[4-[5-(methylsulfonyl)-phenyl] piperazin-1-yl]-(phenyl) methanone derivatives and similar compounds having GFR [alpha] 1-yl]-(phenyl) methanone activity as neuroprotective agents for treatment of neurological disorders

Abstract

The present invention relates to compounds of general formula (I). The invention also relates to the compounds of the invention as neuroprotective and / or neurorepair agents, in particular for use in the treatment of neurological disorders such as central nervous system (CNS) disease, Alzheimer's disease (AD), Parkinson's disease (RD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), dementia, stroke, head trauma, brain tumors, pain and epilepsy. The compound provided by the invention shows GFR (Growth Factor Receptor) alpha 1-RET activity in a luciferase test. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to novel polycyclic sulfones. The compounds of the present invention are suitable for use as neuroprotective agents and / or neurorepairing agents, in particular for the treatment of neurological disorders. Background Art

[0002] Neurological disorders (NDs) are heterogeneous diseases that affect the autonomic nervous system, peripheral peripheral nervous system, and central nervous system 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 have been the most challenging diseases to address. The activity of compounds used to treat the CNS may also be related to other diseases, such as diseases of the peripheral nervous system, eyes, spinal cord, and intestinal system.

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

[0004] Neurons are post-mitotic cells that must survive throughout life. While young neurons have normal functioning of self-healing protective mechanisms, aging or external or internal insults can disturb them, ultimately leading to neurodegeneration. These external / internal hazards are traumatic injuries or excitotoxic compounds, reactive oxygen species (ROS), protein aggregates and other toxic molecules. Fortunately, cells have intrinsic mechanisms to prevent death by activating recovery mechanisms or promoting regenerative pathways. Dysfunction or insufficiency of these self-healing mechanisms has also been described in neurodegenerative diseases.

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

[0006] The fields of application of these proteins are very wide. Preclinical and clinical trials have been conducted to evaluate the effects of neurotrophic factors of the GDNF family for the prevention, treatment or management of Parkinson's disease, chronic pain, Alzheimer's disease, amyotrophic lateral sclerosis, neuropathy, depression, stroke, and these proteins have even been suggested as male contraceptives. However, the clinical application of GDNF is hindered by its poor pharmacokinetic properties, the fact that it cannot cross the blood-brain barrier and therefore requires intracranial delivery by stereotaxic surgery, variable biological activity and high price.

[0007] Small molecules that penetrate the blood-brain barrier, target the GDNF receptor complex, and mimic the biological effects of GDNF in neurons may be a way to overcome these problems and translate into greater clinical efficacy. The superior tissue penetration of such compounds could promote the survival of neurons in all affected neuronal pathways.

[0008] Surprisingly, Applicants have discovered that novel polycyclic sulfones of formula (I) exhibit potent GFRα1-RET activity in a luciferase assay, thus opening a way to overcome the limitations of available therapeutic options. Summary of the invention

[0009] The present invention is directed to compounds of formula (I)

[0010]

[0011] or a pharmaceutically acceptable salt and / or a solvate thereof;

[0012] Among them, W, R A To R D , R 1 To R 4 , Z, R 5To R 7 and R 9 As defined below and / or as claimed.

[0013] According to one embodiment, the compound is selected from the compounds of Table 1 herein and pharmaceutically acceptable salts and / or solvates thereof.

[0014] Another object of the invention is a pharmaceutical composition comprising a compound according to the invention and at least one pharmaceutically acceptable carrier.

[0015] Another object of the invention is a compound according to the invention or a pharmaceutical composition according to the invention for use as a medicament.According to one embodiment, said compound or pharmaceutical composition is for use in the treatment of neurological disorders.

[0016] Another object of the present invention is a process for preparing the compounds according to the invention.

[0017] definition

[0018] In the present invention, the following terms have the following meanings:

[0019] Chemical Definition

[0020] When a chemical substituent is a combination of chemical groups, the point of attachment of the substituent to the molecule is at the last chemical group to the right of the substituent name listed. For example, an arylalkyl substituent is attached to the rest of the molecule through the alkyl portion and can be represented as follows: "aryl-alkyl-".

[0021] Unless otherwise stated, compounds were named using BIOVIA Draw 2021 (Dassault, France).

[0022] Definitions herein concerning optional or mandatory substitution of a particular group apply both to the group itself being considered substituted and to the same group contained in another chemical moiety, both of which may be substituted as described herein. For example, "R x represents hydrogen, (C1-C8)alkyl, (C1-C8)alkyl-O- or cycloalkyl-(C1-C8)alkyl-NH-; wherein the alkyl is optionally substituted with at least one F" means R x Any alkyl group present in the structure may be optionally substituted with at least one F, including the (C1-C8)alkyl group itself (e.g., CF3), the alkyl group contained in the (C1-C8)alkyl-O- group (e.g., OCF3), and the alkyl group contained in the cycloalkyl-(C1-C8)alkyl-NH- group (e.g., cyclopropyl-CH2-CHF-CH2-NH-).

[0023] "Alkoxy" refers to an alkyl-O- group.

[0024] "Alkyl" refers to a saturated straight or branched hydrocarbon chain, which generally contains 1 to 16 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, and even more preferably 1 to 6 carbon atoms. Alkyl can be monovalent or polyvalent (that is, "alkylene", which is a divalent alkyl, is included in the definition of "alkyl"). Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl and isomers thereof (e.g., n-pentyl, isopentyl) and hexyl and isomers thereof (e.g., n-hexyl, isohexyl). Special examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl (including methylene, ethylidene, n-propylene, n-butylidene and n-butylidene).

[0025] "Amine" refers to a derivative of ammonia (NH3) in which one or more hydrogen atoms are replaced by a substituent such as an alkyl or aryl group. "Amino" refers to a -NH2 group.

[0026] "Aryl" refers to a cyclic polyunsaturated aromatic hydrocarbon group comprising at least one aromatic ring and 5 to 12 carbon atoms, preferably 6 to 10 carbon atoms. Aryl can be monovalent or polyvalent (e.g., divalent). Aryl can have a monocyclic ring (e.g., phenyl) or multiple aromatic rings fused together (e.g., naphthyl) or multiple aromatic rings covalently connected. The aromatic ring can optionally include one to two other rings fused thereto (cycloalkyl, heterocycloalkyl, or heteroaryl). The definition of "aryl" encompasses partially hydrogenated derivatives of the carbocyclic ring systems listed herein, as long as at least one ring is aromatic. Aryl can optionally be substituted with 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, biphenylene, 5-tetralinyl or 6-tetralinyl, naphth-1-yl or naphth-2-yl, 4-indenyl, 5-indenyl, 6-indenyl or 7-indenyl, 1-acenaphthyl, 2-acenaphthyl, 3-acenaphthyl, 4-acenaphthyl or 5-acenaphthyl, 3-acenaphthyl , 4-acenaphthenyl or 5-acenaphthenyl, 1-pentalenyl or 2-pentalenyl, 4-indanyl or 5-indanyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 7-tetrahydronaphthyl or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and 1-pyrenyl, and 2-pyrenyl, 3-pyrenyl, 4-pyrenyl or 5-pyrenyl. A particular example of aryl is phenyl.

[0027] "Benzal" refers to a phenyl group bonded to a moiety via an exo carbon-carbon double bond, ie, =CH-Ph bonded to a carbon atom. The moiety is typically cyclic, such as, for example, a heterocycloalkyl group.

[0028] "Cycloalkyl" refers to a cyclic alkyl group, which generally contains 3 to 15 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and even more preferably 3 to 6 carbon atoms. Cycloalkyl groups can be monovalent or multivalent (e.g., divalent). The definition of "cycloalkyl" encompasses polycyclic cycloalkyl (e.g., bicyclic) and bridged cycloalkyl structures, including rings bonded together by one atom ("spirocycle") or two atoms. The definition of "cycloalkyl" encompasses cycloalkyl groups, including cyclic alkyl groups substituted with at least one non-cyclic alkyl group, such as (C1-C8)alkyl (preferably (C1-C4)alkyl, (e.g., methyl). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, adamantyl, bicyclo[2.2.2]octyl, bicyclo[4.4.0]decyl, bicyclo[3.2.1]octyl, bicyclo[3.3.1]nonyl, bicyclo[2.1.1]hexane, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthyl, decahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and octahydropentalenyl.

[0029] According to the common terminology in the chemical field, the “C x -C y " or "(C x -C y )" means that the group contains x to y carbon atoms.

[0030] The "halogen" refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0031] "Heteroalkyl" refers to an alkyl group as defined herein, wherein one or more than one carbon atom is substituted by a heteroatom selected from oxygen, nitrogen and sulfur, and wherein the resulting heteroalkyl group comprises at least one carbon atom. In heteroalkyl groups, heteroatoms are only combined with carbon atoms along the alkyl chain, i.e., each heteroatom is separated from any other heteroatom by at least one carbon atom, usually by at least two carbon atoms. Heteroalkyl groups can be monovalent or polyvalent (e.g., divalent). Nitrogen heteroatoms and sulfur heteroatoms can be optionally oxidized, and nitrogen heteroatoms can be optionally quaternized (e.g., sulfur can be oxidized to SO or SO2). Heteroalkyl groups can also include one or more than one =O group and / or =S group. In one embodiment, at least two carbon atoms are substituted by heteroatoms. In one embodiment, heteroalkyl groups are combined with another group or molecule by carbon atoms, i.e., the combined atom is not selected from the heteroatoms contained therein. In one embodiment, heteroalkyl groups are combined with another group or molecule by one of the heteroatoms contained therein. Unless otherwise stated, when substituted by one or more than one other groups, heteroalkyl groups can be substituted by carbon atoms or heteroatoms (e.g., nitrogen). Non-limiting examples of heteroalkyl groups include alkoxy groups, ethers and polyethers (eg, polyethylene glycol), secondary and tertiary amines and polyamines, thioethers and polythioethers, and combinations thereof.

[0032] "Heteroaryl" refers to an aromatic ring or aromatic ring system containing 5 to 15 carbon atoms, preferably 4 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, having one or two rings fused together or covalently linked, wherein at least one ring is aromatic, and one or more carbon atoms in one or more of these rings are substituted with oxygen atoms, nitrogen atoms and / or sulfur atoms. Heteroaryl groups can be monovalent or polyvalent (e.g., divalent). Nitrogen heteroatoms and sulfur heteroatoms can be optionally oxidized, and nitrogen heteroatoms can be optionally quaternized (e.g., for sulfur atoms, heteroatoms are substituted with oxygen (=O), or for nitrogen atoms, with (→O)). The definition of "heteroaryl" encompasses partially hydrogenated derivatives of the carbocyclic ring systems listed herein, as well as ring systems containing one or more fused non-aromatic cycloalkyls and / or one or more rings of heterocycloalkyls, as long as at least one ring is aromatic. In one embodiment, heteroaryl is combined with another group or molecule through a carbon atom, i.e., the combined atom is not selected from the heteroatom contained therein. In one embodiment, heteroaryl is combined with another group or molecule through one of the heteroatoms contained therein. Unless otherwise indicated, when substituted by one or more than one other groups, heteroaryl can be substituted by carbon atom or heteroatom (e.g., nitrogen). Heteroaryl can be optionally substituted by at least one group, such as halogen (e.g., F or Cl), (C1-C8) alkyl (preferably (C1-C4) alkyl, e.g., methyl) or nitrile (CN).Non-limiting examples of heteroaryl groups include pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, tetrazinyl, imidazo[2,1 -b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thienyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indazolyl, benzo imidazolyl, 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, thienopyridine yl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl and quinoxalinyl. Non-limiting examples of heteroaryl groups containing at least one fused non-aromatic ring include 2,3-dihydrobenzofuranyl, benzo[d][1,3]dioxolyl, indolyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 1,2,3,4-tetrahydroquinoxaline, 3,4-dihydro-2H-benzo[b][1,4]thiazine, and 2,3-dihydrobenzo[b][1,4]oxathiinyl.

[0033] "Heteroarylene" refers to a heteroaryl group bonded to a moiety through an exo carbon-carbon double bond, ie, a =CH-heteroaryl group bonded to a carbon atom. The moiety is typically cyclic, such as, for example, a heterocycloalkyl group.

[0034] "Heterocycloalkyl" refers to a cyclic heteroalkyl group, which generally contains 2 to 15 carbon atoms, preferably 2 to 11 carbon atoms, more preferably 2 to 7 carbon atoms, and even more preferably 2 to 6 carbon atoms. Heterocycloalkyl can be monovalent or polyvalent (e.g., divalent). Heterocycloalkyl is generally 3 to 7 yuan, preferably 5 or 6 yuan. Heterocycloalkyl is generally monocyclic or bicyclic, preferably monocyclic. This definition covers polycyclic heterocycloalkyl (e.g., bicyclic) and bridge heterocycloalkyl structures, including rings that are bound together by one atom ("spirocycle") or two atoms. Nitrogen heteroatoms and sulfur heteroatoms can be optionally oxidized, and nitrogen heteroatoms can be optionally quaternized (e.g., for sulfur atoms, heteroatoms are replaced by oxygen (=O), or for nitrogen atoms, by (→O)). In one embodiment, heterocycloalkyl is combined with another group or molecule through a carbon atom, that is, the combined atom is not selected from the heteroatom contained therein. In one embodiment, heterocycloalkyl is combined with another group or molecule through one of the heteroatoms contained therein. Unless otherwise indicated, when substituted by one or more than one other groups, heterocycloalkyl can be substituted by carbon atom or heteroatom (e.g. nitrogen).Heterocycloalkyl can be optionally substituted by at least one group, such as halogen (e.g. F or Cl), (C1-C8) alkyl (preferably, (C1-C4) alkyl, e.g. methyl), nitrile (CN) or =O.Non-limiting examples of heterocycloalkyl include aziridine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, azepane, azocyclooctane, 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 oxetanes.

[0035] "Prodrug" refers to a pharmacologically acceptable derivative of a therapeutic agent (e.g., a compound according to the invention), the biotransformation product of which is a therapeutic agent (active drug) in vivo. Typical features of prodrugs are increased bioavailability and easy metabolism to active compounds in vivo. Non-limiting examples of prodrugs include amide prodrugs and carboxylate prodrugs.

[0036] "Solvate" refers to a molecular complex comprising a compound and stoichiometric or substoichiometric amounts of one or more than one molecule of one or more than one solvent, typically a pharmaceutically acceptable solvent such as, for example, ethanol. The term "hydrate" refers to a solvate when the solvent is water (H2O).

[0037] "Subunit" refers to a CH group in an exo-carbon-carbon double bond bound to another moiety. The moiety is typically cyclic, such as, for example, a heterocycloalkyl.

[0038] General Definition

[0039] "About" is used herein to mean approximately, roughly, approximately, or within a range thereof. The term "about" before a number means ±10% of the numerical value. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the numerical value by 10%.

[0040] "Administering" or variations thereof refers to providing a therapeutic agent, either alone or as part of a pharmaceutically acceptable composition, to a patient for the condition, symptom or disease to be treated.

[0041] "Including / comprising" or its variants are used herein according to general patent application drafting terminology. Therefore, "including / comprising" is preceded by an object and followed by a component, indicating that a certain component (usually as a certain component of a composition) needs to be present in the object, but does not exclude the presence of any other one or more than one component in the object. In addition, the appearance of "including / comprising" or its variants herein also covers the narrower expression "essentially consisting of", the still narrower expression "consisting of" and any variants thereof, and can be replaced by them, unless otherwise specified.

[0042] "GDNF family receptor alpha-1", "GFRα1" or "GDNFRα1", also known as "RET ligand 1" or "TGF-β-related neurotrophic factor receptor 1", is a protein from the GDNFR family that acts as a receptor for GDNF. It mediates GDNF-induced autophosphorylation and activation of the RET receptor. In humans, GFRα1 is encoded by the GFRA1 gene. An exemplary amino acid sequence of human GFRα1 is given in SEQ ID NO: 1, wherein amino acid residue 1 to amino acid residue 24 correspond to the signal peptide, and amino acid residue 430 to amino acid residue 465 correspond to the propeptide that is removed in the mature form.

[0043]

[0044] "Human" refers to human subjects, male or female, at any stage of development, including neonates, infants, juveniles, adolescents, and adults.

[0045] "Neuroprotection" refers to protecting neuronal cells from damage, events or conditions that would normally result in loss of neuronal cell function and ultimately neuronal cell death. Such damage, events or conditions include, but are not limited to, neuronal stress, such as neuronal stress caused by hypoxia or ischemia; trauma; and exposure to toxic molecules, such as abnormally misfolded proteins, protein aggregates, excitotoxins, reactive oxygen species, endoplasmic reticulum stressors, mitochondrial stressors, Golgi antagonists, etc. The term is also characterized by a detectable biological activity of the compound in reducing the amount or level of neuronal cell function loss and / or neuronal cell death.

[0046] "Neural repair" refers to the repair or rescue of neuronal cells, particularly their function, from the effects of an injury, event, or condition that would normally result in loss of neuronal cell function if not neuronal cell death.

[0047] A "patient" is a person who is awaiting or receiving medical care or who has been / is / will be the subject of a medical procedure, or who is being monitored for the development of a target disease or condition, such as a neurological disorder.

[0048] "Pharmaceutically acceptable" means that the ingredients of the composition are compatible with each other and not deleterious to the subject to which it is administered.

[0049] "Pharmaceutically acceptable carrier" refers to an excipient that does not produce adverse reactions, allergic reactions or other undesirable reactions when applied to animals, preferably humans. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delay agents, etc. For human use, the preparation should meet the sterility, pyrogenicity, general safety and purity standards required by regulatory agencies such as the FDA office or EMA. The example of a pharmaceutically acceptable carrier includes but is not limited to ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (e.g., sodium carboxymethyl cellulose), polyethylene glycol, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0050] "Pharmaceutical composition" refers to a composition comprising at least one therapeutic agent (eg, a compound according to the present invention) and at least one pharmaceutically acceptable carrier.

[0051] "Proto-oncogene tyrosine-protein kinase receptor Ret", or "RET" for short, also known as "cadherin family member 12", is a receptor tyrosine kinase that is involved in many cellular mechanisms including cell proliferation, neuronal navigation, cell migration and cell differentiation. Activation of RET occurs when (i) a neurotrophic factor of the GDNF family (e.g., GDNF, neurturin, artemin or persephin) binds to a receptor of the GDNFR family (e.g., GFRα1, GFRα2, GFRα3 or GFRα4), followed by (ii) formation of a complex with a receptor of the GDNFR family, (iii) dimerization and (iv) trans autophosphorylation. An exemplary amino acid sequence of human RET is given in SEQ ID NO:2, wherein amino acid residue 1 to amino acid residue 28 correspond to the signal peptide.

[0052]

[0053] According to general patent application drafting terminology, "selected from" is used herein to introduce a list of elements from which one or more items are selected. "Selected from" appearing in the specification can be replaced by "selected from a group including or consisting of...", and their meanings do not change from each other.

[0054] "Subject" refers to an animal, typically a warm-blooded animal, preferably a mammal, more preferably a primate, and even more preferably a human. In one embodiment, the subject is a "patient" as defined herein. In one embodiment, the subject is affected by a disease, preferably diagnosed as having a disease. In one embodiment, the subject is at risk of developing a disease. Examples of risk factors include, but are not limited to, a genetic predisposition or a family history of a disease.

[0055] "Therapeutic agent," "active pharmaceutical ingredient," and "active ingredient" refer to compounds that are used for therapeutic purposes and are related to health. In particular, therapeutic agents (e.g., compounds according to the present invention) can be used to treat diseases (e.g., neurological disorders). Active ingredients can also be used to enhance the therapeutic activity of another therapeutic agent.

[0056] "Therapeutically effective amount" (abbreviated as "effective amount") refers to the amount of a therapeutic agent (e.g., a compound according to the present invention) that is sufficient to achieve the desired therapeutic effect, preventive effect, or prophylactic effect in the patient to whom it is administered, without causing significant negative or adverse side effects to the patient. For a prophylactic or preventive effect, a therapeutically effective amount may be administered before the onset of the disease. Alternatively or additionally, for a therapeutic effect, a therapeutically effective amount may be administered after the onset of the disease.

[0057] "Treatment" or "alleviation" refers to both therapeutic treatment and prophylactic or preventative measures, wherein the goal is to prevent or slow down (reduce) the pathological condition or disorder (referred to herein as a "disease") of the target (e.g., a neurological disorder). Subjects in need of treatment include those already suffering from the disease as well as those susceptible to the disease or those in need of prevention of the condition or disease. A patient is successfully "treated" for a disease if, after receiving a therapeutic amount of a therapeutic agent (e.g., a compound according to the invention), the patient exhibits an observable and / or measurable reduction or disappearance of one or more of the following: a decrease in the number of pathogens; a decrease in the percentage of total pathogenic cells; and / or a relief to some extent 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 assessing successful treatment and improvement of a disease can be readily detected by conventional methods familiar to physicians. DETAILED DESCRIPTION

[0058] Compound

[0059] The present invention is directed to compounds of formula (I)

[0060]

[0061] or a pharmaceutically acceptable salt and / or a solvate thereof;

[0062] in

[0063] W represents CH or N;

[0064] R A , R B , R C and R D each independently represents hydrogen, F, Cl, CH3, CF3, CHF2 or CH2F,

[0065] The condition is R A , R B , R C and R D At least one of them does not represent hydrogen;

[0066] R 1 represents hydrogen or (C1-C8)alkyl, wherein the alkyl is optionally substituted with at least one OH, (C1-C3)alkoxy or F; and R 2 , R 3 and R 4 represents hydrogen; or

[0067] R 1 and R 4 Together they form -CH2-O-CH2- or -CH2-CH2-, wherein -CH2-CH2- is optionally substituted with at least one F, OH or OCH3; and R 2 and R 3 Each represents hydrogen;

[0068] R 7 represents 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-, (R 11 O)(R 12 )N-(C1-C8)alkyl-O-, R 11 R 12 N-(C1-C8)alkyl-, R 11 O-(C1-C8)alkyl-、NR 11 R 12、CN、CO2H、CO2R 11 、CONH2、CON(R 11 )H, heterocycloalkyl, or heteroaryl; wherein R 11 and R 12 Each independently represents hydrogen or (C1-C8) alkyl;

[0069] Where R 7 The alkyl or cycloalkyl in is optionally substituted by at least one F, Cl, OH, =O, (C1-C8)alkyl, (C1-C8)alkyl-O-, heterocycloalkyl, aryl or heteroaryl;

[0070] wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR 13 R 14 , R 13 R 14 N-(C1-C8)alkyl-, R 13 O2C-(C1-C8)alkyl-, CO2H, R 13 R 14 NC(O)-、R 13 O-NR 14 - or (C1-C8) alkyl-CO2-substituted; wherein R 13 and R 14 Each independently represents hydrogen or (C1-C8) alkyl;

[0071] Z stands for CH, CR 8 or N;

[0072] Where R 8 represents (C1-C4)alkyl, F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH or (C1-C4)alkoxy; or

[0073] Z is for CR 8 And R 7 and R 8 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocycloalkyl group,

[0074] wherein the cycloalkyl or heterocycloalkyl group is optionally substituted by at least one of F, OH, =O, →O, (C1-C8)alkyl, CF3, HO2C-CH2-, (C1-C4)alkyl-CO2-CH2-, R 15 R 16 N-CH2-, aryl or aryl-(C1-C8)alkyl-substituted, wherein R 15 and R 16Each independently represents hydrogen or (C1-C8) alkyl;

[0075] R 5 represents hydrogen, (C1-C8)alkyl, CH3 substituted by one to three (C1-C8)alkyl, cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C1-C8)alkyl;

[0076] Where R 5 The alkyl or cycloalkyl in the alkyl group is optionally substituted with at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, NR 17 R 18 ,CO2H,R 17 R 18 NC(O)-、R 17 O-NR 18 -, heterocycloalkyl, aryl or heteroaryl; wherein R 17 and R 18 Each independently represents hydrogen or (C1-C8) alkyl;

[0077] wherein heterocycloalkyl, aryl or heteroaryl (i.e., R 5 any heterocycloalkyl, aryl or heteroaryl group representing or being part of any substituent thereof) is optionally substituted with at least one F, Cl, (C1-C8)alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8)alkoxy, NR 19 R 20 ,CO2H,R 19 R 20 NC(O)-、R 19 O-NR 20 -, (C1-C8) alkyl-CO2-, R 19 R 20 N-(C1-C8)alkyl-, R 19 O2C-(C1-C8)alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C1-C8)alkyl-; wherein R 19 and R 20 Each independently represents hydrogen or (C1-C8) alkyl substitution;

[0078] R 6 represents hydrogen, (C1-C8)alkyl, CH3 substituted by one to three (C1-C8)alkyl, cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C1-C8)alkyl;

[0079] Where R 6The alkyl or cycloalkyl in the alkyl group is optionally substituted with at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, NR 21 R 22 ,CO2H,R 21 R 22 NC(O)-、R 21 O-NR 22 -, heterocycloalkyl, aryl or heteroaryl; wherein R 21 and R 22 Each independently represents hydrogen or (C1-C8) alkyl;

[0080] wherein heterocycloalkyl, aryl or heteroaryl (i.e., R 6 any heterocycloalkyl, aryl or heteroaryl group representing or being part of any substituent thereof) is optionally substituted with at least one F, Cl, (C1-C8)alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8)alkoxy, NR 23 R 24 ,CO2H,R 23 R 24 NC(O)-、R 23 O-NR 24 -, (C1-C8) alkyl-CO2-, R 23 R 24 N-(C1-C8)alkyl-, R 23 O2C-(C1-C8)alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C1-C8)alkyl-; wherein R 23 and R 24 Each independently represents hydrogen or (C1-C8) alkyl substitution; or

[0081] R 5 and R 6 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocycloalkyl group,

[0082] wherein a cycloalkyl or heterocycloalkyl group (i.e., R 5 , R 6 and the carbon atoms to which they are attached to form a cycloalkyl or heterocycloalkyl) are optionally substituted with at least one F, Cl, (C1-C8)alkyl, CF3, OCF3, CN, OH, =O, →O, (C1-C8)alkoxy, NR 25 R 26 、CO2H、(C1-C8)alkyl-CO2-、R 25 R 26 NC(O)-、R 25 O-NR 26 -、R 25R 26 N-(C1-C8)alkyl-, R 25 O2C-(C1-C8)alkyl-, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1-C8)alkyl-, heterocycloalkyl-(C1-C8)alkyl-, aryl-(C1-C8)alkyl-, heteroaryl-(C1-C8)alkyl-, aryl-cycloalkyl-, cycloalkyl-O-, heterocycloalkyl-O-, aryl-O-, heteroaryl-O-, cycloalkyl-(C1-C8)alkyl-O-, heterocycloalkyl-(C1-C8)alkyl-O-, aryl-(C1-C8)alkyl-O-, heteroaryl-(C1-C8)alkyl-O-, cycloalkyl-NR 25 -, heterocycloalkyl-NR 25 -, aryl-NR 25 -, heteroaryl-NR 25 -, cycloalkyl-(C1-C8)alkyl-NR 25 -, heterocycloalkyl-(C1-C8)alkyl-NR 25 -, Aryl-(C1-C8)alkyl-NR 25 -, heteroaryl-(C1-C8)alkyl-NR 25 -, benzylidene, heteroarylene, aryl-(C1-C8)alkyl-ylidene- or heteroaryl-(C1-C8)alkyl-ylidene-;

[0083] Where R 25 and R 26 Each independently represents hydrogen or (C1-C8) alkyl;

[0084] wherein heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylene (i.e., R 5 , R 6 any heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylene group as part of any substituent of the heterocycloalkyl group formed by the nitrogen atom to which they are attached, is optionally substituted with at least one F, Cl, (C1-C8)alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8)alkoxy, NR 27 R 28 ,CO2H,R 27 R 28 NC(O)-、R 27 O-NR 28 -, (C1-C8) alkyl-CO2-, R 27 R 28 N-(C1-C8)alkyl-, R 27 O2C-(C1-C8)alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C1-C8)alkyl-substituted; wherein R 27 and R28 Each independently represents hydrogen or (C1-C8) alkyl;

[0085] R 9 represents hydrogen, (C1-C8)alkyl, CH3 substituted by one to three (C1-C8)alkyl, cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C1-C8)alkyl;

[0086] Where R 9 The alkyl or cycloalkyl in the alkyl group is optionally substituted with at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, NR 29 R 30 ,CO2H,R 29 R 30 NC(O)-、R 29 O-NR 30 -, heterocycloalkyl, aryl or heteroaryl; wherein R 29 and R 30 Each independently represents hydrogen or (C1-C8) alkyl;

[0087] wherein heterocycloalkyl, aryl or heteroaryl (i.e., R 9 any heterocycloalkyl, aryl or heteroaryl group representing or being part of any substituent thereof) is optionally substituted by at least one F, Cl, CF3, OCF3, CN, OH, =O, →O, (C1-C8)alkoxy, NR 31 R 32 ,CO2H,R 31 R 32 NC(O)-、R 31 O-NR 32 -, (C1-C8) alkyl-CO2-, R 23 R 24 N-(C1-C8)alkyl-, R 23 O2C-(C1-C8)alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C1-C8)alkyl-substituted; wherein R 31 and R 32 Each independently represents hydrogen or (C1-C8) alkyl.

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

[0089] According to a preferred embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt and / or a solvate thereof; wherein:

[0090] W represents CH or N;

[0091] R A , R B , R C and R D each independently represents hydrogen, F, Cl, CH3, CF3, CHF2 or CH2F,

[0092] The condition is R A , R B , R C and R D At least one of them does not represent hydrogen;

[0093] R 1 represents hydrogen or (C1-C8)alkyl, wherein the alkyl is optionally substituted with at least one OH, (C1-C3)alkoxy or F; and R 2 , R 3 and R 4 represents hydrogen; or

[0094] R 1 and R 4 Together they form -CH2-O-CH2- or -CH2-CH2-, wherein -CH2-CH2- is optionally substituted with at least one F, OH or OCH3; and R 2 and R 3 Each represents hydrogen;

[0095] R 7 represents 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 represents hydrogen or (C1-C8) alkyl;

[0096] wherein the alkyl or cycloalkyl is optionally substituted with at least one F, Cl, heterocycloalkyl, aryl or heteroaryl;

[0097] wherein the heterocycloalkyl, aryl or heteroaryl groups are optionally substituted with at least one F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH, (C1-C8) alkoxy, NR 13 R 14 ,CO2H,R 13 R14 NC(O)- or R 13 O-NR 14 -substituted; wherein R 13 and R 14 Each independently represents hydrogen or (C1-C8) alkyl;

[0098] Z represents CH or N; or

[0099] Z is for CR 8 And R 7 and R 8 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocycloalkyl group,

[0100] wherein the cycloalkyl or heterocycloalkyl group is optionally substituted by at least one of F, OH, CF3, HO2C-CH2-, (C1-C4)alkyl-CO2-CH2- or R 15 R 16 N-CH2-substituted, where R 15 and R 16 Each independently represents hydrogen or (C1-C8) alkyl;

[0101] R 5 represents hydrogen, (C1-C8)alkyl, CH3 substituted by one to three (C1-C8)alkyl, cycloalkyl or cycloalkyl-(C1-C8)alkyl;

[0102] wherein the alkyl or cycloalkyl group is optionally substituted with at least one of F, Cl, CF3, OCF3, CN, OH, (C1-C8) alkoxy, NR 17 R 18 ,CO2H,R 17 R 18 NC(O)-、R 17 O-NR 18 -, heterocycloalkyl, aryl or heteroaryl; wherein R 17 and R 18 Each independently represents hydrogen or (C1-C8) alkyl;

[0103] wherein the heterocycloalkyl, aryl or heteroaryl groups are optionally substituted with at least one F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH, (C1-C8) alkoxy, NR 19 R 20 ,CO2H,R 19 R 20 NC(O)- or R 19 O-NR 20 -substituted; wherein R 19 and R 20 Each independently represents hydrogen or (C1-C8) alkyl;

[0104] R 6 represents hydrogen, (C1-C8)alkyl, CH3 substituted by one to three (C1-C8)alkyl, cycloalkyl or cycloalkyl-(C1-C8)alkyl;

[0105] wherein the alkyl or cycloalkyl group is optionally substituted with at least one of F, Cl, CF3, OCF3, CN, OH, (C1-C8) alkoxy, NR 21 R 22 ,CO2H,R 21 R 22 NC(O)-、R 21 O-NR 22 -, heterocycloalkyl, aryl or heteroaryl; wherein R 21 and R 22 Each independently represents hydrogen or (C1-C8) alkyl;

[0106] wherein the heterocycloalkyl, aryl or heteroaryl groups are optionally substituted with at least one F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH, (C1-C8) alkoxy, NR 23 R 24 ,CO2H,R 23 R 24 NC(O)- or R 23 O-NR 24 -substituted; wherein R 23 and R 24 Each independently represents hydrogen or (C1-C8) alkyl; or

[0107] R 5 and R 6 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocycloalkyl group,

[0108] wherein the cycloalkyl or heterocycloalkyl group is optionally substituted with at least one F, Cl, CF3, OCF3, CN, OH, (C1-C8) alkoxy, NR 25 R 26 ,CO2H,R 25 R 26 NC(O)-、R 25 O-NR 26 -, heterocycloalkyl, aryl, heteroaryl, heterocycloalkyl-(C1-C8)alkyl-, aryl-(C1-C8)alkyl-, heteroaryl-(C1-C8)alkyl-, cycloalkyl-(C1-C8)alkyl-O-, aryl-(C1-C8)alkyl-O-, heteroaryl-(C1-C8)alkyl-O-, cycloalkyl-(C1-C8)alkyl-NR 25 -, Aryl-(C1-C8)alkyl-NR 25-, heteroaryl-(C1-C8)alkyl-NR 25 -, benzylidene, heteroarylene, aryl-(C1-C8)alkyl-ylidene- or heteroaryl-(C1-C8)alkyl-ylidene-;

[0109] Where R 25 and R 26 Each independently represents hydrogen or (C1-C8) alkyl;

[0110] wherein the heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylene group is optionally substituted by at least one F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH, (C1-C8) alkoxy, NR 27 R 28 ,CO2H,R 27 R 28 NC(O)- or R 27 O-NR 28 -substituted; wherein R 27 and R 28 Each independently represents hydrogen or (C1-C8) alkyl;

[0111] R 9 represents hydrogen, (C1-C8)alkyl, CH3 substituted by one to three (C1-C8)alkyl, cycloalkyl or cycloalkyl-(C1-C8)alkyl;

[0112] wherein the alkyl or cycloalkyl group is optionally substituted with at least one of F, Cl, CF3, OCF3, CN, OH, (C1-C8) alkoxy, NR 29 R 30 ,CO2H,R 29 R 30 NC(O)-、R 29 O-NR 30 -, heterocycloalkyl, aryl or heteroaryl; wherein R 29 and R 30 Each independently represents hydrogen or (C1-C8) alkyl;

[0113] wherein the heterocycloalkyl, aryl or heteroaryl groups are optionally substituted with at least one F, Cl, CF3, OCF3, CN, OH, (C1-C8) alkoxy, NR 31 R 32 ,CO2H,R 31 R 32 NC(O)- or R 31 O-NR 32 -substituted; wherein R 31 and R 32 Each independently represents hydrogen or (C1-C8) alkyl.

[0114] According to one embodiment, W represents CH.

[0115] According to one embodiment, R A , R B , R C and R D In one embodiment, at least one of R A , R B , R C and R D In one embodiment, R A , R B , R C and R D In one embodiment, R A , R B , R C and R D There are exactly three of them representing hydrogen.

[0116] In one embodiment, R A and R C In a particular embodiment, at least one of R A In a particular embodiment, R C Represents hydrogen.

[0117] According to one embodiment, R A , R B and R D At least one of represents F or Cl. In one embodiment, R B and R D In one particular embodiment, at least one of R B and R D Each independently represents F or Cl. In a particular embodiment, R B represents F. In a particular embodiment, R B In a particular embodiment, R D represents F. In a particular embodiment, R D In a preferred embodiment, R B Represents F. In a preferred embodiment, R D In a further preferred embodiment, R B Represents F and R D Represents Cl.

[0118] As defined in formula (I) above, R 1may represent (C1-C8)alkyl, wherein the alkyl is optionally substituted by at least one OH, (C1-C3)alkoxy or F, i.e. R 1 The (C1-C8)alkyl in 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 a (C1-C8)alkyl group, wherein the alkyl group is optionally substituted by at least one group selected from OH, (C1-C3)alkoxy and F.

[0119] According to one embodiment, R 1 represents hydrogen or (C1-C8)alkyl, wherein the alkyl is optionally substituted with at least one OH, (C1-C3)alkoxy or F; and R 2 , R 3 and R 4 In one embodiment, R 1 , R 2 , R 3 and R 4 Represents hydrogen.

[0120] According to one embodiment, R 1 and R 4 Together they form -CH2-O-CH2- or -CH2-CH2. In one embodiment, R 1 and R 4 Together they form -CH2-CH2-. In one embodiment, -CH2-CH2- is optionally substituted with at least one F, OH or OCH3. In one embodiment, -CH2-CH2- is not substituted.

[0121] According to one embodiment, R 1 represents methyl, ethyl, CF3 or methoxymethyl (CH3OCH2-). In one embodiment, R 1 represents methyl, ethyl or CF3. In one embodiment, R 1 It represents methoxymethyl (CH3OCH2-).

[0122] According to one embodiment, R 7 represents 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 11and R 12 Each independently represents hydrogen or (C1-C8)alkyl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted as defined above for formula (I).

[0123] According to one embodiment, R 7 represents hydrogen, OH or halogen. In one embodiment, R 7 In a preferred embodiment, R 7 In one embodiment, R 7 In a particular embodiment, R 7 represents F or Cl. In a particular embodiment, R 7 Represents F. In a particularly preferred embodiment, R 7 Represents Cl.

[0124] In a preferred embodiment, R 7 It does not represent hydrogen.

[0125] 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 with at least one F, Cl, OH, (C1-C8)alkoxy or aryl. In a particular embodiment, R 7 Represents OCH3 (methoxy) or HO-CH2-CH2-O-.

[0126] According to one embodiment, R 7 represents (C1-C8)alkyl-O- (i.e., (C1-C8)alkoxy). In one embodiment, alkyl is optionally substituted with at least one F or Cl. In a particular embodiment, halogen is F. In one embodiment, R 7 represents OCH3(methoxy), OCH2CH3 or OCF3.

[0127] According to one embodiment, R 7 represents cycloalkyl-O-. In one embodiment, R 7 represents cyclobutyl-O-.

[0128] According to one embodiment, R 7 represents (C1-C8)alkyl-O- (i.e. (C1-C8)alkoxy), wherein the alkyl group is optionally substituted with at least one OH or (C1-C8)alkoxy group, i.e. RO-(C1-C8)alkyl-O-, wherein R represents H or (C1-C8)alkyl. In one embodiment, R 7It represents HO-CH2-CH2-O- or CH3O-CH2-CH2-O-.

[0129] According to one embodiment, R 7 represents (C1-C8)alkyl-O- (i.e. (C1-C8)alkoxy), wherein the alkyl group is optionally substituted with at least one aryl group. In one embodiment, the aryl group is not substituted. In one embodiment, R 7 It represents phenyl-CH2-O-.

[0130] According to one embodiment, R 7 represents (C1-C8)alkyl-O- (i.e. (C1-C8)alkoxy), wherein the alkyl group is optionally substituted with at least one heteroaryl group. In one embodiment, the heteroaryl group is not substituted. In one embodiment, R 7 Represents heteroaryl -CH2-O-.

[0131] According to one embodiment, R 7 represents (C1-C8) alkyl-O- (i.e. (C1-C8) alkoxy), wherein the alkyl group is optionally substituted with at least one heterocycloalkyl group. 7 represents heterocycloalkyl-(C1-C8)alkyl-O-, i.e. alkyl is substituted by exactly one heterocycloalkyl. In one embodiment, heterocycloalkyl is unsubstituted.

[0132] In a preferred embodiment, R 7 Represents Cl, OH, OCH3, HO-CH2-CH2-O-, CH3(methyl).

[0133] According to one embodiment, Z represents CH or N; or Z represents CR 8 And R 7 and R 8 Together with the carbon atom to which they are attached, they form a cycloalkyl or heterocycloalkyl group; wherein the cycloalkyl or heterocycloalkyl group is optionally substituted as defined above for formula (I). In other words, in this embodiment, R 8 represents hydrogen, unless R 7 and R 8 Together with the carbon atoms to which they are attached they form a cycloalkyl or heterocycloalkyl group.

[0134] According to one embodiment, Z represents CH or N. In one embodiment, Z represents CH. In one embodiment, Z represents N.

[0135] According to a preferred embodiment, Z represents CR 8 ; where R 8represents (C1-C4)alkyl, F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH or (C1-C4)alkoxy. 8 Represents methyl, ethyl, F, Cl, CF3, CN or OH. In a preferred embodiment, R 8 Represents methyl or Cl.

[0136] According to another embodiment, Z represents CR 8 And R 7 and R 8 Together with the carbon atom to which they are attached they form a cycloalkyl or heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted as defined herein for formula (I).

[0137] In a preferred embodiment, Z represents CR 8 And R 7 and R 8 Together with the carbon atom to which they are attached they form a heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted as defined herein for formula (I).

[0138] According to one embodiment, R 5 and R 6 Each independently represents a (C1-C8) alkyl group and R 9 In a preferred embodiment, R 5 and R 6 Each independently represents a methyl group or an ethyl group.

[0139] According to a preferred embodiment, R 5 and R 6 Each independently represents (C1-C8)alkyl or aryl-(C1-C8)alkyl-. In a preferred embodiment, R 5 and R 6 Each independently represents methyl, ethyl, n-propyl, 2-phenylethyl- or 3-phenylpropyl. In a further preferred embodiment, R 9 Represents hydrogen.

[0140] According to one embodiment, R 6 represents a (C1-C8) alkyl or aryl group, and R 5 and R 9 Each represents hydrogen. In one embodiment, R 6 represents propyl (eg isopropyl), tert-butyl or phenyl.

[0141] In one embodiment, R 6 represents (C1-C8) alkyl, R 5 and R 9Each represents hydrogen. In a preferred embodiment, R 6 represents a propyl group (eg isopropyl) or a tert-butyl group.

[0142] According to a preferred embodiment, R 6 represents (C1-C8)alkyl, cycloalkyl-(C1-C8)-alkyl or aryl. In a preferred embodiment, R 6 represents isopropyl, n-propyl, tert-butyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl-CH2- or phenyl. In a further preferred embodiment, R 5 and / or R 9 Represents hydrogen.

[0143] According to one embodiment, R 6 represents an aryl group and R 5 and R 9 Each represents hydrogen. In one embodiment, R 6 Represents phenyl.

[0144] According to one embodiment, R 5 Represents hydrogen.

[0145] According to one embodiment, R 5 represents (C1-C8) alkyl. In one embodiment, R 5 Represents methyl or ethyl.

[0146] According to one embodiment, R 6 represents (C1-C8) alkyl. In one embodiment, R 6 Represents methyl or ethyl.

[0147] According to one embodiment, R 6 In one embodiment, R 6 Represents phenyl.

[0148] According to one embodiment, R 9 represents hydrogen or (C1-C8) alkyl. 9 In a particular embodiment, R 9 In a preferred embodiment, R 9 Represents hydrogen.

[0149] According to one embodiment, R 5 and R 6 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocycloalkyl group, and R 9 In a preferred embodiment, R 5 and R 6Together with the carbon atoms to which they are attached they form cyclobutyl, cyclopentyl, cyclohexyl or oxetane.

[0150] In a preferred embodiment, R 5 and R 6 Together with the carbon atoms to which they are attached they form cyclobutyl, cyclopentyl, cyclohexyl, oxetane, 1-phenyl-4-piperidinyl, 1-(2-phenylethyl)-4-piperidinyl or 1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl.

[0151] According to one embodiment, R 5 and R 6 Together with the carbon atom to which they are attached, they form a cycloalkyl group. 5 and R 6 Together with the carbon atoms to which they are attached they form a cyclobutyl, cyclopentyl or cyclohexyl group.

[0152] According to one embodiment, R 5 and R 6 Together with the carbon atom to which they are attached, they form a heterocycloalkyl group. 5 and R 6 Together with the carbon atom to which they are attached they form an oxetane.

[0153] According to one embodiment, at least one heterocycloalkyl group present in the compound of formula (I) is a water-soluble group, ie the presence of this group in the molecule increases its solubility in water compared to the same molecule not comprising said heterocycloalkyl group.

[0154] According to one embodiment, the compound of formula (I) is a compound of formula (Ia)

[0155]

[0156] or a pharmaceutically acceptable salt and / or a solvate thereof;

[0157] Among them, W, R B , R D , Z, R 1 To R 4 and R 5 To R 7 As defined herein in formula (I).

[0158] In one embodiment, W in formula (Ia) represents CH.

[0159] In one embodiment, R in Formula (Ia) B and R D Each independently represents F or Cl. In a particular embodiment, R BRepresents F, R D Represents Cl.

[0160] According to one embodiment, the compound of formula (I) is selected from the compounds of Table 1 below, and pharmaceutically acceptable salts and / or solvates thereof.

[0161] Table 1

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170] All references to compounds of the invention (e.g., "compounds of formula (I)") herein include references to their salts, solvates, multicomponent complexes, and liquid crystals. All references to compounds of the invention herein include references to their polymorphs and their crystal habits. All references to compounds of the invention herein include references to their isotopically labeled compounds, including their deuterated compounds. All references to compounds of the invention herein include references to their stereoisomers. All references to compounds of the invention herein include references to their pharmaceutically acceptable prodrugs.

[0171] In particular, the compounds of the invention may be in the form of a pharmaceutically acceptable salt. According to one embodiment, the compounds of the invention are in the form of a pharmaceutically acceptable salt.

[0172] Pharmaceutically acceptable salts include acid addition salts and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, esylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydroxybenzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, sucrose, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate. Suitable alkali salts are formed by the base that forms non-toxic salts.Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, 2-(diethylamino)ethanol salts, diethanolamine salts, ethanolamine salts, glycinates, 4-(2-hydroxyethyl)-morpholine salts, lysine salts, magnesium salts, meglumine salts, morpholine salts, olamine (olamine) salts, potassium salts, sodium salts, tromethamine salts and zinc salts.Also can form half salts of acid and base, such as hemisulphate and half calcium salts.When compound contains acidic group and basic group, the compound can also form inner salt, and this compound is within the scope of the present invention.When compound contains hydrogen heteroatom (such as NH), the present invention also encompasses salts and / or isomers formed by transferring the hydrogen atom to the basic group or basic atom in the molecule.

[0173] Pharmaceutically acceptable salts of the compounds of the invention may be prepared by one or more of these methods: (i) by reacting the compound with a desired acid; (ii) by reacting the compound with a desired base; (iii) by removing an acid-labile or base-labile protecting group from a suitable compound precursor, or by ring-opening a suitable cyclic precursor, such as a lactone or lactam, with a desired acid; and / or (iv) by converting one salt of the compound into another salt by reacting with a suitable acid or by passing through a suitable ion exchange column. All of these reactions are typically carried out in solution. The salt may be precipitated from the solution and collected by filtration, or may be recovered by evaporating the solvent. The degree of ionization of the salt may vary from completely ionized to almost non-ionized.

[0174] In particular, the compounds of the present invention may be in the form of pharmaceutically acceptable solvates. According to one embodiment, the compounds of the present invention are pharmaceutically acceptable solvates. According to one embodiment, the compounds of the present invention are pharmaceutically acceptable salts and solvates.

[0175] In particular, the compound of the present invention may include at least one asymmetric center, and therefore may exist in different stereoisomeric forms. Therefore, all references to the compounds of this invention herein include all possible stereoisomers, not only including racemic compounds, but also including single enantiomers and non-racemic mixtures thereof. Non-racemic mixtures may include any amount of each different stereoisomer, such as a stereoisomer may be dominant (such as a mixture of 90 / 10 or 80 / 20), or the enantiomeric ratio may be close to a racemic mixture (such as a mixture of 40 / 60). When the compound in the form of a desired single enantiomer, this single enantiomer can be synthesized by stereospecificity, by the splitting of the final product or any convenient intermediate, or by chiral chromatography methods known in the art to obtain. The splitting of the final product, intermediate or raw material can be carried out by any suitable method known in the art.

[0176] Pharmaceutical composition

[0177] Another object of the invention is a composition comprising a compound according to the invention as described herein. According to one embodiment, the composition further comprises at least one pharmaceutically acceptable carrier, the composition being thus a "pharmaceutical composition" as defined herein.

[0178] In a first embodiment, the pharmaceutical composition comprises a compound according to the invention as the sole therapeutic agent. In a second embodiment, the pharmaceutical composition further comprises at least one other therapeutic agent, for example a therapeutic agent suitable for treating a neurological disorder.

[0179] Another object of the present invention is a medicament comprising a compound according to the invention as described herein.

[0180] Reagent test kit

[0181] Another object of the present invention is a kit of parts (hereinafter referred to as "kit") comprising a compound or composition according to the present invention as described herein. According to one embodiment, the kit comprises an article of manufacture, such as a package or container. According to one embodiment, the kit comprises instructions for use. The kit can be promoted, distributed or sold as a unit for practicing the method of the present invention.

[0182] According to one embodiment, the kit comprises: a pharmaceutical composition comprising a compound according to the invention and another separate pharmaceutical composition comprising at least another therapeutic agent, such as a therapeutic agent suitable for the treatment of a neurological disorder.

[0183] Medical uses of compounds

[0184] Another object of the present invention is a compound or a composition according to the invention as described herein for use as a medicament.

[0185] Another object of the present invention is a compound or composition according to the invention as described herein for use in the treatment of a neurological disorder.

[0186] Another object of the present invention is a method for treating a neurological disorder in a subject in need thereof. Another object of the present invention is the use of a compound or composition according to the present invention as described herein for the preparation 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 as described herein for the treatment of a neurological disorder.

[0187] According to one embodiment, the method or use comprises the step of administering to the subject a therapeutically effective amount of a compound, composition or medicament according to the invention as described herein.

[0188] According to one embodiment, the neurological disorder treated by the method or use of the invention is:

[0189] - Diseases or disorders associated with defective neurogenesis, such as Hirschsprung's disease, schizophrenia, ataxia-telangiectasia, aging-related decline in age-related nervous system function, or neurodevelopmental disorders;

[0190] - a neurodegenerative disease or disorder, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, frontotemporal dementia, a retinal neurodegenerative disease, a neuro-ophthalmological disease, neurotrophic keratitis, Charcot-Marie-Tooth disease, spinal muscular atrophy, epilepsy (e.g., an epileptic disorder, or a seizure disorder, or a chronic neurological disorder manifesting as epilepsy), dementia, age-related decline in nervous system function, a prion disease, Creutzfeldt-Jakob disease, multiple system atrophy (Schay-Dregger syndrome), multiple sclerosis, or Guillain-Barré syndrome.

[0191] - diseases or disorders related to nerve damage or neurotoxicity, such as head injury, brain injury, traumatic brain injury, peripheral nerve injury, traumatic peripheral nerve injury, peripheral neuropathy, nerve transplant complications, spinal cord injury, traumatic spinal cord injury, nerve severance or nerve injury, cerebrospinal nerve severance, brain cell damage or nerve cell damage, syringomyelia, optic neuropathy, trauma, stroke, ischemia, stroke, ischemic stroke, neurotoxicity caused by alcohol abuse or substance abuse (e.g., ecstasy, methamphetamine, etc.), or aphasia;

[0192] - neurodevelopmental disorders such as Rett syndrome, X-linked mental retardation, fragile X syndrome, Down syndrome, autism spectrum disorder, Hirschsprung disease, Tourette syndrome, childhood learning disabilities, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Angelman syndrome, microprematurity, schizophrenia, language disorders, prematurity, perinatal arterial ischemic stroke, spina bifida, mental retardation, non-syndromic X-linked mental retardation, Ondine syndrome or WAGR syndrome;

[0193] - neuropsychiatric disorders, such as depression, major depressive disorder, schizophrenia, schizophrenia-type disorder, schizoaffective disorder, delusional disorder, anxiety, anxiety disorder, panic disorder, phobia, obsessive-compulsive disorder, post-traumatic stress disorder, bipolar disorder, anorexia nervosa, bulimia nervosa, anhedonia, apathy, dementia, substance-induced dementia, movement disorders and / or tic disorders characterized by motor tics and / or vocal tics (e.g. Tourette's disease), substance use behaviors, addiction, mood disorders, suicidal tendencies, cancer-related psychiatric symptoms, Alzheimer's disease, Huntington's disease, frontotemporal dementia, or reward deficiency syndrome (RDS);

[0194] - Movement disorders, such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, movement disorders characterized by motor tics and / or vocal tics (e.g., Tourette's disease), ataxia, ataxic muscle rigidity (spasticity), Charcot-Marie-Tooth disease, spinal muscular atrophy, Werdnig-Hoffmann syndrome, or chronic proximal spinal muscular atrophy;

[0195] - pain disorders such as neuralgia, trigeminal neuralgia, chronic pain, inflammatory pain, pain associated with arthritis, fibromyalgia, back pain, cancer-related pain, pain associated with digestive disorders, pain associated with Crohn's disease, pain associated with autoimmune diseases, pain associated with endocrine diseases, pain associated with diabetic neuropathy, phantom limb pain, spontaneous pain, chronic post-surgical pain, chronic temporomandibular pain, causalgia, post-herpetic neuralgia, AIDS-related pain, complex regional pain syndrome type I and II, trigeminal neuralgia, chronic back pain, pain associated with spinal cord injury, pain associated with drug ingestion and recurrent acute pain, neuropathic pain, or inappropriate neuronal activity leading to nerve tension in diseases such as diabetes, MS and motor neuron disease;

[0196] - an ophthalmic disease or eye condition, such as a retinal disorder, a retinal neurodegenerative disease, retinitis pigmentosa, non-arthritic anterior ischemic optic neuropathy (NAION), macular degeneration, age-related macular degeneration, glaucoma, diabetic retinopathy, optic neuropathy and retinal degeneration, neuro-ophthalmologic disease, age-related cataract, primary open-angle glaucoma (POAG), retinal ganglion cell damage, intraocular hypertension, ischemic optic neuropathy, macular telangiectasia, cystoid macular edema, macular telangiectasia type 2, neurotrophic keratitis, or strabismus;

[0197] - Intestinal system disorders or gastrointestinal disorders, such as intestinal motility disorders, constipation, Hirschsprung's disease, inflammatory bowel disease, enteric neuronal dysplasia, ulcerative colitis, achalasia, esophageal spasm, duodenal ulcer, Zollinger-Ellison syndrome, gastric acid hypersecretion, malabsorption or intestinal inflammation;

[0198] - progressive muscular dystrophy, such as Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Landowy-Dejerine muscular dystrophy, scapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, Von Graefe-Fuchs muscular dystrophy, oculopharyngeal muscular dystrophy, myotonic and congenital muscular dystrophy, congenital or acquired myopathy, Charcot-Marie-Tooth disease, Werdnig-Hoffmann syndrome, or chronic proximal spinal muscular atrophy;

[0199] - Diseases or disorders associated with long-term or short-term memory impairment, such as amnesia, benign forgetfulness, or Alzheimer's disease;

[0200] - Autoimmune diseases such as multiple sclerosis, autoimmune encephalomyelitis, autoimmune encephalitis, autoimmune hemolytic anemia, chronic lymphocytic leukemia, Chargar-Strauss syndrome, anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, thyroid-related orbitopathy, autoimmune thyroiditis, Guillain-Barré syndrome, or autoimmune thrombocytopenic purpura;

[0201] - Neurologic diseases or disorders, such as damage to cochlear sensory cells, auditory perception defects, hearing loss, or tinnitus;

[0202] - Sleep disorders such as narcolepsy, restless legs syndrome, obstructive sleep apnea, chronic insomnia disorder, paradoxical sleep deprivation, or REM sleep deprivation;

[0203] - Cerebrovascular disease or neurovascular disease, such as early brain injury (EBI) after subarachnoid hemorrhage (SAH), cerebral ischemia, stroke, hypoxic-ischemic brain injury, perinatal arterial ischemic stroke, or neovascular age-related macular degeneration (nvAMD);

[0204] - Substance abuse disorders, such as substance dependence, sequelae of substance abuse and substance abuse dependence, substance-induced psychological disorders, substance withdrawal, and substance-induced dementia or amnestic disorders;

[0205] - Neuronal response to viral infection, trypanosome infection, AIDS-related neurological deficits, obesity, temporomandibular joint dysfunction, aphasia, Bell's palsy, encephalitis, kidney disease or renal dysfunction, pheochromocytoma, metabolic syndrome, cancer, eczema, thrombocytopenia; dysplasia; disseminated intravascular coagulation (DIC); bone marrow dysplasia; immune thrombocytopenic purpura (ITP), HIV-induced ITP, neuro-oncological disease or disorder, neuro-immune disease or disorder, multiple endocrine neoplasia type 2, Von Hippel-Lindau disease (VHL), neurofibromatosis type I, scleroderma, epidermal and stromal wound healing disorders and / or scarring disorders; or

[0206] - Diseases or disorders related to aging and / or ageing.

[0207] According to one embodiment, the neurological disorder is epilepsy, such as Dravet syndrome, benign motor epilepsy, frontal lobe epilepsy, infantile spasms, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy, childhood absence epilepsy (e.g. pyknolepsy), febrile seizures, Lafora progressive myoclonic epilepsy, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, generalized epilepsy with febrile seizures (GEFS+), severe myoclonus, severe myoclonic epilepsy of infancy (SMEI), benign familial neonatal convulsions (BFNC), West syndrome, Ohtahara syndrome, early myoclonic cerebral, wandering partial epilepsy, Infantile epileptic encephalopathy, tuberous sclerosis complex (TSC), focal cortical dysplasia, lissencephaly type I, Miller-Dickel syndrome, Angelman syndrome, fragile X syndrome, epilepsy in autism spectrum disorder, epilepsy in subcortical zone heterotopia, epilepsy in Walker-Warburg syndrome, epilepsy in Alzheimer's disease, post-traumatic epilepsy, progressive myoclonic epilepsy, reflex epilepsy, Rasmussen syndrome, temporal lobe epilepsy, limbic epilepsy, status epilepticus, abdominal epilepsy, massive bilateral myoclonus, catamenial epilepsy, Jacksonian seizure disorder, myoclonic epilepsy of the Mediterranean type (Unverricht-Lundborg disease), or photosensitive epilepsy.

[0208] According to one embodiment, the composition or medicine according to the present invention as described herein is administered to a subject, and it can be prepared using methods known in the art. Non-limiting examples of forms suitable for administration include solutions (e.g., sterile aqueous solutions), gels, dispersions, emulsions, suspensions, and solid forms (e.g., powders or liposomes) suitable for preparing solutions or suspensions after adding a liquid before use.

[0209] The compositions or medicaments according to the present invention as described herein can be administered using routes of administration well known in the art, such as parenteral administration, oral administration, inhalation administration, spray administration, rectal administration, nasal administration or administration via an implanted reservoir.

[0210] However, it should be understood that the total daily dosage of the compound, composition or drug will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dosage level for any particular patient will depend on a variety of factors, including the disease being treated and the severity of the disease; the activity of the compound used; the age, weight, general health, sex and diet of the subject; the time of administration, route of administration and excretion rate of the specific therapeutic agent used; the duration of treatment; drugs used in combination or concomitantly with the specific therapeutic agent; and similar factors well known in the medical field. For example, one skilled in the art is fully capable of starting the dosage of the compound at a level lower than that desired to achieve the desired therapeutic effect and gradually increasing the dosage until the desired effect is achieved. The total dosage required for each treatment may be administered in a single dose or in multiple doses.

[0211] In one embodiment, the dosage of the compound is about 0.01 mg to 500 mg per kg of patient body weight per day, which can be administered in a single dose or multiple doses. Preferably, the dosage level will be about 0.1 mg / kg to about 250 mg / kg per day; more preferably about 0.5 mg / kg to about 100 mg / kg per day. Suitable dosage levels can be about 0.01 mg / kg to 250 mg / kg per day, about 0.05 mg / kg to 100 mg / kg per day, or about 0.1 mg / kg to 50 mg / kg per day. Within this range, the dosage can be about 0.05 mg / kg to 0.5 mg / kg, about 0.5 mg / kg to 5 mg / kg, or about 5 mg / kg to 50 mg / kg per day. For oral administration, the composition is preferably provided in the form of a tablet containing about 1.0 mg to 1000 mg of active ingredient, particularly about 1.0 mg, about 5.0 mg, about 10.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 50.0 mg, about 75.0 mg, about 100.0 mg, about 150.0 mg, about 200.0 mg, about 250.0 mg, about 300.0 mg, about 400.0 mg, about 500.0 mg, about 600.0 mg, about 750.0 mg, about 800.0 mg, about 900.0 mg, and about 1000.0 mg of active ingredient, for adjusting the dosage according to the symptoms of the patient to be treated. The compound can be administered in a regimen of 1 to 4 times per day, preferably 1 or 2 times per day. However, it is understood that the specific dosage level and frequency of administration for any particular patient may vary and depend on a variety of factors, including the activity of the specific compound employed, the metabolic stability and duration of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, severity of the particular condition and the host being treated.

[0212] According to a first embodiment, the composition or medicament of the invention as described herein will be administered as the sole therapeutic agent. According to a second embodiment, the composition or medicament of the invention as described herein will be administered before, with, and / or after at least one other therapeutic agent. In one embodiment, the other therapeutic agent is suitable for treating a neurological disorder.

[0213] Another object of the present invention is a method for promoting neuronal cell survival and / or neuronal cell function. Another object of the present invention is a compound or composition according to the present invention as described herein, which is used to promote the survival of neuronal cells and / or the function of neuronal cells. According to one embodiment, the method or use includes the step of contacting neuronal cells with a therapeutically effective amount of a compound, composition or drug of the present invention as described herein. The method or use can be in vitro, ex vivo or in vivo.

[0214] Another object of the present invention is a method for rescuing neuronal cell function after neuronal cells are subjected to damage, events or conditions that are harmful to neuronal cell function. Another object of the present invention is a compound or composition according to the present invention as described herein, which is used to rescue neuronal cell function after neuronal cells are subjected to damage, events or conditions that are harmful to neuronal cell function. Such damage, events or conditions include, but are not limited to, neuronal stress, such as neuronal stress caused by hypoxia or ischemia; trauma; and exposure to toxic molecules, such as abnormal misfolded proteins, protein aggregates, excitotoxins, reactive oxygen species, endoplasmic reticulum stressors, mitochondrial stressors, Golgi antagonists, etc. According to one embodiment, the method or use includes the step of contacting neuronal cells with a therapeutically effective amount of a compound, composition or drug of the present invention as described herein. The method or use can be in vitro, ex vivo or in vivo.

[0215] Another object of the invention is a method of binding or modulating GFRα1 using a compound or composition according to the invention as described herein. Another object of the invention is a compound or composition according to the invention as described herein for binding or modulating GFRα1. According to a preferred embodiment, the compound or composition is used to activate GFRα1. In one embodiment, GFRα1 is human GFRα1, preferably SEQ ID NO: 1.

[0216] Another object of the invention is a method for activating the GFRα1 / RET signaling pathway using a compound or composition according to the invention as described herein. Another object of the invention is a compound or composition according to the invention as described herein for activating the GFRα1 / RET signaling pathway.

[0217] Another object of the invention is a method for detecting GFRα1 in a sample using a compound or composition according to the invention as described herein. Another object of the invention is a compound or composition according to the invention as described herein for detecting GFRα1 in a sample. In one embodiment, GFRα1 is human GFRα1, preferably SEQ ID NO: 1. In one embodiment, the compound according to the invention may be fused to a detectable label, such as a fluorophore or any other part that can re-emit light under light excitation, a radioactive label, a contrast agent, etc.

[0218] Preparation method

[0219] Synthesis of compounds

[0220] The compounds according to the present invention as described herein can be prepared by synthetic methods well known in the art.

[0221] Another object of the present invention is a process for the preparation of the compounds of the invention as described herein. According to one embodiment, the process is a Buchwald-Hartwig amination.

[0222] According to one embodiment, the method comprises the steps of reacting the following substances in the presence of a base and a metal catalyst:

[0223] Compound of formula (II)

[0224]

[0225] Among them, Z, R 5 , R 6 , R 7 and R 9 As defined herein in formula (I), and X represents halogen or -CF3SO3, and a compound of formula (III)

[0226]

[0227] Among them, W, R A To R D and R 1 To R 4 As defined herein in formula (I);

[0228] Thus, the compound of the present invention is obtained.

[0229] In one embodiment, the base is cesium carbonate (Cs2CO3), sodium carbonate (Na2CO3) or potassium carbonate (K2CO3). In a particular embodiment, the base is cesium carbonate (Cs2CO3). In one embodiment, the base is sodium tert-butyrate (t-BuONa), potassium tert-butyrate (t-BuOK) or potassium phosphate. In a particular embodiment, the base is sodium tert-butyrate (t-BuONa).

[0230] In one embodiment, the catalyst is a palladium catalyst. In a particular embodiment, the catalyst is a Pd(OAc)2 and racemic BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) system. In a particular embodiment, the catalyst is XPhos-Pd-G3.

[0231] In one embodiment, X represents halogen. In a particular embodiment, X represents Br.

[0232] In one embodiment, the reaction is carried out in a solvent. In a particular embodiment, the solvent is toluene. In one embodiment, the reaction is carried out under reflux.

[0233] According to another embodiment, the method comprises:

[0234] (a'-1) A step of reacting the following substances in the presence of a base and a metal catalyst:

[0235] Compound of formula (II)

[0236]

[0237] Among them, Z, R 5 , R 6 , R 7 and R 9 As defined herein in formula (I), and X represents halogen or -CF3SO3,

[0238] and a monoprotected piperazine of the formula (MPP) (i.e., wherein only one NH group is protected by a protecting group R P protected piperazine),

[0239]

[0240] Where R 1 To R 4 As defined herein in formula (I);

[0241] Thus, the compound of formula (IV) is obtained

[0242]

[0243] Among them, Z, R 1 To R 4 , R 5 , R 6 , R 7 and R 9 As defined herein in formula (I), and R P is a protecting group; then

[0244] (a'-2) a step of deprotecting the compound of formula (IV);

[0245] Thus, the compound of formula (V) is obtained

[0246]

[0247] Among them, Z, R 1 To R 4 , R 5 , R 6 , R 7 and R 9 As defined herein in formula (I); and

[0248] (a'-3) a step of reacting a compound of formula (V) with a compound of formula (VI) in the presence of a peptide coupling agent and a base.

[0249]

[0250] Where W and R A To R D As defined in formula (I) herein,

[0251] Thus, the compound of the present invention is obtained.

[0252] In one embodiment, the base and / or catalyst in step (a'-1) is as described above in step (a-1). In one embodiment, X represents halogen. In a particular embodiment, X represents Br.

[0253] The protecting group may be any protecting group known in the art, such as tert-butyloxycarbonyl (Boc). The protecting group may be removed in step (a'-2) by any method known in the art appropriate to the nature of the protecting group, such as the addition of a strong Bronsted acid (eg, hydrochloric acid [HCl]).

[0254] The peptide coupling agent in step (a'-3) can be any peptide coupling agent known in the art, such as 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU).

[0255] The base in step (a'-3) can be any base known in the art, such as an amine base. According to one embodiment, the amine is triethylamine (Et3N) or diisopropylethylamine (iPr2NEt).

[0256] In one embodiment, the reaction of step (a'-3) is carried out in a solvent. In a particular embodiment, the solvent is dimethylformamide (DMF) and / or tetrahydrofuran (THF). In a particular embodiment, the solvent is dichloroethane (DCE) and / or acetonitrile (MeCN). In one embodiment, the reaction is carried out at room temperature (RT).

[0257] In one embodiment, the method further comprises a post-processing step (b). In one embodiment, the post-processing step (b) comprises a step of extracting 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 post-processing step (b) comprises a filtration step. In a particular embodiment, the filtration step is carried out at 40 °C. In one embodiment, the post-treatment step (b) comprises a step of concentrating under reduced pressure.

[0258] In one embodiment, the method further comprises a purification step (c). In one embodiment, the purification step (c) comprises purification by chromatography. In a particular embodiment, the chromatography is flash chromatography (FC) (e.g., cHex / EtOAc gradient), preparative thin layer chromatography (PTLC) or semi-preparative high performance liquid chromatography (HPLC).

[0259] Synthetic intermediates

[0260] Another object of the present invention is a compound of formula (II)

[0261]

[0262] Among them, Z, R 5 , R 6 , R 7 and R 9 As defined herein in formula (I), X represents halogen or -CF3SO3.

[0263] Another object of the present invention is a compound of formula (III)

[0264]

[0265] Among them, W, R A To R D and R 1 To R 4 As defined herein in formula (I).

[0266] Another object of the present invention is a compound of formula (IV)

[0267]

[0268] Among them, Z, R 1 To R 4 , R 5 , R 6 , R 7 and R 9 As defined herein in formula (I), and R P is a protecting group (eg Boc).

[0269] Another object of the present invention is a compound of formula (V)

[0270]

[0271] Among them, Z, R 1 To R 4 , R 5 , R 6 , R 7 and R 9 As defined herein in formula (I).

[0272] Example

[0273] The present invention is further illustrated by the following examples.

[0274] Example 1: Synthesis of compounds

[0275] Common Materials and Common Methods

[0276] abbreviation

[0277] List of abbreviations:

[0278] Ac:Acetyl

[0279] Ar: Argon

[0280] BINAP: (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)

[0281] cHex: Cyclohexane

[0282] DCM: dichloromethane

[0283] DMF: dimethylformamide

[0284] Et: Ethyl

[0285] FC: Flash chromatography

[0286] m-CPBA: meta-chloroperbenzoic acid

[0287] MTBE: Methyl tert-butyl ether

[0288] PTLC: Preparative Thin Layer Chromatography

[0289] RT: Room temperature

[0290] TBTU: 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate

[0291] TFA: trifluoroacetic acid

[0292] THF: Tetrahydrofuran

[0293] XPhos: dicyclohexyl[2',4',6'-tri(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphine

[0294] Analytical methods

[0295] Recorded with a Bruker ULTRASHIELD 400 spectrometer 1 H NMR spectroscopy (400 MHz) and 19F NMR spectra (376 MHz). Spectra were processed and analyzed using MestReNova. Data are presented in the following order: chemical shift in ppm, referenced to the internal solvent signal, multiplicity, coupling constant J in Hertz, and number of protons.

[0296] Reverse phase HPLC / MS analysis was performed using a Waters Alliance 2795 HPLC equipped with an autosampler, an online membrane degasser, a column oven 10 (T = 45°C), a UV detector, and a ZQ quadrupole mass detector operating in ionization electrospray mode. The analyzed compounds (0.1 mg to 0.3 mg) were dissolved in a minimum amount of DMSO completed with acetonitrile (total volume: 1 mL). Standard analytical parameters: flow rate: 1 mL / min, V 进样 : 5 μL. Acidic conditions: Waters XSelect CSH C18 column (3.5 μm, 2.1 x 15 50 mm). Gradient: (H2O + 0.04 vol / vol % HCO2H (10 mM)) / ACN from 95 / 5 to 0 / 100 in 2.5 minutes. Basic conditions: Waters Xbridge C18 column (3.5 μm, 2.1 x 50 mm). Gradient: (H2O + 0.06 vol / vol % NH3 (aq.) (10 mM)) / ACN from 95 / 5 to 0 / 100 in 2.5 minutes.

[0297] General synthetic method

[0298] General Scheme 1 (GP-1): Thiol Alkylation

[0299] To a DMF solution of 3-bromo-4-methoxybenzenethiol, an alkyl halide or halide-like compound and KCO are added. The mixture is stirred at the desired temperature for the desired time. The reaction mixture is partitioned between water and MTBE. The layers are separated and the aqueous phase is extracted with MTBE. The combined organic extracts are washed (brine), dried (NaSO), filtered and concentrated under reduced pressure. The residue is purified by FC (cHex / EtOAc gradient) to give the desired thioether.

[0300] General Scheme 2 (GP-2): Thioether Oxidation

[0301] At 0°C, m-CPBA was added to a DCM solution of the thioether from GP-1. The mixture was stirred for the desired time at RT. A saturated aqueous solution of Na2S2O3, a saturated aqueous solution of NaHCO3 and EtOAc were added. The mixture was stirred vigorously for 10 minutes. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc gradient) to obtain the desired sulfone.

[0302] General Scheme 3 (GP-3): Buchwald coupling using Pd(OAc)2 / racemic BINAP

[0303] The aryl bromide from GP-2, the desired piperazine, Cs2CO3, Pd(OAc)2, and racemic BINAP were charged into a microwave reaction bottle. The bottle was flushed with argon and degassed toluene was added. The bottle was sealed and the reaction was stirred at reflux in a preheated heating block for the desired time. After cooling to RT, EtOAc was added and the suspension was stirred at 4 °C for 1 h. Filter (EtOAc rinse). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc gradient) or PTLC to give the desired product.

[0304] General Protocol 4 (GP-4): Buchwald coupling using XPhos-Pd-G3

[0305] The aryl bromide from GP-2, the desired piperazine, t-BuONa, and XPhos-Pd-G3 were charged to a microwave reaction bottle. The bottle was flushed with argon and degassed toluene was added. The bottle was sealed and the reaction was stirred at reflux in a preheated heating block for the desired time. After cooling to RT, EtOAc was added and the suspension was stirred at 4 °C for 1 h. Filter (EtOAc rinse). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc gradient) or PTLC to give the desired product.

[0306] Synthesis of intermediate compounds

[0307] Using GP-1 to synthesize thioether

[0308] 2-Bromo-4-(1-ethylpropylthio)-1-methoxybenzene (I-001)

[0309]

[0310] Using GP-1, I-001 was obtained as a colorless oil in 99% yield using 3-bromo-4-methoxybenzenethiol (156 mg, 712 μmol, 1 eq), 3-bromopentane (215 mg, 1.42 mmol, 2 eq) and K2CO3 (197 mg, 1.42 mmol, 2 eq) in DMF (2.1 mL) at RT for 16 h.

[0311] 1 H NMR (400 MHz, chloroform-d) δ 7.65 (d, J = 2.2 Hz, 1H), 7.37 (dd, J = 8.5, 2.2 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 3.91 (s, 3H), 2.84 (p, J = 6.3 Hz, 1H), 1.82-1.39 (m, 4H), 1.03 (t, J = 7.4 Hz, 6H). MS (ESI + ): [M+H] + 289.0 / 291.0.

[0312] 2-Bromo-4-cyclopentylthio-1-methoxybenzene (I-002)

[0313]

[0314] Using GP-1, I-002 was obtained as a light yellow oil in 80% yield using 3-bromo-4-methoxybenzenethiol (560 mg, 2.56 mmol, 1 eq), iodocyclopentane (442 μL, 3.83 mmol, 1.5 eq) and K2CO3 (530 mg, 3.83 mmol, 1.5 eq) in DMF (13 mL) at RT for 4 h.

[0315] 1 H NMR (400 MHz, chloroform-d) δ 7.54 (d, J = 2.2 Hz, 1H), 7.25 (dd. J = 8.5, 2.2 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 3.80 (s, 3H), 3.43-3.32 (m, 1H), 1.95-1.83 (m, 2H), 1.75-1.62 (m, 2H), 1.58-1.43 (m, 4H). MS (ESI + ): [M+H] + 287.0 / 289.0.

[0316] 2-Bromo-4-cyclohexylthio-1-methoxybenzene (I-003)

[0317]

[0318] Using GP-1, I-003 was obtained as a light yellow oil in 50% yield using 3-bromo-4-methoxybenzenethiol (124 mg, 566 μmol, 1 eq), iodocyclohexane (110 μL, 849 μmol, 1.5 eq) and K2CO3 (117 mg, 849 μmol, 1.5 eq) in DMF (2.3 mL) at RT for 60 h.

[0319] 1 H NMR (400 MHz, chloroform-d) δ 7.67 (d, J = 2.2 Hz, 1H), 7.37 (t, J = 2.0 Hz, 1H), 6.84 (d, J = 2.8 Hz, 1H), 3.91 (s, 3H), 3.03-2.82 (m, 1H), 2.05-1.87 (m, 2H), 1.85-1.72 (m, 2H), 1.69-1.58 (m, 1H), 1.41-1.15 (m, 5H). MS (ESI + ): [M+H] + 301.0 / 303.0.

[0320] 2-Bromo-4-(cyclopropylmethylthio)-1-methoxybenzene (I-004)

[0321]

[0322] Using GP-1, 1-004 was obtained as a light yellow oil in 87% yield using 3-bromo-4-methoxybenzenethiol (120 mg, 548 μmol, 1 eq), (bromomethyl)cyclopropane (80 μL, 0.82 mmol, 1.5 eq) and K2CO3 (114 mg, 822 μmol, 1.5 eq) in DMF (2.7 mL) at RT for 4 h.

[0323] 1 H NMR (400MHz, DMSO-d6) δ7.40 (d, J=2.3Hz, 1H), 7.20 (dd, J=8.6.2.2Hz, 1H).6.88 (d, J=8.6Hz, 1H), 3 .65(s, 3H), 2.66(d, J=7.0Hz, 2H), 0.80-0.69(m, 1H), 0.36-0.25(m, 2H), 0.05-0.06(m, 2H).MS(ESI + ): [M+H] + 273.0 / 275.0.

[0324] 2-Bromo-4-(cyclopropylmethylthio)-1-methoxybenzene (I-005)

[0325]

[0326] Using GP-1, 3-bromo-4-methoxybenzenethiol (170 mg, 776 μmol, 1 eq.), bromocyclobutane (98 μL, 1.2 mmol, 1.5 eq.) and K2CO3 (161 mg, 1.16 mmol, 1.5 eq.) were used in DMF (3.9 mL) at 80° C. for 16 hours to obtain I-005 as a light yellow oil in 71% yield. Purification by FC (cHex / EtOAc=90 / 10 to 60 / 40).

[0327] 1 H NMR (400 MHz, chloroform-d) δ 7.53 (d, J = 2.2 Hz, 1H), 7.24 (d, J = 2.2 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 3.88 (s, 3H), 3.75 (p, J = 7.8 Hz, 1H), 2.42-2.31 (m, 2H), 2.05-1.87 (m, 4H). MS (ESI + ): [M+H] + 273.0 / 275.0.

[0328] 3-(3-Bromo-4-methoxy-phenyl)thioxetane (I-006)

[0329]

[0330] Using GP-1, 3-bromo-4-methoxybenzenethiol (150 mg, 685 μmol, 1 eq.), 3-bromooxetane (78 μL, 1.03 mmol, 1.5 eq.) and K2CO3 (141 mg, 1.03 mmol, 1.5 eq.) were used in DMF (3.4 mL) at RT for 2 hours to obtain I-006 as a light yellow oil in 69% yield. Purification by FC (cHex / EtOAc=90 / 10 to 60 / 40).

[0331] 1 H NMR (400 MHz, chloroform-d) δ 7.54 (d, J = 2.2 Hz, 1H), 7.28 (dd, J = 8.6, 2.4 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 4.95 (t, J = 7.0 Hz, 2H), 4.61 (t, J = 6.5 Hz, 2H), 4.40-4.27 (m, 1H), 3.89 (s, 3H). MS (ESI + ): [M+H] + 275.0 / 277.0.

[0332] 2-Bromo-4-(cyclobutylmethylthio)-1-methoxybenzene (I-007)

[0333]

[0334] Using GP-1, 3-bromo-4-methoxybenzenethiol (120 mg, 548 μmol, 1 eq), (bromomethyl)cyclobutane (92 μL, 0.82 mmol, 1.5 eq) and K2CO3 (114 mg, 0.82 mmol, 1.5 eq) were used in DMF (2.7 mL) at RT for 2 hours to obtain I-007 as a colorless oil in 64% yield. Purification by FC (cHex / EtOAc=90 / 10 to 60 / 40).

[0335] 1 H NMR (400MHz, chloroform-d) δ7.57 (d, J=2.2Hz, 1H), 7.29 (dd, J=8.5.2.3Hz, 1H), 6.81 (d, J=8.5Hz, 1H), 3.88 (s, 3H), 2. 89 (d, J=7.6Hz, 2H), 2.46 (hept, J=7.6Hz, 1H), 2.15-2.02 (m, 2H), 1.90-1.75 (m, 2H), 1.75-1.63 (m, 2H).MS (ES] + ): [M+H] + 287.0 / 289.0.

[0336] 2-Bromo-4-(cyclopentylmethylthio)-1-methoxybenzene (I-008)

[0337]

[0338] Using GP-1, 3-bromo-4-methoxybenzenethiol (120 mg, 548 μmol, 1 eq.), (bromomethyl)cyclobutane (103 μL, 822 μmol, 1.5 eq.) and K2CO3 (114 mg, 822 μmol, 1.5 eq.) were used in DMF (2.7 mL) at RT for 2 hours to obtain I-008 as a colorless oil in 30% yield. Purification by FC (cHex / EtOAc=90 / 10 to 60 / 40).

[0339] 1H NMR (400MHz, chloroform-d) δ7.58 (d, J=2.3Hz, 1H), 7.30 (dd, J=8.5, 2.3Hz, 1H), 6.82 (d, J=8.6Hz, 1H), 3.88 (s, 3H), 2. 84 (d, J=7.3Hz, 2H), 2.05 (hept, J=7.6Hz, 1H), 1.89-1.76 (m, 2H), 1.63-1.50 (m, 4H), 1.33-1.18 (m, 2H).MS (ESI + ): [M+H] + 301.0 / 303.0.

[0340] 4-Benzylthio-2-bromo-1-methoxybenzene (I-009)

[0341]

[0342] Using GP-1, 3-bromo-4-methoxybenzenethiol (170 mg, 776 μmol, 1 eq.), benzyl bromide (142 μL, 1.16 mmol, 1.5 eq.) and K2CO3 (161 mg, 1.16 mmol, 1.5 eq.) were used in DMF (3.9 mL) at RT for 1 hour to obtain I-009 as a colorless oil in 100% yield. Purification by FC (cHex / EtOAc=90 / 10 to 60 / 40).

[0343] 1 H NMR (400 MHz, chloroform-d) δ 7.55 (d, J = 2.2 Hz, 1H), 7.45-7.24 (m, 5H), 7.22 (d, J = 2.1 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 4.03 (s, 2H), 3.89 (s, 3H). MS (ESI + ): [M+H] + 309.0 / 311.0.

[0344] 2-Bromo-4-(2,2-dimethylpropylthio)-1-methoxybenzene (I-010)

[0345]

[0346] Using GP-1, 3-bromo-4-methoxybenzenethiol (170 mg, 776 μmol, 1 eq), 1-bromo-2,2-dimethylpropane (147 μL, 1.16 mmol, 1.5 eq) and K2CO3 (161 mg, 1.16 mmol, 1.5 eq) were used in DMF (3.9 mL) at RT for 1 hour to obtain I-010 as a colorless oil in 22% yield. Purification by FC (cHex / EtOAc=90 / 10 to 60 / 40).

[0347] 1 H NMR (400 MHz, chloroform-d) δ 7.58 (d, J = 2.3 Hz, 1H), 7.31 (dd, J = 8.6, 2.3 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 3.87 (s, 3H), 2.82 (s, 2H), 1.01 (s, 9H). MS (ESI + ): [M+H] + 289.0 / 291.0.

[0348] 2-Bromo-4-isopropylthio-1-methoxybenzene (I-011)

[0349]

[0350] Using GP-1, 3-bromo-4-methoxybenzenethiol (120 mg, 548 μmol, 1 eq), 1-bromo-2,2-dimethylpropane (77 μL, 0.82 mmol, 1.5 eq) and K2CO3 (114 mg, 822 μmol, 1.5 eq) were used in DMF (2.7 mL) at RT for 4 hours to obtain I-011 as a colorless oil in 42% yield. Purification by FC (cHex / EtOAc=90 / 10 to 60 / 40).

[0351] 1 H NMR (400 MHz, chloroform-d) δ 7.57 (d, J = 2.2 Hz, 1H), 7.28 (dd, J = 8.5, 2.2 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 3.81 (s, 3H), 3.13 (hept, J = 6.7 Hz, 1H), 1.17 (d, J = 6.6 Hz, 6H). MS (ES) + ): [M+H] + 261.0 / 263.0.

[0352] 2-Bromo-4-isobutylthio-1-methoxybenzene (I-023)

[0353]

[0354] Using GP-1, 3-bromo-4-methoxy-benzenethiol (219 mg, 999 μmol, 1 eq), 1-bromo-2-methylpropane (120 μL, 1.10 mmol, 1.1 eq) and K2CO3 (145 mg, 1.05 mmol, 1.05 eq) were used in DMF (9.1 mL) at RT for 5 hours to obtain I-023 as a colorless oil in 65% yield. Purification by FC (cHex / EtOAc=100 / 0 to 80 / 20).

[0355] 1 H NMR (400MHz, chloroform-d) δ7.58 (d, J=2.3Hz, 1H), 7.30 (dd, J=8.5, 2.3Hz, 1H), 6.82 (d, J=8.5Hz, 1H), 3 .88 (s, 3H), 2.72 (d, J=6.9Hz, 2H), 1.80 (hcpt, J=13.4, 6.7Hz, 1H), 1.01 (d, J=6.7Hz, 6H).MS (ESI + ): [M+H] + 275.0 / 277.0.

[0356] 2-Bromo-1-methoxy-4-(1-methylthio)benzene (I-025)

[0357]

[0358] Using GP-1, 3-bromo-4-methoxy-benzenethiol (1.37 g, 6.27 mmol, 1 eq), 2-bromopentane (1.16 mL, 9.41 mmol, 1.5 eq) and KCO (1.30 g, 9.41 mmol, 1.5 eq) were used in DMF (25 mL) at RT for 5 hours to obtain I-025 as a colorless oil in 88% yield. The desired product I-025 was contaminated with 10% disulfide and was used in further reactions without further purification.

[0359] 1 H NMR (400 MHz, chloroform-d) δ 7.64 (d, J = 2.2 Hz, 1H), 7.35 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 3.89 (d, J = 1.3 Hz, 4H), 3.13-2.96 (m, 1H), 1.51-1.38 (m, 3H). 1.22 (d, J = 6.7 Hz, 3H), 0.95-0.86 (m, 3H). MS (ESI + ): [M+H] + 288.9 / 290.9.

[0360] 2-Bromo-4-(2-cyclopentylethylthio)-1-methoxybenzene (I-032)

[0361]

[0362] Using GP-1, 3-bromo-4-methoxy-benzenethiol (270 mg, 1.23 mmol, 1 eq), 2-bromoethylcyclopentane (0.21 mL, 1.5 mmol, 1.2 eq) and K2CO3 (255 mg, 1.85 mmol, 1.5 eq) were used in DMF (6.2 mL) at RT for 2 hours to obtain I-032 as a colorless oil in 26% yield. Purification by FC (cHex / EtOAc=95 / 5 to 60 / 40).

[0363] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.57 (d, J = 2.2 Hz, 1H), 7.29 (dd, J = 8.5, 2.3 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 3.88 (s, 3H), 2.87-2.80 (m, 2H), 1.94-1.82 (m, 1H), 1.80-1.72 (m, 2H), 1.61-1.47 (m, 6H), 1.12-1.01 (m, 2H). MS (ESI + ): [M+H] + 315.0 / 317.0.

[0364] 2-Bromo-4-butylthio-1-methoxybenzene (I-033)

[0365]

[0366] Using GP-1, 3-bromo-4-methoxy-benzenethiol (150 mg, 0.685 mmol, 1 eq), 1-bromobutane (0.11 mL, 1.03 mmol, 1.5 eq) and K2CO3 (142 mg, 1.03 mmol, 1.5 eq) were used in DMF (3.4 mL) at RT for 2 hours to obtain I-033 as a colorless oil in 53% yield. Purification by FC (cHex / EtOAc=90 / 10 to 60 / 40).

[0367] 1H NMR (400 MHz, CHLOROFORM-d) δ 7.58 (d, J = 2.2 Hz, 1H), 7.30 (dd, J = 8.5v2.3 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 3.88 (s, 3H), 2.87-2.78 (m, 2H), 1.61-1.55 (m, 2H), 1.49-1.36 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). MS (ESI + ): [M+H] + 275.0 / 277.0.

[0368] 2-Bromo-4-(2-ethylbutylthio)-1-methoxybenzene (I-034)

[0369]

[0370] Using GP-1, 3-bromo-4-methoxy-benzenethiol (170 mg, 0.776 mmol, 1 eq), 3-(bromomethyl)pentane (0.16 mL, 1.2 mmol, 1.5 eq) and K2CO3 (161 mg, 1.16 mmol, 1.5 eq) were used in DMF (3.9 mL) at RT for 16 hours to obtain I-034 as a colorless oil in 90% yield. Purification by FC (cHex / EtOAc=90 / 10 to 60 / 40).

[0371] 1 H NMR (400 MHz, chloroform-d) δ 7.57 (d, J = 2.3 Hz, 1H), 7.29 (dd, J = 8.5, 2.3 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 3.87 (s, 3H), 2.84-2.79 (m, 2H), 1.48-1.38 (m, 5H), 0.88-0.83 (m, 6H). MS (ESI + ): [M+H] + 303.0 / 305.0.

[0372] 2-Bromo-1-methoxy-4-sec-butylthiobenzene (I-035)

[0373]

[0374] Using GP-1, 3-bromo-4-methoxy-benzenethiol (150 mg, 0.684 mmol, 1 eq), 2-bromobutane (0.11 mL, 1.0 mmol, 1.5 eq) and K2CO3 (142 mg, 1.03 mmol, 1.5 eq) were used in DMF (3.4 mL) at RT for 2 hours to obtain I-035 as a colorless oil in 53% yield. Purification by FC (cHex / EtOAc=90 / 10 to 60 / 40).

[0375] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.64 (d, J = 2.2 Hz, 1H), 7.35 (dd, J = 8.5, 2.2 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H), 3.89 (s, 3H), 3.05-2.94 (m, 1H), 1.67-1.56 (m, 1H), 1.53-1.40 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H), 1.00 (t, J = 7.4 Hz, 3H). MS (ESI + ): [M+H] + 275.0 / 277.0.

[0376] 2-Bromo-1-methoxy-4-(1-methyl-3-phenyl-propyl)sulfanyl-benzene (I-036)

[0377]

[0378] Using GP-1, 3-bromo-4-methoxy-benzenethiol (200 mg, 0.913 mmol, 1 eq), (1-methyl-3-phenyl-propyl) methanesulfonate (250 mg, 1.10 mmol, 1.2 eq) and K2CO3 (189 mg, 1.37 mmol, 1.5 eq) were used in DMF (4.6 mL) at RT for 2 hours to obtain I-036 as a colorless oil in 40% yield. Purification by FC (cHex / EtOAc=100 / 0 to 70 / 30).

[0379] 1 H NMR (400 MHz, chloroform-d) δ 7.63 (d, J = 2.2 Hz, 1H), 7.38-7.26 (m, 3H), 7.22-7.12 (m, 3H), 6.83-6.75 (m, 1H), 3.89 (s, 3H), 3.04 (h, J = 6.8 Hz, 1H), 2.81-2.70 (m, 2H), 2.01-1.68 (m, 2H). 1.29-1.25 (d, J = 6.8 Hz, 3H).

[0380] 2-Bromo-1-methoxy-4-(1-methyl-4-phenyl-butyl)sulfanyl-benzene (I-037)

[0381]

[0382] Using GP-1, 3-bromo-4-methoxy-benzenethiol (150 mg, 0.684 mmol, 1 eq), (1-methyl-3-phenyl-butyl) methanesulfonate (199 mg, 0.821 mmol, 1.2 eq) and K2CO3 (142 mg, 1.03 mmol, 1.5 eq) were used in DMF (4.6 mL) at RT for 2 hours to obtain I-037 as a colorless oil in 40% yield. Purification by FC (cHex / EtOAc=100 / 0 to 70 / 30).

[0383] 1 H NMR (400 MHz, chloroform-d) δ 7.62 (d, J = 2.2 Hz, 1H), 7.35-7.27 (m, 3H), 7.23-7.03 (m, 3H), 6.80 (d, J = 8.5 Hz, 1H), 3.89 (s, 3H), 3.05 (h, J = 6.7 Hz, 1H), 2.66-2.56 (m, 2H), 1.88-1.69 (m, 2H), 1.67-1.46 (m, 2H), 1.22 (d, J = 6.7 Hz, 3H).

[0384] 2-Bromo-4-(1-ethyl-3-phenyl-propyl)thio-1-methoxybenzene (I-038)

[0385]

[0386] Using GP-1, 3-bromo-4-methoxy-benzenethiol (200 mg, 0.913 mmol, 1 eq), (1-methyl-3-phenyl-propyl) methanesulfonate (265 mg, 1.10 mmol, 1.2 eq) and K2CO3 (189 mg, 1.37 mmol, 1.5 eq) were used in DMF (4.6 mL) at RT for 2 hours to obtain I-038 as a colorless oil in 40% yield. Purification by FC (cHex / EtOAc=100 / 0 to 70 / 30).

[0387] 1H NMR (400 MHz, chloroform-d) δ 7.63 (d, J = 2.2 Hz, 1H), 7.37-7.26 (m, 3H), 7.23-7.13 (m, 3H), 6.81 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 2.94-2.68 (m, 3H), 1.94-1.72 (m, 2H), 1.69-1.51 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H).

[0388] 2-Bromo-4-(1-ethyl-4-phenyl-butyl)thio-1-methoxybenzene (I-039)

[0389]

[0390] Using GP-1, 3-bromo-4-methoxy-benzenethiol (87 mg, 0.40 mmol, 1.2 eq), (1-ethyl-4-phenyl-butyl) methanesulfonate (85 mg, 0.33 mmol, 1.0 eq) and K2CO3 (69 mg, 0.50 mmol, 1.5 eq) were used in DMF (1.7 mL) at RT for 2 hours to obtain I-039 as a colorless oil in 40% yield. Purification by FC (cHex / EtOAc=100 / 0 to 70 / 30).

[0391] 1 H NMR (400 MHz, chloroform-d) δ 7.53 (d, J = 2.2 Hz, 1H), 7.26-7.16 (m, 3H), 7.16-7.04 (m, 3H), 6.71 (d, J = 8.5 Hz, 1H), 3.81 (s, 3H), 2.79 (p, J = 6.4 Hz, 1H), 2.53 (t, J = 7.6 Hz, 2H), 1.84-1.62 (m, 2H), 1.57-1.38 (m, 4H), 0.90 (t, J = 7.3 Hz, 3H).

[0392] Using GP-2 to synthesize sulfone:

[0393] 2-Bromo-4-(1-ethylpropylsulfonyl)-1-methoxybenzene (I-012)

[0394]

[0395] Using GP-2, I-001 (200 mg, 285 μmol, 1 eq) and m-CPBA (70% wet, 371 mg, 1.51 mmol, 2.2 eq) were used in DCM (3.4 mL) at RT for 2 hours to obtain I-012 as a colorless oil in 96% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0396] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.07 (d, J = 2.2 Hz, 1H), 7.83 (dd, J = 8.6, 2.2 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 4.01 (s, 3H), 2.80 (tt, J = 7.2, 4.8 Hz, 1H), 1.97-1.81 (m, 2H), 1.80-1.63 (m, 2H), 1.03 (t, J = 7.5 Hz, 6H). MS (ESI + ): [M+H] + 321.0 / 323.0.

[0397] 2-Bromo-4-cyclopentylsulfonyl-1-methoxybenzene (I-013)

[0398]

[0399] Using GP-2, I-002 (590 mg, 332 μmol, 1 eq) and m-CPBA (70% wet, 1.01 g, 4.52 mmol, 2.2 eq) were used in DCM (3.4 mL) at RT for 2 hours to obtain I-013 as a colorless oil in 94% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0400] 1 H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 2.3 Hz, 1H), 7.84 (dd, J = 8.6, 2.3 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 4.00 (s, 3H), 3.48 (tt, J = 8.8, 7.2 Hz, 1H), 2.15-1.99 (m, 2H), 1.97-1.72 (m, 4H), 1.69-1.56 (m, 2H). MS (ESI + ): [M+H] + 319.0 / 321.0.

[0401] 2-Bromo-4-cyclohexylsulfonyl-1-methoxybenzene (I-014)

[0402]

[0403] Using GP-2, I-003 (100 mg, 332 μmol, 1 eq) and m-CPBA (70% wet, 275 g, 1.23 mmol, 3.7 eq) were used in DCM (2.2 mL) at RT for 2 hours to obtain I-014 as a colorless oil in 94% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0404] 1 H NMR (400 MHz, chloroform-d) δ 8.03 (d, J = 2.2 Hz, 1H), 7.78 (dd, J = 8.6, 2.2 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 3.98 (s, 3H), 2.87 (tt, J = 12.1.3.4 Hz, 1H), 2.13-2.01 (m, 2H), 1.95-1.81 (m, 2H), 1.39 (qd, J = 12.3, 3.4 Hz, 2H), 1.28-1.09 (m.4H). MS (ESI + ): [M+H] + 333.0 / 335.0.

[0405] 2-Bromo-4-(cyclopropylmethylsulfonyl)-1-methoxybenzene (I-015)

[0406]

[0407] Using GP-2, I-004 (130 mg, 476 μmol, 1 eq) and m-CPBA (70% wet, 258 mg, 1.05 mmol, 2.2 eq) were used in DCM (2.4 mL) at RT for 2 hours to obtain I-015 as a colorless oil in 76% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0408] 1 H NMR (400 MHz, chloroform-d) δ 8.11 (d, J = 2.3 Hz, 1H), 7.86 (dd, J = 8.6, 2.2 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 3.99 (s, 3H), 3.01 (d, J = 7.2 Hz, 2H), 1.09-0.94 (m, 1H), 0.66-0.53 (m, 2H), 0.22-0.09 (m, 2H). MS (ESI + ): [M+H] + 305.0 / 306.9.

[0409] 2-Bromo-4-cyclobutylsulfonyl-1-methoxybenzene (I-016)

[0410]

[0411] Using GP-2, I-005 (150 mg, 549 μmol, 1 eq) and m-CPBA (70% wet, 298 mg, 1.21 mmol, 2.2 eq) were used in DCM (2.7 mL) at RT for 2 hours to obtain I-016 as a colorless oil in 66% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0412] 1 H NMR (400 MHz, chloroform-d) δ 8.03 (d, J = 2.2 Hz, 1H), 7.79 (dd, J = 8.6, 2.3 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 3.97 (s, 3H), 3.84-3.73 (m, 1H), 2.61-2.48 (m, 2H), 2.25-2.13 (m, 2H), 2.05-1.91 (m, 2H). MS (ESI + ): [M+H] + 304.9 / 307.0.

[0413] 3-(3-Bromo-4-methoxy-phenyl)sulfonyloxetane (I-017)

[0414]

[0415] Using GP-2, I-006 (130 mg, 472 μmol, 1 eq) and m-CPBA (70% wet, 256 mg, 1.04 mmol, 2.2 eq) were used in DCM (2.4 mL) at RT for 16 hours to obtain I-017 as a colorless oil in 69% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0416] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.07 (d, J = 2.2 Hz, 1H), 7.85 (dd, J = 8.7, 2.3 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 4.96-4.89 (m, 2H), 4.80 (t, J = 7.7 Hz, 2H), 4.44 (tt, J = 8.1, 6.2 Hz, 1H), 3.99 (s, 3H). MS (ESI + ): [M+H] + 307.0 / 309.0.

[0417] 2-Bromo-4-(cyclobutylmethylsulfonyl)-1-methoxybenzene (I-018)

[0418]

[0419] Using GP-2, I-007 (100 mg, 348 μmol, 1 eq) and m-CPBA (70% wet, 119 mg, 766 μmol, 2.2 eq) were used in DCM (1.7 mL) at RT for 16 hours to obtain I-018 as a colorless oil in 54% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0420] 1 H NMR (400 MHz, chloroform-d) δ 8.03 (d, J = 2.3 Hz, 1H), 7.79 (dd, J = 8.7, 2.3 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 3.97 (s, 3H), 3.18 (d, J = 7.3 Hz. 2H), 2.68 (tt, J = 15.6, 7.7 Hz, 1H), 2.12-2.01 (m, 2H), 1.98-1.68 (m, 4H). MS (ESI + ): [M+H] + 319.0 / 320.9.

[0421] 2-Bromo-4-(cyclopentylmethylsulfonyl)-1-methoxybenzene (I-019)

[0422]

[0423] Using GP-2, I-008 (50 mg, 166 μmol, 1 eq) and m-CPBA (70% wet, 90 mg, 0.37 mmol, 2.2 eq) were used in DCM (0.8 mL) at RT for 16 hours to obtain I-019 as a colorless oil in 100% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0424] 1 H NMR (400 MHz, chloroform-d) δ 8.04 (d, J = 2.3 Hz, 1H), 7.80 (dd, J = 8.6, 2.3 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 3.96 (s, 3H), 3.10 (d, J = 6.8 Hz, 2H), 2.28-2.15 (m, 1H), 1.92-1.81 (m, 2H), 1.66-1.47 (m, 4H), 1.26-1.14 (m, 2H). MS (ESI + ): [M+H] + 332.9 / 335.0.

[0425] 4-Benzylsulfonyl-2-bromo-1-methoxybenzene (I-020)

[0426]

[0427] Using GP-2, I-009 (240 mg, 776 μmol, 1 eq) and m-CPBA (70% wet, 421 mg, 1.70 mmol, 2.2 eq) were used in DCM (3.9 mL) at RT for 2 hours to obtain I-020 as a colorless oil in 100% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0428] 1 H NMR (400 MHz, chloroform-d) δ 7.76 (d, J = 2.3 Hz, 1H), 7.49 (dd, J = 8.6, 2.3 Hz, 1H), 7.38-7.27 (m, 3H), 7.13-7.07 (m, 2H), 6.86 (d, J = 8.7 Hz, 1H), 4.29 (s, 2H), 3.95 (s, 3H). MS (ESI + ): [M+H] + 341.0 / 342.9.

[0429] 2-Bromo-4-(2,2-dimethylpropylsulfonyl)-1-methoxybenzene (I-021)

[0430]

[0431] Using GP-2, I-010 (50 mg, 173 μmol, 1 eq) and m-CPBA (70% wet, 94 mg, 0.38 mmol, 2.2 eq) were used in DCM (0.9 mL) at RT for 16 hours to obtain I-021 as a colorless oil in 72% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0432] 1 H NMR (400 MHz, chloroform-d) δ 8.08 (d, J = 2.3 Hz, 1H), 7.84 (dd, J = 8.7, 2.3 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 3.98 (s, 3H), 3.01 (s, 2H), 1.19 (s, 9H). MS (ESI + ): [M+H] + 321.0 / 322.9.

[0433] 2-Bromo-4-isopropylsulfonyl-1-methoxybenzene (I-022)

[0434]

[0435] Using GP-2, I-011 (60 mg, 230 μmol, 1 eq) and m-CPBA (70% wet, 125 mg, 505 μmol, 2.2 eq) were used in DCM (1.5 mL) at RT for 2 hours to obtain I-022 as a colorless oil in 67% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0436] 1 H NMR (400 MHz, chloroform-d) δ 8.04 (d, J = 2.3 Hz, 1H), 7.80 (dd, J = 8.6, 2.3 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 3.98 (s, 3H), 3.22-3.11 (m, 1H), 1.29 (d, J = 6.8 Hz, 6H). MS (ESI + ): [M+H] + 293.0 / 295.0.

[0437] 2-Bromo-1-methoxy-4-(1-methylbutylsulfonyl)benzene (I-026)

[0438]

[0439] Using GP-2, I-025 (1.64 g, 5.68 mmol, 1 eq) and m-CPBA (70% wet, 3.08 g, 12.5 mmol, 2.2 eq) were used in DCM (28 mL) at RT for 2 hours to obtain I-026 as a colorless oil in 80% yield. Purification by FC (cHex / EtOAc=95 / 5 to 60 / 40).

[0440] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.04 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 8.6, 2.2 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 3.99 (s, 3H), 3.01 (dqd, J = 10.4, 6.9.3.6 Hz, 1H), 1.92 (dddd, J = 12.7, 9.5, 5.7, 3.2 Hz, 1H), 1.53-1.31 (m, 2H), 1.29-1.22 (m, 4H), 0.91 (t, J = 7.2 Hz, 3H). MS (ESI + ): [M+H] + 320.9 / 323.0.

[0441] 2-Bromo-4-(2-cyclopentylethylsulfonyl)-1-methoxybenzene (I-040)

[0442]

[0443] Using GP-2, I-032 (100 mg, 0.317 mmol, 1 eq) and m-CPBA (70% wet, 172 mg, 0.697 mmol, 2.2 eq) were used in DCM (1.6 mL) at RT for 1 hour to obtain I-040 as a colorless oil in 66% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0444] 1 H NMR (400 MHz, chloroform-d) δ 8.07 (d, J = 2.2 Hz, 1H), 7.83 (dd, J = 8.6, 2.3 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 3.99 (s, 3H), 3.12-3.04 (m, 2H), 1.84-1.69 (m, 5H), 1.62-1.40 (m, 4H), 1.11-1.00 (m, 2H). MS (ESI + ): [M+H] + 347.0 / 349.0.

[0445] 2-Bromo-4-butylsulfonyl-1-methoxybenzene (I-041)

[0446]

[0447] Using GP-2, I-033 (100 mg, 0.363 mmol, 1 eq) and m-CPBA (70% wet, 197 mg, 0.800 mmol, 2.2 eq) were used in DCM (1.8 mL) at RT for 16 hours to obtain I-041 as a colorless oil in 36% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0448] 1 H NMR (400 MHz, chloroform-d) 1H NMR (400 MHz, chloroform-d) δ 8.07 (d, J = 2.3 Hz, 1H), 7.83 (dd, J = 8.7, 2.3 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 3.99 (s, 3H) v 3.11-3.03 (m-2H) -1.74-1.64 (m, 2H) -1.50-1.30 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H). MS (ESI + ): [M+H] + 307.0 / 308.9.

[0449] 2-Bromo-4-(2-ethylbutylsulfonyl)-1-methoxybenzene (I-042)

[0450]

[0451] Using GP-2, I-034 (235 mg, 0.775 mmol, 1 eq) and m-CPBA (70% wet, 420 mg, 1.70 mmol, 2.2 eq) were used in DCM (3.9 mL) at RT for 16 hours to obtain I-042 as a colorless oil in 73% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0452] 1 H NMR (400 MHz, chloroform-d) 1H NMR (400 MHz, chloroform-d) δ 8.07 (d, J = 2.3 Hz, 1H), 7.83 (dd, J = 8.6, 2.3 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 3.98 (s, 3H), 3.00 (d, J = 6.0 Hz, 2H), 1.89 (hept, J = 6.1 Hz, 1H), 1.481.41 (m, 4H), 0.83 (t, J = 7.4 Hz, 6H). MS (ESI + ): [M+H] + 335.0 / 337.0.

[0453] 2-Bromo-1-methoxy-4-sec-butylsulfonylbenzene (I-043)

[0454]

[0455] Using GP-2, I-035 (50 mg, 0.182 mmol, 1 eq) and m-CPBA (70% wet, 98 mg, 0.40 mmol, 2.2 eq) were used in DCM (0.9 mL) at RT for 16 hours to obtain I-043 as a colorless oil in 72% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0456] 1H NMR (400 MHz, chloroform-d) 1H NMR (400 MHz, chloroform-d) δ 8.04 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 8.6, 2.2 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 3.99 (s, 3H), 2.98-2.87 (m, 1H), 2.07-1.94 (m, 1H). 1.49-1.36 (m, 1H), 1.27 (d, J = 6.9 Hz, 3H), 0.99 (t, J = 7.5 Hz, 3H). MS (ESI + ): [M+H] + 306.9 / 308.9.

[0457] 2-Bromo-1-methoxy-4-(1-methyl-3-phenyl-propyl)sulfonylbenzene (I-044)

[0458]

[0459] Using GP-2, I-036 (156 mg, 0.444 mmol, 1 eq) and m-CPBA (70% wet, 274 mg, 1.11 mmol, 2.2 eq) were used in DCM (2.2 mL) at RT for 2 hours to obtain I-044 as a colorless oil in 58% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0460] 1 H NMR (400 MHz, chloroform-d) δ 8.00 (d, J = 2.2 Hz, 1H), 7.76 (dd. J = 8.6, 2.3 Hz, 1H), 7.31-7.24 (m, 2H), 7.24-7.17 (m, 1H), 7.14-7.08 (m, 2H), 6.98 (d, J = 8.7 Hz, 1H), 3.98 (s, 3H), 3.00 (dqd, J = 1.3 Hz, 1H). =9.5, 6.9, 3.7Hz, 1H), 2.82 (ddd, J = 14.3, 9.3, 5.3Hz, 1H), 2.60 (ddd, J = 13.9.8.9.7.5Hz , 1H), 2.29 (dddd, J=13.2, 9.3, 7.5, 3.7Hz, 1H), 1.80-1.64 (m, 1H), 1.32 (d, J=6.9Hz, 3H).

[0461] 2-Bromo-1-methoxy-4-(1-methyl-4-phenyl-butyl)sulfonylbenzene (I-045)

[0462]

[0463] Using GP-2, I-037 (185 mg, 0.506 mmol, 1 eq) and m-CPBA (70% wet, 308 mg, 1.25 mmol, 2.5 eq) were used in DCM (2.5 mL) at RT for 2 hours to obtain I-045 as a colorless oil in 50% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0464] 1 H NMR (400 MHz, chloroform-d) δ 8.00 (d, J = 2.2 Hz, 1H), 7.76 (dd. J = 8.6, 2.3 Hz, 1H), 7.31-7.24 (m, 2H), 7.24-7.17 (m, 1H), 7.14-7.08 (m-2H), 6.98 (d, J = 8.7 Hz, 1H), 3.99 (s, 3H), 3.10-2.90 (m, 1H), 2.70-2.50 (m, 2H), 2.02-1.93 (m, 1H), 1.90-1.52 (m, 2H), 1.51-1.39 (m, 1H), 1.35-1.21 (m, 3H).

[0465] 2-Bromo-4-(1-ethyl-3-phenyl-propyl)sulfonyl-1-methoxybenzene (I-046)

[0466]

[0467] Using GP-2, I-038 (228 mg, 0.624 mmol, 1 eq) and m-CPBA (70% wet, 384 mg, 1.56 mmol, 2.2 eq) were used in DCM (3.1 mL) at RT for 2 hours to obtain I-046 as a colorless oil in 75% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0468] 1 H NMR (400 MHz, chloroform-d) δ 8.01 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 8.7, 2.2 Hz, 1H), 7.31-7.23 (m, 2H), 7.22-7.15 (m, 1H), 7.14-7.07 (m, 2H), 6.98 (d, J = 8.7 Hz, 1H), 3.99 (s, 3H), 2 .89-2.74 (m, 2H), 2.67 (dddd, J=13.9, 9.5, 6.6Hz, 1H), 2.14 (dddd, J=14.6, 9.5, 6.6, 5.1Hz, 1H), 1.97-1.82 (m, 2H), 1.69 (dp, J=14.7, 7.4Hz, 1H), 1.00 (t, J=7.5Hz, 3H).

[0469] 2-Bromo-4-(1-ethyl-4-phenyl-butyl)sulfonyl-1-methoxybenzene (I-047)

[0470]

[0471] Using GP-2, I-039 (61 mg, 0.16 mmol, 1 eq) and m-CPBA (70% wet, 98 mg, 0.40 mmol, 2.5 eq) were used in DCM (0.8 mL) at RT for 2 hours to obtain I-047 as a colorless oil in 38% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0472] 1 H NMR (400MHz, chloroform-d) δ8.01 (dJ=2.3Hz, 1H), 7.72 (dd-J=8.6-2.2Hz-1H), 7.30-7.25 (m, 2H)-7.21-7.04 (m, 3H), 6.95 (d, J =8.7Hz, 1H)-3.98(s, 3H)-2.81(dt-J=6.8, 4.5Hz, 1H)-2.59(tJ=6.9Hz, 2H)-1.99-1.57(rn-6H)-0.97(tJ=7.5Hz, 3H).

[0473] Synthesis of common intermediate piperazines I-028 to I-031:

[0474] 4-[4-Fluoro-2-(trifluoromethyl)benzoyl]piperazine-1-carboxylic acid tert-butyl ester (Boc-I-028)

[0475]

[0476] At RT, TBTU (18.5 g, 57.7 mmol, 1 eq) was added to a solution of 4-fluoro-2-(trifluoromethyl)benzoic acid (12.0 g, 57.7 mmol, 1 eq) in THF (180 mL). The mixture was stirred at RT for 15 minutes, and a solution of piperazine-1-carboxylic acid tert-butyl ester (12.9 g, 69.2 mmol, 1.2 eq) and EtN (12.1 mL, 86.5 mmol, 1.5 eq) in THF (60 mL) was added dropwise. The mixture was stirred at RT for 60 hours. The reaction mixture was concentrated under reduced pressure. The reaction mixture was distributed between 1N HCl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc (2*). The combined organic extracts were washed (1N HCl solution, saturated aqueous NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure to give 23.1 g (100%) of tert-butyl 4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazine-1-carboxylate (Boc-I-028) as a brown oil which solidified upon standing.

[0477] 1 H NMR (400 MHz, chloroform-d) δ 7.43 (dd-J = 8.6, 2.1 Hz-1H) -7.34-7.28 (m, 2H), 3.90-3.65 (m-2H), 3.62-3.44 (m-2H) -3.35 (dd-J = 6.4-4.0 Hz, 2H) -3.15 (dd-J = 6.5-4.0 Hz, 2H) -1.46 (s-9H). MS (ESI + ): [M+H] + 377.1.

[0478] [4-Fluoro-2-(trifluoromethyl)phenyl]-piperazine-1-yl-methanone (I-028)

[0479]

[0480] At RT, HCl (4M dioxane solution, 75.0 mL, 300 mmol, 5 eq) was added to a solution of crude 4-(4-fluoro-2-(trifluoromethyl)benzoyl)piperazine-1-carboxylic acid tert-butyl ester Boc-1-028 (23.1 g, 57.9 mmol, 1 eq) in dioxane (25 mL). The mixture was stirred at RT for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was distributed between water and DCM. K2CO3(s) was added in batches until pH>11. The layers were separated, and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (120 g column, dry loading, DCM / MeOH = 98 / 2 to 80 / 20) to give 13.6 g (83%) of [4-fluoro-2-(trifluoromethyl)phenyl]-piperazin-1-yl-methanone 1-028 as an orange solid.

[0481] 1 H NMR (400 MHz, chloroform-d) δ 7.41 (dd. J = 8.8, 2.4 Hz, 1H), 7.32 (qd, J = 8.4, 5.6 Hz, 2H), 3.87-3.69 (m, 2H), 3.15 (t, J = 5.1 Hz, 2H), 2.94 (t, J = 5.2 Hz, 2H), 2.76 (tq, J = 12.1, 6.1, 5.0 Hz, 2H). MS (ES) + ): [M+H] + 277.4.

[0482] 4-(2-Chloro-4-fluorobenzoyl)piperazine-1-carboxylic acid tert-butyl ester (Boc-I-029)

[0483]

[0484] At RT, TBTU (9.20 g, 28.6 mmol, 1 eq) was added to a solution of 2-chloro-4-fluorobenzoic acid (5.00 g, 28.6 mmol, 1 eq) in THF (89 mL). The mixture was stirred at RT for 15 minutes, and a solution of piperazine-1-carboxylic acid tert-butyl ester (6.40 g, 34.4 mmol, 1.2 eq) and EtN (6.0 mL, 43 mmol, 1.5 eq) in THF (30 mL) was added dropwise. The mixture was stirred at RT for 60 hours. The reaction mixture was concentrated under reduced pressure. The reaction mixture was distributed between 1N HCl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc (2*). The combined organic extracts were washed (1N HCl solution, saturated aqueous NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure to give 10.2 g (100%) of tert-butyl 4-(2-chloro-4-fluorobenzoyl)piperazine-1-carboxylate (Boc-I-029) as an orange oil.

[0485] 1 H NMR (400 MHz, chloroform-d) δ 7.32-7.29 (m, 1H), 7.18 (dd, J = 8.5, 2.5 Hz, 1H), 7.07 (td, J = 8.3, 2.5 Hz, 1H), 3.92-3.79 (m, 1H), 3.73 (dt, J = 13.2, 5.7 Hz, 1H), 3.63-3.50 (m, 2H), 3.48-3.34 (m, 2H), 3.34-3.10 (m, 2H), 1.48 (s, 9H). MS (ESI + ): [M+H] + 343.1 / 345.1.

[0486] (2-Chloro-4-fluoro-phenyl)-piperazine-1-ylmethanone (I-029)

[0487]

[0488] At RT, HCl (4M dioxane solution, 37 mL, 148 mmol, 5 eq) was added to a solution of crude 4-(2-chloro-4-fluoro-benzoyl)piperazine-1-carboxylic acid tert-butyl ester Boc-1-029 (10.2 g, 28.6 mmol, 1 eq) in dioxane (37 mL). The mixture was stirred for 16 hours at RT. The reaction mixture was concentrated under reduced pressure, and the residue was distributed between water and DCM. K2CO3(s) was added in batches until pH>11. The layers were separated, and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (80 g column, dry loading, DCM / MeOH = 98 / 2 to 80 / 20) to give 5.24 g (72%) of (2-chloro-4-fluoro-phenyl)-piperazin-1-yl-methanone 1-029 as an orange solid.

[0489] 1 H NMR (400 MHz, chloroform-d) δ 7.41 (dd, J = 8.8, 2.4 Hz, 1H), 7.32 (qd, J = 8.4, 5.6 Hz, 2H), 3.87-3.69 (m, 2H), 3.15 (t, J = 5.1 Hz, 2H), 2.94 (t, J = 5.2 Hz, 2H), 2.80-2.70 (m, 2H). MS (ESI + ): [M+H] + 243.1 / 245.1.

[0490] 3-(2-Chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (Boc-I-030)

[0491]

[0492] At RT, TBTU (18.1g, 56.5 mmoles, 1.2 equivalents) was added to a DMF (118mL) solution of 2-chloro-4-fluorobenzoic acid (9.87g, 56.5 mmoles, 1.2 equivalents). The mixture was stirred at RT for 15 minutes, and 3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (10.0g, 47.1 mmoles, 1 equivalent) and EtN (9.8mL, 71 mmoles, 1.5 equivalents) THF (118mL) solution was added dropwise. The mixture was stirred at RT for 16 hours. The reaction mixture was concentrated under reduced pressure. The reaction mixture was distributed between NH4Cl saturated aqueous solution and EtOAc. Separate the layers, and extract the aqueous phase with EtOAc (2*). The combined organic extracts were washed (saturated NH4Cl solution, saturated aqueous NaHCO3, brine), dried (Na2SO4), filtered and concentrated under reduced pressure to give 21.3 g (76% purity, 93%) of tert-butyl 3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Boc-I-030) as an orange oil.

[0493] 1 H NMR (400 MHz, chloroform-d) δ 7.33 (dd. J = 8.5.5.9 Hz, 0.5H), 7.23-7.09 (m, 1.5H), 7.09-6.97 (m, 1H), 4.54-4.40 (m, 1H), 4.33 (s, 1H), 4.23-4.01 (m, 1H), 3.56-3.17 (m, 1H), 3.17-2.93 (m, 2H), 2.11-1.70 (m, 4H), 1.47 (s, 9H). MS (ESI + ): [M+H] + 369.1 / 371.1.

[0494] (2-Chloro-4-fluoro-phenyl)-(3,8-diazabicyclo[3.2.1]octan-3-yl)methanone (I-030)

[0495]

[0496] At RT, HCl (4M solution in dioxane, 55 mL, 220 mmol, 5 eq) was added to a solution of crude 3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester Boc-I-030 (21.3 g, 76% purity, 43.9 mmol, 1 eq) in dioxane (55 mL). The mixture was stirred at RT for 60 hours. The reaction mixture was concentrated under reduced pressure and the residue was distributed between water and DCM. K2CO3(s) was added in batches until pH>11. The layers were separated and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (220 g column, dry loading, DCM / MeOH(7N NH3)=99 / 1 to 95 / 5) to give 10.3 g (88%) of (2-chloro-4-fluoro-phenyl)-(3,8-diazabicyclo[3.2.1]octan-3-yl)methanone I-030 as a white solid.

[0497] 1 H NMR (400MHz, chloroform-d) δ7.32 (dd, J=8.5, 5.9Hz, 0.5H), 7.20-7.15 (m, 0.5H), 7.15-7.10 (m, 1H), 7.09-6.98 (m, 1H), 4.47-4.3 7(m,1H),3.69-3.56(m,1H),3.44-3.34(m,1.5H),3.22(d,J=11.9Hz,0.5H),3.10-2.98(m,2H),1.95-1.48(m,4H).MS(ESI + ): [M+H] + 269.1 / 271.0.

[0498] 4-(2-Chloro-4-fluorobenzoyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (Boc-I-031)

[0499]

[0500] At RT, TBTU (19.2g, 59.9 mmol, 1 equivalent) was added to a THF (120mL) solution of 2-chloro-4-fluorobenzoic acid (10.5g, 59.9 mmol, 1 equivalent). The mixture was stirred at RT for 15 minutes, and 2-methylpiperazine-1-carboxylic acid tert-butyl ester (10.0g, 49.9 mmol, 1 equivalent) and EtN (6.5mL, 37 mmol, 0.75 equivalent) THF (120mL) solution was added. The mixture was stirred at RT for 60 hours. The reaction mixture was concentrated under reduced pressure. The reaction mixture was distributed between NH4Cl saturated aqueous solution and EtOAc. Separate each layer, and extract the aqueous phase with EtOAc (2*). The combined organic extract was washed (NH4Cl saturated aqueous solution, NaHCO3 saturated aqueous solution, saline), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (220 g column, dry loading, cHex / EtOAc = 90 / 10 to 50 / 50) to give 16.8 g (94%) of 4-(2-chloro-4-fluorobenzoyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (Boc-I-031) as a white solid.

[0501] 1 H NMR (400 MHz, chloroform-d, multiple groups of rotational isomers) δ 7.36-7.21 (m, 1H), 7.20-7.09 (m, 1H), 7.08-6.97 (m, 1H), 4.67-4.13 (m, 2H), 3.99-3.74 (m, 1H), 3.41-3.23 (m, 1H), 3.23-2.83 (m, 3H), 1.44 (s, 9H), 1.29-0.97 (m, 3H). MS (ESI + ): [M+H] + 357.0 / 359.0.

[0502] (2-Chloro-4-fluoro-phenyl)-(3-methylpiperazin-1-yl)methanone (I-031)

[0503]

[0504] At 0 ° C, TFA (72 mL, 941 mmol, 20 eq.) was added to a solution of crude 4-(2-chloro-4-fluoro-benzoyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester Boc-I-031 (16.8 g, 47.1 mmol, 1 eq.) in DCM (235 mL). The mixture was stirred for 2 hours at RT. The reaction mixture was concentrated under reduced pressure and the residue was distributed between water and DCM at 0 ° C. K2CO3(s) was added in batches until pH>11. The layers were separated and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (80 g column, dry loading, DCM / MeOH (7N NH3) = 99 / 1 to 90 / 10) to give 9.8 g (81%) of (2-chloro-4-fluoro-phenyl)-(3-methylpiperazin-1-yl)methanone I-031 as a white solid.

[0505] 1 H NMR (400 MHz, chloroform-d, 2 sets of rotamers) δ 7.32 (ddd, J = 8.6, 5.9, 1.3 Hz, 0.5 H), 7.25 (ddd, J = 8.5, 5.9, 1.4 Hz, 0.5 H), 7.21-7.13 (m, 1 H), 7.09-7.01 (m, 1 H), 4.69-4.56 (m, 1 H), 3.31-2.75 (m, 5 H), 2.51 (m, 1 H), 1.15 (dd, J = 6.3, 2.4 Hz, 1.5 H), 0.98 (dd, J = 6.3, 4.5 Hz, 1.5 H). MS (ESI+): [M+H]+ 257.1 / 259.1.

[0506] Synthesis of intermediates required for final products 016 and 017

[0507] 1-(5-isobutylsulfonyl-2-methoxy-phenyl)-2-methylpiperazine (I-027)

[0508]

[0509] Sulfone I-026 (1.53 g, 4.77 mmol, 1 eq), commercial tert-butyl 3-methylpiperazine-1-carboxylate (1.15 g, 5.73 mmol, 1.2 eq), Cs2CO3 (4.66 g, 14.3 mmol, 3 eq), Pd(OAc)2 (107 mg, 477 micromol, 0.1 eq) and racemic BINAP (297 mg, 477 micromol, 0.1 eq) were charged into a microwave reaction bottle. The bottle was flushed with argon and degassed toluene (24 mL) was added. The bottle was sealed and the reactants were stirred at reflux in a preheated heating block for 16 h. After cooling to RT, EtOAc was added and the suspension was stirred at 40 °C for 1 h. The product was filtered (EtOAc rinse). The filtrate was concentrated under reduced pressure. The residue was directly treated with HCl (4M dioxane solution, 1.68mL, 6.72 mmol, 10 equivalents). The mixture was stirred at RT for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was distributed between water and DCM. NaOH 2M was added dropwise until pH>11. The layers were separated, and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified with FC (24g column, dry load, DCM / MeOH (7N NH3) = 99 / 1 to 95 / 5) to obtain 160mg (through two steps, 9%) of yellow oily I-027.

[0510] 1 H NMR (400 MHz, chloroform-d) δ 7.55 (dd, J = 8.6, 2.3 Hz, 1H), 7.42 (d, J = 2.3 Hz, 1H), 6.97 (d, J = 8.6 Hz, 1H), 3.93 (s, 3H), 3.65-3.51 (m, 1H), 3.25 (ddd, J = 11.2, 5.0, 2.1 Hz, 1H), 3.21-3 .14(m, 1H), 3.14-2.94(m, 3H), 2.84-2.71(m, 2H), 1.95-1.87(m, 1H), 1.54-1.27(m, 3 H), 1.25 (d, J=6.9Hz, 4H), 0.93 (dd, J=6.4, 1.3Hz, 3H), 0.89 (t, J=7.2Hz, 3H).MS (ESI + ): [M+H] + 341.1.

[0511] The intermediates required for the final product 018 are synthesized

[0512] [4-Fluoro-2-(trifluoromethyl)phenyl]-[4-(5-isobutylthio-2-methoxyphenyl)piperazin-1-yl]methanone (I-024)

[0513]

[0514] Thioether I-023 (180 mg, 654 μmol, 1 eq.), piperazine I-028 (271 mg, 981 μmol, 1.5 eq.), Cs2CO3 (426 mg, 1.31 mmol, 2 eq.), Pd(OAc)2 (15 mg, 67 μmol, 0.1 eq.) and racemic BINAP (50 mg, 81 μmol, 0.12 eq.) were charged into a microwave reaction vial. The vial was rinsed with Ar and degassed toluene (3.4 mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating block for 4 h 30. After cooling to RT, EtOAc was added and the suspension was filtered through Celite (EtOAc rinse). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=100 / 0 to 30 / 70) to give I-024 in 83% yield.

[0515] 1 H NMR (400 MHz, chloroform-d) δ 7.43 (dd, J = 8.9, 2.5 Hz, 1H), 7.38 (dd, J = 8.6, 5.3 Hz, 1H), 7.32 (td, J = 8.3, 2.6 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.97-6.89 (m, 1H), 6.80 (d, J = 8.4 Hz, 1H),4.04-3.91(m,2H),3.85(s,3H),3.43-3.30(m,2H),3.20-3.06(m,2H),3.05-2 .88 (m, 2H), 2.73 (d, J = 6.8Hz, 2H), 1.81 (hept, J = 6.7Hz, 1H), 1.01 (d, J = 6.7Hz, 6H). 19 FNMR (376 MHz, chloroform-d) δ -60.24, -109.44. MS (ESI+): [M+H] + 471.1.

[0516] Synthesis of intermediates required for final products 027, 028 and 029

[0517] 4-(3-Bromo-4-methoxy-phenyl)sulfonylpiperidine-1-carboxylic acid tert-butyl ester (I-048)

[0518]

[0519] At RT, 4-(methylsulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester (1.68g, 6.01mmol, 1equiv) and K2CO3 (1.25g, 9.02mmol, 1.5equiv) were added to a solution of 3-bromo-4-methoxybenzenethiol (1.38g, 6.31mmol, 1.05equiv) in MeCN (30mL). The mixture was stirred at 80°C for 16 hours. After cooling to RT, the suspension was filtered on a porous glass, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (26mL) at 0°C, and m-CPBA (70% wet, 9.36g, 41.7mmol, 7equiv) was added. The mixture was stirred at RT for 16 hours. Na2S2O3 saturated aqueous solution, NaHCO3 saturated aqueous solution and EtOAc were added. The mixture was stirred vigorously for 10 minutes. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc = 95 / 5 to 50 / 50) to afford I-048 in 36% yield.

[0520] 1 H NMR (400MHz, chloroform-d) δ8.03 (d, J=2.2Hz, 1H), 7.78 (dd, J=8.7, 2.3Hz, 1H), 7.02 (d, J=8.7Hz, 1H), 4.23 (s, 2H), 3.99 (s, 3H ), 3.01 (tt, J=12.1, 3.6Hz, 1H), 2.66 (s, 2H), 1.98 (d, J=12.9Hz, 2H), 1.59 (dd, J=12.4, 4.9Hz, 2H), 1.44 (s, 9H).MS (ESI + ): [M+H] + 434.1 / 436.1.

[0521] 4-[3-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-methoxy-phenyl]sulfonylpiperidine-1-carboxylic acid tert-butyl ester (I-049)

[0522]

[0523] Sulfone I-048 (500 mg, 1.15 mmol, 1 eq), piperazine I-030 (371 mg, 1.38 mmol, 1.2 eq), Cs2CO3 (1.12 g, 3.45 mmol, 3 eq), Pd(OAc)2 (25.8 mg, 115 micromol, 0.1 eq) and racemic BINAP (108 mg, 172 micromol, 0.15 eq) were charged into a microwave reaction bottle. The bottle was rinsed with Ar and degassed toluene (5.8 mL) was added. The bottle was sealed and the reactants were stirred at reflux in a preheated heating block for 16 hours. After cooling to RT, EtOAc was added and the suspension was filtered through Celite (EtOAc rinse). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=90 / 10 to 0 / 100) to give 1-049 in 76% yield.

[0524] 1 H NMR (400 MHz, chloroform-d, 2 sets of rotamers) δ 7.45-7.32 (m, 1.5H), 7.24-7.12 (m, 2.5H), 7.12-7.00 (m, 1H), 6.97 (d, J = 8.5 Hz, 1H), 4.56-4.45 (m, 1H), 4.35-4.25 (m, 1H), 4.25-4.15 (m, 2H), 4.06 (s, 1H), 3.94 &3.93(s, 3H), 3.67&3.50(d, J=12.4Hz, 1H), 3.33-3.23(m, 1H), 3.20-3.07(m, 1H), 3.02-2.90( m, 1H), 2.64 (s, 2H), 2.00-1.85 (m, 4.5H), 1.75-1.65 (m, 0.5H), 1.60-1.50 (m, 3H), 1.43 (s, 9H). 19 F NMR (376 MHz, chloroform-d.2 group of rotational isomers) δ -109.21, -109.33. MS (ESI+): [M+H] + 622.3 / 624.3.

[0525] (2-Chloro-4-fluoro-phenyl)-[8-[2-methoxy-5-(4-piperidinylsulfonyl)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone; hydrochloride (I-050)

[0526]

[0527] To a solution of I-049 (544 mg, 0.874 mmol, 1.00 equiv) diluted in DCM (4.3 mL) was added HCl 4N in dioxane (4.37 mL, 17.5 mmol, 20.0 equiv) at RT. The resulting solution was stirred at RT for 2 hours. The reaction was concentrated under reduced pressure to afford I-050 in 100% yield.

[0528] 1 H NMR (400 MHz, DMSO-d6, 2 sets of rotamers) δ 9.19 & 9.16 (s, 1H), 8.71 & 8.67 (s, 1H), 7.65-7.40 (m, 2H), 7.39-7.25 (m, 2H), 7.21 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 2.2 Hz, 1H), 4.43-4.23 (m, 2H), 3.89 (s, 3H), 3.55-3.25 (m, 4H), 3.18-2.92 (m, 2H), 2.84 (q, J = 12.0 Hz, 2H), 2.05-1.55 (m, 8H). 19 F NMR (376 MHz, DMSO-d6, 2 sets of rotational isomers) δ -110.01, -110.22. MS (ESI+): [M-C1] + 522.1 / 523.9.

[0529] Synthesis of intermediates required for final products 030 and 031

[0530] 2-Bromo-4-(4-piperidinylsulfonyl)phenol (I-051)

[0531]

[0532] To a solution of I-048 (406 mg, 0.935 mmol, 1.00 eq) in DCM (4.7 mL) was added BBr3 (1.0 M in DCM, 1.87 mL, 1.87 mmol, 2 eq) at RT. The resulting solution was stirred at RT for 30 h. Water was added dropwise, and the pH of the aqueous phase was adjusted to 11 with 2N NaOH. The two phases were concentrated under reduced pressure. The residue was dissolved in DCM / MeOH (50 / 50) and the resulting suspension was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by FC (DCM / MeOH=99 / 1 to 80 / 20) to give I-051 in 97% yield.

[0533] 1H NMR (400MHz, DMSO-d6) δ7.85 (d, J = 2.3Hz, 1H), 7.65 (dd, J = 8.6, 2.3Hz, 1H), 7.17 (d, J = 8.6Hz, 1H ), 3.61-3.47(m, 1H), 3.30-3.25(m, 4H), 2.08-1.94(m, 2H), 1.78-1.51(m, 2H).MS(ESI+): [M+H] + 320.0 / 322.0.

[0534] 1-[4-(3-Bromo-4-hydroxy-phenyl)sulfonyl-1-piperidinyl]-2,2,2-trifluoroethanone (I-052)

[0535]

[0536] To a solution of I-051 (298 mg, 0.93 mmol, 1.00 eq) and Et3N (0.26 mL, 1.9 mmol, 2 eq) in DCM (4.7 mL) was added trifluoroacetic anhydride (0.19 mL, 1.4 mmol, 1.5 eq) at RT. The mixture was stirred for 2 hours at RT. HCl 1N was added. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with 1N HCl, NaHCO3 saturated aqueous solution, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=95 / 5 to 0 / 100) to give I-052 in 39% yield.

[0537] 1 H NMR (400 MHz, chloroform-d) δ 8.00 (d, J = 2.2 Hz, 1H), 7.73 (dd, J = 8.6, 2.2 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 6.19 (s, 1H), 4.63 (d, J = 13.8 Hz, 1H), 4.14 (d, J = 7.1 Hz, 1H), 3.14 (dddd, J = 12.3, 8.5, 6.1, 3.3 Hz, 2H), 2.90-2.73 (m, 1H), 2.14 (t, J = 15.7 Hz, 2H), 1.90-1.69 (m, 2H). 19 F NMR (376 MHz, chloroform-d) δ-69.0. MS (ESI+): [M+H] + 416.0 / 418.0.

[0538] 1-[4-[3-bromo-4-(methoxymethoxy)phenyl]sulfonyl-1-piperidinyl]-2,2,2-trifluoroethanone (I-053)

[0539]

[0540] At RT, to a solution of I-052 (165 mg, 0.353 mmol, 1.00 eq) and iPr2EtN (0.18 mL, 1.1 mmol, 3 eq) in DCM (1.8 mL) was added chloromethyl methyl ether (0.05 mL, 0.7 mmol, 2 eq). The mixture was stirred at RT for 2 hours. HCl 1N was added. The aqueous phase was extracted with DCM. The combined organic layers were washed with HCl 1N and brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give I-053 as a colorless oil in 95% yield.

[0541] 1 H NMR (400MHz, chloroform-d) δ8.05 (d, J=2.3Hz, 1H), 7.75 (dd.J=8.7, 2.3Hz, 1H), 7.31 (d, J=8.7Hz, 1H), 5.35 (s, 2H), 4.63 (d, J=13.9H z, 1H), 4.14 (d, J=14.2Hz, 1H), 3.54 (s, 3H), 3.26-3.04 (m, 2H), 2.80 (t, J=12.1Hz, 1H), 2.22-2.03 (m, 2H), 1.871.66 (m, 2H). 19 FNMR (376 MHz, chloroform-d) δ-69.0. MS (ESI+): [M+H] + 460.0 / 461.9.

[0542] 1-[4-[3-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-(methoxymethoxy)phenyl]sulfonyl-1-piperidinyl]-2,2,2-trifluoroethanone (I-054)

[0543]

[0544] Sulfone I-053 (155 mg, 0.337 mmol, 1 eq), piperazine I-030 (109 mg, 0.404 mmol, 1.2 eq), Cs2CO3 (329 mg, 1.01 mmol, 3 eq), Pd(OAc)2 (11.3 mg, 50.5 micromol, 0.15 eq) and racemic BINAP (62.9 mg, 101 micromol, 0.30 eq) were charged into a microwave reaction bottle. The bottle was rinsed with Ar and degassed toluene (5.7 mL) was added. The bottle was sealed and the reactants were stirred at reflux in a preheated heating block for 4 hours. After cooling to RT, EtOAc was added and the suspension was filtered through Celite (EtOAc rinse). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=90 / 10 to 0 / 100) to give 1-054 in 52% yield.

[0545] 1 H NMR (400 MHz, chloroform-d, 2 sets of rotamers) δ 7.43-7.33 (m, 1.5H), 7.25-7.13 (m, 3.5H), 7.12-6.99 (m, 1H), 5.32-5.25 (m, 2H), 4.67-4.46 (m, 2H), 4.33 (s, 1H), 4.15-4.05 (m, 1H), 3.72-3.42 (m, 4H), 3.35-3.25 (m, 1H), 3.20-3.05 (m, 3H), 2.78 (t, J = 12.7 Hz, 1H), 2.04 (s, 7H), 1.79-1.58 (m, 2H). 19 F NMR (376 MHz, chloroform-d, 2 sets of rotational isomers) δ-69.0.-109.06.-109.20. MS (ESI+): [M+H] + 648.2 / 650.1.

[0546] (2-Chloro-4-fluoro-phenyl)-[8-[2-(methoxymethoxy)-5-(4-piperidinylsulfonyl)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-055)

[0547]

[0548] To a solution of sulfone I-054 (130 mg, 0.177 mmol, 1 eq) in THF / MeOH / H2O (3 / 1 / 1, 2 mL) was added LiOH (21 mg, 0.88 mmol, 5 eq) at RT. The mixture was stirred at RT for 1 hour. Water and DCM were added. The layers were separated and the aqueous phase was extracted with DCM. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to afford I-055 in 76% yield.

[0549] 1 H NMR (400 MHz, chloroform-d, 2 sets of rotamers) δ 7.40-7.32 (m, 1.5H) 7.23-7.12 (m, 3.5H), 7.12-7.00 (m, 1H), 5.29-5.23 (m, 2H), 4.58-4.45 (m, 1H), 4.32 (s, 1H), 4.08 (s, 1H), 3.70-3.45 (m, 4H), 3.28 (d, J = 12.9 Hz, 1H), 3.22- 3.09 (m, 3H), 2.96 (tt. J = 12.2, 3.6 Hz, 1H), 2.55 (td, J = 12.4, 2.6 Hz, 2H), 2.11-1.88 (m, 5.5H), 1.70-1.60 (s, 0.5H), 1.58-1.50 (m, 3H). 19F NMR (376 MHz, chloroform-d, 2 groups of rotational isomers) δ -109.17, -109.31. MS (ESI+): [M+H] + 552.2 / 554.1.

[0550] (2-Chloro-4-fluoro-phenyl)-[8-[2-(methoxymethoxy)-5-[(1-phenyl-4-piperidinyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-056)

[0551]

[0552] Amine I-055 (50 mg, 0.068 mmol, 1 eq), bromobenzene (13 mg, 0.082 mmol, 1.2 eq), Cs2CO3 (55.3 mg, 0.170 mmol, 2.5 eq), Pd(OAc)2 (3.1 mg, 14 micromol, 0.2 eq) and racemic BINAP (16.9 mg, 27.2 micromol, 0.40 eq) were charged into a microwave reaction bottle. The bottle was rinsed with Ar and degassed toluene (0.7 mL) was added. The bottle was sealed and the reactants were stirred at reflux in a preheated heating block for 16 hours. After cooling to RT, EtOAc was added and the suspension was filtered through Celite (EtOAc rinse). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=90 / 10 to 0 / 100) to give 1-056 in 62% yield.

[0553] 1 H NMR (400 MHz, chloroform-d, 2 sets of rotamers) δ 7.50-7.30 (m, 5H), 7.25-7.18 (m, 4H), 7.10-7.00 (m, 1H), 6.95-6.85 (m, 1H), 5.38-5.18 (m, 2H), 4.60-4.48 (m, 1H), 4.33 (s, 1H), 4.09 (s, 1H), 3.80-3.70 (m, 1H), 3.70-3.48 (m, 4H), 3.52 (d, J=3.8Hz, 3H), 3.29 (d, J=13.0Hz, 1H), 3.15 (t, J=10.5Hz, 1H), 3.05 -2.90(m, 1H), 2.72-2.60(m, 2H), 2.20-1.90(m, 3.5H), 1.90-1.70(m, 2H), 1.70-1.60(m, 0.5H). 19 F NMR (376 MHz, chloroform-d, 2 sets of rotational isomers) δ -109.13, -109.27. MS (ESI+): [M+H] + 628.2 / 630.2.

[0554] (2-Chloro-4-fluoro-phenyl)-[8-[2-(methoxymethoxy)-5-[[1-(2-phenylethyl)-4-piperidinyl]sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-057)

[0555]

[0556] To a solution of amine I-055 (50 mg, 0.068 mmol, 1 eq) in DCM (0.7 mL) was added acetic acid (7.8 μL, 0.13 mmol, 2 eq), phenylacetaldehyde (15.8 μL, 0.136 mmol, 2 eq) and NaBH(Oac)3 (14 mg, 0.068 mmol, 1 eq) at RT. The mixture was stirred at RT for 16 h. A saturated aqueous solution of NaHCO3 and DCM were added. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (DCM / MeOH=99 / 1 to 90 / 10) to give I-057 in 80% yield.

[0557] 1 H NMR (400 MHz, chloroform-d, 2 sets of rotamers) δ 7.41-7.30 (m, 3H), 7.23-7.14 (m, 6H), 7.12-6.96 (m, 2H), 5.34-5.19 (m, 2H), 4.56-4.45 (m, 1H), 4.32 (s, 1H), 4.08 (s, 1H), 3.70-3.45 (m, 4H), 3.30 & 3.27 (s, 1H), 3.20-2.97 (m, 3H), 2.97-2.42 (m, 7H), 2.12-1.85 (m, 5.5H), 1.751.60 (m, 2.5H). 19 F NMR (376 MHz, chloroform-d, 2 sets of rotational isomers) δ -109.17, -109.31. MS (ESI+): [M+H] + 656.2 / 658.2.

[0558] Synthesis of intermediates required for final product 032

[0559] 4-(2,2-Dimethylpropylthio)-1-methoxy-2-methylbenzene (I-058)

[0560]

[0561] To a solution of 4-methoxy-3-methylbenzenethiol (350 mg, 2.27 mmol, 1 eq) in dry DMF (2.3 mL) was added sodium hydride (60% in oil, 109 mg, 2.73 mmol, 1.2 eq) at RT. The mixture was stirred at RT for 30 minutes, and 1-bromo-2,2-dimethylpropane (0.34 mL, 2.73 mmol, 1.2 eq) was added. The mixture was stirred at 80 ° C for 1 hour. After cooling to RT, water and MTBE were added. The layers were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=99 / 1 to 90 / 10) to give I-058 in 89% yield.

[0562] 1 H NMR (400 MHz, chloroform-d) δ 7.17-7.11 (m, 2H), 6.66 (d, J = 8.2 Hz, 1H), 3.73 (s, 3H), 2.75 (s, 2H), 2.11 (s, 3H), 0.94 (s, 9H). MS (ESI+): [M+H] + 225.1.

[0563] 4-(2,2-Dimethylpropylsulfonyl)-1-methoxy-2-methylbenzene (I-059)

[0564]

[0565] To a solution of I-058 (453 mg, 2.02 mmol, 1 eq) in DCM (10 mL) was added m-CPBA (70% wet, 1.10 g, 4.44 mmol, 2.2 eq) at 0°C. The mixture was stirred at RT for 1 hour. A saturated aqueous solution of Na2S2O3, a saturated aqueous solution of NaHCO3 and EtOAc were added. The mixture was stirred vigorously for 10 minutes. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=95 / 5 to 50 / 50) to give I-059 in 86% yield.

[0566] 1 H NMR (400 MHz, chloroform-d) δ 7.73 (dd, J = 8.6, 2.5 Hz, 1H), 7.65 (dd, J = 2.4, 0.9 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H), 3.90 (s, 3H), 3.01 (s, 2H), 2.26 (s, 3H), 1.17 (s, 9H). MS (ESI+): [M+H]+ 257.1.

[0567] 4-(2,2-Dimethylpropylsulfonyl)-2-methylphenol (I-060)

[0568]

[0569] To a solution of I-059 (550 mg, 1.74 mmol, 1 eq) in DCM (5 mL) was added BBr3 (1.0 M in DCM, 5.2 mL, 5.2 mmol, 3 eq) at 0°C. The mixture was stirred at RT for 16 h. Water was added dropwise and the layers were separated. The aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=98 / 2 to 75 / 25) to give I-060 in 71% yield.

[0570] 1 H NMR (400 MHz, chloroform-d) δ 1H NMR (400 MHz, chloroform-d) δ 7.67 (dd, J = 2.4, 0.9 Hz, 1H), 7.63 (dd, J = 8.4.2.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.44 (s, 1H), 3.01 (s, 2H), 2.30 (s, 3H), 1.17 (s, 9H). MS (ESI+): [M+H] + 243.1.

[0571] 2-Bromo-4-(2,2-dimethylpropylsulfonyl)-6-methylphenol (I-061)

[0572]

[0573] To a solution of I-060 (300 mg, 1.24 mmol, 1 eq) in DMF (6.2 mL) was added N-bromosuccinimide (242 mg, 1.36 mmol, 1.1 eq) at RT. The mixture was stirred at RT for 1 hour. Water and EtOAc were added and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=97 / 3 to 70 / 30) to give I-061 in 80% yield.

[0574] 1 H NMR (400 MHz, chloroform-d) δ 1H NMR (400 MHz, chloroform-d) δ 7.90-7.87 (m, 1H), 7.64-7.59 (m, 1H), 6.04 (s, 1H), 3.00 (s, 2H), 2.36 (s, 3H), 1.19 (s, 9H). MS (ESI+): [M+H] + 321.0 / 323.0.

[0575] 1-Bromo-5-(2,2-dimethylpropylsulfonyl)-2-(methoxymethoxy)-3-methylbenzene (I-062)

[0576]

[0577] At RT, chloromethyl methyl ether (0.11 mL, 1.5 mmol, 2 eq) was added to I-061 (320 mg, 0.996 mmol, 1.00 eq) and Et3N (0.28 mL, 2.0 mmol, 2 eq) in DCM (4 mL). The mixture was stirred for 2 hours at RT. A saturated aqueous solution of NH4Cl and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=97 / 3 to 70 / 30) to give I-062 in 70% yield.

[0578] 1 H NMR (400 MHz, chloroform-d) δ 7.95 (d, J = 2.3 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 5.14 (s, 2H), 3.64 (s, 3H), 3.00 (s, 2H), 2.42 (s, 3H), 1.21 (s, 9H). MS (ESI+): [M+H] + 365.0 / 367.0.

[0579] (2-Chloro-4-fluoro-phenyl)-[8-[5-(2,2-dimethylpropylsulfonyl)-2-(methoxymethoxy)-3-methyl-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-063)

[0580]

[0581] Sulfone I-062 (255 mg, 0.698 mmol, 1 eq), piperazine I-030 (225 mg, 0.834 mmol, 1.2 eq), t-BuONa (201 mg, 2.09 mmol, 3 eq) and XPhos-Pd-G3 (59.1 mg, 69.8 μmol, 0.1 eq) were charged into a microwave reaction bottle. The bottle was rinsed with Ar and degassed toluene (5.7 mL) was added. The bottle was sealed and the reactants were stirred at reflux in a preheated heating block for 2 hours. After cooling to RT, EtOAc was added and the suspension was filtered through Celite (rinsed with EtOAc). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=96 / 4 to 60 / 40) to give I-063 in 26% yield.

[0582] 1 H NMR (400 MHz, chloroform-d, 2 sets of rotamers) δ 7.32 (s, 1H), 7.23-7.01 (m, 4H), 5.17-5.10 (m, 2H), 4.56-4.48 (m, 1H), 4.30 (s, 1H), 4.08 (s, 1H), 3.62-3.38 (m, 4H), 3.22 (d, J = 12.9 Hz, 1H), 3.14 (t, J = 12.1 Hz, 1H), 2.98 (s, 2H), 2.36 (s, 3H), 2.03-1.85 (m, 3.5H), 1.77-1.67 (m, 0.5H), 1.18 (s, 9H). 19 F NMR (376 MHz, chloroform-d, 2 sets of rotational isomers) δ -109.11, -109.26. MS (ESI+): [M+H] + 553.1 / 555.1.

[0583] Synthesis of intermediates required for final product 033

[0584] 2-Chloro-4-(2,2-dimethylpropylthio)-1-methoxybenzene (I-064)

[0585]

[0586] To a solution of 3-chloro-4-methoxy-benzenethiol (500 mg, 2.86 mmol, 1 eq) in dry DMF (2.9 mL) was added sodium hydride (60% in oil, 137 mg, 3.43 mmol, 1.2 eq) at RT. The mixture was stirred at RT for 30 min and 1-bromo-2,2-dimethylpropane (0.43 mL, 3.44 mmol, 1.2 eq) was added. The mixture was stirred at 80 ° C for 1 hour. After cooling to RT, water and MTBE were added. The layers were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=99 / 1 to 90 / 10) to give I-064 in 92% yield.

[0587] 1 H NMR (400 MHz, chloroform-d) δ 7.44 (d, J = 2.3 Hz, 1H), 7.29 (dd, J = 8.5, 2.3 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 3.90 (s, 3H), 2.85 (s, 2H), 1.04 (s, 9H). MS (ESI+): [M+H] + 245.1 / 247.1.

[0588] 2-Chloro-4-(2,2-dimethylpropylsulfonyl)-1-methoxybenzene (I-065)

[0589]

[0590] To a solution of I-064 (640 mg, 2.59 mmol, 1 eq) in DCM (13 mL) at 0°C was added m-CPBA (70% wet, 1.40 g, 5.69 mmol, 2.2 eq). The mixture was stirred at RT for 1 hour. A saturated aqueous solution of Na2S2O3, a saturated aqueous solution of NaHCO3, and EtOAc were added. The mixture was stirred vigorously for 10 minutes. The layers were separated and the aqueous phase was washed with EtOAc. c The combined organic extracts were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=95 / 5 to 50 / 50) to give I-065 in 98% yield.

[0591] 1H NMR (400 MHz, chloroform-d) δ 7.94 (d, J = 2.3 Hz, 1H), 7.82 (dd, J = 8.7, 2.3 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 4.01 (s, 3H), 3.04 (s, 2H), 1.21 (s, 9H). MS (ESI+): [M+H] + 277.0 / 279.0.

[0592] 2-Chloro-4-(2,2-dimethylpropylsulfonyl)phenol (I-066)

[0593]

[0594] To a solution of I-065 (739 mg, 2.54 mmol, 1 eq) in DCM (5 mL) was added BBr3 (1.0 M in DCM, 5.1 mL, 5.1 mmol, 2 eq) at 0°C. The mixture was stirred at RT for 16 h. Water was added dropwise and the layers were separated. The aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=95 / 5 to 50 / 50) to give I-066 in 92% yield.

[0595] 1 H NMR (400 MHz, chloroform-d) δ 7.94 (d, J = 2.2 Hz, 1H), 7.76 (dd, J = 8.6, 2.2 Hz, 1H), 7.18 (d, J = 8.6 Hz, 1H), 6.17 (s, 1H), 3.04 (s, 2H), 1.21 (s, 9H). MS (ESI+): [M+H] + 263.0 / 265.0.

[0596] 2-Bromo-6-chloro-4-(2,2-dimethylpropylsulfonyl)phenol (I-067)

[0597]

[0598] To a solution of I-066 (624 mg, 2.30 mmol, 1 eq) in DMF (11.5 mL) at RT was added N-bromosuccinimide (451 mg, 2.53 mmol, 1.1 eq). The mixture was stirred at RT for 1 hour. Water and EtOAc were added and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=95 / 5 to 50 / 50) to give I-067 in 94% yield.

[0599] 1 H NMR (400 MHz,

[0600] Chloroform-d) δ 1H NMR (400 MHz, chloroform-d) δ 8.00 (d, J = 2.1 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 6.40 (s, 1H), 3.04 (s, 2H), 1.23 (s, 9H).

[0601] 1-Bromo-3-chloro-5-(2,2-dimethylpropanesulfonyl)-2-(methoxymethoxy)benzene (I-068)

[0602]

[0603] To a solution of I-067 (740 mg, 2.17 mmol, 1.00 eq) and Et3N (0.60 mL, 4.3 mmol, 2 eq) in DCM (8.7 mL) was added chloromethyl methyl ether (0.25 mL, 3.2 mmol, 2 eq) at RT. The mixture was stirred for 2 hours at RT. A saturated aqueous solution of NH4Cl and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed (water, brine), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=97 / 3 to 70 / 30) to give I-068 in 62% yield.

[0604] 1 H NMR (400 MHz, chloroform-d) δ 8.04 (d, J = 2.2 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H), 5.29 (s, 2H), 3.73 (s, 3H), 3.04 (s, 2H), 1.25 (s, 9H). MS (ESI+): [M+H] + 384.9 / 386.9.

[0605] [8-[3-Chloro-5-(2,2-dimethylpropanesulfonyl)-2-(methoxymethoxy)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-069)

[0606]

[0607] Sulfone I-068 (260 mg, 0.674 mmol, 1 eq), piperazine I-030 (235 mg, 0.876 mmol, 1.3 eq), t-BuONa (194 mg, 2.02 mmol, 3 eq) and XPhos-Pd-G3 (57.1 mg, 67.4 μmol, 0.1 eq) were charged into a microwave reaction bottle. The bottle was rinsed with Ar and degassed toluene (5.7 mL) was added. The bottle was sealed and the reactants were stirred at reflux in a preheated heating block for 2 hours. After cooling to RT, EtOAc was added and the suspension was filtered through Celite (EtOAc rinse). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=96 / 4 to 60 / 40) to give I-069 in 53% yield.

[0608] 1 H NMR (400 MHz, chloroform-d, 2 sets of rotamers) δ 7.55-7.50 (m, 1H). 7.39 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.27-7.15 (m, 2.5H), 7.15-7.01 (m, 1H), 5.27-5.18 (m, 2H), 4.60-4.49 (m, 1H), 4.40 (s, 1H), 4.20 & 4.19 (s, 1H), 3.70-3.42 (m, 4H), 3.34-3.12 (m, 2H), 3.02 (s, 2H), 2.05-1.87 (m, 3.5H), 1.72-1.65 (m, 0.5H), 1.22 (s, 9H). 19 F NMR (376 MHz, chloroform-d, 2 sets of rotational isomers) δ -108.93, -109.08. MS (ESI+): [M+H] + 573.1 / 575.1.

[0609] Synthesis of intermediates required for final product 035

[0610] 1-Bromo-2,3-dichloro-5-iodobenzene (I-070)

[0611]

[0612] 3-Bromo-4,5-dichloroaniline (617 mg, 2.56 mmol, 1 eq) was added to a solution of H2SO4 (0.41 mL, 7.7 mmol, 3 eq) in water (9.5 mL). The mixture was stirred at 80°C for 10 minutes before cooling to 5°C. A solution of NaNO2 (177 mg, 2.56 mmol, 1 eq) in water (1.1 mL) was added dropwise. The mixture was stirred at RT for 1 hour and a solution of KI (425 mg, 2.56 mmol, 1 eq) in water (1.1 mL) was added dropwise. The resulting mixture was stirred at RT for 30 minutes and at 40°C for 30 minutes. EtOAc was added and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=99 / 1 to 80 / 20) to give 1-070 in 62% yield.

[0613] 1 H NMR (400 MHz, chloroform-d) δ 7.88 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 1.9 Hz, 1H).

[0614] 1-Bromo-2,3-dichloro-5-(2,2-dimethylpropylthio)benzene (I-071)

[0615]

[0616] I-070 (500 mg, 1.42 mmol, 1 eq) and XantPhos-Pd-G3 (135 mg, 0.142 mmol, 0.1 eq) were loaded into a MW bottle. The bottle was rinsed with Ar and degassed toluene (7.1 mL) was added. iPr2NEt (495 μL, 3.84 mmol, 2 eq) and 2,2-dimethylpropane-1-thiol (172 μL, 1.42 mmol, 1 eq) were added. The bottle was sealed and the reactants were stirred at 100 ° C in a preheated heating block for 1 hour. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=100 / 0 to 80 / 20) to give I-071 in a yield of 66%.

[0617] 1 H NMR (400 MHz, chloroform-d) δ 7.47 (d, J = 2.2 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 2.87 (s, 2H), 1.06 (s, 9H).

[0618] 1-Bromo-2,3-dichloro-5-(2,2-dimethylpropylsulfonyl)benzene (I-072)

[0619]

[0620] Using GP-2, I-071 (308 mg, 939 μmol, 1 eq) and m-CPBA (70% wet, 509 mg, 2.07 mmol, 2.2 eq) were used in DCM (4.7 mL) at RT for 1 hour to obtain I-072 as a white solid in 72% yield. Purification by FC (cHex / EtOAc=100 / 0 to 70 / 30).

[0621] 1 H NMR (400 MHz, chloroform-d) δ 8.08 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 3.04 (s, 2H), 1.23 (s, 9H). MS (ESI + ): [M+H] + 358.9 / 360.9.

[0622] Synthesis of intermediates required for final product 036

[0623] 1-Bromo-3-chloro-5-iodo-2-methylbenzene (I-073)

[0624]

[0625] 3-Bromo-5-chloro-4-methylaniline (363 mg, 1.65 mmol, 1 eq) was added to a solution of H2SO4 (0.26 mL, 4.9 mmol, 3 eq) in water (6.1 mL). The mixture was stirred at 80°C for 10 minutes before cooling to 5°C. A solution of NaNO2 (114 mg, 1.65 mmol, 1 eq) in water (0.7 mL) was added dropwise. The mixture was stirred at RT for 1 hour and a solution of KI (273 mg, 1.65 mmol, 1 eq) in water (0.7 mL) was added dropwise. The resulting mixture was stirred at RT for 30 minutes and at 40°C for 30 minutes. EtOAc was added and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=100 / 0 to 70 / 30) to give 1-073 in 32% yield.

[0626] 1 H NMR (400 MHz, chloroform-d) δ 7.80 (d, J = 1.7 Hz, 1H), 7.66 (d, J = 1.7 Hz, 1H), 2.47 (s, 3H).

[0627] 1-Bromo-3-chloro-5-(2,2-dimethylpropylthio)-2-methylbenzene (I-074)

[0628]

[0629] I-073 (174 mg, 0.525 mmol, 1 eq) and XantPhos-Pd-G3 (50 mg, 0.052 mmol, 0.1 eq) were loaded into a MW bottle. The bottle was rinsed with Ar and degassed toluene (2.6 mL) was added. iPr2NEt (183 μL, 1.05 mmol, 2 eq) and 2,2-dimethylpropane-1-thiol (63.6 μL, 0.525 mmol, 1 eq) were added. The bottle was sealed and the reactants were stirred at 100 ° C in a preheated heating block for 1.5 hours. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=100 / 0 to 80 / 20) to give I-074 in 58% yield.

[0630] 1 H NMR (400 MHz, chloroform-d) δ 7.43 (d, J = 1.9 Hz, 1H), 7.28 (d, J = 1.9 Hz, 1H), 2.86 (s, 2H), 2.46 (s, 3H), 1.05 (s, 9H).

[0631] 1-Bromo-3-chloro-5-(2,2-dimethylpropylsulfonyl)-2-methylbenzene (I-075)

[0632]

[0633] Using GP-2, I-074 (93.0 mg, 302 μmol, 1 eq) and m-CPBA (70% wet, 164 mg, 0.665 mmol, 2.2 eq) were used in DCM (1.5 mL) at RT for 16 hours to obtain I-075 as a white solid in 67% yield. Purification by FC (cHex / EtOAc=100 / 0 to 70 / 30).

[0634] 1 H NMR (400 MHz, chloroform-d) δ 8.00 (d, J = 1.8 Hz, 1H), 7.86 (d, J = 1.8 Hz, 1H), 3.03 (s, 2H), 2.60 (s, 3H), 1.22 (s, 10H). MS (ES) + ): [M+H] + 339.0 / 341.0.

[0635] Synthesis of final compounds

[0636] Synthesis of the final compound

[0637] The synthesis scheme of the final compound is shown in Table 2 below.

[0638] Table 2

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649] Analytical data of final compound

[0650] The analytical data of the final compound are shown in Table 3 below.

[0651] Table 3

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659] Example 2: Biological Activity of Compounds

[0660] The purpose of this experiment was to evaluate the GFRα1-RET activity of compounds 001-036 according to the present invention.

[0661] Materials and methods

[0662] Compounds were tested for their Elk1 signaling activation activity in cells expressing GFRα1-RET (MG87 mouse fibroblasts stably transfected with PathDetect Elk-1, GFRα1, and RET) using a previously developed reporter gene-based system as disclosed in Sidorova, YA et al., “Persephin signaling through GFRα1: The potential for the treatment of Parkinson's disease.” Molecular and Cellular Neuroscience, July 2010, Vol. 44, pp. 223-232. DOI: 10.1016 / j.mcn.2010.03.009. 50 Dose-response tests were performed using 6 concentrations of each test compound. Dose-response curves were fitted using sigmoidal dose-response (variable slope) analysis in the GraphPad Prism program (Graph Pad Inc) and the EC values ​​of the agonists / activators were calculated. 50 The dose-response experiments were performed in duplicate independently.

[0663] result

[0664] The results are shown in Table 4 (* indicates “ 50μM >EC 50 >10μM", ** indicates "1μM≤EC 50 ≤10μM”,*** indicates “EC 50 <1 μM”).

[0665] Table 4

[0666]

[0667]

[0668]

[0669]

[0670] The above results clearly demonstrate that the tested compounds 001 to 036 have significant GFRα1-RET activity. Therefore, the compounds of the present invention are suitable as neuroprotective agents and neurorepairing agents. The tested compounds 001 to 036 well represent the class of compounds of formula (I).

Claims

1. Compound of formula (I) or a pharmaceutically acceptable salt and / or a solvate thereof; in W represents CH or N; R A , R B , R C and R D each independently represents hydrogen, F, Cl, CH3, CF3, CHF2 or CH2F, The condition is R A , R B , R C and R D At least one of them does not represent hydrogen; R 1 represents hydrogen or (C1-C8)alkyl, wherein the alkyl is optionally substituted with at least one OH, (C1-C3)alkoxy or F; and R 2 , R 3 and R 4 represents hydrogen; or R 1 and R 4 Together they form -CH2-O-CH2- or -CH2-CH2-, wherein -CH2-CH2- is optionally substituted with at least one F, OH or OCH3; and R 2 and R 3 Each represents hydrogen; R 7 represents 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-, (R 11 O)(R 12 )N-(C1-C8)alkyl-O-, R 11 R 12 N-(C1-C8)alkyl-, R 11 O-(C1-C8)alkyl-、NR 11 R 12 、CN、CO2H、CO2R 11 、CONH2、CON(R 11 )H, heterocycloalkyl, or heteroaryl; wherein R 11 and R 12 Each independently represents hydrogen or (C1-C8) alkyl; Where R 7 The alkyl or cycloalkyl in is optionally substituted by at least one F, Cl, OH, =O, (C1-C8)alkyl, (C1-C8)alkyl-O-, heterocycloalkyl, aryl or heteroaryl; wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR 13 R 14 , R 13 R 14 N-(C1-C8)alkyl-, R 13 O2C(C1-C8)alkyl-, CO2H, R 13 R 14 NC(O)-、R 13 O-NR 14 - or (C1-C8) alkyl-CO2-substituted; wherein R 13 and R 14 Each independently represents hydrogen or (C1-C8) alkyl; Z stands for CH, CR 8 or N; Where R 8 represents (C1-C4)alkyl, F, Cl, CF3, CHF2, CH2F, OCF3, CN, OH or (C1-C4)alkoxy; or Z is for CR 8 And R 7 and R 8 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group is optionally substituted by at least one of F, OH, =O, →O, (C1-C8)alkyl, CF3, HO2C-CH2-, (C1-C4)alkyl-CO2-CH2-, R 15 R 16 N-CH2-, aryl or aryl-(C1-C8)alkyl-substituted, wherein R 15 and R 16 Each independently represents hydrogen or (C1-C8) alkyl; R 5 represents hydrogen, (C1-C8)alkyl, CH3 substituted by one to three (C1-C8)alkyl, cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C1-C8)alkyl; Where R 5 The alkyl or cycloalkyl in the alkyl group is optionally substituted with at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, NR 17 R 18 ,CO2H,R 17 R 18 NC(O)-、R 17 O-NR 18 -, heterocycloalkyl, aryl or heteroaryl; wherein R 17 and R 18 Each independently represents hydrogen or (C1-C8) alkyl; wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR 19 R 20 ,CO2H,R 19 R 20 NC(O)-、R 19 O-NR 20 -, (C1-C8) alkyl-CO2-, R 19 R 20 N-(C1-C8)alkyl-, R 19 O2C-(C1-C8)alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C1-C8)alkyl-substituted; wherein R 19 and R 20 Each independently represents hydrogen or (C1-C8) alkyl; R 6 represents hydrogen, (C1-C8)alkyl, CH3 substituted by one to three (C1-C8)alkyl, cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C1-C8)alkyl; Where R 6 The alkyl or cycloalkyl in the alkyl group is optionally substituted with at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, NR 21 R 22 ,CO2H,R 21 R 22 NC(O)-、R 21 O-NR 22 -, heterocycloalkyl, aryl or heteroaryl; wherein R 21 and R 22 Each independently represents hydrogen or (C1-C8) alkyl; wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR 23 R 24 ,CO2H,R 23 R 24 NC(O)-、R 23 O-NR 24 -, (C1-C8) alkyl-CO2-, R 23 R 24 N-(C1-C8)alkyl-, R 23 O2C-(C1-C8)alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C1-C8)alkyl-substituted; wherein R 23 and R 24 Each independently represents hydrogen or (C1-C8) alkyl; or R 5 and R 6 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group is optionally substituted with at least one F, Cl, (C1-C8)alkyl, CF3, OCF3, CN, OH, =O, →O, (C1-C8)alkoxy, NR 25 R 26 、CO2H、(C1-C8)alkyl-CO2-、R 25 R 26 NC(O)-、R 25 O-NR 26 -、R 25 R 26 N-(C1-C8)alkyl-, R 25 O2C-(C1-C8)alkyl-, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1-C8)alkyl-, heterocycloalkyl-(C1-C8)alkyl-, aryl-(C1-C8)alkyl-, heteroaryl-(C1-C8)alkyl-, aryl-cycloalkyl-, cycloalkyl-O-, heterocycloalkyl-O-, aryl-O-, heteroaryl-O-, cycloalkyl-(C1-C8)alkyl-O-, heterocycloalkyl-(C1-C8)alkyl-O-, aryl-(C1-C8)alkyl-O-, heteroaryl-(C1-C8)alkyl-O-, cycloalkyl-NR 25 -, heterocycloalkyl-NR 25 -, aryl-NR 25 -, heteroaryl-NR 25 -, cycloalkyl-(C1-C8)alkyl-NR 25 -, heterocycloalkyl-(C1-C8)alkyl-NR 25 -, Aryl-(C1-C8)alkyl-NR 25 -, heteroaryl-(C1-C8)alkyl-NR 25 -, benzylidene, heteroarylene, aryl-(C1-C8)alkyl-ylidene- or heteroaryl-(C1-C8)alkyl-ylidene-; Where R 25 and R 26 Each independently represents hydrogen or (C1-C8) alkyl; wherein the heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylene group is optionally substituted by at least one F, Cl, (C1-C8)alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8)alkoxy, NR 27 R 28 ,CO2H,R 27 R 28 NC(O)-、R 27 -O-NR 28 -, (C1-C8) alkyl-CO2-, R 27 R 28 N-(C1-C8)alkyl-, R 27 O2C-(C1-C8)alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C1-C8)alkyl-substituted; wherein R 27 and R 28 Each independently represents hydrogen or (C1-C8) alkyl; R 9 represents hydrogen, (C1-C8)alkyl, CH3 substituted by one to three (C1-C8)alkyl, cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C1-C8)alkyl; Where R 9 The alkyl or cycloalkyl in the alkyl group is optionally substituted with at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, NR 29 R 30 ,CO2H,R 29 R 30 NC(O)-、R 29 O-NR 30 -, heterocycloalkyl, aryl or heteroaryl; wherein R 29 and R 30 Each independently represents hydrogen or (C1-C8) alkyl; wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR 31 R 32 ,CO2H,R 31 R 32 NC(O)-、R 31 O-NR 32 -, (C1-C8) alkyl-CO2-, R 23 R 24 N-(C1-C8)alkyl-, R 23 O2C-(C1-C8)alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C1-C8)alkyl-substituted; wherein R 31 and R 32 Each independently represents hydrogen or (C1-C8) alkyl.

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

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

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

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

6. A compound according to any one of claims 1 to 5, wherein R 7 represents hydrogen, OH or halogen, preferably R 7 Represents OH or Cl.

7. A compound according to any one of claims 1 to 6, wherein R 7 represents (C1-C8)alkyl-O- or cycloalkyl-O-, wherein the alkyl or cycloalkyl is optionally substituted with at least one F, Cl, OH, (C1-C8)alkoxy or aryl group; preferably R 7 Stands for OCH3 or HO-CH2-CH2-O.

8. A compound according to any one of claims 1 to 7, wherein R 5 and R 6 Each independently represents (C1-C8)alkyl, aryl-(C1-C8)alkyl-, and R 9 represents hydrogen, preferably R 5 and R 6 Each independently represents methyl, ethyl, n-propyl, 2-phenylethyl or 3-phenylpropyl.

9. A compound according to any one of claims 1 to 8, wherein R 6 represents (C1-C8)alkyl, cycloalkyl-(C1-C8)-alkyl or aryl, and R 5 and R 9 Each represents hydrogen, preferably R 6 represents isopropyl, n-propyl, tert-butyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl-CH2- or phenyl.

10. A compound according to any one of claims 1 to 8, wherein R 5 and R 6 Together with the carbon atoms to which they are attached, they form a cycloalkyl or heterocycloalkyl group, and R 9 represents hydrogen; preferably R 5 and R 6 Together with the carbon atoms to which they are attached they form cyclobutyl, cyclopentyl, cyclohexyl, oxetane, 1-phenyl-4-piperidinyl, 1-(2-phenylethyl)-4-piperidinyl or 1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl.

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

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

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

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

15. A method for preparing a compound according to any one of claims 1 to 11, wherein the method comprises the step of reacting the following substances in the presence of a base and a metal catalyst: Compound of formula (II) in Z, R 5 , R 6 , R 7 and R 9 As defined in claim 1, and X represents halogen or -CF3SO3, and a compound of formula (III) Among them, W, R A To R D and R 1 To R 4 As defined in claim 1; Thus, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate thereof is obtained.

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