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

Abstract

The present invention relates to a compound represented by general formula (I) [Formula 1] TIFF2025533979000103.tif41159 or a pharmaceutically acceptable salt and / or solvate thereof. The present invention further relates to the use of the compounds of the present invention as neuroprotective and / or neurorestorative agents, particularly for use in the treatment of neurological disorders.

Description

[Technical Field]

[0001] The present invention relates to novel polycyclic sulfonamides containing at least one unsubstituted and unbridged piperazine. The compounds of the present invention are useful as neuroprotective and / or neurorestorative agents, particularly for use in the treatment of neurological disorders. [Background technology]

[0002] Neuropathy (ND) is a heterogeneous disease that affects the autonomic nervous system, peripheral nervous system and central nervous system 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 tumor, pain and epilepsy are always the most difficult diseases to deal with.Active compounds for treating CNS can also be important for other diseases, such as diseases of the peripheral nervous system, eye, spinal cord and intestinal system.

[0003] The incidence of neurodegenerative disorders (NDs) is expected to increase dramatically in the 21st century, particularly due to increasing life expectancy and demographic changes. Some of these disorders are characterized by a gradual decline in neurological function with aging. In medicine, neurological disorders are a significant and common cause of disability-adjusted life years, or years of healthy life lost due to death or disability, worldwide. CNS disorders represent the largest and fastest-growing therapeutic domain of unmet medical need and are recognized as a global public health challenge and an international health priority. Proper neurological diagnosis presents significant challenges, and patients are increasingly focused on developing new, effective treatments to treat the pathophysiology or symptoms. Neurological disorders affect millions of people worldwide and cause permanent damage. They are progressive diseases with symptoms that can degenerate over time. While complete cures are generally unavailable, supportive treatments exist. The goal of these treatments is primarily to alleviate symptoms and preserve patients' quality of life for as long as possible.

[0004] Neurons are postmitotic cells that must survive throughout life. Young neurons possess adequate functioning of self-healing protective mechanisms, but aging or external or internal injuries disrupt them, ultimately leading to neurodegeneration. These external / internal hazards can be traumatic injuries or excitotoxic compounds, reactive oxygen species (ROS), protein aggregates, and other toxic molecules. Fortunately, cells possess intrinsic mechanisms to prevent death by activating recovery mechanisms or promoting regenerative pathways. Dysfunction or insufficiency of these self-healing mechanisms has also been described 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 in the GDNF family of neurotrophic factors, e.g., neurturin, artemin, and persephin) act as potent trophic factors that promote not only survival and plasticity but also proliferation, differentiation, and protection of dopaminergic neurons, as well as dopamine synthesis and dopaminergic transmission in the developing and adult brain. GDNF can promote neuroprotection by inducing several neuroprotective signaling cascades, including activation of the transcription factor Elk1 via the MAP kinase / ERK, Src kinase, and PI3 kinase / AKT pathways.

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

[0007] Blood-brain barrier-permeable small molecule compounds that target the GDNF receptor complex and mimic the biological effects of GDNF in neurons may be a means to overcome these problems and bring greater clinical efficacy. The excellent tissue penetration of such compounds may promote survival in all affected neuronal pathways.

[0008] International Publication No. 2011 / 070177A2 (BALTIC TECHNOLOGY DEV LTD) discloses polycyclic compounds for treating neurological disorders.Although these compounds have shown significant improvement at this time, they still have limitations in terms of activity against GFRα1-RET target, solubility, membrane permeability (PAMPA and CaCO2), intrinsic clearance microsome and hepatocyte, plasma protein binding, and pharmacokinetic profile.In particular, these compounds are limited in terms of activity against GFRα1-RET target (for example, as demonstrated in luciferase assay).

[0009] IVANOVA, L. et al. (ACS OMEGA, Vol. 3, No. 3, 19 September 2018, pp. 11407-11414, ISSN: 2470-1343, DOI: 10.1021 / acsomega.8b01524) disclose two compounds also disclosed in WO 2011 / 070177 A2, and simulated dynamic molecular modeling of the interaction between the glial cell line-derived neurotrophic factor family receptor GFRα1 and these two compounds.

[0010] WO 2014 / 041179 A1 (CHEMEDEST LTD) also discloses the same polycyclic compounds as WO 2011 / 070177 A2 for treating and / or preventing peripheral neuropathy (peripheral diseases) and therefore has the same limitations.

[0011] Surprisingly, the applicants have found that novel polycyclic sulfonamides of formula (I) exhibit potent GFRα1-RET activity in luciferase assays, thereby paving the way to overcoming the limitations of available therapeutic solutions. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] International Publication No. 2011 / 070177A2 [Patent Document 2] International Publication No. 2014 / 041179 A1 [Non-patent literature]

[0013] [Non-Patent Document 1] IVANOVA,L.et al.ACS OMEGA,Vol.3,No.3,19 September 2018,pp.11407-11414,ISSN:2470-1343,DOI:10.1021 / acsomega.8b01524 Summary of the Invention

[0014] The object of the present invention is to provide a compound of formula (I) [ka] (In the formula, W, R A ~R D , Z and R 5 ~R 7 is as defined herein below and / or as defined in the claims) or a pharmaceutically acceptable salt and / or solvate thereof.

[0015] According to one preferred embodiment, the compound of formula (I) is a compound of formula (Ii) or formula (I-ii) as defined herein below and / or in the claims.

[0016] According to one embodiment, the compound is selected from the compounds of Table 1 herein and pharmaceutically acceptable salts and / or solvates thereof, with the proviso that the compound is not N,N-diethyl-5-[4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-6-methoxy-pyridine-3-sulfonamide or a pharmaceutically acceptable salt and / or solvate thereof.

[0017] Another object of the invention is a pharmaceutical composition comprising a compound according to the invention and at least one pharmaceutically acceptable carrier.

[0018] 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 pharmaceutical composition is for use in the treatment of neurological disorders.

[0019] Another object of the invention is a process for preparing the compounds according to the invention. DETAILED DESCRIPTION OF THE INVENTION

[0020] definition For the purposes of the present invention, the following terms have the following meanings:

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

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

[0023] The definitions herein regarding optional or required substitution of a particular group apply both to the substituted group considered by itself or to the same group contained within another chemical moiety, both of which may be substituted as described herein. For example, "R x represents hydrogen, (C1-C8) alkyl, (C1-C8) alkyl-O—, or cycloalkyl-(C1-C8) alkyl-NH—; said alkyl is optionally substituted with at least one F” represents R x means that any alkyl group present in the structure may be optionally substituted with at least one F, including the (C1-C8)alkyl itself (e.g., CF3), the alkyl contained in the (C1-C8)alkyl-O- (e.g., OCF3), and the alkyl contained in the cycloalkyl-(C1-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 typically containing 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 groups can be monovalent or polyvalent (i.e., divalent alkyl groups, "alkylene" groups, are included in the definition of "alkyl"). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl, pentyl and its isomers (e.g., n-pentyl, iso-pentyl), and hexyl and its isomers (e.g., n-hexyl, iso-hexyl). Specific examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl (including methylene, ethylene, n-propylene, n-butylene, and n-butylene).

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

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

[0028] "Benzylidene" refers to a phenyl group attached to a moiety through an exo carbon-carbon double bond, i.e., a =CH-Ph bond to a carbon atom. The moiety is typically cyclic, such as, for example, a heterocycloalkyl.

[0029] "Cycloalkyl" refers to a cyclic alkyl group typically containing 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" encompasses polycyclic cycloalkyl (e.g., bicyclic) and bridged cycloalkyl structures, including rings joined together through one atom ("spiro") or two atoms. This definition of "cycloalkyl" encompasses cycloalkyls containing a cyclic alkyl group substituted with at least one non-cyclic alkyl, such as, for example, a (C1-C8) alkyl (preferably, a (C1-C4) alkyl, e.g., methyl). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, cyclononanyl, cyclodecanyl, norbornyl, adamantyl, bicyclo[2.2.2]octanyl, bicyclo[4.4.0]decanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[2.1.1]hexane, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, decahydronaphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, and octahydropentalenyl.

[0030] The "C" that precedes the group name x ~C y " or "(C x ~C y )" means, according to common terminology in the chemical art, that the group contains x to y carbon atoms.

[0031] "Halogen" refers to a fluorine, chlorine, bromine or iodine atom.

[0032] "Heteroalkyl" refers to an alkyl group, as defined herein, in which one or more carbon atoms are replaced by a heteroatom selected from oxygen, nitrogen, and sulfur, and the resulting heteroalkyl group contains at least one carbon atom. In a heteroalkyl group, heteroatoms are bonded to carbon atoms only along the alkyl chain, i.e., each heteroatom is separated from any other heteroatom by at least one carbon atom, typically at least two carbon atoms. A heteroalkyl group can be monovalent or polyvalent (e.g., divalent). The nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized (e.g., sulfur can be oxidized as SO or SO). A heteroalkyl group can further contain one or more =0 and / or =S groups. In one embodiment, at least two carbon atoms are replaced by heteroatoms. In one embodiment, a heteroalkyl is bonded to another group or molecule through a carbon atom, i.e., the bonding atom is not selected from among the heteroatoms contained therein. In one embodiment, a heteroalkyl is bonded to another group or molecule through one of the heteroatoms contained therein. When substituted by one or more other groups, heteroalkyl can be substituted through either a carbon atom or a heteroatom (e.g., nitrogen), unless otherwise specified. Non-limiting examples of heteroalkyl include alkoxy, ethers and polyethers (e.g., polyethylene glycol), secondary and tertiary amines and polyamines, thioethers and polythioethers, and combinations thereof.

[0033] "Heteroaryl" refers to an aromatic ring or ring system having one or two rings fused or covalently linked together containing 5 to 15 carbon atoms, preferably 4 to 12 carbon atoms, and more preferably 3 to 10 carbon atoms, wherein at least one ring is aromatic and one or more carbon atoms in one or more of the rings are replaced by oxygen, nitrogen, and / or sulfur atoms. Heteroaryl groups can be monovalent or polyvalent (e.g., divalent). The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized (e.g., the heteroatom is replaced by oxo (=O) for the sulfur atom or (→O) for the nitrogen atom). This definition of "heteroaryl" encompasses partially hydrogenated derivatives of the carbocyclic ring systems enumerated herein, as well as ring systems containing one or more fused non-aromatic cycloalkyl and / or heterocycloalkyl rings, so long as at least one ring is aromatic. In one embodiment, a heteroaryl is bonded to another group or molecule through a carbon atom, i.e., the bonded atom is not selected from among the heteroatoms contained therein. In one embodiment, a heteroaryl is bonded to another group or molecule through one of the heteroatoms contained therein. When substituted with one or more other groups, a heteroaryl can be substituted through either a carbon atom or a heteroatom (e.g., nitrogen) unless otherwise specified. A heteroaryl can optionally be substituted with at least one group, such as halogen (e.g., F or Cl), (C1-C8) alkyl (preferably (C1-C4) alkyl, e.g., methyl), or nitrile (CN).Non-limiting examples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, tetrazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophene, and the like. nyl, 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-benzisothiazolyl Examples include benzothiadiazolyl, 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, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and quinoxalinyl. Non-limiting examples of heteroaryl groups containing at least one fused non-aromatic ring include 2,3-dihydrobenzofuranyl, benzo[d][1,3]dioxolyl, indolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 1,2,3,4-tetrahydroquinoxaline, 3,4-dihydro-2H-benzo[b][1,4]thiazine, and 2,3-dihydrobenzo[b][1,4]oxathiin.

[0034] "Heteroarylidene" refers to a heteroaryl group attached to a moiety via an exo carbon-carbon double bond, i.e., the =CH-heteroaryl bond to a carbon atom. The moiety is typically cyclic, such as, for example, a heterocycloalkyl.

[0035] "Heterocycloalkyl" refers to a cyclic heteroalkyl group typically containing 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 groups can be monovalent or polyvalent (e.g., divalent). Heterocycloalkyl groups are typically 3 to 7 membered, preferably 5 or 6 membered. Heterocycloalkyls are typically monocyclic or bicyclic, preferably monocyclic. This definition encompasses polycyclic heterocycloalkyl (e.g., bicyclic) and bridged heterocycloalkyl structures, including rings joined together through one atom ("spiro") or two atoms. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized (e.g., the heteroatom is substituted by oxo (=O) for the sulfur atom or (→O) for the nitrogen atom). In one embodiment, a heterocycloalkyl is attached to another group or molecule through a carbon atom, i.e., the attaching atom is not selected from among the heteroatoms contained therein. In one embodiment, a heterocycloalkyl is attached to another group or molecule through one of the heteroatoms contained therein. When substituted with one or more other groups, a heterocycloalkyl can be substituted through either a carbon atom or a heteroatom (e.g., nitrogen) unless otherwise specified. A heterocycloalkyl can optionally be substituted with at least one group, such as halogen (e.g., F or Cl), (C1-C8) alkyl (preferably, (C1-C4) alkyl, e.g., methyl), nitrile (CN), or =O.Non-limiting examples of heterocycloalkyls include aziridine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, azepane, azocane, 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] "Prodrug" refers to a pharmacologically acceptable derivative of a therapeutic agent (e.g., a compound according to the present invention) whose in vivo biotransformation product is the therapeutic agent (active drug). Prodrugs are typically characterized by increased bioavailability and are readily metabolized in vivo to the active compound. Non-limiting examples of prodrugs include amide prodrugs and carboxylic acid ester prodrugs.

[0037] "Solvate" refers to a molecular complex that includes a compound with one or more molecules of one or more solvents in stoichiometric or substoichiometric amounts, where the solvent is typically a pharmaceutically acceptable solvent such as, for example, ethanol. The term "hydrate" refers to a solvate where the solvent is water (HO).

[0038] "Ylidene" refers to a C-H group that participates in an exo carbon-carbon double bond that is attached to another moiety, which moiety is typically cyclic, such as, for example, a heterocycloalkyl.

[0039] General definition "About" is used herein to mean approximately, in the region of, around, or in the region of. The term "about" preceding a number means ±10% of the value of the number. When the term "about" is used in conjunction with a numerical range, it modifies that range by expanding the boundaries above and below the numerical values ​​set forth by 10%.

[0040] "Administration" or variations thereof (e.g., "administering") means providing a therapeutic agent, alone or as part of a pharmaceutically acceptable composition, to a patient whose condition, symptom, or disease is to be treated.

[0041] The word "comprise" or variations thereof (e.g., "comprises," "comprising") is used herein in accordance with the terminology used to describe a general patent application. Thus, "comprise," preceded by an object and followed by an element, means that the element is required to be present in the object (typically as a component of a composition), but does not exclude the presence of any additional element(s) in the object. Furthermore, any occurrence of "comprise" or variations thereof herein also encompasses and may be replaced by the narrower expression "substantially consist of," the even narrower expression "consist of," and any variations thereof (e.g., "consists of," "consisting of"), unless otherwise specified.

[0042] "GDNF family receptor alpha-1," "GFRα1," or "GDNFRα1," also known as "RET ligand 1" or "TGF-beta-related neurotrophic factor receptor 1," is a protein from the GDNFR family that acts as a receptor for GDNF. It mediates 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 shown in SEQ ID NO: 1, where amino acid residues 1-24 correspond to the signal peptide and amino acid residues 430-465 correspond to the propeptide, which is removed in the mature form. SEQ ID NO: 1 MFLATLYFALPLLDLLLSAEVSGGDRLDCVKASDQCLKEQSCSTKYRTLRQCVAGKETNFSLASGLEAKDECRSAMEALKQKSLYNCRCKRGMKKEKNCLRIYWSMYQSLQGNDLL EDSPYEPVNSRLSDIFRVVPFISDVFQQVEHIPKGNNCLDAAKACNLDDICKKYRSAYITPCTTSVSNDVCNRRKCHKALRQFFDKVPAKHSYGMLFCSCRDIACTERRRQTIVPV CSYEEREKPNCLNLQDSCKTNYICRSRLADFFTNCQPESRSVSSCLKENYADCLLAYSGLIGTVMTPNYIDSSSLSVAPWCDCSNSGNDLEECLKFLNFFKDNTCLKNAIQAFGNG SDVTVWQPAFPVQTTTATTTTALRVKNKPLGPAGSENEIPTHVLPPCANLQAQKLKSNVSGNTHLCISNGNYEKELGASSHITTKSMAAPPSCGLSPLLVLVVTALSTLLSLTETS

[0043] "Human" refers to a male or female human subject at any stage of development, including a neonate, infant, juvenile, adolescent and adult.

[0044] "Neuroprotective" refers to the protection of neurons from injuries, events, or conditions that would normally result in loss of neuronal function and ultimately neuronal death. Such injuries, events, or conditions include, but are not limited to, 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, etc. This term also characterizes the detectable biological activity of a compound that reduces the amount or level of neuronal loss of function and / or neuronal death.

[0045] "Neurorestorative" refers to the restoration or rescue of a neuron, particularly its function, from the effects of an injury, event, or condition that would normally result in loss of neuron function, if not neuron death.

[0046] "Patient" refers to a subject who is awaiting or receiving medical care, has been the subject of a medical procedure, is the subject of a medical procedure, will be the subject of a medical procedure, or is being monitored for the development of a target disease or condition, e.g., a neurological disorder.

[0047] "Pharmaceutically acceptable" means the components of the composition are compatible with each other and not harmful to the subject to which they are administered.

[0048] A "pharmaceutically acceptable carrier" refers to an excipient that does not produce adverse allergic or other untoward reactions when administered to animals, preferably humans. This includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. For human administration, preparations must meet sterility, pyrogenicity, general safety and purity standards required by regulatory authorities, such as the FDA or EMA. Examples of pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, 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 silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances (e.g., sodium carboxymethylcellulose), polyethylene glycol, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0049] 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.

[0050] "Proto-oncogene tyrosine-protein kinase receptor Ret," or "RET" for short, also known as "cadherin family member 12," is a receptor tyrosine kinase involved in numerous cellular mechanisms, including cell proliferation, neural navigation, cell migration, and cell differentiation. RET is activated upon (i) binding of GDNF family neurotrophic factors (e.g., GDNF, neurturin, artemin, or persephin) to GDNFR family receptors (e.g., GFRα1, GFRα2, GFRα3, or GFRα4), followed by (ii) complex formation between RET and the GDNFR family receptor, (iii) dimerization, and (iv) transautophosphorylation. An exemplary amino acid sequence of human RET is shown in SEQ ID NO: 2, where amino acid residues 1-28 correspond to the signal peptide. SEQ ID NO: 2

[0051] "Selected from" is used herein in accordance with general patent application writing language to introduce a list of elements from which one or more items are selected. Any occurrence of "selected from" herein may be interchangeably replaced with "selected from the group comprising or consisting of" without changing the meaning thereof.

[0052] "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 suffering from, and preferably has been diagnosed with, a disease. In one embodiment, the subject is at risk of developing a disease. Examples of risk factors include, but are not limited to, a genetic predisposition or family history of a disease.

[0053] "Therapeutic agent," "active pharmaceutical ingredient," and "active ingredient" refer to a compound for therapeutic use and related to health. In particular, a therapeutic agent (e.g., a compound according to the invention) may be indicated for treating a disease (e.g., a neurological disorder). An active ingredient may also be indicated for improving the therapeutic activity of another therapeutic agent.

[0054] A "therapeutically effective amount" (abbreviated "effective amount") refers to an amount of a therapeutic agent (e.g., a compound according to the present invention) sufficient to achieve a desired therapeutic, prophylactic, or preventative effect in a patient to which it is administered, without causing significant negative or harmful side effects to the patient. A therapeutically effective amount can be administered prior to the onset of disease for a prophylactic or preventative effect. Alternatively, or additionally, a therapeutically effective amount can be administered after the onset of disease for a therapeutic effect.

[0055] "Treating," "treatment," or "alleviating" refers to both therapeutic treatment and prophylactic or preventative measures, where the goal is to prevent or slow (reduce) the targeted pathological condition or disorder (herein "disease") (e.g., neurological disorder). Those in need of treatment include those already with the disease, as well as those prone to having the disease, or those in whom the condition or disease is to be prevented. After receiving a therapeutic amount of a therapeutic agent (e.g., a compound according to the present invention), a patient has been successfully "treated" for a disease if the patient exhibits an observable and / or measurable reduction in one or more of the following, or the absence of one or more of the following: a reduction in the number of pathogens; a reduction in the percentage of total cells that are pathogenic; and / or some alleviation of one or more of the symptoms associated with the 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 a disease are readily measurable by routine procedures familiar to physicians.

[0056] compound The object of the present invention is to provide a compound of formula (I) [ka] (In the formula, W represents CH or N; R A , R B , R C and R D each independently represent hydrogen, F, Cl, CH3, CF3, CHF2, or CH2F; R 7 is hydrogen, OH, halogen, (C1-C8) alkyl, cycloalkyl, (C1-C8) alkyl-O-, cycloalkyl-O-, cycloalkyl-(C1-C8) alkyl-O-, heterocycloalkyl-O-, heterocycloalkyl-(C1-C8) alkyl-O-, aryl-(C1-C8) alkyl-O-, heteroaryl-(C1-C8) alkyl-O-, R 11 O-(C1-C8) alkyl-O-, R 11 R12 N-(C1-C8) alkyl-O-, (R 11 O)(R 12 )N-(C1-C8) alkyl-O-, R 11 R 12 N-(C1-C8) alkyl-, R 11 -O-(C1-C8) alkyl-, NR 11 R 12 , CN, CO2H, CO2R 11 , CONH2, CON(R 11 ) H, heterocycloalkyl or heteroaryl; R 11 and R 12 each independently represents hydrogen or (C1-C8) alkyl; R 7 wherein said alkyl or cycloalkyl is optionally substituted by at least one F, Cl, OH, ═O, (C1-C8)alkyl, (C1-C8)alkyl-O—, heterocycloalkyl, aryl, or heteroaryl; The heterocycloalkyl, aryl, or heteroaryl (i.e., R 7 or any heterocycloalkyl, aryl, or heteroaryl that is part of any substituent thereof, is selected from the group consisting of at least one of F, Cl, (C1-C8)alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, ═O, →O, (C1-C8)alkoxy, NR 13 R 14 , R 13 R 14 N-(C1-C8) alkyl-, R 13 O2C-(C1~C8) alkyl-, CO2H, R 13 R 14 NC(O)-, R 13 O-NR 14 - or (C1-C8) alkyl-CO2-, optionally substituted; R 13 and R 14 each independently represents hydrogen or (C1-C8) alkyl; Z is CH, CR 8 Or represents N; R 8represents (C1-C4) alkyl, F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH or (C1-C4) alkoxy; or Z is CR 8 represents R 7 and R 8 together with the carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl; The cycloalkyl or heterocycloalkyl may be selected from the group consisting of at least one of F, OH, ═O, →O, (C1-C8)alkyl, CF3, HO2C—CH2—, (C1-C4)alkyl-CO2—CH2—, R 15 R 16 optionally substituted by N—CH—, aryl or aryl-(C-C)alkyl-; R 15 and R 16 each independently represents hydrogen or (C1-C8) alkyl; R 5 represents hydrogen, (C1-C8) alkyl, CH3 substituted by 1 to 3 (C1-C8) alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl-(C1-C8) alkyl; R 5 The alkyl or cycloalkyl may be selected from at least one of F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, ═O, (C1-C8) alkoxy, NR 17 R 18 , CO2H, R 17 R 18 NC(O)-, R 17 O-NR 18 -, optionally substituted by heterocycloalkyl, aryl, or heteroaryl; R 17 and R 18 each independently represents hydrogen or (C1-C8) alkyl; The heterocycloalkyl, aryl, or heteroaryl (i.e., R 5or any heterocycloalkyl, aryl, or heteroaryl that is part of any substituent thereof, is selected from the group consisting of at least one of F, Cl, (C1-C8)alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, ═O, →O, (C1-C8)alkoxy, NR 19 R 20 , CO2H, R 19 R 20 NC(O)-, R 19 O-NR 20 -, (C1-C8) alkyl-CO2-, R 19 R 20 N-(C1-C8) alkyl-, R 19 optionally substituted by OC—(C1-C8)alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl-(C1-C8)alkyl-; R 19 and R 20 each independently represents hydrogen or (C1-C8) alkyl; R 6 represents (C1-C8) alkyl, CH3 substituted by 1 to 3 (C1-C8) alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl-(C1-C8) alkyl; R 6 The alkyl or cycloalkyl may be selected from at least one of F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, ═O, (C1-C8) alkoxy, NR 21 R 22 , CO2H, R 21 R 22 NC(O)-, R 21 O-NR 22 -, optionally substituted by heterocycloalkyl, aryl, or heteroaryl; R 21 and R 22 each independently represents hydrogen or (C1-C8) alkyl; The heterocycloalkyl, aryl, or heteroaryl (i.e., R 6or any heterocycloalkyl, aryl, or heteroaryl that is part of any substituent thereof, is selected from the group consisting of at least one of F, Cl, (C1-C8)alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, ═O, →O, (C1-C8)alkoxy, NR 23 R 24 , CO2H, R 23 R 24 NC(O)-, R 23 O-NR 24 -, (C1-C8) alkyl-CO2-, R 23 R 24 N-(C1-C8) alkyl-, R 23 optionally substituted by OC—(C1-C8)alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl-(C1-C8)alkyl-; R 23 and R 24 each independently represents hydrogen or (C1-C8) alkyl; Or, R 5 and R 6 together with the nitrogen atom to which they are attached form a heterocycloalkyl; The heterocycloalkyl (i.e., R 5 , R 6 and heterocycloalkyl formed by the nitrogen atom to which they are attached) may be selected from the group consisting of at least one of F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, ═O, →O, (C1-C8) alkoxy, NR 25 R 26 , CO2H, (C1-C8) alkyl-CO2-, R 25 R 26 NC(O)-, R 25 O-NR 26 -, R 25 R 26 N-(C1-C8) alkyl-, R 25OC-(C1-C8)alkyl-, cycloalkyl, heterocycloalkyl, aryl, cycloalkyl-(C1-C8)alkyl-, heterocycloalkyl-(C1-C8)alkyl-, aryl-(C1-C8)alkyl-, heteroaryl-(C1-C8)alkyl-, aryl-cycloalkyl-, cycloalkyl-O-, heterocycloalkyl-O-, aryl-O-, heteroaryl-O-, cycloalkyl-(C1-C8)alkyl-O-, heterocycloalkyl-(C1-C8)alkyl-O-, aryl-(C1-C8)alkyl-O-, heteroaryl-(C1-C8)alkyl-O-, cycloalkyl-NR 25 -, heterocycloalkyl-NR 25 -, aryl-NR 25 -, heteroaryl-NR 25 -, cycloalkyl-(C1-C8) alkyl-NR 25 -, heterocycloalkyl-(C1-C8)alkyl-NR 25 -, aryl-(C1-C8) alkyl-NR 25 -, heteroaryl-(C1-C8)alkyl-NR 25 optionally substituted by -, benzylidene, heteroarylidene, aryl-(C1-C8)alkyl-ylidene- or heteroaryl-(C1-C8)alkyl-ylidene-; R 25 and R 26 each independently represents hydrogen or (C1-C8) alkyl; The heterocycloalkyl, aryl, heteroaryl, benzylidene, or heteroarylidene (i.e., R 5 , R 6 and any heterocycloalkyl, aryl, heteroaryl, benzylidene, or heteroarylidene that is part of any substituent of a heterocycloalkyl formed by the nitrogen atom to which they are attached) may be selected from at least one of F, Cl, (C1-C8)alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, ═O, →O, (C1-C8)alkoxy, NR 27 R 28 , CO2H, R 27 R28 NC(O)-, R 27 O-NR 28 -, (C1-C8) alkyl-CO2-, R 27 R 28 N-(C1-C8) alkyl-, R 27 optionally substituted by OC—(C1-C8)alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl-(C1-C8)alkyl-; R 27 and R 28 and each independently represent hydrogen or (C1-C8) alkyl), or a pharmaceutically acceptable salt and / or solvate thereof.

[0057] According to a preferred embodiment, R A , R B and R C exactly two groups selected from represent hydrogen, and R D represents CF3, and R 7 If represents OCH3 and Z represents CH, then R A , R B and R C The remaining groups in the formula do not represent F.

[0058] In any one of the following embodiments regarding specific limitations on the structure of the compounds of formula (I), unless otherwise specified, any alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, benzylidene, or heteroarylidene may independently be optionally substituted as shown under formula (I) herein.

[0059] According to a preferred embodiment, R D represents hydrogen, F, Cl, CH3, CHF2, or CH2F. In this embodiment, formula (I) is designated "formula (Ii)."

[0060] According to a preferred embodiment, R 7is hydrogen, OH, halogen, (C1-C8) alkyl, cycloalkyl, (C2-C8) alkyl-O-, cycloalkyl-O-, cycloalkyl-(C1-C8) alkyl-O-, heterocycloalkyl-O-, heterocycloalkyl-(C1-C8) alkyl-O-, aryl-(C1-C8) alkyl-O-, heteroaryl-(C1-C8) alkyl-O-, R 11 O-(C1-C8) alkyl-O-, R 11 R 12 N-(C1-C8) alkyl-O-, (R 11 O)(R 12 )N-(C1-C8) alkyl-O-, R 11 R 12 N-(C1-C8) alkyl-, R 11 O-(C1-C8) alkyl-, NR 11 R 12 , CN, CO2H, CO2R 11 , CONH2, CON(R 11 ) H, heterocycloalkyl or heteroaryl; R 11 and R 12 each independently represent hydrogen or (C1-C8) alkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted as defined under formula (I) herein above. In this embodiment, formula (I) is designated "formula (I-ii)."

[0061] According to one preferred embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein W represents CH or N; R A , R B , R C and R D each independently represent hydrogen, F, Cl, CH3, CF3, CHF2, or CH2F; R 7is hydrogen, OH, halogen, (C1-C8) alkyl, cycloalkyl, (C1-C8) alkyl-O-, cycloalkyl-O-, cycloalkyl-(C1-C8) alkyl-O-, heterocycloalkyl-O-, R 11 O-(C1-C8) alkyl-O-, R 11 R 12 N-(C1-C8) alkyl-O- or (R 11 O)(R 12 )N-(C1-C8)alkyl-O-; R 11 and R 12 each independently represents hydrogen or (C1-C8) alkyl; said alkyl or cycloalkyl is optionally substituted with at least one F, Cl, heterocycloalkyl, aryl, or heteroaryl; The heterocycloalkyl, aryl, or heteroaryl may be selected from the group consisting of at least one of F, Cl, CF, CHF, CHF, OCF, CN, OH, (C1-C8)alkoxy, NR 13 R 14 , CO2H, R 13 R 14 NC(O)- or R 13 O-NR 14 - optionally substituted by; R 13 and R 14 each independently represents hydrogen or (C1-C8) alkyl; Z represents CH or N; or Z is CR 8 represents R 7 and R 8 together with the carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl; The cycloalkyl or heterocycloalkyl may be selected from the group consisting of at least one of F, OH, CF, HOC—CH—, (C1-C4) alkyl-CO—CH—, or R 15 R 16 optionally substituted by N-CH2-; R 15 and R 16each independently represents hydrogen or (C1-C8) alkyl; R 5 represents hydrogen, (C1-C8) alkyl, CH3 substituted by 1 to 3 (C1-C8) alkyl groups, cycloalkyl or cycloalkyl-(C1-C8) alkyl; The alkyl or cycloalkyl may be selected from the group consisting of at least one of F, Cl, CF3, OCF3, CN, OH, (C1-C8)alkoxy, NR 17 R 18 , CO2H, R 17 R 18 NC(O)-, R 17 O-NR 18 -, optionally substituted by heterocycloalkyl, aryl, or heteroaryl; R 17 and R 18 each independently represents hydrogen or (C1-C8) alkyl; The heterocycloalkyl, aryl, or heteroaryl may be selected from the group consisting of at least one of F, Cl, CF, CHF, CHF, OCF, CN, OH, (C1-C8)alkoxy, NR 19 R 20 , CO2H, R 19 R 20 NC(O)- or R 19 O-NR 20 - is replaced by; R 19 and R 20 each independently represents hydrogen or (C1-C8) alkyl; R 6 represents (C1-C8) alkyl, CH3 substituted by 1 to 3 (C1-C8) alkyl groups, cycloalkyl or cycloalkyl-(C1-C8) alkyl; The alkyl or cycloalkyl may be selected from the group consisting of at least one of F, Cl, CF3, OCF3, CN, OH, (C1-C8)alkoxy, NR 21 R 22 , CO2H, R 21 R 22 NC(O)-, R 21 O-NR 22-, optionally substituted by heterocycloalkyl, aryl, or heteroaryl; R 21 and R 22 each independently represents hydrogen or (C1-C8) alkyl; The heterocycloalkyl, aryl, or heteroaryl may be selected from the group consisting of at least one of F, Cl, CF, CHF, CHF, OCF, CN, OH, (C1-C8)alkoxy, NR 23 R 24 , CO2H, R 23 R 24 NC(O)- or R 23 O-NR 24 - optionally substituted by; R 23 and R 24 each independently represents hydrogen or (C1-C8) alkyl; Or, R 5 and R 6 together with the nitrogen atom to which they are attached form a heterocycloalkyl; The heterocycloalkyl may be selected from the group consisting of at least one of F, Cl, CF, OCF, CN, OH, (C1-C8)alkoxy, NR 25 R 26 , CO2H, R 25 R 26 NC(O)-, R 25 O-NR 26 -, heterocycloalkyl, aryl, heteroaryl, heterocycloalkyl-(C1-C8)alkyl-, aryl-(C1-C8)alkyl-, heteroaryl-(C1-C8)alkyl-, cycloalkyl-(C1-C8)alkyl-O-, aryl-(C1-C8)alkyl-O-, heteroaryl-(C1-C8)alkyl-O-, cycloalkyl-(C1-C8)alkyl-NR 25 -, aryl-(C1-C8) alkyl-NR 25 -, heteroaryl-(C1-C8)alkyl-NR 25 optionally substituted by -, benzylidene, heteroarylidene, aryl-(C1-C8)alkyl-ylidene- or heteroaryl-(C1-C8)alkyl-ylidene-; R 25 and R 26 each independently represents hydrogen or (C1-C8) alkyl; The heterocycloalkyl, aryl, heteroaryl, benzylidene, or heteroarylidene may be selected from the group consisting of at least one of F, Cl, CF, CHF, CHF, OCF, CN, OH, (C1-C8)alkoxy, NR 27 R 28 , CO2H, R 27 R 28 NC(O)- or R 27 O-NR 28 - optionally substituted by; R 27 and R 28 each independently represents hydrogen or (C1-C8) alkyl; However, R A , R B and R C exactly two groups selected from represent hydrogen, and R D represents CF3, and R 7 If represents OCH3 and Z represents CH, then R A , R B and R C The remaining groups in the formula do not represent F.

[0062] According to one embodiment, W represents CH.

[0063] 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 In one embodiment, exactly one of R A , R B , R C and R D In one embodiment, exactly two of R A , R B , R C and R DExactly three of these represent hydrogen.

[0064] In one embodiment, R A and R C At least one of R represents hydrogen. A represents hydrogen. In one particular embodiment, R C represents hydrogen.

[0065] According to one embodiment, R A , R B and R D At least one of R represents F or Cl. B and R D At least one of R represents F or Cl. B and R D each independently represents F or Cl. In one particular embodiment, R B represents F. In one particular embodiment, R B represents Cl. In one particular embodiment, R D represents F. In one particular embodiment, R D represents Cl. In one preferred embodiment, R B represents F. In one preferred embodiment, R D represents Cl. In a further preferred embodiment, R B represents F and R D represents Cl.

[0066] According to one embodiment, R A , R B and R D At least one of R represents CHF or CF. B and R D At least one of R represents CHF or CF. B and R D each independently represents H, F, CHF2, or CF3. In one embodiment, R B represents H or F. In a further preferred embodiment, R Brepresents F. In one preferred embodiment, R D represents CHF2 or CF3. In a further preferred embodiment, R B represents H or F, and R D represents CHF2 or CF3.

[0067] According to one embodiment, R 7 is hydrogen, OH, halogen, (C1-C8) alkyl, cycloalkyl, (C1-C8) alkyl-O-, cycloalkyl-O-, cycloalkyl-(C1-C8) alkyl-O-, heterocycloalkyl-O-, R 11 O-(C1-C8) alkyl-O-, R 11 R 12 N-(C1-C8) alkyl-O- or (R 11 O)(R 12 )N-(C1-C8)alkyl-O-; R 11 and R 12 each independently represent hydrogen or (C1-C8) alkyl; said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally substituted as defined under formula (I) herein above.

[0068] According to one embodiment, R 7 represents hydrogen, OH or halogen. 7 represents hydrogen. In one preferred embodiment, R 7 represents hydroxyl (OH). In one embodiment, R 7 represents a halogen. In one particularly preferred embodiment, R 7 represents F or Cl. In one particularly preferred embodiment, R 7 represents F. In one particular embodiment, R 7 represents Cl.

[0069] In one preferred embodiment, R 7 does not represent hydrogen.

[0070] According to one embodiment, R 7represents (C1-C8)alkyl-O- (i.e., (C1-C8)alkoxy) or cycloalkyl-O-. In one embodiment, the alkyl or cycloalkyl is optionally substituted with at least one F, Cl, OH, (C1-C8)alkoxy, or aryl. In one particular embodiment, R 7 represents OCH3 (methoxy), OCH2CH3, OCF3, cyclobutyl-O-, HO-CH2-CH2-O-, CH3O-CH2-CH2-O- or phenyl-CH2-O-.

[0071] According to one embodiment, R 7 represents (C1-C8) alkyl-O- (i.e., (C1-C8) alkoxy). In one embodiment, the alkyl is optionally substituted with at least one F or Cl. In one particular embodiment, the halogen is F. In one embodiment, R 7 represents OCH3 (methoxy), OCH2CH3 or OCF3. In one preferred embodiment, R 7 represents OCH3 (methoxy).

[0072] According to one embodiment, R 7 represents cycloalkyl-O-. In one embodiment, R 7 represents cyclobutyl-O—.

[0073] According to one embodiment, R 7 represents (C1-C8) alkyl-O- (i.e., (C1-C8) alkoxy), wherein the alkyl is substituted by at least one OH or (C1-C8) alkoxy, i.e., RO-(C1-C8) alkyl-O- (wherein R represents H or (C1-C8) alkyl). In one preferred embodiment, R 7 represents HO-CH2-CH2-O- or CH3O-CH2-CH2-O-.

[0074] According to one embodiment, R 7represents (C1-C8) alkyl-O- (i.e., (C1-C8) alkoxy), wherein the alkyl is optionally substituted with at least one aryl. In one embodiment, the aryl is unsubstituted. In one embodiment, R 7 represents phenyl-CH2-O-.

[0075] According to one embodiment, R 7 represents (C1-C8) alkyl-O- (i.e., (C1-C8) alkoxy), wherein the alkyl is optionally substituted with at least one heteroaryl. In one embodiment, the heteroaryl is unsubstituted. In one embodiment, R 7 represents heteroaryl-CH2-O-.

[0076] According to one embodiment, R 7 represents (C1-C8) alkyl-O- (i.e., (C1-C8) alkoxy), wherein the alkyl is optionally substituted with at least one heterocycloalkyl. In one embodiment, R 7 represents heterocycloalkyl-(C1-C8)alkyl-O—, i.e., the alkyl is substituted with exactly one heterocycloalkyl. In one embodiment, the heterocycloalkyl is unsubstituted.

[0077] In one preferred embodiment, R 7 represents hydrogen, F, Cl, OH, OCH3 (methoxy), HO-CH2-CH2-O-, CH3O-CH2-CH2-O- or phenyl-CH2-O-.

[0078] In a further preferred embodiment, R 7 represents F, OH, OCH3 (methoxy) or phenyl-CH2-O-.

[0079] According to one embodiment, Z represents CH or N, or Z is CR 8 represents R 7 and R 8taken together with the carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl, said cycloalkyl or heterocycloalkyl being optionally substituted as defined under formula (I) herein above. In other words, in this embodiment, R 7 and R 8 except when, together with the carbon atom to which they are attached, they form a cycloalkyl or heterocycloalkyl. 8 represents hydrogen.

[0080] According to one embodiment, Z represents CH or N. In one embodiment, Z represents CH. In one embodiment, Z represents N.

[0081] According to another embodiment, Z is CR 8 represents R 7 and R 8 together with the carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl, which is optionally substituted as defined under formula (I) herein.

[0082] According to one preferred embodiment, Z does not represent N.

[0083] In one preferred embodiment, Z is CR 8 represents R 8 represents (C1-C4) alkyl, F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH or (C1-C4) alkoxy. 8 represents methyl, ethyl, F, Cl, CF, CN or OH. In a preferred embodiment, R 8 represents methyl or Cl.

[0084] In one preferred embodiment, Z is CR 8 represents R 7 and R 8taken together with the carbon atom to which they are attached form a heterocycloalkyl, which is optionally substituted as defined herein under formula (I). In one particular embodiment, the heterocycloalkyl contains at least one oxygen atom, i.e., the heterocycloalkyl is a cyclic ether. In one particular embodiment, the heterocycloalkyl contains exactly one oxygen atom. In one particular embodiment, the heterocycloalkyl contains at least one nitrogen atom, i.e., the heterocycloalkyl is a cyclic amine. In one particular embodiment, the heterocycloalkyl is 6- or 5-membered. In one particular embodiment, the heterocycloalkyl is unsubstituted. In one preferred embodiment, the heterocycloalkyl is tetrahydrofuran (e.g., where -R 7 -R 8 - represents -O-CH2CH2-).

[0085] According to one embodiment, R 5 represents hydrogen or (C1-C8) alkyl. In one embodiment, R 5 represents hydrogen. In one embodiment, R 5 represents (C1-C8) alkyl. In one preferred embodiment, R 5 represents hydrogen, methyl or ethyl. In one particular embodiment, R 5 represents hydrogen. In one particular embodiment, R 5 represents methyl or ethyl. In a further particular embodiment, R 5 represents methyl. In a further particular embodiment, R 5 represents ethyl.

[0086] According to one embodiment, R 6 represents (C1-C8) alkyl, cycloalkyl, or cycloalkyl-(C1-C8) alkyl-. In one embodiment, the alkyl or cycloalkyl is optionally substituted with at least one F. In one embodiment, the alkyl or cycloalkyl is unsubstituted. In one embodiment, R 6represents methyl, ethyl, n-propyl, 1-fluoro-n-propane, tert-butyl, cyclopropyl, cyclobutyl or cyclopropyl-CH2-.

[0087] According to one embodiment, R 6 represents (C1-C8)alkyl, cycloalkyl, heterocycloalkyl, cycloalkyl-(C1-C8)alkyl- or aryl-(C1-C8)alkyl-. In one embodiment, the alkyl, cycloalkyl, heterocycloalkyl or aryl is optionally substituted with at least one methyl, Cl or F.

[0088] In one embodiment, R 6 represents ethyl, propyl (e.g., n-propyl), butyl (e.g., tert-butyl), cyclopentyl, cyclohexyl, 2-adamantyl, 3-methyloxetan-3-yl, cyclopropyl-CH2-, cyclobutyl-CH2-, cyclohexyl-CH2-, phenyl-CH2-(benzyl), 3-chlorophenyl-CH2- or 4-fluorophenyl-CH2-.

[0089] In a further preferred embodiment, R 6 represents propyl (eg, n-propyl), butyl (eg, tert-butyl), cyclohexyl, cyclopropyl-CH2- or 3-chlorophenyl-CH2-.

[0090] According to one embodiment, R 6 represents (C1-C8) alkyl. In one embodiment, alkyl is optionally substituted with at least one F. In one embodiment, alkyl is unsubstituted. In one particular embodiment, R 5 represents methyl, ethyl, n-propyl, 1-fluoro-n-propane or tert-butyl.

[0091] According to one embodiment, R 6 represents cycloalkyl. In one embodiment, R 6 represents cyclopropyl or cyclobutyl.

[0092] According to one embodiment, R 6 represents cycloalkyl-(C1-C8)alkyl. In one particular embodiment, R 6 represents cyclopropylmethyl (cyclopropyl-CH2-).

[0093] According to one embodiment, R 5 and R 6 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl. In one embodiment, the heterocycloalkyl is optionally substituted with at least one F. In one embodiment, R 5 and R 6 together with the nitrogen atom to which they are attached 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-phenethylpiperidine. In one particular embodiment, R 5 and R 6 together with the nitrogen atom to which they are attached 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.

[0094] In one preferred embodiment, R 5 and R 6together with the nitrogen atom to which they are attached, represent pyrrolidine, 4-benzyl-piperidine, 4-phenyl-4-hydroxy-piperidine, 4-benzyl-4-hydroxy-piperidine, 4-benzyl-piperazine, tert-butyl 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate, 4-benzylidene-1-piperidine, 4-(2-phenylethyl)-piperidine, 4-phenylpiperidine, 3-phenylpiperidine, 3-benzyl-piperidine, 3-phenylpyrrolidine, 3-benzylpyrrolidine, 4-trimethyl ... to form trifluoromethylpiperidine, 2-azabicyclo[2.2.1]heptane, 3-benzyloxypiperidine, 3-benzyloxypyrrolidine, 2-benzyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrolidine, 4-(4-fluorophenyl)piperidine, [2-(4-chlorophenyl)ethyl]piperazine, [2-(4-fluorophenyl)ethyl]piperazine, 2-(phenylpropyl)piperazine, [2-(4-fluorophenyl)propyl]piperazine, 4-fluoropiperidine or 2,2-dimethylpyrrolidine.

[0095] In one preferred embodiment, R 5 and R 6 together with the nitrogen atom to which they are attached form pyrrolidine, 4-benzyl-piperidine, 4-benzylidene-1-piperidine, 4-(2-phenylethyl)-piperidine, 4-phenylpiperidine, 3-phenylpiperidine, 3-benzyl-piperidine, 3-phenylpyrrolidine, 4-trifluoromethylpiperidine, 3-benzyloxypiperidine, 3-benzyloxypyrrolidine, 4-(4-fluorophenyl)piperidine, [2-(4-chlorophenyl)ethyl]piperazine, [2-(4-fluorophenyl)ethyl]piperazine, 2-(phenylpropyl)piperazine, [2-(4-fluorophenyl)propyl]piperazine, 4-fluoropiperidine or 2,2-dimethylpyrrolidine.

[0096] According to one embodiment, at least one heterocycloalkyl present in the compound of formula (I) is a water-solubilizing group, i.e., the presence of this group in the molecule increases its solubility in water compared to the same molecule without the heterocycloalkyl.

[0097] According to one embodiment, the compound of formula (I) has the formula (Ia) [ka] (In the formula, W, R B , R D , Z and R 5 ~R 7 is a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein

[0098] In one embodiment, W in formula (Ia) represents CH.

[0099] In one embodiment, R of formula (Ia) B and R D each independently represents F or Cl, R 7 represents alkoxy. In one particular embodiment, R B represents F and R D represents Cl.

[0100] In one embodiment, R of formula (Ia) 7 represents alkoxy. In one particular embodiment, R 7 represents methoxy (-OCH3).

[0101] In one embodiment, R of formula (Ia) B and R D each independently represents F or CF. In one particular embodiment, R B represents F and R D represents CF3.

[0102] In one embodiment, Z in formula (Ia) represents N.

[0103] According to one embodiment, the compound of formula (I) is selected from the compounds in Table 1 below and pharmaceutically acceptable salts and / or solvates thereof. [Table 1] TIFF2025533979000006.tif219159TIFF2025533979000007.tif221159TIFF202 5533979000008.tif213159TIFF2025533979000009.tif236159TIFF20255339790 00010.tif213159TIFF2025533979000011.tif199159TIFF2025533979000012.t if224159TIFF2025533979000013.tif224159TIFF2025533979000014.tif224159

[0104] According to one preferred embodiment, the compound is selected from the compounds of Table 1 herein and pharmaceutically acceptable salts and / or solvates thereof, with the proviso that the compound is not N,N-diethyl-5-[4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-6-methoxy-pyridine-3-sulfonamide (045) or a pharmaceutically acceptable salt and / or solvate thereof. [ka]

[0105] According to one embodiment, in the compound of formula (I), R D represents CF3, and R 7 If represents OCH3 and Z represents CH, then R A , R B and R C does not represent F and Cl. According to one embodiment, in the compounds of formula (I), R D represents CF3, and R 7 If represents OCH3, then R A , R B and R Cdoes not represent F. According to one embodiment, in the compounds of formula (I), R D If represents CF3, then R A , R B and R C does not represent F. In one embodiment, in the compound of formula (I), R D If represents CF3, then R A , R B and R C does not represent F and Cl. According to one embodiment, in the compounds of formula (I), R 7 If represents OCH3, then R A , R B and R C does not represent F. In one embodiment, in the compound of formula (I), R 7 If represents OCH3, then R A , R B and R C does not represent F and Cl. According to one embodiment, R D does not represent CF. In one embodiment, R D does not represent CF3, CHF2 and CH2F. According to one embodiment, R 7 does not represent methoxy (-OCH). In one embodiment, R 7 does not represent alkoxy.

[0106] All references herein to a compound of the invention (e.g., "a compound of Formula (I)") include references to salts, solvates, multi-component complexes, and liquid crystals thereof. All references herein to a compound of the invention include references to its polymorphs and crystal habits. All references herein to a compound of the invention include references to its isotopically labeled compounds, including its deuterated compounds. All references herein to a compound of the invention include references to its stereoisomers. All references herein to a compound of the invention include references to its pharmaceutically acceptable prodrugs.

[0107] In particular, the compound of the present invention can be in the form of a pharmaceutically acceptable salt.According to one embodiment, the compound of the present invention is a pharmaceutically acceptable salt.Pharmaceutically acceptable salts include its acid addition and base salts.Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate. Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)-morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine, and zinc salts. Hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, can also be formed. When a compound contains an acidic and a basic group, the compound can also form internal salts, and such compounds are within the scope of the present invention. When a compound contains a hydrogen-donating heteroatom (e.g., NH), the present invention also encompasses salts and / or isomers formed by the transfer of the hydrogen atom to a basic group or atom within the molecule.

[0108] Pharmaceutically acceptable salts of the compounds of the present invention can be prepared by one or more of the following methods: (i) reacting the compound with a desired acid; (ii) reacting the compound with a desired base; (iii) using the desired acid to remove an acid-labile or base-labile protecting group from a suitable precursor of the compound or to open a suitable cyclic precursor, such as a lactone or lactam, and / or (iv) converting one salt of the compound to another by reaction with a suitable acid or using a suitable ion exchange column. All of these reactions are typically carried out in solution. The salt may precipitate from the solution and be recovered by filtration or by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

[0109] 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.

[0110] In particular, the compounds of the present invention may contain at least one asymmetric center and therefore may exist in different stereoisomeric forms. Thus, all references to the compounds of the present invention herein include all possible stereoisomers, including not only racemates but also individual enantiomers and non-racemic mixtures thereof. Non-racemic mixtures may contain any amount of each distinct stereoisomer, for example, one stereoisomer may predominate (e.g., a 90 / 10 or 80 / 20 mixture), or the enantiomeric ratio may be close to that of a racemic mixture (e.g., a 40 / 60 mixture). If a compound is desired as a single enantiomer, such a single enantiomer can be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatography, each of which is known in the art. Resolution of the final product, intermediate, or starting material can be carried out by any suitable method known in the art.

[0111] Pharmaceutical Composition Another object of the present invention is a composition comprising a compound according to the invention as described herein. According to one embodiment, the composition further comprises at least one pharmaceutically acceptable carrier, such that the composition is a "pharmaceutical composition" as defined herein.

[0112] In a first embodiment, the pharmaceutical composition comprises a compound according to the invention as the only therapeutic agent, in a second embodiment, the pharmaceutical composition further comprises at least another therapeutic agent, for example a therapeutic agent suitable for treating a neurological disorder.

[0113] Another object of the present invention is a medicament comprising a compound according to the invention as described herein.

[0114] kit Another object of the present invention is a kit of parts (abbreviated "kit") comprising a compound or composition according to the invention as described herein. According to one embodiment, the kit comprises an article of manufacture, such as a package or container. According to one embodiment, the kit comprises instructions for use. The kit can be promoted, distributed, or sold as a unit for carrying out the method of the invention.

[0115] 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, such as a therapeutic agent suitable for treating a neurological disorder.

[0116] Medical Uses of the Compound Another object of the invention is a compound or composition according to the invention as described herein for use as a medicament.

[0117] Another object of the invention is a compound or composition according to the invention as described herein for use in the treatment of neurological disorders.

[0118] 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 as described herein in the manufacture of a medicament for treating a neurological disorder. Another object of the present invention is the use of a compound or composition according to the present invention as described herein for treating a neurological disorder.

[0119] 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 invention as described herein.

[0120] According to one embodiment, the neurological disorders treated by the method or use of the present invention are: - a disease or disorder associated with defective neurogenesis, such as Hirschsprung's disease, schizophrenia, ataxia-telangiectasia, age-related decline in nervous system function, or a neurodevelopmental disorder, neurodegenerative diseases or disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, frontotemporal dementia, retinal neurodegenerative diseases, neuro-ophthalmological diseases, neurotrophic keratitis, Charcot-Marie-Tooth disease, spinal muscular atrophy, epilepsy (e.g. epileptic disorders, or seizure disorders, or chronic neurological disorders presenting with epilepsy), dementia, age-related decline in nervous system function, prion diseases, Creutzfeldt-Jakob disease, multiple system atrophy (Shy-Drager syndrome), multiple sclerosis, or Guillain-Barré syndrome, - a disease or disorder associated with nerve injury or neurotoxicity, such as head injury, brain injury, traumatic brain injury, peripheral nerve injury, traumatic peripheral nerve injury, peripheral neuropathy, nerve transplant complications, spinal cord injury, traumatic spinal cord injury, nerve or nerve injury disruption, cerebrospinal cord disruption, damage to brain or nerve cells, syringomyelia, optic neuropathy, trauma, stroke, ischemia, ischemic stroke, neurotoxicity or aphasia caused by alcohol or substance abuse (e.g., ecstasy, methamphetamine, etc.); Neurodevelopmental disorders, such as Rett syndrome, X-linked mental retardation, Fragile X syndrome, Down syndrome, autism spectrum disorder, Hirschsprung's disease, Tourette's syndrome, childhood learning disabilities, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Angelman syndrome, micropleemia, schizophrenia, language disorders, preterm birth, perinatal arterial ischemic stroke, spina bifida, mental retardation, non-syndromic X-linked mental retardation, Ondine syndrome, or WAGR syndrome. neuropsychiatric disorders, such as depression, major depressive disorder, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, anxiety, 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 and / or tic disorders characterized by motor and / or vocal tics (e.g. Tourette's syndrome), substance use behavior, addiction, mood disorders, suicidality, cancer-related psychiatric symptoms, Alzheimer's disease, Huntington's disease, frontotemporal dementia or reward deficiency syndrome (RDS), movement disorders, such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, movement and tic disorders characterized by motor and / or vocal tics (e.g. Tourette's syndrome), ataxia, ataxic rigidity (spasticity), Charcot-Marie-Tooth disease, spinal muscular atrophy, Werdnig-Hoffmann disease or chronic proximal spinal muscular atrophy, Pain disorders, such as neuralgia, trigeminal neuralgia, chronic pain, inflammatory pain, pain associated with arthritis, fibromyalgia, back pain, pain associated with cancer, pain associated with digestive disorders, pain associated with Crohn's disease, pain associated with autoimmune diseases, pain associated with endocrine disorders, pain associated with diabetic neuropathy, phantom limb pain, spontaneous pain, chronic post-operative pain, chronic, temporomandibular joint pain, burning pain, post-herpetic neuralgia, pain associated with AIDS, complex regional pain syndrome types I and II, trigeminal neuralgia, chronic back pain, pain associated with spinal cord injury, pain associated with drug intake and recurrent acute pain, neuropathic pain, or inappropriate neural activity resulting in neurodystonia in diseases such as diabetes, MS and motor neuron disease ophthalmic diseases or disorders, such as retinal disorders, retinal neurodegenerative diseases, retinitis pigmentosa, non-arteritic anterior ischemic optic neuropathy (NAION), macular degeneration, age-related macular degeneration, glaucoma, diabetic retinopathy, optic neuropathy and retinal degeneration, neuro-ophthalmological diseases, age-related cataracts, primary open-angle glaucoma (POAG), retinal ganglion cell damage, ocular hypertension, ischemic optic neuropathy, macular telangiectasia, cystoid macular edema, macular telangiectasia type 2, neurotrophic keratitis or strabismus, intestinal or gastrointestinal disorders, such as disorders of intestinal motility, constipation, Hirschsprung's disease, inflammatory bowel disease, enteric neurodysplasia, ulcerative colitis, achalasia, esophageal spasms, duodenal ulcers, Zollinger-Ellison syndrome, gastric acid hypersecretion, malabsorption disorders or intestinal inflammation, - progressive muscular dystrophies, such as Duchenne, Becker, Emery-Dreyfuss, Landwehr-Dejerine, glenohumeral, limb-girdle, von Graefe-Fuchs, oculopharyngeal, myotonic and congenital, congenital or acquired myopathies, such as Charcot-Marie-Tooth disease, Werdnig-Hoffmann disease or chronic proximal spinal muscular atrophy, - a disease or disorder associated with deficient long-term or short-term memory, such as memory loss, benign forgetfulness or Alzheimer's disease, autoimmune disorders, such as multiple sclerosis, autoimmune encephalomyelitis, autoimmune encephalitis, autoimmune hemolytic anemia, chronic lymphocytic leukemia, Churg-Strauss syndrome, anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, thyroid-associated orbitopathy, autoimmune thyroiditis, Guillain-Barré syndrome, or autoimmune thrombocytopenic purpura, Neuro-ontological diseases or disorders, such as cochlear sensory cell damage, hearing impairment, hearing loss or tinnitus, Sleep disorders, such as narcolepsy, restless legs syndrome, obstructive sleep apnea, chronic insomnia disorder, paradoxical sleep deprivation or REM sleep deprivation, cerebrovascular 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), Substance abuse disorders, such as substance dependence, substance abuse and sequelae of substance abuse dependence, substance-induced psychological disorders, substance withdrawal and substance-induced dementia or amnestic disorders, neurological deficits related to neuronal response to viral infection, trypanosome infection, AIDS, obesity, temporomandibular joint dysfunction, aphasia, Bell's palsy, encephalitis, kidney disease or insufficiency, pheochromocytoma, metabolic syndrome, cancer, eczema, thrombocytopenia; hypoplasia; disseminated intravascular coagulation (DIC); myelodysplasia; immune thrombocytopenic purpura (ITP), HIV-induced ITP, neuro-oncological disease or disorder, neuro-immunological disease or disorder, multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), neurofibromatosis type 1, scleroderma, epidermal and interstitial wound healing and / or scarring disorders, or - Ageing and / or aging-related diseases or disorders.

[0121] According to one embodiment, the neurological disorder is epilepsy, e.g., Dravet syndrome, benign rolandic epilepsy, frontal lobe epilepsy, infantile spasms, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy, childhood absence epilepsy (e.g., pycnolepsy), febrile seizures, Lafora's progressive myoclonic epilepsy, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, generalized epilepsy with febrile seizures (GEFS+), severe myoclonus, infantile epilepsy (SMEI), benign familial neonatal convulsions (BFNC), West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, migratory partial epilepsy, infantile epileptic encephalopathy. , tuberous sclerosis complex (TSC), focal cortical dysplasia, lissencephaly type I, Miller-Diecker 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, giant bilateral myoclonus, catamenial epilepsy, Jacksonian seizure disorder, Unverricht-Lundborg disease or photosensitive epilepsy.

[0122] According to one embodiment, the compositions or medicaments according to the present invention described herein are to be administered to a subject and can be formulated using methods known in the art. Non-limiting examples of the forms that can be used for administration include solutions (such as sterile aqueous solutions), gels, dispersions, emulsions, suspensions, and solid forms (such as powders or liposome forms) that are suitable for use in preparing solutions or suspensions by adding liquid before use.

[0123] The compositions or medicaments according to the invention described herein may be administered using routes of administration well known in the art, such as parenterally, orally, by inhalation, by spray, rectally, nasally, or via an implanted reservoir.

[0124] However, it should be understood that the total daily amount of compound, composition or medicament to be used should be determined by the attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific patient will depend on various factors, including the disease to be treated and the severity of the disease, the activity of the compound used; the age, weight, general health condition, sex and leanness of the subject; the administration time, route of administration and excretion rate of the specific therapeutic agent used; treatment period; drugs used in combination with or simultaneously with the specific therapeutic agent used; and similar factors well known in the medical field.For example, it is well within the skill of those skilled in the art to start the dose of compound at a level lower than the level required to achieve desired therapeutic effect, and gradually increase the dose until desired effect is achieved.The total dose required for each treatment can be administered in multiple doses or in a single dose.

[0125] In one embodiment, the dosage of the compound is about 0.01 to 500 mg / kg of patient body weight per day, and can be administered in single or multiple doses. Preferably, the dosage level is about 0.1 to about 250 mg / kg / day, more preferably about 0.5 to about 100 mg / kg / day. Suitable dosage levels can be about 0.01 to 250 mg / kg / day, about 0.05 to 100 mg / kg / day, or about 0.1 to 50 mg / kg / day. Within this range, the dosage can be about 0.05 to 0.5, about 0.5 to 5, or about 5 to 50 mg / kg / day. For oral administration, the composition is preferably provided in the form of a tablet containing about 1.0 to 1000 milligrams of active ingredient, particularly about 1.0, about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, and about 1000.0 milligrams of active ingredient, for symptomatic adjustment of the dosage to the patient being treated. The compound may be administered on a regimen of 1 to 4 times daily, preferably once or twice daily. It will be understood, however, that the specific dose level and frequency of administration for any particular patient may vary and will depend upon a variety of factors including the activity of the particular compound employed, the metabolic stability and length of action of that compound, age, body weight, general health, sex, leanness, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition and the host being treated.

[0126] According to a first embodiment, the composition or medicament according to the invention described herein is administered as the only therapeutic agent. According to a second embodiment, the composition or medicament according to the invention described herein is administered before, simultaneously with, and / or after at least another therapeutic agent. In one embodiment, the other therapeutic agent is suitable for treating a neurological disorder.

[0127] Another object of the present invention is a method for promoting neuronal cell survival and / or neuronal function. Another object of the present invention is a compound or composition according to the present invention as described herein for use in promoting neuronal cell survival and / or neuronal function. According to one embodiment, the method or use comprises contacting a neuronal cell with a therapeutically effective amount of a compound, composition or medicament according to the present invention as described herein. The method or use may be in vitro, ex vivo or in vivo.

[0128] Another object of the present invention is a method for rescuing neuronal function after exposure to an injury, event, or condition detrimental to neuronal function. Another object of the present invention is a compound or composition according to the present invention described herein for use in rescuing neuronal function after exposure to an injury, event, or condition detrimental to neuronal function. Such injuries, events, or conditions include, but are not limited to, neuronal stress caused by, for example, hypoxia or ischemia; traumatic injury; or exposure to toxic molecules, such as abnormally misfolded proteins, protein aggregates, excitotoxins, reactive oxygen species, endoplasmic reticulum stressors, mitochondrial stressors, Golgi antagonists, etc. According to one embodiment, the method or use comprises contacting a neuronal cell with a therapeutically effective amount of a compound, composition, or medicament according to the present invention described herein. The method or use may be in vitro, ex vivo, or in vivo.

[0129] Another object of the present invention is a method for binding to or modulating GFRα1 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 as described herein for binding to or modulating GFRα1. According to a preferred embodiment, the compound or composition is for activating GFRα1. In one embodiment, the GFRα1 is preferably human GFRα1 having SEQ ID NO: 1.

[0130] Another object of the present invention is a method for activating the GFRα1 / RET signaling pathway 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 as described herein for activating the GFRα1 / RET signaling pathway.

[0131] 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 as described herein for detecting GFRα1 in a sample. In one embodiment, the GFRα1 is preferably human GFRα1 having 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 moiety capable of re-emitting light upon light excitation, a radiolabel, an imaging agent, etc.

[0132] Manufacturing method Compound synthesis The compounds according to the invention described herein can be prepared by synthetic methods well known in the art.

[0133] Another object of the present invention is a method for preparing the compounds of the present invention described herein. According to one embodiment, the method is a Buchwald-Hartwig amination.

[0134] According to one embodiment, the method comprises: (a-1) Formula (II) [ka] (In the formula, Z, R 5 , R 6 and R 7 is as defined herein under formula (I), and X represents a halide or -CF3SO3, Formula (III) [ka] (Wherein W and R A ~R D is as defined under formula (I) herein; and reacting in the presence of a base and a metal catalyst, thereby obtaining the compound of the present invention.

[0135] In one embodiment, the base in step (a-1) is cesium carbonate (CsCO), sodium carbonate (NaCO), or potassium carbonate (KCO). In one particular embodiment, the base is cesium carbonate (CsCO). In one embodiment, the base is sodium tert-butanoate (t-BuONa), potassium tert-butanoate (t-BuOK), or potassium phosphate. In one particular embodiment, the base is sodium tert-butanoate (t-BuONa).

[0136] In one embodiment, the catalyst in step (a-1) is a palladium catalyst. In a particular embodiment, the catalyst is Pd(OAc) and rac-BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) system. In a particular embodiment, the catalyst is XPhos-Pd-G3.

[0137] In one embodiment, X represents a halide. In one particular embodiment, X represents Br.

[0138] In one embodiment, the reaction in step (a-1) is carried out in a solvent. In one particular embodiment, the solvent is toluene. In one embodiment, the reaction is carried out at reflux.

[0139] According to another embodiment, the method comprises: (a'-1) Formula (II) [ka] (In the formula, Z, R 5 , R 6 and R 7is as defined herein under formula (I), and X represents a halide or -CF3SO3, Monoprotected piperazines (i.e., only one of the NH groups is protected by a protecting group R P a piperazine protected by reacting in the presence of a base and a metal catalyst, Thereby, formula (IV) [ka] (In the formula, Z, R 5 , R 6 and R 7 is as defined under formula (II) above, and R P is a protecting group, (a'-2) deprotecting the compound of formula (IV); Thereby, formula (V) [ka] (In the formula, Z, R 5 , R 6 and R 7 is as defined under formula (II) above, and (a'-3) The compound of formula (V) is reacted with a compound of formula (VI) [ka] (Wherein W and R A ~R D is as defined under formula (I) herein; and reacting in the presence of a peptide coupling agent and a base, thereby obtaining the compound of the present invention.

[0140] In one embodiment, the base and / or catalyst in step (a'-1) are as described herein above under step (a-1). In one embodiment, X represents a halide. In one particular embodiment, X represents Br.

[0141] The protecting group can be any protecting group known in the art, such as, for example, tert-butyloxycarbonyl (Boc), and can be removed in step (a'-2) by any method known in the art that is appropriate to the nature of the protecting group, such as, for example, the addition of a strong Bronsted acid (e.g., hydrochloric acid [HCl]).

[0142] The peptide coupling agent in step (a'-3) can be any peptide coupling agent known in the art, such as, for example, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU).

[0143] The base in step (a'-3) can be any base known in the art, such as, for example, an amine base. According to one embodiment, the amine is triethylamine (EtN) or diisopropylethylamine (iPrNEt).

[0144] In one embodiment, the reaction in step (a'-3) is carried out in a solvent. In one particular embodiment, the solvent is dimethylformamide (DMF) and / or tetrahydrofuran (THF). In one particular embodiment, the solvent is dichloroethane (DCE) and / or acetonitrile (MeCN). In one embodiment, the reaction is carried out at room temperature (RT).

[0145] According to another embodiment, the method comprises: (a''-1) Formula (III) [ka] (Wherein W and R A ~R D is as defined under formula (I) herein) with Formula (VII) [ka] (wherein R 7 and Z is as defined under formula (I) herein; reacting in the presence of a base and a metal catalyst, Thereby, formula (VIII) [ka] (In the formula, W, R A ~R D , R 7 and Z is as defined under formula (III) and (VII) above, (a''-2) Reacting the compound of formula (VIII) with chlorosulfonic acid (HSO3Cl), Thereby, formula (IX) [ka] (In the formula, W, R A ~R D , R 7 and Z is as defined under formula (III) and (VII) above, (a''-3) A compound of formula (IX) is reacted with a compound of formula (X) NHR 5 R 6 (X) (In the formula, R 5 and R 6 is as defined under formula (I) herein; and reacting in the presence of a base, thereby obtaining the compound of the present invention.

[0146] According to an alternative embodiment, the process comprises step (a''-1) of reacting a compound of formula (III) herein above with a compound of formula (VII), thereby obtaining a compound of formula (VIII), but does not comprise step (a''-2) of reacting a compound of formula (VIII) with chlorosulfonic acid (HSO3Cl), and Z may represent N.

[0147] In one embodiment, the base and / or catalyst in step (a"-1) are as described herein above under step (a-1). In one embodiment, X represents a halide. In one particular embodiment, X represents Br.

[0148] The base in step (a''-3) can be any base known in the art, such as, for example, an amine base. According to one embodiment, the amine is triethylamine (EtN) or diisopropylethylamine (iPrNEt).

[0149] In one embodiment, the reaction in step (a''-3) is carried out in a solvent. In one particular embodiment, the solvent is dichloromethane (DCM).

[0150] In one embodiment, the method further comprises a work-up step (b). In one embodiment, the work-up step (b) comprises an extraction step with a solvent. In one particular embodiment, the solvent is ethyl acetate (EtOAc). In one particular embodiment, the solvent is water or a 1N HCl solution. In one particular embodiment, the solvent is dichloromethane (DCM). In one embodiment, the work-up step (b) comprises a filtration step. In one particular embodiment, the filtration is over Celite®. In one embodiment, the work-up step (b) comprises a concentration step under reduced pressure.

[0151] 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 flash chromatography (FC) (e.g., cHex / EtOAc gradient), preparative thin layer chromatography (PTLC), or semi-preparative high performance liquid chromatography (HPLC).

[0152] Synthetic Intermediates Another object of the present invention is to provide a compound of formula (II) [ka] (In the formula, Z, R 5 , R 6 and R 7 is as defined under formula (I) herein, and X represents a halide or —CF 3 SO 3 .

[0153] Another object of the present invention is to provide a compound of formula (III) [ka] (Wherein W and R A ~R D is a compound of formula (I) as defined herein.

[0154] Another object of the present invention is to provide a compound of formula (IV) [ka] (In the formula, Z, R 5 , R 6 and R 7 is as defined under formula (I) herein, and R P represents a protecting group (e.g., Boc).

[0155] Another object of the present invention is to provide a compound of formula (V) [ka] (In the formula, Z, R 5 , R 6 and R 7 is a compound of formula (I) as defined herein.

[0156] Another object of the present invention is to provide a compound of formula (VIII) [ka] (In the formula, W, R A ~R D , R 7 and Z is as defined under formula (I) herein.

[0157] According to one preferred embodiment, Z does not represent N in formula (VIII) herein above.

[0158] Another object of the present invention is to provide a compound of formula (IX) [ka] (In the formula, W, R A ~R D , R 7 and Z is as defined under formula (I) herein.

[0159] According to one preferred embodiment, Z does not represent N in formula (IX) herein above.

[0160] Example The present invention is further illustrated by the following examples.

[0161] Example 1: Synthesis of compounds General Materials and Methods Abbreviation List of abbreviations: Ac: Acetyl Ar: Argon BINAP: (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) t-Bu: tert-butyl cHex: cyclohexane dba: dibenzylidene acetone DCM: dichloromethane DCE: dichloroethane DMF: dimethylformamide Et: Ethyl FC: flash chromatography HPLC: High-performance liquid chromatography iPr: Isopropyl PTLC: Preparative Thin-Layer Chromatography RT: room temperature TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate THF: tetrahydrofuran TPTU: O-(2-oxo-1(2H)pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate XPhos: Dicyclohexyl[2',4',6'-tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane XantPhos: (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)

[0162] Analysis method 1 H NMR spectrum (400 MHz) and 19 F NMR spectra (376 MHz) were recorded on a Bruker ULTRASHIELD 400 spectrometer. Spectral processing and analysis was performed using MestReNova. The data are presented in the following order: chemical shift (ppm) relative to the internal solvent signal, multiplicity, coupling constant J (Hertz) and number of protons.

[0163] Reverse-phase HPLC / MS analysis was performed using a Waters Alliance 2795 HPLC equipped with an autosampler, an in-line membrane degasser, a column oven temperature of 10°C (T = 45°C), a UV detector, and a ZQ quadrupole mass detector operating in ionization electrospray mode. The compounds to be analyzed (0.1-0.3 mg) were solubilized in a minimal amount of DMSO (total volume: 1 mL) completed with acetonitrile. Standard analytical parameters were: flow rate: 1 mL / min, V inj. : 5 μL. Acidic conditions: Waters XSelect CSH C18 column (3.5 μm, 2.1 × 15 50 mm). Gradient: 95 / 5 to 0 / 100 in 2.5 min (H2O + 0.04% v / v HC02H (10 mM)) / ACN. Alkaline conditions: Waters Xbridge C18 column (3.5 μm, 2.1 × 50 mm). Gradient: 95 / 5 to 0 / 100 in 2.5 min (H2O + 0.06% v / v NH3 (aq) (10 mM)) / ACN.

[0164] General synthesis method General Protocol 1 (GP-1): Peptide Coupling Using TBTU To a solution of the required carboxylic acid in DMF at room temperature was added TBTU. The mixture was stirred at room temperature for 15 minutes, and a solution of the required piperazine and Et3N in THF was added dropwise. The mixture was stirred at room temperature for the required time. The volatiles were removed under reduced pressure, and the residue was partitioned between 1N HCl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1N HCl, saturated aqueous NaHCO3, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc gradient) or PTLC to give the required product.

[0165] General Protocol 2 (GP-2): Peptide Coupling (Small Scale) Using TPTU To a solution of the required carboxylic acid in DCE / MeCN (1 / 1) at room temperature was added iPr2NEt and TPTU. After stirring for 5 min at room temperature, the required piperazine was added and the mixture was stirred at room temperature for the required time. Two drops of ethylenediamine were added and the reaction mixture was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc gradient), PTLC or semi-preparative HPLC to give the required product.

[0166] General Protocol 3 (GP-3): Chlorosulfonylation To chlorosulfonic acid at 0°C was added a solution of the required arene in DCM dropwise. The mixture was warmed to room temperature and stirred at room temperature for the required time. The reaction mixture was poured dropwise onto crushed ice with stirring (highly exothermic quench). At the end of the addition, the remaining ice was allowed to melt, DCM was added, and the layers were separated. The aqueous phase was extracted with DCM, and the combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to give the desired sulfonyl chloride.

[0167] General Protocol 4 (GP-4): Sulfonamide Formation To a solution of the required sulfonyl chloride in DCM at room temperature was added a solution of the required amine and either Et3N or iPr2NEt in DCM. The reaction mixture was stirred at room temperature for the required time. The reaction mixture was partitioned between EtOAc and saturated aqueous NH4Cl. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (saturated aqueous NH4Cl, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc gradient), PTLC, or semi-preparative HPLC to give the required product.

[0168] General Protocol 5 (GP-5): Buchwald Coupling Using Pd(OAc)2 / rac-BINAP A microwave reaction vial was charged with the required aryl bromide, the required piperazine, Cs2CO3, Pd(OAc)2, and rac-BINAP. The vial was flushed with argon, and degassed toluene was added. The vial was sealed, and the reaction was stirred under reflux in a preheated heating block for the required time. After cooling to room temperature, EtOAc was added, and the suspension was filtered through Celite® (EtOAc rinse). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc gradient) or PTLC to give the required product.

[0169] General Protocol 6 (GP-6): Buchwald Coupling Using Xantphos-Pd-G3 A microwave reaction vial was charged with the required aryl bromide, required piperazine, t-BuONa, and Xantphos-Pd-G3. The vial was flushed with argon, and degassed toluene was added. The vial was sealed, and the reaction was stirred under reflux in a preheated heating block for the required time. After cooling to room temperature, EtOAc was added, and the suspension was filtered through Celite® (EtOAc rinse). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc gradient) or PTLC to give the required product.

[0170] General Protocol 7 (GP-7): Buchwald Coupling Using XPhos-Pd-G3 A microwave reaction vial was charged with the required aryl bromide, the required piperazine, t-BuONa, and XPhos-Pd-G3. The vial was flushed with argon, and degassed toluene was added. The vial was sealed, and the reaction was stirred under reflux in a preheated heating block for the required time. After cooling to room temperature, EtOAc was added, and the suspension was filtered through Celite® (EtOAc rinse). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc gradient) or PTLC to give the required product.

[0171] Synthesis of intermediate compounds The intermediate compound [4-fluoro-2-(trifluoromethyl)phenyl]-piperazin-1-yl-methanone was prepared as described in JI, D. et al.: "Design, synthesis and biological evaluation of anthranilamide derivatives as potent SMO inhibitors", Bioorganic and medicinal chemistry, 05 February 2020, Vol. 28, No. 6, pp. 1-12.

[0172] The intermediate compound 3-bromo-N,N-diethyl-benzenesulfonamide was prepared as described in SUTHERLAND, M. et al.: "Rational Design and Synthesis of Selective PRMT4 Inhibitors: A New Chemotype for Development of Cancer Therapeutics", ChemMedChem, 29 January 2021, Vol. 16, No. 7, pp. 1116-1125.

[0173] Synthesis of intermediates required for final products 001 and 002 3-Bromo-N,N-diethyl-4-methoxy-benzenesulfonamide (I-001) [ka] GP-4 afforded I-001 as a yellow oil in 93% yield using 3-bromo-4-methoxy-benzenesulfonyl chloride (5.00 g, 17.5 mmol, 1 equiv), diethylamine (2.72 mL, 26.3 mmol, 1.5 equiv), and triethylamine (3.66 mL, 26.3 mmol, 1.5 equiv) in DCM (70 mL) at room temperature for 16 h. 1 H NMR (400 MHz, chloroform-d) δ 7.91 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 8.8, 2.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H), 3.15 (q, J = 7.2 Hz, 4H), 1.07 (t, J = 7.2 Hz, 6H).

[0174] tert-Butyl 4-[5-(diethylsulfamoyl)-2-methoxy-phenyl]piperazine-1-carboxylate (I-002) [ka] GP-5 purification of I-001 (5.20 g, 16.1 mmol, 1 equiv.), tert-butyl piperazine-1-carboxylate (4.51 g, 24.2 mmol, 1.5 equiv.), CsCO (15.8 g, 48.4 mmol, 3 equiv.), Pd(OAc) (363 mg, 1.61 mmol, 0.1 equiv.), and rac-BINAP (1.51 g, 2.42 mmol, 0.15 equiv.) in toluene (81 mL) under reflux for 16 h afforded I-002 as a dark oil in 93% yield. Purification by FC (cHex / EtOAc = 95 / 5 to 40 / 60). 1 H NMR(400MHz,DMSO-d6)δ 7.42(dd,J=8.5,2.2Hz,1H),7.17-7.08(m,2H),3.88(s,3H),3.47(t,J=5.0Hz,4H) ,3.13(q,J=7.1Hz,4H),2.95(t,J=5.0Hz,4H),1.43(s,9H),1.03(t,J=7.1Hz,6H).

[0175] N,N-Diethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide (I-003) [ka] To a solution of I-002 (6.48 g, 15.2 mmol, 1 equiv) in dioxane (38 mL) at 0 °C was added HCl (4 M solution in dioxane, 38.0 mL, 152 mmol, 10 equiv). The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and DCM. Na2CO3 was added portionwise until pH > 11. The layers were separated, and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (DCM / MeOH (7N NH3) = 99:1 to 90:10) to give 4.87 g (98%) of I-003 as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 7.39(dd,J=8.5,2.3Hz,1H),7.20-7.05(m,2H),3.87(s,3H),3.43(m,1H),3.13(q,J=7.1Hz,4H),3.05-2.56(m,8H),1.03(t,J=7.1Hz,6H).MS(ESI + ):[M+H] + 328.

[0176] Synthesis of intermediates required for final products 003 and 004 1-(3-Bromo-4-methoxy-phenyl)sulfonylpyrrolidine (I-004) [ka] GP-4 afforded I-004 as a white solid in 95% yield using 3-bromo-4-methoxy-benzenesulfonyl chloride (5.00 g, 17.5 mmol, 1 equiv), pyrrolidine (2.16 mL, 26.3 mmol, 1.5 equiv) and triethylamine (3.66 mL, 26.3 mmol, 1.5 equiv) in DCM (70 mL) at room temperature for 1 h. 1H NMR(400MHz,DMSO-d6)δ 7.91(d,J=2.3Hz,1H),7.81(dd,J=8.7,2.2Hz,1H),7.32(d,J=8.7Hz,1H),3.95(s,3H),3.13(m,4H),1.66(m,4H).MS(ESI + ):[M+H] + 320 / 322.

[0177] tert-Butyl 4-(2-methoxy-5-pyrrolidin-1-ylsulfonyl-phenyl)piperazine-1-carboxylate (I-005) [ka] GP-5 purification using I-004 (5.10 g, 15.9 mmol, 1 equiv.), tert-butyl piperazine-1-carboxylate (4.45 g, 23.9 mmol, 1.5 equiv.), CsCO (15.6 g, 47.8 mmol, 3 equiv.), Pd(OAc) (358 mg, 1.59 mmol, 0.1 equiv.), and rac-BINAP (1.49 g, 2.39 mmol, 0.15 equiv.) in toluene (80 mL) under reflux for 28 h afforded I-005 as a dark oil in 83% yield. Purification by FC (cHex / EtOAc = 95 / 5 to 40 / 60). 1 H NMR(400MHz,DMSO-d6)δ 7.44(dd,J=8.5,2.2Hz,1H),7.17(s,1H),7.16(d,J=5.2Hz,1H),3.89(s,3H),3.47(t,J=4. 9Hz,4H),3.15-3.07(m,4H),2.96(t,J=5.0Hz,4H),1.71-1.59(m,4H),1.43(s,9H).MS(ESI + ):[M+H] + 426.

[0178] 1-(2-Methoxy-5-pyrrolidin-1-ylsulfonyl-phenyl)piperazine (I-006) [ka] To a solution of I-005 (5.90 g, 13.9 mmol, 1 equiv) in dioxane (35 mL) at 0 °C was added HCl (4 M solution in dioxane, 39.0 mL, 139 mmol, 10 equiv). The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and DCM. Na2CO3 was added portionwise until pH > 11. The layers were separated, and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (DCM / MeOH (7N NH3) = 99:1 to 90:10) to give 4.37 g (97%) of I-006 as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 7.41(dd,J=8.5,2.2Hz,1H),7.16(m,2H),4.11(m,1H),3.88(s,3H),3.16 -3.06(m,4H),3.05-2.99(m,4H),2.91(m,4H),1.63-1.66(m,4H).MS(ESI + ):[M+H] + 326.

[0179] Synthesis of intermediates required for final products 005 and 006 3-Bromo-4-methoxy-N-methyl-N-propyl-benzenesulfonamide (I-007) [ka] GP-4 afforded I-007 as a yellow oil in 96% yield using 3-bromo-4-methoxy-benzenesulfonyl chloride (5.00 g, 17.5 mmol, 1 equiv), N-methylpropylamine (2.69 mL, 26.3 mmol, 1.5 equiv) and triethylamine (3.66 mL, 26.3 mmol, 1.5 equiv) in DCM (70 mL) at room temperature for 16 h. 1H NMR (400 MHz, chloroform-d) δ 7.98 (d, J = 2.2 Hz, 1H), 7.74 (dd, J = 8.6, 2.2 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 3.99 (s, 3H), 3.02-2.96 (m, 2H), 2.74 (s, 3H), 1.65-1.52 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). MS (ESI + ):[M+H] + 322 / 324.

[0180] tert-Butyl 4-[2-methoxy-5-[methyl(propyl)sulfamoyl]phenyl]piperazine-1-carboxylate (I-008) [ka] GP-5 purification of I-007 (1.71 g, 5.50 mmol, 1 equiv.), tert-butyl piperazine-1-carboxylate (1.54 g, 8.24 mmol, 1.5 equiv.), CsCO (5.38 g, 16.5 mmol, 3 equiv.), Pd(OAc) (123 mg, 0.550 mmol, 0.1 equiv.), and rac-BINAP (513 mg, 0.824 mmol, 0.15 equiv.) in toluene (80 mL) under reflux for 28 h afforded I-005 as a dark oil in 74% yield. Purification by FC (cHex / EtOAc = 98 / 2 to 50 / 50). 1 H NMR(400MHz,chloroform-d)δ 7.46(dd,J=8.5,2.2Hz,1H),7.26(d,J=2.6Hz,1H),6.93(d,J=8.6Hz,1H),3.94(s,3H),3.64-3.53(m,4H),3.02(t,J =5.0Hz,4H),2.94(dd,J=7.9,6.6Hz,2H),2.69(s,3H),1.55-1.50(m,2H),1.49(s,9H),0.93(d,J=7.3Hz,3H).MS(ESI + ):[M+H] + 428.

[0181] 4-Methoxy-N-methyl-3-piperazin-1-yl-N-propyl-benzenesulfonamide (I-009) [ka] To a solution of I-008 (3.70 g, 8.65 mmol, 1 equiv) in DCM (47 mL) at 0 °C was added HCl (4 M solution in dioxane, 21.6 mL, 86.5 mmol, 10 equiv). The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM. Na2CO3 was added portionwise until pH > 11. The layers were separated and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (DCM / MeOH (7N NH3) = 99:1 to 90:10) to give 2.70 g (96%) of I-009 as an orange oil. 1 H NMR(400MHz,chloroform-d)δ 7.44(dd,J=8.5,2.2Hz,1H),7.28(d,J=2.3Hz,1H),6.93(d,J=8.6Hz,1H),3.93(s,3H),3.10-3.00(m,8H) ),2.94(t,J=7.2Hz,2H),2.70(s,3H),1.93(s,1H),1.54(h,J=7.4Hz,2H),0.92(t,J=7.4Hz,3H).MS(ESI + ):[M+H] + 328.

[0182] Synthesis of intermediates necessary for final products 007-010 4-Benzyl-1-(3-bromo-4-methoxy-phenyl)sulfonyl-piperidine (I-010) [ka] GP-4 afforded I-010 as a yellow oil in 100% yield using 3-bromo-4-methoxy-benzenesulfonyl chloride (1.00 g, 3.50 mmol, 1 equiv), 4-benzylpiperidine (798 mg, 4.55 mmol, 1.3 equiv) and triethylamine (0.73 mL, 5.2 mmol, 1.5 equiv) in DCM (14 mL) at room temperature for 16 h. 1H NMR(400MHz,chloroform-d)δ 7.94(d,J=2.2Hz,1H),7.69(dd,J=8.7,2.2Hz,1H),7.35-7.24(m,2H),7.24-7.04(m,3H),6.98(d,J=8.6Hz,1H),3. 99(s,3H),3.77(d,J=11.4Hz,2H),2.54(d,J=6.9Hz,2H),2.35-2.14(m,2H),1.80-1.63(m,2H),1.53-1.24(m,3H).

[0183] tert-Butyl 4-[5-[(4-benzyl-1-piperidyl)sulfonyl]-2-methoxy-phenyl]piperazine-1-carboxylate (I-011) [ka] GP-5 purification of I-010 (1.35 g, 3.18 mmol, 1 equiv.), tert-butyl piperazine-1-carboxylate (889 mg, 4.77 mmol, 1.5 equiv.), CsCO (2.07 g, 6.36 mmol, 2 equiv.), Pd(OAc) (35.7 mg, 0.159 mmol, 0.05 equiv.), and rac-BINAP (119 mg, 0.191 mmol, 0.06 equiv.) in toluene (16 mL) under reflux for 24 h afforded I-011 as a brown foam in 89% yield. Purification by FC (cHex / EtOAc = 95 / 5 to 50 / 50). 1 H NMR(400MHz,chloroform-d)δ 7.43(dd,J=8.5,2.2Hz,1H),7.35-7.15(m,4H),7.15-7.05(m,2H),6.94(d,J=8.6Hz,1H),3.95(s,3H),3.76(d,J=11.5Hz,2H),3.66-3.58 (m,4H),3.08-2.98(m,4H),2.53(d,J=6.6Hz,2H),2.19(td,J=11.7,2.4Hz,2H),1.81-1.62(m,2H),1.51(s,9H),1.45-1.30(m,3H).MS(ESI + ):[M+H] + 530.

[0184] 1-[5-[(4-benzyl-1-piperidyl)sulfonyl]-2-methoxy-phenyl]piperazine (I-012) [ka] To a solution of I-011 (2.40 g, 3.35 mmol, 1 equiv.) in DCM (16 mL) at 0 °C was added HCl (4 M solution in dioxane, 8.4 mL, 34 mmol, 10 equiv.). The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and DCM. Na2CO3 was added portionwise until pH > 11. The layers were separated, and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (DCM / MeOH (7N NH3) = 99:1 to 90:10) to give 1.45 g (100%) of I-012 as a white solid. 1 H NMR(400MHz,chloroform-d)δ 7.41(dd,J=8.5,2.2Hz,1H),7.32-7.23(m,3H),7.23-7.16(m,1H),7.15-7.05(m,2H),6.93(d,J=8.5Hz,1H),3.95(s,3H),3.76(dt,J= MS(ESI) + ):[M+H] + 430.

[0185] Synthesis of intermediates necessary for final products 011-036 (2-chloro-4-fluoro-phenyl)-[4-(2-methoxyphenyl)piperazin-1-yl]methanone (I-013) [ka] GP-1 afforded I-013 as a colorless oil in 85% yield using 2-chloro-4-fluorobenzoic acid (5.99 g, 34.3 mmol, 1.2 equiv.), EtN (8.0 mL, 57 mmol, 2 equiv.), TBTU (11.0 g, 34.3 mol, 1.2 equiv.), and 1-(2-methoxyphenyl)piperazine (5.50 g, 28.6 mmol, 1 equiv.) in THF (140 mL) at room temperature for 16 h. The residue was purified by FC (cHex / EtOAc = 90 / 10 to 0 / 100). 1 H NMR(400MHz,chloroform-d)δ 7.35(dd,J=8.5,5.9Hz,1H),7.20(dd,J=8.5,2.5Hz,1H),7.13-7.03(m,2H),6.98-6.89( m,3H),4.02(tt,J=12.5,8.3Hz,2H),3.90(s,3H),3.56-3.37(m,2H),3.26-2.93(m,4H). 19 F NMR (376 MHz, chloroform-d) δ-109.5. MS (ESI + ):[M+H] + 349 / 351.

[0186] 3-[4-(2-chloro-4-fluoro-benzoyl)piperazin-1-yl]-4-methoxy-benzenesulfonyl chloride (I-014) [ka] GP-3 afforded I-014 as a white solid in 86% yield using I-013 (5.00 g, 14.3 mmol, 1 equiv) and HSO3Cl (19.1 mL, 287 mmol, 20 equiv) in DCM (72 mL) for 2 h. 1 H NMR(400MHz,chloroform-d)δ 7.76(dd,J=8.7,2.4Hz,1H),7.49(d,J=2.4Hz,1H),7.35(dd,J=8.5,5.9Hz,1H),7.20(dd,J=8.5,2.4Hz,1H), 7.10(td,J=8.2,2.5Hz,1H),7.03(d,J=8.8Hz,1H),4.08-3.93(m,5H),3.57-3.36(m,2H),3.30-3.00(m,4H).19 F NMR (376 MHz, chloroform-d) δ -109.1.

[0187] Synthesis of intermediates required for final product 037 3-[4-(2-chloro-4-fluoro-benzoyl)piperazin-1-yl]-4-methoxy-N-(4,4,4-trifluorobutyl)benzenesulfonamide (I-015) [ka] GP-4 afforded I-015 in 64% yield using sulfonyl chloride I-014 (120 mg, 0.268 mmol, 1 equiv.), 4,4,4-trifluorobutylamine hydrochloride (66 mg, 0.40 mmol, 1.5 equiv.), and iPrNEt (140 μL, 0.804 mmol, 3 equiv.) in DCM (2 mL) at room temperature for 2 h. Purification by FC (cHex / EtOAc = 20 / 80) was performed. 1 H NMR(400MHz,DMSO-d6)δ 7.58(dt,J=9.1,2.2Hz,1H),7.55-7.48(m,2H),7.44(dt,J=8.6,2.0Hz,1H),7.34(tt,J=8.5,2.1Hz,1H),7.25(t,J=2.0Hz,1H),7.14(dd,J=8.7 ,1.8Hz,1H),3.88(s,3H),3.84-3.73(m,2H),3.31-3.27(m,2H),3.15-2 .91(m,4H),2.78(q,J=6.7Hz,2H),2.30-2.15(m,2H),1.61-1.50(m,2H). 19 F NMR (376 MHz, chloroform-d) δ -64.8, -110.1. MS (ESI + ):[M+H] + 538 / 540.

[0188] Synthesis of intermediates required for final product 038 Rac-(2-chloro-4-fluoro-phenyl)-[4-[5-[(3-hydroxy-1-piperidyl)sulfonyl]-2-methoxy-phenyl]piperazin-1-yl]methanone (I-016) [ka] GP-4 afforded I-016 in 79% yield using sulfonyl chloride I-014 (150 mg, 0.335 mmol, 1 equiv.), rac-piperidin-3-ol hydrochloride (69 mg, 0.50 mmol, 1.5 equiv.), and iPrNEt (175 μL, 1.00 mmol, 3 equiv.) in DCM (2 mL) at room temperature for 16 h. Purification by FC (DCM / MeOH = 98 / 2 to 90 / 10). 1 H NMR (400 MHz, chloroform-d) δ 7.46 (dd, J = 8.5, 2.2 Hz, 1H), 7.36-7.30 (m, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.18 (dd, J = 8.4, 2.4 Hz, 1H), 7.07 (td, J = 8.2, 2.5 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 4.02-3.96 (m, 2H), 3.94 (s, 3H), 3.91-3.83 (m, 1H), 3.52-3.44 (m, 1H),3.43-3.35(m,1H),3.31(d,J=11.2Hz,1H),3.24-3.07(m,4H),3.02-2.94(m,1H),2.83-2.75(m,1H),2.7 3-2.66(m,1H),1.90-1.80(m,2H),1.79-1.70(m,1H),1.68-1.56(m,1H),1.40(dtd,J=12.6,8.4,3.9Hz,1H). 19 F NMR (376 MHz, chloroform-d) δ-109.2. MS (ESI + ):[M+H] + 512 / 514.

[0189] Synthesis of intermediates required for final product 039 (2-chloro-4-fluoro-phenyl)-[4-[5-(3-hydroxypyrrolidin-1-yl)sulfonyl-2-methoxy-phenyl]piperazin-1-yl]methanone (I-017) [ka] GP-4 afforded I-017 in 90% yield using sulfonyl chloride I-014 (150 mg, 0.335 mmol, 1 equiv.), rac-pyrrolidin-3-ol (44 mg, 0.50 mmol, 1.5 equiv.), and iPrNEt (175 μL, 1.00 mmol, 3 equiv.) in DCM (2 mL) at room temperature for 16 h. Purification by FC (DCM / MeOH = 98 / 2 to 90 / 10). 1 H NMR (400 MHz, chloroform-d) δ 7.54 (dd, J = 8.6, 2.1 Hz, 1H), 7.36-7.29 (m, 2H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 7.07 (td, J = 8.3, 2.5 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 4.42-4.35 (m, 1H), 3.99 (t, J = 5.2 Hz) ,2H),3.94(s,3H),3.52-3.28(m,5H),3.25-3.07(m,4H),2.99(dd,J=11.2,6.6Hz, 1H),1.97(dtd,J=13.7,8.8,4.9Hz,1H),1.88-1.79(m,1H),1.51(d,J=4.7Hz,1H). 19 F NMR (376 MHz, chloroform-d) δ-109.2. MS (ESI + ):[M+H] + 498 / 500.

[0190] Synthesis of intermediates required for final product 040 [4-[5-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-ylsulfonyl)-2-methoxy-phenyl]piperazin-1-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-018) [ka] To a solution of 022 (300 mg, 0.481 mmol, 1 equiv) in DCM (2.4 mL) at 0 °C was added HCl (4 M solution in dioxane, 1.2 mL, 4.8 mmol, 10 equiv). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and DCM. K2CO3 was added portionwise until pH > 11. The layers were separated, and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to give 250 mg (99%) of I-018 as a white foam. 1 H NMR (400 MHz, DMSO-d6) δ 7.58(dd,J=9.0,2.4Hz,1H),7.52(dd,J=8.5,6.1Hz,1H),7.41(dd,J=8.6,2.1Hz, 1H),7.34(td,J=8.5,2.5Hz,1H),7.18(d,J=8.6Hz,1H),7.13(d,J=2.2Hz,1H),3. 89(s,3H),3.86-3.69(m,2H),3.30-3.26(m,3H),3.17(d,J=3.9Hz,2H),3.14-3.0 6(m,4H),2.98(t,J=5.0Hz,2H),2.81-2.71(m,4H),2.42(dd,J=10.8,2.9Hz,2H). 19 F NMR (376 MHz, chloroform-d) δ-109.2. MS (ESI + ):[M+H] + 523 / 525.

[0191] Synthesis of intermediates required for final product 042 3-Bromo-4-fluoro-N-methyl-N-propyl-benzenesulfonamide (I-019) [ka] GP-4 afforded I-019 as a yellow oil in 95% yield using 3-bromo-4-fluoro-benzenesulfonyl chloride (200 μL, 1.35 mmol, 1 equiv), N-methylpropylamine (145 μL, 1.41 mmol, 1.05 equiv), and triethylamine (281 μL, 2.02 mmol, 1.5 equiv) in DCM (7 mL) at room temperature for 1 h.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), 7.33-7.15 (m, 1H), 3.08-2.90 (m, 2H), 2.75 (s, 3H), 1.67-1.55 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 19 F NMR (376 MHz, chloroform-d) δ-99.9. MS (ESI + ):[M+H] + 310 / 312.

[0192] Synthesis of intermediates required for final product 043 [4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]-[4-fluoro-2-(trifluoromethyl)phenyl]methanone (I-020) [ka] A microwave reaction vial was charged with 7-bromo-2,3-dihydrobenzofuran (300 mg, 1.51 mmol, 1 equiv.), [4-fluoro-2-(trifluoromethyl)phenyl]-piperazin-1-yl-methanone (614 mg, 2.22 mmol, 1.5 equiv.), Pd2dba3 (94 mg, 0.10 mmol, 0.07 equiv.), tri(2-tolyl)phosphine (55 mg, 0.18 mmol, 0.12 equiv.), and sodium tert-butylate (212 mg, 2.21 mmol, 1.5 equiv.). The vial was flushed with argon, and degassed toluene (10 mL) was added. The vial was sealed, and the mixture was stirred at 110 °C for 22 h. The suspension was cooled to room temperature, filtered through Celite (with an EtOAc rinse), and concentrated. The residue was purified by FC (cHex / EtOAc = 95 / 5 to 0 / 100) to give 136 mg (23%) of I-020 as a brown foam. 1H NMR(400MHz,chloroform-d)δ 7.42(dd,J=8.8,2.5Hz,1H),7.37(dd,J=8.5,5.3Hz,1H),7.31(td,J=8.1,2.6Hz,1H),6.90(dd,J=7.4,1.2Hz,1H),6.81(t,J=7.6Hz,1H),6.67 (dd,J=7.9,1.2Hz,1H),4.59(t,J=8.8Hz,2H),3.97(qt,J=13.2,5.1Hz,2H),3.34(dd,J=5.9,4.4Hz,2H),3.27-3.11(m,4H),3.10-2.94(m,2H). 19 F NMR (376 MHz, chloroform-d) δ -60.2, -109.4. MS (ESI + ):[M+H] + 395.

[0193] 7-[4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2,3-dihydrobenzofuran-5-sulfonyl chloride (I-021) [ka] GP-3 afforded I-021 as a white solid in 83% yield using I-020 (135 mg, 0.342 mmol, 1 equiv) and HSO3Cl (0.50 mL, 7.5 mmol, 22 equiv) in DCM (2 mL) for 2 h. 1 H NMR (400 MHz, chloroform-d) δ 7.58-7.55 (m, 1H), 7.45 (dd, J = 8.8, 2.4 Hz, 1H), 7.41-7.32 (m, 2H), 7.32-7.28 (m, 1H), 4.78 (t, J = 8.9 Hz, 2H), 3.98 (t, J = 5.2 Hz, 2H), 3.43-3.20 (m, 6H), 3.18-2.99 (m, 2H). 19 F NMR (376 MHz, chloroform-d) δ -60.2, -109.0.

[0194] Synthesis of intermediates required for final products 044 and 045 5-Bromo-6-chloro-N,N-diethyl-pyridine-3-sulfonamide (I-022) [ka] GP-4 afforded I-022 as a yellow solid in 100% yield using 5-bromo-6-chloro-pyridine-3-sulfonyl chloride (438 mg, 1.50 mmol, 1.1 equiv), diethylamine (100 mg, 1.37 mmol, 1 equiv), and triethylamine (229 μL, 1.64 mmol, 1.2 equiv) in DCM (6.8 mL) at room temperature for 1 h. 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).

[0195] 5-Bromo-6-methoxy-N,N-diethyl-pyridine-3-sulfonamide (I-023) [ka] To a solution of I-022 (150 mg, 0.458 mmol, 1 equiv) in anhydrous MeOH (1.8 mL) at room temperature was added MeONa (124 mg, 2.29 mol, 5 equiv). The mixture was stirred at room temperature for 60 h. 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 afford 138 mg (93%) of I-023 as a pale yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 8.55 (d, J = 2.2 Hz, 1H), 8.18 (d, J = 2.2 Hz, 1H), 4.10 (s, 3H), 3.28 (q, J = 7.2 Hz, 4H), 1.20 (t, J = 7.1 Hz, 6H).

[0196] Synthesis of intermediates required for final products 046 and 047 3-Bromo-4-hydroxy-N-methyl-N-propyl-benzenesulfonamide (I-024) [ka] To a solution of I-007 (200 mg, 0.620 mmol, 1 equiv) in DCM (7.7 mL) at 0 °C was added BBr (1.86 mL of a 1 M solution in DCM, 1.86 mmol, 2 equiv). The mixture was stirred at room temperature for 48 h. After cooling to 0 °C, water was added dropwise (exothermic). 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 give 214 mg (quantitative) of I-024 as an orange oil. 1 H NMR (400 MHz, chloroform-d) δ (ppm) 7.95 (d, J = 2.2 Hz, 1H), 7.74 (dd, J = 8.6 and 2.2 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 6.05 (br s, 1H), 3.02-2.95 (m, 2H), 2.75 (s, 3H), 1.65-1.52 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). MS (ESI + ):[M+H] + 308 / 310.

[0197] 3-Bromo-4-(2-methoxyethoxy)-N-methyl-N-propyl-benzenesulfonamide (I-025) [ka] To a solution of I-024 (191 mg, 0.620 mmol, 1 equiv.) in DMF (2.5 mL) at room temperature was added K2CO3 (257 mg, 1.86 mmol, 3 equiv.) and 2-bromomethyl methyl ether (129 mg, 0.930 mmol, 1.5 equiv.). The mixture was stirred at 50 °C for 16 h. The reaction mixture was partitioned between saturated aqueous NH4Cl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc (2*). The combined organic extracts were washed (saturated aqueous NH4Cl, saturated aqueous NaHCO3, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc = 90 / 10 to 50 / 50) to give 200 mg (88%) of I-025 as a yellow oil. 1H NMR(400MHz,chloroform-d)δ 7.98(d,J=2.2Hz,1H),7.71(dd,J=8.6,2.3Hz,1H),7.02(d,J=8.7Hz,1H),4.32-4.22(m,2H),3.91-3.83(m, 2H),3.51(s,3H),2.98(dd,J=8.0,6.5Hz,2H),2.74(s,3H),1.70-1.50(m,2H),0.95(t,J=7.4Hz,3H).MS(ESI + ):[M+H] + 366 / 368.

[0198] 4-Benzyloxy-3-bromo-N-methyl-N-propyl-benzenesulfonamide (I-026) [ka] To a solution of I-024 (315 mg, 0.961 mmol, 1 equiv.) in DMF (10 mL) at room temperature was added K2CO3 (266 mg, 1.92 mmol, 2 equiv.) and benzyl bromide (114 μL, 0.961 mmol, 1 equiv.). The mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between saturated aqueous NH4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (2*). The combined organic extracts were washed (saturated aqueous NH4Cl, saturated aqueous NaHCO3, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc = 100 / 0 to 50 / 50) to give 330 mg (86%) of I-026 as a yellow oil. 1 H NMR(400MHz,chloroform-d)δ 7.99(d,J=2.3Hz,1H),7.67(dd,J=8.6,2.2Hz,1H),7.49-7.44(m,2H),7.44-7.38(m,2H),7.38-7.31(m,1H),7.0 1(d,J=8.7Hz,1H),5.23(s,2H),3.05-2.91(m,2H),2.72(s,3H),1.67-1.49(m,2H),0.93(t,J=7.4Hz,3H).MS(ESI + ):[M+H] + 398 / 400.

[0199] Synthesis of intermediates required for piperazine I-027 tert-Butyl 4-(2-chloro-4-fluoro-benzoyl)piperazine-1-carboxylate (Boc-I-027) [ka] To a solution of 2-chloro-4-fluorobenzoic acid (5.00 g, 28.6 mmol, 1 equiv.) in THF (89 mL) at room temperature was added TBTU (9.20 g, 28.6 mmol, 1 equiv.). The mixture was stirred at room temperature for 15 minutes, and a solution of tert-butyl piperazine-1-carboxylate (6.40 g, 34.4 mmol, 1.2 equiv.) and EtN (6.0 mL, 43 mmol, 1.5 equiv.) in THF (30 mL) was added dropwise. The mixture was stirred at room temperature for 60 hours. The reaction mixture was concentrated under reduced pressure. The reaction mixture was partitioned between 1N HCl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc (2*). The combined organic extracts were washed (1N aqueous HCl, saturated aqueous NaHCO, brine), dried (NaSO), filtered, and concentrated under reduced pressure to give 10.2 g (100%) of tert-butyl 4-(2-chloro-4-fluoro-benzoyl)piperazine-1-carboxylate (Boc-I-027) as an orange oil. 1 H NMR(400MHz,chloroform-d)δ 7.32-7.29(m,1H),7.18(dd,J=8.5,2.5Hz,1H),7.07(td,J=8.3,2.5Hz,1H),3.92-3.79(m,1H),3.73( dt,J=13.2,5.7Hz,1H),3.63-3.50(m,2H),3.48-3.34(m,2H),3.34-3.10(m,2H),1.48(s,9H).MS(ESI + ):[M+H] + 343.1 / 345.1.

[0200] (2-Chloro-4-fluoro-phenyl)-piperazin-1-yl-methanone (I-027) [ka] To a solution of crude tert-butyl 4-(2-chloro-4-fluoro-benzoyl)piperazine-1-carboxylate Boc-I-027 (10.2 g, 28.6 mmol, 1 equiv.) in dioxane (37 mL) at room temperature was added HCl (4 M solution in dioxane, 37 mL, 148 mmol, 5 equiv.). The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and DCM. K2CO3 was added portionwise until pH > 11. The layers were separated, and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (80 g column, dry loading, DCM / MeOH=98 / 2 to 80 / 20) to give 5.24 g (72%) of (2-chloro-4-fluoro-phenyl)-piperazin-1-yl-methanone I-027 as an orange solid. 1 H NMR (400 MHz, chloroform-d) δ 7.41 (dd, J = 8.8, 2.4 Hz, 1H), 7.32 (qd, J = 8.4, 5.6 Hz, 2H), 3.87-3.69 (m, 2H), 3.15 (t, J = 5.1 Hz, 2H), 2.94 (t, J = 5.2 Hz, 2H), 2.80-2.70 (m, 2H). MS (ESI + ):[M+H] + 243.1 / 245.1.

[0201] Synthesis of intermediates required for final products 054 and 55 1-Bromo-2-(methoxymethoxy)-3-methyl-benzene (I-028) [ka] To a solution of 2-bromo-6-methyl-phenol (1.00 g, 5.35 mmol, 1 equiv.) and iPrNEt (1.4 mL, 8.1 mmol, 1.5 equiv.) in DCM (21 mL) at room temperature was added chloromethyl methyl ether (0.49 mL, 6.4 mmol, 1.2 equiv.). The mixture was stirred at room temperature for 60 h. 1N HCl was added. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (NaSO), filtered, and concentrated under reduced pressure to give 1.22 g of I-028 (99%) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 7.42 (ddd, J = 8.0, 1.6, 0.7 Hz, 1H), 7.15 (ddd, J = 7.6, 1.6, 0.8 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 5.11 (s, 2H), 3.68 (s, 3H), 2.39 (s, 3H).

[0202] (2-chloro-4-fluoro-phenyl)-[4-[2-(methoxymethoxy)-3-methyl-phenyl]piperazin-1-yl]methanone (I-029) [ka] GP-5 purification of I-028 (400 mg, 1.73 mmol, 1 equiv.), piperazine I-027 (504 mg, 2.08 mmol, 1.2 equiv.), CsCO (1.69 g, 5.19 mmol, 3 equiv.), Pd(OAc) (38.9 mg, 173 μmol, 0.1 equiv.), and rac-BINAP (162 mg, 260 μmol, 0.15 equiv.) in toluene (8.7 mL) under reflux for 2 h afforded I-029 as an oil in 44% yield. Purification by FC (cHex / EtOAc = 95 / 5 to 50 / 50). 1H NMR(400MHz,chloroform-d)δ 7.32(dd,J=8.5,5.9Hz,1H),7.18(dd,J=8.4,2.4Hz,1H),7.07(td,J=8.2,2.5Hz,1H),6.98(t,J=7.7Hz,1H),6.94-6.86(m,1H),6.79(dd, J=8.0,1.7Hz,1H),5.17(s,2H),3.96(t,J=5.1Hz,2H),3.60(s,3H),3.50-3.28(m,2H),3.28-3.02(m,3H),3.02-2.88(m,1H),2.32(s,3H). 19 F NMR (376 MHz, chloroform-d) δ-109.4. MS (ESI + ):[M+H] + 393.1 / 395.1.

[0203] 3-[4-(2-chloro-4-fluoro-benzoyl)piperazin-1-yl]-4-hydroxy-5-methyl-benzenesulfonyl chloride (I-030) [ka] GP-3 was used with I-029 (300 mg, 0.748 mmol, 1 equiv.) and HSO3Cl (1.2 mL, 19 mmol, 25 equiv.) in DCM (3 mL) at room temperature for 1 h to afford I-030 as a yellow solid in 50% yield. The material was used directly in the next step.

[0204] Synthesis of intermediates required for final products 057-59 1-Bromo-3-chloro-2-(methoxymethoxy)benzene (I-031) [ka] To a solution of 2-bromo-6-chlorophenol (3.17 g, 10.5 mmol, 1 equiv.) and iPrNEt (3.73 mL, 15.7 mmol, 1.5 equiv.) in DCM (21 mL) at room temperature was added chloromethyl methyl ether (0.95 mL, 13 mmol, 1.2 equiv.). The mixture was stirred at room temperature for 16 h. Volatiles were removed under reduced pressure. EtOAc was added, and the organic solution was washed (1 N HCl, brine), dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc = 95 / 5) to give 2.59 g of I-031 (98%) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 7.50 (dd, J = 8.0, 1.6 Hz, 1H), 7.37 (dd, J = 8.1, 1.5 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 5.21 (s, 2H), 3.74 (s, 3H).

[0205] (2-chloro-4-fluoro-phenyl)-[4-[3-chloro-2-(methoxymethoxy)phenyl]piperazin-1-yl]methanone (I-032) [ka] GP-5 purification using aryl bromide I-031 (1.23 g, 4.89 mmol, 1 equiv.), piperazine I-027 (1.42 g, 5.87 mmol, 1.2 equiv.), CsCO (4.78 g, 14.7 mmol, 3 equiv.), Pd(OAc) (110 mg, 489 μmol, 0.1 equiv.), and rac-BINAP (365 mg, 587 μmol, 0.12 equiv.) in toluene (24.5 mL) under reflux for 16 h afforded I-032 as a white foam in 62% yield. Purification by FC (cHex / EtOAc = 95 / 5 to 50 / 50). 1H NMR(400MHz,chloroform-d)δ 7.30(dd,J=8.5,5.9Hz,1H),7.18(dd,J=8.4,2.4Hz,1H),7.12-7.03(m,2H),7.00(t,J=8.1Hz,1H),6.83( dd,J=8.1,1.5Hz,1H),5.22(s,2H),4.01-3.86(m,2H),3.66(s,3H),3.50-3.29(m,2H),3.25-2.91(m,4H). 19 F NMR (376 MHz, chloroform-d) δ-109.2. MS (ESI + ):[M+H] + 413.0 / 415.0 / 417.0.

[0206] (2-chloro-4-fluoro-phenyl)-[4-(3-chloro-2-hydroxy-phenyl)piperazin-1-yl]methanone (I-033) [ka] To a solution of I-032 (1.26 g, 3.05 mmol, 1 equiv.) in DCM (15 mL) at room temperature was added CFCOH (4.7 mL, 61 mmol, 20 equiv.). The mixture was stirred at room temperature for 1 h. It was concentrated under reduced pressure, and the residue was azeotroped with toluene. The residue was purified by FC (cHex / EtOAc = 95 / 5 to 20 / 80) to give 1.12 g of I-033 (97%) as a white foam. 1 H NMR (400 MHz, chloroform-d) δ 7.35 (dd, J = 8.5, 5.8 Hz, 1H), 7.24-7.16 (m, 2H), 7.14-7.02 (m, 2H), 6.86 (t, J = 8.1 Hz, 1H), 6.26 (s, 1H), 4.22-4.06 (m, 1H), 4.06-3.93 (m, 1H), 3.59-3.38 (m, 2H), 3.28-2.86 (m, 4H). 19 F NMR (376 MHz, chloroform-d) δ-108.1. MS (ESI + ):[M+H] + 369.0 / 371.0 / 373.0.

[0207] 3-chloro-5-[4-(2-chloro-4-fluoro-benzoyl)piperazin-1-yl]-4-hydroxy-benzenesulfonyl chloride (I-034) [ka] GP-3 afforded I-034 as a beige solid in 80% yield using I-033 (500 mg, 1.35 mmol, 1 equiv) and HSO3Cl (2.3 mL, 34 mmol, 25 equiv) in DCM (7 mL) under reflux for 4 h. 1 H NMR(400MHz,chloroform-d)δ 7.88(d,J=2.2Hz,1H),7.62(d,J=2.2Hz,1H),7.34(dd,J=8.5,5.8Hz,1H),7.19(dd,J=8.4,2.4Hz,1H),7.09(td,J=8.2,2.5Hz,1H),5.75(br s,1H),4.03(t,J=5.1Hz,2H),3.61-3.34(m,2H),3.19-2.85(m,4H). 19 F NMR (376 MHz, chloroform-d) δ -108.5.

[0208] Synthesis of the final compound Method for synthesizing the final compound The synthesis protocols for the final compounds are shown in Table 2 below. [Table 2] TIFF2025533979000068.tif231159TIFF2025533979000069.tif227159TIFF2025533979000070.tif233159TIFF2025533979000071.tif23115 9TIFF2025533979000072.tif225159TIFF2025533979000073.tif208159TIFF2025533979000074.tif235159TIFF2025533979000075.tif35159

[0209] Analytical data of the final compound Analytical data for the final compound is shown in Table 3 below. [Table 3] TIFF2025533979000077.tif199159TIFF2025533979000078.tif232159TIFF2025533979000079.t if215159TIFF2025533979000080.tif203159TIFF2025533979000081.tif186159TIFF20255339790 00082.tif232159TIFF2025533979000083.tif221159TIFF2025533979000084.tif211159TIFF202 5533979000085.tif203159TIFF2025533979000086.tif233159TIFF2025533979000087.tif231159

[0210] Example 2: Biological activity of compounds The purpose of this experiment was to evaluate the GFRα1-RET activity of compounds 001 to 060 according to the present invention.

[0211] material and method Compounds were tested for their Elk1 signaling activation activity using a previously developed reporter gene-based system in cells expressing GFRα1-RET (PathDetect Elk-1, MG87 mouse fibroblasts stably transfected with GFRα1 and RET) 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. EC 50Dose-response studies were performed using six concentrations of each test compound to determine the EC of agonist / activator activity. Dose-response curves were fitted using sigmoidal dose-response (variable slope) analysis in the GraphPad Prism program (Graph Pad Inc). 50 All dose-response experiments were performed twice independently in duplicate.

[0212] result The results are shown in Table 4 below (* indicates "10 μM" <EC 50 <50 μM, and ** means "5 μM" <EC 50 <10 μM, and *** means "1 μM" <EC 50 **** means "EC < 5 μM" 50 <1 μM). [Table 4] TIFF2025533979000089.tif224159TIFF2025533979000090.tif228159TIFF2025533979000091.tif227159TIFF2025533979000092.tif41159

[0213] The above results clearly demonstrate that test compounds 001-060 have significant GFRα1-RET activity. Therefore, the compounds of the present invention are useful as neuroprotective and neurorestorative agents. Test compounds 001-060 are well representative of the class of compounds of formula (I).

[0214] Example 3: Biological activity of comparative compounds The aim of this experiment was to compare the GFRα1-RET activity of compounds 001, 009 and 010 according to the invention with the GFRα1-RET activity of comparison compounds CO1 and CO2.

[0215] material and method Comparative compounds CO1 and CO2 were prepared by using the same synthetic routes and methods as described above for compounds according to the invention, using general knowledge in the art to adapt reactants and experimental conditions as necessary.

[0216] The structures of comparative compounds C01 and C02 are shown in Table 5 below. [Table 5]

[0217] The compounds were tested for their activation activity of Elk1 signaling using the same materials and methods as the compounds according to the invention (Example 2, "Materials and Methods" section herein).

[0218] result The results for comparative compounds C01 and C02 are shown in Table 6 below. For easier comparison, the corresponding values ​​from Table 4 above for compounds 009, 010 and 001 according to the invention are also reported in Table 6 (AL is "EC 50 >50μM, * means "10μM" <EC 50 <50 μM, and ** means "5 μM" <EC 50 <10 μM, and *** means "1 μM" <EC 50 **** means "EC < 5 μM" 50 <1 μM). [Table 6]

[0219] The above results clearly demonstrate that the compounds according to the present invention have significantly higher GFRα1-RET activity than the comparative compounds CO1 and CO2. In fact, compounds CO1 and CO2 have EC 50 whereas compounds 001, 009 and 010 have EC values ​​lower than or even lower than 10 μM. 50 In the context of medical use according to the present invention, it has an EC 50is actually quite high and may be considered "inactive" or "not active enough to be of therapeutic interest" by those skilled in the art.

[0220] The only structural difference between compounds C01 and C02 and compounds 009 and 010 or compound 001, respectively, is the oxo-phenyl substitution, i.e., R A ~R D It is worth noting that the definition of the substituents is D does not represent CF3 in compounds 009 and 010, but rather CHF2(010) or Cl(009), while in compound C01, R D The substituent corresponding to represents CF3. Similarly, R D does not represent CF3 in compound 001, but rather Cl, whereas in compound CO2, R D The corresponding substituent represents CF3.

[0221] Therefore, these results clearly demonstrate that the compounds of the present invention are better activators of GFRa1-RET and therefore better candidates for neuroprotection and neurorestoration than the comparative compounds.Furthermore, this surprising technical effect is directly related to the specific structural features of the compounds of the present invention.

Claims

1. Formula (I-i) 【Chemical 1】 or a pharmaceutically acceptable salt and / or solvate thereof, During the ceremony, W represents CH or N; R Ａ , R Ｂ and R Ｃ are each independently hydrogen, F, Cl, or CH ３ , C.F. ３ , CHF ２ or CH ２ represents F; R Ｄ is hydrogen, F, Cl, CH ３ , CHF ２ or CH ２ represents F; R ７ is hydrogen, OH, halogen, (C １ ~C ８ ) alkyl, cycloalkyl, (C １ ~C ８ ) alkyl-O-, cycloalkyl-O-, cycloalkyl-(C １ ~C ８ ) alkyl-O-, heterocycloalkyl-O-, heterocycloalkyl-(C １ ~C ８ ) alkyl-O-, aryl-(C １ ~C ８ ) alkyl-O-, heteroaryl-(C １ ~C ８ ) alkyl-O-, R １１ O-(C １ ~C ８ ) alkyl-O-, R １１ R １２ N-(C １ ~C ８ ) alkyl-O—, (R １１ O) (R １２ ) N-(C １ ~C ８ ) alkyl-O-, R １１ R １２ N-(C １ ~C ８ ) alkyl-, R １１ O-(C １ ~C ８ ) alkyl-, NR １１ R １２ , C.N., C.O. ２ H, CO ２ R １１ , C.O.N.H. ２ , CON(R １１ ) H, heterocycloalkyl or heteroaryl; R １１ and R １２ are each independently hydrogen or (C １ ~C ８ ) represents alkyl; R ７ The alkyl or cycloalkyl may be at least one of F, Cl, OH, ═O, (C １ ~C ８ ) alkyl, (C １ ~C ８ ) optionally substituted by alkyl-O-, heterocycloalkyl, aryl or heteroaryl; The heterocycloalkyl, aryl or heteroaryl may be selected from the group consisting of at least one of F, Cl, (C １ ~C ８ ) alkyl, CF ３ , CHF ２ , C.H. ２ F, OCF ３ ,CN,OH,=O,→O,(C １ ~C ８ ) alkoxy, NR １３ R １４ , R １３ R １４ N-(C １ ~C ８ ) alkyl-, R １３ O ２ C (C １ ~C ８ ) alkyl-, CO ２ H, R １３ R １４ N—C(O)—, R １３ O-NR １４ - or (C １ ~C ８ ) alkyl-CO ２ optionally substituted by -; R １３ and R １４ are each independently hydrogen or (C １ ~C ８ ) represents alkyl; Z is C-H, C-R ８ or represents N; R ８ is (C １ ~C ４ ) Alkyl, F, Cl, CF ３ , CHF ２ , C.H. ２ F, OCF ３ , CN, OH or (C １ ~C ４ ) represents alkoxy; or Z is C-R ８ represents R ７ and R ８ together with the carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl; The cycloalkyl or heterocycloalkyl may be selected from the group consisting of at least one of F, OH, ═O, →O, (C １ ~C ８ ) alkyl, CF ３ , H.O. ２ C-CH ２ -, (C １ ~C ４ ) alkyl-CO ２ -CH ２ -, R １５ R １６ N-CH ２ -, aryl or aryl-(C １ ~C ８ ) optionally substituted by alkyl-; R １５ and R １６ are each independently hydrogen or (C １ ~C ８ ) represents alkyl; R ５ is hydrogen, (C １ ~C ８ ) alkyl, 1 to 3 (C １ ~C ８ ) CH substituted by alkyl groups ３ , cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C １ ~C ８ ) represents alkyl; R ５ The alkyl or cycloalkyl may be at least one of F, Cl, (C １ ~C ８ ) alkyl, CF ３ , OCF ３ ,CN,OH,=O,(C １ ~C ８ ) alkoxy, NR １７ R １８ , CO ２ H, R １７ R １８ N—C(O)—, R １７ O-NR １８ -, heterocycloalkyl, aryl, or heteroaryl; R １７ and R １８ are each independently hydrogen or (C １ ~C ８ ) represents alkyl; The heterocycloalkyl, aryl or heteroaryl may be selected from the group consisting of at least one of F, Cl, (C １ ~C ８ ) alkyl, CF ３ , CHF ２ , C.H. ２ F, OCF ３ ,CN,OH,=O,→O,(C １ ~C ８ ) alkoxy, NR １９ R ２０ , CO ２ H, R １９ R ２０ N—C(O)—, R １９ O-NR ２０ -, (C １ ~C ８ ) alkyl-CO ２ -, R １９ R ２０ N-(C １ ~C ８ ) alkyl-, R １９ O ２ C-(C １ ~C ８ ) alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C １ ~C ８ ) optionally substituted by alkyl-; R １９ and R ２０ are each independently hydrogen or (C １ ~C ８ ) represents alkyl; R ６ is (C １ ~C ８ ) alkyl, 1 to 3 (C １ ~C ８ ) CH substituted by alkyl groups ３ , cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C １ ~C ８ ) represents alkyl; R ６ The alkyl or cycloalkyl may be at least one of F, Cl, (C １ ~C ８ ) alkyl, CF ３ , OCF ３ ,CN,OH,=O,(C １ ~C ８ ) alkoxy, NR ２１ R ２２ , CO ２ H, R ２１ R ２２ N—C(O)—, R ２１ O-NR ２２ -, heterocycloalkyl, aryl, or heteroaryl; R ２１ and R ２２ are each independently hydrogen or (C １ ~C ８ ) represents alkyl; The heterocycloalkyl, aryl or heteroaryl may be selected from the group consisting of at least one of F, Cl, (C １ ~C ８ ) alkyl, CF ３ , CHF ２ , C.H. ２ F, OCF ３ ,CN,OH,=O,→O,(C １ ~C ８ ) alkoxy, NR ２３ R ２４ , CO ２ H, R ２３ R ２４ N—C(O)—, R ２３ O-NR ２４ -, (C １ ~C ８ ) alkyl-CO ２ -, R ２３ R ２４ N-(C １ ~C ８ ) alkyl-, R ２３ O ２ C-(C １ ~C ８ ) alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C １ ~C ８ ) optionally substituted by alkyl-; R ２３ and R ２４ are each independently hydrogen or (C １ ~C ８ ) represents alkyl; Or, R ５ and R ６ together with the nitrogen atom to which they are attached form a heterocycloalkyl; The heterocycloalkyl may be selected from the group consisting of at least one of F, Cl, (C １ ~C ８ ) alkyl, CF ３ , OCF ３ ,CN,OH,=O,→O,(C １ ~C ８ ) alkoxy, NR ２５ R ２６ , CO ２ H, (C １ ~C ８ ) alkyl-CO ２ -, R ２５ R ２６ N—C(O)—, R ２５ O-NR ２６ -, R ２５ R ２６ N-(C １ ~C ８ ) alkyl-, R ２５ O ２ C-(C １ ~C ８ ) alkyl-, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C １ ~C ８ ) alkyl-, heterocycloalkyl-(C １ ~C ８ ) alkyl-, aryl-(C １ ~C ８ ) alkyl-, heteroaryl-(C １ ~C ８ ) alkyl-, aryl-cycloalkyl-, cycloalkyl-O-, heterocycloalkyl-O-, aryl-O-, heteroaryl-O-, cycloalkyl-(C １ ~C ８ ) alkyl-O-, heterocycloalkyl-(C １ ~C ８ ) alkyl-O-, aryl-(C １ ~C ８ ) alkyl-O-, heteroaryl-(C １ ~C ８ ) alkyl-O-, cycloalkyl-NR ２５ -, heterocycloalkyl-NR ２５ -, aryl-NR ２５ -, heteroaryl-NR ２５ -, cycloalkyl-(C １ ~C ８ ) alkyl-NR ２５ -, heterocycloalkyl-(C １ ~C ８ ) alkyl-NR ２５ -, aryl-(C １ ~C ８ ) alkyl-NR ２５ -, heteroaryl-(C １ ~C ８ ) alkyl-NR ２５ -, benzylidene, heteroarylidene, aryl-(C １ ~C ８ ) alkyl-ylidene- or heteroaryl-(C １ ~C ８ ) optionally substituted by alkyl-ylidene-; R ２５ and R ２６ are each independently hydrogen or (C １ ~C ８ ) represents alkyl; The heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylidene may be substituted with at least one of F, Cl, (C １ ~C ８ ) alkyl, CF ３ , CHF ２ , C.H. ２ F, OCF ３ ,CN,OH,=O,→O,(C １ ~C ８ ) alkoxy, NR ２７ R ２８ , CO ２ H, R ２７ R ２８ N—C(O)—, R ２７ O-NR ２８ -, (C １ ~C ８ ) alkyl-CO ２ -, R ２７ R ２８ N-(C １ ~C ８ ) alkyl-, R ２７ O ２ C-(C １ ~C ８ ) alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C １ ~C ８ ) optionally substituted by alkyl-; R ２７ and R ２８ are each independently hydrogen or (C １ ~C ８ ) represents alkyl, A compound of formula (Ii) or a pharmaceutically acceptable salt and / or solvate thereof:

2. Formula (I-ii) 【Chemistry 2】 or a pharmaceutically acceptable salt and / or solvate thereof, During the ceremony, W represents CH or N; R Ａ , R Ｂ , R Ｃ and R Ｄ are each independently hydrogen, F, Cl, or CH ３ , C.F. ３ , CHF ２ or CH ２ represents F; R ７ is hydrogen, OH, halogen, (C １ ~C ８ ) alkyl, cycloalkyl, (C ２ ~C ８ ) alkyl-O-, cycloalkyl-O-, cycloalkyl-(C １ ~C ８ ) alkyl-O-, heterocycloalkyl-O-, heterocycloalkyl-(C １ ~C ８ ) alkyl-O-, aryl-(C １ ~C ８ ) alkyl-O-, heteroaryl-(C １ ~C ８ ) alkyl-O-, R １１ O-(C １ ~C ８ ) alkyl-O-, R １１ R １２ N-(C １ ~C ８ ) alkyl-O—, (R １１ O) (R １２ ) N-(C １ ~C ８ ) alkyl-O-, R １１ R １２ N-(C １ ~C ８ ) alkyl-, R １１ O-(C １ ~C ８ ) alkyl-, NR １１ R １２ , C.N., C.O. ２ H, CO ２ R １１ , C.O.N.H. ２ , CON(R １１ ) H, heterocycloalkyl or heteroaryl; R １１ and R １２ are each independently hydrogen or (C １ ~C ８ ) represents alkyl; R ７ The alkyl or cycloalkyl may be at least one of F, Cl, OH, ═O, (C １ ~C ８ ) alkyl, (C １ ~C ８ ) optionally substituted by alkyl-O-, heterocycloalkyl, aryl or heteroaryl; The heterocycloalkyl, aryl or heteroaryl may be selected from the group consisting of at least one of F, Cl, (C １ ~C ８ ) alkyl, CF ３ , CHF ２ , C.H. ２ F, OCF ３ ,CN,OH,=O,→O,(C １ ~C ８ ) alkoxy, NR １３ R １４ , R １３ R １４ N-(C １ ~C ８ ) alkyl-, R １３ O ２ C (C １ ~C ８ ) alkyl-, CO ２ H, R １３ R １４ N—C(O)—, R １３ O-NR １４ - or (C １ ~C ８ ) alkyl-CO ２ optionally substituted by -; R １３ and R １４ are each independently hydrogen or (C １ ~C ８ ) represents alkyl; Z is C-H, C-R ８ or represents N; R ８ is (C １ ~C ４ ) Alkyl, F, Cl, CF ３ , CHF ２ , C.H. ２ F, OCF ３ , CN, OH or (C １ ~C ４ ) represents alkoxy; or Z is C-R ８ represents R ７ and R ８ together with the carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl; The cycloalkyl or heterocycloalkyl may be selected from the group consisting of at least one of F, OH, ═O, →O, (C １ ~C ８ ) alkyl, CF ３ , H.O. ２ C-CH ２ -, (C １ ~C ４ ) alkyl-CO ２ -CH ２ -, R １５ R １６ N-CH ２ -, aryl or aryl-(C １ ~C ８ ) optionally substituted by alkyl-; R １５ and R １６ are each independently hydrogen or (C １ ~C ８ ) alkyl; and R ５ and R ６ are each independently as defined in claim 1; A compound of formula (I-ii) or a pharmaceutically acceptable salt and / or solvate thereof:

3. 3. A compound according to claim 1 or claim 2, wherein W represents CH.

4. R Ａ , R Ｂ , R Ｃ and R Ｄ At least one of R represents hydrogen, preferably R Ａ and R Ｃ At least one of R represents hydrogen, more preferably Ｃ represents hydrogen; and / or R Ａ , R Ｂ and R Ｄ At least one of R represents F or Cl, preferably R Ｂ and R Ｄ At least one of R represents F or Cl, more preferably R Ｂ and R Ｄ each independently represents F or Cl; A compound according to any one of claims 1 to 3.

5. R ７ represents hydrogen, OH or halogen; preferably, R ７ 5. A compound according to any one of claims 1 to 4, wherein represents OH or F.

6. R ７ However, (C １ ~C ８ ) alkyl-O- or cycloalkyl-O-, wherein said alkyl or cycloalkyl is at least one of F, Cl, OH, (C １ ~C ８ ) optionally substituted by alkoxy or aryl; preferably R ７ But OCH ３ , HO-CH ２ -CH ２ -O-, CH ３ O-CH ２ -CH ２ —O— or phenyl-CH ２ 6. A compound according to any one of claims 1 or 3 to 5, wherein -O- is represented by

7. Z is C-R ８ represents R ８ is (C １ ~C ４ ) Alkyl, F, Cl, CF ３ , CHF ２ , C.H. ２ F, OCF ３ , CN, OH or (C １ ~C ４ ) alkoxy; preferably, R ８ 7. A compound according to any one of claims 1 to 6, wherein represents methyl or Cl.

8. Z is C-R ８ represents R ７ and R ８ together with the carbon atom to which they are attached form a heterocycloalkyl, said heterocycloalkyl being at least one of F, OH, ═O, (C １ ~C ８ ) alkyl, CF ３ , H.O. ２ C-CH ２ -, (C １ ~C ４ ) alkyl-CO ２ -CH ２ - or R １５ R １６ N-CH ２ -, and R １５ and R １６ are each independently hydrogen or (C １ ~C ８ 7. The compound according to claim 1, wherein R represents 1 or 2. 8.) alkyl-.

9. R ５ is hydrogen or (C １ ~C ８ ) alkyl; preferably, R ５ represents hydrogen, methyl or ethyl; and / or R ６ However, (C １ ~C ８ ) alkyl, cycloalkyl, heterocycloalkyl, cycloalkyl-(C １ ~C ８ ) alkyl- or aryl-(C １ ~C ８ ) alkyl-, wherein said alkyl, cycloalkyl, heterocycloalkyl or aryl is optionally substituted by at least one methyl, Cl or F; preferably, R ６ ethyl, propyl, butyl, cyclopentyl, cyclohexyl, 2-adamantyl, 3-methyloxetan-3-yl, cyclopropyl-CH ２ -, cyclobutyl-CH ２ -, cyclohexyl-CH ２ -, phenyl-CH ２ -(benzyl), 3-chlorophenyl-CH ２ - or 4-fluorophenyl-CH ２ 9. The compound according to claim 1, wherein R represents -.

10. R ５ and R ６ together with the nitrogen atom to which they are attached form a heterocycloalkyl, said heterocycloalkyl being optionally substituted with at least one F; preferably R ５ and R ６ together with the nitrogen atom to which they are attached, form pyrrolidine, 4-benzyl-piperidine, 4-phenyl-4-hydroxy-piperidine, 4-benzyl-4-hydroxy-piperidine, 4-benzyl-piperazine, tert-butyl 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate, 4-benzylidene-1-piperidine, 4-(2-phenylethyl)-piperidine, 4-phenylpiperidine, 3-phenylpiperidine, 3-benzyl-piperidine, 3-phenylpyrrolidine, 3-benzylpyrrolidine, 4-trifluoromethylpiperidin 10. The compound according to any one of claims 1 to 9, which forms 2-(4-fluorophenyl)piperidine, 2-azabicyclo[2.2.1]heptane, 3-benzyloxypiperidine, 3-benzyloxypyrrolidine, 2-benzyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrolidine, 4-(4-fluorophenyl)piperidine, [2-(4-chlorophenyl)ethyl]piperazine, [2-(4-fluorophenyl)ethyl]piperazine, 2-(phenylpropyl)piperazine, [2-(4-fluorophenyl)propyl]piperazine, 4-fluoropiperidine, or 2,2-dimethylpyrrolidine.

11. The compound is 【Table 1】 3. The compound of claim 1 or claim 2, selected from: and pharmaceutically acceptable salts and / or solvates thereof.

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

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

15. 12. A method for producing a compound according to any one of claims 1 to 11, said method comprising: Formula (II) 【Chemistry 3】 (In the formula, Z, R ５ , R ６ and R ７ is either as defined in claim 1 or as defined in claim 2, X is a halide or —CF ３ SO ３ a compound of formula (I) Formula (III) 【Chemistry 4】 (Wherein W and R Ａ ~R Ｄ is either as defined in claim 1 or as defined in claim 2; reacting in the presence of a base and a metal catalyst, thereby obtaining either said compound of formula (I-i) or a pharmaceutically acceptable salt and / or solvate thereof, or said compound of formula (I-ii) or a pharmaceutically acceptable salt and / or solvate thereof, method.

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