Diazepane derivatives, methods for their preparation, and their use for the remission, prevention and / or treatment of mental and neurological disorders.

Abstract

The present invention relates to a compound represented by formula (I), 1 , R 2 , R 3 wherein L and Y have the designations described herein) or a pharma- ceutically or veterinarily acceptable salt, hydrate or solvate thereof. The present invention further relates to a process for the preparation of a compound of formula (I) or a pharma- ceutically or veterinarily acceptable salt, hydrate or solvate thereof. The present invention also relates to a compound of formula (I) or a pharma- ceutically or veterinarily acceptable salt, hydrate or solvate thereof for use as a medicament. The present invention further relates to a compound of formula (I) or a pharma- ceutically or veterinarily acceptable salt, hydrate or solvate thereof for use in the amelioration, prevention and / or treatment of diseases caused by or associated with delipidation of nervous tissue. In particular, the disease is a neurodegenerative disease.

Description

[Technical Field]

[0001] The present invention relates to formula (I)

[0002] [ka]

[0003] (In the formula, R 1 , R 2 , R 3 (L and Y have the designations described herein) The present invention relates to the compound of formula (I), or its pharmaceutically or veterinarily acceptable salts, hydrates, or solvates. Furthermore, the present invention relates to a method for preparing the compound of formula (I), or its pharmaceutically or veterinarily acceptable salts, hydrates, or solvates. The present invention also relates to the compound of formula (I), or its pharmaceutically or veterinarily acceptable salts, hydrates, or solvates for use as a pharmaceutical. Furthermore, the present invention relates to the compound of formula (I), or its pharmaceutically or veterinarily acceptable salts, hydrates, or solvates for use in the remission, prevention, and / or treatment of diseases caused by or related to the degreasing of nerve tissue. In particular, the diseases are neurodegenerative diseases. [Background technology]

[0004] Mental and neurological disorders remain a public health issue worldwide. Mental disorders are behavioral or mental patterns that cause marked distress or impairment of personal functioning. Examples of mental disorders include depression and impairments of recent and remote memory (loss of short-term and long-term memory). For example, major depressive disorder is a common and complex disorder characterized by prolonged suppressed mood and loss of interest in all or almost all activities.

[0005] Neurological disorders are diseases that affect the central nervous system (CNS) or peripheral nervous system, potentially resulting in loss of function in the brain, spinal cord, peripheral nerves, or neuromuscular system. In the past decade, the incidence of CNS diseases, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD), has increased. CNS diseases, specifically neurodegenerative diseases, have a significant impact on quality of life and represent a considerable burden on both family members and society as a whole. To date, only a limited number of treatment options exist, and a cure remains elusive.

[0006] Several mental and neurological disorders have been found to be caused by or associated with delipidation of nerve tissue, particularly delipidation of myelin sheets. It has been suggested that several mental and neurological disorders can be treated or prevented by pharmacologically or genetically inhibiting the enzyme carnitine palmitoyltransferase-1 (CPT-1) (Scientific Reports, 9, 13299, pp. 1-11, September 16, 2019). A. Skottrup Morkholt et al. (Scientific Reports, 7, 2158, pp. 1-9, May 19, 2017) found that blocking CPT-1 reduced stress-induced depression in rats. Furthermore, MS Trabjerg et al. (Scientific Reports, 10, 15583, pp. 1-19, 2020 and Nature Communications, 4, 509, pp. 1-23, April 30, 2021) demonstrate that it is possible to reverse or slow the progression of several CNS diseases in experimental models by downregulating lipid metabolism via CPT-1.

[0007] Lipids have several functions in the central nervous system (CNS). One key function of lipids is the construction and maintenance of myelin sheaths on neuronal axons. In multiple sclerosis (MS) lesions, CPT-1 expression is greatly increased, which correlates with a decrease in lipid concentration in myelin due to increased beta-oxidation. In Parkinson's disease (PD), several mechanisms leading to neurodegeneration, such as mitochondrial dysfunction and oxidative stress, are linked to lipid metabolism. In amyotrophic lateral sclerosis (ALS), decreased lipid levels may lead to disease progression and lipid metabolism that appears to be upregulated prior to the disease.

[0008] WO2009 / 156479A1 describes arylalkyl and aryloxyalkyl-substituted oxirane carboxylic acid derivatives as CPT-1 inhibitors for use in treating and / or preventing damage caused by delipidation of nerve tissue. Human data, oral administration studies, or specific dosages for treatment are not provided.

[0009] WO2007 / 063012A1 describes heteroaryl-substituted piperidine derivatives modulated by L-CPT1 inhibitors for use as therapeutic active substances for the treatment and / or prevention of disease.

[0010] WO2018 / 122254A1 describes etomoxyl having the chemical formula 2-[6-(4-chlorophenoxy)hexyl]-oxirane-2-carboxylic acid for use in the treatment, prevention and / or remission of cerebral diseases caused by delipidation of nerve tissue.

[0011] As described above, no compounds suitable for the effective prevention and / or treatment of mental and neurological disorders have yet been found.

[0012] Therefore, there is a need for novel compounds that specifically inhibit carnitine palmitoyltransferase-1 (CPT-1) and are suitable for pharmaceutical use. In particular, novel compounds that can be used in the remission, prevention, and / or treatment of mental and neurological disorders, especially multiple sclerosis (MD), autoimmune encephalomyelitis, Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are of interest. [Prior art documents] [Patent Documents]

[0013] [Patent Document 1] WO2009 / 156479A1 [Patent Document 2] WO2007 / 063012A1 [Patent Document 3] WO2018 / 122254A1 [Non-patent literature]

[0014] [Non-Patent Document 1] Scientific Reports, 9, 13299, pp. 1-11, September 16, 2019 [Non-Patent Document 2] Scientific Reports, 7, 2158, pp. 1-9, May 19, 2017 [Non-Patent Document 3] Scientific Reports, 10, 15583, pp. 1-19, 2020 [Non-Patent Document 4] Nature Communications, 4, 509, pp. 1-23, April 30, 2021 [Overview of the project] [Means for solving the problem]

[0015] In one embodiment, the present invention is based on formula (I)

[0016] [ka]

[0017] (wherein R 1 is unsubstituted or substituted aryl, preferably unsubstituted or substituted phenyl, naphthyl, tetrahydronaphthyl, indenyl, indanyl, pentalenyl, or fluorenyl, unsubstituted or substituted heteroaryl, preferably unsubstituted or substituted pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 2-oxo-1,2-dihydropyridinyl, oxazolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiazolyl, and thienyl, quinolinyl, isoquinolinyl, cinnolinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, quinoxalinyl, benzothiazolyl, benzotriazolyl, indolyl, or indazolyl, unsubstituted or substituted 5- or 6-membered saturated or partially unsaturated heterocyclyl, or unsubstituted or substituted C3-C8-cycloalkyl, or cyclohexenyl; L is a single bond, or a bifunctional linker, preferably * -O-, * -OCH2-, * -CH2O-, * -CH2-, * -CH2-CH2-, * -CH2-CH2-CH2-, or * -CH2-C(CH3)2-, or a trifunctional linker, preferably, * -CH=, wherein * indicates the attachment point to the carbonyl (C=O) group; R 2 is unsubstituted or substituted phenyl, naphthyl, or pyridyl, or C1-C4-alkyl; R 3 is H, C1-C8-alkyl, halogen-C1-C4-alkyl, or C3-C8-cycloalkyl, Unsubstituted or substituted 4-membered, 5-membered or 6-membered saturated or partially unsaturated heterocyclyls, Unsubstituted or substituted phenyl; Y is either a -(C=O)-, -(SO2)-, or a single bond. This relates to compounds or stereoisomers thereof, and their pharmaceutically or veterinarily acceptable salts, hydrates, or solvates.

[0018] In one embodiment, the present invention relates to formula (I)

[0019] [ka]

[0020] (In the formula, R 1 This includes unsubstituted or substituted aryls, preferably unsubstituted or substituted phenyls, naphthyls, tetrahydronaphthyls, indenyls, indanyls, pentarenyls, or fluorenyls. Unsubstituted or substituted heteroaryls, preferably unsubstituted or substituted pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, 2-oxo-1,2-dihydropyridinyl, oxazolyl, oxydiazolyl, isoxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiazolyl and thienyl, quinolinyl, isoquinolinyl, sinnolinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, quinoxalinyl, benzothiazolyl, benzotriazolyl, indolyl, or indazolyl Unsubstituted or substituted 5-membered or 6-membered saturated or partially unsaturated heterocyclyls, It is an unsubstituted or substituted C3-C8 cycloalkyl or cyclohexenyl group; L is a single bond or a bifunctional linker, preferably * -O-, * -OCH2-, * -CH2O-, * -CH2-, * -CH2-CH2-, *-CH2-CH2-CH2-, or * It is -CH2-C(CH3)2-, and here, * This indicates the attachment site to the carbonyl (C=O) group; R 2 These are unsubstituted or substituted phenyl, naphthyl, or pyridyl. R 3 These are H, C1-C8-alkyl, halogen-C1-C4-alkyl, or C3-C8-cycloalkyl. Unsubstituted or substituted 4-membered, 5-membered or 6-membered saturated or partially unsaturated heterocyclyls, Unsubstituted or substituted phenyl; Y is either a -(C=O)-, -(SO2)-, or a single bond. This relates to compounds or stereoisomers thereof, and their pharmaceutically or veterinarily acceptable salts, hydrates, or solvates.

[0021] In one embodiment, the present invention relates to a compound of formula (I) as defined herein, wherein, R 1 This includes unsubstituted or substituted phenyl, naphthyl, or tetrahydronaphthyl. Unsubstituted or substituted pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, oxydiazolyl, isoxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, or quinolinyl, Unsubstituted or substituted pyrrolidinyl, piperidinyl, tetrahydropiperidinyl, or piperazinyl, Unsubstituted or substituted cyclopentyl; cyclohexyl or cyclohexenyl; L is a single bond or a bifunctional linker, preferably * -O-, * -OCH2-, * -CH2O-, * -CH2-, or * -CH2-CH2-, and here, * This indicates the attachment site to the carbonyl (C=O) group; R 2is an unsubstituted or substituted phenyl, naphthyl, or pyridyl; R 3 This includes H, C1-C4-alkyl, halogen-C1-C4-alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Unsubstituted or substituted azetidinil, pyrrolidinil, piperidinil, or oxetanil,

[0022] [ka]

[0023] or Unsubstituted or substituted phenyl; Y is -(C=O)-, -(SO2)-, or a single bond, preferably -(C=O)-.

[0024] In another embodiment, the present invention relates to a compound of formula (I) as defined herein, wherein, R 1 This includes unsubstituted or substituted phenyl, naphthyl, or tetrahydronaphthyl. Unsubstituted or substituted pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, oxydiazolyl, isoxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, or quinolinyl, Unsubstituted or substituted pyrrolidinyl, piperidinyl, tetrahydropiperidinyl, or piperazinyl, Unsubstituted or substituted cyclopentyl, cyclohexyl, or cyclohexenyl, Each R 1 The following residues are selected independently and at will: -CN, Halogen, preferably -F or -Cl, C1-C4 alkyl, preferably methyl, Halogen-C1~C4-alkyl, preferably difluoromethyl or trifluoromethyl, SO2Me, or CO2C1~C4-alkyl, preferably CO2Me It is replaced by one or more of them, preferably one.

[0025] In another embodiment, the present invention relates to a compound of formula (I) as defined herein, wherein, R 1 This includes unsubstituted or substituted phenyl, Unsubstituted or substituted pyridyl, pyrazolyl, thienyl, or quinolinyl Unsubstituted or substituted piperidinyl, or tetrahydropiperidinyl, Unsubstituted or substituted cyclohexyl or cyclohexenyl; Each R 1 The following residues are selected independently and at will: -CN, -F or -Cl, C1-C4 alkyl, preferably methyl, Halogen-C1~C4-alkyl, preferably trifluoromethyl, SO2Me, or CO2C1~C4-alkyl, preferably CO2Me It is replaced by one or more of them, preferably one.

[0026] In another embodiment, the present invention relates to a compound of formula (I) as defined herein, wherein, R 1 These are unsubstituted or substituted phenyl or pyridyl, Each R 1 The following residues are selected independently and at will: -F or -Cl, C1-C4 alkyl, preferably methyl, Trifluoromethyl, SO2Me, or CO2C1~C4-alkyl, preferably CO2Me It is replaced by one or more of them, preferably one.

[0027] In another embodiment, the present invention relates to a compound of formula (I) as defined herein, wherein, L is a single bond, * -CH2O-, or * -CH2-, preferably * It is -CH2O-, and here, * This indicates the attachment site to the carbonyl (C=O) group.

[0028] In another embodiment, the present invention relates to a compound of formula (I) as defined herein, wherein, R 2 is an unsubstituted or substituted phenyl, naphthyl, or pyridyl; preferably phenyl. Each R 2 The following residues are selected independently and at will: -CN, Halogen, preferably -F or -Cl, C1-C4 alkyl, preferably methyl, Halogen-C1~C4-alkyl, preferably difluoromethyl or trifluoromethyl, SO2Me, CO2C1~C4-alkyl, preferably CO2Me, Adamantite, It is replaced by one or more of them, preferably one, Unsubstituted or substituted phenyl compounds are optional. Halogen, preferably -F or -Cl, Halogen-C1~C4-alkyl, preferably trifluoromethyl, C3-C8 cycloalkyl, preferably cyclohexyl, or Pyridyl It is substituted with one or more substituents selected from, preferably one substituent.

[0029] In another embodiment, the present invention relates to a compound of formula (I) as defined herein, wherein, R 3This includes H, C1-C4-alkyl, halogen-C1-C4-alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Unsubstituted or substituted azetidinil, pyrrolidinil, piperidinil, or oxetanil, Unsubstituted or substituted phenyl Each azetidinil, pyrrolidinil, piperidinil, oxetanil, or phenyl may be optionally and independently replaced with the following residues: -CN, Halogen, preferably -F or -Cl; C1-C4 alkyl, preferably methyl; Halogen-C1~C4-alkyl, preferably chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, or 2,2-difluoro-3-methyl-butyl, particularly preferably difluoromethyl or trifluoromethyl, SO2Me, CO2C1~C4-alkyl, preferably CO2Me, or CO-C1~C4 alkyl, preferably CO-Me It is replaced by one or more of them, preferably one.

[0030] In another embodiment, the present invention relates to a compound of formula (I) as defined herein, wherein, R 3 The element is C1-C4 alkyl, preferably methyl.

[0031] In another embodiment, the present invention relates to a compound of formula (I) as defined herein or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate or solvate thereof, for use as a pharmaceutical.

[0032] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined herein or a stereoisomer thereof, a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof, and a therapeutically inactive carrier.

[0033] In another embodiment, the present invention relates to a compound of formula (I) as defined herein for use in the remission, prevention, or treatment of diseases caused by or related to depilation of nerve tissue, preferably by inhibiting the expression and / or activity of the enzyme carnitine palmitoyltransferase-1 (CPT-1).

[0034] In another embodiment, the present invention relates to a compound of formula (I) as defined herein for use in the remission, prevention or treatment of diseases modulated by CPT-1 inhibitors.

[0035] In preferred embodiments, diseases caused by or associated with delipidation of nerve tissue include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), inflammatory diseases, acute traumatic events, e.g., surgery or injury, AIDS-related wasting due to reverse transcriptase inhibitor toxicity, mitochondrial myopathy, aging and senescence, neuronal ischemia, polyglutamine diseases, dystonia, Leber hereditary optic neuropathy (LHON), schizophrenia, stroke, myodegenerative disorders, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy associated with red rag fibers (MERRF), neuropathy, Ataxia, and retinitis pigmentosa (NARP), progressive extraocular palsy (PEO), Leigh disease, Kearns-Sayre syndrome, muscular dystrophy, myotonic dystrophy, chronic fatigue syndrome, Friedreich's ataxia; developmental delay in cognitive, motor, language, executive function or social skills; epilepsy, peripheral neuropathy, optic neuropathy, autonomic neuropathy, neurogenic bowel dysfunction, sensorineural hearing loss, neurogenic bladder dysfunction, migraine; renal tubular acidosis, hepatic failure, lactic acidemia, periodontitis, Duchenne muscular dystrophy, Becker muscular dystrophy, McArdle disease, abnormalities in testosterone synthesis and / or hypoparathyroidism.

[0036] In a particularly preferred embodiment, the disease caused by or associated with the delipidation of nerve tissue is amyotrophic lateral sclerosis (ALS).

[0037] In another embodiment, the present invention relates to a method for producing a compound of formula (I) as described herein.

[0038] In one embodiment, the present invention relates to compounds of formulas (C), (D), and (F) as defined herein. [Brief explanation of the drawing]

[0039] [Figure 1]This figure shows the efficacy of the CPT1 inhibitor, Example 1 (Ex.1, racemic mixture), as tested in a fatty acid uptake assay using HEK293 cells with an IC50 of 0.3 μM. [Figure 2] This figure shows the efficacy of CPT1 inhibitors by improving the survival of SOD1 G93A mice in Example 1-E1 (Ex.1) (n=10) and Example 1-E2 (Exp.1) (n=10) compared to SOD1 G93A mice that accept either vehicle (n=9), edaravone (n=10), or riluzole (n=10). [Modes for carrying out the invention]

[0040] definition As used herein, the substituents and terms used collectively, including in the appended claims, have the following meanings:

[0041] As used herein, the term "aryl" means monocyclic, bicyclic, or polycyclic aromatic systems, such as unsubstituted or substituted phenyl, naphthyl, tetrahydronaphthyl, indenyl, indanyl, pentarenyl, fluorenyl, etc., preferably unsubstituted or substituted phenyl and naphthyl, and particularly preferably unsubstituted or substituted phenyl.

[0042] As used herein, the term "heteroaryl" means an aromatic or partially unsaturated five- or six-membered ring containing one, two, or three atoms selected from nitrogen, oxygen, and / or sulfur, such as pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, 2-oxo-1,2-dihydropyridinyl, oxazolyl, oxydiazolyl, isoxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiazolyl, and thienyl. The term "heteroaryl" further refers to a bicyclic aromatic or partially unsaturated group comprising two five-membered or six-membered rings, where one or both rings may contain one, two, or three atoms selected from nitrogen, oxygen, or sulfur, such as quinolinyl, isoquinolinyl, sinnolinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, quinoxalinyl, benzothiazolyl, benzotriazolyl, indolyl, and indazolyl. Preferred heteroaryl groups are pyridyl, pyrazolyl, thienyl, and pyrazinyl.

[0043] As used herein, the term “4-membered, 5-membered, or 6-membered saturated or partially unsaturated heterocyclyl” refers to an unsubstituted or substituted saturated or partially unsaturated ring system containing 4, 5, or 6 ring atoms and, in addition to the C ring atoms, 1 to 3 nitrogen atoms and / or oxygen or sulfur atoms, or 1 or 2 oxygen and / or sulfur atoms. In a particularly preferred embodiment, “4-membered, 5-membered, or 6-membered saturated heterocyclyl” refers to an unsubstituted or substituted saturated ring system containing 4, 5, or 6 ring atoms and, in addition to the C ring atoms, 1 to 3 nitrogen atoms and / or oxygen or sulfur atoms, or 1 or 2 oxygen and / or sulfur atoms. In a preferred embodiment, the 4-membered, 5-membered, or 6-membered saturated heterocyclyl contains 1 N and optionally 1 additional heteroatom in addition to the C ring atom. The additional heteroatom is preferably selected from O, N, or S. Particularly preferred is a heterocycle having only one N as the heteroatom. Preferably, these substituted heterocycles are single or double-substituted. The 4-membered, 5-membered, or 6-membered saturated heterocycles may be substituted with a C atom, an O atom, a N atom, or an S atom. Examples of 4-membered, 5-membered, or 6-membered saturated heterocyclyls include, but are not limited to, oxetanyl, azetidinyl, 1,3-diazethinyl, thietanyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2- Oxazolidinyl, 4-Oxazolidinyl, 5-Oxazolidinyl, 2-Thiazolidinyl, 4-Thiazolidinyl, 5-Thiazolidinyl, 2-Imidazolidinyl, 4-Imidazolidinyl, 1,2,4-Oxadiazolidine-3-yl, 1,2,4-Oxadiazolidine-5-yl, 1,2,4-Thiadasiazolidine-3-yl, 1,2,4-Thiadasiazolidine-5-yl, 1,2,4-Triazolidine-3-yl, 1,3,4-Oxadiazolidine-2-yl, 1,3,4-Thiadasiazolidine-2-yl, 1,3,4-Triazolidine-2-yl, 2,3-dihydrofluor-2-yl, 2,3-dihydrofluor-3-yl, 2,4-dihydrofluor-2-yl, 2,4-dihydrofluor-3-yl, 2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl, 2,4-dihydrothien-3-yl, 2,3-pyrroline-2-yl, 2,3-pyrroline-3-yl, 2,4-pyrroline-2-yl, 2,4-pyrroline-3-yl, 2,3-isoxazoline-3-yl, 3,4-isoxazoline-3-yl, 4,5-isoxazoline-3- Il, 2,3-isoxazolin-4-yl, 3,4-isoxazolin-4-yl, 4,5-isoxazolin-4-yl, 2,3-isoxazolin-5-yl, 3,4-isoxazolin-5-yl, 4,5-isoxazolin-5-yl, 2,3-isothiazolin-3-yl, 3,4-isothiazolin-3-yl, 4,5-isothiazolin-3-yl, 2,3-isothiazolin-4-yl, 3,4-isothiazolin-4-yl, 4,5-isothiazolin-4-yl, 2,3-isothiazolin-5-yl, 3,4-isothia Zorin-5-yl, 4,5-isothiazolin-5-yl, 2,3-dihydropyrazole-1-yl, 2,3-dihydropyrazole-2-yl, 2,3-dihydropyrazole-3-yl, 2,3-dihydropyrazole-4-yl, 2,3-dihydropyrazole-5-yl, 3,4-dihydropyrazole-1-yl, 3,4-dihydropyrazole-3-yl, 3,4-dihydropyrazole-4-yl, 3,4-dihydropyrazole-5-yl, 4,5-dihydropyrazole-1-yl, 4,5-dihydropyrazole-3-yl, 4, 5-dihydropyrazole-4-yl, 4,5-dihydropyrazole-5-yl, 2,3-dihydroxazole-2-yl, 2,3-dihydroxazole-3-yl, 2,3-dihydroxazole-4-yl, 2,3-dihydroxazole-5-yl, 3,4-dihydroxazole-2-yl, 3,4-dihydroxazole-3-yl, 3,4-dihydroxazole-4-yl, 3,4-dihydroxazole-5-yl, 3,4-dihydroxazole-2-yl, 3,4-dihydroxazole-3-yl, 3,4-Dihydrooxazole-4-yl, 2-Piperidinyl, 3-Piperidinyl, 4-Piperidinyl, 1-Piperadinyl, 2-Piperadinyl, 1,3-Dioxan-5-yl, 2-Tetrahydropyranyl, 4-Tetrahydropyranyl, 2-Tetrahydrothienyl, 3-Tetrahydropyridazinyl, 4-Tetrahydropyridazinyl, 2-Tetrahydropyridazinyl, 4-Tetrahydropyrimidinyl, 5-Tetrahydropyrimidinyl, 2-Tetrahydropyrazine, Examples include 1,3,5-tetrahydrotriazine-2-yl and 1,2,4-tetrahydrotriazine-3-yl, preferably piperidine-1-yl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperazinyl, 2-piperazinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl, tetrahydropyridinyl, preferably 1,2,3,6-tetrahydropyridinyl, 1,2-oxazinyl, 1,3-oxazinyl, and 1,4-oxazinyl.

[0044] As used herein, the term "C3-C8-cycloalkyl" means a carbocyclic saturated ring system having 3 to 8 carbon atoms, preferably 3 to 6, and particularly preferably 5 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, preferably cyclopentyl and cyclohexyl.

[0045] Aryl, heteroaryl, 4-membered, 5-membered, or 6-membered saturated or partially unsaturated heterocyclyl, or C3-C8 cycloalkyl, each optionally and independently, may be used to represent the following residues: -CN, Halogen, preferably -F or -Cl, C1-C4 alkyl, preferably methyl, Halogen-C1~C4-alkyl, preferably difluoromethyl or trifluoromethyl, SO2Me, or CO2C1~C4-alkyl, preferably CO2Me It may be replaced by one or more of them, preferably by one.

[0046] As used herein, the term "C1-C4-alkyl" means a linear or branched alkyl group having one to four carbon atoms, respectively. Examples of linear and branched groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, preferably methyl and ethyl, and most preferably methyl.

[0047] As used herein, the term "halogen-C1~C4-alkyl" means a linear or branched alkyl group having one to four carbon atoms (as described above), where the hydrogen atoms in these groups can be partially or completely replaced by halogen atoms as described above, such as C1~C2-halogen alkyl groups, e.g., chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl and pentafluoroethyl, preferably trifluoromethyl.

[0048] As used herein, the terms “substituted” or “substituted” mean one or more substituents that are commonly known in the art or as specifically defined herein.

[0049] As used herein, the term "halogen" refers to fluoro, chloro, bromo, or iodine, and preferably refers to fluoro and chloro.

[0050] As used herein, the term “stereoisomer” means any possible enantiomer or diastereomer of the compound of formula (I) and its salts or hydrates, when it relates to the compound of formula (I) and its intermediate compounds. In particular, the term “stereoisomer” means a single compound or a mixture of two or more compounds, where at least one chiral center is predominantly present in one distinct isomeric form of the compound of formula (I), particularly the S-enantiomer, R-enantiomer, and racemate. It is also possible that two or more stereocenters are predominantly present in one distinct isomeric form of a derivative of the compound of formula (I) as defined above. In the sense of the present invention, “primarily” means at least 60%, preferably at least 70%, particularly preferably at least 80%, and most preferably at least 90%. According to the present invention, furthermore, stereoisomers of the compound of formula (I) can exist as salts or hydrates.

[0051] As used herein, the term “salt” means, when it relates to the compound of formula (I) as defined above, a physiologically acceptable acid addition salt and base salt of the compound of formula (I), i.e., a pharmaceutically or veterinarily acceptable salt thereof, or a derivative thereof, or a stereoisomer thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include, but are not limited to, acetates, aspartates, benzoates, besilates, bicarbonates, carbonates, bisulfates, sulfates, borates, cansilates, citrates, edisylates, esylates, formates, fumarates, gluceptates, glucons, glucurons, hexafluorophosphates, hibenzates, hydrochlorides / chlorides, hydrobroms, bromides, hydroiodides, iodides, isethionates, lactates, malates, maleates, malons, mesilates, methylsulfates, naphthylates, nicotinates, nitrates, orotates, oxalates, palmitates, pamoates, phosphates, hydrogen phosphates, dihydrogen phosphates, sugarates, stearates, succinates, tartrates, tosilates, and trifluoroacetates. Suitable base salts are formed from bases that form non-toxic salts. Examples include, but are not limited to, salts of aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc.

[0052] As used herein, the term “hydrate” means, when relating to a compound of formula (I), a compound of formula (I) or a stereoisomer thereof containing water, or a salt thereof. A “hydrate” is formed by the addition of water or elements thereof. In one embodiment, a compound of formula (I) or a stereoisomer thereof as defined above can form crystals that incorporate water into their crystalline structure without chemical modification.

[0053] The terms stereoisomer, salt, and hydrate can also be used together. For example, the stereoisomer of the compound of formula (I) may have a salt. Combinations of these terms are considered to be within the scope of the present invention.

[0054] Technical terms are used by their common meaning. If a specific meaning is conveyed by a particular term, then the definition of the term is given below in the context in which the term is used.

[0055] The general or preferred residue definitions described below apply to both the final product of formula (I) and its specific embodiments, and, accordingly, to the starting materials or intermediates of formulas (A) through (G) required in each case of preparation. These residue definitions can be combined with each other as desired, i.e., including combinations between given preferred residues. Furthermore, individual definitions may not always apply.

[0056] As used herein, the terms “CPT-I inhibitor” or “inhibitor” mean any compound that can downregulate, reduce, decrease, suppress or inactivate the amount and / or activity of carnitine palmitoyltransferase-1 (CPT-I), a key enzyme in the fatty acid oxidation pathway and having the following catalytic activity: palmitoyl-CoA + L-carnitine = CoA + L-palmitoylcarnitine. The enzyme is known, in addition, under the following synonyms: EC 2.3.1.21, CPT I, CPTI-L, carnitine palmitoyltransferase IA, carnitine palmitoyltransferase IB, carnitine palmitoyltransferase 1C, CPT IM. Generally, CPT-I inhibitors or inhibitors can be proteins, oligo- and polypeptides, nucleic acids, genes, and chemical molecules. Suitable protein inhibitors may be, for example, monoclonal or polyclonal antibodies that bind to one of the enzymes listed below. Enzyme inhibition can be achieved by any of the various mechanisms known in the art, including, but not limited to, direct binding to the enzyme (e.g., enzyme inhibitor compound-binding complexes or substrate mimics), denaturation or otherwise inactivation of the enzyme, inhibition of the expression of the gene encoding the enzyme (e.g., transcription into mRNA, translation into nascent polypeptides), and / or final modification of the mature protein.

[0057] As used herein, the terms “inhibit” or “inhibit” mean any effect in downregulating, reducing, decreasing, suppressing or inactivating (moreover, in part) the amount and / or activity of the carnitine palmitoyltransferase-1 enzyme.

[0058] As used herein, the term “modulating expression and / or activity” generally refers to any process that functions to control or modulate the quantity or activity (functionality) of a cellular component, particularly an enzyme. Static regulation maintains expression and / or activity at a given level. Upregulation refers to a relative increase in expression and / or activity. Thus, downregulation refers to a decrease in expression and / or activity. Downregulation is synonymous with inhibition of the expression and / or activity of a given cellular component.

[0059] Generally, CPT-I inhibitors can be identified by screening test compounds, e.g., compounds of formula (I) or a library of test compounds, for their ability to inhibit carnitine palmitoyltransferase-1 activity. In this context, cells or cell lysates are incubated with radioactive palmitate and the generation of radioactive ketones and / or 14 Their ability to decompose palmitate can be tested by measuring the release of CO2. Furthermore, in silico screening is possible based on the structures of known enzymes involved in fatty acid oxidation.

[0060] Novel diazepane derivative CPT-1 inhibitors As indicated above, there is a need for novel compounds that specifically inhibit carnitine palmitoyltransferase-1 (CPT-1) and are suitable for pharmaceutical use. Of particular interest are novel compounds that can be used in the remission, prevention, and / or treatment of mental and neurological disorders, especially multiple sclerosis (MD), autoimmune encephalomyelitis, Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

[0061] Therefore, the problem of the present invention was to provide a novel compound having the desired characteristics described above, which is particularly suitable for use in the remission, prevention and / or treatment of mental and neurological disorders.

[0062] In one embodiment, the present invention is based on formula (I)

[0063] [ka]

[0064] (In the formula, R 1 This includes unsubstituted or substituted aryls, preferably unsubstituted or substituted phenyls, naphthyls, tetrahydronaphthyls, indenyls, indanyls, pentarenyls, or fluorenyls. Unsubstituted or substituted heteroaryls, preferably unsubstituted or substituted pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, 2-oxo-1,2-dihydropyridinyl, oxazolyl, oxydiazolyl, isoxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiazolyl and thienyl, quinolinyl, isoquinolinyl, sinnolinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, quinoxalinyl, benzothiazolyl, benzotriazolyl, indolyl, or indazolyl Unsubstituted or substituted 5-membered or 6-membered saturated or partially unsaturated heterocyclyls, It is an unsubstituted or substituted C3-C8 cycloalkyl or cyclohexenyl group; L is a single bond or a bifunctional linker, preferably * -O-, * -OCH2-, * -CH2O-, * -CH2-, * -CH2-CH2-, * -CH2-CH2-CH2-, or * -CH2-C(CH3)2-, or a trifunctional linker, preferably, * -CH=, and here, * This indicates the attachment site to the carbonyl (C=O) group; R 2 is an unsubstituted or substituted phenyl, naphthyl, or pyridyl, or C1-C4 alkyl group; R 3These are H, C1-C8-alkyl, halogen-C1-C4-alkyl, or C3-C8-cycloalkyl. Unsubstituted or substituted 4-membered, 5-membered or 6-membered saturated or partially unsaturated heterocyclyls, Unsubstituted or substituted phenyl; Y is either a -(C=O)-, -(SO2)-, or a single bond. This relates to compounds or stereoisomers thereof, and their pharmaceutically or veterinarily acceptable salts, hydrates, or solvates.

[0065] In one embodiment, the present invention relates to formula (I)

[0066] [ka]

[0067] (In the formula, R 1 This includes unsubstituted or substituted aryls, preferably unsubstituted or substituted phenyls, naphthyls, tetrahydronaphthyls, indenyls, indanyls, pentarenyls, or fluorenyls. Unsubstituted or substituted heteroaryls, preferably unsubstituted or substituted pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, 2-oxo-1,2-dihydropyridinyl, oxazolyl, oxydiazolyl, isoxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiazolyl and thienyl, quinolinyl, isoquinolinyl, sinnolinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, quinoxalinyl, benzothiazolyl, benzotriazolyl, indolyl, or indazolyl Unsubstituted or substituted 5-membered or 6-membered saturated or partially unsaturated heterocyclyls, It is an unsubstituted or substituted C3-C8 cycloalkyl or cyclohexenyl group; L is a single bond or a bifunctional linker, preferably * -O-, * -OCH2-, * -CH2O-,* -CH2-, * -CH2-CH2-, * -CH2-CH2-CH2-, or * It is -CH2-C(CH3)2-, and here, * This indicates the attachment site to the carbonyl (C=O) group; R 2 These are unsubstituted or substituted phenyl, naphthyl, or pyridyl. R 3 These are H, C1-C8-alkyl, halogen-C1-C4-alkyl, or C3-C8-cycloalkyl. Unsubstituted or substituted 4-membered, 5-membered or 6-membered saturated or partially unsaturated heterocyclyls, Unsubstituted or substituted phenyl; Y is either a -(C=O)-, -(SO2)-, or a single bond. This relates to compounds or stereoisomers thereof, and their pharmaceutically or veterinarily acceptable salts, hydrates, or solvates.

[0068] In a particularly preferred embodiment, Y is -(C=O)-.

[0069] The thiazole ring of the compound of formula (I) is R at position 4 or position 5. 1 It is acceptable for it to be replaced with [this].

[0070] In a particularly preferred embodiment, the thiazole ring is R at the 4-position. 1 It has been replaced with.

[0071] Furthermore, the compounds include pharmaceutically or veterinarily acceptable salts, hydrates, or solvates of the compound of formula (I), or intermediate compounds thereof disclosed herein.

[0072] As shown in the examples, the inventors have hereby found, surprisingly and unexpectedly, that the compound of formula (I) or its pharmaceutically or veterinarily acceptable salts, hydrates, or solvates are useful in the remission, prevention, and / or treatment of diseases caused by or related to delipidation of nerve tissue. Specifically, the compound of formula (I) or its pharmaceutically or veterinarily acceptable salts, hydrates, or solvates were found to inhibit the expression and / or activity of the enzyme carnitine palmitoyltransferase-1 (CPT-1).

[0073] The following describes preferred groups of compounds of formula (I) of the present invention. These preferred groups constitute preferred embodiments of compounds of formula (I). Any combination of embodiments of compounds of formula (I) of the present invention described herein is considered to fall within the scope of the present invention.

[0074] In one embodiment, the present invention relates to a compound of formula (I) as defined herein, wherein, R 1 This includes unsubstituted or substituted aryls, preferably unsubstituted or substituted phenyls, naphthyls, tetrahydronaphthyls, indenyls, indanyls, pentarenyls, or fluorenyls. Unsubstituted or substituted heteroaryls, preferably unsubstituted or substituted pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, 2-oxo-1,2-dihydropyridinyl, oxazolyl, oxydiazolyl, isoxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiazolyl and thienyl, quinolinyl, isoquinolinyl, sinnolinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, quinoxalinyl, benzothiazolyl, benzotriazolyl, indolyl, or indazolyl Unsubstituted or substituted 5-membered or 6-membered saturated or partially unsaturated heterocyclyls, It is an unsubstituted or substituted C3-C8 cycloalkyl or cyclohexenyl group; Each R 1The following residues are selected independently and at will: -CN, Halogen, preferably -F or -Cl, C1-C4 alkyl, preferably methyl, Halogen-C1~C4-alkyl, preferably difluoromethyl or trifluoromethyl, SO2Me, or CO2C1~C4-alkyl, preferably CO2Me It is replaced by one to three of the following; L is a single bond or a bifunctional linker, preferably * -O-, * -OCH2-, * -CH2O-, * -CH2-, * -CH2-CH2-, * -CH2-CH2-CH2-, or * It is -CH2-C(CH3)2-, and here, * This indicates the attachment site to the carbonyl (C=O) group; R 2 is an unsubstituted or substituted phenyl, naphthyl, or pyridyl; Each R 2 The following residues are selected independently and at will: -CN, Halogen, preferably -F or -Cl, C1-C4 alkyl, preferably methyl, Halogen-C1~C4-alkyl, preferably difluoromethyl or trifluoromethyl, SO2Me, CO2C1~C4-alkyl, preferably CO2Me, Adamantyl It is replaced by one to three, preferably one, Unsubstituted or substituted phenyls Halogen, preferably -F or -Cl, Halogen-C1~C4-alkyl, preferably trifluoromethyl, C3-C8 cycloalkyl, preferably cyclohexyl, or Pyridyl Optionally substituted with one or more substituents selected from, preferably one substituent; R 3 These are H, C1-C8-alkyl, halogen-C1-C4-alkyl, or C3-C8-cycloalkyl. Unsubstituted or substituted 4-membered, 5-membered or 6-membered saturated or partially unsaturated heterocyclyls, Unsubstituted or substituted phenyl; Each of the 5-membered or 6-membered saturated or partially unsaturated heterocyclyl or phenyl compounds can be optionally and independently selected from the following residues: -CN, Halogen, preferably -F or -Cl; C1-C4 alkyl, preferably methyl; Halogen-C1~C4-alkyl, preferably chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, or 2,2-difluoro-3-methyl-butyl, particularly preferably difluoromethyl or trifluoromethyl, SO2Me, CO2C1~C4-alkyl, preferably CO2Me, or CO-C1~C4 alkyl, preferably CO-Me It is replaced by one or more of them, preferably one, Y is either a -(C=O)-, -(SO2)-, or a single bond;

[0075] In one embodiment, the present invention relates to a compound of formula (I) as defined herein, wherein, R 1 This includes unsubstituted or substituted phenyl, naphthyl, or tetrahydronaphthyl. Unsubstituted or substituted pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, oxydiazolyl, isoxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, or quinolinyl, Unsubstituted or substituted pyrrolidinyl, piperidinyl, tetrahydropiperidinyl, or piperazinyl, or Unsubstituted or substituted cyclopentyl; cyclohexyl or cyclohexenyl; L is a single bond, or a bifunctional linker, preferably * -O-, * -OCH2-, * -CH2O-, * -CH2-, or * -CH2-CH2-, where * represents the attachment point to the carbonyl (C=O) group; R 2 is unsubstituted or substituted phenyl, naphthyl, or pyridyl; R 3 is H, C1-C4-alkyl, halogen-C1-C4-alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, unsubstituted or substituted azetidinyl, pyrrolidinyl, piperidinyl, or oxetanyl,

[0076]

Chemical formula

[0077] or unsubstituted or substituted phenyl; Y is -(C=O)-, -(SO2)- or a single bond, preferably -(C=O)-.

[0078] In another embodiment, the present invention relates to a compound of formula (I) as defined herein, wherein R 1 is unsubstituted or substituted phenyl, naphthyl, or tetrahydronaphthyl, Unsubstituted or substituted pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, oxydiazolyl, isoxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, or quinolinyl, Unsubstituted or substituted pyrrolidinyl, piperidinyl, tetrahydropiperidinyl, or piperazinyl, Unsubstituted or substituted cyclopentyl, cyclohexyl, or cyclohexenyl, Each R 1 The following residues are selected independently and at will: -CN, Halogen, preferably -F or -Cl, C1-C4 alkyl, preferably methyl, Halogen-C1~C4-alkyl, preferably difluoromethyl or trifluoromethyl, SO2Me, or CO2C1~C4-alkyl, preferably CO2Me It is replaced by one or more of them, preferably one.

[0079] In another embodiment, the present invention relates to a compound of formula (I) as defined herein, wherein, R 1 This includes unsubstituted or substituted phenyl, Unsubstituted or substituted pyridyl, pyrazolyl, thienyl, or quinolinyl Unsubstituted or substituted piperidinyl, or tetrahydropiperidinyl, Unsubstituted or substituted cyclohexyl or cyclohexenyl; Each R 1 The following residues are selected independently and at will: -CN, -F or -Cl, C1-C4 alkyl, preferably methyl, Halogen-C1~C4-alkyl, preferably trifluoromethyl, SO2Me, or CO2C1~C4-alkyl, preferably CO2Me It is replaced by one or more of them, preferably one.

[0080] In another embodiment, with respect to a compound of formula (I) as defined herein, in which, R 1 These are unsubstituted or substituted phenyl or pyridyl, Each R 1 The following residues are selected independently and at will: -F or -Cl, C1-C4 alkyl, preferably methyl, Trifluoromethyl, SO2Me, or CO2C1~C4-alkyl, preferably CO2Me It is replaced by one or more of them, preferably one.

[0081] In another embodiment, the present invention relates to a compound of formula (I) as defined herein, wherein, L is a single bond, * -CH2O-, or * -CH2-, preferably * It is -CH2O-, and here, * This indicates the attachment site to the carbonyl (C=O) group.

[0082] In another embodiment, the present invention relates to a compound of formula (I) as defined herein, wherein, R 2 is an unsubstituted or substituted phenyl, naphthyl, or pyridyl; preferably phenyl. Each R 2 The following residues are selected independently and at will: -CN, Halogen, preferably -F or -Cl, C1-C4 alkyl, preferably methyl, Halogen-C1~C4-alkyl, preferably difluoromethyl or trifluoromethyl, SO2Me, CO2C1~C4-alkyl, preferably CO2Me, Adamantyl It is replaced by one or more of them, preferably one, Unsubstituted or substituted phenyl compounds are optional. Halogen, preferably -F or -Cl, Halogen-C1~C4-alkyl, preferably trifluoromethyl, C3-C8 cycloalkyl, preferably cyclohexyl, or Pyridyl It is substituted with one or more substituents, preferably one, selected from the following.

[0083] In another embodiment, the present invention relates to a compound of formula (I) as defined herein, wherein, R 3 This includes H, C1-C4-alkyl, halogen-C1-C4-alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Unsubstituted or substituted azetidinil, pyrrolidinil, piperidinil, or oxetanil, Unsubstituted or substituted phenyl Each azetidinil, pyrrolidinil, piperidinil, oxetanil, or phenyl may be optionally and independently replaced with the following residues: -CN, Halogen, preferably -F or -Cl; C1-C4 alkyl, preferably methyl; Halogen-C1~C4-alkyl, preferably chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, or 2,2-difluoro-3-methylbutyl, Particularly preferred are difluoromethyl or trifluoromethyl, SO2Me, CO2C1~C4-alkyl, preferably CO2Me, or CO-C1~C4 alkyl, preferably CO-Me It is replaced by one or more of them, preferably one.

[0084] In another embodiment, the present invention relates to a compound of formula (I) as defined herein, wherein, R 3 The element is C1-C4 alkyl, preferably methyl.

[0085] In one embodiment, the present invention relates to a compound of formula (I) as defined herein, wherein, R 1 This includes unsubstituted or substituted phenyl, Unsubstituted or substituted pyridyl, pyrazolyl, thienyl, or quinolinyl Unsubstituted or substituted piperidinyl, tetrahydropiperidinyl, or piperazinyl, Unsubstituted or substituted cyclopentyl; cyclohexyl or cyclohexenyl; Each R 1 The following residues are selected independently and at will: -CN, -F or -Cl, C1-C4 alkyl, preferably methyl or trifluoromethyl It is replaced by one of the following: L is a single bond, * -OCH2-, or * -CH2-, or * And here, * This indicates the attachment site to the carbonyl (C=O) group; R 2 is unsubstituted or substituted phenyl or naphthyl; Each R 2 The following residues are selected independently and at will: -CN, -F or -Cl, C1-C4 alkyl, preferably methyl or trifluoromethyl It is replaced by one of the following: Unsubstituted or substituted phenyls are -F or -Cl, trifluoromethyl or cyclohexyl, or Pyridyl It is optionally substituted with one substituent selected from the following: R 3 This includes C1-C4-alkyl, halogen-C1-C4-alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Unsubstituted or substituted azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, or phenyl; Each azetidinil, pyrrolidinil, piperidinil, oxetanil, or phenyl may be optionally and independently replaced with the following residues: Methyl; trifluoromethyl, 2,2-difluoro-3-methylbutyl, or CO-Me It is replaced by one of the following: Y is -(C=O)-.

[0086] In another embodiment, the present invention is

[0087] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0088] This relates to compounds of formula (I) selected from the following.

[0089] Method for preparing the compound of formula (I) In another embodiment, the present invention provides a novel method for preparing the compound of formula (I) of the present invention.

[0090] In one embodiment, the present invention relates to a method for preparing a compound of general formula (I), comprising the following steps: (i) Equation (A)

[0091] [ka]

[0092] (In the formula, Hal is a halogen, preferably Br, and Boc is a tert-butoxycarbonyl protecting group.) The compound is given by formula (B) R3 -Y-Cl (B), (In the formula, R 3 (and Y are as defined above.) By reacting it with the compound of formula (C),

[0093] [ka]

[0094] (In the formula, R 3 (Y, Hal, and Boc are as defined above.) Steps to obtain the compound; (j) By reacting the compound of formula (C) with a deprotecting agent, formula (D) is obtained.

[0095] [ka]

[0096] (In the formula, R 3 (Y and Hal are as defined above.) Steps to obtain the compound; (k) Compound of formula (D) R 2 -L-CO-Cl (E) (In the formula, R 2 (and L are as defined above.) By reacting it with the compound of formula (F),

[0097] [ka]

[0098] (In the formula, R 2 , R 3 (L and Y are as defined above.) Steps to obtain the compound; (l) Compound of formula (F) of formula (H) R 1 -B(OH)2(H), (where R 1 is as defined above) react the compound of with a compound of formula (I), and, if appropriate, in the presence of a catalyst, to obtain a compound of formula (I)

[0099]

Chemical Formula

[0100] (where R 1、 R 2 R 3 L and Y are as defined above) to obtain the compound of .

[0101] Illustrative preparations of the compounds of formula (I) are described in Scheme 2 and in the Examples.

[0102]

Chemical Formula

[0103] Scheme 2: Illustrative preparation of the compound of formula (I) (Example 1) The compound of formula (A) used as starting material in method step (i) can be prepared as described in the literature procedures or as in the preparation method of Specific Example 9. An illustrative method for the preparation of the compound of formula (A) is shown in Scheme 1 below:

[0104]

Chemical Formula

[0105] Scheme 1: Illustrative preparation of the compound of formula (9) The compound of formula (B) used as starting material in method step (i) is commercially available or can be obtained by standard procedures known to those skilled in the art.

[0106] In step (i) of the method, the desired diazepane derivative of formula (C) can be prepared according to a standard N-acetylation procedure known in the art. Further guidance can be found in Scheme 2 and the examples disclosed below. Step (i) of the method is carried out preferably in the presence of a solvent and a base, preferably in the presence of dichloromethane and triethylamine.

[0107] Method step (j) can be carried out according to standard procedures known in state-of-the-art techniques for the removal of protecting groups, particularly tert-butoxycarbonyl protecting groups.

[0108] In step (k) of the method, the desired diazepane derivative of formula (F) can be prepared according to a standard N-acetylation procedure known in the art. Further guidance can be found in Scheme 2 and the examples disclosed below. Step (k) of the method is carried out preferably in the presence of a solvent and a base, preferably in the presence of dichloromethane and diisopropylethylamine.

[0109] The compound of formula (E) used as a starting material in step (k) of the method is commercially available or can be obtained by standard procedures known to those skilled in the art.

[0110] Method step (l) can be carried out according to standard procedures known in state-of-the-art techniques for CC coupling. The compound of formula (I) can be prepared by a standard Suzuki coupling reaction. Further guidance can be found in Scheme 2 and the examples disclosed below. Method step (l) is preferably carried out in the presence of a solvent and a catalyst.

[0111] The compound of formula (G) used as a starting material in step (k) of the method is commercially available or can be obtained by standard procedures known to those skilled in the art.

[0112] The compounds of formulas (C), (D), and (F) are novel. Therefore, in another embodiment, the present invention relates to the compounds of formulas (C), (D), and (F).

[0113] In another embodiment, the present invention relates to a method for preparing a compound of general formula (I), comprising the steps shown in Scheme 3.

[0114] For example, Examples 2, 4, 5, 7, 10, 12, 17, 23, 26, 27, 40, 98, and 99 in Table 1 (see Table 1 - Compounds of Formula (I) of the present invention) were obtained according to the method of the present invention described in Scheme 3. Each arylboronic acid Ar-B(OH)2 used as a starting material is commercially available or can be synthesized according to methods known to those skilled in the art.

[0115] [ka]

[0116] Scheme 3: Exemplary preparation of compounds of formula (I) (Examples 2, 4, 5, 7, 10, 12, 17, 23, 26, 27, 40, 98, and 99) In another embodiment, the present invention relates to a method for preparing a compound of general formula (I), comprising the steps shown in Scheme 4.

[0117] For example, Examples 41-44, 50, 56, 72, 74, 77, and 100-102 in Table 1 (see Table 1 - Compounds of Formula (I) of the present invention) were obtained according to the method of the present invention described in Scheme 4.

[0118] [ka]

[0119] Scheme 4: Exemplary preparation of compounds of formula (I) (Examples 41-44, 50, 56, 72, 74, 77, and 100-102) Each of the compounds of formulas (9) and (12) used as starting materials and arylboronic acid Ar-B(OH)2 (14) is commercially available or can be synthesized according to methods known to those skilled in the art.

[0120] Use of the novel compound of formula (I) as a medicament Furthermore, the compounds of formula (I) have been found to be suitable for use as medicaments. Specifically, it has been found that the compounds of formula (I) can be used in the remission, prevention and / or treatment of diseases modulated by CPT-1 inhibitors.

[0121] CPT-1 inhibitors have been previously described as having an effect on neuronal cells. WO2009 / 156479A1 describes a method for investigating the effect of at least one CPT-I inhibitor in vitro, said method comprising culturing cells under conditions essential for cell growth, adding at least one CPT-I inhibitor to the cells, and monitoring the growth rate and signal transduction of the cells. The cells are preferably neurons / neurons or dendrocytes, more preferably neurons of human origin.

[0122] Furthermore, WO2009 / 156479A1 describes a method for investigating the effect of at least one CPT-I inhibitor on neurological conditions in vivo, said method comprising administering at least one fatty acid oxidation inhibitor to the nervous system cells of an animal model of an affective disorder, and monitoring the neurological condition and animal function. Suitable animal models are known in the state of the art. Methods for determining neurological conditions are also known in the art.

[0123] The method of the present invention for investigating the effect of a CPT-I inhibitor on a neurological condition is particularly applicable when the concentration and / or amount of the inhibitor in a pharmaceutical composition is to be tested.

[0124] In a further embodiment, the present invention relates to a pharmaceutical composition for treating and / or preventing damage caused by depilation of nerve tissue, comprising at least one CPT-I inhibitor and at least one excipient and / or adjuvant.

[0125] As described in the examples below, the compounds of formula (I) of the present invention were surprisingly and unexpectedly effective in a fatty acid uptake assay for activity determination using HEK293 cells in vitro (see Example 4.1) and in vivo in efficacy studies in a SOD1 mouse model of ALS (Example 4.2).

[0126] Accordingly, the compounds of formula (I) of the present invention and their pharmaceutically or veterinarily acceptable salts, hydrates, or solvates exhibit valuable pharmacological properties and are therefore useful as pharmaceuticals or medicinal products. The pharmaceuticals or medicinal products can be further formulated, for example, in the form of tablets for oral administration, together with additional pharmaceutically or veterinarily acceptable carriers and / or excipients. The tablets may contain suitable binders, lubricants, disintegrants, colorants, flavorings, flow inducers, and / or melting agents that are generally known in the art.

[0127] Accordingly, in one embodiment, the present invention relates to compounds of general formula (I) as defined herein, or stereoisomers thereof, pharmaceutically or veterinarily acceptable salts, hydrates, or solvates for use as pharmaceuticals.

[0128] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined herein or a stereoisomer thereof, a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof, and a therapeutically inactive carrier.

[0129] The compounds of formula (I) of the present invention exhibit significant and selective inhibitory effects on the expression and / or activity of the enzyme carnitine palmitoyltransferase-1 (CPT-1). This can be determined, for example, in an in vitro fatty acid uptake assay for activity determination and efficacy studies (see Example 4.1). Those skilled in the art, however, may use different assays to determine direct or indirect inhibition of CPT-1.

[0130] Accordingly, in another embodiment, the present invention relates to a compound of formula (I) as defined herein for use in the remission, prevention or treatment of diseases associated with inhibiting the expression and / or activity of the enzyme carnitine palmitoyltransferase-1 (CPT-1).

[0131] It is already known that numerous neurological and psychiatric disorders are caused by delipidation of nerve tissue and, in particular, myelin sheets, and that CPT-1 is significantly upmodulated in various tissues from patients suffering from numerous mental and neurological disorders. Disorders that can be remitted, prevented and / or treated with CPT-1 inhibitors are, in particular, mental and / or neurological disorders.

[0132] As described above, the compounds of formula (I) of the present invention, or their pharmaceutically or veterinarily acceptable salts, hydrates, or solvates, have been found to be useful in the remission, prevention, and / or treatment of diseases caused by or associated with the degreasing of nerve tissue. Accordingly, in another embodiment, the present invention relates to the compounds of formula (I) as defined herein for use in the remission, prevention, and / or treatment of diseases caused by or associated with the degreasing of nerve tissue.

[0133] In one embodiment, a disorder is an organic mental disorder, including symptomatic disorders. This term encompasses a range of mental disorders grouped together on the basis that they share a common, demonstrable etiology leading to cerebral disease, brain injury, or other injury resulting in cerebral dysfunction. Dysfunction may be primary in cases of diseases, injuries, and disorders that directly and selectively affect the brain; or secondary in cases of systemic diseases and disorders that attack the brain as only one of several organs or systems of the body involved.

[0134] In a preferred embodiment, the organic mental disorder can be selected from dementias, including, for example, dementia in Alzheimer's disease and vascular dementia. In a particularly preferred embodiment, the disorder is a loss of recent memory and a loss of remote memory.

[0135] In another embodiment, the compounds of formula (I) of the present invention can be used to treat mental and / or behavioral disorders caused by the use of psychoactive substances. More specifically, disorders resulting from the use of psychoactive substances such as alcohol, opioids, cannabinoids, cocaine, caffeine, hallucinogens, tobacco, volatile solvents, and multiple drug use.

[0136] In further embodiments, compounds of formula (I) of the present invention are useful for treating and / or preventing mood disorders, including manic episodes, bipolar affective disorder, depression, depressive episodes, and recurrent depressive disorder, as well as persistent mood disorders such as cyclothymic disorder and dysthymia.

[0137] In further embodiments, the disorders are neurotic, stress-related, and somatoform disorders, and include phobic anxiety disorders, such as panic disorder, obsessive-compulsive disorder, reactions to severe stress and adjustment disorders, dissociative conversion disorder, and somatoform disorders.

[0138] In further embodiments, compounds of formula (I) of the present invention are useful in treating and / or preventing disorders that are behavioral syndromes associated with physiological disorders and physical factors, including non-organic sleep disorders, sexual dysfunction, and eating disorders, such as disorders selected from anorexia nervosa and bulimia nervosa.

[0139] In further embodiments, compounds of formula (I) of the present invention are useful for treating personality and behavioral disorders in adults, such as paranoid personality disorder, obsessive-compulsive personality disorder, antisocial personality disorder, emotionally unstable personality disorder, histrionic personality disorder, obsessive-compulsive personality disorder, anxious personality disorder, dependent personality disorder, and habitual and impulsive disorders, such as pathological gambling, pathological arson, pathological theft, and trichotillomania.

[0140] In further embodiments, the compounds of formula (I) of the present invention are useful for intellectual disability, including mild, moderate, severe, and profound intellectual disability.

[0141] In further embodiments, the compounds of formula (I) of the present invention are useful for disorders of the nervous system, including multiple sclerosis and autoimmune neuropathy.

[0142] Further disorders that can be treated according to the present invention include, for example, Guillain-Barré syndrome, encephalomyelitis, senile plaques, brain tumors, i.e., glioblastoma polymorphoni, Huntington's disease, Lou Gehrig's disease, pain, chronic pain, myasthenia gravis, Sjögren's syndrome, Tourette's syndrome, peripheral neuropathy, occipital neuralgia, motor neuron disease, meningitis, chronic Lyme disease, encephalitis, Schilder's disease or diffuse myelin-destroying sclerosis, chronic inflammatory demyelinating polyneuropathy, cerebral atrophy, acute disseminated encephalomyelitis, attention deficit hyperactivity disorder, cataplexy, fibromyalgia, generalized anxiety disorder, hypersexuality, impulse control disorder, narcolepsy, obsessive-compulsive disorder, panic disorder, post-traumatic stress syndrome, premenstrual dysphoric disorder, social phobia, chronic pain, intermittent explosive disorder, substance abuse and addiction (including alcoholism).

[0143] In a further embodiment of the present invention, a method is provided for preventing and / or treating damage caused by delipidation of nerve tissue by administering a compound of formula (I) as described herein in a pharmacologically effective amount to a patient in need thereof.

[0144] As used herein, the term “pharmaceutically effective dose” of a CPT-I inhibitor means the amount effective in achieving the desired physiological outcome in either cells treated in vitro or subjects treated in vivo. Specifically, a pharmaceutically effective dose is the amount sufficient to inhibit one or more clinically defined pathological effects associated with damage caused by delipidation of nerve tissue over a given period of time. The pharmaceutically effective dose can vary depending on the specific CPT-I inhibitor selected, and moreover, on various factors and conditions related to the subject to be treated, as well as the severity of the disease. For example, if the inhibitor is to be administered in vivo, factors such as the patient's age, weight, sex, and overall health, as well as dose-response curves and toxicity data obtained in preclinical animal studies, are among the factors to be considered. If the CPT-I inhibitor is to be in contact with cells in vitro, various preclinical in vitro studies should also be designed to determine parameters such as uptake, half-life, dose, and toxicity. Determining the pharmaceutically effective dose for a given drug (inhibitor) is well within the capabilities of those skilled in the art. Preferably, the inhibitor is present at a concentration of 0.01% to 50%, more preferably 1% to 30%, per mass of the pharmaceutical composition.

[0145] Administration to an individual or patient may be a single dose or a repeated dose. A repeated dose, particularly once or twice daily, is preferred until symptoms disappear or are significantly reduced. Patients to be treated by the method of the present invention are preferably humans. However, animals, preferably mammals such as horses, cattle, dogs, or cats, and more preferably primates, can also be treated by the present invention.

[0146] The administration of compounds of formula (I) is not limited to a specific route. Preferred routes of administration to an individual include, but are not limited to, oral, systemic, parenteral, and especially cutaneous, intradermal, intradermal, transdermal, subcutaneous, topical, or transdermal application. In this context, systemic application is an application that brings about the distribution of the CPT-I inhibitor throughout the body.

[0147] In preferred embodiments, the present invention relates to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), inflammatory diseases, acute traumatic events, such as surgery or injury, AIDS-related wasting due to reverse transcriptase inhibitor toxicity, mitochondrial myopathy, aging and aging, neuronal ischemia, polyglutamine diseases, dystonia, Leber hereditary optic neuropathy (LHON), schizophrenia, stroke, muscle degenerative disorders, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy associated with red ragged fibers (MERRF), neuropathy, ataxia, and retinitis pigmentosa (NARP), progressive extraocular palsy (PEO), Leigh disease, Carr's disease, and Carr's disease. The present invention relates to compounds of formula (I) as defined herein for use in the remission, prevention, or treatment of diseases associated with numbness-Thayer syndrome, muscular dystrophy, myotonic dystrophy, chronic fatigue syndrome, Friedreich's ataxia; developmental delays in cognitive, motor, language, executive function, or social skills; epilepsy, peripheral neuropathy, optic neuropathy, autonomic neuropathy, neurogenic intestinal dysfunction, sensorineural hearing loss, neurogenic bladder dysfunction, migraine; renal tubular acidosis, hepatic failure, lactic acidemia, periodontitis, Duchenne muscular dystrophy, Becker muscular dystrophy, McArdle disease, abnormalities in testosterone synthesis, and / or hypoparathyroidism.

[0148] The present invention further comprises the step of administering, preferably to a human, a therapeutically effective dose of the compound of formula (I) as described herein, for mental or neurological disorders, preferably Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), inflammatory diseases, acute traumatic events, such as surgery or injury, AIDS-related wasting due to the toxicity of reverse transcriptase inhibitors, mitochondrial myopathy, aging and senescence, neuronal ischemia, polyglutamine diseases, dystonia, Leber's hereditary optic neuropathy (LHON), schizophrenia, stroke, myodegenerative disorders, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy associated with red rag fibers (MERR). F) Methods for treating patients suffering from neuropathy, ataxia, and retinitis pigmentosa (NARP), progressive extraocular palsy (PEO), Leigh disease, Kearns-Sayre syndrome, muscular dystrophy, myotonic dystrophy, chronic fatigue syndrome, Friedreich's ataxia; developmental delays in cognitive, motor, language, executive function or social skills; epilepsy, peripheral neuropathy, optic neuropathy, autonomic neuropathy, neurogenic bowel dysfunction, sensorineural hearing loss, neurogenic bladder dysfunction, migraine; renal tubular acidosis, hepatic failure, lactic acidemia, periodontitis, Duchenne muscular dystrophy, Becker muscular dystrophy, McArdle disease, abnormalities in testosterone synthesis and / or hypoparathyroidism.

[0149] In a particularly preferred embodiment, the disease caused by or associated with the delipidation of nerve tissue is amyotrophic lateral sclerosis (ALS). [Examples]

[0150] Abbreviations and acronyms The following abbreviations and acronyms are used in the chemical descriptions and in the following examples: Boc tert-butoxycarbonyl CDCl3 (deuterated chloroform) DCM Dichloromethane DIPEA Diisopropylethylamine Example h time 1 1H-NMR Compound of formula (I) of the present invention 1 H-NMR data Isolera Flash Column Chlorography (Make:Isolera) LCMS data of the compound of formula (I) of the present invention Pd2(dba)3 Tris(dibenzylideneacetone) Dipalladium(0) PPTS Pyridinium p-toluenesulfonate RT room temperature Structure of the compound of formula (I) of the present invention THF (Tetrahydrofuran) TLC (Thin-Layer Chromatography) Xphos 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl

[0151] 1. Experimental Procedure 1.1 LCMS method Ultra-high-performance liquid chromatography (UHPLC) and mass spectrometry equipment including the SQ 6135 (from Agilent) and SQ 2020 (from Shimadzu) are available. Electrospray and atmospheric pressure chemical ionization sources (multimode sources using ESI / APCI). Column: Column Zorbax Eclipse Plus C18 (50 × 2.1 mm) 1.8 mμ (for the formic acid method), or Acquity BEH C18 (2.1 × 50 mm), 1.7 mμ (for the ammonium bicarbonate method) Flow rate: 0.800 mL / min or 0.600 mL / min Eluent: A: H2O with 0.05% formic acid and B: MeCN, or A: H2O with 10 mM ammonium bicarbonate and B: MeCN Gradient: Initial hold for 0.5 minutes and final hold at 95% B for 1.0 minute, followed by elution from 5% to 100% B over 2.5 minutes. Total run time: 4 minutes. The gradients described can be modified as a function of the physicochemical properties of the compound being analyzed, and are not constrained in any way.

[0152] HPLC purity was obtained using Shimadzu equipment. Column: X-Select C18 (4.6 × 150 mm, 5 μm) Alternatively, use an X-Bridge column C8 (4.6 × 150 mm, 5 μm). Flow rate: 0.800 mL / min or 0.600 mL / min Eluent: A: H2O with 0.05% formic acid and B: MeCN, or A: H2O with 0.05% ammonium bicarbonate and B: MeCN Gradient: Elute from 5% to 100% B over 8 minutes, then hold at 5% B for 2 minutes. Total run time: 10 minutes. The gradients described can be modified as a function of the physicochemical properties of the compound being analyzed, and are not constrained in any way.

[0153] 1.2 NMR method proton( 1 H) Nuclear magnetic resonance (NMR) spectra are measured using an Avance Neo Nanobay (400 MHz) spectrometer with residual protonated solvents (CDCl3 δ 7.28; CD3OD δ 3.31 and DMSO δ 2.50) as standards. The NMR data of the synthesized examples are consistent with their corresponding structural assignments.

[0154] 2. Method for preparing the compound of formula (I) An illustrative synthesis of the compound of formula (I) is described below in Schemes 1 and 2. The compound of formula (I) of the present invention can be obtained according to the methods described in Schemes 1 and 2.

[0155] The starting materials are either commercially available or prepared in the same manner as described in the literature procedures or specific examples.

[0156] It should be obvious to those skilled in the art that the order of the synthesis steps depends on the availability of starting materials and the compatibility of functional groups, and can vary depending on the compound.

[0157] 3. Examples of compounds of formula (I) of the present invention The following examples are merely specific embodiments of the present invention and are intended to be illustrative rather than limiting.

[0158] 3.1 Preparation of intermediates for the preparation of the compound of formula (I) 3.1.1 Preparation of tert-butyl 7-(4-bromothiazol-2-yl)-1,4-diazepan-1-carboxylate (9) Tert-butyl 7-(4-bromothiazol-2-yl)-1,4-diazepane-1-carboxylate (9) was obtained according to the method described in Scheme 1.

[0159] [ka]

[0160] Scheme 1: Exemplary preparation of the compound of formula (9) Step (a): Preparation of (E)-N-(3-(1,3-dioxoisoindolin-2-yl)propyridene)-2-methylpropane-2-sulfinamide (2) 3-(1,3-dioxoisoindolin-2-yl)propanal (1) (14 g, 68.9 mmol) was stirred in anhydrous DCM (200 mL), to which 2-methylpropan-2-sulfinamide (9.1 g, 75.8 mmol) was added at room temperature. PPTS (0.86 g, 3.4 mmol) and anhydrous magnesium sulfate (41 g, 344 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC. The mixture was filtered through Celite. The filtrate was concentrated to obtain the crude product, which was purified by silica column chromatography using Isolera by elution with 30% ethyl acetate in petroleum ether to obtain (E)-N-(3-(1,3-dioxoisoindolin-2-yl)propyridene)-2-methylpropan-2-sulfinamide (2) (15 g, yield: 71%). 1H-NMR (400 MHz, CDCl3): δ 8.14 (t, J = 3.60 Hz, 1H), 7.89-7.87 (m, 2H), 7.77-7.74 (m, 2H), 4.11-4.02 (m, 2H), 3.01-2.96 (m, 2H), 1.19 (s, 9H), LCMS: 307 (M+1).

[0161] Step (b): Preparation of 2-(3-amino-3-(4-bromothiazole-2-yl)propyl)isoindoline-1,3-dione (3) To a stirred solution of 2,4-dibromothiazole (23.7 g, 97.97 mmol) in anhydrous toluene (150 mL), n-BuLi (1.6 M in THF, 61.2 mL, 97.97 mmol) was added dropwise at -100°C. The mixture was stirred with a mechanical stirrer at the same temperature for 3 hours.

[0162] In a separate setting, a solution of (E)-N-(3-(1,3-dioxoisoindorin-2-yl)propyridene)-2-methylpropane-2-sulfinamide (2) (15 g, 48.98 mmol) in anhydrous toluene (100 mL) was to be mixed dropwise with boron trifluoride diethyl etherate (13.8 mL) at -78 °C and stirred for 3 hours. After 3 hours, this mixture was added dropwise to the above mixture containing 2,4-dibromothiazole and n-butyllithium via cannula at -100 °C. The resulting mixture was slowly warmed to room temperature and stirred for 4 hours. The reaction was monitored by TLC. The reactants were cooled to 0 °C and then quenched by the slow addition of ice-cooled water (100 mL). The mixture was extracted with ethyl acetate (2 × 500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica column chromatography using Isolera, by eluting with 40% ethyl acetate in petroleum ether, to obtain 8 g of (67% pure by LCMS) N-(1-(4-bromothiazole-2-yl)-3-(1,3-dioxoisoindorin-2-yl)propyl)-2-methylpropane-2-sulfinamide (3).1 H-NMR (400 MHz, CDCl3): δ 7.77-7.75 (m, 2H), 7.70-7.68 (m, 2H), 6.85 (s, 1H), 5.18 (d, J = 9.60 Hz, 1H), 4.88-4.84 (m, 1H), 4.07-3.99 (m, 1H), 3.96-3.90 (m, 1H), 2.98-2.90 (m, 1H), 2.52-2.45 (m, 1H), 1.41 (s, 9H). LCMS: 470 & 472 (M+1).

[0163] Step (c): Preparation of 2-(3-amino-3-(4-bromothiazole-2-yl)propyl)isoindoline-1,3-dione (4) To a solution of N-(1-(4-bromothiazole-2-yl)-3-(1,3-dioxoisoindoline-2-yl)propyl)-2-methylpropane-2-sulfinamide (3) (8 g) in MeOH (50 mL), concentrated HCl (8 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC. By concentrating the mixture under reduced pressure, 7 g of 2-(3-amino-3-(4-bromothiazole-2-yl)propyl)isoindoline-1,3-dione (4) was obtained.

[0164] Step (d): Preparation of tert-butyl(1-(4-bromothiazol-2-yl)-3-(1,3-dioxoisoindorin-2-yl)propyl)carbamate (5) To a stirred solution of 2-(3-amino-3-(4-bromothiazole-2-yl)propyl)isoindoline-1,3-dione (4) (5 g, 13.66 mmol) in dioxane / water (55 mL, 10:1), sodium bicarbonate (7.1 g, 68.3 mmol) was added at room temperature. Di-tert-butyl dicarbonate (5.9 mL, 27.3 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica column chromatography using Isolera, by elution with 15% to 20% ethyl acetate in petroleum ether, to obtain tert-butyl(1-(4-bromothiazole-2-yl)-3-(1,3-dioxoisoindorin-2-yl)propyl)carbamate (5) (2.4 g, yield: 38%). 1 H-NMR (400 MHz, CDCl3): δ 7.84-7.82 (m, 2H), 7.75-7.71 (m, 2H), 7.04 (s, 1H), 5.60-5.58 (m, 1H), 5.15-5.13 (m, 1H), 3.90-3.85 (m, 2H), 2.46-2.45 (m, 2H), 1.48 (s, 9H), LCMS: 466 & 468 (M+1).

[0165] Step (e): Preparation of tert-butyl(3-amino-1-(4-bromothiazole-2-yl)propyl)carbamate (6) To a stirred solution of tert-butyl(1-(4-bromothiazole-2-yl)-3-(1,3-dioxoisoindoline-2-yl)propyl)carbamate (5) (2.4 g, 5.15 mmol) in ethanol (20 mL), hydrazine hydrate (0.5 mL, 10.3 mmol) was added. The mixture was heated at 50 °C for 4 hours. The reaction was monitored by TLC, the solid was filtered through Celite, and the filtrate was concentrated. The crude product was purified by silica column chromatography using Isolera by elution with 10% MeOH in DCM to obtain tert-butyl(3-amino-1-(4-bromothiazole-2-yl)propyl)carbamate (6) (1.5 g, 81% pure). LCMS: 336 & 338 (M+1).

[0166] Step (f): Preparation of tert-butyl(1-(4-bromothiazol-2-yl)-3-(2-chloroacetamido)propyl)carbamate (7) To a stirred solution of tert-butyl(3-amino-1-(4-bromothiazole-2-yl)propyl)carbamate (6) (1.5 g, 4.46 mmol) in anhydrous DCM (20 mL), triethylamine (0.9 mL, 6.69 mmol) was added at 0°C. Chloroacetyl chloride (0.53 mL, 6.69 mmol) was added dropwise to the mixture and stirred for 4 hours. The reaction was monitored by TLC and the mixture was diluted with water (50 mL) and DCM (100 mL). The organic layer was separated and washed with 10% aqueous sodium bicarbonate (50 mL x 2) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain tert-butyl(1-(4-bromothiazole-2-yl)-3-(2-chloroacetamido)propyl)carbamate (7) (1.7 g crude). LCMS: 412 & 414 (M+1).

[0167] Step (g): Preparation of tert-butyl 7-(4-bromothiazol-2-yl)-3-oxo-1,4-diazepan-1-carboxylate (8) To an ice-cooled solution of tert-butyl(1-(4-bromothiazole-2-yl)-3-(2-chloroacetamido)propyl)carbamate (7) (1.7 g, 4.12 mmol) in anhydrous THF (200 mL), sodium hydride (60% dispersion in mineral oil, 0.95 g, 23.8 mmol) was added in three portions, and the mixture was stirred at room temperature for 16 hours. The reaction product was quenched with ice-cooled water (200 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica column chromatography using Isolera by elution with 65% ethyl acetate in petroleum ether to obtain tert-butyl7-(4-bromothiazole-2-yl)-3-oxo-1,4-diazepane-1-carboxylate (8) (0.2 g, yield: 13%). LCMS:322 (M+1, t-butyl cleavage).

[0168] Step (h): Preparation of tert-butyl 7-(4-bromothiazol-2-yl)-1,4-diazepan-1-carboxylate (9) A 1 M solution of BH3.THF (1.59 mL, 1.59 mmol) was added to an ice-cooled solution of tert-butyl 7-(4-bromothiazol-2-yl)-3-oxo-1,4-diazepan-1-carboxylate (8) (0.2 g, 0.531 mmol) in anhydrous THF (5 mL). The mixture was stirred at room temperature for 2 hours. The reaction product was quenched with water (5 mL) and methanol (5 mL). The mixture was heated at 70 °C for 36 hours to cleave the borane complex. The mixture was diluted with ice-cooled water (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain tert-butyl 7-(4-bromothiazol-2-yl)-1,4-diazepan-1-carboxylate (9) (0.18 g, yield: 93%). LCMS:362 & 364(M+1).

[0169] 3.2 Preparation of the compound of formula (I) Example 1 was obtained according to the method described in Scheme 2.

[0170] [ka]

[0171] Scheme 2: Exemplary preparation of the compound of formula (I) (Example 1) Step (i): Preparation of tert-butyl 4-acetyl-7-(4-bromothiazol-2-yl)-1,4-diazepan-1-carboxylate (10) Triethylamine (0.2 mL, 1.49 mmol) was added to a stirred solution of tert-butyl 7-(4-bromothiazol-2-yl)-1,4-diazepan-1-carboxylate (9) (0.18 g, 0.497 mmol) in DCM (5 mL). Acetyl chloride (0.047 g, 0.596 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC, then quenched with water (10 mL), and extracted with DCM (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by neutral alumina column chromatography using Isolera, by elution with 40% ethyl acetate in petroleum ether, to obtain tert-butyl 4-acetyl-7-(4-bromothiazol-2-yl)-1,4-diazepane-1-carboxylate (10) (0.11 g, 63% pure). LCMS: 404 & 406 (M+1).

[0172] Step (j): Preparation of 1-(5-(4-bromothiazol-2-yl)-1,4-diazepan-1-yl)ethane-1-one (11) To a solution of tert-butyl 4-acetyl-7-(4-bromothiazol-2-yl)-1,4-diazepan-1-carboxylate (10) (0.11 g, 0.272 mmol) in anhydrous DCM (5 mL), 4N HCl in dioxane (0.14 mL, 0.54 mmol) was added at 0°C. The mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure to obtain 1-(5-(4-bromothiazol-2-yl)-1,4-diazepan-1-yl)ethane-1-one (11) (0.09 g, 75% pure). LCMS: 304 & 306 (M+1).

[0173] Step (k): Preparation of 1-(4-acetyl-7-(4-bromothiazol-2-yl)-1,4-diazepan-1-yl)-2-phenoxyethane-1-one (12) To an ice-collapsed solution of 1-(5-(4-bromothiazol-2-yl)-1,4-diazepan-1-yl)ethane-1-one (11) (0.09 g, 0.264 mmol) in DCM (5 mL), DIPEA (0.13 mL, 0.738 mmol) was added. Phenoxyacetyl chloride (46 mg, 0.27 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction was monitored by TLC. The mixture was diluted with DCM (15 mL), washed with water (2 × 10 mL) and brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica column chromatography using Isolera by elution with 7% MeOH in DCM to obtain 1-(4-acetyl-7-(4-bromothiazole-2-yl)-1,4-diazepan-1-yl)-2-phenoxyethane-1-one (12) (0.09 g, yield: 75%). LCMS: 438 & 440 (M+1).

[0174] Step (l): Preparation of 1-(4-acetyl-7-(4-(pyridine-4-yl)thiazol-2-yl)-1,4-diazepan-1-yl)-2-phenoxyethane-1-one (Example 1) Potassium phosphate (87 mg, 0.410 mmol) was added to a solution of 1-(4-acetyl-7-(4-bromothiazol-2-yl)-1,4-diazepan-1-yl)-2-phenoxyethane-1-one (12) (90 mg, 0.205 mmol) in n-butanol (10 mL). The mixture was degassed with nitrogen for 10 minutes. Pyridine-4-ylboronic acid (38 mg, 0.308 mmol), Xphos (10 mg, 0.0205 mmol), and Pd2(dba)3 (10 mg, 0.01 mmol) were added, and the mixture was degassed with nitrogen for another 10 minutes, then heated at 100°C for 3 hours. The reaction was monitored by TLC, the mixture was filtered through Celite, and the filtrate was concentrated. The crude product was purified by silica column chromatography using Isolera, eluting it with 6% MeOH in DCM, to obtain 1-(4-acetyl-7-(4-(pyridine-4-yl)thiazole-2-yl)-1,4-diazepan-1-yl)-2-phenoxyethane-1-one (Example 1) (0.08 g, yield: 89%). 1 H-NMR (400 MHz, MeOH-d4): δ 8.64 (d, J = 4.40 Hz, 2H), 8.32 (br s, 1H), 7.87 (d, J = 4.80 Hz, 2H), 7.28-7.26 (m, 2H), 6.98-6.94 (m, 3H), 6.10-5.68 (m, 1H), 5.02-4.94 (m, 2H), 4.40-4.05 (m, 3H), 3.80-3.60 (m, 2H), 3.40-3.20 (m, 1H), 2.85-2.70 (m, 2H), 2.35-2.10 (m, 3H). LCMS: 437 (M+1).

[0175] Examples 2, 4, 5, 7, 10, 12, 17, 23, 26, 27, 40, 98 and 99 (see Table 1 - Compounds of Formula (I) of the present invention) were synthesized according to the general method of the present invention shown in Scheme 3 and as described below.

[0176] [ka]

[0177] Scheme 3: Exemplary preparation of the compound of formula (I) (Examples 2, 4, 5, 7, 10, 12, 17, 23, 26, 27, 40, 98, and 99) To a stirred solution of bromothiazole compound 12 (1.0 equivalent) obtained according to step (k) in n-butanol, tribasic potassium phosphate (3.0 equivalents), each arylboronic acid (1.2 equivalents), and Xphos (10 mol%) were added under a nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 10 minutes. Pd2(dba)3 (10 mol%) was added to this solution and heated at 100°C for 3 to 5 hours. The reaction progress was monitored by TLC. After the completion of the reaction, the reaction mixture was diluted with water (20 ml) and extracted with CH2Cl2 (50 ml x 3). The combined organic extract was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh) using MeOH / CH2Cl2 (0-3%) as the eluent to obtain the compounds of Examples 2, 4, 5, 7, 10, 12, 17, 23, 26, 27, 40, 98, and 99. In some cases, both enantiomers were separated on a chiral SFC using a LUX-C4 column, with isopropyl alcohol and liquid carbon dioxide as the mobile phases.

[0178] Examples 41-44, 50, 56, 72, 74, 77, and 100-102 (see Table 1 - Compounds of Formula (I) of the present invention) were synthesized according to the general method of the present invention shown in Scheme 4 and as described below.

[0179] [ka]

[0180] Scheme 4: Exemplary preparation of the compound of formula (I) (Examples 41-44, 50, 56, 72, 74, 77, and 100-102) Step (a): Preparation of 4-bromothiazole-2-carbaldehyde (2) To a solution of 2,4-dibromothiazole (1) (20 g, 82 mmol) in THF (200 ml), isopropyl magnesium chloride (49.4 ml, 99 mmol) was added dropwise at -78°C, and the reaction mixture was stirred at the same temperature for 2 hours. To this reaction mixture, DMF (37.6 g, 515 mmol) was added dropwise at -78°C, and the reaction mixture was then slowly warmed to room temperature and stirred for 8 hours. The reaction mixture was quenched with an aqueous NH4Cl solution and extracted in CH2Cl2 (500 mL x 3). The combined organic extracts were washed with water (100 mL) and brine solution (100 mL), dried on anhydrous Na2SO4, filtered, and evaporated under vacuum to obtain the crude product. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh) using ethyl acetate / hexane (0-20%) as the eluent to obtain 4-bromothiazole-2-carbaldehyde(2) (9.6 g, 50.0 mmol, 60% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3): 7.69 (d, J = 1.2 Hz, 1H), 9.96 (d, J = 1.2 Hz, 1H).

[0181] Step (b): Preparation of 1-(4-bromothiazol-2-yl)propa-2-en-1-ol (4) Vinyl magnesium bromide (21.87 ml, 1.0 M in THF, 21.87 mmol) was added dropwise at -10°C to a stirred solution of 4-bromothiazole-2-carbaldehyde (2) (3.5 g, 18.23 mmol) in THF (30 ml). The reaction mixture was slowly brought to room temperature and stirred for 5 hours. The progress of the reaction was monitored by TLC. After the reaction was completed as indicated by TLC, the reaction mixture was quenched with an aqueous solution of NH4Cl. The reaction mixture was diluted with RINKAN, and the layers were separated. The aqueous layer was extracted with RINKAN (50 mL x 2). The combined organic extracts were washed with water (50 mL) and brine solution (50 mL), dried on anhydrous Na2SO4, filtered, and evaporated under vacuum to obtain the crude product. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh) using ethyl acetate / hexane (0-20%) as the eluent to obtain 1-(4-bromothiazole-2-yl)propa-2-en-1-ol (4) (2 g, 9.09 mmol, 50% yield) as a yellow, rubbery liquid. 1 H-NMR (400 MHz, CDCl3): δ 7.24 (s, 1H), 6.15-6.13 (m, 1H), 5.51-5.49 (m, 2H), 4.94 (d, J = 6.40 Hz, 1H), 3.22 (s, 1H).

[0182] Step (c): Preparation of 1-(4-bromothiazol-2-yl)propa-2-en-1-one (5) To a stirred solution of 1-(4-bromothiazole-2-yl)propa-2-en-1-ol (4) (2 g, 9.09 mmol) in CH2Cl2 (20 ml), Des-Martin periodinane (4.63 g, 10.90 mmol) was added at 0°C under an inert atmosphere. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was quenched with saturated sodium thiosulfate solution. The reaction mixture was diluted with Â, and the layers were separated. The aqueous layer was extracted again in  (50 mL x 2). The combined organic extracts were washed with water (50 mL) and brine solution (50 mL), dried on anhydrous Na2SO4, and evaporated under vacuum to obtain the crude product. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh) using ethyl acetate / hexane (0-10%) as the eluent to obtain 1-(4-bromothiazole-2-yl)propa-2-en-1-one (5) (1.2 g, 5.50 mmol, 60% yield) as an off-white solid. 1 H-NMR (400 MHz, CDCl3): δ 7.63 (s, 1H), 7.52 (dd, J = 10.40 Hz, J = 17.60 Hz, 1H), 6.76 (dd, J = 17.60 Hz, J = 1.60 Hz, 1H), 6.07 (dd, J = 10.40 Hz, J = 1.60 Hz, 1H).

[0183] Step (d): Preparation of tert-butyl(2-(benzyl(3-(4-bromothiazol-2-yl)-3-oxopropyl)amino)ethyl)carbamate (7) To a stirred solution of 1-(4-bromothiazole-2-yl)propa-2-en-1-one (5) (3.0 g, 13.76 mmol) in 1,2-DCE (3 mL), tert-butyl(2-(benzylamino)ethyl)carbamate (3.44 g, 13.76 mmol) was added and the mixture was stirred at 50°C for 2 hours. By evaporating the solvent, tert-butyl(2-(benzyl(3-(4-bromothiazole-2-yl)-3-oxopropyl)amino)ethyl)carbamate (7) was obtained in quantitative yield. 1 H-NMR (400 MHz, CDCl3): δ 7.57 (s, 1H), 7.40-7.20 (m, 5H), 4.91 (s, 1H), 3.65 (s, 2H), 3.30 (t, J = 6.8 Hz, 2H), 3.20 (s, 2H), 3.02 (t, J = 6.8, 2H), 2.62-2.59 (m, 2H), 1.45 (s, 9H).

[0184] Step (e): Preparation of 2-(1-benzyl-1,4-diazepan-5-yl)-4-bromothiazole (8) To a stirred solution of tert-butyl(2-(benzyl(3-(4-bromothiazole-2-yl)-3-oxopropyl)amino)ethyl)carbamate (7) (8g, 17.08 mmol) in CH2Cl2 (80 ml), 2,2,2-trifluoroacetic acid (19.60 ml, 256 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure to obtain a residue. EtOH (80 ml) was added to this residue, and the mixture was stirred for 2 hours. NaCNBH3 (4.29 g, 68.3 mmol) was added in small amounts to this stirred solution, and the resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated, and the residue was dissolved in CH2Cl2 (100 mL). 2M NaOH was added to this solution. aq(30 mL) was added and stirred for 20 minutes. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (50 mL x 2). The combined organic extract was then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh) using CH2Cl2 / MeOH (0-5%) as the eluent to obtain 2-(1-benzyl-1,4-diazepan-5-yl)-4-bromothiazole (8) (3.1 g, 8.80 mmol, 51% yield) as an off-white solid. LCMS (ESI, +ve) m / z 352.20 [M+H] + .

[0185] Step (f): Synthesis of compound 10 in scheme 4 To a stirred solution of tert-butyl(2-(benzyl(3-(4-bromothiazole-2-yl)-3-oxopropyl)amino)ethyl)carbamate (8) (1.0 equivalent) in CH2Cl2, triethylamine (3.0 equivalents) was added, and the reaction mixture was cooled to 0°C. Acid chloride 9 (1.2 equivalents) was added dropwise to this solution. The resulting reaction mixture was warmed to room temperature and stirred for 30 minutes. The completion of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was diluted with CH2Cl2 (50 mL x 2), washed with water (20 mL) and brine (20 mL), then dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh) using CH2Cl2 / MeOH (0-5%) as the eluent to obtain N-benzyl-homopiperazine derivatives (10).

[0186] Step (g): Synthesis of compound 11 in scheme 4 To a stirred solution of N-benzyl-homopiperazine derivative (10) (1.0 equivalent) in CH2Cl2, 1-chloroethyl carbonochloride (3.0 equivalents) was added at room temperature and stirred for 16 hours. After this time, volatile substances were removed under a rotary evaporator, and MeOH was added to the crude material and refluxed for 3 hours. The solvent was evaporated, and the residue was redissolved in CH2Cl2 and evaporated. 5-10 mL of CH2Cl2 was added again and sonicated for 5 minutes. At this point, a white precipitate was formed, which was filtered and washed with CH2Cl2 to obtain the crude product of homopiperazine hydrochloride derivative 11 as a solid. This was used directly in the next step without further purification.

[0187] Step (h): Synthesis of compound 13 in scheme 4 Triethylamine (5.0 equivalents) was added to a stirred solution of homopiperazine hydrochloride derivative 11 (1.0 equivalent) in CH2Cl2, and the reaction mixture was cooled to 0°C. Acetyl chloride 12 (1.2 equivalents) was added to this reaction mixture, and the resulting reaction mixture was warmed to room temperature and stirred for 1 hour. After the reaction was complete, the reaction mixture was diluted with water (10 ml) and extracted with CH2Cl2 (20 ml x 3). The combined organic layer was dried on anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. Compound 13 was obtained by purification of the crude product by flash column chromatography (silica gel, 100-200 mesh) using MeOH / CH2Cl2 (0-3%) as the eluent.

[0188] Step (i): Synthesis of the compounds of the present invention, i.e., Examples 41-44, 50, 56, 72, 74, 77, and 100-102. To a stirred solution of compound 13 (1.0 equivalent) in n-butanol, tribasic potassium phosphate (3.0 equivalents), the respective arylboronic acids (14) (1.2 equivalents), and Xphos (10 mol%) were added under a nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 10 minutes. Pd2(dba)3 (10 mol%) was added to this solution and heated at 100°C for 3-5 hours. The reaction progress was monitored by TLC. After the completion of the reaction, the reaction mixture was diluted with water (20 ml) and extracted with CH2Cl2 (50 ml x 3). The combined organic extract was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh) using MeOH / CH2Cl2 (0-3%) as the eluent to provide the corresponding products.

[0189] 3.2 Examples 2 to 102 Compounds illustrating the present invention are listed in Table 1.

[0190] The compounds listed in Table 1 can be obtained according to the methods described in Schemes 1, 2, 3, and 4.

[0191] [Table 1A]

[0192] [Table 1B]

[0193] [Table 1C]

[0194] [Table 1D]

[0195] [Table 1E]

[0196] Table 1F

[0197]

Table 1G

[0198] Table 1H

[0199]

Table 1I

[0200]

Table 1J

[0201] Table 1K

[0202]

Table 1L

[0203]

Table 1M

[0204]

Table 1N

[0205]

Table 10

[0206] [Table 1P]

[0207]

Table 1Q

[0208]

Table 1R

[0209]

Table 1S

[0210]

Table 1T

[0211]

Table 1U

[0212]

Table 1V

[0213]

Table 1W

[0214]

Table 1X

[0215]

Table 1Y

[0216] [Table 1Z]

[0217] [Table 1AA]

[0218] 4. Fatty acid uptake assay for activity determination and efficacy studies in a SOD1 G93A mouse model of ALS. 4.1 In vitro fatty acid uptake assay 4.1.1 HEK293 cells were thawed and centrifuged at 400 g per minute, then the supernatant was discarded. The cells were resuspended in DMEM+GlutaMax medium (Cat. 10566016, Invitrogen) containing 10% fetal bovine serum (Cat. 10270-106, Invitrogen) and 1% penicillin / streptomycin (Cat. 15140-122, Life Technologies). HEK293 cells were seeded in T25 flasks and incubated at 37 degrees Celsius to 80% concentration. When the HEK293 cells reached concentration, the cells were counted and seeded into 96-well plates at a volume of 10,000 cells / well in medium (as described above), and incubated overnight. Three wells were used as control cells.

[0219] The cells were divided into two groups: 1) Example 1 and 2) untreated. A fatty acid uptake assay (Cat number 408-100, BioVision) was performed according to the protocol provided by BioVision. The only exception to the protocol was that measurements were performed overnight on a PerkinElmer Multimode Plate Reader Enspire instrument.

[0220] 4.1.2 Statistics Statistical analysis was performed using GraphPad Prism version 8.0. A repeated measures two-way ANOVA was conducted, testing the group multiple times, followed by a multiple comparison Bonferroni post-hoc test.

[0221] 4.1.3 Results of fatty acid uptake assay Figure 1 shows the efficacy of the CPT1 inhibitor, Example 1 (Ex.1, racemic mixture), tested in a fatty acid uptake assay using HEK293 cells with an IC50 of 0.3 μM.

[0222] 4.2 In Vivo-ALS SOD1 G93A Mouse Model 4.2.1 animal All experiments were approved by the Danish Animal Experimentation Inspection Service (2017-15-0202-00088) and followed national and European guidelines for conducting animal experiments. Animal experiments were conducted in accordance with the ARRIVE guidelines. Mice were housed in IVC cages at a high-barrier facility at Aalborg University, Denmark, with a room temperature of 21°C. Mice were kept in a 12-hour light / dark cycle and had unlimited access to food and water.

[0223] SOD1 G93A Mouse Model B6.Cg-Tg(SOD1 *G93A)1Gur / J mice (stock number 004435) (SOD1) were purchased from Jackson Laboratory (Bar Harbor, USA). Congenic SOD1 mice were maintained in our animal facility by crossing hemizygous SOD1 male mice with female C57Bl / 6J mice. Lumpoffs were genotyped according to an established protocol using DNA extracted from ear tissue punches. Colonies were maintained using male SOD1 mice, and SOD1 females and their wild-type lumpoffs were used for experiments. All animals were assessed daily for human endpoints, twice-weekly for body weight, and once-weekly for neurological scores. SOD1 females (n=4) were evaluated at baseline and day 128 for cylinder, dark-light, and y-maze tests, and at baseline and day 142 for neurological scores, grip strength, hang wire test, and rotarod. Female C57Bl / 6J mice were used as a placebo (n=8) for PBS treatment and tested accordingly. In addition, survival was assessed using neurological scores, disease onset, and survival analysis as described below.

[0224] Clinical behavioral testing All clinical behavioral tests were conducted between 9 a.m. and 2 p.m. All tests were performed in the same laboratory, and mice were placed in the room one hour before each test session to allow time for acclimatization. Between each animal, the test equipment was cleaned with 70% ethanol.

[0225] Neurological scores, disease onset, and survival analysis Mice were evaluated weekly by the same experimenter. The experimenter was blinded to the treatment group and genotype. Mice were assigned a neurological score between 0 and 5, as previously described. Zero = When suspended by its tail, there is no tremor in the hind limbs, and the hind limbs are fully extended. 1 = When suspended by its tail, the hind limbs tremble and fully extend. 2 = When suspended by its tail, the hind limbs tremble and are unable to extend. 3 = When suspended by its tail, the hind limbs tremor, inability to extend the hind limbs, and an unsteady gait occur. 4 = When suspended by its tail, the animal exhibits tremors in the hind limbs, inability to extend the hind limbs, and difficulty walking due to paralysis of one of the hind limbs. 5 = When placed on its side, it exhibits tremors in the hind limbs, inability to extend the hind limbs, and inability to get up within 30 seconds.

[0226] Disease onset was defined as the point at which tremors in the hind legs were present as previously described. For ethical reasons and in accordance with animal facility guidelines, mice were sacrificed if they reached a neurological score of 4 or the final score on day 160. Based on this, survival was defined as a neurological score of less than 4 on the final day of the experimental method. Due to the fact that some mice had to be sacrificed on day 160, some mice did not reach a neurological score of 4, and therefore, some of this group have censored data in the survival analysis.

[0227] Hang wire testing The mouse was gently placed on a wire grid cover and then inverted. The latency to fall was recorded. The maximum cutoff time was set to 180 seconds. Each mouse received three trials per session. The highest latency to fall was used for subsequent statistics.

[0228] Rotor rod test The Rotarod test (Rotamex-5RotaRod, Columbus Instruments, Columbus, Ohio, USA) was used with accelerations ranging from 4 RPM to 40 RPM over a 5-minute period. Mice were acclimatized to the Rotarod for three consecutive days prior to the first test session. Each mouse was tested three times per test session to obtain the average latency to fall.

[0229] Grip strength test Grip strength was assessed using a grip strength meter (Bioseb, France). Briefly, mice were placed on a wire grid while being pulled by their tails. Each mouse underwent four trials in each session, and the maximum tension was measured in grams. The average grip strength was then calculated. The average grip strength was normalized to the weights already described.

[0230] Cylinder test Sensorimotor function and spontaneous activity were assessed using the cylinder test. Mice were moved to a quiet, low-light room and placed in a glass cylinder. The test was recorded for 3 minutes using a video camera. The number of times the mice stood upright was counted by four blind evaluators.

[0231] Y-maze test The y-maze test was constructed according to Maze Engineers (USA). Mice were placed in the y-maze for 5 minutes to freely explore the three arms. The y-maze test was videotaped, and the number of entries and triplets was recorded by a blinded evaluator. The average spontaneous alternation percentage was calculated.

[0232] Light and dark test To measure anxiety-like behavior in mice, a light-dark test was used. Mice were placed in the light-filled side of a box and allowed to explore the box freely for 5 minutes. The light-dark test was videotaped, and the time spent in the dark and the time spent in the dark were recorded by a blinded evaluator.

[0233] 4.2.2 Statistics Statistical analysis was performed using GraphPad Prism version 8.0. A repeated measures two-way ANOVA was conducted, testing the group multiple times, followed by a multiple comparison Bonferroni post-hoc test.

[0234] 4.2.3 Results of efficacy studies in the SOD1 G93A mouse model for ALS Figure 2 demonstrates the efficacy of CPT1 inhibitors by showing improved survival in SOD1 G93A mice in Examples 1-E1 (Ex.1) (n=10) and 1-E2 (Exp.1) (n=10) compared to SOD1 G93A mice treated with either vehicle (n=9), edaravone (n=10), or riluzole (n=10).

Claims

1. Equation (I) 【Chemistry 1】 (In the formula, R 1 is an unsubstituted or substituted aryl, It is an unsubstituted or substituted heteroaryl; L is a single bond, *-O-, * -OCH 2 -, * -CH 2 O- * -CH 2 -, or * -CH 2 -CH 2 -, where * indicates the attachment point to the carbonyl (C=O) group; R 2 This includes unsubstituted or substituted phenyl, naphthyl, pyridyl, or C. 1 ~C 4 -It is alkyl; R 3 H, C 1 ~C 8 -alkyl, halogen-C 1 ~C 4 -alkyl, or C 3 ~C 8 -Cycloalkyl, Unsubstituted or substituted 4-member, 5-member, or 6-member saturated or partially unsaturated heterocyclyls; Y is -(C=O)- or -(SO 2 )-is) Compounds or stereoisomers thereof, or their pharmaceutically or veterinarily acceptable salts, hydrates, or solvates.

2. R 1 However, unsubstituted or substituted phenyl, naphthyl, or tetrahydronaphthyl, Unsubstituted or substituted pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, oxydiazolyl, isoxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, or quinolinyl; L is a single bond, *-O-, * -OCH 2 -, * -CH 2 O-, * -CH 2 -, or * -CH 2 -CH 2 -and here, * This indicates the attachment site to the carbonyl (C=O) group; R 2 However, it is an unsubstituted or substituted phenyl, naphthyl, or pyridyl; R 3 However, H, C 1 ~C 4 -alkyl, halogen-C 1 ~C 4 -Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl Unsubstituted or substituted azetidinil, pyrrolidinil, piperidinil, or oxetanil, 【Chemistry 2】 and; Y is -(C=O)- or -(SO 2 The compound according to claim 1, wherein the compound is )-.

3. R 1 However, unsubstituted or substituted phenyl, naphthyl, or tetrahydronaphthyl, Unsubstituted or substituted pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, oxydiazolyl, isoxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, or quinolinyl, Each R 1 The following residues are selected independently and at will: -CN, halogen, C 1 ~C 4 -Alkyl, Halogen-C 1 ~C 4 -Alkyl, SO 2 Me, or CO 2 C 1 ~C 4 -Alkyl, The compound according to claim 1 or 2, which is substituted with one or more of the following.

4. R1 is an unsubstituted or substituted phenyl, naphthyl, or tetrahydronaphthyl Unsubstituted or substituted pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, oxydiazolyl, isoxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, or quinolinyl, Each R1 is optionally and independently selected from the following residues: -CN, -F or -Cl, Methyl, Difluoromethyl or trifluoromethyl, SO₂Me, or CO2Me The compound according to claim 1, which is substituted with one of the following.

5. R 1 However, unsubstituted or substituted phenyl, Unsubstituted or substituted pyridyl, pyrazolyl, thienyl, or quinolinyl; Each R 1 The following residues are selected independently and at will: -CN, -F or -Cl, C 1 ~C 4 -Alkyl, Halogen-C 1 ~C 4 -Alkyl, SO 2 Me, or CO 2 C 1 ~C 4 -Alkyl, The compound according to claim 1, which is substituted with one or more of the following.

6. R 1 However, it is an unsubstituted or substituted phenyl or pyridyl, Each R 1 The following residues are selected independently and at will: -F or -Cl, C 1 ~C 4 -Alkyl, Trifluoromethyl, SO 2 Me, or CO 2 C 1 ~C 4 -Alkyl, The compound according to claim 1, which is substituted with one or more of the following.

7. L is a single bond, * -CH 2 O-, or * -CH 2 -and here, * The compound according to claim 1, wherein is an attachment site to a carbonyl (C=O) group.

8. The compound according to claim 1, wherein L is *-CH2O-, where * indicates an attachment site to a carbonyl (C=O) group.

9. R 2 However, it is an unsubstituted or substituted phenyl, naphthyl, or pyridyl. Each R 2 The following residues are selected independently and at will: -CN, halogen, C 1 ~C 4 -Alkyl, Halogen-C 1 ~C 4 -Alkyl, SO 2 Me、 CO 2 C 1 ~C 4 -Alkyl, Adamantyl It is replaced by one or more of the following: Unsubstituted or substituted phenyls halogen, Halogen-C 1 ~C 4 -Alkyl, C 3 ~C 8 -Cycloalkyl, Pyridyl The compound according to claim 1, wherein it is optionally substituted with one or more substituents selected from the following.

10. R 3 is H, C 1 ~C 4 -alkyl, halogen-C 1 ~C 4 -alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, Unsubstituted or substituted azetidinil, pyrrolidinil, piperidinil, or oxetanil, Each azetidinil, pyrrolidinil, piperidinil, or oxetanil can be optionally and independently replaced with the following residues: -CN, halogen; C 1 ~C 4 -alkyl; Halogen-C 1 ~C 4 -Alkyl, SO 2 Me、 CO 2 C 1 ~C 4 -alkyl, or CO-C 1 ~C 4 -Alkyl, The compound according to claim 1, which is substituted with one or more of the following.

11. R 3 However, C 1 ~C 4 - The compound according to claim 1, wherein it is alkyl. 【Request Item 12】 【Chemistry 3A】 【Chemistry 3B】 【Chemicals 3C】 [3D Transformation] 【3E Transformation】 【Chemical 3F】 [3G Transformation] 【Chemical 3H】 【Chemical 3I】 【Chemical 3J】 [3K] [3L] [3M] A compound according to claim 1, selected from the following.

13. A pharmaceutical composition comprising the compound or stereoisomer described in claim 1, a pharmaceutically or veterinarily acceptable salt, hydrate, or solvate thereof, and a therapeutically inactive carrier.

14. A pharmaceutical composition comprising the compound according to claim 1 for use in the remission, prevention and / or treatment of diseases caused by or related to the depilation of nerve tissue.

15. The diseases caused by or associated with delipidation of nerve tissue include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), inflammatory diseases, acute traumatic events such as surgery or injury, AIDS-related wasting due to the toxicity of reverse transcriptase inhibitors, mitochondrial myopathy, aging and senescence, neuronal ischemia, polyglutamine diseases, dystonia, Leber hereditary optic neuropathy (LHON), schizophrenia, stroke, muscle degenerative disorders, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy associated with red ragged fibers (MERRF), neuropathy, ataxia, and retinitis pigmentosa. The pharmaceutical composition according to claim 14, which is (NARP), progressive extraocular palsy (PEO), Leigh disease, Kearns-Sayre syndrome, muscular dystrophy, myotonic dystrophy, chronic fatigue syndrome, Friedreich's ataxia; developmental delay in cognitive, motor, language, executive function or social skills; epilepsy, peripheral neuropathy, optic neuropathy, autonomic neuropathy, neurogenic intestinal dysfunction, sensorineural hearing loss, neurogenic bladder dysfunction, migraine; renal tubular acidosis, hepatic failure, lactic acidemia, periodontitis, Duchenne muscular dystrophy, Becker muscular dystrophy, McArdle disease, abnormalities in testosterone synthesis and / or hypoparathyroidism.

16. The pharmaceutical composition according to claim 14, wherein the disease caused by or associated with the delipidation of nerve tissue is amyotrophic lateral sclerosis (ALS).

Images