Novel piperazinyl sulfonamides and application thereof as neuroprotective agent and / or nerve repairing agent

Abstract

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

Description

Field of the Invention

[0001] The present invention relates to novel polycyclic sulfonamides containing at least one unsubstituted piperazine and an unbridged piperazine. The compounds of the present invention can be used as neuroprotective agents and / or neurorestorative agents, in particular for the treatment of neurological disorders. Background Art

[0002] Neurological disorders (NDs) are heterogeneous diseases that affect the autonomic, peripheral, and central nervous systems of the body. Among central nervous system (CNS) diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), dementia, stroke, head trauma, brain tumors, pain, and epilepsy have been the most challenging diseases to be addressed. Compound actives used to treat the CNS may also be associated with other diseases, such as those of the peripheral nervous system, eyes, spinal cord, and intestinal system.

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

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

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

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

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

[0008] WO 2011 / 070177A2 (BALTIC TECHNOLOGY DEV LTD) discloses polycyclic compounds for the treatment of neurological disorders. Although these compounds represent a significant improvement at the time, their activity on the GFRα1-RET target, solubility, membrane permeability (PAMPA and CaCO 2 ), intrinsic clearance from microsomes and hepatocytes, plasma protein binding and pharmacokinetic profiles. In particular, these compounds have limited activity on the GFRα1-RET target (as demonstrated, for example, in luciferase assays).

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

[0010] WO 2014 / 041179 A1 (CHEMEDEST LTD) likewise discloses the same polycyclic compounds as WO 2011 / 070177 A2 for the treatment and / or prevention of peripheral neuropathy (peripheral diseases), and thus has the same limitations.

[0011] Applicants have surprisingly discovered that the novel polycyclic sulfonamide drugs of formula (I) exhibit potent GFRα1-RET activity in a luciferase assay, thus opening a way to overcome the limitations of existing treatment options. Summary of the invention

[0012] The present invention is directed to compounds of formula (I)

[0013]

[0014] or a pharmaceutically acceptable salt and / or a solvate thereof;

[0015] Among them, W, R A To R D , Z and R 5 To R 7 As defined below and / or in the claims.

[0016] According to a preferred embodiment, the compound of formula (I) is a compound of formula (Ii) or a compound of formula (I-ii) as defined below and / or in the claims.

[0017] According to one embodiment, the compound is selected from the compounds of Table 1 herein and pharmaceutically acceptable salts and / or solvates thereof, with the proviso that the compound is not N,N-diethyl-5-[4-[4-fluoro-2-(trifluoroethyl)benzoyl]piperazin-1-yl]-6-methoxy-pyridine-3-sulfonamide or a pharmaceutically acceptable salt and / or solvate thereof.

[0018] Another object of the invention is a pharmaceutical composition comprising a compound according to the invention and at least one pharmaceutically acceptable carrier.

[0019] Another object of the invention is a compound according to the invention or a pharmaceutical composition according to the invention for use as a medicament.According to one embodiment, the compound or the pharmaceutical composition is for use in the treatment of a neurological disorder.

[0020] Another object of the present invention is a process for preparing the compounds according to the invention.

[0021] definition

[0022] In the present invention, the following terms have the following meanings:

[0023] Chemical Definition

[0024] When a chemical substituent is a combination of chemical groups, the point of attachment of the substituent to the molecule is at the last chemical group to the right of the substituent name. For example, an arylalkyl substituent is attached to the rest of the molecule through the alkyl portion and can be represented as follows: "aryl-alkyl-".

[0025] Unless otherwise stated, the compounds are named using BIOVIA Draw 2021 (Dassault, France).

[0026] Definitions herein relating to optional or mandatory substitution of a particular group apply to the group considered as such substituted or to the same group contained in another chemical moiety, both of which may be substituted as described herein. For example, "R x represents hydrogen, (C 1 To C 8 ) alkyl, (C 1 To C 8 )alkyl-O- or cycloalkyl-(C 1 To C 8 )alkyl-NH-; wherein the alkyl group is optionally substituted with at least one F" refers to the presence of x Any alkyl group in the structure may be optionally substituted with at least one F, including the (C 1 To C 8 ) alkyl (e.g. CF 3 ), said (C 1 To C 8 )alkyl-O-alkyl (e.g. OCF 3 ) and the cycloalkyl-(C 1 To C 8 ) The alkyl group contained in alkyl-NH- (e.g. cyclopropylCH 2 -CHF-CH 2 -NH-).

[0027] "Alkoxy" refers to an alkyl-O- group.

[0028] "Alkyl" refers to a saturated straight or branched hydrocarbon chain, which generally contains 1 to 16 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, and even more preferably 1 to 6 carbon atoms. Alkyl can be monovalent or polyvalent (i.e., "alkyl" includes "alkylene" groups in the definition, which are divalent alkyl groups). Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl and isomers thereof (e.g., n-pentyl, isopentyl) and hexyl and isomers thereof (e.g., n-hexyl, isohexyl). Special examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl (including methylene, ethylene, n-propylene, n-butylene and n-butylene).

[0029] "Amine" refers to ammonia (NH 3 ) derivatives in which one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. "Amino" refers to -NH 2 Group.

[0030] "Aryl" refers to a cyclic polyunsaturated aromatic hydrocarbon group containing at least one aromatic ring and containing 5 to 12 carbon atoms, preferably 6 to 10 carbon atoms. Aryl can be monovalent or polyvalent (e.g., divalent). Aryl can have a single ring (e.g., phenyl) or multiple aromatic rings fused together (e.g., naphthyl) or multiple aromatic rings covalently linked. The aromatic ring may optionally contain one to two other rings fused thereto (cycloalkyl, heterocycloalkyl, or heteroaryl). This definition of "aryl" includes partially hydrogenated derivatives of the carbocyclic ring systems listed herein, as long as at least one ring is an aromatic ring. Aryl may optionally be substituted with at least one group, such as halogen (e.g., F or Cl), (C 1 To C 8 )alkyl (e.g., methyl) or nitrile (CN). Non-limiting examples of aryl include phenyl, biphenyl, biphenylenyl, 5-tetrahydronaphthyl or 6-tetrahydronaphthyl, naphth-1-yl or naphth-2-yl, 4-indenyl, 5-indenyl, 6-indenyl or 7-indenyl, 1-acenaphthyl, 2-acenaphthyl, 3-acenaphthyl, 4-acenaphthyl or 5-acenaphthyl, 3-acenaphthyl, 4-acenaphthyl or 5-acenaphthyl. 5-acenaphthenyl, 1-pentalenyl or 2-pentalenyl, 4-indanyl or 5-indanyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 7-tetrahydronaphthyl or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and 1-, 2-, 3-, 4- or 5-pyrenyl. A particular example of aryl is phenyl.

[0031] "Benzal" refers to a phenyl group attached to a moiety via an exo-carbon-carbon double bond, ie, =CH-Ph, bonded to a carbon atom. The moiety is typically cyclic, such as a heterocycloalkyl group.

[0032] "Cycloalkyl" refers to a cyclic alkyl group, which generally contains 3 to 15 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and even more preferably 3 to 6 carbon atoms. Cycloalkyl groups can be monovalent or polyvalent (e.g., divalent). This definition of "cycloalkyl" includes polycyclic cycloalkyl groups (e.g., bicyclic) and bridged cycloalkyl structures, including rings bonded together by one atom ("spirocyclic") or by two atoms. This definition of "cycloalkyl" includes cycloalkyl groups that include cyclic alkyl groups substituted with at least one non-cyclic alkyl group, such as (C 1 To C 8 ) alkyl (preferably (C 1 To C 4 )alkyl, such as methyl). Non-limiting examples of cycloalkyl 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.

[0033] According to common terminology in the chemical field, the “C x To C y " or "(C x To C y )" means that the group contains x to y carbon atoms.

[0034] The "halogen" refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0035] "Heteroalkyl" refers to an alkyl group as defined herein in which one or more carbon atoms are replaced with a heteroatom selected from oxygen, nitrogen and sulfur, and wherein the resulting heteroalkyl group contains at least one carbon atom. In a heteroalkyl group, the heteroatoms along the alkyl chain are bonded only to carbon atoms, i.e., each heteroatom is separated from any other heteroatom by at least one carbon atom, typically at least two carbon atoms. A heteroalkyl group may be monovalent or multivalent (e.g., divalent). The nitrogen heteroatom and the sulfur heteroatom may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized (e.g., sulfur may be oxidized to SO or SO 2). The heteroalkyl group may also contain one or more than one =O group and / or =S group. In one embodiment, at least two carbon atoms are substituted with heteroatoms. In one embodiment, the heteroalkyl group is bonded to another group or molecule through a carbon atom, i.e., the bonding atom is not selected from the heteroatoms contained therein. In one embodiment, the heteroalkyl group is bonded to another group or molecule through a heteroatom contained therein. Unless otherwise indicated, when substituted with one or more than one other group, the heteroalkyl group may be substituted by a carbon atom or by a heteroatom (e.g., nitrogen). Non-limiting examples of heteroalkyl groups include alkoxy, ethers and polyethers (e.g., polyethylene glycol), secondary and tertiary amines and polyamines, thioethers and polythioethers, and combinations thereof.

[0036] "Heteroaryl" refers to an aromatic ring or aromatic ring system containing 5 to 15 carbon atoms, preferably 4 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, with one or two rings fused together or covalently linked, wherein at least one ring is aromatic, and one or more carbon atoms in one or more rings are substituted with oxygen atoms, nitrogen atoms and / or sulfur atoms. Heteroaryl groups can be monovalent or polyvalent (e.g., divalent). Nitrogen heteroatoms and sulfur heteroatoms can be optionally oxidized and nitrogen heteroatoms can be optionally quaternized (e.g., for sulfur atoms, heteroatoms are substituted with oxo (=O), or for nitrogen atoms, heteroatoms are substituted with oxo (→O)). This definition of "heteroaryl" includes partially hydrogenated derivatives of the carbocyclic ring systems listed herein as well as ring systems comprising one or more fused non-aromatic cycloalkyl and / or one or more heterocycloalkyl rings, as long as at least one ring is aromatic. In one embodiment, the heteroaryl group is bonded to another group or molecule via a carbon atom, i.e., the bonding atom is not selected from the heteroaryl atoms contained therein. In one embodiment, the heteroaryl group is bonded to another group or molecule via a heteroatom contained therein. Unless otherwise indicated, when substituted by one or more than one other group, the heteroaryl group may be substituted via a carbon atom or via a heteroatom (e.g., nitrogen). The heteroaryl group may optionally be substituted by at least one group, such as a halogen (e.g., F or Cl), (C 1 To C 8 ) alkyl (preferably (C 1 To C 4)alkyl, such as methyl) or nitrile (CN). Non-limiting examples of heteroaryl include pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, tetrazinyl, imidazo[2,1-b][ 1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thienyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl , thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxo-pyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxo-pyridin-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]dioxolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 1,2,3,4-tetrahydroquinoxaline, 3,4-dihydro-2H-benzo[b][1,4]thiazine, and 2,3-dihydrobenzo[b][1,4]oxathiin.

[0037] "Heteroarylene" refers to a heteroaryl group bonded to a moiety through an exo carbon-carbon double bond, ie, a =CH-heteroaryl bond, to a carbon atom. The moiety is typically cyclic, such as a heterocycloalkyl group.

[0038] "Heterocycloalkyl" refers to a cyclic heteroalkyl group, which generally contains 2 to 15 carbon atoms, preferably 2 to 11 carbon atoms, more preferably 2 to 7 carbon atoms, and even more preferably 2 to 6 carbon atoms. Heterocycloalkyl can be monovalent or polyvalent (e.g., divalent). Heterocycloalkyl is generally 3 to 7 members, preferably 5 or 6 members. Heterocycloalkyl is generally monocyclic or bicyclic, preferably monocyclic. This definition includes polycyclic heterocycloalkyl (e.g., bicyclic) and bridged heterocycloalkyl structures, including rings bonded together by one atom ("spiro") or by two atoms. Nitrogen heteroatoms and sulfur heteroatoms may be optionally oxidized and nitrogen heteroatoms may be optionally quaternized (e.g., for sulfur atoms, heteroatoms are substituted by oxo (=O), or for nitrogen atoms, heteroatoms are substituted by oxo (→O)). In one embodiment, heterocycloalkyl is bonded to another group or molecule through a carbon atom, i.e., the bonding atom is not selected from the heteroatoms contained therein. In one embodiment, a heterocycloalkyl is bonded to another group or molecule via one of the heteroatoms contained therein. Unless otherwise indicated, when substituted with one or more than one other group, a heterocycloalkyl may be substituted via a carbon atom or via a heteroatom (e.g., nitrogen). A heterocycloalkyl may be optionally substituted with at least one group such as a halogen (e.g., F or Cl), (C 1 To C 8 ) alkyl (preferably (C 1 To C 4 )alkyl, such as methyl), nitrile (CN) or =0. Non-limiting examples of heterocycloalkyl include aziridine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, azepane, azacyclooctane, octahydro-1H-isoindole, decahydroisoquinoline, tetrahydrofuran, tetrahydropyran, tetrahydroisoquinoline (e.g., 1,2,3,4-tetrahydroisoquinoline), hexahydropyridazine, hexahydropyrazine, hexahydropyrimidine, decahydroquinoline, octahydropyrrolo[3,4-c]pyrrole, isoindoline, 1,2,3,4-tetrahydroquinoline, and oxetane.

[0039] "Prodrug" refers to a pharmaceutically acceptable derivative of a therapeutic agent (e.g., a compound according to the invention), the biotransformation product of which in vivo is the therapeutic agent (active drug). Typically, prodrugs are characterized by increased bioavailability and are easily metabolized to active compounds in vivo. Non-limiting examples of prodrugs include amide prodrugs and carboxylate prodrugs.

[0040] "Solvate" refers to a molecular complex comprising a compound and stoichiometric or substoichiometric amounts of one or more than one solvent, typically a pharmaceutically acceptable solvent such as ethanol. The term "hydrate" refers to a complex comprising a compound and stoichiometric or substoichiometric amounts of one or more than one solvent, typically a pharmaceutically acceptable solvent such as ethanol. 2 O).

[0041] "Subunit" refers to a CH group that participates in an exo-carbon-carbon double bond to another moiety. The moiety is typically cyclic, such as a heterocycloalkyl.

[0042] General Definition

[0043] "About" is used herein to mean approximately, roughly, approximately, or within a range thereof. The term "about" before a number means the numerical value ±10%. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the numerical value by 10%.

[0044] "Administering" or variations thereof refers to providing a therapeutic agent, either alone or as part of a pharmaceutically acceptable composition, to a patient whose condition, symptom or disease is to be treated.

[0045] "Includes" or its variants are used herein according to common patent application drafting terms. Therefore, "includes" is preceded by an object and followed by a component, which means that the component is required to be present in the object (usually as a component of a composition), but does not exclude the presence of any other components in the object. In addition, unless otherwise specified, any occurrence of "includes" or its variants herein also includes the narrow expression "essentially composed of...", the narrower expression "consisting of..." and any variants thereof, and may therefore be replaced by them.

[0046] "GDNF family receptor alpha-1", "GFRα1" or "GDNFRα1", also known as "RET ligand 1" or "neurotrophin receptor associated with TGF-β 1", is a protein in the GDNFR family that is a receptor for GDNF. It mediates GDNF-induced autophosphorylation and activation of the RET receptor. In humans, GFRα1 is encoded by the GFRA1 gene. An exemplary amino acid sequence of human GFRα1 is given in SEQ ID NO: 1, wherein amino acid residue 1 to amino acid residue 24 correspond to the signal peptide and amino acid residue 430 to amino acid residue 465 correspond to the propeptide that is removed in the mature form.

[0047]

[0048] "Human" refers to male or female human subjects at any stage of development, including neonates, infants, juveniles, adolescents, and adults.

[0049] "Neuroprotection" refers to protecting neuronal cells from damage, events or conditions that would normally result in loss of neuronal cell function and ultimately neuronal cell death. These damages, events or conditions include, but are not limited to, neuronal stress, such as neuronal stress caused by hypoxia or ischemia; traumatic injury; and exposure to toxic molecules, such as abnormal 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.

[0050] "Neural repair" refers to the restoration or rescue of neuronal cells, and particularly their function, from insults, events or conditions that would normally result in loss of neuronal cell function or even neuronal cell death.

[0051] A "patient" is a subject who is awaiting or receiving medical treatment, or who has been / is / will be the subject of a medical procedure, or who is being monitored for the development of a target disease or target condition, such as a neurological disorder.

[0052] "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.

[0053] "Pharmaceutically acceptable carrier" refers to an excipient that does not produce harmful reactions, allergic reactions or other adverse reactions when applied to animals, preferably humans. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents, etc. For application to humans, the preparation should meet the sterility, pyrogenicity, general safety and purity standards required by regulatory agencies such as the FDA office or EMA. Examples of pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (such as sodium carboxymethyl cellulose), polyethylene glycol, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0054] A "pharmaceutical composition" refers to a composition comprising at least one therapeutic agent (eg, a compound according to the present invention) and at least one pharmaceutically acceptable carrier.

[0055] "Proto-oncogene tyrosine-protein kinase receptor Ret", or "RET" for short, also known as "cadherin family member 12", is a receptor tyrosine kinase that is involved in a variety of cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation. RET is activated under the following conditions: (i) binding of a neurotrophic factor of the GDNF family (e.g., GDNF, neurturin, artemin, or persephin) to a receptor of the GDNFR family (e.g., GFRα1, GFRα2, GFRα3, or GFRα4), followed by (ii) formation of a complex between RET and a GDNFR family receptor, (iii) dimerization, and (iv) trans-autophosphorylation. An exemplary amino acid sequence of human RET is given in SEQ ID NO: 2, wherein amino acid residue 1 to amino acid residue 28 correspond to the signal peptide.

[0056]

[0057] "Selected from" herein is used according to common patent application drafting terms to introduce a list of elements, wherein one or more items are selected from the list of elements. Any occurrence of "selected from" in this specification can be replaced with "selected from a group comprising or consisting of ...", and can be replaced with each other without changing its meaning.

[0058] "Subject" refers to an animal, typically a warm-blooded animal, preferably a mammal, more preferably a primate, and even more preferably a human. In one embodiment, the subject is a "patient" as defined herein. In one embodiment, the subject is affected by a disease, preferably diagnosed with a disease. In one embodiment, the subject is at risk of the disease. Examples of risk factors include, but are not limited to, a genetic predisposition or a family history of a disease.

[0059] "Therapeutic agent," "active pharmaceutical ingredient," and "active ingredient" refer to compounds that are used for therapeutic purposes and are relevant to health. In particular, therapeutic agents (e.g., compounds according to the present invention) may be useful for treating diseases (e.g., neurological disorders). Active ingredients may also be useful for improving the therapeutic activity of another therapeutic agent.

[0060] "Therapeutically effective amount" ("effective amount" for short) refers to an amount of a therapeutic agent (e.g., a compound according to the present invention) sufficient to achieve the desired therapeutic effect, prophylactic effect, or preventive effect in a patient to which it is administered without causing significant negative or harmful side effects to the patient. A therapeutically effective amount may be administered before the onset of a disease to implement preventive or prophylactic actions. Alternatively or additionally, a therapeutically effective amount may be administered after the onset of a disease to implement a therapeutic action.

[0061] "Treatment" or "alleviation" refers to therapeutic treatment as well as prophylactic or preventative measures, wherein the purpose is to prevent or slow down (reduce) the target pathological condition or target disorder (herein, "disease") (e.g., neurological disorders). Those in need of treatment include those already suffering from the disease as well as those susceptible to the disease or those in need of prevention of symptoms or disease. A patient is successfully "treated" for a disease if, after receiving a therapeutic amount of a therapeutic agent (e.g., a compound according to the invention), the patient exhibits an observable and / or measurable reduction or absence of one or more of the following aspects: a reduction in the number of pathogens; a reduction in the percentage of pathogenic cells to total cells; and / or a relief to some extent of one or more symptoms associated with a particular disease; a reduction in morbidity and mortality and an improvement in quality of life issues. The above parameters for assessing successful treatment and improvement of the disease can be readily measured by routine methods familiar to physicians. DETAILED DESCRIPTION

[0062] Compound

[0063] The present invention is directed to compounds of formula (I)

[0064]

[0065] or a pharmaceutically acceptable salt and / or a solvate thereof;

[0066] in

[0067] W represents CH or N;

[0068] R A , R B , R C and R D Each independently represents hydrogen, F, Cl, CH 3 CF 3 , CHF 2 or CH 2 F;

[0069] R 7 represents hydrogen, OH, halogen, (C 1 To C 8 ) alkyl, cycloalkyl, (C 1 To C 8 )alkyl-O-, cycloalkyl-O-, cycloalkyl-(C 1 To C 8 )alkyl-O-, heterocycloalkyl-O-, heterocycloalkyl-(C 1 To C 8 )alkyl-O-, aryl-(C 1 To C 8 )alkyl-O-, heteroaryl-(C1 To C 8 )alkyl-O-, R 11 O-(C 1 To C 8 )alkyl-O-, R 11 R 12 N-(C 1 To C 8 )alkyl-O-, (R 11 O)(R 12 )N-(C 1 To C 8 )alkyl-O-, R 11 R 12 N-(C 1 To C 8 )alkyl-, R 11 O-(C 1 To C 8 )alkyl-、NR 11 R 12 、CN、CO 2 H, CO 2 R 11 ,CONH 2 、CON(R 11 )H, heterocycloalkyl or heteroaryl; wherein R 11 and R 12 Each independently represents hydrogen or (C 1 To C 8 )alkyl;

[0070] Where R 7 The alkyl or cycloalkyl in the 1 To C 8 ) alkyl, (C 1 To C 8 ) substituted with alkyl-O-, heterocycloalkyl, aryl or heteroaryl;

[0071] Wherein heterocycloalkyl, aryl or heteroaryl (i.e. R 7 Any heterocycloalkyl, aryl or heteroaryl represented by or as part of any substituent thereof) is optionally substituted with at least one F, Cl, (C 1 To C 8 ) alkyl, CF 3 , CHF 2 , CH 2 F. OCF 3 、CN、OH、=O、→O、(C 1 To C 8 ) alkoxy, NR 13 R 14 , R 13 R 14N-(C 1 To C 8 )alkyl-, R 13 O 2 C-(C 1 To C 8 )alkyl-, CO 2 H.R 13 R 14 NC(O)-、R 13 O-NR 14 -or (C 1 To C 8 )alkyl-CO 2 -substituted; wherein R 13 and R 14 Each independently represents hydrogen or (C 1 To C 8 )alkyl;

[0072] Z stands for CH, CR 8 or N;

[0073] Where R 8 Indicates (C 1 To C 4 )alkyl, F, Cl, CF 3 , CHF 2 , CH 2 F. OCF 3 , CN, OH or (C 1 To C 4 ) alkoxy; or

[0074] Z stands for CR 8 And R 7 and R 8 together with the carbon atoms to which they are bound, form a cycloalkyl or heterocycloalkyl group,

[0075] wherein the cycloalkyl or heterocycloalkyl group is optionally substituted by at least one of F, OH, =O, →O, (C 1 To C 8 ) alkyl, CF 3 HO 2 C-CH 2 -、(C 1 To C 4 )alkyl-CO 2 -CH 2 -、R 15 R 16 N-CH 2 -, aryl or aryl-(C 1 To C 8 ) alkyl-substituted, wherein R 15 and R 16 Each independently represents hydrogen or (C1 To C 8 )alkyl;

[0076] R 5 represents hydrogen, (C 1 To C 8 ) alkyl, one to three (C 1 To C 8 ) alkyl substituted CH 3 , cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C 1 To C 8 )alkyl;

[0077] Where R 5 The alkyl or cycloalkyl group in the 1 To C 8 ) alkyl, CF 3 、OCF 3 、CN、OH、=O、(C 1 To C 8 ) alkoxy, NR 17 R 18 , CO 2 H.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 (C 1 To C 8 )alkyl;

[0078] Wherein heterocycloalkyl, aryl or heteroaryl (i.e. R 5 Any heterocycloalkyl, aryl or heteroaryl represented by or as part of any substituent thereof) is optionally substituted with at least one F, Cl, (C 1 To C 8 ) alkyl, CF 3 , CHF 2 , CH 2 F. OCF 3 、CN、OH、=O、→O、(C 1 To C 8 ) alkoxy, NR 19 R 20 , CO 2 H.R 19 R 20 NC(O)-、R 19 O-NR 20 -、(C 1 To C 8 )alkyl-CO2 -、R 19 R 20 N-(C 1 To C 8 )alkyl-, R 19 O 2 C-(C 1 To C 8 )alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C 1 To C 8 ) alkyl-substituted; wherein R 19 and R 20 Each independently represents hydrogen or (C 1 To C 8 )alkyl;

[0079] R 6 Indicates (C 1 To C 8 ) alkyl, one to three (C 1 To C 8 ) alkyl substituted CH 3 , cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C 1 To C 8 )alkyl;

[0080] Where R 6 The alkyl or cycloalkyl group in the 1 To C 8 ) alkyl, CF 3 、OCF 3 、CN、OH、=O、(C 1 To C 8 ) alkoxy, NR 21 R 22 , CO 2 H.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 (C 1 To C 8 )alkyl;

[0081] wherein the heterocycloalkyl, aryl or heteroaryl (i.e., R 6 Any heterocycloalkyl, aryl or heteroaryl represented by or as part of any substituent thereof) is optionally substituted with at least one F, Cl, (C 1 To C 8 ) alkyl, CF 3 , CHF 2 , CH2 F. OCF 3 、CN、OH、=O、→O、(C 1 To C 8 ) alkoxy, NR 23 R 24 , CO 2 H.R 23 R 24 NC(O)-、R 23 O-NR 24 -、(C 1 To C 8 )alkyl-CO 2 -、R 23 R 24 N-(C 1 To C 8 )alkyl-, R 23 O 2 C-(C 1 To C 8 )alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C 1 To C 8 ) alkyl-substituted; wherein R 23 and R 24 Each independently represents hydrogen or (C 1 To C 8 ) alkyl; or

[0082] R 5 and R 6 together with the nitrogen atom to which they are bound, form a heterocycloalkyl group,

[0083] wherein the heterocycloalkyl group (i.e., R 5 , R 6 and the nitrogen atom to which it is bonded) are optionally substituted with at least one F, Cl, (C 1 To C 8 ) alkyl, CF 3 、OCF 3 、CN、OH、=O、→O、(C 1 To C 8 ) alkoxy, NR 25 R 26 , CO 2 H、(C 1 To C 8 )alkyl-CO 2 -、R 25 R 26 NC(O)-、R 25 O-NR 26 -、R 25 R 26 N-(C 1 To C8 )alkyl-, R 25 O 2 C-(C 1 To C 8 )alkyl-, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C 1 To C 8 )alkyl-, heterocycloalkyl-(C 1 To C 8 ) alkyl-, aryl-(C 1 To C 8 )alkyl-, heteroaryl-(C 1 To C 8 )alkyl-, aryl-cycloalkyl-, cycloalkyl-O-, heterocycloalkyl-O-, aryl-O-, heteroaryl-O-, cycloalkyl-(C 1 To C 8 )alkyl-O-, heterocycloalkyl-(C 1 To C 8 )alkyl-O-, aryl-(C 1 To C 8 )alkyl-O-, heteroaryl-(C 1 To C 8 )alkyl-O-, cycloalkyl-NR 25 -, heterocycloalkyl-NR 25 -, aryl-NR 25 -, heteroaryl-NR 25 -, cycloalkyl-(C 1 To C 8 )Aryl-NR 25 -, heterocycloalkyl-(C 1 To C 8 )alkyl-NR 25 -, aryl-(C 1 To C 8 )alkyl-NR 25 -, heteroaryl-(C 1 To C 8 )alkyl-NR 25 -, benzylidene, heteroarylidene, aryl-(C 1 To C 8 )alkyl-ylidene- or heteroaryl-(C 1 To C 8 ) alkyl-ylidene-substituted;

[0084] Where R 25 and R 26 Each independently represents hydrogen or (C 1 To C 8 )alkyl;

[0085] wherein the heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylene (i.e., R 5 , R 6 and the nitrogen atom to which it is bonded) to form any heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylene group, optionally substituted with at least one F, Cl, (C 1 To C 8 ) alkyl, CF 3 , CHF 2 , CH 2 F. OCF 3 、CN、OH、=O、→O、(C 1 To C 8 ) alkoxy, NR 27 R 28 , CO 2 H.R 27 R 28 NC(O)-、R 27 O-NR 28 -、(C 1 To C 8 )alkyl-CO 2 -、R 27 R 28 N-(C 1 To C 8 )alkyl-, R 27 O 2 C-(C 1 To C 8 )alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C 1 To C 8 ) alkyl-substituted; wherein R 27 and R 28 Each independently represents hydrogen or (C 1 To C 8 )alkyl.

[0086] According to a preferred embodiment, when exactly two are selected from R A , R B and R C The group represents hydrogen, R D CF 3 , R 7 Indicates OCH 3 and Z represents CH, then R A , R B and R C The remaining groups in do not represent F.

[0087] Unless otherwise stated, in any of the following embodiments involving specific limitations on the structure of compounds of Formula (I), any alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylene group may independently be optionally substituted as shown herein for Formula (I).

[0088] According to a preferred embodiment, R D Represents hydrogen, F, Cl, CH 3 , CHF 2 or CH 2 F. In this embodiment, formula (I) is referred to as "formula (Ii)".

[0089] According to a preferred embodiment, R 7 represents hydrogen, OH, halogen, (C 1 To C 8 ) alkyl, cycloalkyl, (C 2 To C 8 )alkyl-O-, cycloalkyl-O-, cycloalkyl-(C 1 To C 8 )alkyl-O-, heterocycloalkyl-O-, heterocycloalkyl-(C 1 To C 8 )alkyl-O-, aryl-(C 1 To C 8 )alkyl-O-, heteroaryl-(C 1 To C 8 )alkyl-O-, R 11 O-(C 1 To C 8 )alkyl-O-, R 11 R 12 N-(C 1 To C 8 )alkyl-O-, (R 11 O)(R 12 )N-(C 1 To C 8 )alkyl-O-, R 11 R 12 N-(C 1 To C 8 )alkyl-, R 11 O-(C 1 To C 8 )alkyl-、NR 11 R 12 、CN、CO 2 H, CO 2 R 11 ,CONH 2 、CON(R 11 )H, heterocycloalkyl, or heteroaryl; wherein R 11and R 12 Each independently represents hydrogen or (C 1 To C 8 )alkyl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted as defined above for formula (I). In this embodiment, formula (I) is referred to as "formula (I-ii)".

[0090] According to a preferred embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt or a solvate thereof; wherein

[0091] W represents CH or N;

[0092] R A , R B , R C and R D Each independently represents hydrogen, F, Cl, CH 3 CF 3 , CHF 2 or CH 2 F,

[0093] R 7 represents hydrogen, OH, halogen, (C 1 To C 8 ) alkyl, cycloalkyl, (C 1 To C 8 )alkyl-O-, cycloalkyl-O-, cycloalkyl-(C 1 To C 8 )alkyl-O-, heterocycloalkyl-O-, R 11 O-(C 1 To C 8 )alkyl-O-, R 11 R 12 N-(C 1 To C 8 )alkyl-O- or (R 1 O)(R 12 )N-(C 1 To C 8 )alkyl-O-; wherein R 11 and R 12 Each independently represents hydrogen or (C 1 To C 8 )alkyl;

[0094] wherein the alkyl or cycloalkyl is optionally substituted with at least one F, Cl, heterocycloalkyl, aryl or heteroaryl;

[0095] wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted with at least one F, Cl, CF 3 , CHF 2 , CH 2F. OCF 3 、CN、OH、(C 1 To C 8 ) alkoxy, NR 13 R 14 , CO 2 H.R 13 R 14 NC(O)- or R 13 O-NR 14 -substituted; wherein R 13 and R 14 Each independently represents hydrogen or (C 1 To C 8 )alkyl;

[0096] Z represents CH or N; or

[0097] Z stands for CR 8 And R 7 and R 8 together with the carbon atoms to which they are bound, form a cycloalkyl or heterocycloalkyl group,

[0098] wherein the cycloalkyl or heterocycloalkyl group is optionally substituted with at least one F, OH, CF 3 HO 2 C-CH 2 -、(C 1 To C 4 )alkyl-CO 2 -CH 2 - or R 15 R 16 N-CH 2 -substituted, where R 15 and R 16 Each independently represents hydrogen or (C 1 To C 8 )alkyl;

[0099] R 5 represents hydrogen, (C 1 To C 8 ) alkyl, one to three (C 1 To C 8 ) alkyl substituted CH 3 , cycloalkyl, or cycloalkyl-(C 1 To C 8 )alkyl;

[0100] wherein the alkyl or cycloalkyl group is optionally substituted with at least one F, Cl, CF 3 、OCF 3 、CN、OH、(C 1 To C 8 ) alkoxy, NR 17 R18 , CO 2 H.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 (C 1 To C 8 )alkyl;

[0101] wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted with at least one F, Cl, CF 3 , CHF 2 , CH 2 F. OCF 3 、CN、OH、(C 1 To C 8 ) alkoxy, NR 19 R 20 , CO 2 H.R 19 R 20 NC(O)- or R 19 O-NR 20 -substituted; wherein R 19 and R 20 Each independently represents hydrogen or (C 1 To C 8 )alkyl;

[0102] R 6 Indicates (C 1 To C 8 ) alkyl, one to three (C 1 To C 8 ) alkyl substituted CH 3 , cycloalkyl or cycloalkyl-(C 1 To C 8 )alkyl;

[0103] wherein the alkyl or cycloalkyl group is optionally substituted with at least one of F, Cl, CF 3 、OCF 3 、CN、OH、(C 1 To C 8 ) alkoxy, NR 21 R 22 , CO 2 H.R 21 R 22 NC(O)-、R 21 O-NR 22 -, heterocycloalkyl, aryl or heteroaryl; wherein R 21 and R 22Each independently represents hydrogen or (C 1 To C 8 )alkyl;

[0104] wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted with at least one F, Cl, CF 3 , CHF 2 , CH 2 F. OCF 3 、CN、OH、(C 1 To C 8 ) alkoxy, NR 23 R 24 , CO 2 H.R 23 R 24 NC(O)- or R 23 O-NR 24 -substituted; wherein R 23 and R 24 Each independently represents hydrogen or (C 1 To C 8 ) alkyl; or

[0105] R 5 and R 6 together with the nitrogen atom to which they are bound, form a heterocycloalkyl group,

[0106] wherein the heterocycloalkyl group is optionally substituted with at least one F, Cl, CF 3 、OCF 3 、CN、OH、(C 1 To C 8 ) alkoxy, NR 25 R 26 , CO 2 H.R 25 R 26 NC(O)-、R 25 O-NR 26 -, heterocycloalkyl, aryl, heteroaryl, heterocycloalkyl-(C 1 To C 8 ) alkyl-, aryl-(C 1 To C 8 )alkyl-, heteroaryl-(C 1 To C 8 )alkyl-, cycloalkyl-(C 1 To C 8 )alkyl-O-, aryl-(C 1 To C 8 )alkyl-O-, heteroaryl-(C 1 To C 8 )alkyl-O-, cycloalkyl-(C 1 To C 8 )alkyl-NR25 -, aryl-(C 1 To C 8 )alkyl-NR 25 -, heteroaryl-(C 1 To C 8 )alkyl-NR 25 -, benzylidene, heteroarylidene, aryl-(C 1 To C 8 )alkyl-ylidene- or heteroaryl-(C 1 To C 8 ) alkyl-ylidene-substituted;

[0107] Where R 25 and R 26 Each independently represents hydrogen or (C 1 To C 8 )alkyl;

[0108] wherein the heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylene group is optionally substituted with at least one F, Cl, CF 3 , CHF 2 , CH 2 F. OCF 3 、CN、OH、(C 1 To C 8 ) alkoxy, NR 27 R 28 , CO 2 H.R 27 R 28 NC(O)- or R 27 O-NR 28 -substituted; wherein R 27 and R 28 Each independently represents hydrogen or (C 1 To C 8 )alkyl;

[0109] The premise is that when there are exactly two selected from R A , R B and R C The group represents hydrogen, R D CF 3 , R 7 Indicates OCH 3 and Z represents CH, then R A , R B and R C The remaining groups in do not represent F.

[0110] According to one embodiment, W represents CH.

[0111] According to one embodiment, R A , R B, R C and R D at least one represents hydrogen. In one embodiment, R A , R B , R C and R D exactly one represents hydrogen. In one embodiment, R A , R B , R C and R D exactly two represent hydrogen. In one embodiment, R A , R u , R C and R D exactly three represent hydrogen.

[0112] In one embodiment, R A and R C at least one represents hydrogen. In a particular embodiment, R A represents hydrogen. In a particular embodiment, R C represents hydrogen.

[0113] According to one embodiment, R A , R B and R D at least one represents F or Cl. In one embodiment, R B and R D at least one represents F or Cl. In a particular embodiment, R B and R D each independently represent F or Cl. In a particular embodiment, R B represents F. In a particular embodiment, R B represents Cl. In a particular embodiment, R D represents F. In a particular embodiment, R D represents Cl. In a preferred embodiment, R B represents F. In a preferred embodiment, R D represents Cl. In an even more preferred embodiment, R B represents F and R D represents Cl.

[0114] According to one embodiment, R A , R B and R D at least one represents CHF 2 or CF 3 . In one embodiment, R B and R D at least one represents CHF2 or CF 3 In a particular embodiment, R B and R D Each independently represents H, F, CHF 2 or CF 3 In one embodiment, R B represents H or F. In a further preferred embodiment, R B In a preferred embodiment, R D Indicates CHF 2 or CF 3 In a further preferred embodiment, R B Indicates H or F and R D Indicates CHF 2 or CF 3 .

[0115] According to one embodiment, R 7 represents hydrogen, OH, halogen, (C 1 To C 8 ) alkyl, cycloalkyl, (C 1 To C 8 )alkyl-O-, cycloalkyl-O-, cycloalkyl-(C 1 To C 8 )alkyl-O-, heterocycloalkyl-O-, R 11 O-(C 1 To C 8 )alkyl-O-, R 11 R 12 N-(C 1 To C 8 )alkyl-O- or (R 11 O)(R 12 )N-(C 1 To C 8 )alkyl-O-; wherein R 11 and R 12 Each independently represents hydrogen or (C 1 To C 8 )alkyl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted as defined above for formula (I).

[0116] According to one embodiment, R 7 represents hydrogen, OH or halogen. In one embodiment, R 7 In a preferred embodiment, R 7 In one embodiment, R 7 In a particularly preferred embodiment, R 7In a particularly preferred embodiment, R 7 In a particular embodiment, R 7 Indicates Cl.

[0117] In a preferred embodiment, R 7 Does not represent hydrogen.

[0118] According to one embodiment, R 7 Indicates (C 1 To C 8 )alkyl-O-(i.e. (C 1 To C 8 In one embodiment, the alkyl or cycloalkyl group is optionally substituted with at least one F, Cl, OH, (C 1 To C 8 ) is substituted with alkoxy or aryl. In a particular embodiment, R 7 Indicates OCH 3 (Methoxy), OCH 2 CH 3 、OCF 3 , cyclobutyl-O-, HO-CH 2 -CH 2 -O-、CH 3 O-CH 2 -CH 2 -O- or phenyl-CH 2 -O-.

[0119] According to one embodiment, R 7 Indicates (C 1 To C 8 )alkyl-O-(i.e. (C 1 To C 8 )alkoxy). In one embodiment, the alkyl is optionally substituted with at least one F or Cl. In a particular embodiment, the halogen is F. In one embodiment, R 7 Indicates OCH 3 (Methoxy), OCH 2 CH 3 、OCF 3 In a preferred embodiment, R 7 Indicates OCH 3 (methoxy).

[0120] According to one embodiment, R 7 In one embodiment, R 7 It represents cyclobutyl-O-.

[0121] According to one embodiment, R7 Indicates (C 1 To C 8 )alkyl-O-(i.e. (C 1 To C 8 ) alkoxy), wherein the alkyl group is optionally substituted with at least one OH or (C 1 To C 8 ) alkoxy substitution, i.e. RO-(C 1 To C 8 )alkyl-O-, wherein R represents H or (C 1 To C 8 In a preferred embodiment, R 7 Indicates HO-CH 2 -CH 2 -O- or CH 3 O-CH 2 -CH 2 -O-.

[0122] According to one embodiment, R 7 Indicates (C 1 To C 8 )alkyl-O-(i.e. (C 1 To C 8 )alkoxy), wherein the alkyl group is optionally substituted with at least one aryl group. In one embodiment, the aryl group is unsubstituted. In one embodiment, R 7 represents phenyl-CH 2 -O-.

[0123] According to one embodiment, R 7 Indicates (C 1 To C 8 )alkyl-O-(i.e. (C 1 To C 8 )alkoxy), wherein the alkyl group is optionally substituted with at least one heteroaryl group. In one embodiment, the heteroaryl group is unsubstituted. In one embodiment, R 7 Represents heteroaryl -CH 2 -O-.

[0124] According to one embodiment, R 7 Indicates (C 1 To C 8 )alkyl-O-(i.e. (C 1 To C 8 )alkoxy), wherein the alkyl group is optionally substituted with at least one heterocycloalkyl group. In one embodiment, R 7 represents heterocycloalkyl-(C 1 To C 8Alkyl-O-, i.e., the alkyl is substituted by exactly one heterocycloalkyl. In one embodiment, the heterocycloalkyl is unsubstituted.

[0125] In a preferred embodiment, R 7 represents hydrogen, F, Cl, OH, OCH 3 (methoxy), HO-CH 2 -CH 2 -O-, CH 3 O-CH 2 -CH 2 -O- or phenyl-CH 2 -O-.

[0126] In an even more preferred embodiment, R 7 represents F, OH, OCH 3 (methoxy) or phenyl-CH 2 -O-.

[0127] According to one embodiment, Z represents C-H or N; or Z represents C-R 8 and R 7 and R 8 and the carbon atom to which they are bonded together form a cycloalkyl or heterocycloalkyl; where the cycloalkyl or heterocycloalkyl is optionally substituted as defined in formula (I) above. In other words, in this embodiment, in addition to R 7 and R 8 and the carbon atom to which they are bonded together form a cycloalkyl or heterocycloalkyl, R 8 represents hydrogen.

[0128] According to one embodiment, Z represents C-H or N. In one embodiment, Z represents C-H. In one embodiment, Z represents N.

[0129] According to another embodiment, Z represents C-R 8 and R 7 and R 8 and the carbon atom to which they are bonded together form a cycloalkyl or heterocycloalkyl; where the cycloalkyl or heterocycloalkyl is optionally substituted as defined in formula (I) herein.

[0130] According to a preferred embodiment, Z does not represent N.

[0131] In a preferred embodiment, Z represents C-R 8 ; where R 8 represents (C 1 to C 4 )alkyl, F, Cl, CF 3 , CHF 2 , CH 2 F, OCF3 , CN, OH or (C 1 To C 4 In a particular embodiment, R 8 Indicates methyl, ethyl, F, Cl, CF 3 , CN or OH. In a preferred embodiment, R 8 It represents methyl or Cl.

[0132] In a preferred embodiment, Z represents CR 8 And R 7 and R 8 and the carbon atoms to which they are bonded together form a heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted as defined herein in formula (I). In a particular embodiment, the heterocycloalkyl comprises at least one oxygen atom, i.e., the heterocycloalkyl is a cyclic ether. In a particular embodiment, the heterocycloalkyl comprises exactly one oxygen atom. In a particular embodiment, the heterocycloalkyl comprises at least one nitrogen atom, i.e., the heterocycloalkyl is a cyclic amine. In a particular embodiment, the heterocycloalkyl is six-membered or five-membered. In one embodiment, the heterocycloalkyl is unsubstituted. In a preferred embodiment, the heterocycloalkyl is tetrahydrofuran (e.g., wherein -R 7 -R 8 - means -O-CH 2 CH 2 -).

[0133] According to one embodiment, R 5 represents hydrogen or (C 1 To C 8 ) alkyl. In one embodiment, R 5 In one embodiment, R 5 Indicates (C 1 To C 8 In a preferred embodiment, R 5 represents hydrogen, methyl or ethyl. In a particular embodiment, R 5 In a particular embodiment, R 5 In a further particular embodiment, R 5 In a further particular embodiment, R 5 It represents ethyl.

[0134] According to one embodiment, R 6 Indicates (C 1 To C 8 )alkyl, cycloalkyl or cycloalkyl-(C 1 To C 8)alkyl-. In one embodiment, the alkyl or cycloalkyl is optionally substituted with at least one F. In one embodiment, the alkyl or cycloalkyl is unsubstituted. In one embodiment, R 6 represents methyl, ethyl, n-propyl, 1-fluoro-n-propane, tert-butyl, cyclopropyl, cyclobutyl or cyclopropyl-CH 2 -.

[0135] According to one embodiment, R 6 Indicates (C 1 To C 8 )alkyl, cycloalkyl, heterocycloalkyl, cycloalkyl-(C 1 To C 8 )alkyl- or aryl-(C 1 To C 8 In one embodiment, the alkyl, cycloalkyl, heterocycloalkyl or aryl group is optionally substituted with at least one methyl, Cl or F.

[0136] In one embodiment, R 6 represents ethyl, propyl (e.g., n-propyl), butyl (e.g., tert-butyl), cyclopentyl, cyclohexyl, 2-adamantyl, 3-methyloxetan-3-yl, cyclopropyl-CH 2 -, cyclobutyl-CH 2 -、cyclohexyl-CH 2 -, phenyl-CH 2 -(Benzyl), 3-chlorophenyl-CH 2 - or 4-fluorophenyl-CH 2 -.

[0137] In a further preferred embodiment, R 6 represents propyl (e.g., n-propyl), butyl (e.g., tert-butyl), cyclohexyl, cyclopropyl-CH 2 - or 3-chlorophenyl-CH 2 .

[0138] According to one embodiment, R 6 Indicates (C 1 To C 8 ) alkyl. In one embodiment, the alkyl group is optionally substituted with at least one F. In a preferred embodiment, the alkyl group is unsubstituted. In a particular embodiment, R 5 represents methyl, ethyl, n-propyl, 1-fluoro-n-propane or tert-butyl.

[0139] According to one embodiment, R 6 In one embodiment, R 6 represents cyclopropyl or cyclobutyl.

[0140] According to one embodiment, R6 represents a cycloalkyl-(C 1 To C 8 In a particular embodiment, R 6 Cyclopropylmethyl (cyclopropyl-CH 2 -).

[0141] According to one embodiment, R 5 and R 6 Together with the nitrogen atom to which they are bound, form a heterocycloalkyl. In one embodiment, the heterocycloalkyl is optionally substituted with at least one F. In one embodiment, R 5 and R 6 Together with the nitrogen atom to which they are bound, they form pyrrolidine, piperidine, 4-fluoropiperidine, 3-fluoropyrrolidine, 4-trifluoromethylpiperidine, 4-benzyl-piperidine, 3-benzylpyrrolidine, 3-benzyl-piperidine, 4-phenylpiperidine, 4-benzylidenepiperidine, octahydro-1H-isoindole, 2-benzyloctahydropyrrolo[3,4-c]pyrrole, 3-(benzyloxy)pyrrole, 3-(methoxymethyl)azetidine, 2-azabicyclo[2.2.1]heptane, 5-(4-methylpiperazin-1-yl)pyrimidine and 4-phenylethylpiperidine. In a particular embodiment, R 5 and R 6 Together with the nitrogen atom to which they are bound, they form pyrrolidine, 4-fluoropiperidine, 3-fluoropyrrolidine, 4-trifluoromethylpiperidine, 4-benzyl-piperidine, 3-benzylpyrrolidine, 3-benzyl-piperidine, 4-phenylpiperidine, 4-benzylidenepiperidine, octahydro-1H-isoindole, 3-(benzyloxy)pyrrole, 2-azabicyclo[2.2.1]heptane, 5-(4-methylpiperazin-1-yl)pyrimidine or 4-phenethylpiperidine.

[0142] In a preferred embodiment, R 5 and R 6Together with the nitrogen atom to which they are bound, they form pyrrolidine, 4-benzyl-piperidine, 4-phenyl-4-hydroxy-piperidine, 4-benzyl-4-hydroxy-piperidine, 4-benzyl-piperazine, tert-butyl 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate, 4-benzylidene-1-piperidine, 4-(2-phenylethyl)-piperidine, 4-phenylpiperidine, 3-phenylpiperidine, 3-benzyl-piperidine, 3-phenylpyrrolidine, 4- trifluoromethylpiperidine, 2-azabicyclo[2.2.1]heptane, 3-benzyloxypiperidine, 3-benzyloxypyrrolidine, 2-benzyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrolidine, 4-(4-fluorophenyl)piperidine, [2-(4-chlorophenyl)ethyl]piperazine, [2-(4-fluorophenyl)ethyl]piperazine, 2-(phenylpropyl)piperazine, [2-(4-fluorophenyl)propyl]piperazine, 4-fluoropiperidine or 2,2-dimethylpyrrolidine.

[0143] In a preferred embodiment, R 5 and R 6 Together with the nitrogen atom to which they are bound, they form pyrrolidine, 4-benzyl-piperidine, 4-benzylidene-1-piperidine, 4-(2-phenylethyl)-piperidine, 4-phenylpiperidine, 3-phenylpiperidine, 3-benzyl-piperidine, 3-phenylpyrrolidine, 4-trifluoromethylpiperidine, 3-benzyloxypiperidine, 3-benzyloxypyrrolidine, 4-(4-fluorophenyl)piperidine, [2-(4-chlorophenyl)ethyl]piperazine, [2-(4-fluorophenyl)ethyl]piperazine, 2-(phenylpropyl)piperazine, [2-(4-fluorophenyl)propyl]piperazine, 4-fluoropiperidine or 2,2-dimethylpyrrolidine.

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

[0145] According to one embodiment, the compound of formula (I) is a compound of formula (Ia)

[0146]

[0147] or a pharmaceutically acceptable salt and / or a solvate thereof;

[0148] Among them, W, R B , R D , Z and R 5 To R 7 As defined herein in formula (I).

[0149] In one embodiment, W in formula (Ia) represents CH.

[0150] In one embodiment, R in Formula (Ia) B and R D Each independently represents F or Cl and R 7 In a particular embodiment, R B Indicates F and R D Indicates Cl.

[0151] In one embodiment, R in Formula (Ia) 7 In a particular embodiment, R 7 Denotes methoxy (-OCH 3 ).

[0152] In one embodiment, R in Formula (Ia) B and R D Each independently represents F or CF 3 In a particular embodiment, R B Indicates F and R D CF 3 .

[0153] In one embodiment, Z in formula (Ia) represents N.

[0154] 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.

[0155] Table 1

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168] According to a preferred embodiment, the compound is selected from the compounds of Table 1 herein and pharmaceutically acceptable salts and / or solvates thereof, with the proviso that the compound is not N,N-diethyl-5-[4-[4-fluoro-2-(trifluoroethyl)benzoyl]piperazin-1-yl]-6-methoxy-pyridine-3-sulfonamide (045) or a pharmaceutically acceptable salt and / or solvate thereof.

[0169]

[0170] According to one embodiment, in the compounds of formula (I), when R D CF 3 , R 7 Indicates OCH 3 and Z represents CH, then R A , R B and R C does not represent F or Cl. According to one embodiment, in the compound of formula (I), when R D CF 3 And R 7 Indicates OCH 3 When R A , R B and R C does not represent F. According to one embodiment, in the compound of formula (I), when R D CF 3 When R A , R B and R C does not represent F. According to one embodiment, in the compound of formula (I), when R D CF 3 When R A , R B and R C does not represent F or Cl. According to one embodiment, in the compound of formula (I), when R 7 Indicates OCH 3 When R A , R B and R C does not represent F. According to one embodiment, in the compound of formula (I), when R 7 Indicates OCH 3 When R A , R B and R C does not represent F or Cl. According to one embodiment, R D Does not indicate CF 3In one embodiment, R D Does not indicate CF 3 , CHF 2 or CH 2 F. According to one embodiment, R 7 Does not represent methoxy (-OCH 3 In one embodiment, R 7 Alkoxy groups are not represented.

[0171] 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 thereof. 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.

[0172] In particular, the compounds of the present invention may be in the form of pharmaceutically acceptable salts. According to one embodiment, the compounds of the present invention are pharmaceutically acceptable salts. Pharmaceutically acceptable salts include acid addition salts thereof and base salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, and xinafoate. Suitable alkali salts are formed by the alkali that forms non-toxic salts.Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, 2-(diethylamino)ethanol salts, diethanolamine salts, aminoethanol salts, glycine salts, 4-(2-hydroxyethyl)-morpholine salts, lysine salts, magnesium salts, meglumine salts, morpholine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts and zinc salts.Also can form the half salt of acid and base, for example hemisulfate and hemicalcium salt.When compound contains acidic group and basic group, described compound also can form inner salt, and these compounds are within the scope of the present invention.When compound contains hydrogen heteroatom (for example NH), the present invention also includes the salt and / or isomer formed by transferring described hydrogen atom to the basic group or basic atom in molecule.

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

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

[0176] Pharmaceutical composition

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

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

[0179] As described herein, another object of the present invention is a medicament comprising a compound according to the present invention.

[0180] Reagent test kit

[0181] As described herein, another object of the present invention is a kit (hereinafter referred to as a "kit") comprising a compound or composition according to the present invention. According to one embodiment, the kit comprises an article such as a package or a container. According to one embodiment, the kit comprises instructions for use. The kit may be promoted, distributed or sold as a unit for carrying out the methods of the present invention.

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

[0183] Medical uses of compounds

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

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

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

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

[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, age-related decline in nervous system performance, or neurodevelopmental disorders;

[0190] - a neurodegenerative disease or disorder of the nervous system, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, frontotemporal dementia, a retinal neurodegenerative disease, a neuro-ophthalmological disease, neurotrophic keratitis, Charcot-Marie-Tooth disease, spinal muscular atrophy, epilepsy (e.g., epilepsy, or seizure disorder, or a chronic neurological disorder manifesting as epilepsy), dementia, age-related decline in nervous system performance, prion disease, Creutzfeldt-Jakob disease, multiple system atrophy (Schaef-Drosselgren 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, complications of nerve transplantation, spinal cord injury, traumatic spinal cord injury, neurectomy or nerve injury, cerebrospinal nerve rupture, brain cell or nerve cell damage, syringomyelia, optic neuropathy, trauma, stroke, ischemia, stroke, ischemic stroke, neurotoxicity caused by alcohol abuse or substance abuse (e.g., ecstasy, methamphetamine, etc.), or aphasia;

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

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

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

[0195] - pain disorders such as neuralgia, trigeminal neuralgia, chronic pain, inflammatory pain, arthritis-related pain, fibromyalgia, back pain, cancer-related pain, digestive disease-related pain, Crohn's disease-related pain, autoimmune disease-related pain, endocrine disease-related pain, diabetic neuropathy-related pain, phantom limb pain, spontaneous pain, chronic postoperative pain, chronic temporomandibular pain, causalgia, postherpetic neuralgia, AIDS-related pain, complex regional pain syndrome type I and II, trigeminal neuralgia, chronic back pain, spinal cord injury-related pain, pain associated with medication ingestion and recurrent acute pain, neuropathic pain or neuroesthesia caused by inappropriate neuronal activity in diseases such as diabetes, multiple sclerosis (MS) and motor neuron disease;

[0196] - Ophthalmological diseases or eye diseases, such as retinal diseases, retinal neurodegenerative diseases, retinitis pigmentosa, non-arteritic anterior ischemic optic neuropathy (NAION), macular degeneration, age-related macular degeneration, glaucoma, diabetic retinopathy, optic neuropathy and retinitis pigmentosa, neuro-ophthalmological diseases, age-related cataracts, primary open-angle glaucoma (POAG), retinal ganglion cell damage, ocular hypertension, ischemic optic neuropathy, macular telangiectasia, cystoid macular edema, macular telangiectasia type 2, neurotrophic keratitis, or paraopia;

[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 syndrome or intestinal inflammation;

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

[0199] - Diseases or disorders related to long-term or short-term memory deficits, such as memory loss, benign amnesia, or Alzheimer's disease;

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

[0201] - Neurological 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 dependence, substance-induced psychological disorders, dementia or amnestic disorders caused by substance withdrawal, and substance-induced dementia or amnestic disorders;

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

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

[0208] According to one embodiment, as described herein, the composition or medicine according to the present invention is administered to a subject, and it can be formulated using methods well 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., powder forms or liposomal forms) suitable for adding liquids to prepare solutions or suspensions prior to use.

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

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

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

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

[0213] Another object of the present invention is a method for promoting neuronal cell survival and / or neuronal cell function. As described herein, another object of the present invention is a compound or composition according to the present invention for promoting neuronal cell survival and / or neuronal cell function. According to one embodiment, as described herein, the method or use includes the step of contacting neuronal cells with a therapeutically effective amount of a compound, composition or drug according to the present invention. The method or use may 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. As described herein, another object of the present invention is a compound or composition according to the present invention, which is used to rescue neuronal cell function after neuronal cells are subjected to damage, events or conditions that are harmful to neuronal cell function. These injuries, events or conditions include but are not limited to neuronal stress, such as neuronal stress caused by hypoxia or ischemia; traumatic injury; and exposure to toxic molecules, such as abnormal misfolded proteins, protein aggregates, excitotoxins, reactive oxygen species, endoplasmic reticulum stressors, mitochondrial stressors, Golgi antagonists, etc. According to one embodiment, as described herein, the method or use includes a step of contacting neuronal cells with a therapeutically effective amount of a compound, composition or drug according to the present invention. The method or use may be in vitro, ex vivo or in vivo.

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

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

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

[0218] Preparation method

[0219] Synthesis of compounds

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

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

[0222] According to one embodiment, the method comprises:

[0223] (a-1) A step of reacting the following compounds in the presence of a base and a metal catalyst:

[0224] Compound of formula (II)

[0225]

[0226] Among them, Z, R 5 , R 6 and R 7 As defined herein in formula (I) and X represents halogen or -CF 3 SO 3 , and a compound of formula (III),

[0227]

[0228] Where W and R A To R D As defined herein in formula (I);

[0229] Thus, the compound of the present invention is obtained.

[0230] In one embodiment, the base in step (a-1) is cesium carbonate (Cs 2 CO 3 ), sodium carbonate (Na 2 CO 3 ) or potassium carbonate (K 2 CO 3 In a particular embodiment, the base is cesium carbonate (Cs 2 CO 3 In one embodiment, the base is sodium tert-butoxide (t-BuONa), potassium tert-butoxide (t-BuOK) or potassium phosphate. In a particular embodiment, the base is sodium tert-butoxide (t-BuONa).

[0231] In one embodiment, the catalyst of step (a-1) is a palladium catalyst. In a particular embodiment, the catalyst is Pd(OAc) 2 and racemic-BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) system. In a particular embodiment, the catalyst is Xphos-Pd-G3.

[0232] In one embodiment, X represents halogen. In a particular embodiment, X represents Br.

[0233] In one embodiment, the reaction of step (a-1) is carried out in a solvent. In a particular embodiment, the solvent is toluene. In one embodiment, the reaction is carried out under reflux.

[0234] According to another embodiment, the method comprises:

[0235] (a'-1) In the presence of a base and a metal catalyst, the following compounds are reacted

[0236] Compound of formula (II)

[0237]

[0238] Among them, Z, R 5 , R 6 and R 7 As defined herein in formula (I) and X represents halogen or -CF 3 SO 3 ,

[0239] With monoprotected piperazine (i.e., in which only one NH group is protected by a protecting group R P protected piperazine);

[0240] Thus, a compound of formula (IV) is obtained

[0241]

[0242] Among them, Z, R 5 , R 6 and R 7 As defined in formula (II) above and R P is a protecting group; subsequently

[0243] (a'-2) deprotection step of the compound of formula (IV);

[0244] Thus, a compound of formula (V) is obtained

[0245]

[0246] Among them, Z, R 5 , R 6 and R 7 As defined above in formula (II); and

[0247] (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

[0248]

[0249] wherein W and R A to R D are as defined in formula (I) herein;

[0250] to obtain the compound of the present invention.

[0251] In one embodiment, the base and / or catalyst in step (a'-1) are as described in step (a-1) above. In one embodiment, X represents a halogen. In a particular embodiment, X represents Br.

[0252] The protecting group can be any protecting group known in the art, such as tert-butoxycarbonyl (Boc). The protecting group can be removed in step (a'-2) by any method known in the art suitable for the nature of the protecting group, such as adding a strong Bronsted acid (such as hydrochloric acid [HCl]).

[0253] 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).

[0254] 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 (Et 3 N) or diisopropylethylamine (iPr 2 NEt).

[0255] In one embodiment, the reaction in step (a'-3) is carried out in a solvent. In a particular embodiment, the solvent is dimethylformamide (DMF) and / or tetrahydrofuran (THF). In a particular embodiment, the solvent is dichloroethane (DCE) and / or acetonitrile (MeCN). In one embodiment, the reaction is carried out at room temperature (RT).

[0256] According to another embodiment, the method comprises:

[0257] (a”-1) a step of reacting the following compounds in the presence of a base and a metal catalyst:

[0258] a compound of formula (III)

[0259]

[0260] wherein W and R A to R D are as defined in formula (I) herein;

[0261] with a compound of formula (VII)

[0262]

[0263] Wherein, except that Z does not represent N, R 7 and Z are as defined in formula (I) herein and X represents halogen or -CF 3 SO 3 ;

[0264] Thereby obtaining a compound of formula (VIII)

[0265]

[0266] Wherein W, R A to R D , R 7 and Z are as defined in formula (III) and formula (VII) above;

[0267] (a”-2) The step of reacting the compound of formula (VIII) with chlorosulfonic acid (HSO 3 Cl);

[0268] Thereby obtaining a compound of formula (IX);

[0269]

[0270] Wherein W, R A to R D , R 7 and Z are as defined in formula (iii) and formula (VII) above;

[0271] (a”-3) The step of reacting the compound of formula (IX) with a secondary amine of formula (X) in the presence of a base

[0272] NHR 5 R 6 (X)

[0273] Wherein R 5 and R 6 are as defined in formula (I) herein;

[0274] Thereby obtaining the compound of the present invention.

[0275] According to an alternative embodiment, the method comprises step (a”-1) of reacting a compound of formula (III) with a compound of formula (VII) as described above, thereby obtaining a compound of formula (VIII); but without step (a”-2) of reacting the compound of formula (VIII) with chlorosulfonic acid (HSO 3 Cl); and Z may represent N.

[0276] In one embodiment, the base and / or catalyst in step (a"-1) is as described above for step (a-1). In one embodiment, X represents halogen. In a particular embodiment, X represents Br.

[0277] 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 (Et 3 N) or diisopropylethylamine (iPr 2 NEt).

[0278] In one embodiment, the reaction in step (a"-3) is carried out in a solvent. In a particular embodiment, the solvent is dichloromethane (DCM).

[0279] In one embodiment, the method further comprises a post-processing step (b). In one embodiment, the post-processing step (b) comprises a step of extraction by solvent. In a particular embodiment, the solvent is ethyl acetate (EtOAc). In a particular embodiment, the solvent is water or 1N HCl solution. In a particular embodiment, the solvent is dichloromethane (DCM). In one embodiment, the post-processing step (b) comprises a step of filtration ... ethyl acetate (EtOAc). In a particular embodiment, the solvent is ethyl acetate (EtOAc). In a particular embodiment, the solvent is ethyl acetate (EtOAc). In a particular embodiment, the solvent is ethyl acetate (EtOAc). In a particular embodiment, the solvent is ethyl acetate (EtOAc). In a particular embodiment, the solvent is ethyl acetate (EtOAc). Filtration. In one embodiment, the post-treatment step (b) comprises a step of concentration under reduced pressure.

[0280] In one embodiment, the method further comprises a purification step (c). In one embodiment, the purification step (c) comprises purification by chromatography. In a particular embodiment, the chromatography is fast liquid chromatography (FC) (e.g., cHex / EtOAc gradient), preparative thin layer chromatography (PTLC) or semi-preparative high performance liquid chromatography (HPLC).

[0281] Synthetic intermediates

[0282] Another object of the present invention is a compound of formula (II)

[0283]

[0284] Among them, Z, R 5 , R 6 and R 7 As defined herein in formula (I) and X represents halogen or -CF 3 SO 3 .

[0285] Another object of the present invention is a compound of formula (III)

[0286]

[0287] Where W and R A To R D As defined herein in formula (I).

[0288] Another object of the present invention is a compound of formula (IV)

[0289]

[0290] Among them, Z, R 5 , R 6 and R 7 As defined herein in formula (I) and R P is a protecting group (eg Boc). Another object of the present invention is a compound of formula (V)

[0291]

[0292] Among them, Z, R 5 , R 6 and R 7 As defined herein in formula (I).

[0293] Another object of the present invention is a compound of formula (VIII)

[0294]

[0295] Among them, W, R A To R D , R 7 and Z are as defined herein for formula (I).

[0296] According to a preferred embodiment, in formula (VIII) above, Z does not represent N.

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

[0298]

[0299] Among them, W, R A To R D , R 7 and Z are as defined herein for formula (I).

[0300] According to a preferred embodiment, in formula (IX) above, Z does not represent N.

[0301] Example

[0302] The present invention is further illustrated by the following examples.

[0303] Example 1: Synthesis of compounds

[0304] Common Materials and Common Methods

[0305] abbreviation

[0306] List of abbreviations:

[0307] Ac:Acetyl

[0308] Ar: Argon

[0309] BINAP: (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)

[0310] t-Bu: tert-butyl

[0311] cHex: Cyclohexane

[0312] dba: dibenzylideneacetone

[0313] DCM: dichloromethane

[0314] DCE: dichloroethane

[0315] DMF: dimethylformamide

[0316] Et: Ethyl

[0317] FC: fast liquid chromatography

[0318] HPLC: High Performance Liquid Chromatography

[0319] iPr: isopropyl

[0320] PTLC: Preparative Thin Layer Chromatography

[0321] RT: Room temperature

[0322] TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate

[0323] THF: Tetrahydrofuran

[0324] TPTU: O-(2-oxo-1(2H)pyridinyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate

[0325] XPhos: dicyclohexyl[2′,4′,6′-tri(propan-2-yl)[1,1′-diphenyl]-2-yl]phosphane

[0326] XantPhos: (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)

[0327] Analytical methods

[0328] Recorded with a Bruker ULTRASHIELD 400 spectrometer 1H NMR spectroscopy (400 MHz) and 19 F NMR spectra (376 MHz). Spectral processing and analysis were performed using MestReNova. The 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.

[0329] 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 compounds to be analyzed (0.1 mg to 0.3 mg) were dissolved in a minimum amount of DMSO and made up with acetonitrile (total volume: 1 mL). Standard analytical parameters: Flow rate: 1 mL / min, V 进样 : 5 μL. Acidic conditions: Waters XSelect CSH C18 column (3.5 μm, 2.1×15 50 mm). Gradient: (H 2 O + 0.04 vol / vol % HCO 2 H (10 mM)) / ACN from 95 / 5 to 0 / 100 in 2.5 minutes. Basic conditions: Waters Xbridge C18 column (3.5 μm, 2.1×50 mm). Gradient: (H 2 O + 0.06% vol / vol NH 3 (aqueous solution) (10 mM)) / ACN from 95 / 5 to 0 / 100 in 2.5 minutes.

[0330] General synthetic method

[0331] General Protocol 1 (GP-1): Peptide Coupling Using TBTU

[0332] TBTU was added to a solution of the desired carboxylic acid in DMF at RT. The mixture was stirred at RT for 15 min and the desired piperazine and Et 3 The mixture was stirred at RT for the required time. The volatiles were removed under reduced pressure and the residue was partitioned between 1N HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1N HCl, NaHCO 3 saturated aqueous solution, brine), dry (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc gradient) or PTLC to give the desired product.

[0333] General Protocol 2 (GP-2): Peptide Coupling Using TPTU (Small Scale)

[0334] iPr 2 NEt and TPTU are added to a DCE / MeCN (1 / 1) solution of the desired carboxylic acid. After stirring for 5 minutes at RT, the desired piperazine is added and the mixture is stirred for the required time at RT. 2 drops of ethylenediamine are added and the mixture is concentrated under reduced pressure. The residue is purified by FC (cHex / EtOAc gradient), PTLC or semi-preparative HPLC to obtain the desired product.

[0335] General Scheme 3 (GP-3): Chlorosulfonylation

[0336] A solution of the desired aromatic in DCM was added dropwise to the chlorosulfonic acid at 0°C. The mixture was warmed to RT and stirred at RT for the desired time. The reaction mixture was poured dropwise onto crushed ice while stirring (very exothermic quench). At the end of the addition, the remaining ice was melted, DCM was added and the layers were separated. The aqueous phase was extracted with DCM and the combined organic extracts were dried (Na2O3) and the column was concentrated to 4% ethanol. 2 SO 4 ), filtered and concentrated under reduced pressure to give the desired sulfonyl chloride.

[0337] General Scheme 4 (GP-4): Formation of sulfonamide

[0338] The desired amine and Et 3 N or iPr 2 A solution of NEt in DCM was added to a solution of the desired sulfonyl chloride in DCM. The reaction mixture was stirred at RT for the desired time. The reaction mixture was stirred in EtOAc and NH 4 The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with (NH 4 Cl saturated aqueous solution, brine), dry (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc gradient), PTLC or semi-preparative HPLC to give the desired product.

[0339] General Protocol 5 (GP-5): Using Pd(OAc) 2 Buchwald coupling of racemic-BINAP

[0340] The desired aryl bromide, the desired piperazine, Cs 2 CO 3 、Pd(OAc) 2The microwave reaction bottle was charged with rac-BINAP. 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 washed with water. The product was purified by FC (cHex / EtOAc gradient) or PTLC.

[0341] General Protocol 6 (GP-6): Buchwald coupling using XantPhos-Pd-G3

[0342] The desired aryl bromide, the desired piperazine, t-BuONa and XantPhos-Pd-G3 were charged to a microwave reaction vial. The vial was flushed with argon and degassed toluene was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating block for the desired time. After cooling to RT, EtOAc was added and the suspension was heated to 40 °C. The product was purified by FC (cHex / EtOAc gradient) or PTLC.

[0343] General Scheme 7 (GP-7): Buchwald coupling using XPhos-Pd-G3

[0344] The desired aryl bromide, the desired piperazine, t-BuONa and XPhos-Pd-G3 were charged to a microwave reaction vial. The vial was flushed with argon and degassed toluene was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating block for the desired time. After cooling to RT, EtOAc was added and the suspension was washed with water. The product was purified by FC (cHex / EtOAc gradient) or PTLC.

[0345] Synthesis of intermediate compounds

[0346] The intermediate compound [4-fluoro-2-(trifluoromethyl)phenyl]-piperazine-1-yl-methanone was prepared as described in JI, D. et al.: “Design, synthesis and biological evaluation of anthranilamide derivatives as potent SMO inhibitors”, Bioorganic and medicinal chemistry, 05February 2020, Vol.28, No.6, pp.1-12.

[0347] The intermediate compound 3-bromo-N,N-diethyl-benzenesulfonamide was prepared as described in SUTHERLAND, M. et al.: “Rational Design and Synthesis of Selective PRMT4Inhibitors: A New Chemotype for Development of Cancer Therapeutics”, ChemMedChem, 29 January 2021, Vo1.16, No.7, pp.1116-1125.

[0348] Synthesis of intermediates required for final products 001 and 002

[0349] 3-Bromo-N,N-diethyl-4-methoxy-benzenesulfonamide (I-001)

[0350]

[0351] According to GP-4, I-001 was obtained as a yellow oil in 93% yield using 3-bromo-4-methoxy-benzenesulfonyl chloride (5.00 g, 17.5 mmol, 1 eq), diethylamine (2.72 mL, 26.3 mmol, 1.5 eq) and triethylamine (3.66 mL, 26.3 mmol, 1.5 eq) in DCM (70 mL) at RT for 16 h.

[0352] 1 H NMR (400 MHz, chloroform-d) δ 7.91 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 8.8, 2.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H), 3.15 (q, J = 7.2 Hz, 4H), 1.07 (t, J = 7.2 Hz, 6H).

[0353] 4-[5-(Diethylsulfamoyl)-2-methoxy-phenyl]piperazine-1-carboxylic acid tert-butyl ester (I-002)

[0354]

[0355] According to GP-5, I-001 (5.20 g, 16.1 mmol, 1 eq), piperazine-1-carboxylic acid tert-butyl ester (4.51 g, 24.2 mmol, 1.5 eq), Cs 2 CO 3 (15.8 g, 48.4 mmol, 3 eq), Pd(OAc) 2(363 mg, 1.61 mmol, 0.1 eq) and rac-BINAP (1.51 g, 2.42 mmol, 0.15 eq) in toluene (81 mL) at reflux for 16 h afforded I-002 as a dark oil in 93% yield. Purification by FC (cHex / EtOAc=95 / 5 to 40 / 60).

[0356] 1 H NMR (400 MHz, DMSO-d 6 )δ7.42 (dd.J=8.5, 2.2Hz, 1H), 7.17-7.08 (m, 2H), 3.88 (s, 3H), 3.47 (t, J=5.0Hz, 4H ), 3.13 (q, J=7.1Hz, 4H), 2.95 (t, J=5.0Hz, 4H), 1.43 (s, 9H), 1.03 (t, J=7.1Hz, 6H).

[0357] N,N-Diethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide (I-003)

[0358]

[0359] HCl (4M in dioxane, 38.0 mL, 152 mmol, 10 eq) was added to a solution of I-002 (6.48 g, 15.2 mmol, 1 eq) in dioxane (38 mL) at 0°C. The mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM. Na was added in batches. 2 CO 3 (s) until pH>11. Separate the layers and extract the aqueous phase with DCM (2*). Dry the combined organic extracts (Na 2 SO 4 ), filtered and concentrated under reduced pressure. 3 )=99:1 to 90:10) to purify the residue to give 4.87 g (98%) of I-003 as a colorless oil.

[0360] 1 H NMR (400 MHz.DMSO-d 6 )δ7.39 (dd, J=8.5, 2.3Hz, 1H), 7.20-7.05 (m, 2H), 3.87 (s, 3H), 3.43 (m, 1H), 3.13 (q, J=7.1Hz, 4H), 3.05-2.56 (m, 8H), 1.03 (t, J=7.1Hz, 6H).MS (ESI + ): [M+H] +328.

[0361] Synthesis of intermediates required for final products 003 and 004

[0362] 1-(3-Bromo-4-methoxy-phenyl)sulfonylpyrrolidine (I-004)

[0363]

[0364] According to GP-4, I-004 was obtained as a white solid in 95% yield using 3-bromo-4-methoxy-benzenesulfonyl chloride (5.00 g, 17.5 mmol, 1 eq), pyrrolidine (2.16 mL, 26.3 mmol, 1.5 eq) and triethylamine (3.66 mL, 26.3 mmol, 1.5 eq) in DCM (70 mL) at RT for 1 h.

[0365] 1 H NMR (400 MHz, DMSO-d 6 )δ7.91 (d, J=2.3Hz, 1H), 7.81 (dd, J=8.7, 2.2Hz, 1H), 7.32 (d, J=8.7Hz, 1H), 3.95 (s, 3H), 3.13 (m, 4H), 1.66 (m, 4H).MS (ESI + ): [M+H] + 320 / 322.

[0366] 4-(2-Methoxy-5-pyrrolidin-1-ylsulfonyl-phenyl)piperazine-1-carboxylic acid tert-butyl ester (I-005)

[0367]

[0368] According to GP-5, I-004 (5.10 g, 15.9 mmol, 1 eq), piperazine-1-carboxylic acid tert-butyl ester (4.45 g, 23.9 mmol, 1.5 eq), Cs 2 CO 3 (15.6 g, 47.8 mmol, 3 eq), Pd(OAc) 2 (358 mg, 1.59 mmol, 0.1 eq) and rac-BINAP (1.49 g, 2.39 mmol, 0.15 eq) in toluene (80 mL) at reflux for 28 h afforded I-005 as a dark oil in 83% yield. Purification by FC (cHex / EtOAc=95 / 5 to 40 / 60).

[0369] 1 H NMR (400 MHz, DMSO-d 6)δ7.44 (dd, J=8.5, 2.2Hz, 1H), 7.17 (s, 1H), 7.16 (d, J=5.2Hz, 1H), 3.89 (s, 3H), 3.47 (t, J=4 .9Hz, 4H), 3.15-3.07 (m, 4H), 2.96 (t, J=5.0Hz, 4H), 1.71-1.59 (m, 4H), 1.43 (s, 9H).MS (ESI + ): [M+H] + 426.

[0370] 1-(2-Methoxy-5-pyrrolidin-1-ylsulfonyl-phenyl)piperazine (I-006)

[0371]

[0372] HCl (4M in dioxane, 39.0 mL, 139 mmol, 10 eq) was added to a solution of I-005 (5.90 g, 13.9 mmol, 1 eq) in dioxane (35 mL) at 0°C. The mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM. Na was added in batches. 2 CO 3 (s) until pH>11. Separate the layers and extract the aqueous phase with DCM (2*). Dry the combined organic extracts (Na 2 SO 4 ), filtered and concentrated under reduced pressure. 3 )=99:1 to 90:10) to purify the residue to give 4.37 g (97%) of I-006 as a colorless oil.

[0373] 1 H NMR (400 MHz, DMSO-d 6 )δ7.41(dd,J=8.5,2.2Hz,1H),7.16(m,2H),4.11(m,1H),3.88(s,3H),3.1 6-3.06(m, 4H), 3.05-2.99(m, 4H), 2.91(m, 4H), 1.63-1.66(m, 4H).MS(ESI + ): [M+H] + 326.

[0374] Synthesis of intermediates required for final products 005 and 006

[0375] 3-Bromo-4-methoxy-N-methyl-N-propyl-benzenesulfonamide (I-007)

[0376]

[0377] According to GP-4, I-007 was obtained as a yellow oil in 96% yield using 3-bromo-4-methoxy-benzenesulfonyl chloride (5.00 g, 17.5 mmol, 1 eq), N-methylpropylamine (2.69 mL, 26.3 mmol, 1.5 eq) and triethylamine (3.66 mL, 26.3 mmol, 1.5 eq) in DCM (70 mL) at RT for 16 h.

[0378] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.98 (d, J = 2.2 Hz, 1H), 7.74 (dd, J = 8.6, 2.2 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 3.99 (s, 3H), 3.02-2.96 (m, 2H), 2.74 (s, 3H), 1.65-1.52 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). MS (ESI + ): [M+H] + 322 / 324.

[0379] 4-[2-Methoxy-5-[methyl(propyl)sulfamoyl]phenyl]piperazine-1-carboxylic acid tert-butyl ester (I-008)

[0380]

[0381] According to GP-5, I-007 (1.71 g, 5.50 mmol, 1 eq), piperazine-1-carboxylic acid tert-butyl ester (1.54 g, 8.24 mmol, 1.5 eq), Cs 2 CO 3 (5.38 g, 16.5 mmol, 3 eq), Pd(OAc) 2 (123 mg, 0.550 mmol, 0.1 eq) and rac-BINAP (513 mg, 0.824 mmol, 0.15 eq) in toluene (80 mL) at reflux for 28 h afforded I-005 as a dark oil in 74% yield. Purification by FC (cHex / EtOAc=98 / 2 to 50 / 50).

[0382] 1H NMR (400MHz. Chloroform-d) δ7.46 (dd, J=8.5, 2.2Hz, 1H), 7.26 (d, J=2.6Hz, 1H), 6.93 (d, J=8.6Hz, 1H), 3.94 (s, 3H), 3.64-3.53 (m, 4H), 3.02 (t, J=5.0Hz, 4H), 2.94 (dd, J=7.9, 6.6Hz, 2H), 2.69 (s, 3H), 1.55-1.50 (m, 2H), 1.49 (s, 9H), 0.93 (d, J=7.3Hz, 3H).MS (ESI + ): [M+H] + 428.

[0383] 4-Methoxy-N-methyl-3-piperazin-1-yl-N-propyl-benzenesulfonamide (I-009)

[0384]

[0385] HCl (4M in dioxane, 21.6 mL, 86.5 mmol, 10 eq) was added to a solution of I-008 (3.70 g, 8.65 mmol, 1 eq) in DCM (47 mL) at 0°C. The mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM. Na2CO3(s) was added in portions until pH>11. The layers were separated and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. 3 )=99:1 to 90:10) to give 2.70 g (96%) of I-009 as an orange oil.

[0386] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.44 (dd, J = 8.5, 2.2 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 3.93 (s, 3H), 3.10-3.00 (m, 8H), 2.94 (t, J = 7.2 Hz, 2H), 2.70 (s, 3H), 1.93 (s, 1H), 1.54 (h, J = 7.4 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H). MS (ESI + ): [M+H] + 328.

[0387] Synthesis of intermediates required for final products 007 to 010

[0388] 4-Benzyl-1-(3-bromo-4-methoxy-phenyl)sulfonyl-piperidine (I-010)

[0389]

[0390] According to GP-4, I-010 was obtained as a yellow oil in 100% yield using 3-bromo-4-methoxy-benzenesulfonyl chloride (1.00 g, 3.50 mmol, 1 eq), 4-benzylpiperidine (798 mg, 4.55 mmol, 1.3 eq) and triethylamine (0.73 mL, 5.2 mmol, 1.5 eq) in DCM (14 mL) at RT for 16 h.

[0391] 1 H NMR (400 MHz, chloroform-d) δ 7.94 (d, J = 2.2 Hz, 1H), 7.69 (dd, J = 8.7, 2.2 Hz, 1H), 7.35-7.24 (m, 2H), 7.24-7.04 (m, 3H), 6.98 (d, J = 8.6 Hz, 1H), 3.99 (s, 3H), 3.77 (d, J = 11.4 Hz, 2H), 2.54 (d, J = 6.9 Hz, 2H), 2.35-2.14 (m, 2H), 1.80-1.63 (m, 2H), 1.53-1.24 (m, 3H).

[0392] 4-[5-[(4-Benzyl-1-piperidinyl)sulfonyl]-2-methoxy-phenyl]piperazine-1-carboxylic acid tert-butyl ester (I-011)

[0393]

[0394] According to GP-5, I-010 (1.35 g, 3.18 mmol, 1 eq), piperazine-1-carboxylic acid tert-butyl ester (889 mg, 4.77 mmol, 1.5 eq), Cs 2 CO 3 (2.07 g, 6.36 mmol, 2 eq), Pd(OAc) 2 (35.7 mg, 0.159 mmol, 0.05 eq) and rac-BINAP (119 mg, 0.191 mmol, 0.06 eq) in toluene (16 mL) at reflux for 24 h to afford I-011 as a brown foam in 89% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0395] 1H NMR (400MHz, chloroform-d) δ7.43 (dd, J=8.5, 2.2Hz, 1H), 7.35-7.15 (m, 4H), 7.15- 7.05 (m, 2H), 6.94 (d, J=8.6Hz, 1H), 3.95 (s, 3H), 3.76 (d, J=11.5Hz, 2H), 3 .66-3.58(m, 4H), 3.08-2.98(m, 4H), 2.53(d, J=6.6Hz, 2H), 2.19(td, J=11 .7, 2.4Hz, 2H), 1.81-1.62(m, 2H), 1.51(s, 9H), 1.45-1.30(m, 3H).MS(ESI + ): [M+H] + 530.

[0396] 1-[5-[(4-benzyl-1-piperidinyl)sulfonyl]-2-methoxy-phenyl]piperazine-(I-012)

[0397]

[0398] HCl (4M in dioxane, 8.4 mL, 34 mmol, 10 eq) was added to a solution of I-011 (2.40 g, 3.35 mmol, 1 eq) in DCM (16 mL) at 0°C. The mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM. Na was added in batches. 2 CO 3 (s) until pH>11. Separate the layers and extract the aqueous phase with DCM (2*). Dry the combined organic extracts (Na 2 SO 4 ), filtered and concentrated under reduced pressure. 3 )=99:1 to 90:10) to purify the residue to give 1.45 g (100%) of I-012 as a white solid.

[0399] 1H NMR (400 MHz, CHLOROFORM-d) δ 7.41 (dd, J = 8.5, 2.2 Hz, 1H), 7.32-7.23 (m, 3H), 7.23-7.16 (m, 1H), 7.15-7.05 (m, 2H), 6.93 (d, J = 8.5 Hz, 1H), 3.95 (s, 3H), 3.76 (dt, J = 12.0, 3.4 Hz, 2H), 3.12-3.00 (m, 8H), 2.53 (d, J = 6.6 Hz, 2H), 2.19 (td, J = 11.7, 2.4 Hz, 2H), 1.72-1.65 (m, 2H), 1.50-1.30 (m, 3H). MS (ESI + ): [M+H] + 430.

[0400] Synthesis of intermediates required for final products 011 to 036

[0401] (2-Chloro-4-fluoro-phenyl)-[4-(2-methoxyphenyl)piperazin-1-yl]methanone ((I-013)

[0402]

[0403] According to GP-1, 2-chloro-4-fluoro-benzoic acid (5.99 g, 34.3 mmol, 1.2 eq.), Et 3 N (8.0 mL, 57 mmol, 2 eq), TBTU (11.0 g, 34.3 mol, 1.2 eq) and 1-(2-methoxyphenyl)piperazine (5.50 g, 28.6 mmol, 1 eq) in THF (140 mL) at RT for 16 h afforded I-013 as a colorless oil in 85% yield. The residue was purified by FC (cHex / EtOAc=90 / 10 to 0 / 100).

[0404] 1 H NMR (400 MHz. CHLOROFORM-d) δ 7.35 (dd, J = 8.5, 5.9 Hz, 1H), 7.20 (dd, J = 8.5, 2.5 Hz, 1H), 7.13-7.03 (m, 2H), 6.98-6.89 (m, 3H), 4.02 (tt, J = 12.5, 8.3 Hz, 2H), 3.90 (s, 3H), 3.56-3.37 (m, 2H), 3.26-2.93 (m, 4H). 19 F NMR (376 MHz, chloroform-d) δ-109.5.MS (ESI + ): [M+H] + 349 / 351.

[0405] 3-[4-(2-Chloro-4-fluoro-benzoyl)piperazin-1-yl]-4-methoxy-benzenesulfonyl chloride (I-014)

[0406]

[0407] According to GP-3, I-013 (5.00 g, 14.3 mmol, 1 eq.) and HSO 3 Cl (19.1 mL, 287 mmol, 20 equiv) in DCM (72 mL) for 2 h afforded I-014 as a white solid in 86% yield.

[0408] 1 H NMR (400MHz, chloroform-d) δ7.76 (dd, J=8.7, 2.4Hz, 1H), 7.49 (d, J=2.4Hz.1H), 7.35 (dd, J=8.5, 5.9Hz, 1H), 7.20 (dd, J=8.5, 2 .4Hz, 1H), 7.10 (td, J=8.2, 2.5Hz, 1H), 7.03 (d, J=8.8Hz, 1H), 4.08-3.93 (m, 5H), 3.57-3.36 (m, 2H), 3.30-3.00 (m, 4H). 19 F NMR (376 MHz, chloroform-d) δ-109.1.

[0409] Synthesis of intermediates required for final product 037

[0410] 3-[4-(2-Chloro-4-fluoro-benzoyl)piperazin-1-yl]-4-methoxy-N-(4,4,4-trifluorobutyl)benzenesulfonamide (I-015)

[0411]

[0412] According to GP-4, sulfonyl chloride I-014 (120 mg, 0.268 mmol, 1 eq), 4,4,4-trifluorobutylamine hydrochloride (66 mg, 0.40 mmol, 1.5 eq) and iPr 2 NEt (140 μL, 0.804 mmol, 3 eq) in DCM (2 mL) at RT for 2 h afforded I-015 in 64% yield. Purification by FC (cHex / EtOAc=20 / 80).

[0413] 1 H NMR (400 MHz, DMSO-d 6) δ7.58 (dt, J=9.1, 2.2Hz, 1H), 7.55-7.48 (m, 2H), 7.44 (dt, J=8.6, 2.0Hz, 1H), 7.34 (tt, J=8.5, 2.1Hz, 1H), 7.25 (t, J=2.0Hz, 1H), 7.14 (dd, J=8. 7, 1.8Hz, 1H), 3.88 (s, 3H), 3.84-3.73 (m, 2H), 3.31-3.27 (m, 2H), 3.15-2 .91(m, 4H), 2.78(q, J=6.7Hz, 2H), 2.30-2.15(m, 2H), 1.61-1.50(m, 2H). 19 F NMR (376 MHz, chloroform-d) δ -64.8, -110.1. MS (ESI + ): [M+H] + 538 / 540.

[0414] Synthesis of intermediates required for final product 038

[0415] rac-(2-chloro-4-fluoro-phenyl)-[4-[5-[(3-hydroxy-1-piperidinyl)sulfonyl]-2-methoxy-phenyl]piperazin-1-yl]methanone (I-016)

[0416]

[0417] According to GP-4, sulfonyl chloride I-014 (150 mg, 0.335 mmol, 1 eq), rac-piperidin-3-ol hydrochloride (69 mg, 0.50 mmol, 1.5 eq) and iPr 2 NEt (175 μL, 1.00 mmol, 3 eq) in DCM (2 mL) at RT for 16 h afforded I-016 in 79% yield. Purification by FC (DCM / MeOH=98 / 2 to 90 / 10).

[0418] 1H NMR (400 MHz, chloroform-d) δ 7.46 (dd, J = 8.5, 2.2 Hz, 1H), 7.36-7.30 (m, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.18 (dd, J = 8.4, 2.4 Hz, 1H), 7.07 (td, J = 8.2, 2.5 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 4.02-3.96 (m, 2H), 3.94 (s, 3H), 3.91-3.83 (m, 1H), 3.52 -3.44(m, 1H), 3.43-3.35(m, 1H), 3.31(d, J=11.2Hz, 1H), 3.24-3.07(m, 4H), 3.02-2.94(m, 1H), 2.83-2.75(m, 1H) , 2.73-2.66 (m, 1H), 1.90-1.80 (m, 2H), 1.79-1.70 (m, 1H), 1.68-1.56 (m, 1H), 1.40 (dtd, J=12.6, 8.4, 3.9Hz, 1H). 19 F NMR (376 MHz, chloroform-d) δ-109.2.MS (ESI + ): [M+H] + 512 / 514.

[0419] Synthesis of intermediates required for final product 039

[0420] (2-Chloro-4-fluoro-phenyl)-[4-[5-(3-hydroxypyrrolidin-1-yl)sulfonyl-2-methoxy-phenyl]piperazin-1-yl]methanone (I-017)

[0421]

[0422] According to GP-4, sulfonyl chloride I-014 (150 mg, 0.335 mmol, 1 eq), rac-piperidin-3-ol (44 mg, 0.50 mmol, 1.5 eq) and iPr 2 NEt (175 μL, 1.00 mmol, 3 eq) in DCM (2 mL) at RT for 16 h afforded I-017 in 90% yield. Purification by FC (DCM / MeOH=98 / 2 to 90 / 10).

[0423] 1H NMR (400 MHz, chloroform-d) δ 7.54 (dd, J = 8.6, 2.1 Hz, 1H), 7.36-7.29 (m, 2H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 7.07 (td, J = 8.3, 2.5 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 4.42-4.35 (m, 1H), 3.99 (t , J=5.2Hz, 2H), 3.94 (s, 3H), 3.52-3.28 (m, 5H), 3.25-3.07 (m, 4H), 2.99 (dd, J=11.2, 6. 6Hz, 1H), 1.97 (dtd, J=13.7, 8.8, 4.9Hz, 1H), 1.88-1.79 (m, 1H), 1.51 (d, J=4.7Hz, 1H). 19 F NMR (376 MHz, chloroform-d) δ-109.2.MS (ESI + ): [M+H] + 498 / 500.

[0424] Synthesis of intermediates required for final product 040

[0425] [4-[5-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-ylsulfonyl)-2-methoxy-phenyl]piperazin-1-yl]-(2-chloro-4-fluoro-phenyl)methanone ((I-018)

[0426]

[0427] HCl (4M in dioxane, 1.2 mL, 4.8 mmol, 10 eq) was added to a solution of 022 (300 mg, 0.481 mmol, 1 eq) in DCM (2.4 mL) at 0°C. The mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM. K was added in portions. 2 CO 3 (s) until pH>11. Separate the layers and extract the aqueous phase with DCM (2*). Dry the combined organic extracts (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give 250 mg (99%) of I-018 as a white foam.

[0428] 1 H NMR (400 MHz, DMSO-d 6)δ7.58 (dd, J=9.0, 2.4Hz, 1H), 7.52 (dd, J=8.5, 6.1Hz, 1H), 7.41 (dd, J=8.6, 2.1H z, 1H), 7.34 (td, J = 8.5, 2.5Hz, 1H), 7.18 (d, J = 8.6Hz, 1H), 7.13 (d, J = 2.2Hz, 1H), 3 .89 (s, 3H), 3.86-3.69 (m, 2H), 3.30-3.26 (m, 3H), 3.17 (d, J=3.9Hz, 2H), 3.14-3. 06 (m, 4H), 2.98 (t, J=5.0Hz, 2H), 2.81-2.71 (m, 4H), 2.42 (dd, J=10.8, 2.9Hz, 2H). 19 F NMR (376 MHz, chloroform-d) δ-109.2.MS (ESI + ): [M+H] + 523 / 525.

[0429] Synthesis of intermediates required for final product 042

[0430] 3-Bromo-4-fluoro-N-methyl-N-propyl-benzenesulfonamide (I-019)

[0431]

[0432] According to GP-4, I-019 was obtained as a yellow oil in 95% yield using 3-bromo-4-fluoro-benzenesulfonyl chloride (200 μL, 1.35 mmol, 1 eq), N-methylpropylamine (145 μL, 1.41 mmol, 1.05 eq) and triethylamine (281 μL, 2.02 mmol, 1.5 eq) in DCM (7 mL) at RT for 1 h.

[0433] 1 H NMR (400 MHz, chloroform-d) δ 8.01 (dd, J = 6.3, 2.3 Hz, 1H), 7.73 (ddd, J = 8.6, 4.5, 2.2 Hz, 1H), 7.33-7.15 (m, 1H), 3.08-2.90 (m, 2H), 2.75 (s, 3H), 1.67-1.55 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 19 F NMR (376 MHz, chloroform-d) δ-99.9.MS (ESI + ): [M+H] + 310 / 312.

[0434] Synthesis of intermediates required for final product 043

[0435] [4-(2,3-Dihydrobenzofuran-7-yl)piperazin-1-yl]-[4-fluoro-2-(trifluoromethyl)phenyl]methanone (I-020)

[0436]

[0437] 7-Bromo-2,3-dihydrobenzofuran (300 mg, 1.51 mmol, 1 eq.), [4-fluoro-2-(trifluoromethyl)phenyl]-piperazine-1-yl-methanone (614 mg, 2.22 mmol, 1.5 eq.), Pd 2 dba 3 (94 mg, 0.10 mmol, 0.07 eq), tri(2-methylphenyl)phosphine (55 mg, 0.18 mmol, 0.12 eq) and sodium tert-butoxide (212 mg, 2.21 mmol, 1.5 eq) were loaded into a microwave reaction bottle. The bottle was flushed with argon and degassed toluene (10 mL) was added. The bottle was sealed and the mixture was stirred at 110° C. for 22 h. The suspension was cooled to room temperature, filtered with diatomaceous earth (EtOAc rinse) and concentrated. The residue was purified by FC (cHex / EtOAc=95 / 5 to 0 / 100) to give 136 mg (23%) of I-020 as a brown foam.

[0438] 1 H NMR (400MHz, chloroform-d) δ7.42 (dd, J=8.8, 2.5Hz.1H), 7.37 (dd, J=8.5, 5.3Hz, 1H) , 7.31 (td, J=8.1, 2.6Hz, 1H), 6.90 (dd, J=7.4.1.2Hz, 1H), 6.81 (t, J=7.6Hz, 1H), 6.67 (dd, J=7.9, 1.2Hz, 1H), 4.59 (t, J=8.8Hz, 2H), 3.97 (qt, J=13.2, 5. 1Hz, 2H), 3.34 (dd, J=5.9, 4.4Hz, 2H), 3.27-3.11 (m, 4H), 3.10-2.94 (m, 2H). 19 F NMR (376 MHz, chloroform-d) δ -60.2, -109.4. MS (ESI + ): [M+H] + 395.

[0439] 7-[4-[4-Fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2,3-dihydrobenzofuran-5-sulfonyl chloride (I-021)

[0440]

[0441] According to GP-3, I-020 (135 mg, 0.342 mmol, 1 eq.) and HSO 3 Cl (0.50 mL, 7.5 mmol, 22 equiv) in DCM (2 mL) for 2 h afforded I-021 as a white solid in 83% yield.

[0442] 1 H NMR (400 MHz, chloroform-d) δ 7.58-7.55 (m, 1H), 7.45 (dd, J = 8.8, 2.4 Hz, 1H), 7.41-7.32 (m, 2H), 7.32-7.28 (m, 1H), 4.78 (t, J = 8.9 Hz, 2H), 3.98 (t, J = 5.2 Hz, 2H), 3.43-3.20 (m, 6H), 3.18-2.99 (m, 2H). 19 F NMR (376 MHz, chloroform-d) δ -60.2, -109.0.

[0443] Synthesis of intermediates required for final products 044 and 045

[0444] 5-Bromo-6-chloro-N,N-diethyl-pyridine-3-sulfonamide (I-022)

[0445]

[0446] According to GP-4, I-022 was obtained as a yellow solid in 100% yield using 5-bromo-6-chloro-pyridine-3-sulfonyl chloride (438 mg, 1.50 mmol, 1.1 eq), diethylamine (100 mg, 1.37 mmol, 1 eq) and triethylamine (229 μL, 1.64 mmol, 1.2 eq) in DCM (6.8 mL) at RT for 1 h.

[0447] 1 H NMR (400 MHz, chloroform-d) δ 8.74 (d, J = 2.2 Hz, 1H), 8.32 (d, J = 2.2 Hz, 1H), 3.31 (q, J = 7.2 Hz, 4H), 1.21 (t, J = 7.1 Hz, 6H).

[0448] 5-Bromo-6-methoxy-N,N-diethyl-piperidine-3-sulfonamide (I-023)

[0449]

[0450] MeONa (124 mg, 2.29 mol, 5 eq) was added to a solution of I-022 (150 mg, 0.458 mmol, 1 eq) in dry MeOH (1.8 mL) at RT. The mixture was stirred at RT for 60 h. The RM was stirred in NH 4 The mixture was partitioned between saturated aqueous Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to afford 138 mg (93%) of I-023 as a light yellow solid.

[0451] 1 H NMR (400 MHz, chloroform-d) δ 8.55 (d, J = 2.2 Hz, 1H), 8.18 (d, J = 2.2 Hz, 1H), 4.10 (s, 3H), 3.28 (q, J = 7.2 Hz, 4H), 1.20 (t, J = 7.1 Hz, 6H).

[0452] Synthesis of intermediates required for final products 046 and 047

[0453] 3-Bromo-4-hydroxy-N-methyl-N-propyl-benzenesulfonamide (I-024)

[0454]

[0455] At 0°C, BBr 3 (1M in DCM, 1.86 mmol, 2 eq) was added to a solution of I-007 (200 mg, 0.620 mmol, 1 eq) in DCM (7.7 mL). The mixture was stirred at RT for 48 h. Cooled to 0 °C and water was added dropwise (exothermic). The layers were separated and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na2SO4) and concentrated to room temperature. 2 SO 4 ), filtered and concentrated under reduced pressure to give 214 mg (quantitative) of I-024 as an orange oil.

[0456] 1 H NMR (400 MHz, CHLOROFORM-d) δ (ppm) 7.95 (d, J = 2.2 Hz, 1H), 7.74 (dd, J = 8.6 and 2.2 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 6.05 (br s, 1H), 3.02-2.95 (m, 2H), 2.75 (s, 3H), 1.65-1.52 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). MS (ESI + ): [M+H] + 308 / 310.

[0457] 3-Bromo-4-(2-methoxyethoxy)-N-methyl-N-propyl-benzenesulfonamide (I-025)

[0458]

[0459] At RT, K 2 CO 3 (257 mg, 1.86 mmol, 3 eq.) and 2-bromomethyl methyl ether (129 mg, 0.930 mmol, 1.5 eq.) were added to a solution of I-024 (191 mg, 0.620 mmol, 1 eq.) in DMF (2.5 mL). The mixture was stirred at 50 °C for 16 h. The reaction mixture was heated in NH 4 Partition between saturated aqueous Cl and EtOAc. Separate the layers and extract the aqueous phase with EtOAc (2*). Wash the combined organic extracts (NH 4 Cl saturated aqueous solution, NaHCO 3 saturated aqueous solution, brine), dry (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=90 / 10 to 50 / 50) to give 200 mg (88%) of I-025 as a yellow oil.

[0460] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.98 (d, J = 2.2 Hz, 1H), 7.71 (dd, J = 8.6, 2.3 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 4.32-4.22 (m, 2H), 3.91-3.83 (m, 2H), 3.51 (s, 3H), 2.98 (dd, J = 8.0, 6.5 Hz, 2H), 2.74 (s, 3H), 1.70-1.50 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). MS (ESI + ): [M+H] + 366 / 368.

[0461] 4-Benzyloxy-3-bromo-N-methyl-N-propyl-benzenesulfonamide (I-026)

[0462]

[0463] At RT, K 2 CO 3(266 mg, 1.92 mmol, 2 eq) and benzyl bromide (114 μL, 0.961 mmol, 1 eq) were added to a solution of I-024 (315 mg, 0.961 mmol, 1 eq) in DMF (10 mL). The mixture was stirred at RT for 16 h. The reaction mixture was heated in NH 4 Partition between saturated aqueous Cl and EtOAc. Separate the layers and extract the aqueous phase with EtOAc (2*). Wash the combined organic extracts (NH 4 Cl saturated aqueous solution, NaHCO 3 saturated aqueous solution, brine), dry (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=100 / 0 to 50 / 50) to give 330 mg (86%) of I-026 as a yellow oil.

[0464] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.99 (d, J = 2.3 Hz, 1H), 7.67 (dd, J = 8.6, 2.2 Hz, 1H), 7.49-7.44 (m, 2H), 7.44-7.38 (m, 2H), 7.38-7.31 (m, 1H), 7.01 (d, J = 8.7 Hz, 1H), 5.23 (s, 2H), 3.05-2.91 (m, 2H), 2.72 (s, 3H), 1.67-1.49 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). MS (ESI + ): [M+H] + 398 / 400.

[0465] Synthesis of intermediates required for piperazine I-027

[0466] 4-(2-Chloro-4-fluoro-benzoyl)piperazine-1-carboxylic acid tert-butyl ester (Boc-I-027)

[0467]

[0468] 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) at RT. The mixture was stirred at RT for 15 min, and tert-butyl piperazine-1-carboxylate (6.40 g, 34.4 mmol, 1.2 eq) and Et 3N (6.0 mL, 43 mmol, 1.5 eq) in THF (30 mL). The mixture was stirred at RT for 60 h. 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 aqueous solution, NaHCO 3 saturated aqueous solution, brine), dry (Na 2 SO 4 ), filtered and concentrated under reduced pressure to give 10.2 g (100%) of tert-butyl 4-(2-chloro-4-fluoro-benzoyl)piperazine-1-carboxylate (Boc-I-027) as an orange oil.

[0469] 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.

[0470] (2-Chloro-4-fluoro-phenyl)-piperazine-1-yl-methanone (I-027)

[0471]

[0472] At RT, HCl (4M in dioxane, 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-I-027 (10.2 g, 28.6 mmol, 1 eq) in dioxane (37 mL). The mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was distributed between water and DCM. K was added in batches. 2 CO 3 (s) until pH>11. Separate the layers and extract the aqueous phase with DCM (2*). Dry the combined organic extracts (Na 2 SO 4 ), 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)-piperazine-1-yl-methanone I-027 as an orange solid.

[0473] 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.

[0474] Synthesis of intermediates required for final products 054 and 055

[0475] 1-Bromo-2-(methoxymethoxy)-3-methyl-benzene (I-028)

[0476]

[0477] Chloromethyl methyl ether (0.49 mL, 6.4 mmol, 1.2 eq) was added to 2-bromo-6-methyl-phenol (1.00 g, 5.35 mmol, 1 eq) and iPr 2 NEt (1.4 mL, 8.1 mmol, 1.5 eq) in DCM (21 mL). The mixture was stirred at RT for 60 h. 1 N HCl was added. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2O3) and the mixture was stirred for 2 h. 2 SO 4 ), filtered and concentrated under reduced pressure to give 1.22 g of I-028 (99%) as a colorless oil.

[0478] 1 H NMR (400 MHz, chloroform-d) δ 7.42 (ddd, J = 8.0, 1.6, 0.7 Hz, 1H), 7.15 (ddd, J = 7.6, 1.6.0.8 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 5.11 (s, 2H), 3.68 (s, 3H), 2.39 (s, 3H).

[0479] (2-Chloro-4-fluoro-phenyl)-[4-[2-(methoxymethoxy)-3-methyl-phenyl]piperazine-1-yl]methanone (I-029)

[0480]

[0481] According to GP-5, I-028 (400 mg, 1.73 mmol, 1 eq), piperazine I-027 (504 mg, 2.08 mmol, 1.2 eq), Cs2 CO 3 (1.69 g, 5.19 mmol, 3 eq), Pd(OAc) 2 (38.9 mg, 173 μmol, 0.1 eq.) and rac-BINAP (162 mg, 260 μmol, 0.15 eq.) in toluene (8.7 mL) at reflux for 2 h afforded I-029 as an oil in 44% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0482] 1 H NMR (400MHz, chloroform-d) δ7.32 (dd, J=8.5, 5.9Hz, 1H), 7.18 (dd, J=8.4, 2.4Hz, 1H), 7.07 (td, J=8.2, 2.5Hz, 1H), 6.98 (t, J=7.7Hz, 1H), 6.94-6.86 (m, 1H), 6.79 (dd, J=8.0, 1.7Hz, 1H), 5.17 (s, 2H), 3.96 (t, J=5.1Hz, 2H), 3.60 (s, 3 H), 3.50-3.28(m, 2H), 3.28-3.02(m, 3H), 3.02-2.88(m, 1H), 2.32(s, 3H). 19 F NMR (376MHz.Chloroform-d)δ-109.4.MS (ESI + ): [M+H] + 393.1 / 395.1.

[0483] 3-[4-(2-Chloro-4-fluoro-benzoyl)piperazin-1-yl]-4-hydroxy-5-methyl-benzenesulfonyl chloride (I-030)

[0484]

[0485] According to GP-3, I-029 (300 mg, 0.748 mmol, 1 eq.) and HSO 3 Cl (1.2 mL, 19 mmol, 25 eq) in DCM (3 mL) at RT for 1 h afforded 1-030 as a yellow solid in 50% yield. The material was directly taken to the next step.

[0486] Synthesis of intermediates required for final products 057 to 059

[0487] 1-Bromo-3-chloro-2-(methoxymethoxy)benzene (I-031)

[0488]

[0489] Chloromethyl methyl ether (0.95 mL, 13 mmol, 1.2 eq) was added to 2-bromo-6-chlorophenol (3.17 g, 10.5 mmol, 1 eq) and iPr 2 NEt (3.73 mL, 15.7 mmol, 1.5 eq) in DCM (21 mL). The mixture was stirred at RT for 16 h. The volatiles were removed under reduced pressure. EtOAc was added and the organic extracts were washed (1N HCl, brine), dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex / EtOAc=95 / 5) to give 2.59 g (98%) of I-031 as a colorless oil.

[0490] 1 H NMR (400 MHz, chloroform-d) δ 7.50 (dd, J = 8.0, 1.6 Hz, 1H), 7.37 (dd, J = 8.1, 1.5 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 5.21 (s, 2H), 3.74 (s, 3H).

[0491] (2-Chloro-4-fluoro-phenyl)-[4-[3-chloro-2-(methoxymethoxy)phenyl]piperazin-1-yl]methanone ((I-032)

[0492]

[0493] According to GP-5, aryl bromide I-031 (1.23 g, 4.89 mmol, 1 eq), piperazine I-027 (1.42 g, 5.87 mmol, 1.2 eq), Cs 2 CO 3 (4.78 g, 14.7 mmol, 3 eq), Pd(OAc) 2 (110 mg, 489 μmol, 0.1 eq.) and rac-BINAP (365 mg, 587 μmol, 0.12 eq.) in toluene (24.5 mL) at reflux for 16 h afforded I-032 as a white foam in 62% yield. Purification by FC (cHex / EtOAc=95 / 5 to 50 / 50).

[0494] 1H NMR (400MHz, chloroform-d) δ7.30 (dd, J=8.5.5.9Hz, 1H), 7.18 (dd, J=8.4, 2.4Hz, 1H), 7.12-7.03 (m, 2H), 7.00 (t, J=8.1Hz, 1 H), 6.83 (dd, J=8.1, 1.5Hz, 1H), 5.22 (s, 2H), 4.01-3.86 (m, 2H), 3.66 (s, 3H), 3.50-3.29 (m, 2H), 3.25-2.91 (m, 4H). 19 F NMR (376 MHz, chloroform-d) δ-109.2.MS (ESI + ): [M+H] + 413.0 / 415.0 / 417.0.

[0495] (2-Chloro-4-fluoro-phenyl)-[4-(3-chloro-2-hydroxy-phenyl)piperazin-1-yl]methanone ((I-033)

[0496]

[0497] CF at RT 3 CO 2 H (4.7 mL, 61 mmol, 20 eq) was added to a solution of I-032 (1.26 g, 3.05 mmol, 1 eq) in DCM (15 mL). The mixture was stirred for 1 h at RT. It was concentrated under reduced pressure and the residue was azeotroped with toluene. The residue was purified by FC (cHex / EtOAc=95 / 5 to 20 / 80) to give 1.12 g of I-033 (97%) as a white foam.

[0498] 1 H NMR (400 MHz, CHLOROFORM-d) δ7.35 (dd, J=8.5, 5.8 Hz, 1H), 7.24-7.16 (m, 2H), 7.14-7.02 (m, 2H), 6.86 (t, J=8.1 Hz, 1H), 6.26 (s, 1H), 4.22-4.06 (m, 1H), 4.06-3.93 (m, 1H), 3.59-3.38 (m, 2H), 3.28-2.86 (m, 4H). 19F NMR (376 MHz, CHLOROFORM-d) δ-108.1. MS (ESI + ): [M+H] + 369.0 / 371.0 / 373.0.

[0499] 3-Chloro-5-[4-(2-chloro-4-fluoro-benzoyl)piperazin-1-yl]-4-hydroxy-benzenesulfonyl chloride (I-034)

[0500]

[0501] According to GP-3, I-033 (500 mg, 1.35 mmol, 1 eq.) and HSO 3 Cl (2.3 mL, 34 mmol, 25 eq) in DCM (7 mL) at reflux for 4 h afforded I-034 as a beige solid in 80% yield.

[0502] 1 H NMR (400MHz, chloroform-d) δ7.88 (d, J=2.2Hz, 1H), 7.62 (d, J=2.2Hz, 1H), 7.34 (dd, J=8. 5, 5.8Hz, 1H), 7.19 (dd, J=8.4, 2.4Hz, 1H), 7.09 (td, J=8.2, 2.5Hz, 1H), 5.75 (br s, 1H), 4.03 (t, J=5.1Hz, 2H), 3.61-3.34 (m, 2H), 3.19-2.85 (m, 4H). 19 F NMR (376 MHz, chloroform-d) δ-108.5.

[0503] Synthesis of final compounds

[0504] Synthesis of the final compound

[0505] The synthesis scheme of the final compound is shown in Table 2 below.

[0506] Table 2

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515] Analytical data of final compound

[0516] The analytical data of the final compound are shown in Table 3 below.

[0517] Table 3

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528] Example 2: Biological Activity of Compounds

[0529] The purpose of this experiment was to evaluate the GFRα1-RET activity of Compounds 001 to 060 according to the present invention.

[0530] Materials and methods

[0531] The Elkl signaling activation activity of these compounds was tested in cells expressing GFRα1-RET (MG87 mouse fibroblasts stably transfected with PathDetect Elk-1, GFRα1 and RET) using a previously developed reporter gene-based system as disclosed in Sidorova, YA et al.: "Persephin signaling through GFRα1: The potential for the treatment of Parkinson's disease." Molecular and Cellular Neuroscience, July 2010, Vol. 44, pp. 223-232. DOI: 10.1016 / j.mcn.2010.03.009. For EC 50 The dose-response assay was performed using 6 concentrations for each test compound. The dose-response curves were fitted using sigmoidal dose-response (variable slope) analysis in the GraphPadPrism program (Graph Pad Inc) and the EC50 values ​​of the agonists / activators were calculated. 0All dose-response experiments were performed in duplicate independently.

[0532] result

[0533] The results are shown in Table 4 below (* indicates "10 μM <EC 50 <50μM”, ** indicates “5μM <EC 50 <10μM”, *** indicates “1μM <EC 50 <5μM", and **** indicates "EC 50 <1 μM”).

[0534] Table 4

[0535]

[0536]

[0537]

[0538]

[0539] The above results clearly demonstrate that test compounds 001 to 060 have significant GFRα1-RET activity. Therefore, the compounds of the present invention can be used as neuroprotective agents and neurorepairing agents. Test compounds 001 to 060 well represent the class of compounds of formula (I).

[0540] Example 3: Biological activity of comparative compounds

[0541] The purpose of this experiment is to compare the GFRα1-RET activities of Compound 001, Compound 009 and Compound 010 according to the present invention with the GFRα1-RET activities of Comparative Compound C01 and Comparative Compound C02.

[0542] Materials and methods

[0543] Comparative Compound C01 and Comparative Compound C02 were prepared by using the same synthetic route and synthetic method as the compounds according to the present invention described above, adjusting the reactants and experimental conditions as needed using general knowledge in the art.

[0544] The structures of comparative compound C01 and comparative compound C02 are shown in Table 5 below.

[0545] Table 5

[0546]

[0547] These compounds were tested for their Elk1 signaling activation activity using the same materials and methods as the compounds according to the present invention (see Example 2 herein, "Materials and Methods" section).

[0548] result

[0549] The results of the comparative compound C01 and the comparative compound C02 are shown in Table 6 below. For the convenience of comparison, the corresponding values ​​of the compound 009, compound 010 and compound 001 according to the present invention in Table 4 are also reported in Table 6 (AL represents "EC 50 >50μM”, * indicates “10μM <EC 50 <50μM", ** indicates "5μM <EC 50 <10μM", *** indicates "1μM <EC 50 <5μM", and **** indicates "EC 50 <1 μM”).

[0550] Table 6

[0551]

[0552] The above results clearly show that the compounds according to the present invention have significantly higher GFRα1-RET activity than the comparative compounds C01 and C02. In fact, the EC values ​​of the compounds C01 and C02 are 50 higher than 50 μM, while the EC values ​​of compound 001, compound 009 and compound 010 were 50 In the context of the medical use according to the invention, an EC above 50 μM 50 Quite high in fact, and might be considered "inactive" or "not active enough to be therapeutically significant" by one skilled in the art.

[0553] It is worth noting that the only structural difference between Compound C01 and Compound C02 and Compound 009 and Compound 010 or Compound 001, respectively, is the substitution of oxo-phenyl, i.e., R A To R D In particular, in Compound 009 and Compound 010, R D Does not indicate CF 3 Instead, it means CHF 2 (010) or Cl(009), and in compound C01, corresponding to R in formula (I) D The substituent represents CF 3 Similarly, in compound 001, R D Does not indicate CF 3 Instead, it represents Cl, and in compound C02, it corresponds to R in formula (I) D The substituent represents CF 3 .

[0554] Therefore, these results clearly show that the compounds of the present invention are better GFRa1-RET activators and therefore better candidates for neuroprotection and neurorepair than comparative compounds. Furthermore, this unexpected technical effect is directly related to the specific structural features of the compounds according to the present invention.

Claims

1. A compound of formula (Ii) or a pharmaceutically acceptable salt and / or a solvate thereof; in W represents CH or N; R A , R B and R C Each independently represents hydrogen, F, Cl, CH 3 CF 3 , CHF 2 or CH 2 F; R D Represents hydrogen, F, Cl, CH 3 , CHF 2 or CH 2 F; R 7 represents hydrogen, OH, halogen, (C 1 To C 8 ) alkyl, cycloalkyl, (C 1 To C 8 )alkyl-O-, cycloalkyl-O-, cycloalkyl-(C 1 To C 8 )alkyl-O-, heterocycloalkyl-O-, heterocycloalkyl-(C 1 To C 8 )alkyl-O-, aryl-(C 1 To C 8 )alkyl-O-, heteroaryl-(C 1 To C 8 )alkyl-O-, R 11 O-(C 1 To C 8 )alkyl-O-, R 11 R 12 N-(C 1 To C 8 )alkyl-O-, (R 11 O)(R 12 )N-(C 1 To C 8 )alkyl-O-, R 11 R 12 N-(C 1 To C 8 )alkyl-, R 11 O-(C 1 To C 8 )alkyl-、NR 11 R 12 、CN、CO 2 H, CO 2 R 11 ,CONH 2 、CON(R 11 )H, heterocycloalkyl or heteroaryl; wherein R 11 and R 12 Each independently represents hydrogen or (C 1 To C 8 )alkyl; Where R 7 The alkyl or cycloalkyl in the 1 To C 8 ) alkyl, (C 1 To C 8 ) substituted with alkyl-O-, heterocycloalkyl, aryl or heteroaryl; wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted with at least one F, Cl, (C 1 To C 8 ) alkyl, CF 3 , CHF 2 , CH 2 F. OCF 3 、CN、OH、=O、→O、(C 1 To C 8 ) alkoxy, NR 13 R 14 , R 13 R 14 N-(C 1 To C 8 )alkyl-, R 13 O 2 C(C 1 To C 8 )alkyl-, CO 2 H. R 13 R 14 NC(O)-、R 13 O-NR 14 -or (C 1 To C 8 )alkyl-CO 2 -substituted; wherein R 13 and R 14 Each independently represents hydrogen or (C 1 To C 8 )alkyl; Z stands for CH, CR 8 or N; Where R 8 Indicates (C 1 To C 4 )alkyl, F, Cl, CF 3 , CHF 2 , CH 2 F. OCF 3 , CN, OH or (C 1 To C 4 ) alkoxy; or Z stands for CR 8 And R 7 and R 8 together with the carbon atoms to which they are bound, form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group is optionally substituted by at least one of F, OH, =O, →O, (C 1 To C 8 ) alkyl, CF 3 HO 2 C-CH 2 -、(C 1 To C 4 )alkyl-CO 2 -CH 2 -、R 15 R 16 N-CH 2 -, aryl or aryl-(C 1 To C 8 ) alkyl-substituted, wherein R 15 and R 16 Each independently represents hydrogen or (C 1 To C 8 )alkyl; R 5 represents hydrogen, (C 1 To C 8 ) alkyl, one to three (C 1 To C 8 ) alkyl substituted CH 3 , cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C 1 To C 8 )alkyl; Where R 5 The alkyl or cycloalkyl group in the 1 To C 8 ) alkyl, CF 3 , OCF 3 、CN、OH、=O、(C 1 To C 8 ) alkoxy, NR 17 R 18 , CO 2 H.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 (C 1 To C 8 )alkyl; wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted with at least one F, Cl, (C 1 To C 8 ) alkyl, CF 3 , CHF 2 , CH 2 F. OCF 3 、CN、OH、=O、→O、(C 1 To C 8 ) alkoxy, NR 19 R 20 , CO 2 H.R 19 R 20 NC(O)-、R 19 O-NR 20 -、(C 1 To C 8 )alkyl-CO 2 -、 R 19 R 20 N-(C 1 To C 8 )alkyl-, R 19 O 2 C-(C 1 To C 8 )alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C 1 To C 8 ) alkyl-substituted; wherein R 19 and R 20 Each independently represents hydrogen or (C 1 To C 8 )alkyl; R 6 Indicates (C 1 To C 8 ) alkyl, one to three (C 1 To C 8 ) alkyl substituted CH 3 , cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C 1 To C 8 ) alkyl substitution; Where R 6 The alkyl or cycloalkyl group in the 1 To C 8 ) alkyl, CF 3 , OCF 3 、CN、OH、=O、(C 1 To C 8 ) alkoxy, NR 21 R 22 , CO 2 H.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 (C 1 To C 8 )alkyl; wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted with at least one F, Cl, (C 1 To C 8 ) alkyl, CF 3 , CHF 2 , CH 2 F. OCF 3 、CN、OH、=O、→O、(C 1 To C 8 ) alkoxy, NR 23 R 24 , CO 2 H.R 23 R 24 NC(O)-、R 23 O-NR 24 -、(C 1 To C 8 )alkyl-CO 2 -、 R 23 R 24 N-(C 1 To C 8 )alkyl-, R 23 O 2 C-(C 1 To C 8 )alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C 1 To C 8 ) alkyl-substituted; wherein R 23 and R 24 Each independently represents hydrogen or (C 1 To C 8 ) alkyl; or R 5 and R 6 together with the nitrogen atom to which they are bound, form a heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with at least one F, Cl, (C 1 To C 8 ) alkyl, CF 3 、OCF 3 、CN、OH、=O、→O、(C 1 To C 8 ) alkoxy, NR 25 R 26 , CO 2 H、(C 1 To C 8 )alkyl-CO 2 -、R 25 R 26 NC(O)-、R 25 O-NR 26 -、R 25 R 26 N-(C 1 To C 8 )alkyl-, R 25 O 2 C-(C 1 To C 8 )alkyl-, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C 1 To C 8 )alkyl-, heterocycloalkyl-(C 1 To C 8 ) alkyl-, aryl-(C 1 To C 8 )alkyl-, heteroaryl-(C 1 To C 8 )alkyl-, aryl-cycloalkyl-, cycloalkyl-O-, heterocycloalkyl-O-, aryl-O-, heteroaryl-O-, cycloalkyl-(C 1 To C 8 )alkyl-O-, heterocycloalkyl-(C 1 To C 8 )alkyl-O-, aryl-(C 1 To C 8 )alkyl-O-, heteroaryl-(C 1 To C 8 )alkyl-O-, cycloalkyl-NR 25 -, heterocycloalkyl-NR 25 -, aryl-NR 25 -, heteroaryl-NR 25 -, cycloalkyl-(C 1 To C 8 )Aryl-NR 25 -, heterocycloalkyl-(C 1 To C 8 )alkyl-NR 25 -, aryl-(C 1 To C 8 )alkyl-NR 25 -, heteroaryl-(C 1 To C 8 )alkyl-NR 25 -, benzylidene, heteroarylidene, aryl-(C 1 To C 8 )alkyl-ylidene- or heteroaryl-(C 1 To C 8 ) alkyl-ylidene-substituted; Where R 25 and R 26 Each independently represents hydrogen or (C 1 To C 8 )alkyl; wherein the heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylene group is optionally substituted with at least one F, Cl, (C 1 To C 8 ) alkyl, CF 3 , CHF 2 , CH 2 F. OCF 3 、CN、OH、=O、→O、(C 1 To C 8 ) alkoxy, NR 27 R 28 , CO 2 H.R 27 R 28 NC(O)-、R 27 O-NR 28 -、(C 1 To C 8 )alkyl-CO 2 -、R 27 R 28 N-(C 1 To C 8 )alkyl-, R 27 O 2 C-(C 1 To C 8 )alkyl-, heterocycloalkyl, heteroaryl, aryl or aryl-(C 1 To C 8 ) alkyl-substituted; Where R 27 and R 28 Each independently represents hydrogen or (C 1 To C 8 )alkyl.

2. A compound of formula (I-ii) 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, CH 3 CF 3 , CHF 2 or CH 2 F; R 7 represents hydrogen, OH, halogen, (C 1 To C 8 ) alkyl, cycloalkyl, (C 2 To C 8 )alkyl-O-, cycloalkyl-O-, cycloalkyl-(C 1 To C 8 )alkyl-O-, heterocycloalkyl-O-, heterocycloalkyl-(C 1 To C 8 )alkyl-O-, aryl-(C 1 To C 8 )alkyl-O-, heteroaryl-(C 1 To C 8 )alkyl-O-, R 11 O-(C 1 To C 8 )alkyl-O-, R 11 R 12 N-(C 1 To C 8 )alkyl-O-, (R 11 O)(R 12 )N-(C 1 To C 8 )alkyl-O-, R 11 R 12 N-(C 1 To C 8 )alkyl-, R 11 O-(C 1 To C 8 )alkyl-、NR 11 R 12 、CN、CO 2 H, CO 2 R 11 ,CONH 2 、CON(R 11 )H, heterocycloalkyl, or heteroaryl; wherein R 11 and R 12 Each independently represents hydrogen or (C 1 To C 8 )alkyl; Where R 7 The alkyl or cycloalkyl in the 1 To C 8 ) alkyl, (C 1 To C 8 ) substituted with alkyl-O-, heterocycloalkyl, aryl or heteroaryl; wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted with at least one F, Cl, (C 1 To C 8 ) alkyl, CF 3 , CHF 2 , CH 2 F. OCF 3 、CN、OH、=O、→O、(C 1 To C 8 ) alkoxy, NR 13 R 14 , R 13 R 14 N-(C 1 To C 8 )alkyl-, R 13 O 2 C-(C 1 To C 8 )alkyl-, CO 2 H.R 13 R 14 NC(O)-、R 13 O-NR 14 -or (C 1 To C 8 )alkyl-CO 2 -substituted; wherein R 13 and R 14 Each independently represents hydrogen or (C 1 To C 8 )alkyl; Z stands for CH, CR 8 or N; Where R 8 Indicates (C 1 To C 4 )alkyl, F, Cl, CF 3 , CHF 2 , CH 2 F. OCF 3 , CN, OH or (C 1 To C 4 ) alkoxy; or Z stands for CR 8 And R 7 and R 8 together with the carbon atoms to which they are bound, form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group is optionally substituted by at least one of F, OH, =O, →O, (C 1 To C 8 ) alkyl, CF 3 HO 2 C-CH 2 -、(C 1 To C 4 )alkyl-CO 2 -CH 2 -、R 15 R 16 N-CH 2 -, aryl or aryl-(C 1 To C 8 ) alkyl-substituted, wherein R 15 and R 16 Each independently represents hydrogen or (C 1 To C 8 )alkyl; and R 5 and R 6 Each independently as defined in claim 1.

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

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

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

6. A compound according to any one of claims 1 or 3 to 5, wherein R 7 Indicates (C 1 To C 8 )alkyl-O- or cycloalkyl-O-, wherein the alkyl or cycloalkyl group is optionally substituted with at least one of F, Cl, OH, (C 1 To C 8 ) alkoxy or aryl substituted; preferably R 7 Indicates OCH 3 , HO-CH 2 -CH 2 -O-、CH 3 O-CH 2 -CH 2 -O- or phenyl-CH 2 -O-.

7. A compound according to any one of claims 1 to 6, wherein Z represents CR 8 , where R 8 Indicates (C 1 To C 4 )alkyl, F, Cl, CF 3 , CHF 2 , CH 2 F. OCF 3 , CN, OH or (C 1 To C 4 ) alkoxy; preferably wherein R 8 It represents methyl or Cl.

8. A compound according to any one of claims 1 to 6, wherein Z represents CR 8 And R 7 and R 8 and the carbon atoms to which they are bonded together form a heterocycloalkyl group; wherein the heterocycloalkyl group is optionally substituted by at least one F, OH, =O, (C 1 To C 8 ) alkyl, CF 3 HO 2 C-CH 2 -、(C 1 To C 4 )alkyl-CO 2 -CH 2 - or R 15 R 16 N-CH 2 -substituted, where R 15 and R 16 Each independently represents hydrogen or (C 1 To C 8 )alkyl-.

9. A compound according to any one of claims 1 to 8, wherein R 5 represents hydrogen or (C 1 To C 8 ) alkyl; preferably R 5 represents hydrogen, methyl or ethyl; and / or R 6 Indicates (C 1 To C 8 )alkyl, cycloalkyl, heterocycloalkyl, cycloalkyl-(C 1 To C 8 )alkyl or aryl-(C 1 To C 8 )alkyl-, wherein the alkyl, cycloalkyl, heterocycloalkyl or aryl is optionally substituted with at least one methyl, Cl or F; preferably R 6 represents ethyl, propyl, butyl, cyclopentyl, cyclohexyl, 2-adamantyl, 3-methyloxetane-3-yl, cyclopropyl-CH 2 -, cyclobutyl-CH 2 -、cyclohexyl-CH 2 -, phenyl-CH 2 -(Benzyl), 3-chlorophenyl-CH 2 - or 4-fluorophenyl-CH 2 -.

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

11. The compound according to claim 1 or 2, wherein the compound is selected from: and pharmaceutically acceptable salts and / or solvates thereof.

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

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

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

15. A method for preparing a compound according to any one of claims 1 to 11, wherein the method comprises the step of reacting the following compounds in the presence of a base and a metal catalyst: Compound of formula (II) in Z, R 5 , R 6 and R 7 as defined in claim 1 or as defined in claim 2, and X represents halogen or -CF 3 SO 3 , With the compound of formula (III) Where W and R A To R D as defined in claim 1 or as defined in claim 2; Thus, a compound of formula (Ii) or a pharmaceutically acceptable salt and / or a solvate thereof, or a compound of formula (I-ii) or a pharmaceutically acceptable salt and / or a solvate thereof is obtained.

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