulfonyl]indoline (I-106)

[0867]

[0868] NaH (60%, 84 mg, 2.1 mmol, 1.5 eq. in mineral oil) was added to a DMF (5.6 mL) solution of I-105 (530 mg, 1.39 mmol, 1 eq.) at 0°C. The mixture was stirred at RT for 30 minutes and iodomethane (0.13 mL, 2.09 mmol, 1.5 eq.) was added. The resulting mixture was stirred at RT for 16 h. A saturated aqueous solution of NH4Cl and EtOAc were added. Each layer was added 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 / DCM (70 / 30) / EtOAc=98 / 2 to 80 / 20) to obtain 333 mg of I-106 (67%) as a white solid.

[0869] 1 H NMR (400 MHz, CHLOROFORM-d) δ7.54 (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.

[0870] 7-Bromo-1-methyl-5-[(4-phenyl-1-piperidinyl)sulfonyl]indoline (I-107)

[0871]

[0872] N-Bromosuccinimide (237 mg, 1.33 mmol, 1.6 eq) was added to a solution of I-106 (333 mg, 0.831 mmol, 1 eq) in DMF (8.3 mL) at 0°C. The mixture was stirred for 2 h at RT. 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 (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=97 / 3 to 70 / 30) to give 341 mg of I-107 (90%) as a white solid.

[0873] 1H NMR (400MHz, benzene-d6) δ7.95(d,J=1.8Hz,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=11.4,2.1H z,2H),2.77-2.70(m,5H),2.32(t,J=8.8Hz,2H),1.99(td,J=11.9,2.6Hz,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.

[0874] Synthesis of intermediates required for final product 121

[0875] 1-(3-Bromo-4-fluoro-phenyl)sulfonyl-4-phenyl-piperidine (I-108)

[0876]

[0877] According to GP-4, I-108 was obtained as a white solid in 100% yield using commercially available 3-bromo-4-fluorobenzenesulfonyl chloride (500 mg, 1.83 mmol, 1 eq), 4-phenylpiperidine (442 mg, 2.74 mmol, 1.5 eq) and Et3N (510 μL, 3.66 mmol, 2 eq) in DCM (7.3 mL) at RT for 2 h.

[0878] 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.

[0879] 2-Bromo-N,N-dimethyl-4-[(4-phenyl-1-piperidinyl)sulfonyl]aniline (I-109)

[0880]

[0881] A mixture of I-108 (725 mg, 1.82 mmol, 1 eq) and dimethylamine (2M solution in THF, 4.55 mL, 9.10 mmol, 5 eq) was stirred at 50 °C for 18 h. 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 give 685 mg of I-109 (89%) as a beige solid.

[0882] 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.

[0883] Synthesis of intermediates required for final product 122

[0884] Benzyl 8-[2-fluoro-5-[(4-phenyl-1-piperidinyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (I-110)

[0885]

[0886] According to GP-5, aryl bromide I-108 (0.40 g, 1.0 mmol, 1.2 eq), benzyl 3,8-diazabicyclo [3.2.1] octane-3-carboxylate (205 mg, 0.832 mmol, 1 eq), Cs2CO3 (542 mg, 1.66 mmol, 2 eq), Pd(OAc)2 (19 mg, 83 μmol, 0.1 eq) and racemic-BINAP (77.7 mg, 125 μmol, 0.15 eq) were used in toluene (4.2 mL) under reflux for 16 h to obtain I-110 as a white foam in 64% yield. Purification by FC (cHex / EtOAc=90 / 10 to 50 / 50).

[0887] 1H NMR (400 MHz, chloroform-d, multiple groups 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 rotational isomers) δ-115.9.MS (ESI + ):[M+H] + 564.2.

[0888] Benzyl 8-[2-(dimethylamino)-[(4-phenyl-1-piperidinyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (I-111)

[0889]

[0890] Dimethylamine hydrochloride (393 mg, 4.82 mmol, 20 equivalents) and iPr2NEt (840 μL, 1.82 mmol, 20 equivalents) were added to a solution of I-110 (136 mg, 0.241 mmol, 1 equivalent) in NMP (4.8 mL) at RT. The mixture was stirred at 150 ° C for 40 h under MW irradiation. The reaction mixture was distributed 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 dissolved in DCM (1 mL) and Et3N (67 μL, 0.48 mmol, 2 equivalents) and CbzCl (34 μL, 0.24 mmol, 1 equivalent) were added. The mixture was stirred for 16 h at RT. The mixture was concentrated under reduced pressure, and the residue was purified by FC (cHex / EtOAc=95 / 5 to 50 / 50) to give 127 mg of 1-111 (89%) as a white solid.

[0891] 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.

[0892] Synthesis of intermediates required for final product 123

[0893] Tert-butyl N-[1-[2-bromo-4-[(4-phenyl-1-piperidinyl)sulfonyl]phenyl]azetidin-3-yl]-N-methyl-carbamate (I-112)

[0894]

[0895] A mixture of I-108 (200 mg, 0.502 mmol, 1 eq), tert-butylazetidin-3-yl (methyl) carbamate hydrochloride (335 mg, 1.50 mmol, 3 eq) and K2CO3 (386 mg, 3.12 mmol, 6 eq) in dry DMF (2 mL) was stirred at 80 ° C for 48 h. The mixture was distributed 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 give 166 mg of I-112 (59%) as a yellow solid.

[0896] 1 H NMR (400MHz, chloroform-d) δ7.81(d,J=2.1Hz,1H),7.56(dd,J=8.6,2.1Hz,1H),7.33-7.27(m,2H),7.24-7.13(m,3H),6.50(d,J=8.6Hz,1H),5.08-4.77(brs ,1H),4.48(t,J=8.3Hz,2H),4.17(dd,J=8.7,6.0Hz,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.

[0897] Tert-butyl N-[1-[2-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-[(4-phenyl-1-piperidinyl)sulfonyl]phenyl]azetidin-3-yl]-N-methyl-carbamate (I-113)

[0898]

[0899] According to GP-5, aryl bromide I-112 (73.0 mg, 129 μmol, 1 eq), piperazine I-001 (52.1 mg, 194 μmol, 1.5 eq), Cs2CO3 (126 mg, 0.388 mmol, 3 eq), Pd(OAc)2 (2.9 mg, 13 μmol, 0.1 eq) and racemic-BINAP (9.7 mg, 15 μmol, 0.12 eq) were used in toluene (0.7 mL) under reflux for 16 h to obtain I-113 as a white foam in 50% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0900] 1 H NMR (400 MHz, chloroform-d, multiple rotational isomers) 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 (brs, 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.

[0901] Synthesis of intermediates required for final product 124

[0902] 3,5-Dibromo-4-methyl-benzenesulfonyl chloride (I-114)

[0903]

[0904] Sulfuryl chloride (2.2mL, 30 mmoles, 8 equivalents) was added dropwise to a water (13mL) solution of CuCl (45mg, 0.45 mmoles, 0.12 equivalents) at 0°C. The mixture was stirred at RT for 16h. Meanwhile, a water (13mL) solution of 37% HCl (14mL) and NaNO2 (286mg, 4.15 mmoles, 1.1 equivalents) was added to a water (30mL) solution of 3,5-dibromo-4-methylaniline (1.00g, 3.77 mmoles, 1 equivalent) at 0°C. The mixture was stirred at 0°C for 30 minutes. The first solution was then added dropwise and the resulting mixture was vigorously stirred at RT for 2h. It was filtered with sintered 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 obtain 1.09g (82%) of I-114 as an orange solid.

[0905] 1 H NMR (400 MHz, chloroform-d) δ 8.16 (s, 2H), 2.69 (s, 3H).

[0906] 1-(3,5-Dibromo-4-methyl-phenyl)sulfonyl-4-phenyl-piperidine (I-115)

[0907]

[0908] According to GP-4, I-114 (1.08 g, 3.10 mmol, 1 eq.), 4-phenylpiperidine (600 mg, 3.72 mmol, 1.2 eq.) and iPr2NEt (0.81 mL, 4.7 mmol, 1.5 eq.) were used in DCM (15 mL) at RT for 1 h to obtain I-115 as a beige solid in 62% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0909] 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.

[0910] 3-Bromo-2-methyl-5-[(4-phenyl-1-piperidinyl)sulfonyl]phenol (I-116)

[0911]

[0912] I-115 (573 mg, 1.21 mmol, 1 eq), KOAc (356 mg, 3.63 mmol, 3 eq), PdCl2(dppf).CH2Cl2 complex (99 mg, 0.12 mmol, 0.1 eq) and B2pin2 (277 mg, 1.09 mmol, 0.9 eq) were charged into MW. The bottle was purged with Ar and degassed 1,4-dioxane (6.1 mL) was added. The mixture was stirred at 80 °C for 16 h. 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 (6 mL) at RT and a solution of potassium peroxymonosulfonate (oxone) (968 mg, 1.57 mmol, 1.3 eq) in water (4 mL) was added. The mixture was stirred at RT for 20 minutes. Na2S2O5 aqueous solution 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 give 100 mg of I-116 as an orange solid (20% for two steps).

[0913] 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.

[0914] 1-[3-Bromo-5-(methoxymethoxy)-4-methyl-phenyl]sulfonyl-4-phenyl-piperidine (I-117)

[0915]

[0916] Chloromethyl methyl ether (22 μL, 0.29 mmol, 1.2 eq) was added to a solution of phenol I-116 (100 mg, 0.243 mmol, 1 eq) and iPr2NEt (64 μL, 0.37 mmol, 1.5 eq) in DCM (1.2 mL) at RT. The mixture was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=97 / 3 to 70 / 30) to give 72 mg of I-117 (65%) as a white solid.

[0917] 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.

[0918] (2-Chloro-4-fluoro-phenyl)-[8-[3-(methoxymethoxy)-2-methyl-5-[(4-phenyl-1-piperidinyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-118)

[0919]

[0920] According to GP-7, aryl bromide I-117 (72 mg, 0.16 mmol, 1 eq), piperazine I-001 (47 mg, 0.17 mmol, 1.1 eq), t-BuONa (46 mg, 0.48 mmol, 3 eq), XPhos-Pd-G3 (13 mg, 16 micromol, 0.1 eq) were used in toluene (0.8 mL) under reflux for 4 h to obtain I-118 as a white solid in 59% yield. Purification was performed by PTLC (cHex / EtOAc=70 / 30).

[0921] 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 rotational isomers) δ -109.2, -109.3. MS (ESI + ): [M+H] + 642.2 / 644.1.

[0922] Synthesis of intermediates required for final product 125

[0923] 3-Bromo-4-cyano-benzenesulfonyl chloride (I-119)

[0924]

[0925] Sulfuryl chloride (5.9mL, 81 mmoles, 8 equivalents) was added dropwise to a solution of CuCl (121mg, 1.22 mmoles, 0.12 equivalents) in water (34mL) at 0°C. The mixture was stirred at RT for 14h. Meanwhile, a solution of 37% HCl (37mL) and NaNO2 (770mg, 11.2 mmoles, 1.1 equivalents) in water (34mL) was added to a solution of 4-amino-2-bromobenzonitrile (2.00g, 10.1 mmoles, 1 equivalent) in water (130mL). The mixture was stirred at 0°C for 30 minutes. The first solution was then added dropwise and the resulting mixture was vigorously stirred at RT for 1h. It was filtered with sintered 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 obtain 2.5g (88%) of I-119 as an orange solid.

[0926] 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).

[0927] 2-Bromo-4-[(4-phenyl-1-piperidinyl)sulfonyl]benzonitrile (I-120)

[0928]

[0929] According to GP-4, I-119 (2.5 g, 8.91 mmol, 1 eq), 4-phenylpiperidine (2.16 g, 13.4 mmol, 1.5 eq) and Et3N (1.86 mL, 13.4 mmol, 1.5 eq) were used in DCM (45 mL) at RT for 1 h to obtain I-120 as a beige solid in 47% yield. Purification by FC (DCM / EtOAc=96 / 4 to 60 / 40).

[0930] 1H 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.

[0931] Synthesis of intermediates required for final product 139

[0932] 3-Bromo-1-chloro-4-fluoro-2-(methoxymethoxy)benzene (I-121)

[0933]

[0934] Chloromethyl methyl ether (0.37 mL, 4.9 mmol, 1.1 eq) was added to a solution of 2-bromo-6-chloro-3-fluorophenol (1.11 g, 4.44 mmol, 1 eq) and iPr2NEt (0.933 mL, 5.33 mmol, 1.2 eq) in DCM (22 mL) at RT. The mixture was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=95 / 5 to 50 / 50) to give 756 mg of I-121 (55%) as a colorless oil.

[0935] 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.

[0936] [8-[3-Chloro-6-fluoro-2-(methoxymethoxy)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-122)

[0937]

[0938] According to GP-5, aryl bromide I-121 (756 mg, 2.81 mmol, 1 eq), piperazine I-001 (905 mg, 3.37 mmol, 1.2 eq), Cs2CO3 (2.74 g, 8.41 mmol, 3 eq), Pd(OAc)2 (63 mg, 0.28 mmol, 0.1 eq) and racemic-BINAP (210 mg, 337 micromol, 0.12 eq) were used in toluene (14 mL) under reflux for 16 h to obtain I-122 as a yellow viscous oil in 26% yield. Purification by FC (cHex / EtOAc=97 / 3 to 70 / 30).

[0939] 1 H NMR (400 MHz, chloroform-d, 2 sets of rotational isomers) 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), 3.56-3.3 4(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 rotational isomers) δ -109.4, -109.5, -126.8, 126.9. MS (ESI + ): [M+H] + 457.0 / 459.0.

[0940] [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)

[0941]

[0942] HCl (4M in dioxane, 3.67 mL, 14.7 mmol, 20 eq) was added to a solution of I-122 (336 mg, 0.735 mmol, 1 eq) in DCM (3.7 mL) at RT. The mixture was stirred for 16 h at RT. It was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=95 / 5 to 50 / 50) to give 222 mg of I-123 (73%) as a white foam.

[0943] 1 H NMR (400 MHz, chloroform-d, 2 sets of rotamers) 87.30 (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 (brs, 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). '9F NMR (376MHz, chloroform-d, 2 groups of rotational isomers) δ -109.2, -109.3, -124.3, -124.5. MS (ESI + ): [M+H] + 413.1 / 415.1.

[0944] 5-Chloro-3-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-2-fluoro-4-hydroxy-benzenesulfonyl chloride (I-124)

[0945]

[0946] According to GP-3, 1-124 was obtained as a beige solid in 89% yield using 1-123 (110 mg, 0.215 mmol, 1 eq) in HSO 3 Cl (0.32 mL, 4.8 mmol, 20 eq) at 50° C. for 16 h followed by 80° C. for 4 h.

[0947] 1 H NMR (400 MHz, chloroform-d, 2 sets of rotamers) 87.62 & 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 FNMR (376 MHz, chloroform-d, 2 sets of rotational isomers) δ -108.6, -108.7, -120.3, -120.5.

[0948] Synthesis of final compounds

[0949] Synthesis of the final compound

[0950] The synthesis scheme of the final compound is shown in Table 2 below.

[0951] Table 2

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970] Analytical data of final compound

[0971] The analytical data of the final compound are shown in Table 3 below.

[0972] Table 3

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997] Example 2: Biological Activity of Compounds

[0998] The purpose of this experiment was to evaluate the GFRα1-RET activity of Compounds 001 to 139 according to the present invention.

[0999] Materials and methods

[1000] The Elk1 signaling activation activity of these compounds was tested in cells expressing GFRα1-RET (MG87 mouse fibroblasts stably transfected with PathDetect Elk-1, GFRα1 and RET) using a previously developed reporter gene-based system as disclosed in Sidorova, YA et al.: "Persephin signaling through GFRα1: The potential for the treatment of Parkinson's disease." Molecular and Cellular Neuroscience, July 2010, Vol. 44, pp. 223-232. DOI: 10.1016 / j.mcn.2010.03.009. For EC 50 Dose-response experiments were performed using 6 concentrations of each test compound. Dose-response curves were fitted using sigmoidal dose-response (variable slope) analysis in the GraphPadPrism program (Graph Pad Inc) and the EC values ​​of the agonists / activators were calculated. 50 All dose-response experiments were performed in duplicate independently.

[1001] result

[1002] The results are shown in Table 4 below (* indicates " 50μM >EC 50 >10μM”, ** indicates “1μM≤EC 50 ≤10μM”,*** indicates “EC 50 <1μM”).

[1003] Table 4

[1004]

[1005]

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014] The above results clearly demonstrate that test compounds 001 to 139 have significant GFRα1-RET activity. Therefore, the compounds of the present invention can be used as neuroprotective agents and neurorepairing agents. Test compounds 001 to 139 well represent the class of compounds of formula (I).

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof; in W represents CH or N; R A , R B , R C and R D each independently represents hydrogen, F, Cl, CH3, CF3, CHF2 or CH2F, The premise is R A , R B , R C and R D At least one of them does not represent hydrogen; R 1 represents a (C1 to C8)alkyl group, wherein the alkyl group is optionally substituted with at least one OH, (C1 to C3)alkoxy group or F; and R 2 , R 3 and R 4 represents hydrogen; or R 1 and R 4 Together they form -CH2-O-CH2- or -CH2-CH2-, wherein said -CH2-CH2- is optionally substituted with at least one F, OH or OCH3; and R 2 and R 3 each independently represents hydrogen; R 7 represents hydrogen, OH, halogen, (C1 to C8) alkyl, cycloalkyl, (C1 to C8) alkyl-O-, cycloalkyl-O-, cycloalkyl-(C1 to C8) alkyl-O-, heterocycloalkyl-O-, R 11 O-(C1 to C8)alkyl-O-, R 11 R 12 N-(C1 to C8)alkyl-O-, (R 11 O)(R 12 )N-(C1 to C8)alkyl-O-, R 11 R 12 N-(C1 to C8)alkyl-, R 11 O-(C1 to C8)alkyl-, NR 11 R 12 、CN、CO2H、CO2R 11 、CONH2、CON(R 11 )H, heterocycloalkyl or heteroaryl; wherein R 11 and R 12 each independently represents hydrogen or (C1 to C8) alkyl; Where R 7 The alkyl or cycloalkyl in is optionally substituted with at least one F, Cl, OH, =O, (C1 to C8)alkyl, (C1 to C8)alkyl-O-, heterocycloalkyl, aryl or heteroaryl; wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted with at least one F, Cl, (C1 to C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1 to C8) alkoxy, NR 13 R 14 , R 13 R 14 N-(C1 to C8)alkyl-, R 13 O2C(C1 to C8)alkyl-, CO2H, R 13 R 14 NC(O)-、R 13 O-NR 14 - or (C1 to C8) alkyl-CO2-substituted; wherein R 13 and R 14 each independently represents hydrogen or (C1 to C8) alkyl; Z stands for CH, CR 8 or N; Where R 8 represents (C1 to C4)alkyl, F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH or (C1 to C4)alkoxy; or Z stands for CR 8 And R 7 and R 8 together with the carbon atoms to which they are bound, form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by at least one of F, OH, =O, →O, (C1 to C8)alkyl, CF3, HO2C-CH2-, (C1 to C4)alkyl-CO2-CH2-, R 15 R 16 N-CH2-, aryl or aryl-(C1 to C8)alkyl-substituted, wherein R 15 and R 16 each independently represents hydrogen or (C1 to C8) alkyl; R 5 represents hydrogen, (C1 to C8)alkyl, CH3 substituted by one to three (C1 to C8)alkyl, cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C1 to C8)alkyl; Where R 5 The alkyl or cycloalkyl in the OCF3, CN, OH, =O, (C1 to C8) alkoxy, NR 17 R 18 ,CO2H,R 17 R 18 NC(O)-、 R 17 O-NR 18 -, heterocycloalkyl, aryl or heteroaryl; wherein R 17 and R 18 each independently represents hydrogen or (C1 to C8) alkyl; wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, (C1 to C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1 to C8) alkoxy, NR 19 R 20 ,CO2H,R 19 R 20 NC(O)-、R 19 O-NR 20 -, (C1 to C8) alkyl-CO2-, R 19 R 20 N-(C1 to C8)alkyl-, R 19 O2C-(C1 to C8)alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C1 to C8)alkyl-substituted; wherein R 19 and R 20 each independently represents hydrogen or (C1 to C8) alkyl; R 6 represents (C1 to C8)alkyl, CH3 substituted by one to three (C1 to C8)alkyl, cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C1 to C8)alkyl; Where R 6 The alkyl or cycloalkyl in the OCF3, CN, OH, =O, (C1 to C8) alkoxy, NR 21 R 22 ,CO2H,R 21 R 22 NC(O)-、 R 21 O-NR 22 -, heterocycloalkyl, aryl or heteroaryl; wherein R 21 and R 22 each independently represents hydrogen or (C1 to C8) alkyl; wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, (C1 to C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1 to C8) alkoxy, NR 23 R 24 ,CO2H,R 23 R 24 NC(O)-、R 23 O-NR 24 -, (C1 to C8) alkyl-CO2-, R 23 R 24 N-(C1 to C8)alkyl-, R 23 O2C-(C1 to C8)alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C1 to C8)alkyl-substituted; wherein R 23 and R 24 each independently represents hydrogen or (C1 to C8)alkyl; or R 5 and R 6 together with the nitrogen atom to which they are bound, form a heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with at least one F, Cl, (C1 to C8) alkyl, CF3, OCF3, CN, OH, =O, →O, (C1 to C8) alkoxy, NR 25 R 26 、CO2H、(C1 to C8) alkyl-CO2-, R 25 R 26 NC(O)-、R 25 O-NR 26 -、R 25 R 26 N-(C1 to C8)alkyl-, R 25 O2C-(C1 to C8)alkyl-, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1 to C8)alkyl-, heterocycloalkyl-(C1 to C8)alkyl-, aryl-(C1 to C8)alkyl-, heteroaryl-(C1 to C8)alkyl-, aryl-cycloalkyl-, cycloalkyl-O-, heterocycloalkyl-O-, aryl-O-, heteroaryl-O-, cycloalkyl-(C1 to C8)alkyl-O-, heterocycloalkyl-(C1 to C8)alkyl-O-, aryl-(C1 to C8)alkyl-O-, heteroaryl-(C1 to C8)alkyl-O-, cycloalkyl-NR 25 -, heterocycloalkyl-NR 25 -, aryl-NR 25 -, heteroaryl-NR 25 -, cycloalkyl-(C1 to C8)alkyl-NR 25 -, heterocycloalkyl-(C1 to C8)alkyl-NR 25 -, aryl-(C1 to C8)alkyl-NR 25 -, heteroaryl-(C1 to C8)alkyl-NR 25 -, benzylidene, heteroarylene, aryl-(C1 to C8)alkyl-ylidene- or heteroaryl-(C1 to C8)alkyl-ylidene-; Where R 25 and R 26 each independently represents hydrogen or (C1 to C8) alkyl; wherein the heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylene group is optionally substituted by at least one F, Cl, (C1 to C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1 to C8) alkoxy, NR 27 R 28 ,CO2H,R 27 R 28 NC(O)-、 R 27 O-NR 28 -, (C1 to C8) alkyl-CO2-, R 27 R 28 N-(C1 to C8)alkyl-, R 27 O2C-(C1 to C8)alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C1 to C8)alkyl-substituted; wherein R 27 and R 28 each independently represents hydrogen or (C1 to C8)alkyl; and and R E represents hydrogen, (C1 to C3) alkyl or halogen.

2. The compound according to claim 1, wherein R A , R B , R C and R D At least one of them represents hydrogen, preferably R A and R C At least one of them represents hydrogen, more preferably R C represents hydrogen; and / or wherein R E Represents hydrogen.

3. The compound according to claim 1 or 2, wherein R A , R B and R D At least one of them represents F or Cl, preferably R B and R D At least one of them represents F or Cl; more preferably R B and R D Each independently represents F or Cl.

4. A compound according to any one of claims 1 to 3, wherein R 1 and R 4 Together they form -CH2-O-CH2- or -CH2-CH2-, preferably R 1 and R 4 Together they form -CH2-CH2-; wherein the -CH2-CH2- is optionally substituted with at least one F, OH or OCH3.

5. A compound according to any one of claims 1 to 4, wherein R 1 It represents methyl, ethyl, CF3 or CH3OCH2-.

6. A compound according to any one of claims 1 to 5, wherein R 7 represents hydrogen, OH or halogen; or wherein R 7 represents (C1 to C8)alkyl-O- or cycloalkyl-O-, wherein the alkyl or cycloalkyl is optionally substituted with at least one F, Cl, OH, (C1 to C8)alkoxy or aryl group; preferably R 7 It represents F, Cl, OCH3, OCH2CH3, OCF3, cyclobutyl-O-, HO-CH2-CH2-O-, CH3O-CH2-CH2-O-, phenyl-CH2-O-, 1H-imidazol-4-yl-, 1-methyl-imidazol-4-yl-, CH3, CN, CO2H, CH2OH, C(CH3)2OH, CH2N(CH3)2, cyclopropyl, cyclobutyl-O-, (4-pyridine)-CH2-O-, (3-pyridine)-CH2-O- or benzyl-O-.

7. A compound according to any one of claims 1 to 6, wherein Z represents CR 8 , where R 8 represents (C1 to C4) alkyl, F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH or (C1 to C4) alkoxy; preferably wherein R 8 represents methyl, ethyl, F, Cl, CF3, CN or OH.

8. A compound according to any one of claims 1 to 6, wherein or Z represents CR 8 And R 7 and R 8 and the carbon atoms to which they are bonded together form a heterocycloalkyl group; wherein the heterocycloalkyl group is optionally substituted by at least one F, OH, =O, (C1 to C8) alkyl, CF3, HO2C-CH2-, (C1 to C4) alkyl-CO2-CH2-, or R 15 R 16 N-CH2-substituted, where R 15 and R 16 Each independently represents hydrogen or (C1 to C8) alkyl.

9. A compound according to any one of claims 1 to 8, wherein R 5 represents hydrogen or (C1 to C8) alkyl; preferably R 5 represents hydrogen, methyl or ethyl; and / or wherein R 6 represents (C1 to C8)alkyl, cycloalkyl, cycloalkyl-(C1 to C8)alkyl- or heterocycloalkyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted with at least one F, CN or CF3; preferably R 6 It represents methyl, ethyl, isopropyl, n-propyl, isobutyronitrile, 3-fluoro-n-propane, tert-butyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, 1-methylcyclobutyl, cyclopropyl-CH2-, (CN)(Me)2C-, (F3C)C(Me)2-, 3-methyloxetan-3-yl or oxetan-3-yl.

10. A compound according to any one of claims 1 to 8, wherein R 5 and R 6 Together with the nitrogen atom to which they are bound, they form a heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with at least one F; preferably R 5 and R 6 Together with the nitrogen atom to which they are bound, they form 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-piperidinyl)benzonitrile, 3-(4-piperidinyl)benzoic acid methyl ester, 4-(4-piperidinyl)benzoic acid methyl ester, 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.

11. The compound according to any one of claims 1 to 10, wherein the compound is selected from: and pharmaceutically acceptable salts and / or solvates thereof.

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

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

14. The compound or pharmaceutical composition according to claim 13, for use in the treatment of a neurological disorder.

15. A method for preparing a compound according to any one of claims 1 to 11, wherein the method comprises the step of reacting the following compounds in the presence of a base and a metal catalyst: Compound of formula (II) in Z, R 5 , R 6 , R 7 and R E As defined in claim 1, and X represents halogen or -CF3SO3, With the compound of formula (III) Among them, W, R A To R D and R 1 To R 4 As defined in claim 1; Thus, the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is obtained.

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