Novel sulfonamides and their use as neuroprotective agents and / or nerve repair agents

Abstract

The present invention relates to a compound of general formula (I): [Chemical 1] TIFF2025525078000332.tif38159 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 agents and / or nerve repair agents, particularly for use in the treatment of neurological diseases.

Description

Technical Field

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

Background Art

[0002] Neurological diseases (ND) are heterogeneous diseases that affect the autonomic, peripheral, and central nervous systems of the body. Among the central nervous system (CNS) diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), dementia, stroke, head trauma, brain tumors, pain, and epilepsy are always the most difficult diseases to deal with. Compounds effective for treating the CNS may also be applicable to other diseases, such as those of the peripheral nervous system, eyes, spinal cord, and intestinal tract.

[0003] The incidence of ND is expected to increase dramatically in the 21st century, particularly due to the increase in average life expectancy and demographic changes. Some of these diseases are characterized by a gradual decline in neurological function associated with aging. Neurological diseases are a globally important and common cause of disability-adjusted life years, i.e., the healthy life years lost due to death or physical disability. CNS diseases are representative of the largest and most rapidly growing therapeutic area of unmet medical needs, are being recognized as a global public health issue, and have become a major global health priority. Appropriate neurological diagnosis is representative of a very major challenge, and patients are increasingly interested in the development of new effective treatments for the disease state or symptoms. Neurological diseases affect millions of people worldwide and cause permanent damage. This disorder is a progressive disease with symptoms that may worsen over time. Generally, there is no definitive treatment, but supportive treatment exists. The aim of these treatments is mainly to relieve symptoms and maintain the quality of life of the patient for as long as possible.

[0004] Neurons are terminally differentiated cells that must survive throughout life. In young neurons, self-healing protection mechanisms function properly, but they are impaired by aging or external or internal damage, ultimately leading to neurodegeneration. These external / internal risk factors are traumatic injury or excitotoxic compounds, reactive oxygen species (ROS), protein aggregates, and other toxic molecules. Fortunately, cells have intrinsic mechanisms to prevent death by activating resilience mechanisms or promoting regenerative pathways. Dysfunction or sufficiency of these self-healing mechanisms has also been reported in neurodegenerative diseases.

[0005] Among natural self-healing substances, glial cell line-derived neurotrophic factor (GDNF) functions as a potent neurotrophic factor and promotes survival in different neuronal populations such as spinal motor neurons, retinal cells, central noradrenergic neurons, or sympathetic neurons. Similarly, GDNF (and other proteins of the GDNF family of neurotrophic factors such as neurturin, artemin, and persephin) functions as a potent trophic factor that promotes survival and plasticity, as well as proliferation, differentiation, and protection of dopaminergic neurons and dopamine synthesis and dopamine transmission in the developing and adult brain. GDNF can promote neuroprotection via the MAP kinase / ERK, Src kinase, and PI3 kinase / AKT pathways by inducing several neuroprotective signaling cascades, including activation of the transcription factor Elk1 by activation of the GFRα1-RET receptor complex.

[0006] The application fields of these proteins are very broad. Preclinical and clinical trials have been conducted to evaluate the effects of GDNF family neurotrophic factors for the prevention, treatment, or management of Parkinson's disease, chronic pain, Alzheimer's disease, amyotrophic lateral sclerosis, peripheral neuropathy, depression, and stroke, and these proteins have even been proposed as male contraceptives. However, the clinical application of GDNF is hampered by its poor pharmacokinetic properties, the fact that it does not cross the blood-brain barrier, and thus the need for intracranial delivery by stereotactic surgery, its various biological activities, and its high cost.

[0007] Small molecule compounds that cross the blood-brain barrier and target the GDNF receptor complex and mimic the biological effects of GDNF in neurons can overcome these problems and can be a means leading to higher efficacy in clinical practice. The excellent tissue permeability of such compounds can promote survival in all affected neuronal pathways.

[0008] International Publication No. WO 2011 / 070177 A2 (BALTIC TECHNOLOGY DEV LTD) discloses polycyclic compounds for treating neurological diseases. These compounds have shown significant improvement at this point, but are still limited in terms of activity against the GFRα1-RET target, solubility, membrane permeability (PAMPA and CaCO2), intrinsic clearance in microsomes and hepatocytes, plasma protein binding, and pharmacokinetic profiles. In particular, these compounds are limited in terms of activity against the GFRα1-RET target (as demonstrated, for example, in luciferase assays).

[0009] Surprisingly, the present applicants have discovered that the novel polycyclic sulfonamide of formula (I) exhibits strong GFRα1-RET activity in luciferase assays, thereby opening the way to overcome the limitations of available therapeutic solutions. SUMMARY OF THE INVENTION

[0010] The object of the present invention is a compound of formula (I):

Chemical formula

[0011] According to one embodiment, the compound is selected from the compounds in Table 1 herein and their pharmaceutically acceptable salts and / or solvates.

[0012] Another object of the present invention is a pharmaceutical composition comprising the compound according to the present invention and at least one pharmaceutically acceptable carrier.

[0013] Another object of the present invention is the compound according to the present invention or the pharmaceutical composition according to the present invention for use as a medicine. According to one embodiment, the compound or the pharmaceutical composition is for use in the treatment of neurological diseases.

[0014] Another object of the present invention is a process for producing the compound according to the present invention.

[0015] Definitions In the present invention, the following terms have the following meanings.

[0016] Chemical definitions When a chemical substituent is a combination of chemical groups, the point of attachment of the substituent to the molecule is by the last chemical group listed on the right side of the name of the substituent. For example, an arylalkyl substituent is attached to the rest of the molecule through the alkyl moiety, which may be represented as "aryl-alkyl-".

[0017] Unless otherwise specified, the compound was named using BIOVIA Draw 2021 (Dassault, France).

[0018] The definitions in this specification referring to optional or essential substitution of a specified group apply to both the substituted group as considered as such and the same group contained in another chemical moiety, both of which may be substituted as described in this specification. For example, "R" xrepresents hydrogen, (C1-C8) alkyl, (C1-C8) alkyl-O- or cycloalkyl-(C1-C8) alkyl-NH-, where the alkyl is optionally substituted by at least one F. Here, R x any alkyl group present in the structure of x may be optionally substituted by at least one F, including the alkyl as it is (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-).

[0019] "Alkoxy" refers to an alkyl-O- group.

[0020] "Alkyl" typically refers to a straight-chain or branched-chain saturated hydrocarbon chain 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. The alkyl group can be monovalent or polyvalent (i.e., the divalent "alkylene" group is 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, t-butyl, pentyl and its isomers (e.g., n-pentyl, isopentyl), hexyl and its isomers (e.g., n-hexyl, isohexyl). 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).

[0021] "Amine" refers to a derivative of ammonia (NH3) in which one or more hydrogen atoms are substituted by substituents such as alkyl or aryl. "Amino" refers to the -NH2 group.

[0022] "Aryl" refers to a cyclic polyunsaturated aromatic hydrocarbyl group containing at least one aromatic ring and having 5 to 12 carbon atoms, preferably 6 to 10 carbon atoms. The aryl group may be monovalent or polyvalent (e.g., divalent). The aryl group may have a single ring (e.g., phenyl) or multiple aromatic rings (e.g., naphthyl) fused or covalently bonded to each other. The aromatic ring may optionally contain 1 to 2 additional rings (any of cycloalkyl, heterocycloalkyl or heteroaryl) fused thereto. This definition of "aryl" includes partially hydrogenated derivatives of the carbocyclic systems listed herein as long as at least one ring is aromatic. Aryl may optionally be substituted by at least one group such as, for example, halogen (e.g., F or Cl), (C1-C8)alkyl (e.g., methyl) or nitrile (CN). Non-limiting examples of aryl groups include phenyl, biphenyl, biphenylenyl, 5- or 6-tetralinyl, naphthalene-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1-2-, 3-, 4- or 5-acephenanthrenyl, 3-, 4- or 5-acephenanthryl, 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 specific example of an aryl group is phenyl.

[0023] "Benzylidene" refers to a phenyl group bonded to a moiety via an exocyclic carbon-carbon double bond, i.e., =CH-Ph bonded to a carbon atom. The moiety is typically cyclic, for example, heterocycloalkyl.

[0024] "Cycloalkyl" typically refers to a cyclic alkyl group 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. The cycloalkyl group may be monovalent or polyvalent (e.g., divalent). This definition of "cycloalkyl" encompasses polycyclic (e.g., bicyclic) cycloalkyl and bridged cycloalkyl structures containing a cyclic structure ("spiro") bonded to each other through one atom or a cyclic structure bonded to each other through two atoms. This definition of "cycloalkyl" encompasses cycloalkyl containing a cyclic alkyl group substituted by at least one acyclic alkyl such as, for example, (C1-C8)alkyl (preferably (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.

[0025] The "C x ~C y " or "(C x ~C y )" before the name of the group means that the group contains x to y carbon atoms according to the common terms in the chemical field.

[0026] "Halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0027] "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, the heteroatoms are bonded only to carbon atoms 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 may be monovalent or polyvalent (e.g., divalent). Nitrogen and sulfur heteroatoms may optionally be oxidized, and nitrogen heteroatoms may optionally be quaternized (e.g., sulfur may be oxidized as SO or SO2). A heteroalkyl group may further contain one or more =O and / or =S groups. In one embodiment, at least two carbon atoms are replaced by a heteroatom. In one embodiment, the heteroalkyl is 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, the heteroalkyl is bonded to another group or molecule through one of the heteroatoms contained therein. When substituted by one or more other groups, the heteroalkyl may be substituted through either a carbon atom or a heteroatom (e.g., nitrogen) unless otherwise specified. Non-limiting examples of heteroalkyls include alkoxy, ethers, and polyethers (e.g., polyethylene glycol), secondary and tertiary amines, polyamines, thioethers, polythioethers, and combinations thereof.

[0028] "Heteroaryl" refers to an aromatic ring or aromatic ring system having one or two rings that are fused or covalently bonded to each other, with at least one ring being aromatic and one or more carbon atoms of these rings being substituted by one or more oxygen, nitrogen, and / or sulfur atoms, containing 5 to 15 carbon atoms, preferably 4 to 12 carbon atoms, more preferably 3 to 10 carbon atoms. The heteroaryl group may be monovalent or polyvalent (e.g., divalent). The nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized (e.g., the heteroatom is substituted by oxo (=O) in the case of a sulfur atom or (→O) in the case of a nitrogen atom). This definition of "heteroaryl" includes partially hydrogenated derivatives of the carbocyclic systems listed herein as well as ring systems containing one or more fused non-aromatic cycloalkyl and / or heterocycloalkyl rings, as long as at least one ring is aromatic. In one embodiment, the heteroaryl is bonded to another group or molecule via a carbon atom, i.e., the bonding atom is not selected from among the heteroatoms contained therein. In one embodiment, the heteroaryl is bonded to another group or molecule via one of the heteroatoms contained therein. When substituted by one or more other groups, the heteroaryl may be substituted via either a carbon atom or a heteroatom (e.g., nitrogen) unless otherwise specified. The heteroaryl may be optionally substituted by at least one group such as a halogen (e.g., F or Cl), (C1-C8) alkyl (preferably (C1-C4) alkyl, such as 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, isobenzothiophenyl, 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-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]thiazinyl and 2,3-dihydrobenzo[b][1,4]oxathiin.

[0029] "Heteroaryliden" refers to a heteroaryl group attached to a moiety via an exocyclic carbon-carbon double bond, i.e., =CH-heteroaryl attached to a carbon atom. The moiety is typically cyclic, such as heterocycloalkyl for example.

[0030] "Heterocycloalkyl" typically refers to a cyclic heteroalkyl group 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. The heterocycloalkyl group may be monovalent or polyvalent (e.g., divalent). The heterocycloalkyl group is typically a 3- to 7-membered ring, preferably a 5- or 6-membered ring. Heterocycloalkyl is typically monocyclic or bicyclic, preferably monocyclic. This definition includes polycyclic (e.g., bicyclic) heterocycloalkyl and bridged heterocycloalkyl structures containing a cyclic structure bonded through one atom ("spiro") or a cyclic structure bonded through two atoms. Nitrogen and sulfur heteroatoms may optionally be oxidized, and nitrogen heteroatoms may optionally be quaternized (e.g., the heteroatom is replaced by oxo (=O) in the case of a sulfur atom or (→O) in the case of a nitrogen atom). In one embodiment, heterocycloalkyl 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, heterocycloalkyl is bonded to another group or molecule through one of the heteroatoms contained therein. When substituted by one or more other groups, heterocycloalkyl may be substituted through either a carbon atom or a heteroatom (e.g., nitrogen) unless otherwise specified. Heterocycloalkyl may be optionally substituted by at least one group such as, for example, halogen (e.g., F or Cl), (C1-C8) alkyl (preferably (C1-C4) alkyl, such as methyl), nitrile (CN), or =O.Non-limiting examples of heterocycloalkyl include aziridine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, azepane, azocane, octahydro-1H-isoindole, decahydroisoquinoline, tetrahydrofuran, tetrahydropyran, tetrahydroisoquinoline (e.g., 1,2,3,4-tetrahydroisoquinoline), hexahydropyridazine, hexahydropyrazine, hexahydropyrimidine, decahydroquinoline, octahydropyrrolo[3,4-c]pyrrole, isoindoline, 1,2,3,4-tetrahydroquinoline, and oxetane.

[0031] “Isobutyronitrile” refers to the (NC)(CH3)2C- group of the following formula.

Chemical formula

[0032] “Prodrug” refers to a pharmacologically acceptable derivative of a therapeutic agent (e.g., a compound according to the present invention) whose in vivo metabolite is a therapeutic agent (active drug). Prodrugs are typically characterized by increased bioavailability and are readily metabolized to the active compound in vivo. Non-limiting examples of prodrugs include amide prodrugs and carboxylic acid ester prodrugs.

[0033] “Solvate” refers to a molecular complex that includes a compound with a stoichiometric or sub-stoichiometric amount of one or more molecules of one or more solvents, and typically the solvent is a pharmaceutically acceptable solvent such as ethanol. The term “hydrate” refers to a solvate where the solvent is water (H2O).

[0034] “Ilydene” refers to a CH group involved in an exocyclic carbon-carbon double bond with another moiety. This moiety is typically cyclic, such as heterocycloalkyl for example.

[0035] General definitions As used herein, "about" means "approximately", "substantially", "around", or "in the range of". The term "about" before a number means ±10% of the value of that number. When the term "about" is used with a numerical range, it modifies that range by expanding the upper and lower limits of the recited numerical values by 10%.

[0036] "Administer" or a variation thereof (e.g., "administering") means to give a therapeutic agent, alone or as part of a pharmaceutically acceptable composition, to a patient having a condition, symptom, or disease to be treated.

[0037] "Comprise" or a variation thereof (e.g., "comprises", "comprising") is used herein according to the terminology for drafting general patent applications. Thus, when there is a thing before "comprise" and components follow it, the presence of the components in that thing (typically as components of a composition) is required, but the presence of any additional components in that thing is not excluded. Further, any occurrence of "comprise" or a variation thereof in this specification also includes the narrower expression "substantially consist of", the even narrower expression "consist of", and any variations thereof (e.g., "consists of", "consisting of"), and may be replaced thereby, unless otherwise specified.

[0038] "GDNF family receptor alpha-1", also named "RET ligand 1" or "TGF-β-related neurotrophic factor receptor 1", "GFRα1" or "GDNFRα1", is a protein of the GDNFR family that functions as a receptor for GDNF. It mediates GDNF-induced autophosphorylation and activation of the RET receptor. GFRα1 in humans 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 to 24 correspond to the signal peptide and amino acid residues 430 to 465 correspond to the propeptide that is removed in the mature form. [Chemical formula]

[0039] "Human" refers to a human subject, male or female, at any stage of growth, including neonates, infants, children, adolescents, young adults, and adults.

[0040] "Neuroprotective agent" refers to the protection of nerve cells from injuries, events, or conditions that normally cause loss of nerve cell function and ultimately lead to nerve cell death. Such injuries, events, or conditions include, but are not limited to, for example, neuronal stress caused by hypoxia or ischemia, traumatic injury, and exposure to toxic molecules such as abnormally folded proteins, protein aggregates, excitotoxins, reactive oxygen species, endoplasmic reticulum stress factors, mitochondrial stress factors, and Golgi antagonists. The term is also characterized by the detectable biological activity of a compound in reducing the amount or level of nerve cell function loss and / or nerve cell death.

[0041] "Neurorepair" refers to the repair or rescue of nerve cells, particularly their function, from the effects of injuries, events, or conditions that normally cause loss of nerve cell function but do not cause nerve cell death.

[0042] "Patient" refers to an individual who is waiting for or receiving medical care, or who has been or is currently or will be the subject of medical treatment, or who is being observed for the occurrence of a target disease or condition such as a neurological disorder.

[0043] "Pharmaceutically acceptable" means that the components of the composition are compatible with each other and not harmful to the subject to which it is administered.

[0044] "Pharmaceutically acceptable carrier" refers to an excipient that does not cause side effects, allergic reactions or other harmful reactions when administered to animals, preferably humans. It includes all kinds of solvents, i.e., dispersion media, coating agents, antibacterial agents, antifungal agents, isotonic agents and absorption delaying agents, etc. For administration to humans, the formulation must meet the 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, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, salts or electrolytes such as sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances (e.g., sodium carboxymethylcellulose), polyethylene glycol, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol and lanolin.

[0045] "Pharmaceutical composition" refers to a composition comprising at least one therapeutic agent (e.g., a compound according to the present invention) and at least one pharmaceutically acceptable carrier.

[0046] "Proto-oncogene tyrosine-protein kinase receptor Ret", also named "cadherin family member 12" or simply "RET", is a receptor tyrosine kinase involved in numerous cellular mechanisms including cell proliferation, neuron navigation, cell migration and cell differentiation. RET is activated by (i) the binding of a neurotrophic factor of the GDNF family (e.g., GDNF, neurturin, artemin or persephin) to a receptor of the GDNFR family (e.g., GFRα1, GFRα2, GFRα3 or GFRα4), then (ii) the formation of a complex between RET and the receptor of the GDNFR family, (iii) dimerization, and (iv) trans-autophosphorylation. An exemplary amino acid sequence of human RET is shown in SEQ ID NO: 2, where amino acid residues 1 to 28 correspond to the signal peptide. [Chemical formula]

[0047] "Selected from" is used herein according to the common patent application drafting terminology to introduce a list of elements from which one or more items are selected. Any occurrence of "selected from" in this specification may be mutually replaced with "comprising or selected from the group consisting of" without changing its meaning.

[0048] "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 a disease, preferably 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, genetic predisposition or family history of the disease.

[0049] "Therapeutic agent", "active pharmaceutical ingredient" and "active ingredient" refer to health-related compounds for therapeutic use. In particular, a therapeutic agent (e.g., a compound according to the present invention) may be adapted to treat a disease (e.g., a neurological disease). Also, an active ingredient may be adapted to enhance the therapeutic activity of another therapeutic agent.

[0050] "Therapeutically effective amount" (abbreviated as "effective amount") refers to the amount of a therapeutic agent (e.g., a compound according to the present invention) sufficient to achieve the desired therapeutic or prophylactic effect in a patient without causing significant adverse effects or harmful side effects in that patient. A therapeutically effective amount may be administered prior to the onset of the disease for prophylactic treatment. Alternatively or in addition, a therapeutically effective amount may be administered after the onset of the disease for therapeutic treatment.

[0051] "Treat" or "treatment" or "alleviate" refers to both therapeutic treatment and prophylactic treatment, the purpose of which is to prevent or slow down (alleviate) a targeted pathological condition or disorder (referred to herein as a "disease") (e.g., a neurological disease). Those in need of treatment include those already suffering from the disease, as well as those susceptible to the disease or having a condition or disease to be prevented. A patient is considered to have a "successful treatment" of a disease when, after administration of a therapeutic amount of a therapeutic agent (e.g., a compound according to the present invention), the patient shows one or more observable and / or measurable decreases or absences in the number of pathogens, the proportion of total pathogenic cells, and / or a degree of alleviation of one or more symptoms associated with a particular disease, a decrease in morbidity and mortality, and an improvement in quality of life issues. The above parameters for evaluating treatment success and disease improvement are readily measurable by conventional procedures with which a physician is familiar.

Mode for Carrying Out the Invention

[0052] Compound An object of the present invention is a compound of formula (I):

Chemical formula

[0053] In any one of the following embodiments regarding specific limitations on the structure of the compound of formula (I), any alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylidene is independently optionally substituted as indicated under formula (I) herein unless otherwise specified.

[0054] According to a preferred embodiment, the compound of formula (I) is a compound of formula (I'):

Chemical formula

[0055] According to one embodiment, W represents CH.

[0056] According to one embodiment, R A , R B , R C and R D at least one of represents hydrogen. In one embodiment, R A , R B , R C and R D exactly one of represents hydrogen. In one embodiment, R A , R B , R C and R D exactly two of represent hydrogen. In one embodiment, R A , R B , R C and R D exactly three of represent hydrogen.

[0057] In one embodiment, at least one of R A and R C represents hydrogen. In a particular embodiment, R A represents hydrogen. In a particular embodiment, R C represents hydrogen.

[0058] According to one embodiment, at least one of R A , R B and R D represents F or Cl. In one embodiment, at least one of R B and R D represents F or Cl. In a particular embodiment, R B and R D each independently represents F or Cl. In a particular embodiment, R B represents F. In a particular embodiment, R B represents Cl. In a particular embodiment, RD represents F. In a specific embodiment, R D represents Cl. In a preferred embodiment, R B represents F. In a preferred embodiment, R D represents Cl. In a further preferred embodiment, R B represents F, and R D represents Cl.

[0059] As defined under formula (I) above in this specification, R 1 may represent (C1-C8) alkyl, where the alkyl is optionally substituted by at least one OH, (C1-C3) alkoxy or F, that is, the (C1-C8) alkyl in R 1 is optionally substituted by at least one group, and the group may be OH, (C1-C3) alkoxy or F. According to one embodiment, R 1 represents (C1-C8) alkyl, where the alkyl is optionally substituted by at least one group selected from OH, (C1-C3) alkoxy and F.

[0060] According to one embodiment, R 1 and R 4 together form -CH2-O-CH2- or -CH2-CH2. In one embodiment, R 1 and R 4 together form -CH2-CH2-. In one embodiment, -CH2-CH2- is optionally substituted by at least one F, OH or OCH3. In one embodiment, -CH2-CH2- is unsubstituted.

[0061] According to one embodiment, R 1 represents methyl, ethyl, CF3 or methoxymethyl (CH3OCH2-). In one embodiment, R 1 represents methyl, ethyl or CF3. In one embodiment, R 1 represents methoxymethyl (CH3OCH2-).

[0062] According to one embodiment, R7 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-, wherein R 11 and R 12 each independently represent hydrogen or (C1-C8)alkyl, where alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted as defined above under formula (I) herein.

[0063] According to one embodiment, R 7 represents hydrogen, OH or halogen. In one embodiment, R 7 represents hydrogen. In a preferred embodiment, R 7 represents hydroxyl (OH). In one embodiment, R 7 represents halogen. In a particular preferred embodiment, R 7 represents F or Cl. In a particular embodiment, R 7 represents F. In a particular embodiment, R 7 represents Cl.

[0064] In a preferred embodiment, R 7 does not represent hydrogen.

[0065] According to one embodiment, R 7 represents (C1-C8)alkyl-O- (i.e., (C1-C8)alkoxy) or cycloalkyl-O-. In one embodiment, the alkyl or cycloalkyl is optionally substituted by at least one F, Cl, OH, (C1-C8)alkoxy or aryl. In a particular embodiment, R 7represents OCH3 (methoxy), OCH2CH3, OCF3, cyclobutyl - O -, HO - CH2 - CH2 - O -, CH3O - CH2 - CH2 - O - or phenyl - CH2 - O -.

[0066] According to one embodiment, R 7 represents (C1 - C8) alkyl - O - (i.e., (C1 - C8) alkoxy). In one embodiment, the alkyl is optionally substituted by at least one F or Cl. In a particular embodiment, the halogen is F. In one embodiment, R 7 represents OCH3 (methoxy), OCH2CH3 or OCF3.

[0067] According to one embodiment, R 7 represents cycloalkyl - O -. In one embodiment, R 7 represents cyclobutyl - O -.

[0068] According to one embodiment, R 7 represents (C1 - C8) alkyl - O - (i.e., (C1 - C8) alkoxy) (wherein the alkyl is optionally substituted by at least one OH or (C1 - C8) alkoxy), i.e., RO - (C1 - C8) alkyl - O - (wherein R represents H or (C1 - C8) alkyl). In one embodiment, R 7 represents HO - CH2 - CH2 - O - or CH3O - CH2 - CH2 - O -.

[0069] According to one embodiment, R 7 represents (C1 - C8) alkyl - O - (i.e., (C1 - C8) alkoxy), where the alkyl is optionally substituted by at least one aryl. In one embodiment, the aryl is unsubstituted. In one embodiment, R 7 represents phenyl - CH2 - O -.

[0070] According to one embodiment, R 7represents (C1-C8) alkyl-O- (i.e., (C1-C8) alkoxy), where the alkyl is optionally substituted by at least one heteroaryl. In one embodiment, the heteroaryl is unsubstituted. In one embodiment, R 7 represents heteroaryl-CH2-O-.

[0071] According to one embodiment, R 7 represents (C1-C8) alkyl-O- (i.e., (C1-C8) alkoxy), where the alkyl is optionally substituted by at least one heterocycloalkyl. In one embodiment, R 7 represents heterocycloalkyl-(C1-C8) alkyl-O-, i.e., the alkyl is substituted by exactly one heterocycloalkyl. In one embodiment, the heterocycloalkyl is unsubstituted.

[0072] In a preferred embodiment, R 7 represents F, Cl, OCH3 (methoxy), OCH2CH3, OCF3, cyclobutyl-O-, HO-CH2-CH2-O-, CH3O-CH2-CH2-O-, phenyl-CH2-O-, 1H-imidazol-4-yl-, 1-methyl-imidazol-4-yl-, CH3, CN, CO2H, Cl, F, CH2OH, C(CH3)2OH, CH2N(CH3)2, cyclopropyl, cyclobutyl-O-, (4-pyridine)-CH2-O-, (3-pyridine)-CH2-O- or benzyl-O-. In a particular preferred embodiment, R 7 represents 1H-imidazol-4-yl-, 1-methyl-imidazol-4-yl-, CH3, CN, CO2H, CH2OH, C(CH3)2OH, CH2N(CH3)2, cyclopropyl, cyclobutyl-O-, (4-pyridine)-CH2-O-, (3-pyridine)-CH2-O- or benzyl-O-.

[0073] According to one embodiment, Z represents C-H or N, or Z represents C-R 8 and R 7 and R 8together with the carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl is optionally substituted as defined herein under formula (I). In other words, in this embodiment, R 7 and R 8 represent hydrogen, except when together with the carbon atom to which they are attached they form a cycloalkyl or heterocycloalkyl. 8 represents hydrogen.

[0074] According to one embodiment, Z represents C-H or N. In one embodiment, Z represents C-H. In one embodiment, Z represents N.

[0075] According to a preferred embodiment, Z represents C-R 8 wherein R 8 represents (C1-C4) alkyl, F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH or (C1-C4) alkoxy. In a preferred embodiment, R 8 represents methyl, ethyl, F, Cl, CF3, CN or OH.

[0076] According to another embodiment, Z represents C-R 8 and R 7 and R 8 together with the carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl is optionally substituted as defined herein under formula (I).

[0077] In a preferred embodiment, Z represents C-R 8 and R 7 and R 8Together with the carbon atoms to which they are attached, they form a heterocycloalkyl, where the heterocycloalkyl is optionally substituted as defined herein under formula (I). In certain embodiments, the heterocycloalkyl contains at least one oxygen atom, i.e., the heterocycloalkyl is a cyclic ether. In certain embodiments, the heterocycloalkyl contains at least one nitrogen atom, i.e., the heterocycloalkyl is a cyclic amine. In certain embodiments, the heterocycloalkyl is a 6-membered or 5-membered ring. In certain embodiments, the heterocycloalkyl contains exactly one oxygen atom, two oxygen atoms or one nitrogen atom.

[0078] According to one embodiment, R 5 represents hydrogen or (C1-C8)alkyl. In one embodiment, R 5 represents hydrogen. In one embodiment, R 5 represents (C1-C8)alkyl. In a preferred embodiment, R 5 represents hydrogen, methyl or ethyl. In certain embodiments, R 5 represents hydrogen. In certain embodiments, R 5 represents methyl or ethyl.

[0079] 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 by at least one F. In a preferred embodiment, the alkyl or cycloalkyl is unsubstituted. In one embodiment, R 6 represents methyl, ethyl, n-propyl, 1-fluoro-n-propane, tert-butyl, cyclopropyl, cyclobutyl or cyclopropyl-CH2-.

[0080] According to one embodiment, R 6represents (C1-C8) alkyl, cycloalkyl or cycloalkyl-(C1-C8) alkyl- or heterocycloalkyl. In one embodiment, the alkyl or cycloalkyl is optionally substituted by at least one F, CN or CF3. In a preferred embodiment, the alkyl or cycloalkyl is unsubstituted. In one embodiment, R 6 represents methyl, ethyl, i-propyl, isobutyronitrile, n-propyl, 3-fluoro-n-propane, tert-butyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, 1-methylcyclobutyl, cyclopropyl-CH2-, (F3C)C(Me)2-, 3-methyloxetan-3-yl or oxetan-3-yl.

[0081] According to one embodiment, R 6 represents (C1-C8) alkyl. In one embodiment, the alkyl is optionally substituted by at least one F. In one embodiment, the alkyl is unsubstituted. In a particular embodiment, R 5 represents methyl, ethyl, n-propyl, 1-fluoro-n-propane or tert-butyl.

[0082] According to one embodiment, R 6 represents cycloalkyl. In one embodiment, R 6 represents cyclopropyl or cyclobutyl.

[0083] According to one embodiment, R 6 represents cycloalkyl-(C1-C8) alkyl. In a particular embodiment, R 6 represents cyclopropylmethyl (cyclopropyl-CH2-).

[0084] According to one embodiment, R 5 and R 6 together with the nitrogen atom to which they are attached form heterocycloalkyl. In one embodiment, the heterocycloalkyl is optionally substituted by at least one F. In a preferred embodiment, R 5 and R 6together with the nitrogen atom to which they are attached, form pyrrolidine, piperidine, 4-fluoropiperidine, 3-fluoropyrrolidine, 4-trifluoromethylpiperidine, 4-benzylpiperidine, 3-benzylpyrrolidine, 3-benzylpiperidine, 4-phenylpiperidine, 4-benzylidenepiperidine, octahydro-1H-isoindole, 2-benzyl octahydropyrrolo[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 certain embodiments, R 5 and R 6 together with the nitrogen atom to which they are attached, form pyrrolidine, 4-fluoropiperidine, 3-fluoropyrrolidine, 4-trifluoromethylpiperidine, 4-benzylpiperidine, 3-benzylpyrrolidine, 3-benzylpiperidine, 4-phenylpiperidine, 4-benzylidenepiperidine, octahydro-1H-isoindole, 3-(benzyloxy)pyrrole, 2-azabicyclo[2.2.1]heptane, 5-(4-methylpiperazin-1-yl)pyrimidine, or 4-phenethylpiperidine.

[0085] In a preferred embodiment, R 5 and R 6Together with the nitrogen atom to which they are attached, they form pyrrolidine, 3,3-dimethylmorpholine, 4-fluoropiperidine, 3-fluoropyrrolidine, 4-trifluoromethylpiperidine, 4-benzylpiperidine, 3-benzylpyrrolidine, 3-benzylpiperidine, 4-phenylpiperidine, 4-(4-fluorophenyl)piperidine, 4-benzylidenepiperidine, octahydro-1H-isoindole, 3-(benzyloxy)pyrrolidine, 3-phenoxypyrrolidine, N-methyl-N-phenylpyrrolidin-3-amine, 2-azabicyclo[2.2.1]heptane, 5-(4-methylpiperazin-1-yl)pyrimidine, 4-phenethylpiperidine, phenylpiperazine, 4-benzylpiperazine, 3-(4-piperidyl)benzonitrile, methyl 3-(4-piperidyl)benzoate, methyl 4-(4-piperidyl)benzoate, 4-(3-pyrazol-1-ylphenyl)piperidine, 1-[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]piperazine, 1-[2-(4-fluorophenyl)propyl]piperazine, 1-[2-(4-fluorophenyl)ethyl]piperazine, 1-[2-(4-chlorophenyl)ethyl]piperazine, 1-(2-phenylpropyl)piperazine or 1-(4-fluorophenyl)-2-piperazin-1-yl-ethanol.

[0086] According to one embodiment, at least one heterocycloalkyl present in the compound of formula (I) is a water-soluble group, i.e., the presence of this group in the molecule enhances its solubility in water compared to the same molecule without the heterocycloalkyl.

[0087] According to one embodiment, R E represents hydrogen or a halogen. In a preferred embodiment, R E represents hydrogen or F. In a further preferred embodiment, R E represents hydrogen. According to one embodiment, R E represents (C1-C3)alkyl. According to one embodiment, R E represents a halogen.

[0088] According to one embodiment, the compound of formula (I) is a compound of formula (I-a): [Chemical formula] or a pharmaceutically acceptable salt and / or solvate thereof, wherein W, R B , R D , Z, R 1 ~R 4 , R 5 , R 6 , R 7 and R E are as defined below formula (I) herein.

[0089] In one embodiment, W in formula (I-a) represents CH.

[0090] In one embodiment, R B and R D each independently represent F or Cl. In a specific embodiment, R B represents F and R D represents Cl.

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

[0092] According to one embodiment, the compound of formula (I) is selected from the compounds in Table 1 below and pharmaceutically acceptable salts and / or solvates thereof. [Table 1] TIFF2025525078000010.tif205159TIFF2025525078000011.tif213159TIFF2025525078000012.tif221159TIFF2025525078000013.tif235159TIFF2025525078000014.tif242149TIFF2025525078000015.tif242148TIFF2025525078000016.tif205159TIFF2025525078000017.tif242149TIFF2025525078000018.tif242149TIFF2025525078000019.tif205159TIFF2025525078000020.tif213159TIFF2025525078000021.tif229159TIFF2025525078000022.tif242153TIFF2025525078000023.tif236159TIFF2025525078000024.tif221159TIFF2025525078000025.tif213159TIFF2025525078000026.tif221159TIFF2025525078000027.tif237159TIFF2025525078000028.tif222159TIFF2025525078000029.tif242148TIFF2025525078000030.tif205159TIFF2025525078000031.tif222159TIFF2025525078000032.tif222159TIFF2025525078000033.tif221159TIFF2025525078000034.tif228159TIFF2025525078000035.tif221159TIFF2025525078000036.tif236159TIFF2025525078000037.tif228159TIFF2025525078000038.tif206159TIFF2025525078000039.tif220159TIFF2025525078000040.tif221159TIFF2025525078000041.tif228159TIFF2025525078000042.tif236159TIFF2025525078000043.tif242148TIFF2025525078000044.tif214159TIFF2025525078000045.tif222159TIFF2025525078000046.tif227159TIFF2025525078000047.tif228159TIFF2025525078000048.tif212159TIFF2025525078000049.tif237159TIFF2025525078000050.tif213159TIFF2025525078000051.tif220159TIFF2025525078000052.tif220159TIFF2025525078000053.tif82159.

[0093] All references in this specification to a compound of the invention (e.g., "a compound of formula (I)") include references to its salts, solvates, multicomponent complexes and liquid crystals. All references in this specification to a compound of the invention include references to its polymorphs and crystal habits. All references in this specification to a compound of the invention include references to its isotopically labeled compounds, including its deuterated compounds. All references in this specification to a compound of the invention include references to its stereoisomers. All references in this specification to a compound of the invention include references to its pharmaceutically acceptable prodrugs.

[0094] In particular, the compounds of the invention may be in the form of pharmaceutically acceptable salts. According to one embodiment, the compounds of the invention are pharmaceutically acceptable salts.

[0095] Pharmaceutically acceptable salts include acid addition salts 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, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, 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, may also be formed. When a compound contains acidic and basic groups, the compound may form an internal salt, 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 an atom within the molecule.

[0096] Pharmaceutically acceptable salts of the compounds of the present invention may 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) removing an acid- or base-labile protecting group from a suitable precursor of the compound, or ring-opening a suitable cyclic precursor, such as a lactone or lactam, with a desired acid, and / or (iv) reacting with a suitable acid or converting one salt of the compound to another salt using a suitable ion-exchange column. All of these reactions are typically carried out in solution. The salt may be precipitated from the solution and recovered by filtration, or alternatively recovered by evaporation of the solvent. The degree of ionization in the salt may vary from fully ionized to hardly ionized.

[0097] In particular, the compounds of the present invention may be in the form of a pharmaceutically acceptable solvate. 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.

[0098] In particular, the compounds of the present invention may contain at least one asymmetric center and thus may exist as different stereoisomers. Accordingly, all references to the compounds of the present invention herein include all possible stereoisomers, including not only racemic compounds but also individual enantiomers and their non-racemic mixtures. The non-racemic mixture may contain any amount of each different stereoisomer, for example, one stereoisomer may be dominant (e.g., 90 / 10 or 80 / 20 mixture), or the enantiomeric ratio may be close to that of a racemic mixture (e.g., 40 / 60 mixture). If a single enantiomer of the compound is desired, such a single enantiomer may be obtained by stereoselective synthesis, resolution of the final product or any convenient intermediate, or chiral chromatography, as is known in the art. Resolution of the final product, intermediate or starting material may be carried out by any suitable method known in the art.

[0099] Pharmaceutical Composition Another object of the present invention is a composition comprising a compound according to the present invention 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.

[0100] In a first embodiment, the pharmaceutical composition comprises the compound according to the present invention as the sole therapeutic agent. In a second embodiment, the pharmaceutical composition further comprises at least one other therapeutic agent, such as a therapeutic agent suitable for treating neurological diseases.

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

[0102] Kit Another object of the present invention is a kit of parts (hereinafter abbreviated as "kit") comprising a compound or composition according to the present invention described herein. According to one embodiment, the kit comprises a product such as a package or a container. According to one embodiment, the kit comprises instructions for use. The kit may be promoted, distributed or sold as a unit for performing the method of the present invention.

[0103] According to one embodiment, the kit comprises a pharmaceutical composition comprising a compound according to the present invention and another separate pharmaceutical composition comprising at least one other therapeutic agent, such as a therapeutic agent suitable for treating neurological diseases.

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

[0105] Another object of the present invention is a compound or composition according to the present invention described herein for use in the treatment of neurological diseases.

[0106] Another object of the present invention is a method for treating a neurological disorder in a subject in need thereof. Another object of the present invention is the use of a compound or composition according to the present invention described herein in the manufacture of a medicament for the treatment of a neurological disorder. Another object of the present invention is the use of a compound or composition according to the present invention described herein for the treatment of a neurological disorder.

[0107] According to one embodiment, the method or the use comprises administering to the subject a therapeutically effective amount of a compound, composition or medicament according to the present invention described herein.

[0108] According to one embodiment, the neurological disorder treated by the method or use of the present invention is · Diseases or disorders associated with abnormal neurogenesis, such as, for example, Hirschsprung's disease, schizophrenia, ataxia telangiectasia, age-related decline in nervous system function or neurodevelopmental disorders, · Neurodegenerative diseases or disorders, such as, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, frontotemporal dementia, retinal neurodegenerative diseases, neuro-ophthalmic diseases, neurotrophic keratitis, Charcot-Marie-Tooth disease, spinal muscular atrophy, epilepsy (e.g., epileptic disorders or seizure disorders or chronic neurological diseases presenting epilepsy), dementia, age-related decline in nervous system function, prion disease, Creutzfeldt-Jakob disease, multiple system atrophy (Shy-Drager syndrome), multiple sclerosis or Guillain-Barré syndrome, · Diseases or disorders related to nerve injury or neurotoxicity, such as, for example, head injury, brain injury, traumatic brain injury, peripheral nerve injury, traumatic peripheral nerve injury, peripheral neuropathy, nerve graft complications, spinal cord injury, traumatic spinal cord injury, nerve transection i.e. nerve injury, cerebrospinal nerve tract transection, brain or nerve cell injury, syringomyelia, optic neuropathy, trauma, stroke, ischemia, stroke, ischemic stroke, neurotoxicity or aphasia caused by alcohol or drug abuse (e.g., ecstasy, methamphetamine, etc.), · Neurodevelopmental disorders such as, for example, Rett syndrome, X-linked mental retardation, fragile X syndrome, Down syndrome, autism spectrum disorder, Hirschsprung disease, Tourette disorder, childhood learning disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Angelman syndrome, micro-premature infants, schizophrenia, language disorder, premature birth, perinatal arterial ischemic stroke, split spine, mental retardation, non-symptomatic X-linked mental retardation, Ondine syndrome or WAGR syndrome, · Neuropsychiatric disorders such as, for example, depression, major depressive disorder, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, anxiety disorder, anxiety disorder, panic disorder, phobia, obsessive-compulsive disorder, post-traumatic stress disorder, bipolar disorder, anorexia nervosa, bulimia nervosa, anhedonia, apathy, dementia, substance-induced dementia, movement and / or tic disorders characterized by movement and / or vocal tics (e.g., Tourette disorder), substance use behavior, addiction, mood disorder, suicidal tendency, cancer-related psychiatric symptoms, Alzheimer's disease, Huntington's disease, frontotemporal dementia or reward deficiency syndrome (RDS), · Movement disorders such as, for example, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, movement and / or tic disorders characterized by movement and / or vocal tics (e.g., Tourette disorder), ataxia, ataxia muscular rigidity (spasm), Charcot-Marie-Tooth disease, spinal muscular atrophy, Werdnig-Hoffmann disease or chronic proximal spinal muscular atrophy, · Painful disorders such as, for example, neuralgia, trigeminal neuralgia, chronic pain, inflammatory pain, pain associated with arthritis, fibromyalgia, back pain, pain associated with cancer, pain associated with digestive diseases, pain associated with Crohn's disease, pain associated with autoimmune diseases, pain associated with endocrine diseases, pain associated with diabetic peripheral neuropathy, phantom limb pain, spontaneous pain, chronic postoperative pain, chronic temporomandibular joint pain, burning pain, postherpetic neuralgia, AIDS-related pain, complex regional pain syndrome type I and II, trigeminal neuralgia, chronic back pain, pain associated with spinal cord injury, pain associated with drug intake, recurrent acute pain, neuropathic pain or inappropriate neuronal activity that causes abnormal sensation in diseases such as diabetes, MS and motor neuron diseases, · For example, eye diseases or eye disorders such as retinopathy, retinal neurodegenerative diseases, retinitis pigmentosa, non-arteritic anterior ischemic optic neuropathy (NAION), macular degeneration, age-related macular degeneration, glaucoma, diabetic retinopathy, optic neuropathy, retinal degeneration, neuro-ophthalmic diseases, age-related cataract, primary open-angle glaucoma (POAG), retinal ganglion cell disorders, ocular hypertension, ischemic optic neuropathy, macular telangiectasia, cystoid macular edema, macular telangiectasia type 2, neurotrophic keratitis or strabismus, · For example, bowel disorders or gastrointestinal disorders such as bowel motility disorders, constipation, Hirschsprung's disease, inflammatory bowel disease, intestinal neurogenic dysplasia, ulcerative colitis, achalasia, esophageal spasm, duodenal ulcer, Zollinger-Ellison syndrome, excessive secretion of gastric acid, malabsorption disorders or enteritis, · For example, progressive muscular dystrophies such as Duchenne type, Becker type, Emery-Dreifuss type, Landowy-Dejerine type, scapulohumeral type, limb-girdle type, Von Graefe-Fuchs type, oculopharyngeal type, myotonic / congenital, congenital or acquired myopathy, Charcot-Marie-Tooth disease, Werdnig-Hoffmann disease or chronic proximal spinal muscular atrophy, · For example, diseases or disorders related to long-term or short-term memory impairment such as memory loss, benign forgetfulness or Alzheimer's disease, · For example, 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 ophthalmopathy, autoimmune thyroiditis, Guillain-Barré syndrome or autoimmune thrombocytopenic purpura, · For example, neurological tumor diseases or disorders such as cochlear sensory cell damage, auditory cognitive defects, hearing loss or tinnitus, · For example, sleep disorders such as narcolepsy, restless legs syndrome, obstructive sleep apnea, chronic sleep disorders, paradoxical sleep deprivation i.e., REM sleep deprivation, · For example, cerebrovascular or neurovascular disorders 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), · For example, substance use disorders such as substance dependence, substance abuse and sequelae of substance abuse dependence, substance-induced mental disorders, substance withdrawal, and substance-induced dementia or amnestic disorder, · Viral infection, Trypanosoma infection, AIDS, obesity, temporomandibular joint disorder, aphasia, Bell's palsy, encephalitis, kidney disease or renal insufficiency, pheochromocytoma, metabolic syndrome, cancer, eczema, neuronal response to neurological diseases associated with thrombocytopenia, hypoplasia, disseminated intravascular coagulation (DIC), spinal dysraphism, immune thrombocytopenic purpura (ITP), HIV-induced ITP, neuro-oncological diseases or disorders, neuro-immune diseases or disorders, multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), neurofibromatosis type 1, scleroderma, epidermal and stromal wound healing disorders and / or scarring disorders, or · Diseases or disorders associated with aging and / or senescence are involved.

[0109] According to one embodiment, the neurological disorder is, for example, 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, progressive myoclonic epilepsy of Lafora, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, generalized epilepsy with febrile seizures plus (GEFS+), severe myoclonic epilepsy of infancy (SMEI), benign familial neonatal convulsions (BFNC), West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, migrating partial epilepsy, infantile epileptic encephalopathy, tuberous sclerosis. These include epilepsies such as Transcranial Spontaneous Cortical Dysplasia (TSC), focal cortical dysplasia, type I lissencephaly, Miller-Dieker 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 system, status epilepticus, abdominal epilepsy, widespread bilateral myoclonus, menstrual epilepsy, Jacksonian seizure disorder, Unverricht-Lundborg disease or photosensitive seizures.

[0110] According to one embodiment, the compositions or medicaments of the present invention described herein can be administered to a subject and may be formulated using methods well known in the art. Non-limiting examples of forms suitable for administration include solutions (such as sterile aqueous solutions), gels, dispersions, emulsions, suspensions, and bulk pharmaceutical forms (such as powders or liposomal forms) suitable for use in preparing solutions or suspensions by adding a liquid prior to use.

[0111] The compositions or medicaments of the present invention described herein may be administered using routes of administration well known in the art, for example, parenterally, orally, by inhalation, spray, rectally, nasally, or via an implantable reservoir.

[0112] However, it will be understood that the total daily dosage of the present compound, the present composition or the present medicine is to be determined by the attending physician within the scope of appropriate medical judgment. The specific therapeutically effective amount level for any particular patient will depend on various factors including the disease being treated and its severity, the activity of the compound being used, the patient's age, weight, health status, gender and diet, the administration time, route and excretion rate of the specific therapeutic agent being used, the duration of treatment, drugs combined with or co-administered with the specific therapeutic agent being used as well as similar factors well-known in the medical art. For example, it is well within the skill of the art to initiate administration of the compound at a level less than that required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. The total dosage required for each treatment may be administered in multiple doses or in a single dose.

[0113] In one embodiment, the dosage of the present compound is about 0.01 to 500 mg per kg of the patient's body weight per day, which can be administered as a single dose or multiple doses. Preferably, the dosage level is about 0.1 to about 250 mg / kg per day, more preferably about 0.5 to about 100 mg / kg per day. Suitable dosage levels may be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day or about 0.1 to 50 mg / kg per day. Within this range, the dosage may be about 0.05 to 0.5, about 0.5 to 5 or about 5 to 50 mg / kg per day. For oral administration, the present composition is preferably provided in the form of tablets containing about 1.0 to 1000 milligrams of the active ingredient, in particular about 1.0, about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0 and about 1000.0 milligrams of the active ingredient, for symptomatic adjustment of the dosage to the patient being treated. The present compound may be administered on a dosing schedule of 1 to 4 times per day, preferably once or twice per day. However, the specific dosage level and dosing frequency for any particular patient may vary and will be determined by a variety of factors including the activity of the specific compound being used, the metabolic stability and duration of action of that compound, age, body weight, health status, gender, diet, mode of administration, time of administration, excretion rate, drug combination, severity of the particular condition and the host being treated.

[0114] According to a first embodiment, the composition or medicament according to the invention described herein can be administered as the sole therapeutic agent. According to a second embodiment, the composition or medicament according to the invention described herein can be administered before, simultaneously with and / or after at least one other therapeutic agent. In one embodiment, the other therapeutic agent is suitable for treating a neurological disorder.

[0115] Another object of the present invention is a method for promoting the survival and / or function of nerve cells. Another object of the present invention is a compound or composition according to the present invention described herein for use in promoting the survival and / or function of nerve cells. According to one embodiment, the method or the use comprises contacting the nerve cells with a therapeutically effective amount of a compound, composition or drug according to the present invention described herein. The method or the use may be in vitro, ex vivo or in vivo.

[0116] Another object of the present invention is a method for rescuing the function of nerve cells after the nerve cells have been exposed to an injury, event or condition harmful to the function of nerve cells. Another object of the present invention is a compound or composition according to the present invention described herein for use in rescuing the function of nerve cells after the nerve cells have been exposed to an injury, event or condition harmful to the function of nerve cells. Such injuries, events or conditions include, but are not limited to, for example, neuronal stress caused by hypoxia or ischemia, traumatic injury and exposure to toxic molecules such as abnormally folded proteins, protein aggregates, excitotoxins, reactive oxygen species, endoplasmic reticulum stress factors, mitochondrial stress factors and Golgi antagonists. According to one embodiment, the method or the use comprises contacting the nerve cells with a therapeutically effective amount of a compound, composition or drug according to the present invention described herein. The method or the use may be in vitro, ex vivo or in vivo.

[0117] Another object of the present invention is a method for binding or modulating GFRα1 using a compound or composition according to the present invention described herein. Another object of the present invention is a compound or composition according to the present invention described herein for binding or modulating GFRα1. According to a preferred embodiment, the compound or composition is for activating GFRα1. In one embodiment, GFRα1 is preferably human GFRα1 having SEQ ID NO: 1.

[0118] Another object of the present invention is a method for activating the GFRα1 / RET signaling pathway using the compound or composition according to the present invention described herein. Another object of the present invention is the compound or composition according to the present invention described herein for activating the GFRα1 / RET signaling pathway.

[0119] Another object of the present invention is a method for detecting GFRα1 in a sample using the compound or composition according to the present invention described herein. Another object of the present invention is the compound or composition according to the present invention described herein for detecting GFRα1 in a sample. In one embodiment, 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 phosphor or any other moiety capable of re-emitting light upon photoexcitation, a radiolabel, and a contrast agent.

[0120] Manufacturing process Synthesis of the present compound The compound according to the present invention described herein may be produced using synthetic methods well known in the art.

[0121] Another object of the present invention is a process for producing the compound of the present invention described herein. According to one embodiment, this process is a backward Hartwig amination.

[0122] According to one embodiment, this process is a compound of formula (II):

Chemical formula

Chemical formula

[0123] In one embodiment, the base is cesium carbonate (Cs2CO3), sodium carbonate (Na2CO3) or potassium carbonate (K2CO3). In a specific embodiment, the base is cesium carbonate (Cs2CO3). In one embodiment, the base is sodium tert-butoxide (t-BuONa), potassium tert-butoxide (t-BuOK) or potassium phosphate. In a specific embodiment, the base is sodium tert-butoxide (t-BuONa).

[0124] In one embodiment, the catalyst is a palladium catalyst. In a specific embodiment, the catalyst is a Pd(Oac)2 and rac-BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) system. In a specific embodiment, the catalyst is Xphos-Pd-G3.

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

[0126] In one embodiment, the reaction is carried out in a solvent. In a specific embodiment, the solvent is toluene. In one embodiment, the reaction is carried out while refluxing.

[0127] According to another embodiment, the process is (a'-1) a compound of formula (II):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0128] In one embodiment, the base and / or catalyst in step (a'-1) are as described above in this specification under step (a-1). In one embodiment, X represents a halide. In a specific embodiment, X represents Br.

[0129] The protecting group may be any protecting group known in the art, such as, for example, tert-butyloxycarbonyl (Boc). The protecting group may be removed in step (a'-2) by any method known in the art suitable for the nature of the protecting group, such as, for example, the addition of a strong Bronsted acid (such as hydrochloric acid [HCl]).

[0130] The peptide coupling agent in step (a'-3) may 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).

[0131] The base in step (a'-3) may be any base known in the art, such as, for example, an amine base. According to one embodiment, the amine is triethylamine (Et3N) or diisopropylethylamine (iPr2Net).

[0132] In one embodiment, the reaction in step (a'-3) is carried out in a solvent. In a specific embodiment, the solvent is dimethylformamide (DMF) and / or tetrahydrofuran (THF). In a specific embodiment, the solvent is dichloroethane (DCE) and / or acetonitrile (MeCN). In one embodiment, the reaction is carried out at room temperature (RT).

[0133] According to another embodiment, the process is Compound of formula (III) (a’’-1):

Chem.

Chem.

Chem.

Chem.

[0134] According to another embodiment, the process comprises step (a’’-1) of reacting a compound of formula (III) with a compound of formula (VII) described above herein to obtain a compound of formula (VIII), but does not comprise step (a’’-2) of reacting the compound of formula (VIII) with chlorosulfonic acid (HSO3Cl), and Z may represent N.

[0135] In one embodiment, the base and / or catalyst in step (a’’-1) are as described above herein under step (a-1). In one embodiment, X represents a halide. In a particular embodiment, X represents Br.

[0136] The base in step (a’’-3) may be any base known in the art, such as an amine base. According to one embodiment, the amine is triethylamine (Et3N) or diisopropylethylamine (iPr2Net).

[0137] In one embodiment, the reaction of step (a’’-3) is carried out in a solvent. In a particular embodiment, the solvent is dichloromethane (DCM).

[0138] In one embodiment, the process further includes a work-up step (b). In one embodiment, the work-up step (b) includes an extraction step with a solvent. In a particular embodiment, the solvent is ethyl acetate (EtOAc). In a particular embodiment, the solvent is water or 1N HCl solution. In a particular embodiment, the solvent is dichloromethane (DCM). In one embodiment, the work-up step (b) includes a filtration step. In a particular embodiment, the filtration is by Celite®. In one embodiment, the work-up step (b) includes a concentration step under reduced pressure.

[0139] In one embodiment, the process further includes a purification step (c). In one embodiment, the purification step (c) includes 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).

[0140] Synthetic intermediate Another object of the present invention is a compound of formula (II):

Chemical formula

[0141] Another object of the present invention is a compound of formula (III):

Chemical formula

[0142] Another object of the present invention is a compound of formula (IV):

Chemical formula

[0143] Another object of the present invention is a compound of formula (V):

Chemical formula

[0144] Another object of the present invention is a compound of formula (VIII):

Chemical formula

[0145] According to a preferred embodiment, in formula (VIII) above herein, Z does not represent N.

[0146] Another object of the present invention is a compound of formula (IX): [Chemistry] (wherein, W, Z, R A ~R D 、R 1 ~R 4 、R 7 and R E are as defined below formula (I) in this specification) is.

[0147] According to a preferred embodiment, in formula (IX) above in this specification, Z does not represent N.

Examples

[0148] The present invention is further illustrated by the following examples. Example 1: Synthesis of this compound General materials and methods

[0149] Abbreviations List of abbreviations Ac: Acetyl Ar: Argon BINAP: (2,2’-Bis(diphenylphosphino)-1,1’-binaphthyl) t-Bu: tert-Butyl cHex: Cyclohexane dba: Dibenzylideneacetone DCM: Dichloromethane DCE: Dichloroethane DMF: Dimethylformamide Et: Ethyl FC: Flash chromatography JohnPhos: 2-(Di-tert-butylphosphino)biphenyl MTBE: tert-Butyldimethyl ether PTLC: Preparative thin layer chromatography RT: Room temperature TBTU: 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate TPTU: O-(2-Oxo-1(2H)-pyridyl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate TFA: Trifluoroacetic acid THF: Tetrahydrofuran XPhos: Dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane XantPhos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0150] Analysis method 1 1H NMR spectra (400 MHz) and 19 19F NMR spectra (376 MHz) were recorded using a Bruker ULTRASHIELD 400 spectrometer. Processing and analysis of these spectra were performed using MestReNova. The data are reported in the order of chemical shift (in ppm) relative to the internal solvent signal, multiplicity, coupling constant J (in Hz), and number of protons.

[0151] 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 10 (T° = 45 °C), a UV detector, and a ZQ quadrupole mass detector operating in electrospray ionization mode. The analyte compound (0.1 - 0.3 mg) was solubilized in the minimum amount of DMSO with added acetonitrile (total volume: 1 mL). Standard analytical parameters: 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 - 0 / 100 of "H2O + 0.04% v / v HCO2H (10 mM)" / ACN in 2.5 minutes. Alkaline conditions: Waters Xbridge C18 column (3.5 μm, 2.1 × 50 mm). Gradient: 95 / 5 - 0 / 100 of "H2O + 0.06% v / v NH3 (aqueous solution) (10 mM)" / ACN in 2.5 minutes.

[0152] General synthetic method General Protocol 1 (GP-1): Peptide Bonding Using TBTU TBTU was added to a DMF solution of the required carboxylic acid at room temperature. The mixture was stirred at room temperature for 15 minutes, and a THF solution of the required piperazine and Et3N was added dropwise. The mixture was stirred at room temperature for the required time. 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 obtain the required product.

[0153] General Protocol 2 (GP-2): Peptide Bonding Using TPTU (Small Scale) iPr2NEt and TPTU were added to a DCE / MeCN (1 / 1) solution of the required carboxylic acid at room temperature. After stirring at room temperature for 5 minutes, 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) or PTLC to obtain the required product.

[0154] General Protocol 3 (GP-3): Chlorosulfonylation A DCM solution of the required arene was added dropwise to chlorosulfonic acid at 0 °C. The mixture was left to warm to the required temperature and stirred at the required temperature for the required time. The reaction mixture was added dropwise onto crushed ice with stirring (highly exothermic deactivation). The remaining ice at the end of the addition was dissolved, 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 obtain the desired sulfonyl chloride.

[0155] General Protocol 4 (GP-4): Sulfonamide Formation A solution of the required sulfonyl chloride in DCM was added to a solution of the required amine and Et3N or iPr2NEt in DCM at room temperature. 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) or PTLC to afford the required product.

[0156] General Protocol 5 (GP-5): Buchwald Coupling Using Pd(OAc)2 or Pd2(dba)3 / rac-BINAP A microwave reaction vial was charged with the required aryl bromide, the required piperazine, Cs2CO3, Pd(OAc)2 or Pd2(dba)3, and rac-BINAP. The vial was flushed with argon and degassed toluene was added. The vial was sealed and stirred for the required time while refluxing in a preheated heating block. After cooling to room temperature, EtOAc was added and the suspension was filtered through Celite® (EtOAc wash). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc gradient) or PTLC to afford the required product.

[0157] General Protocol 6 (GP-6): Buchwald Coupling Using XantPhos-Pd-G3 A microwave reaction vial was charged with the required aryl bromide, the required piperazine, t-BuONa, and XantPhos-Pd-G3. The vial was flushed with argon and degassed toluene was added. The vial was sealed and stirred for the required time while refluxing in a preheated heating block. After cooling to room temperature, EtOAc was added and the suspension was filtered through Celite® (EtOAc wash). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc gradient) or PTLC to afford the required product.

[0158] General Protocol 7 (GP-7): Buchwald Coupling with 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 at 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 wash). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc gradient) or PTLC to give the required product.

[0159] Synthesis of intermediate compounds Synthesis of common intermediate piperazines tert-Butyl 3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Boc-I-001) [ka] To a solution of 2-chloro-4-fluorobenzoic acid (9.87 g, 56.5 mmol, 1.2 eq) in DMF (118 mL) at room temperature was added TBTU (18.1 g, 56.5 mmol, 1.2 eq). The mixture was stirred at room temperature for 15 minutes, and a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10.0 g, 47.1 mmol, 1 eq) and Et3N (9.8 mL, 71 mmol, 1.5 eq) in THF (118 mL) was added dropwise. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. 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 to give 21.3 g (purity 76%, 93%) of tert-butyl 3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Boc-I-001) as an orange-yellow oil. 1 H NMR (400 MHz, chloroform-d, set of two rotamers) δ 7.33 (dd, J = 8.5, 5.9 Hz, 0.5H), 7.23 - 7.09 (m, 1.5H), 7.09 - 6.97 (m, 1H), 4.54 - 4.40 (m, 1H), 4.33 (s, 1H), 4.23 - 4.01 (m, 1H), 3.56 - 3.17 (m, 1H), 3.17 - 2.93 (m, 2H), 2.11 - 1.70 (m, 4H), 1.47 (s, 9H). MS (ESI + ): [M+H] + 369.1 / 371.1.

[0160] (2-Chloro-4-fluorophenyl)-(3,8-diazabicyclo[3.2.1]octan-3-yl)methanone (I-001)

Chemical Structure

[0161] 3-[4-Fluoro-2-(trifluoromethyl)benzoyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl (Boc-I-002)

Chemical Structure

[0162] 3,8-Diazabicyclo[3.2.1]octan-3-yl-[4-fluoro-2-(trifluoromethyl)phenyl]methanone (I-002)

Chemical Structure

[0163] tert-butyl 4-(2-chloro-4-fluorobenzoyl)-2-methylpiperazine-1-carboxylate (Boc-I-003)

Chemical Structure

[0164] (2-Chloro-4-fluorophenyl)-(3-methylpiperazin-1-yl)methanone (I-003)

Chem.

[0165] tert-Butyl 3-(2-chloro-4,5-difluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Boc-I-033)

Chemical Structure

[0166] (2-Chloro-4,5-difluorophenyl)-(3,8-diazabicyclo[3.2.1]octan-3-yl)methanone (I-033)

Chemical Structure

[0167] Synthesis of the required amine tert-Butyl 4-(3-pyrazol-1-ylphenyl)piperidine-1-carboxylate (Boc-I-034)

Chemical formula

[0168] 4-(3-Pyrazol-1-ylphenyl)piperidine hydrochloride (I-034)

Chem.

[0169] 2-(4-Fluorophenyl)cyclopropanol (I-035)

Chem.

[0170] trans 4-[rac-(1R,2S)-2-(4-Fluorophenyl)cyclopropyl]piperazine-1-carboxylic acid tert-butyl (Boc-I-036)

Chemical Structure

[0171] trans 1-[rac-(1R,2S)-2-(4-fluorophenyl)cyclopropyl]piperazine (I-036)

Chemical Structure

[0172] Synthesis of the intermediate required for the final product 001 1-(2-methoxyphenyl)-2-methylpiperazine (I-004)

Chemical formula

[0173] (2-Chloro-4-fluorophenyl)-[4-(2-methoxyphenyl)-3-methylpiperazin-1-yl]methanone (I-005)

Chemical Structure

[0174] 3-[4-(2-Chloro-4-fluorobenzoyl)-2-methylpiperazin-1-yl]-4-methoxybenzenesulfonyl chloride (I-006)

Chemical Structure

[0175] Synthesis of Intermediates Required for Final Products 002 - 015 and 039 - 048 (2-Chloro-4-fluorophenyl)-[8-(2-methoxyphenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-007)

Chemical Structure

[0176] 3-[3-(2-Chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-methoxybenzenesulfonyl chloride (I-008)

Chemical Structure

[0177] Synthesis of Intermediates Required for Final Products 049 - 054 (2-Chloro-4,5-difluorophenyl)-[8-(2-methoxyphenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-038) [Chemical Structure Diagram] According to GP-5, 2-bromoanisole (1.08 mL, 8.66 mmol, 1.2 equiv), piperazine I-033 (2.07 g, 7.22 mmol, 1 equiv), Cs2CO3 (2.00 g, 14.4 mmol, 2 equiv), Pd(OAc)2 (162 mg, 722 μmol, 0.1 equiv) and rac-BINAP (670 mg, 1.08 mmol, 0.15 equiv) in toluene (34 mL) were used while refluxing for 16 h to obtain I-038 as an orange-yellow solid in 90% yield. Purification by FC (cHex / EtOAc = 95 / 5 - 40 / 60) and FC (DCM / MeOH = 99:1 - 95:5). 11H NMR (400 MHz, chloroform-d, set of two rotamers) δ 7.37 - 7.20 (m, 1.5H), 7.10 - 6.8 (m, 4.5H), 4.55 - 4.40 (m, 1H), 4.30 - 4.22 (m, 1H), 4.08 (s, 1H), 3.89 & 3.88 (s, 3H), 3.76 - 3.52 (m, 1H), 3.42 - 3.34 (m, 1H), 3.13 (t, J = 12.2 Hz, 1H), 2.15 - 1.84 (m, 3.5H), 1.65 - 1.55 (m, 0.5H). MS (ESI + ): [M+H] + 393.1 / 395.1。

[0178] 3-[3-(2-Chloro-4,5-difluorobenzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-methoxybenzenesulfonyl chloride (I-039)

Chem.

[0179] Synthesis of intermediates required for final products 055 - 060 (2-Chloro-4-fluorophenyl)-[8-(2,3-dihydrobenzofuran-7-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-040)

Chem.

[0180] 7-[3-(2-Chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,3-dihydrobenzofuran-5-sulfonyl chloride (I-041)

Chemical Structure

[0181] Synthesis of the intermediate required for the final product 061 (2-Chloro-4,5-difluorophenyl)-[8-(2,3-dihydrobenzofuran-7-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-042) [Chemical formula] According to GP-5, 7-bromo-2,3-dihydrobenzofuran (162 mg, 816 μmol, 1.2 equiv), piperazine I-033 (200 mg, 680 μmol, 1.2 equiv), Cs2CO3 (0.44 g, 1.4 mmol, 2 equiv), Pd(OAc)2 (15 mg, 68 μmol, 0.1 equiv) and rac-BINAP (51 mg, 82 μmol, 0.12 equiv) were used in toluene (3.4 mL) while refluxing for 16 h to obtain I-042 as a white solid in 33% yield. Purification by FC (cHex / EtOAc = 96 / 4 - 60 / 40). 11H NMR (400 MHz, chloroform-d, set of two rotamers) δ 7.35 - 7.17 (m, 1.5H), 7.01 - 6.93 (m, 0.5H), 6.82 - 6.75 (m, 2H), 6.60 (s, 1H), 4.55 & 4.54 (t, J = 8.8 Hz, 2H), 4.44 - 4.31 (m, 2H), 4.27 (s, 1H), 3.70 - 3.45 (m, 1H), 3.36 - 3.27 (m, 1H), 3.19 (t, J = 8.8 Hz, 2H), 3.02 (t, J = 13.6 Hz, 1H), 2.12 - 1.82 (m, 3.5H), 1.65 - 1.55 (m, 0.5H). MS (ESI + ): [M+H] + 405.1 / 407.1.

[0182] 7-[3-(2-Chloro-4,5-difluorobenzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,3-dihydrobenzofuran-5-sulfonyl chloride (I-043)

Chemical Structure

[0183] Synthesis of the Intermediate Required for the Final Product 016 3-Bromo-4-methoxy-N-methyl-N-propylbenzenesulfonamide (I-009)

Chem.

[0184] 4-Methoxy-N-methyl-N-propyl-3-[2-(trifluoromethyl)piperazin-1-yl]benzenesulfonamide (I-010)

Chem.

[0185] Synthesis of the intermediate required for the final product 017 3-(2-Ethylpiperazin-1-yl)-4-methoxy-N-methyl-N-propylbenzenesulfonamide (I-011)

Chem.

[0186] Synthesis of Intermediates Required for Final Products 018 and 019 4-Benzyl-1-(3-bromo-4-methoxyphenyl)sulfonyl-piperidine (I-012)

Chemical Structure

[0187] 1-[5-[(4-Benzyl-1-piperidyl)sulfonyl]-2-methoxyphenyl]-2-methylpiperazine (I-013)

Chemical Structure

[0188] Synthesis of the intermediate required for the final product 020 3-Bromo-N-tert-butyl-4-methoxybenzenesulfonamide (I-014)

Chem.

[0189] N-tert-butyl-4-methoxy-3-(2-methylpiperazin-1-yl)benzenesulfonamide (I-015)

Chem.

[0190] Synthesis of the intermediate required for the final product 021 4-Methoxy-N-methyl-3-(2-methylpiperazin-1-yl)-N-propylbenzenesulfonamide (I-016)

Chemical formula

[0191] Synthesis of the intermediate required for the final product 022 4-Methoxy-3-[2-(methoxymethyl)piperazin-1-yl]-N-methyl-N-propylbenzenesulfonamide (I-017)

Chemical formula

[0192] Synthesis of the intermediate required for the final product 023 4-Methoxy-N-methyl-3-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-N-propylbenzenesulfonamide (I-018)

Chemical formula

[0193] Synthesis of the intermediate required for the final product 026 3-Bromo-4-fluoro-N-methyl-N-propylbenzenesulfonamide (I-019)

Chem.

[0194] Synthesis of the intermediate required for the final product 027 3-Bromo-N-methyl-N-propyl-4-(trifluoromethoxy)benzenesulfonamide (I-020)

Chem.

[0195] Synthesis of the intermediate required for the final product 028 3-Bromo-N-methyl-N-propylbenzenesulfonamide (I-021)

Chemical formula

[0196] Synthesis of the intermediate required for the final product 029 3-Bromo-4-hydroxy-N-methyl-N-propylbenzenesulfonamide (I-022)

Chemical formula

[0197] 3-Bromo-4-ethoxy-N-methyl-N-propylbenzenesulfonamide (I-023)

Chemical Structure

[0198] Synthesis of the intermediate required for the final product 030 3-Bromo-4-(cyclobutoxy)-N-methyl-N-propylbenzenesulfonamide (I-024)

Chemical Structure

[0199] Synthesis of the intermediate required for the final product 031 3-Bromo-4-(cyclobutoxy)-N-methyl-N-propylbenzenesulfonamide and 3-bromo-4-(methoxymethoxy)-N-methyl-N-propylbenzenesulfonamide (I-025)

Chem.

[0200] Synthesis of the intermediate required for the final product 032 5-Bromo-6-chloro-N,N-diethylpyridine-3-sulfonamide (I-026)

Chem.

[0201] Synthesis of the intermediate required for the final product 033 5-Bromo-N,N-diethyl-6-methoxypyridine-3-sulfonamide (I-027)

Chemical Structure

[0202] Synthesis of the intermediate required for the final product 034 6-Benzyloxy-5-bromo-N,N-diethylpyridine-3-sulfonamide (I-028)

Chem.

[0203] Synthesis of the intermediate required for the final product 036 4-Benzyloxy-3-bromo-N-methyl-N-propylbenzenesulfonamide (I-029)

Chem.

[0204] 4-Benzyloxy-3-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-N-methyl-N-propylbenzenesulfonamide (I-030)

Chemical Structure

[0205] Synthesis of the intermediate required for the final product 037 (2-Chloro-4-fluorophenyl)-[8-[5-(3-hydroxypyrrolidin-1-yl)sulfonyl-2-methoxyphenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-031)

Chemical Structure

[0206] Synthesis of the intermediate required for the final product 038 3-[4-(2-Chloro-4-fluorobenzoyl)-2-methylpiperazin-1-yl]-N-(3-fluoropropyl)-4-methoxybenzenesulfonamide (I-032)

Chemical Structure

[0207] Synthesis of the intermediate required for final products 046 - 048 4-[3-[3-(2-Chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-methoxyphenyl]sulfonylpiperazine-1-carboxylic acid tert-butyl (Boc-I-037)

Chemical Structure

[0208] (2-Chloro-4-fluorophenyl)-[8-(2-methoxy-5-piperazin-1-ylsulfonylphenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-037)

Chemical Structure

[0209] Synthesis of the intermediate required for the final product 062 1-(3-Bromo-4-methoxyphenyl)sulfonyl-4-(2-phenylethyl)piperidine (I-044)

Chemical Structure

[0210] 1-[3-Bromo-4-(methoxymethoxy)phenyl]sulfonyl-4-(2-phenylethyl)piperidine (I-045)

Chemical Structure

[0211] (2-Chloro-4-fluorophenyl)-[8-[2-(methoxymethoxy)-5-[[4-(2-phenylethyl)-1-piperidyl]sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-046)

Chem.

[0212] Synthesis of the intermediate required for the final product 063 1-(3-Bromo-4-methoxyphenyl)sulfonyl-4-phenylpiperidine (I-047) [Chemical formula] According to GP-4, 3-bromo-4-methoxybenzenesulfonyl chloride (1.50 g, 5.25 mmol, 1 equivalent), 4-phenylpiperidine (1.02 g, 6.30 mmol, 1.2 equivalents), and Et3N (1.1 mL, 7.9 mmol, 1.5 equivalents) in DCM (10 mL) were used at room temperature for 2 hours to obtain I-047 as a white solid in 99% yield. 11H NMR (400 MHz, chloroform-d) δ 8.00 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 8.6, 2.2 Hz, 1H), 7.40 - 7.27 (m, 2H), 7.27 - 7.19 (m, 1H), 7.19 - 7.14 (m, 2H), 7.03 (d, J = 8.7 Hz, 1H), 4.01 (s, 3H), 3.98 - 3.89 (m, 2H), 2.62 - 2.32 (m, 3H), 2.01 - 1.73 (m, 4H). MS (ESI + ): [M+H] + 410.0 / 412.0。

[0213] 1-[3-Bromo-4-(methoxymethoxy)phenyl]sulfonyl-4-phenylpiperidine (I-048)

Chemical Structure

[0214] (2-Chloro-4-fluorophenyl)-[8-[2-(methoxymethoxy)-5-[(4-phenyl-1-piperidyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-049)

Chemical Structure

[0215] Synthesis of the intermediate required for the final product 064 2-Bromo-4-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-phenol (I-050)

Chem.

[0216] 1-[3-Bromo-4-(methoxymethoxy)phenyl]sulfonyl-4-[2-(4-chlorophenyl)ethyl]piperazine (I-051)

Chem.

[0217] (2-Chloro-4-fluorophenyl)-[8-[5-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-2-(methoxymethoxy)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-052)

Chemical Structure

[0218] Synthesis of the intermediate required for the final product 065 1-(3-Bromo-4-methoxyphenyl)sulfonyl-4-(4-fluorophenyl)piperidine (I-053)

Chemical Structure

[0219] 2-Bromo-4-[[4-(4-fluorophenyl)-1-piperidyl]sulfonyl]phenol (I-054)

Chem.

[0220] 1-[3-Bromo-4-(methoxymethoxy)phenyl]sulfonyl-4-(4-fluorophenyl)piperidine (I-055)

Chem.

[0221] (2-Chloro-4-fluorophenyl)-[8-[5-[[4-(4-fluorophenyl)-1-piperidyl]sulfonyl]-2-(methoxymethoxy)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-056)

Chemical Structure

[0222] Synthesis of the intermediate required for the final product 066 1-(3-Bromo-4-chloro-phenyl)sulfonyl-4-phenylpiperidine (I-057) [Chemical Structure Diagram] According to GP-4, commercially available 3-bromo-4-chlorobenzenesulfonyl chloride (200 mg, 690 μmol, 1 equiv), 4-phenylpiperidine (122 mg, 759 μmol, 1.1 equiv), and Et3N (144 μL, 1.03 mmol, 1.5 equiv) in DCM (3.4 mL) were used at room temperature for 16 h to obtain I-057 as a white solid in 58% yield. Purification by FC (cHex / EtOAc = 97 / 3 - 70 / 30). 1 1H NMR (400 MHz, chloroform-d) δ 8.07 (d, J = 2.0 Hz, 1H), 7.73 - 7.61 (m, 2H), 7.38 - 7.30 (m, 2H), 7.27 - 7.21 (m, 1H), 7.21 - 7.14 (m, 2H), 4.06 - 3.89 (m, 2H), 2.59 - 2.34 (m, 3H), 2.03 - 1.77 (m, 4H). MS (ESI + ): [M + H] + 414.0 / 416.0 / 418.0.

[0223] Synthesis of the intermediate required for the final product 067 1-(3-Bromo-4-methylphenyl)sulfonyl-4-phenylpiperidine (I-058)

Chem.

[0224] Synthesis of the intermediate required for the final product 068 3-Bromo-N,4-dimethyl-N-propylbenzenesulfonamide (I-059)

Chem.

[0225] Synthesis of the intermediate required for the final product 069 Methyl 2-bromo-4-[(4-phenyl-1-piperidyl)sulfonyl]benzoate (I-060)

Chemical Structure

[0226] Synthesis of the intermediate required for the final product 074 3-Bromo-5-chloro-4-methyl-aniline (I-061)

Chemical Structure

[0227] 3-Bromo-5-chloro-4-methylbenzenesulfonyl chloride (I-062)

Chemical formula

[0228] 3-Bromo-N-tert-butyl-5-chloro-4-methylbenzenesulfonamide (I-063)

Chem.

[0229] Synthesis of the intermediate required for the final product 075 3-Bromo-4,5-dichlorobenzenesulfonyl chloride (I-064)

Chem.

[0230] 3-Bromo-N-tert-butyl-4,5-dichloro-benzenesulfonamide (I-065)

Chemical formula

[0231] Synthesis of the intermediate required for the final product 079 [2-[3-(2-Chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-[methyl(propyl)sulfamoyl]phenyl]trifluoromethanesulfonate (I-066)

Chemical formula

[0232] Synthesis of intermediates required for final products 080 & 81 [2-[3-(2-Chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-[(4-phenyl-1-piperidyl)sulfonyl]phenyl]trifluoromethanesulfonate (I-067) [Chemical Structure] To a solution of 063 (100 mg, 171 μmol, 1 equiv) in dry DCM (1.7 mL) at 0 °C were added Et3N (0.12 mL, 0.86 mmol, 5 equiv) and Tf2O (0.060 mL, 0.34 mmol, 2 equiv). The mixture was stirred at room temperature for 2 h. Saturated aqueous NH4Cl and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (with water, brine), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by FC (cHex / EtOAc = 96 / 4 to 60 / 40) to give 115 mg (94%) of I-067 as a yellow foam. 1 H NMR (400 MHz, chloroform-d, set of two rotamers) δ 7.46 - 7.33 (m, 3.5H), 7.33 - 7.27 (m, 2H), 7.24 - 7.18 (m, 2H), 7.18 - 7.11 (m, 2.5H), 7.12 - 7.02 (m, 1H), 4.60 & 4.56 (s, 1H), 4.23 - 4.12 (m, 1H), 3.98 - 3.85 (m, 3H), 3.77 & 3.61 (d, J = 12.5 Hz, 1H), 3.36 & 3.33 (s, 1H), 3.18 (d, J = 12.5 Hz, 1H), 2.52 - 2.37 (m, 3H), 2.10 - 1.74 (m, 7.5H), 1.73 - 1.62 (m, 0.5H). 19 F NMR (376 MHz, chloroform-d, set of two rotamers) δ -73.78, -73.81, -108.9, -109.1. MS (ESI + ): [M + H] + 716.2 / 718.2.

[0233] Synthesis of the intermediate required for the final product 083 3-Bromo-5-fluoro-4-hydroxybenzenesulfonyl chloride (I-068)

Chemical Structure

[0234] 2-Bromo-6-fluoro-4-[(4-phenyl-1-piperidyl)sulfonyl]phenol (I-069)

Chemical formula

[0235] 1-[3-Bromo-5-fluoro-4-(methoxymethoxy)phenyl]sulfonyl-4-phenylpiperidine (I-070)

Chemical formula

[0236] (2-Chloro-4-fluorophenyl)-[8-[3-fluoro-2-(methoxymethoxy)-5-[(4-phenyl-1-piperidyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-071)

Chemical Structure

[0237] Synthesis of intermediates required for final products 084 - 86 1-Bromo-3-fluoro-2-(methoxymethoxy)benzene (I-072)

Chemical Structure

[0238] (2-Chloro-4-fluorophenyl)-[8-[3-fluoro-2-(methoxymethoxy)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-073) [Chemical formula] According to GP-5, aryl bromide I-072 (920 mg, 3.91 mmol, 1 equiv), piperazine I-001 (1.16 g, 4.31 mmol, 1.1 equiv), Cs2CO3 (3.82 g, 11.7 mmol, 3 equiv), Pd(OAc)2 (87.9 mg, 391 μmol, 0.1 equiv) and rac-BINAP (292 mg, 470 μmol, 0.12 equiv) in toluene (20 mL) were used while refluxing for 16 hours to obtain I-073 as white foam in a yield of 73%. Purification by FC (cHex / EtOAc = 92 / 8~20 / 80). 11H NMR (400 MHz, chloroform-d, set of two rotamers) δ 7.36 (dd, J = 8.5, 5.9 Hz, 0.5H), 7.24 - 6.99 (m, 2.5H), 6.97 - 6.88 (m, 1H), 6.74 - 6.66 (m, 1H), 6.58 (dd, J = 8.2, 4.0 Hz, 1H), 5.17 - 5.10 (m, 2H), 4.55 - 4.45 (m, 1H), 4.28 (d, J = 6.4 Hz, 1H), 4.15 - 4.08 (m, 1H), 3.65 - 3.40 (m, 4H), 3.27 & 3.24 (m, 1H), 3.16 - 3.06 (m, 1H), 2.06 - 1.82 (m, 3.5H), 1.65 - 1.55 (m, 0.5H). 19 19F NMR (376 MHz, chloroform-d, set of two rotamers) δ -109.3, -109.4, -129.2, -129.3. MS (ESI + ): [M+H] + 423.1 / 425.1.

[0239] (2-Chloro-4-fluorophenyl)-[8-(3-fluoro-2-hydroxyphenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-074)

Chemical Structure

[0240] 3-[3-(2-Chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-fluoro-4-hydroxybenzenesulfonyl chloride (I-075)

Chemical Structure

[0241] Synthesis of intermediates required for final products 087 - 89 1-Bromo-2-(methoxymethoxy)-3-(trifluoromethyl)benzene (I-076)

Chemical Structure

[0242] (2-Chloro-4-fluorophenyl)-[8-[2-(methoxymethoxy)-3-(trifluoromethyl)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-077)

Chemical Structure

[0243] (2-Chloro-4-fluorophenyl)-[8-[2-hydroxy-3-(trifluoromethyl)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-078)

Chemical Structure

[0244] 3-[3-(2-Chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-hydroxy-5-(trifluoromethyl)benzenesulfonyl chloride (I-079)

Chemical Structure

[0245] Synthesis of the intermediate required for the final product 090 3-Bromo-4-hydroxy-5-methylbenzenesulfonyl chloride (I-080)

Chemical formula

[0246] 2-Bromo-6-methyl-4-[(4-phenyl-1-piperidyl)sulfonyl]phenol (I-081)

Chemical formula

[0247] 1-[3-Bromo-4-(methoxymethoxy)-5-methylphenyl]sulfonyl-4-phenylpiperidine (I-082)

Chemical Structure

[0248] (2-Chloro-4-fluorophenyl)-[8-[2-(methoxymethoxy)-3-methyl-5-[(4-phenyl-1-piperidyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-083)

Chemical Structure

[0249] Synthesis of intermediates required for final products 091 - 93 1 - Bromo - 2 - (methoxymethoxy) - 3 - methylbenzene (I - 084)

Chem.

[0250] (2 - Chloro - 4 - fluorophenyl) - [8 - [2 - (methoxymethoxy) - 3 - methylphenyl] - 3,8 - diazabicyclo[3.2.1]octan - 3 - yl]methanone (I - 085)

Chem.

[0251] (2-Chloro-4-fluorophenyl)-[8-(2-hydroxy-3-methylphenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-086)

Chemical Structure

[0252] 3-[3-(2-Chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-hydroxy-5-methylbenzenesulfonyl chloride (I-087)

Chemical Structure

[0253] Synthesis of the Intermediate Required for the Final Product 094 1-Bromo-3-ethyl-2-(methoxymethoxy)benzene (I-088)

Chem.

[0254] (2-Chloro-4-fluorophenyl)-[8-[3-ethyl-2-(methoxymethoxy)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-089)

Chem.

[0255] (2-Chloro-4-fluorophenyl)-[8-(3-ethyl-2-hydroxyphenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-090)

Chemical Structure

[0256] 3-[3-(2-Chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-ethyl-4-hydroxybenzenesulfonyl chloride (I-091)

Chemical Structure

[0257] Synthesis of Intermediates Required for Final Products 095 - 109 1 - Bromo - 3 - chloro - 2 - (methoxymethoxy)benzene (I - 092)

Chem.

[0258] (2 - Chloro - 4 - fluorophenyl)-[8 - [3 - chloro - 2 - (methoxymethoxy)phenyl]-3,8 - diazabicyclo[3.2.1]octan - 3 - yl]methanone (I - 093)

Chem.

[0259] (2-Chloro-4-fluorophenyl)-[8-(3-chloro-2-hydroxyphenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-094)

Chemical Structure

[0260] 3-Chloro-5-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-hydroxybenzenesulfonyl chloride (I-095)

Chemical Structure

[0261] Synthesis of the intermediate required for the final product 110 (2-Chloro-4-fluorophenyl)-[(3S)-4-[3-chloro-2-(methoxymethoxy)phenyl]-3-methylpiperazin-1-yl]methanone ((S)-I-096) [Chemical formula] According to GP-5, aryl bromide I-092 (0.41 g, 1.63 mmol, 1 equivalent), piperazine (S)-I-003 (502 mg, 1.96 mmol, 1.2 equivalents), Cs2CO3 (4.66 g, 4.89 mmol, 3 equivalents), Pd(OAc)2 (36.6 mg, 163 μmol, 0.1 equivalent) and rac-BINAP (122 mg, 196 μmol, 0.12 equivalents) in toluene (8.2 mL) were used with reflux for 6 hours to obtain (S)-I-096 as white foam in a 4% yield. Purification by FC (cHex / EtOAc = 94 / 6~40 / 60) and PTLC (cHex / EtOAc = 70 / 30). 1 1H NMR (400 MHz, chloroform-d, set of multiple rotational isomers) δ 7.27 - 7.20 (m, 1H), 7.16 - 6.88 (m, 4H), 6.88 - 6.73 (m, 1H), 5.26 - 5.18 (m, 2H), 5.17 - 5.10 (m, 1H), 4.17 - 3.81 (m, 1H), 3.80 - 3.50 (m, 4H), 3.48 - 2.95 (m, 3H), 2.87 - 2.50 (m, 1H), 1.02 - 0.70 (m, 3H). 19 19F NMR (376 MHz, chloroform-d, set of multiple rotational isomers) δ -109.17, -109.20, -109.24, -109.27. MS (ESI + ): [M+H] + 427.0 / 429.0 / 431.0.

[0262] (2-Chloro-4-fluorophenyl)-[(3S)-4-(3-chloro-2-hydroxyphenyl)-3-methylpiperazin-1-yl]methanone ((S)-I-097)

Chem.

[0263] 3-Chloro-5-[(2S)-4-(2-chloro-4-fluorobenzoyl)-2-methylpiperazin-1-yl]-4-hydroxybenzenesulfonyl chloride ((S)-I-098)

Chem.

[0264] Synthesis of the intermediate required for the final product 111 3-Chloro-5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-methylpiperazin-1-yl]-4-hydroxybenzenesulfonyl chloride ((R)-I-098) (R)-I-098 was obtained using the same synthetic procedure except for one procedure used for (S)-I-098 starting from (R)-I-003. 1 1H NMR (400 MHz, chloroform-d, set of multiple rotational isomers) δ 7.90 - 7.86 (m, 1H), 7.66 - 7.62 (m, 1H), 7.36 - 7.08 (m, 3H), 7.08 - 6.98 (m, 1H), 4.82 - 4.54 (m, 1H), 3.50 - 2.72 (m, 6H), 0.95 - 0.65 (m, 3H). 19 19F NMR (376 MHz, chloroform-d, set of multiple rotational isomers) δ -108.40, -108.46, -108.49, -108.53.

[0265] Synthesis of the intermediate required for the final product 115 3-Bromo-4-chloro-N-methyl-N-propylbenzenesulfonamide (I-099) [Chemical formula] According to GP-4, commercially available 3-bromo-4-chlorobenzenesulfonyl chloride (300 mg, 1.03 mmol, 1 equiv), methyl-N-propylamine (120 μL, 1.14 mmol, 1.1 equiv) and Et3N (216 μL, 2.55 mmol, 1.5 equiv) in DCM (5 mL) were used at room temperature for 16 h to obtain I-099 as a white solid in 89% yield. 1 H NMR (400 MHz, chloroform-d) δ 8.04 (d, J = 2.0 Hz, 1H), 7.66 (dd, J = 8.4, 2.0 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 3.00 (dd, J = 7.9, 6.6 Hz, 2H), 2.76 (s, 3H), 1.59 (h, J = 7.3 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). MS (ESI + ): [M + H] + 326.0 / 328.0 / 329.9.

[0266] Synthesis of the intermediate required for the final product 116 1-(3-Bromo-4-methylphenyl)sulfonyl-4-[2-(4-fluorophenyl)ethyl]piperazine (I-100)

Chemical formula

[0267] Synthesis of the intermediate required for the final product 117 [8-(1,3-Benzodioxol-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluorophenyl)methanone (I-101)

Chemical Structure

[0268] 7-[3-(2-Chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-1,3-benzodioxole-5-sulfonyl chloride (I-102)

Chem.

[0269] Synthesis of the intermediate required for the final product 118 1-[(5-Bromo-2,3-dihydro-1,4-benzodioxin-7-yl)sulfonyl]-4-phenylpiperidine (I-103)

Chem.

[0270] Synthesis of intermediates required for final products 119&120 1-[5-[(4-Phenyl-1-piperidyl)sulfonyl]indolin-1-yl]ethanone (I-104)

Chemical formula

[0271] 5-[(4-Phenyl-1-piperidyl)sulfonyl]indoline (I-105)

Chem.

[0272] 1-Methyl-5-[(4-phenyl-1-piperidyl)sulfonyl]indoline (I-106)

Chem.

[0273] 7-Bromo-1-methyl-5-[(4-phenyl-1-piperidyl)sulfonyl]indoline (I-107)

Chemical Structure

[0274] Synthesis of the intermediate required for the final product 121 1-(3-Bromo-4-fluorophenyl)sulfonyl-4-phenylpiperidine (I-108)

Chemical Structure

[0275] 2-Bromo-N,N-dimethyl-4-[(4-phenyl-1-piperidyl)sulfonyl]aniline (I-109)

Chemical Structure

[0276] Synthesis of the Intermediate Required for the Final Product 122 8-[2-Fluoro-5-[(4-phenyl-1-piperidyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl (I-110)

Chemical Structure

[0277] 8-[2-(Dimethylamino)-5-[(4-phenyl-1-piperidyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl (I-111)

Chemical Structure

[0278] Synthesis of the Intermediate Required for the Final Product 123 tert-Butyl N-[1-[2-bromo-4-[(4-phenyl-1-piperidyl)sulfonyl]phenyl]azetidin-3-yl]-N-methyl-carbamate (I-112)

Chemical Structure

[0279] tert-Butyl N-[1-[2-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-[(4-phenyl-1-piperidyl)sulfonyl]phenyl]azetidin-3-yl]-N-methyl-carbamate (I-113)

Chemical Structure

[0280] Synthesis of the intermediate required for the final product 124 3,5-Dibromo-4-methylbenzenesulfonyl chloride (I-114)

Chemical Structure

[0281] 1-(3,5-Dibromo-4-methylphenyl)sulfonyl-4-phenylpiperidine (I-115)

Chemical formula

[0282] 3-Bromo-2-methyl-5-[(4-phenyl-1-piperidyl)sulfonyl]phenol (I-116)

Chem.

[0283] 1-[3-Bromo-5-(methoxymethoxy)-4-methylphenyl]sulfonyl-4-phenylpiperidine (I-117)

Chem.

[0284] (2-Chloro-4-fluorophenyl)-[8-[3-(methoxymethoxy)-2-methyl-5-[(4-phenyl-1-piperidyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-118)

Chemical Structure

[0285] Synthesis of the intermediate required for the final product 125 3-Bromo-4-cyanobenzenesulfonyl chloride (I-119) [Chemical formula] Thionyl chloride (5.9 mL, 81 mmol, 8 equivalents) was added dropwise to an aqueous solution of CuCl (121 mg, 1.22 mmol, 0.12 equivalent) at 0 °C. The mixture was stirred at room temperature for 14 hours. During that time, an aqueous solution of 37% HCl (37 mL) and an aqueous solution of NaNO2 (770 mg, 11.2 mmol, 1.1 equivalents) were added to an aqueous solution of 4-amino-2-bromobenzonitrile (2.00 g, 10.1 mmol, 1 equivalent) at 0 °C. The mixture was stirred at 0 °C for 30 minutes. Then, the first solution was added dropwise, and the resulting mixture was stirred vigorously at room temperature for 1 hour. It was filtered through a fritted glass, and the filter cake was washed with water. The filter cake was dissolved in DCM, and the resulting wet organic solution was dried (Na2SO4), filtered, and concentrated under reduced pressure to obtain 2.5 g (88%) of I-119 as an orange-yellow solid. 1 1H NMR (400 MHz, chloroform-d) δ 8.16 δ 7.67 (d, J = 1.8 Hz, 1H), 7.42 (dd, J = 8.3, 1.9 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H).

[0286] 2-Bromo-4-[(4-phenyl-1-piperidyl)sulfonyl]benzonitrile (I-120)

Chem.

[0287] Synthesis of the intermediate required for the final product 139 3-Bromo-1-chloro-4-fluoro-2-(methoxymethoxy)benzene (I-121)

Chem.

[0288] [8-[3-Chloro-6-fluoro-2-(methoxymethoxy)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluorophenyl)methanone (I-122)

Chemical Structure

[0289] [8-(3-Chloro-6-fluoro-2-hydroxyphenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluorophenyl)methanone (I-123)

Chem.

[0290] 5-Chloro-3-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-4-hydroxybenzenesulfonyl chloride (I-124)

Chem.

[0291] Synthesis of the final compound Synthesis method for the final compound The synthesis protocol for the final compound is shown in Table 2 below.

Table 2

[0292] Analysis data of the final compound The analysis data of the final compound is shown in Table 3 below.

Table 3

[0293] Example 2: Biological Activity of This Compound The purpose of this experiment was to evaluate the GFRα1-RET activities of Compounds 001 to 139 according to the present invention.

[0294] Materials and Methods These compounds were tested for their ability to activate Elk1 signaling using a previously developed reporter gene-based system in cells expressing GFRα1-RET (MG87 murine fibroblasts stably transfected with PathDetect Elk-1, GFRα1, and RET, as disclosed in Sidorova, Y.A. 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 50 To determine EC 50 , dose-response experiments were performed using six concentrations of each test compound. Dose-response curves were fitted using sigmoid dose-response (variable slope) analysis in the GraphPad Prism program (GraphPad), and the EC

[0295] Results These results are shown in Table 4 below (* means "50 μM > EC 50 > 10 μM", ** means "1 μM ≤ EC 50 ≤ 10 μM", and *** means "EC 50 < 1 μM").

Table 4

[0296] The above results clearly demonstrate that test compounds 001 to 139 have significant GFRα1-RET activity. Therefore, the compounds of the present invention are useful as neuroprotective agents and nerve repair agents. Test compounds 001 to 139 sufficiently represent the class of compounds of formula (I).

Claims

1. A compound of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt and / or solvate thereof (wherein, W represents CH or N, R Ａ 、 R Ｂ 、 R Ｃ and R Ｄ under the condition that at least one of them does not represent hydrogen, R Ａ 、 R Ｂ 、 R Ｃ and R Ｄ each independently represents hydrogen, F, Cl, CH ３ 、 CF ３ 、 CHF ２ or CH ２ F, R １ represents (C １ -C ８ ) alkyl, wherein said alkyl is optionally substituted by at least one OH, (C １ -C ３ ) alkoxy or F, and R ２ , R ３ and R ４ represent hydrogen, or R １ and R ４ together form -CH ２ -O-CH ２ - or -CH ２ -CH ２ - to form, said -CH ２ -CH ２ - is optionally substituted by at least one F, OH or OCH ３ and R ２ and R ３ each represent hydrogen, R ７ represents hydrogen, OH, halogen, (C １ ~C ８ )-alkyl, cycloalkyl, (C １ ~C ８ )-alkyl-O-, cycloalkyl-O-, cycloalkyl-(C １ ~C ８ )-alkyl-O-, heterocycloalkyl-O-, R １１ O-(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 , CN, CO ２ H, CO ２ R １１ , CONH ２ , CON(R １１ )H, heterocycloalkyl or heteroaryl, wherein R １１ and R １２ each independently represent hydrogen or (C １ ~C ８ )-alkyl, R ７ The alkyl or cycloalkyl therein is optionally substituted by at least one F, Cl, OH, =O, (C １ ~C ８ -C １ ~C ８ -C)alkyl, (C The heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, (C １ -C ８ ) alkyl, CF ３ , CHF ２ , CH 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 -, wherein R １３ and R １４ each independently represent hydrogen or (C １ -C ８ ) alkyl, Z represents C-H, C-R ８ or N, and In the formula, R ８ represents (C １ to C ４ ) alkyl, F, Cl, CF ３ , CHF ２ , CH ２ F, OCF ３ , CN, OH or (C １ to C ４ ) alkoxy, or Z is C—R ８ and R ７ and R ８ together with the carbon atom to which they are attached form cycloalkyl or heterocycloalkyl, The cycloalkyl or heterocycloalkyl is optionally substituted by at least one F, OH, ═O, →O, (C １ -C ８ )alkyl, CF ３ , HO ２ C-CH ２ -, (C １ -C ４ )alkyl-CO ２ -CH ２ -, R １５ R １６ N-CH ２ (C １ -C ８ )alkyl-, aryl or aryl-(C １５ and R １６ each independently represent hydrogen or (C １ -C ８ )alkyl, R ５ represents hydrogen, (C １ -C ８ )alkyl, CH substituted by 1 to 3 (C １ -C ８ )alkyl groups, cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C ３ )alkyl, １ -C ８ ), In the formula, R ５ The alkyl or cycloalkyl in is optionally substituted by at least one F, Cl, (C １ ~C ８ )alkyl, CF ３ , OCF ３ , CN, OH, =O, (C １ ~C ８ )alkoxy, NR １７ R １８ , CO ２ H, R １７ R １８ N-C(O)-, R １７ O-NR １８ -, heterocycloalkyl, aryl or heteroaryl, and in the formula, R １７ and R １８ each independently represent hydrogen or (C １ ~C ８ )alkyl, The heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, (C １ ~C ８ )alkyl, CF ３ , CHF ２ , CH ２ F, OCF ３ , CN, OH, =O, →O, (C １ ~C ８ )alkoxy, NR １９ R ２０ , CO ２ H, R １９ R ２０ N-C(O)-, R １９ O-NR ２０ -, (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 )alkyl-, wherein R １９ and R ２０ each independently represent hydrogen or (C １ ~C ８ )alkyl, R ６ is (C １ ~C ８ ) alkyl, CH １ substituted by 1 to 3 (C ８ ) alkyl groups, cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C ３ ~C １ ) alkyl, and ８ represents R ６ The alkyl or cycloalkyl in is optionally substituted by at least one F, Cl, (C １ -C ８ )alkyl, CF ３ , OCF ３ , CN, OH, =O, (C １ -C ８ )alkoxy, NR ２１ R ２２ , CO ２ H, R ２１ R ２２ N-C(O)-, R ２１ O-NR ２２ -, heterocycloalkyl, aryl or heteroaryl, wherein R ２１ and R ２２ each independently represent hydrogen or (C １ -C ８ )alkyl, The heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, (C １ ~C ８ )alkyl, CF ３ , CHF ２ , CH 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 )alkyl, wherein R ２３ and R ２４ each independently represent hydrogen or (C １ ~C ８ )alkyl, or R ５ and R ６ together with the nitrogen atom to which they are attached form a heterocycloalkyl The heterocycloalkyl is 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 to C ８ )alkyl-NR ２５ - heterocycloalkyl-(C １ to C ８ )alkyl-NR ２５ - aryl-(C １ to C ８ )alkyl-NR ２５ - heteroaryl-(C １ to C ８ )alkyl-NR ２５ - benzylidene, heteroarylidene, aryl-(C １ to C ８ )alkyl-iden- or heteroaryl-(C １ to C ８ )alkyl-iden- optionally substituted by, wherein, R ２５ and R ２６ each independently represents hydrogen or (C １ ~C ８ ) alkyl, The heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylidene is optionally substituted by at least one F, Cl, (C １ -C ８ )alkyl, CF ３ , CHF ２ , CH 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 )alkyl-, wherein R ２７ and R ２８ each independently represent hydrogen or (C １ -C ８ )alkyl, and R Ｅ represents hydrogen, (C １ to C ３ ) alkyl or halogen).

2. R Ａ 、 R Ｂ 、 R Ｃ and R Ｄ at least one of which represents hydrogen, preferably R Ａ and R Ｃ at least one of which represents hydrogen, more preferably R Ｃ represents hydrogen, and / or R Ｅ represents hydrogen, the compound according to claim 1.

3. R Ａ , R Ｂ and R Ｄ at least one of which represents F or Cl, preferably R Ｂ and R Ｄ at least one of which represents F or Cl, more preferably R Ｂ and R Ｄ each independently represents F or Cl, the compound according to claim 1 or claim 2.

4. R １ and R ４ together form -CH ２ -O-CH ２ - or -CH ２ -CH ２ to form, preferably R １ and R ４ together form -CH ２ -CH ２ - to form, wherein the -CH ２ -CH ２ - is optionally substituted by at least one F, OH or OCH ３ The compound according to any one of claims 1 to 3.

5. R １ is methyl, ethyl, CF ３ or CH ３ OCH ２ -, a compound according to any one of claims 1 to 4.

6. R ７ represents hydrogen, OH or halogen, or R ７ (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 are F, Cl, OCH ３ , OCH ２ CH ３ , OCF ３ , cyclobutyl-O-, HO-CH ２ -CH ２ -O-, CH ３ O-CH ２ -CH ２ —O—, phenyl-CH ２ -O-, 1H-imidazol-4-yl-, 1-methyl-imidazol-4-yl-, CH ３ , C.N., C.O. ２ H, CH ２ OH, C(CH ３ ) ２ OH, CH ２ N (CH ３ ) ２ , cyclopropyl, cyclobutyl-O-, (4-pyridine)-CH ２ —O—, (3-pyridine)-CH ２ The compound according to any one of claims 1 to 5, wherein the aryl group represents -O- or benzyl-O-.

7. Z is C-R ８ represents, and R ８ is (C １ to C ４ ) alkyl, F, Cl, CF ３ , CHF ２ , CH ２ F, OCF ３ , CN, OH or (C １ to C ４ ) alkoxy, preferably R ８ is methyl, ethyl, F, Cl, CF ３ , CN or OH, and the compound according to any one of claims 1 to 6.

8. Z is C-R ８ represents, and R ７ and R ８ together with the carbon atom to which they are attached form a heterocycloalkyl, said heterocycloalkyl being optionally substituted by at least one F, OH, =O, (C １ to C ８ )alkyl, CF ３ , HO ２ C-CH ２ -, (C １ to C ４ )alkyl-CO ２ -CH ２ - or R １５ R １６ N-CH ２ -, and R １５ and R １６ each independently represent hydrogen or (C １ to C ８ )alkyl, a compound according to any one of claims 1 to 6.

9. R ５ represents hydrogen or (C １ ~C ８ ) alkyl, preferably R ５ represents hydrogen, methyl or ethyl, and / or R ６ is (C １ ~C ８ ) alkyl, cycloalkyl, cycloalkyl-(C １ ~C ８ ) alkyl- or heterocycloalkyl, and the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by at least one F, CN or CF ３ , preferably R ６ is methyl, ethyl, i-propyl, n-propyl, isobutyronitrile, 3-fluoro-n-propane, tert-butyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, 1-methylcyclobutyl, cyclopropyl-CH ２ -, (CN)(Me) ２ C-, (F ３ C)C(Me) ２ -, 3-methyloxetan-3-yl or oxetan-3-yl, and the compound according to any one of claims 1 to 8

10. R ５ and R ６ together with the nitrogen atom to which they are attached form a heterocycloalkyl, said heterocycloalkyl being optionally substituted by at least one F, preferably R ５ and R ６ together with the nitrogen atom to which they are attached form pyrrolidine, 3,3-dimethylmorpholine, 4-fluoropiperidine, 3-fluoropyrrolidine, 4-trifluoromethylpiperidine, 4-benzylpiperidine, 3-benzylpyrrolidine, 3-benzylpiperidine, 4-phenylpiperidine, 4-(4-fluorophenyl)piperidine, 4-benzylidenepiperidine, octahydro-1H-isoindole, 3-(benzyloxy)pyrrolidine, 3-phenoxypyrrolidine, N-methyl-N-phenylpyrrolidin-3-amine, 2-azabicyclo[2.2.1]heptane, 5-(4-methylpiperazin-1-yl)pyrimidine, 4-phenethylpiperidine, phenylpiperazine, 4-benzylpiperazine, 3-(4-piperidyl)benzonitrile, methyl 3-(4-piperidyl)benzoate, methyl 4-(4-piperidyl)benzoate, 4-(3-pyrazol-1-ylphenyl)piperidine, 1-[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]piperazine, 1-[2-(4-fluorophenyl)propyl]piperazine, 1-[2-(4-fluorophenyl)ethyl]piperazine, 1-[2-(4-chlorophenyl)ethyl]piperazine, 1-(2-phenylpropyl)piperazine or 1-(4-fluorophenyl)-2-piperazin-1-yl-ethanol, a compound according to any one of claims 1 to 8.

11. The compound is as follows: 【Table 1】 and a pharmaceutically acceptable salt and / or solvate thereof, and the compound according to any one of Claims 1 to 10, which is selected from

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

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

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

15. A process for producing the compound according to any one of Claims 1 to 11, the process comprising a compound of formula (II): 【Chemical 2】 (wherein, Z, R ５ , R ６ , R ７ and R Ｅ are as defined in claim 1, and X represents a halide or -CF ３ SO ３ (wherein it represents) reacting with a compound of formula (III) in the presence of a base and a metal catalyst: 【Chemical Formula 3】 (wherein W, R Ａ ~R Ｄ and R １ ~R ４ are as defined in claim 1) to obtain a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof A process comprising.

Images