Substitutive condensed ring compounds and their pharmaceutical compositions, methods of production, and uses

Abstract

The present invention provides a substituted fused ring compound represented by formula (I) and its pharmaceutical composition, preparation method and use, which has good LRRK2 kinase regulating / inhibiting activity and can be used for treating symptoms and diseases associated with LRRK2 kinase activity, and for producing drugs for such symptoms and diseases.

Description

Detailed description of the invention

[0001] This application claims priority over two prior Chinese invention patent applications, namely application number 202210178818.7, filed by the applicant with the China National Intellectual Property Administration on February 25, 2022, with the title "Substitutive Condensed Ring Compounds and their Pharmaceutical Compositions, Methods of Production and Uses," and namely application number 202210470959.6, filed with the China National Intellectual Property Administration on April 28, 2022, with the title "Substitutive Condensed Ring Compounds and their Pharmaceutical Compositions, Methods of Production and Uses." Both of the aforementioned prior patent applications are incorporated herein by reference in their entirety.

[0002] [Technical Field] This disclosure relates to the field of LRRK2 kinase drugs, and more specifically to substituted condensed ring compounds and their pharmaceutical compositions, methods of production, and uses.

[0003] [Background technology] Parkinson's disease (PD) is one of the most common neurodegenerative diseases, affecting 1-2% of the elderly population. Genome-wide association studies (GWAS) have identified 28 correlated genetic risk mutations in 24 sites of non-familial PD. Among these, mutations in LRRK2 (Park8) were found in terms of inheritance pattern, confirming a disease pathogenesis driven by a common molecular pathway in familial and non-familial PD, and identifying it as the most common cause of the disease (Simon-Sanchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet, 2009, 41, 1308-1312). The PD pathogenic LRRK2 mutation map is primarily associated with kinases (G2019S, I2020T) and ROC-COR domains (R1441C / G / H, Y1699C), indicating that the activity of these enzymes is crucial for disease progression. Pathogenic mutations are very rare, accounting for approximately 2% of all mutations. However, in certain ethnic groups, the most common mutation, G2019S, is found in up to 40% of patients, resulting in 2-3 times increased kinase activity (West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, et al. From The Cover: Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proceedings of the National Academy of Sciences, 2005, 102, 16842-16847).In addition to pathogenic mutations, common genetic variants of LRRK2 are risk factors for sporadic Parkinson's disease (Tan, EK Identification of a common genetic risk variant (LRRK2 Gly2385Arg) in Parkinson's disease. Ann Acad Med Singapore. 2006, 35, 840-842.).

[0004] In 2004, LRRK2 was identified as the gene responsible for PD inheritance, correlated with the PARK8 site, and composed of 51 exons, producing a single large (268kDa) protein. Subsequently, many LRRK2 primary structure variants were identified, including dominant mutations detached from familial PD that also appear in sporadic PD, and polymorphisms at the LRRK2 locus. These polymorphisms were found to increase the lifetime risk of developing sporadic PD.

[0005] LRRK2 is a multi-domain protein with two enzymatic functions in its core. The GTP enzyme domain contains the complex protein RAS (Ras of complex protein, ROC), which terminates with a spacer domain at the C-terminus (COR) of one Roc domain, followed by a kinase domain belonging to the serine / threonine kinase group. This enzyme core is surrounded by protein-protein interaction domains and contains Armadillo, ankyrin, and a leucine-rich repeat (LRR) domain at the N-terminus of LRRK2. The C-terminus of LRRK2 contains the WD40 domain, a region essential for protein folding that can regulate LRRK2 function and kinase activity (Rudenko IN, Kaganovich A, Hauser DN, Beylina A, Chia R, et al. The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson's disease is a partial loss-of-function mutation. Biochemical Journal, 2012, 446, 99-111.). Interestingly, this new description of dominant pathogenic mutations occurring within the LRRK2 enzyme core reveals that modifications to LRRK2 activity have a significant impact on the development and progression of PD.

[0006] To date, nearly 40 single-amino acid substitution mutations in the LRRK2 mutation group have been associated with autosomal dominant Parkinson's disease (PD). The most common LRRK2 mutation pattern in Europe, including the Gly2019 amino acid substitution at the Ser residue, accounts for approximately 6% of familial PD cases and 3% of sporadic PD cases. Gly2019 is associated with conservative DYG-Mg 2+It is located within the binding motif and in subdomain-VII of the kinase domain. Recent reports have shown that such mutations enhance LRRK2 autophosphorylation and increase its phosphorylation capacity for myelin basic proteins by 2-3 times. Overexpression of G2019S-LRRK2 in cell lines and primary neuron cultures, regardless of oxidative stress, leads to cytotoxicity and inclusion body formation. These results, along with genetic inactivation of LRRK2 kinase activity, demonstrate a protective effect against such toxic phenotypes, suggesting that alterations in LRRK2 kinase activity may be related to the neurotoxicity and pathogenicity mechanisms of LRRK2-PD.

[0007] Studies have shown that induced pluripotent stem cells (iPSCs) from LRRK2 G2019S Parkinson's disease patients exhibit neurite proliferation defects and increased sensitivity to rotenone, which can be mitigated by genetic modification of the G2019S mutation or by treating the cells with small molecule inhibitors of LRRK2 kinase activity (Reinhardt P, Schmid B, Burbulla Lena F, Schoendorf David C, Wagner L, et al. Genetic Correction of a LRRK2 Mutation in Human iPSCs Links Parkinsonian Neurodegeneration to ERK-Dependent Changes in Gene Expression. Cell Stem Cell, 2013, 12, 354-367). Increased mitochondrial damage correlated with the LRRK2 G2019S mutation in iPSCs can also be blocked by genetic modification of the G2019S mutation.

[0008] [Summary of the Invention] To improve the above technical problems, the present disclosure provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled compound, N-oxide, hydrate, solvate, crystal polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester or its prodrug compound,

[0009]

Chemical formula

[0010] Among them, W is selected from N or O, R 1 is an unsubstituted or C a alkyl group, C 1-10 cycloalkyl group, 3-10 member heterocyclyl group, which is selected from, 3-10 Each R a is the same or different, and independently of each other is halogen, hydroxy group, C 1-10 alkyl group, C 1-10 alkyloxy group, C 3-10 cycloalkyl group, C 3-10 cycloalkyloxy group, 3-10 member heterocyclyl group, 3-10 member heterocyclyloxy group, which is selected from, Alternatively, as a choice, two R a together with the atoms to which they are attached form an unsubstituted or optionally C c alkyl group, C 1-10 alkyl group, C 1-10 alkyloxy group, C 3-10 cycloalkyl group, C 3-10 cycloalkyloxy group, 3-10 member heterocyclyl group, 3-10 member heterocyclyloxy group which is substituted with one, two or more R R 2 is absent or is selected from H or C 1-10 alkyl group, among which, when W is selected from O, R 2 is absent, when W is selected from N, R 2 is selected from H or C 1-10 alkyl group, Alternatively, as an option, R 1 , R 2 R is either unsubstituted or optionally one, two, or more Rs along with W. b Forms a 3-10 membered heterocyclyl group substituted with, Each R b These are homologous or different, and independently of each other, they are halogens, hydroxyl groups, and C 1-10 Alkyl alkyl group, C 1-10 Alkyloxy group, C 3-10 Cycloalkyl groups, C 3-10 Selected from cycloalkyloxy groups, 3-10 membered heterocyclyl groups, and 3-10 membered heterocyclyloxy groups, Alternatively, as an option, two R b These atoms, along with the atoms they are linked to, either unsubstituted or optionally, contain one, two, or more R atoms. c C replaced by 1-10 Alkyl alkyl group, C 1-10 Alkyloxy group, C 3-10 Cycloalkyl groups, C 3-10 Forming a cycloalkyloxy group, a 3-10 membered heterocyclyl group, and a 3-10 membered heterocyclyloxy group, Each R c These are homologous or different, and independently of each other, they are halogens, hydroxyl groups, and C 1-10 Alkyl alkyl group, C 1-10 Alkyloxy group, C 3-10 Cycloalkyl groups, C 3-10 Selected from cycloalkyloxy groups, 3-10 membered heterocyclyl groups, and 3-10 membered heterocyclyloxy groups, X is one, two or more R 3 Selected from 5-10 member heteroaryl groups substituted with, Each R 3 These are homologous or different, and are independently unsubstituted or have one, two or more Rs. 4 C replaced by 1-10 Alkyl alkyl group, C 3-10 Selected from cycloalkyl groups, 3-10 membered heterocyclyl groups, and 5-10 membered heteroaryl groups, Alternatively, as an option, two R 3These atoms, along with the atoms they are linked to, either unsubstituted or optionally, contain one, two, or more R atoms. 4 C replaced by 3-10 Forming a cycloalkyl group, a 3-10 membered heterocyclyl group, Each R 4 These are homologous or different, and independently of each other, they are halogens, hydroxyl groups, cyano groups, unsubstituted or one, two or more R groups. d C replaced by 1-10 Alkyl alkyl group, C 1-10 Alkylene group, C 3-10 Selected from cycloalkyl groups, 3-10 membered heterocyclyl groups, and 5-10 membered heteroaryl groups, of which R 4 C 1-6 If selected from alkylene groups, R 4 The carbon atom in R 3 This means forming a double bond with the carbon atom that is linked to it. Each R d These are homologous or different, and independently of each other are halogens, hydroxyl groups, cyano groups, and C 1-6 Alkyl alkyl group, C 1-6 Alkyloxy group, C 3-10 Cycloalkyl groups, C 3-10 Selected from cycloalkyloxy groups, 3-10 membered heterocyclyl groups, 3-10 membered heterocyclyloxy groups, 5-10 membered heteroaryl groups, and 5-10 membered heteroaryloxy groups.

[0011] According to embodiments of this disclosure, R 1 This is either unsubstituted or with one, two, or more Rs. a C replaced by 1-8 Alkyl alkyl group, C 3-8 Selected from cycloalkyl groups and 3- to 8-membered heterocyclyl groups, For example, R 1 This is either unsubstituted or with one, two, or more Rs. a C replaced by 1-6 Alkyl alkyl group, C 3-7 Selected from cycloalkyl groups and 3- to 7-membered heterocyclyl groups, According to embodiments of this disclosure, each R aThese are homologous or different, and are independent of each other as F, Cl, Br, and C. 1-6 Selected from alkyl groups, As an example, R 1 teeth,

[0012] [ka]

[0013] -CH2CF3 is selected from -CH(CH3)CF3.

[0014] According to embodiments of this disclosure, R 1 , R 2 R is either unsubstituted or optionally one, two, or more Rs along with W. b Replaced with

[0015] [ka]

[0016] It forms.

[0017] According to embodiments of this disclosure, X is one, two or more R 3 Selected from 5-6 member heteroaryl groups substituted with, For example, X is one, two or more R 3 Replaced with

[0018] [ka]

[0019] Selected from, As an example, X is,

[0020] [ka]

[0021] They are selected from among them.

[0022] According to an embodiment of the present disclosure, R 3 is an unsubstituted or C 4 alkyl group, C 1-6 cycloalkyl group, 3-8 member heterocyclyl group, or 5-6 member heteroaryl group, substituted with one, two, or more R 3-8 groups, and is selected from the group consisting of: For example, R 3 is an unsubstituted or methyl group, ethyl group, propyl group, isopropyl group, cyclopropane group, cyclobutane group, 4 substituted with one, two, or more R

[0023]

Chemical formula

[0024] and is selected from the group consisting of: Each R 4 is the same or different, and independently of one another is fluorine, chlorine, bromine, hydroxy group, cyano group, an unsubstituted or C d alkyl group, C 1-6 alkylene group, C 1-6 cycloalkyl group, or 3-8 member heterocyclyl group, substituted with one, two, or more R 3-8 groups, and is selected from the group consisting of: As an example, R 3 is an isopropyl group,

[0025]

Chemical formula

[0026] and is selected from the group consisting of:

[0027] According to a preferred embodiment of the present disclosure, the compound represented by formula (I) is preferably a compound represented by the following formula (II),

[0028]

Chemical formula

[0029] Among them, R 5 is a C 1-6 alkyl group substituted with one, two or more halogens, preferably a C 1-6 alkyl group substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 halogens, such as a methyl group or an ethyl group substituted with 1, 2, 3, 4 or 5 fluorine or chlorine atoms, such as a trifluoromethyl group, and is selected from R 6 is a C 1-6 alkyl group, such as a methyl group, an ethyl group, a propyl group or an isopropyl group, and is selected from R 7 , R 8 , R 9 , R 10 are the same or different and are independently of each other H or a C 1-6 alkyl group, such as H, a methyl group, an ethyl group, a propyl group or an isopropyl group, and is selected from R 11 , R 12 are the same or different and are independently of each other H or a C 1-6 alkyl group, such as H, a methyl group, an ethyl group, a propyl group or an isopropyl group, and is selected from.

[0030] According to a preferred embodiment of the present disclosure, the compound represented by formula (I) is preferably a compound represented by the following formula (III),

[0031]

Chemical formula

[0032] Among them, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 have the definitions described above.

[0033] According to an exemplary embodiment of the present disclosure, the compound represented by formula (I) is the following compound, namely,

[0034] [ka] JPEG0007870838000011.jpg235169JPEG0007870838000012.jpg80169

[0035] You may be chosen from among them.

[0036] This disclosure further provides a method for producing a compound represented by formula (I), its racemic mixture, stereoisomer, tautomer, isotope-labeled compound, N-oxide, hydrate, solvate, crystalline polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, or prodrug compound thereof, including the following reactions:

[0037] [ka]

[0038] Eventually, R 1 , R 2 W and X have the definitions described above, P 1 It is selected from amino protecting groups.

[0039] Preferably, the compound of formula (M2) has a protecting group P 1 The reaction is carried out under conditions that eliminate the compound, yielding the compound shown in formula (I).

[0040] According to the manufacturing method embodiment of the present disclosure, the above P 1The amino protecting group is selected from amino protecting groups known to those skilled in the art. For example, a suitable amino protecting group may be selected from alkyloxycarbonyl groups (e.g., tert-butoxycarbonyl group), cycloalkylalkoxycarbonyl groups (e.g., cyclohexylmethoxycarbonyl group), substituted alkyloxycarbonyl groups (e.g., trichloroethoxycarbonyl group), substituted arylalkyloxycarbonyl groups (e.g., p-nitrobenzyloxycarbonyl group), arylalkyl groups (e.g., triphenylmethyl group or diphenylmethyl group), heteroarylalkyl groups (e.g., pyridylalkyl groups, e.g., 2-pyridylmethyl group, 4-pyridylmethyl group), alkoxyarylalkyl groups (e.g., alkoxyphenylalkyl groups, e.g., p-methoxybenzyl group, abbreviated as "PMB"), etc.

[0041] According to embodiments of the manufacturing method of this disclosure, a method for producing a compound of formula (M2), comprising the following reaction, is further provided:

[0042] [ka]

[0043] Eventually, R 1 , R 2 W, X and P 1 It has the definition described above, L 1 and L 2 These are selected from leaving groups that are homologous or different and that enable coupling reactions independently of each other.

[0044] According to embodiments of this disclosure, the compound of formula (M2) can be produced by a coupling reaction known in the art, for example, by a Stille coupling reaction or a Suzuki coupling reaction.

[0045] As a Stille coupling reaction or Suzuki coupling reaction known to those skilled in the art, L according to the requirements of the reaction 1 and L 2This is known to those skilled in the art. For example, L 1 L may be selected from halogens such as iodine. 2 This may be selected from alkyltin groups or borate ester groups.

[0046] This disclosure further provides pharmaceutical compositions comprising at least one of the following: a compound represented by formula (I), its racemic mixture, stereoisomer, tautomer, isotope-labeled compound, N-oxide, hydrate, solvate, crystalline polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, or prodrug compound thereof.

[0047] The disclosure further provides pharmaceutical compositions comprising at least one of the following: a therapeutically effective amount of a compound represented by formula (I), its racemic mixture, stereoisomer, tautomer, isotope-labeled compound, N-oxide, hydrate, solvate, crystalline polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, or prodrug compound thereof.

[0048] According to embodiments of the present disclosure, the pharmaceutical composition further comprises one or more pharmaceutically acceptable adjuvants.

[0049] According to embodiments of the present disclosure, the pharmaceutical composition may further comprise one or more additional therapeutic agents.

[0050] According to embodiments of the present disclosure, a compound represented by formula (I), its racemic mixture, stereoisomer, tautomer, isotope-labeled compound, N-oxide, hydrate, solvate, crystalline polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester or prodrug compound thereof, or the pharmaceutical composition thereof, can be used to modulate the activity of LRRK kinase, particularly LRRK2 kinase.

[0051] According to embodiments of the present disclosure, a compound represented by formula (I), its racemic mixture, stereoisomer, tautomer, isotope-labeled compound, N-oxide, hydrate, solvate, crystalline polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester or prodrug compound thereof, or the pharmaceutical composition thereof, can be used for the prevention and / or treatment of diseases or conditions, which include neurodegenerative diseases, proliferative disorders, protein kinase-related diseases, lysosomal disorders, tau diseases and dysplasia. This may include one, two, or more diseases selected from those resulting from decreased pamine levels, such as cancer, Parkinson's disease (PD) associated with GBA mutations, other alpha-synuclein disorders, tauopathies, Alzheimer's disease, Gaucher disease, Niemann-Pick disease type C (NPC), argyrophilic granulopathy, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, hereditary frontotemporal dementia and Parkinson's disease associated with chromosome 17 (FTDP-17), and withdrawal symptoms / relapses associated with drug addiction.

[0052] The disclosure further provides a method for modulating the activity of LRRK kinase, particularly LRRK2 kinase, comprising administering to a patient at least one of the following: a compound represented by formula (I), a racemate, stereoisomer, tautomer, isotope-labeled compound thereof, an N-oxide, a hydrate, a solvate, a crystalline polymorph, a metabolite, a pharmaceutically acceptable salt, a pharmaceutically acceptable ester, or a prodrug compound thereof.

[0053] According to embodiments of this disclosure, the LRRK kinase is preferably LRRK2 kinase, its mutant or isoform, or a combination thereof.

[0054] This disclosure further provides at least one of the following: compounds represented by formula (I) used for diseases or conditions related to LRRK kinase, particularly LRRK2 kinase activity; racemates, stereoisomers, tautomers, isotope-labeled compounds thereof; N-oxides; hydrates; solvates; crystalline polymorphs; metabolites; pharmaceutically acceptable salts; pharmaceutically acceptable esters or prodrug compounds thereof; or pharmaceutical compositions thereof.

[0055] According to embodiments of this disclosure, the LRRK kinase is preferably LRRK2 kinase, its mutant or isoform, or a combination thereof.

[0056] The diseases or conditions associated with the above-mentioned LRRK kinase, particularly LRRK2 kinase activity, include one, two, or more selected from neurodegenerative diseases, proliferative disorders, protein kinase-related diseases, lysosomal disorders, tau diseases and diseases resulting from decreased dopamine levels, such as cancer, Parkinson's disease (PD) associated with GBA mutations, other alpha-synuclein disorders, tauopathies, Alzheimer's disease, Gaucher disease, Niemann-Pick disease type C (NPC), argyrophilic granulopathy, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, hereditary frontotemporal dementia and Parkinson's disease associated with chromosome 17 (FTDP-17), and withdrawal symptoms / relapses associated with drug addiction.

[0057] This disclosure relates to methods for preventing and / or treating a disease or condition, comprising administering to a patient at least one of the following: a compound represented by formula (I), its racemic mixture, stereoisomer, tautomer, isotope-labeled compound, N-oxide, hydrate, solvate, crystalline polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, or prodrug compound thereof, wherein the disease or condition is a neurodegenerative disease, a proliferative disorder, a protein kinase-related disease, a lysosomal disorder, a tau disease, and a dowry. The present invention further provides a method that may include one, two, or more selected from diseases resulting from decreased pamine levels, such as cancer, Parkinson's disease (PD) associated with GBA mutations, other alpha-synuclein disorders, tauopathies, Alzheimer's disease, Gaucher disease, Niemann-Pick disease type C (NPC), argyrophilic granulopathy, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, hereditary frontotemporal dementia and Parkinson's disease associated with chromosome 17 (FTDP-17), and withdrawal symptoms / relapses associated with drug addiction.

[0058] In some embodiments, the patient with the above-mentioned disease or condition is a human being.

[0059] The disclosure further provides a method for treating or preventing a disease or condition related to LRRK kinase, particularly LRRK2 kinase activity, comprising administering to a patient at least one of the following: a compound represented by formula (I), a racemate, stereoisomer, tautomer, isotope-labeled compound thereof, an N-oxide, a hydrate, a solvate, a crystalline polymorph, a metabolite, a pharmaceutically acceptable salt, a pharmaceutically acceptable ester, or a prodrug compound thereof.

[0060] This disclosure further provides the use of at least one of the following in the manufacture of a drug: a compound represented by formula (I), its racemic mixture, stereoisomer, tautomer, isotope-labeled compound, N-oxide, hydrate, solvate, crystalline polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, or a prodrug compound thereof.

[0061] The above-mentioned drugs can be used for the prevention and / or treatment of diseases or conditions related to LRRK kinase, particularly LRRK2 kinase activity.

[0062] Alternatively, the above-mentioned drugs may be used for the prevention and / or treatment of diseases or conditions, of which the above-mentioned diseases or conditions may include one, two or more selected from neurodegenerative diseases, proliferative disorders, protein kinase-related diseases, lysosomal disorders, tau diseases and diseases resulting from decreased dopamine levels, such as cancer, Parkinson's disease (PD) associated with GBA mutations, other alpha-synucleidosis, tauopathy, Alzheimer's disease, Gaucher disease, Niemann-Pick disease type C (NPC), argyrophilic granulopathy, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, hereditary frontotemporal dementia and Parkinson's disease associated with chromosome 17 (FTDP-17), and withdrawal symptoms / relapses associated with drug addiction.

[0063] When used as a drug, the compounds of this disclosure can be administered in the form of pharmaceutical compositions. These compositions can be manufactured according to methods well known in the pharmaceutical field and can be administered via various routes depending on whether topical or systemic treatment is required and the area to be treated. Topical administration (e.g., administration to mucous membranes including transdermal, skin, eyes, and nose, vagina and rectum), pulmonary administration (e.g., by inhaling or blowing powders or aerosols, including by sprayers; intratracheal, intranasal administration), oral or parenteral administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion, or intracranial administration such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus or by continuous perfusion pump, for example. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, powder formulations and powders. Conventional drug carriers, water, powder or oily substrates, thickeners, etc., are essential or may be required.

[0064] When preparing the compositions of this disclosure, the active ingredient is generally mixed with an excipient, diluted with the excipient, or placed in a carrier such as a capsule, pill bag, paper, or other container. When used as a diluent, the excipient may be a solid, semi-solid, or liquid substance used as a solvent, carrier, or medium for the active ingredient. Accordingly, the compositions may be in the form of tablets, pills, powders, topical ointments, pill bags, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (dissolved in a solid or liquid solvent), ointments containing, for example, up to 10% by weight of the active compound, soft or hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaging powders.

[0065] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations may further contain lubricants, wetting agents, emulsifiers, and suspending agents such as talc powder, sodium stearate, magnesium stearate, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, and mineral oil, as well as preservatives, sweeteners, and flavoring agents such as methyl benzoate and hydroxypropyl benzoate. The compositions of this disclosure can be manufactured by methods known in the art so as to provide an action that provides immediate, sustained, or delayed release of the active ingredient after administration to a patient.

[0066] The above pharmaceutical compositions may be manufactured in unit dosage forms, each unit dosage form may contain approximately 1 to 1000 mg, for example, approximately 5 to 1000 mg, more generally approximately 5 to 500 mg, for example, 5 to 100 mg, 100 to 500 mg of the active ingredient, or 50 to 200 mg of the active ingredient. For example, each dose may contain 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, or 300 mg of the active ingredient. The term "unit dosage form" refers to a physically separated, single-dose unit suitable for use in human patients and other mammals, each unit containing a predetermined amount of active substance mixed with a suitable drug excipient, calculated to produce the desired therapeutic effect.

[0067] The effective dose range for active compounds can be very wide, and they are usually administered in pharmaceutically effective doses. However, it is understood that the actual amount of compound administered is usually determined by the physician based on relevant circumstances, including the disease being treated, the route of administration chosen, the actual compound administered, the patient's age, weight and response, and the severity of the patient's symptoms.

[0068] The therapeutic dose of the compounds disclosed herein may be determined, for example, by the specific use of the treatment, the method of administration of the compound, the patient's health and condition, and the judgment of the prescribing physician. The ratio or concentration of the compounds disclosed herein in a pharmaceutical composition may not be constant and may depend on various factors, including dose, chemical properties (e.g., hydrophobicity), and route of administration. For example, at least one of the compounds disclosed herein, its racemates, stereoisomers, tautomers, isotope-labeled compounds, N-oxides, hydrates, solvates, crystalline polymorphs, metabolites, pharmaceutically acceptable salts, pharmaceutically acceptable esters, or prodrug compounds thereof may be provided for parenteral administration in a physiologically buffered aqueous solution containing about 0.1–10% (w / v) of the compound. Some typical dose ranges are about 1 μg / kg to about 1 g / kg body weight / day. In some embodiments, the dose range is approximately 0.01 mg / kg to approximately 100 mg / kg body weight / day, for example, 0.1 mg / kg body weight / day, 0.2 mg / kg body weight / day, 0.3 mg / kg body weight / day, 0.4 mg / kg body weight / day, 0.5 mg / kg body weight / day, 0.6 mg / kg body weight / day, 0.7 mg / kg body weight / day, 0.8 mg / kg body weight / day, 0.9 mg / kg body weight / day, 1 mg / kg body weight / day, 5 mg / kg body weight / day, 10 mg / kg body weight / day, 15 mg / kg body weight / day, 20 mg / kg body weight / day, 25 mg / kg body weight / day, 30 mg / kg body weight / day, 35 mg / kg body weight / day, 40 mg / kg body weight / day, 45 mg / kg body weight / day, and 50 mg / kg body weight / day. For example, when the target of administration is a human, the dose administered to the patient may be 57 mg / 70 kg to 171 mg / 70 kg. The dose is likely to depend on variables such as the type and progression of the disease or condition, the general health status of the specific patient, the relative biological potency of the selected compound, the excipient formulation, and the route of administration. The effective dose can be obtained by extrapolating from dose-response curves derived from in vitro or animal model test systems.

[0069] For the manufacture of solid compositions such as tablets, the main active ingredient is mixed with a drug excipient to form a solid pre-formulation composition which is a homogeneous mixture containing the compound of the Disclosure. When these pre-formulation compositions are referred to as homogeneous, it means that the active ingredient is usually uniformly distributed throughout the composition, so that the composition can be easily divided into equally effective unit dosage forms such as tablets, pills, and capsules. The solid pre-formulation is then divided into the above-mentioned unit dosage forms, for example, containing about 0.1 to 1000 mg of the active ingredient of the Disclosure, and each unit dosage form may contain about 1 to 1000 mg, for example about 5 to 1000 mg, more generally about 5 to 500 mg, for example 5 to 100 mg, 100 to 500 mg of the active ingredient, or 50 to 200 mg of the active ingredient. For example, each dose may contain 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, or 300 mg of the active ingredient.

[0070] The tablets or pills of this disclosure can be coated or compounded to obtain dosage forms that offer the advantage of sustained action. For example, the tablets or pills contain an internal dose composition and an external dose composition, the latter being a coating of the former. The two compositions can be separated by an enteric coating to prevent disintegration in the stomach, so that the internal composition passes completely through the duodenum or is released with delayed release. Multiple substances can be used for such enteric coatings or coatings, and such substances include multiple high molecular weight acids, and mixtures of high molecular weight acids with substances such as shellac, cetyl alcohol, and cellulose acetate.

[0071] Liquid forms for oral or injectable administration, in which the compounds and compositions of the present disclosure can be incorporated, include aqueous solutions, appropriately flavored syrups, water or oil suspensions, emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, elixirs and similar medicinal solvents.

[0072] Compositions used for inhalation or blowing include solutions and suspensions dissolved in pharmaceutically acceptable water or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions are administered orally or via nasal breathing to achieve local or systemic effects. Compositions can be atomized using an inert gas. The atomized solution may be inhaled directly by an atomizer, or the atomizer may be connected to a face mask tent or an intermittent positive pressure ventilator. Solutions, suspensions, or powder compositions may be administered orally or nasally by a device that delivers the formulation in an appropriate manner.

[0073] The amount of a compound, its racemic mixture, stereoisomer, tautomer, isotope-labeled compound, N-oxide, hydrate, solvate, crystalline polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester or its prodrug compound, or pharmaceutical composition administered to a patient is not fixed and depends on the drug being administered, the purpose of administration (such as prevention or treatment), the patient's condition, and the method of administration. In therapeutic applications, a sufficient amount of the composition to cure or at least partially inhibit the symptoms of the disease and its complications may be administered to a patient suffering from the disease. The effective dose should depend on the state of the disease being treated and the judgment of the attending clinician, which depends on factors such as the severity of the disease, the patient's age, weight, and general condition. Some typical dose ranges are approximately 1 μg / kg to approximately 1 g / kg body weight / day. In some embodiments, the dose range is approximately 0.01 mg / kg to approximately 100 mg / kg body weight / day, for example, 0.1 mg / kg body weight / day, 0.2 mg / kg body weight / day, 0.3 mg / kg body weight / day, 0.4 mg / kg body weight / day, 0.5 mg / kg body weight / day, 0.6 mg / kg body weight / day, 0.7 mg / kg body weight / day, 0.8 mg / kg body weight / day, 0.9 mg / kg body weight / day, 1 mg / kg body weight / day, 5 mg / kg body weight / day, 10 mg / kg body weight / day, 15 mg / kg body weight / day, 20 mg / kg body weight / day, 25 mg / kg body weight / day, 30 mg / kg body weight / day, 35 mg / kg body weight / day, 40 mg / kg body weight / day, 45 mg / kg body weight / day, and 50 mg / kg body weight / day. For example, if the target of administration is a human, the dose administered to the patient may be 57 mg / 70 kg to 171 mg / 70 kg.

[0074] The compositions administered to patients may be in the form of the pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or by filtration sterilization. The aqueous solution packaging can be used as is, or it can be freeze-dried and the freeze-dried formulation mixed with a sterile aqueous carrier before administration. The pH of the compound formulation is generally 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It can be understood that pharmaceutical salts are formed by using some of the excipients, carriers, or stabilizers described above.

[0075] This disclosure provides the use of at least one of the compounds described in formula (I), its racemates, stereoisomers, tautomers, isotope-labeled compounds, N-oxides, hydrates, solvates, crystalline polymorphs, metabolites, pharmaceutically acceptable salts, pharmaceutically acceptable esters, or prodrug compounds thereof in analytical testing, wherein the analytical test is used to identify compounds that can inhibit one or more kinases, the kinase being preferably LRRK, more preferably LRRK2.

[0076] Preferably, the above analytical measurement is a competitive binding activity measurement.

[0077] More preferably, the competitive binding test includes contacting the compound of the disclosure with a kinase and detecting any changes in the interaction between the compound of the disclosure and the kinase.

[0078] Another aspect of the present disclosure provides a method for detecting the binding of a compound of the present disclosure to a kinase, the method being: (i) In the presence of the kinase and a known substrate, the step of contacting at least one of the compounds of the Disclosure, its racemic mixture, stereoisomer, tautomer, isotope-labeled compound, N-oxide, hydrate, solvate, crystalline polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester or prodrug compound thereof with the kinase, (ii) The step of detecting any change in the interaction between the kinase and the known substrate.

[0079] Beneficial effects The compounds provided herein have good LRRK2 kinase modulating / inhibitory activity and can be used for the treatment of symptoms and diseases associated with LRRK2 kinase activity, and for the manufacture of drugs used for such symptoms and diseases. The compounds provided herein are easy to manufacture and have good application prospects.

[0080] Definitions and explanations of terms Unless otherwise specified, the definitions of groups and terms described in the specification and claims of this application include illustrative definitions, exemplary definitions, preferred definitions, definitions listed in tables, and definitions of specific compounds in examples, and can be arbitrarily combined or linked to one another. Such combinations and the resulting definitions of groups and structures of compounds should be understood to be within the scope described in the specification and / or claims of this application.

[0081] Unless otherwise specified, numerical ranges described herein and in the claims are equivalent to describing at least each specific integer value within that range. For example, the numerical range "1 to 10" is equivalent to describing the integer values ​​1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 within the numerical range "1 to 10". Furthermore, when some numerical ranges are defined as "numbers", it should be understood that the two endpoints of the range, each integer within the range, and each decimal within the range are described. For example, "numbers from 0 to 10" should be understood not only to describe the integers 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also to describe at least the sum of each integer with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9.

[0082] In this specification, when referring to one, two or more, “more than” should be understood to mean integers greater than 2, such as 3 or more, e.g., 3, 4, 5, 6, 7, 8, 9, or 10.

[0083] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0084] "C 1-40 The term "alkyl group" should be understood to refer to a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1 to 40 carbon atoms. For example, "C 1-10 "Alkyl group" refers to a linear or branched alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and "C 1-6"Alkyl group" refers to linear and branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of the alkyl groups are methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isopentyl group, 2-methylbutyl group, 1-methylbutyl group, 1-ethylpropyl group, 1,2-dimethylpropyl group, neopentyl group, 1,1-dimethylpropyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 2-ethylbutyl group, 1-ethylbutyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 2,3-dimethylbutyl group, 1,3-dimethylbutyl group, or 1,2-dimethylbutyl group, or their isomers.

[0085] "C 3-10 The term "cycloalkyl group" should be understood to represent a saturated monovalent monocyclic, bicyclic (e.g., bridging ring, spiro ring) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 3-10 The cycloalkyl group may be a monocyclic hydrocarbon group such as a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, or cyclodecyl group; or a bicyclic hydrocarbon group such as a bornyl group, indolyl group, hexahydroindolyl group, tetrahydronaphthyl group, decahydronaphthyl group, dicyclo[2.1.1]hexyl group, dicyclo[2.2.1]heptyl group, dicyclo[2.2.1]heptene group, 6,6-dimethyldicyclo[3.1.1]heptyl group, 2,6,6-trimethyldicyclo[3.1.1]heptyl group, dicyclo[2.2.2]octyl group, 2,7-diazaspiro[3,5]nonane group, 2,6-diazaspiro[3,4]octane group; or a tricyclic hydrocarbon group such as an adamantyl group.

[0086] Unless otherwise defined, the term “3- to 10-membered heterocyclyl group” refers to a saturated or unsaturated non-aromatic ring or ring system, such as a 4-, 5-, 6-, or 7-membered monocyclic ring, a 7-, 8-, 9-, or 10-membered bicyclic ring (e.g., a fused ring, a bridging ring, a spiro-ring), or a 10-membered tricyclic ring system, and containing at least one heteroatom selected from O, S, and N, for example, 1, 2, 3, 4, 5, or more, of which N and S may be optionally oxidized to various oxidation states such that nitrogen oxide, -S(O)-, or -S(O)2- states are formed. Preferably, the heterocyclyl group may be selected from “3- to 10-membered heterocyclyl groups”. The heterocyclyl group can be linked to the rest of the molecule by any one of the carbon atoms or a nitrogen atom (if present). The heterocyclyl group may include fused or bridging rings and spiro-ring rings. In particular, the heterocyclyl group may include, but is not limited to, a four-membered ring such as an azetidinyl group or an oxetanyl group, a five-membered ring such as a tetrahydrofuranyl group, a dioxolyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, or a six-membered ring such as a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group, a dithianyl group, a thiomorpholinyl group, a piperazinyl group, or a trithianyl group, or a seven-membered ring such as a diazepanyl group. Optionally, the heterocyclyl group may be benzo-condensed. The heterocyclyl group may also be bicyclic, for example, a five-, five-membered ring such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a five-, six-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring. The heterocyclyl group may be partially unsaturated, that is, it may contain one or more double bonds, for example, a dihydrofuranyl group, a dihydropyranyl group, a 2,5-dihydro-1H-pyrrolyl group, a 4H-[1,3,4]thiadiazine group, a 4,5-dihydroxazolyl group, or a 4H-[1,4]thiadinyl group, but is not limited to these, or may be benzo-condensed, for example, a dihydroisoquinolyl group, but is not limited to these.When the above-mentioned 3- to 10-membered heterocyclyl group is linked with other groups to constitute a compound of the present disclosure, the carbon atoms in the 3- to 10-membered heterocyclyl group may be linked with other groups, or the heterocyclic atoms in the 3- to 10-membered heterocyclyl ring may be linked with other groups. For example, if the 3- to 10-membered heterocyclyl group is selected from piperazinyl groups, the nitrogen atom in the piperazinyl group may be linked with other groups. Alternatively, if the 3- to 10-membered heterocyclyl group is selected from piperidinyl groups, the nitrogen atom in the piperidinyl ring and the carbon atom at its para position may be linked with other groups.

[0087] "C 6-10 The term "aryl group" preferably refers to a monovalent aromatic or partially aromatic monocyclic or bicyclic (e.g., fused ring, bridged ring, spiro ring) hydrocarbon ring having 6 to 10 carbon atoms, and includes monoaromatic rings or polyaromatic rings fused together, particularly rings having 6 carbon atoms such as phenyl or biphenyl groups ("C6 aryl group"), or rings having 9 carbon atoms such as indanyl or indenyl groups ("C9 aryl group"), or rings having 10 carbon atoms such as naphthyl groups ("C9 aryl group"). 10 It should be understood that it may also be an aryl group. 6-10 When an aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, the substitution site is not limited and may be, for example, at the ortho, para, or meta position.

[0088] The term "5-10 membered heteroaryl group" should be understood to include monocyclic, bicyclic (e.g., fused ring, bridging ring, spiro ring), or tricyclic aromatic ring systems having 5-10 ring atoms and containing 1-5 heteroatoms independently selected from N, O, and S, preferably 1-3 heteroatoms independently selected from N, O, and S, and which may further be benzo-condensed in each case. A "heteroaryl group" also refers to a group in which the heteroaryl ring is fused with one or more aryl groups, alicyclic groups, or heterocyclyl rings, where the linking base or point is located on the heteroaryl ring. Non-restrictive examples include 1-, 2-, 3-, 5-, 6-, 7- or 8-indadinyl groups, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl groups, 2-, 3-, 4-, 5-, 6- or 7-indolyl groups, 2-, 3-, 4-, 5-, 6- or 7-indazolyl groups, 2-, 4-, 5-, 6-, 7- or 8-purine groups, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinoazinyl groups, 2-, 3-, 4-, 5 -, 6-, 7- or 8-quinolyl group, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl group, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl group, 2-, 3-, 4-, 5- or 6-naphthalidinyl group, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl group, 3-, 4-, 5-, 6-, 7- or 8-sinnolinyl group, 2-, 4-, 6- or 7-pteridyl group, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH carbazolyl group, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazolyl carbazolyl group, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl group, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenantridinyl group, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl group, 1- , 2-, 4-, 5-, 6-, 7-, 8- or 9-dinyl group, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinyl group, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenadinyl group, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazinyl group, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenadinyl group, 2-, 3-, 4-, 5-,6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinolyl group, 2-, 3-, 4- or thieno[2,3-b]furanyl group, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazino[2,3-c]carbazolyl group, 2-, 3-, 5-, 6- or 7-2H-flo[3,2-b]-pyranyl group, 2-, 3-, 4-, 5-, 7- or 8 -5H-pyrido[2,3-d]-o-azinyl group, 1-,3- or 5-1H-pyrazolo[4,3-d]-thiazolyl group, 2-,4- or 54H-imidazo[4,5-d]thiazolyl group, 3-,5- or 8-pyrazino[2,3-d]pyridazinyl group, 2-,3-,5- or 6-imidazo[2,1-b]thiazolyl group, 1-,3-,6-,7-,8- or 9-flo[3,4-c]sinno Linyl group, 1-,2-,3-,4-,5-,6-,8-,9-,10- or 11-4H-pyrido[2,3-c]carbazolyl group, 2-,3-,6- or 7-imidazo[1,2-b][1,2,4]triazinyl group, 7-benzo[b]thienyl group, 2-,4-,5-,6- or 7-benzoxazolyl group, 2-,4-,5-,6- or 7-benzimidazolyl group, 2-,4-,4- It contains a 5-,6- or 7-benzothiazolyl group, a 1-,2-,4-,5-,6-,7-,8- or 9-benzoxapinyl group, a 2-,4-,5-,6-,7- or 8-benzoazinyl group, and a 1-,2-,3-,5-,6-,7-,8-,9-,10- or 11-1H-pyrrolo[1,2-b][2]benzoazapinyl group. Typical condensed heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl groups, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl groups, 2-, 3-, 4-, 5-, 6- or 7-indolyl groups, 2-, 3-, 4-, 5-, 6- or 7-benzo[b]thienyl groups, 2-, 4-, 5-, 6- or 7-benzoxazolyl groups, 2-, 4-, 5-, 6- or 7-benzimidazolyl groups, and 2-, 4-, 5-, 6- or 7-benzothiazolyl groups. When the above 5- to 10-membered heteroaryl groups are linked with other groups to constitute the compounds of this disclosure, the carbon atoms in the 5- to 10-membered heteroaryl ring may be linked with other groups.The heteroatoms in the 5-10 membered heteroaryl ring may be linked to other groups. When the 5-10 membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, the substitution site is not limited; for example, the hydrogen linked to the carbon atom in the heteroaryl ring may be substituted, or the hydrogen linked to the heteroatom in the heteroaryl ring may be substituted.

[0089] The term "spiro ring" refers to a ring system in which two rings share a single ring-forming atom.

[0090] The term "condensed ring" refers to a ring system in which two rings share two ring-forming atoms.

[0091] The term "bridged ring" refers to a ring system in which two rings share three or more ring-forming atoms.

[0092] Unless otherwise specified, heterocyclyl groups, heteroaryl groups, or heteroalylene groups include all possible isomeric forms thereof, e.g., their positional isomers. Thus, for some non-limiting examples for the sake of explanation, these may include forms in which they are substituted at one, two or more positions (if any), such as the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-positions, or bonded to other groups, and include thienyl or thienylene groups including pyridine-2-yl, pyridylidene-2-yl, pyridine-3-yl, pyridylidene-3-yl, pyridylidene-3-yl, pyridine-4-yl and pyridylidene-4-yl, thienyl groups or thienylene groups including thien-2-yl, thienylene-2-yl, thienylene-3-yl and thienylene-3-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, and pyrazole-5-yl.

[0093] The term "oxo" refers to an oxy substitution (=O) formed by the oxidation of a carbon, nitrogen, or sulfur atom in a substituent.

[0094] Unless otherwise specified, the definitions of terms herein apply similarly to the basis in which the term is included, for example, C 1-10 The definition of an alkyl group is C1-10 Alkyloxy group, C 3-10 This also applies to cycloalkyloxy groups, etc.

[0095] Those skilled in the art will understand that the compound represented by formula (I) can exist in various pharmaceutically acceptable salt forms. If these compounds have a basic center, they can form acid addition salts; if they have an acidic center, they can form base addition salts; and if they contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can further form internal salts.

[0096] The compounds of this disclosure may exist in the form of solvates (e.g., hydrates), of which the compounds of this disclosure include a polar solvent, particularly, water, methanol, or ethanol, which constitutes a component of the crystal lattice of the compound. The amount of the polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.

[0097] The compounds of this disclosure may be chiral due to their molecular structure, and therefore may exist in various enantiomer forms. Accordingly, these compounds may exist in racemic or optically active forms. The compounds of this disclosure include isomers or mixtures thereof, and racemates, in which each chiral carbon is in an R or S configuration. The compounds of this disclosure or their intermediates may be isolated into enantiomer compounds or used in this form for synthesis by chemical or physical methods well known to those skilled in the art. In the case of racemicamines, diastereomers are produced from mixtures by reaction with optically active resolution reagents. Examples of suitable resolution reagents include, for example, tartaric acid in R and S configurations, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or optically active acids such as various optically active camphorsulfonic acids. Enantiomer resolution by chromatography can also be effectively performed using optically active resolution reagents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are solvent mixtures containing water or alcohol, such as hexane / isopropanol / acetonitrile.

[0098] The corresponding stable isomers can be isolated by known methods, for example, by extraction, filtration, or column chromatography.

[0099] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans.

[0100] The term "therapeutic dose" refers to the amount of an active compound or drug that elicits a desired biological or medical response in a tissue, system, animal, individual or human, and includes one or more of the following: (1) prevention of disease: for example, preventing a disease, disorder or illness in an individual that is susceptible to infection but has not experienced or manifested the pathology or symptoms of the disease; (2) inhibition of disease: for example, inhibiting a disease, disorder or illness in an individual that has experienced or manifested the pathology or symptoms of the disease; (3) alleviation of disease: for example, alleviating a disease, disorder or illness in an individual that has experienced or manifested the pathology or symptoms of the disease; (4) relieving disease: for example, alleviating a disease, disorder or illness in an individual that has experienced or manifested the pathology or symptoms of the disease; (5) reversing the pathology and / or symptoms. The therapeutic dose can be initially estimated by cell culture measurements, and initial doses may be estimated from in vivo data. According to these initial guidelines, a person skilled in the art can determine the effective dose in humans. Furthermore, by standard pharmaceutical methods in cell cultures or experimental animals, for example, LD 50 and ED 50 By measuring [the specified value], the toxicity and therapeutic effect of the compounds described herein can be determined.

[0101] The term “disease or condition associated with LRRK kinase or LRRK2 kinase activity” refers to a disease or condition characterized by inappropriate kinase activity or hyperactivity of the kinase as defined herein. Inappropriate activity refers to (i) kinase expression in cells that do not normally express the kinase, (ii) increased kinase expression that causes undesirable cell proliferation, differentiation and / or growth, or (iii) decreased kinase expression that causes undesirable reduction in cell proliferation, differentiation and / or growth. Hyperactivity of a kinase refers to amplification of a gene encoding a particular kinase or the occurrence of a certain level of kinase activity that correlates with abnormalities in cell proliferation, differentiation and / or growth (i.e., the severity of symptoms of one or more cellular abnormalities increases with increasing kinase levels). Hyperactivity may be a result of a mutation, unrelated to ligand binding or constitutive activation, such mutation being, for example, a deletion of a kinase fragment responsible for ligand binding.

[0102] Examples of “excipients” as described in this disclosure are shown in “Handbook of Pharmaceutical Excipients, 2nd edition, 1994, edited by A Wade & PJ Weller.”

[0103] The “carriers” or “diluents” described herein are well known in the pharmaceutical field and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (edited by AR Gennaro 1985).

[0104] The choice of drug carrier, adjuvant, or diluent can be made according to the desired route of administration and standard pharmaceutical practice. The pharmaceutical composition may contain, or additionally contains, any suitable binder as a carrier, adjuvant, or diluent, lubricant, suspending agent, coating agent, solubilizer, buffer, flavoring agent, surfactant, thickener, preservative (including antioxidant), etc., and substances included to make the preparation isotonic with the target blood.

[0105] Of these, pharmaceutical formulations for oral administration with a solid carrier are most preferably in unit dose formulation form, such as pills, capsules, or tablets, each containing a predetermined amount of the active compound. Tablets can be manufactured by pressurizing or molding, in combination with one or more auxiliary components as optional. Pressurized tablets can be manufactured by compressing the active compound in a free-flowing form (e.g., powder or particles) in suitable equipment and mixing it with an optional binder, lubricant, inert diluent, lubricating substance, surfactant, or dispersant. Mold-formed tablets can be manufactured by placing the active compound and an inert liquid diluent into a mold and molding it. Tablets may be optionally coated, or if not coated, a code may be optionally printed on them. Capsules can be manufactured by filling a capsule shell with the active compound alone or in combination with one or more auxiliary components and sealing it in a conventional manner. Cachets are similar to capsules, in which the active compound is sealed in a rice paper film along with optional auxiliary components. The active compound may also be prepared in dispersible particles, for example, by suspending it in water before administration or sprinkling it on food. The particles may be packaged, for example, in small bags. The carrier may be a liquid formulation suitable for oral administration, or it may be an aqueous or non-aqueous liquid solution or suspension, or it may be shown as an oil-in-water liquid emulsion.

[0106] The term "pharmaceutically acceptable salt" includes preferred acid addition salts and alkali salts. Preferred pharmaceutical salts are shown in J Pharm Sci, 66, 199, 1977, Berge, et al. For example, salts are formed using inorganic strong acids such as hydrohalic acids (e.g., hydrochloric acid, hydrobromic acid, and hydroiodic acid), sulfuric acid, phosphate sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, and mineral acids such as sulfonic acid; organic strong carboxylic acids such as acetaldehyde, which is unsubstituted or substituted (e.g., by halogens) and has 1 to 4 carbon atoms; saturated or unsaturated dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, and 4-phthalic acid; hydroxycarboxylic acids such as ascorbic acid, ethanolic acid, lactic acid, malic acid, tartaric acid, and citric acid; amino acids such as aspartic acid and glutamic acid; benzoic acid; and organic sulfonic acids such as methane- and p-toluenesulfonic acid, which is unsubstituted or substituted (e.g., by halogens) and (C1-C4)-alkyl- or aryl-sulfonic acids.

[0107] Suitable salts include, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipine, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanecarboxylate, glucoheptone, glycerophosphate, oxalate, heptane, caproate, fumarate, nicotinate, palmitate, pectinate, 3-phenylpropionate, picrinate, neopentaneate, pro This includes organic sulfonic acids such as pionates, tartrates, lactobionates, pivolates, camphorates, undecanoates and succinates, methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, camphorsulfonates, 2-naphthalenesulfonates, benzenesulfonates, p-chlorobenzenesulfonates and p-toluenesulfonates, as well as inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, hydrogen sulfate, hemisulfuric acid, thiocyanic acid, persulfuric acid, phosphoric acid and sulfonic acids.

[0108] The term "pharmaceutically acceptable ester" refers to the formation of an ester using an organic acid or alcohol / hydroxide in combination with an esterifiable functional group in the structure of the compounds of this disclosure. Organic acids include carboxylic acids such as unsubstituted or substituted (e.g., by halogens) alkanecarboxylic acids having 1 to 12 carbon atoms, such as acetic acid; saturated or unsaturated dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid and 4-phthalic acid; hydroxycarboxylic acids such as ascorbic acid, ethanolic acid, lactic acid, malic acid, tartaric acid and citric acid; amino acids such as aspartic acid and glutamic acid; benzoic acid; and organic sulfonic acids such as unsubstituted or substituted (e.g., by halogens) (C1-C4)-alkyl- or aryl-sulfonic acids, such as methane- and p-toluenesulfonic acid. Preferred hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide and aluminum hydroxide. Alcohols include alkanols that have 1 to 12 carbon atoms, which may be unsubstituted or substituted (e.g., by halogens).

[0109] The term "isotope-labeled compound" indicates that at least one atom of the compounds of this disclosure is substituted with an isotope. Examples of such isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, their corresponding 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 Contains Cl. Deuterium (i.e., 2Substitution with isotopes such as H) may be preferable because it can provide greater metabolic stability, for example, several therapeutic benefits resulting from an increased in vivo half-life or reduced dose requirements. For example, the present disclosure includes compounds of general formula (I) in which any one of the hydrogen atoms is substituted with a deuterium atom.

[0110] The term “prodrug compound” refers to a covalently bonded compound that releases an active parent drug according to general formula (I) in vivo. Such prodrugs are generally compounds of the present disclosure in which one or more preferred groups are already modified so that such modification can be reversed after administration to a human or mammalian subject. Although it is possible to administer a second drug together with such a prodrug for in vivo reversal, the reversal is generally carried out by enzymes naturally occurring in such subjects. Examples of such modifications include the pharmaceutically acceptable esters described above, of which the reversal can be carried out by esterases, etc.

[0111] The term "crystalline polymorph" refers to the compounds of this disclosure in various crystalline, polycrystalline, and hydrated forms. In the pharmaceutical industry, it is clear that chemical compounds can be separated in any of these forms by methods such as the purification and / or separation of solvents used in the synthesis and manufacture of such compounds.

[0112] The term "administration" indicates that the pharmaceutical composition of this disclosure is applicable to rectal, intranasal, intrabronchial, topical (including oral and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, intra-arterial, and intradermal), intraperitoneal, or intrasacral administration. Preferably, the formulation is an oral formulation. The formulation can conveniently be expressed in unit dosage form, i.e., in form including a unit dose or discrete portions of multiple units or subunits of a unit dose. In practice, the formulation may be in the form of tablets and sustained-release capsules and can be manufactured by any method well known in the pharmaceutical field.

[0113] The oral formulations of this disclosure may be expressed as discrete units such as capsules, gels, drops, cachets, pills, or tablets containing a predetermined amount of the activator, as powders or particles, as solutions, emulsions, or suspensions of the activator in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as bolus formulations, etc. Preferably, these compositions contain 1 to 250 mg, and more preferably 10 to 100 mg, of the active ingredient per dose.

[0114] Compositions for oral administration (e.g., tablets and capsules) may further include solvents and / or commonly used adjuvants, such as binders like syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sucrose and starch; fillers and carriers such as corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metal stearate esters, glyceryl stearate, stearic acid, silicone fluids, paraffin wax, oils and colloidal silica. Flavorings, such as mint, wintergreen oil, and cherry flavoring, may also be used. Colorants may be added to facilitate identification of the dosage form. Tablets may be coated in methods well known in the art.

[0115] Other formulations applicable for oral administration generally include topical ointments containing a flavoring substrate, which is an activator in sucrose and gum arabic or tragacanth; lozenges containing an activator in an inert substrate such as gelatin and glycerin, or sucrose and gum arabic; and mouthwashes containing an activator in a suitable liquid carrier.

[0116] Other forms of administration include solutions or emulsions prepared in sterile or sterile solutions and administered by intravenous, intra-arterial, intra-shelter, subcutaneous, intradermal, intraperitoneal, or intramuscular injection. The injectable forms generally contain between 10 and 1000 mg, preferably between 10 and 250 mg, of the active ingredient per dose.

[0117] The above-described form of administration may be a combination administration in which one or more compounds of the present disclosure are administered in combination with one or more other activators. In this case, the compounds of the present disclosure and one or more other activators may be administered sequentially, simultaneously, or sequentially.

[0118] Analytical testing Another aspect of this disclosure relates to the use of the above compounds in analytical testing, which is used to identify other candidate compounds capable of inhibiting one or more kinases, more preferably LRRK, and even more preferably LRRK2.

[0119] Preferably, the analytical test is a competitive coupling test.

[0120] More preferably, competitive binding tests include contacting the compounds of the Disclosure with a kinase, preferably LRRK, more preferably LRRK2, and a candidate compound, and detecting any changes in the interaction between the compounds of the Disclosure and the kinase.

[0121] Preferably, candidate compounds are generated by SAR modification of the compounds of this disclosure.

[0122] As used in this application, the term "SAR modification" refers to a standard method for modifying a given compound by chemical derivatization.

[0123] Therefore, in one embodiment, the identified compound can be used as a model (e.g., a template) in the development of other compounds. The compound used in this measurement can be free in solution, immobilized on a solid support, mounted on a cell surface, or present inside a cell. The scavenging of activity or the formation of a binding complex between the compound and the drug awaiting measurement can be measured.

[0124] Since the analytical tests in this disclosure may be screening tests, many drugs were measured. In one embodiment, the analytical measurement method in this disclosure is a high-throughput screening test.

[0125] This disclosure further considers the use of competitive drug screening tests, in which a neutralizing antibody capable of binding to a compound and the measurement compound for binding to the compound specifically compete.

[0126] For high-throughput screening (HTS) of reagents having suitable binding affinity to a substance, another technique for screening is provided, which is based on the method described in detail in WO84 / 03564.

[0127] The analytical testing method described herein is expected to be applicable to both small-scale and large-scale screening of the target compound, as well as to quantitative testing.

[0128] Preferably, the competitive binding test involves contacting the compound of the disclosure with a kinase in the presence of a known substrate of the kinase and detecting any change in the interaction between the kinase and the known substrate.

[0129] Another aspect of this disclosure provides a method for detecting the binding of a ligand to a kinase, the method being described as follows: (i) The step of contacting the ligand with the kinase in the presence of a known substrate of the kinase, (ii) The step of detecting any change in the interaction between the kinase and the known substrate, Furthermore, the ligand is one of the compounds of this disclosure.

[0130] One aspect of this disclosure is, (a) The step of performing the above measurement method, (b) The step of identifying one or more ligands that can bind to the ligand-binding domain, (c) A step of modifying one or more ligands capable of binding to the ligand-binding domain, (d) The step of performing the above measurement method, (e) A step of optionally producing a pharmaceutical composition containing one or more of the above-mentioned ligands, Regarding methods including

[0131] This disclosure further relates to ligands identified by the above method.

[0132] Another aspect of this disclosure relates to a pharmaceutical composition comprising a ligand identified by the method described above.

[0133] Another aspect of this disclosure relates to the use of ligands identified by the above method in the manufacture of a pharmaceutical composition, wherein the pharmaceutical composition is used to treat one or more medical conditions.

[0134] The above method can be used to screen ligands that can be used as inhibitors of one or more kinases.

[0135] [Brief explanation of the drawing] [Figure 1] This is an exemplary figure of the Western blot results for LRRK2 expression levels in LRRK2-G2019S mouse brain tissue from Example 12.

[0136] [Figure 2] This figure shows the effect of compound 527 of Example 12 on the phosphorylation level of LRRK2 in LRRK2-G2019S mouse brain tissue. The data are mean ± sample standard deviation (mean ± SE), n=8, * represents p<0.05 relative to the solvent control group, and *** represents p<0.001 relative to the solvent control group. Single-way ANOVA was used.

[0137] [Modes for carrying out the invention] The technical proposals of this disclosure will be described in more detail below, in conjunction with specific embodiments. The embodiments described below are merely illustrative and should not be interpreted as limiting the scope of the claims of this disclosure. Any technology realized based on the above-mentioned content of this disclosure falls within the scope of the claims of this disclosure.

[0138] Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available or can be manufactured by known methods.

[0139] In the context of this disclosure, abbreviations have the following meanings: DBU 1,8-Diazabicyclo[5.4.0]Undeca-7-Ene DCM Dichloromethane DEA (Diethylamine) DIEA (Diisopropylethylamine) DMA N,N-dimethylacetamide DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) EA, HCl ethyl acetate IPA Isopropanol MTBE tert-butylmethyl ether NIS N-iodosuccinimide NMR nuclear magnetic resonance PE (Petroleum Ether) PMBCl p-methoxybenzyl chloride RT, t R retention time SFC Supercritical Fluid Chromatography Tf trifluoromethylsulfonyl group TfOH Trifluoromethanesulfonic acid TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) UV ultraviolet light.

[0140] chromatography High-pressure liquid chromatography was used and monitored with a multi-wavelength UV detector. Typical mobile phases used in the separation process are PE / EA, DCM / MeOH, or water / MeCN.

[0141] Analysis method Unless otherwise specified, the above solvents are measured at room temperature using a Bruker AV 400 spectrometer. 1 Nuclear magnetic resonance (NMR) spectroscopy was performed. In all cases, the NMR data were consistent with the submitted structure. Common abbreviations were used to specify the main peaks, indicating characteristic chemical shifts (δ) in units of parts per million: e.g., s, singleline; d, doubleline; t, tripleline; q, quadrupleline; dd, doubleline of doubleline; br, broadline. Mass spectrometry was recorded using Agilent 1290 Infinity / 6460 triple Quad LC-MS. When thin-layer chromatography (TLC) was used, it referred to silica gel TLC.

[0142] Manufacturing of compounds Where the preparation of the starting materials is not described, these starting materials may be commercially available, known in the literature, or readily obtainable by a person skilled in the art using standard procedures. Where the preparation of a compound by conventional examples or intermediates is described, a person skilled in the art will understand that the reaction time, equivalent amounts of reagents, and temperature of each specific reaction may be modified, and that the use of different post-treatment or purification techniques may be essential or desirable.

[0143] Example 1: Preparation of Compound 390

[0144] [ka]

[0145] Step 1: Synthesis of (2S,6R)-4-(6-chloropyrimidine-4-yl)-2,6-dimethylmorpholine (1-1) At room temperature, DIEA (87.7 g, 0.680 mol) and (2R,6S)-2,6-dimethylmorpholine (40.5 g, 0.350 mol) were added to a solution of 4,6-dichloropyrimidine (50.0 g, 0.340 mol) in IPA (1000 mL). The mixture was stirred at room temperature for 1 hour. The solution was concentrated to remove the solvent, and the residue was diluted with SiO2 (500 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to obtain a white solid (2S,6R)-4-(6-chloropyrimidine-4-yl)-2,6-dimethylmorpholine (1-1, 76.0 g, 98.4%). m / z (ESI) + : 228.0 [M+H] + .

[0146] Step 2: Synthesis of (2S,6R)-2,6-dimethyl-4-(6-(trimethylstannyl)pyrimidine-4-yl)morpholine (1-2) A dry three-necked flask containing xylene (100 mL) was heated to 150°C under an N2 atmosphere. Then, a solution of compound 1-1 (10.0 g, 44.1 mmol) in xylene (50 mL), a degassed mixture of 1,1,1,2,2,2-hexamethylstilbene (18.8 g, 57.3 mmol), Pd(PPh3)2Cl2 (3.00 g, 4.40 mmol), and PPh3 (2.30 g, 8.80 mmol) was added dropwise. The resulting mixture was stirred at 150°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with PE, and then filtered through diatomaceous earth. The filtrate was concentrated under vacuum to obtain a crude product (1-2, 16.0 g, approximately 60% purity) as a yellow solid, which was used in the next step without requiring further purification. m / z (ESI) + : 358.1 [M+H] + .

[0147] Step 3: Synthesis of 4-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine(1-3) At room temperature, 88.0 g, 0.390 mol of NIS was added to a 500 mL solution of 4-chloro-1H-pyrazolo[4,3-c]pyridine in DMF. After the addition was complete, the mixture was heated to 80°C and stirred for 2 hours. The mixture was then concentrated to obtain a residue, which was treated with 500 mL of saturated NaHSO3 aqueous solution and stirred for 30 minutes. The resulting solid was collected by filtration, washed with 2 L of water, and then dried under vacuum to obtain a brown solid product (1-3, 83.0 g, 91.2%). m / z (ESI) + : 279.8 [M+H] + .

[0148] Step 4: Synthesis of 4-chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine(1-4) In an ice bath, a solution of compound 1-3 (80.0 g, 0.290 mol) in DMF (800 mL) was mixed with PMBCl (49.6 g, 0.320 mol) and NaOH (23.2 g, 0.580 mol). The mixture was stirred at room temperature for 20 hours, concentrated to remove the solvent, dissolved in SiO2 (500 mL), washed with brine, dried over anhydrous Na2SO4, filtered, and the solution was concentrated to obtain the residue. This residue was then slurryed with PE and EA (PE / EA = 1:1) and stirred overnight. After filtration, the solid was dried to obtain compound 1-4 (104 g, 89.7%), a grayish-white solid. m / z (ESI) + : 399.7 [M+H] + .

[0149] Step 5: Synthesis of N-cyclopropyl-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-4-amine(1-5) A mixture of compounds 1-4 (7.00 g, 17.5 mmol) and cyclopropanamine (10.0 g, 175 mmol) in DIEA (50 mL) was heated to 140°C and stirred for 2 days. The mixture was concentrated under vacuum to remove the solvent, and then diluted with EA and brine. The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (100% EA) to obtain compound 1-5 (5.00 g, 68.0%) in brown solid form. m / z (ESI) + : 421.1 [M+H] + .

[0150] Step 6: Synthesis of N-cyclopropyl-3-(6-((2S,6R)-2,6-dimethylmorpholino)pyrimidine-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-4-amine(1-6) Under an N2 atmosphere, a mixture of compounds 1-5 (200 mg, 0.476 mmol) in DMF (10 mL) and the crude product compound 1-2 (approximately 60% purity, 425 mg, 0.714 mmol) was added to Pd(PPh3)2Cl2 (34 mg, 0.048 mmol), PPh3 (25 mg, 0.095 mmol), and CuI (9 mg, 0.043 mmol). The mixture was degassed, purged three times with nitrogen gas, and then stirred at 120°C for 1 hour. After cooling to room temperature, it was diluted with EA, the organic matter was washed with saturated KF aqueous solution and brine, the organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (DCM / MeOH = 19:1) to obtain compound 1-6 (50.0 mg, 21.6%) in a light brown solid form. m / z (ESI) + : 486.1 [M+H] + .

[0151] Step 7: Synthesis of N-(3,3-difluorocyclobutyl)-3-(6-(2S,6R)-2,6-dimethylmorpholino)pyrimidine-4-yl)-1H-pyrazolo[4,3-c]pyridine-4-amine (390) To a solution of compound 1-6 (50.0 mg, 0.103 mmol) in TFA (5 mL), TfOH (0.5 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated to remove the solvent and diluted with DCM. Next, it was washed with 1 M aqueous NaOH solution and brine to separate the organic layer, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to obtain compound 390 (6 mg), a grayish-white solid. 1 HNMR (400 MHz, CD3OD) δ 8.68 (d, J = 1.0 Hz, 1H), 7.72-7.65 (m, 2H), 7.10 (d, J = 7.2 Hz, 1H), 4.26-4.72 (m, 2H), 3.76-3.64 (m, 2H), 2.94-2.86 (m, 1H), 2.78-2.65 (m, 2H), 1.28 (d, J = 6.2 Hz, 6H), 1.20-1.13 (m, 2H), 0.95-0.88 (m, 2H). m / z (ESI) + : 366.0 [M+H] + .

[0152] Referring to Example 1, the compounds shown in Table 1 were prepared by using the corresponding starting materials in Step 5.

[0153] [Table 1]

[0154] Example 2: Preparation of Compound 397

[0155] [ka]

[0156] Step 1: Synthesis of (cis)-2,6-dimethyltetrahydro-2H-pyran-4-ol (2-1) To a solution of 2,6-dimethyl-4H-pyran-4-one (5.00 g, 40.3 mmol) in ethanol (50 mL), Pd / C (10%, 0.500 g) was added, and the reaction mixture was stirred at 35°C and H2 (4 atm) for 20 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain compound 2-1 (5.00 g, 95.4%) in pale yellow crystalline form. m / z (ESI) + : 131.1 [M+H] + .

[0157] Step 2: Synthesis of 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-1H-pyrazole(2-2) At room temperature, 2-iodopropane (6.57 g, 38.6 mmol) was added to a suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)-1H-pyrazole (5.00 g, 25.8 mmol) and Cs2CO3 (12.6 g, 38.6 mmol) in acetonitrile (100 mL). The mixture was heated to 60°C and stirred for 20 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 4:1) to obtain a colorless oily compound 2-2 (5.80 g, 95.2%). 1 HNMR (300 MHz, CDCl3) δ 7.78 (s, 1H), 7.73 (s, 1H), 4.51 (hept, J = 6.7 Hz, 1H), 1.49 (d, J = 6.7 Hz, 6H), 1.31 (s, 12H).

[0158] Step 3: Synthesis of 4-((2R,4R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine(2-3): At room temperature, 10 mL of DMA solution of compound 2-1 (510 mg, 3.90 mmol) was mixed with 60% NaH (187 mg, 4.68 mmol). After stirring for 10 minutes, compound 1-4 (1.57 g, 3.9 mmol) was added. The resulting mixture was heated to 120°C and stirred for 20 hours. After cooling to room temperature, 100 mL of water was added, and the resulting mixture was extracted with RINKAN (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (PE / EA=3:2) to obtain compound 2-3 (680 mg, 35.3%), a pale yellow oily substance. m / z (ESI) + : 493.7 [M+H] + .

[0159] Step 4: Synthesis of 4-((2R,4R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-3-(1-isopropyl-1H-pyrazole-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine(2-4): Compounds 2-3 (176 mg, 0.357 mmol), 2-2 (90 mg, 0.38 mmol), and Na2CO3 (121 mg, 1.14 mmol) were mixed in DMSO / H2O (5 mL / 0.5 mL) with Pd(dppf)Cl2 (27 mg, 0.038 mmol). The mixture was degassed, purged three times with nitrogen gas, and then stirred at 80°C in a nitrogen atmosphere for 20 hours. After cooling to room temperature, EA and water were added. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (PE / EA = 32:3) to obtain compound 2-4 (100 mg, 59.0%) in a light brown solid form. m / z (ESI) + : 475.8 [M+H] + .

[0160] Step 5: Synthesis of 4-((2R,4R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-3-(1-isopropyl-1H-pyrazole-4-yl)-1H-pyrazolo[4,3-c]pyridine (397): Similar to step 7 of Example 1, 4-((2R,4R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-3-(1-isopropyl-1H-pyrazole-4-yl)-1H-pyrazolo[4,3-c]pyridine (397) was synthesized from compound 2-4 to obtain a white solid. 1 HNMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 8.14 (s, 1H), 7.86 (d, J = 6.1 Hz, 1H), 7.07 (d, J = 6.1 Hz, 1H), 5.54-5.45 (m, 1H), 4.67-4.59 (m, m / z (ESI) + : 355.8 [M+H] + .

[0161] Referring to Example 2, the compounds shown in Table 2 were prepared using appropriate starting materials.

[0162] [Table 2]

[0163] Example 3: Preparation of Compounds 407 and 421

[0164] [ka]

[0165] Step 1: Synthesis of (2R,6S)-2,6-dimethyltetrahydro-4H-pyran-4-one (3-1) To a solution of 2,6-dimethyl-4H-pyran-4-one (100 g, 0.810 mol) in ethanol (800 mL), Pd / C (10%, 10 g) was added, and the mixture was stirred for 8 hours at 30°C with H2 (2 atm). The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA=3:1) to obtain a crude product of colorless oily compound 3-1 (53.0 g, 51.1%). m / z (ESI)+: 129.1 [m+H] + .

[0166] Step 2: Synthesis of (2R,6S)-2,6-dimethyltetrahydro-4H-pyran-4-oneoxime (3-2) A suspension of compound 3-1 (15 g, 0.12 mol), hydroxylamine hydrochloride (8.1 g, 0.12 mol), and NaOAc (19.7 g, 0.24 mol) in ethanol (150 mL) was heated to 60°C and stirred for 3 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the residue. The residue was diluted with SiO2 and washed with brine. The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (PE / EA=3:7) to obtain compound 3-2 (16.0 g, 95.6%), a white solid. m / z (ESI)+: 144.2 [m+H] + .

[0167] Step 3: Synthesis of (2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-amine (3-3) To a suspension of LiAlH4 (5.7 g, 0.15 mol) in THF (200 mL), a solution of compound 3-2 (7.2 g, 0.050 mol) was added dropwise at 0°C. The mixture was then heated to 60°C and stirred for 6 hours. After cooling to 0°C in an ice bath, the reaction was quenched by sequentially adding water (5.7 mL), 15% NaOH aqueous solution (5.7 mL), and water (17.1 mL). Mg2SO4 was then added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3-3 (6.10 g, 94.5%), a colorless oil. m / z (ESI)+: 130.1[m+H] + .

[0168] Step 4: Synthesis of 4-((2R,4R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)oxy)-3-(1-isopropyl-1H-pyrazole-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine(3-4) A mixture of compounds 1-4 (18.6 g, 46.5 mmol) and 3-3 (6.00 g, 46.5 mmol) in DIEA (100 mL) was stirred at 140°C for 36 hours. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (DCM / MeOH = 97:3) to obtain compound 3-4 (10.0 g, 43.7%), which was a brown solid. m / z (ESI)+: 492.8[m+H] + .

[0169] Step 5: Synthesis of 3-(6-((2S,6R)-2,6-dimethylmorpholino)pyrimidine-4-yl)-N-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-4-amine(3-5) Under nitrogen gas protection, Pd(PPh3)2Cl2 (280 mg, 0.400 mmol) and CuI (76 mg, 0.400 mmol) were added to a mixture of intermediate 3-4 (1.00 g, 2.00 mmol) and the crude product of intermediate 1-2 (purity about 60%, 1.4 g, 2.35 mmol) in DMF (20 mL). The mixture was degassed and purged three times with nitrogen gas, and then stirred at 120 °C for 2 hours. After cooling to room temperature and diluting with EtOAc and water, the separated organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (PE / EA = 1:9) to obtain intermediate 3-5 (300 mg, 26.9%) as a light brown solid. m / z (ESI)+: 557.7 [m+H] + .

[0170] Step 6: Synthesis of 3-(6-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)-N-((2R,4R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-4-amine (407) and 3-(6-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)-N-((2R,4S,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-4-amine (421) TfOH (2 mL) was added to a solution of intermediate 3-5 (300 mg, 0.54 mol) in TFA (20 mL). The mixture was stirred at room temperature for 1 hour. It was concentrated, diluted with EtOAc, washed with 1 mol / L aqueous NaOH solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (PE / EA = 1:9), and then separated by preparative HPLC (water, Gemini 5 μm, C18 150×21.2 mm, 20 mL / min, ACN / H2O (0.1% TFA) = 33%:67%, held for 10 min) to obtain white solids of compound 407 (16.5 mg) RT = 6.55 min and compound (8.3 mg) RT = 8.07 min

[0171] Compound 407: 1 HNMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 7.68 (s, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 4.50 - 4.30 (m, 2H), 4.08 - 3.96 (m, 1H), 3.74 - 3.64 (m, 4H), 2.70 (t, J = 11.8 Hz, 2H), 2.23 - 2.16 (m, 2H), 1.46 - 1.35 (m, 2H), 1.31 - 1.24 (m, 12H); m / z (ESI) + : 437.9 [M+H] + 。

[0172] Compound 421: 1 HNMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 7.74 (s, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H), 4.63 - 4.36 (m, 2H), 4.32 (s, 1H), 4.01 - 3.93 (m, 2H), 3.73 - 3.64 (m, 2H), 2.70 (t, J = 11.8 Hz, 2H), 2.03 - 1.94 (m, 2H), 1.76 - 1.66 (m, 2H), 1.30 - 1.24 (m, 12H); m / z (ESI) + : 437.9 [M+H] + 。

[0173] Referring to Example 1 and Example 3, appropriate amines were used instead of (2R,6S)-2,6-dimethylmorpholine in Step 1 of Example 1 and / or appropriate amines were used instead of 3-3 in Step 4 of Example 3 to synthesize the compounds in Table 3. Among them, Compounds 527, 528, 561 and 562 for which the retention time RT is not specified were produced by selecting chiral raw materials.

[0174]

Table 3

[0175] Example 4: Preparation of Compound 422 and Compound 445

[0176] [ka]

[0177] Step 1: Synthesis of 4-iodo-1-isopropyl-1H-imidazole (4-1) Cs2CO3 (50 g, 0.15 mol) was added to a solution of 4-iodo-1H-imidazole (20 g, 0.1 mol) and 2-iodopropane (21 g, 0.12 mol) in CH3CN (50 mL). The resulting mixture was stirred overnight at 60°C. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated. The residue was dissolved in SiO4, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to obtain compound 4-1 (20 g, 82%), a colorless oil. m / z (ESI)+: 236.8 [m+H] + .

[0178] Step 2: Synthesis of (1-isopropyl-1H-imidazole-4-yl)boronic acid (4-2) Under nitrogen gas protection, at -75°C, a solution of n-butyllithium (n-BuLi) in n-hexane (2.4 M, 16 mL, 38 mmol) was gradually added dropwise to a solution of compound 4-1 (3 g, 13 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde (7.1 g, 38 mmol) in THF (20 mL). After the addition was complete, the mixture was stirred at -75°C for 2 hours. The reaction was quenched by adding NH4Cl (saturated aqueous solution, 50 mL) to the mixture. The organic layer was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (DCM / MeOH = 10:1) to obtain compound 4-2 (1.7 g, 87%), a white solid. m / z (ESI)+: 155.2 [m+H] + .

[0179] Step 3: Synthesis of N-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-isopropyl-1H-imidazole-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-4-amine(4-3) N-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-isopropyl-1H-imidazole-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-4-amine (4-3) was synthesized from compounds 4-2 and 3-4 by a method similar to step 4 of Example 2, and was a white solid. m / z (ESI)+: 475.2 [m+H] + .

[0180] Step 4: Synthesis of N-((2R,4R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-isopropyl-1H-imidazole-4-yl)-1H-pyrazolo[4,3-c]pyridine-4-amine (422) and N-((2R,4S,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-isopropyl-1H-imidazole-4-yl)-1H-pyrazolo[4,3-c]pyridine-4-amine (445) TfOH (0.5 mL) was added to a TFA (10 mL) solution of intermediate 4-3 (200 mg, 0.42 mol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated, diluted with ELISA, washed with 1 M NaOH aqueous solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (PE / EA = 1:9), then separated by SFC (chiral chromatography column chiralpak IC column, 4.6 mm × 250 mm, 5 μm, eluted with CO2-EtOH (0.2% NH4OH)) to obtain compound 422 (9 mg) RT = 15.6 min and compound 445 (3 mg) RT = 10.09 min, which were white solids.

[0181] Compound 422: 1 HNMR (400 MHz, CD3OD) δ 7.95 (s, 1H), 7.79 (s, 1H), 7.59 (d, J = 6.6 Hz, 1H), 6.76 (d, J = 6.6 Hz, 1H), 4.60-4.52 (m, 1H), 4.17-4.07 (m, m / z (ESI) + : 355.2 [M+H] + .

[0182] Compound 445: 1HNMR (400 MHz, CD3OD) 7.88 (s, 1H), 7.84 (s, 1H), 7.61 (d, J = 6.6 Hz, 1H), 6.78 (d, J = 6.6 Hz, 1H), 4.65-4.55 (m, 1H), 4.45-4.37 (m, 1H), 4.15-4.05 (m, 2H), 1.98-1.88 (m, 2H), 1.73-1.63 (m, 2H), 1.59 (d, J = 6.6 Hz, 6H), 1.25 (d, J = 6.1 Hz, 1H); m / z (ESI) + : 355.2 [M+H] + 。

[0183] Referring to Example 3 and Example 4, appropriate amines can be used instead of amine 3-3 in step 4 of Example 3 to produce the compounds shown in Table 4.

[0184]

Table 4

[0185] Example 5: Preparation of Compounds 423 and 439

[0186]

Chemical Structure

[0187] Step 1: Synthesis of 1-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)-1H-pyrazole (5-1) Under a nitrogen atmosphere at 0°C, 3-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)-1H-pyrazole (1.04 g, 5.36 mmol) was added to a suspension of NaH (60%, 0.24 g, 6 mmol) in DMF (10 mL). The mixture was stirred at 30°C for 30 minutes. It was then cooled to 0°C, and 2-iodopropane (0.8 mL, 8 mmol) was added dropwise. The resulting mixture was stirred at room temperature for a further 30 minutes. The reaction was quenched by adding saturated aqueous solution of NH4Cl to the mixture, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (PE / EA=4:1) to obtain compound 5-1 (550 mg, 43%), a colorless oil. 1 HNMR (300 MHz, CD3OD) δ 7.67 (d, J = 2.3 Hz, 1H), 6.59 (d, J = 2.3 Hz, 1H), 4.66-4.52 (m, 1H), 1.48 (d, J = 6.7 Hz, 6H), 1.19(s, 12H).

[0188] Step 2: Synthesis of N-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-isopropyl-1H-pyrazole-3-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-4-amine(5-2): N-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-isopropyl-1H-imidazole-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-4-amine (5-2) was synthesized from compounds 5-1 and 3-4 by a method similar to step 4 of Example 2, and was a white solid. m / z (ESI) + : 475.2 [M+H] + .

[0189] Step 3: Synthesis of N-((2R,4R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-isopropyl-1H-pyrazole-3-yl)-1H-pyrazolo[4,3-c]pyridine-4-amine (423) and N-((2R,4S,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-isopropyl-1H-pyrazole-3-yl)-1H-pyrazolo[4,3-c]pyridine-4-amine (439) TfOH (0.5 mL) was added to a solution of intermediate 5-2 (200 mg, 0.42 mmol) in TFA (10 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated, diluted with ELISA, washed with 1 M aqueous NaOH solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (DCM / MeOH = 10:1), then separated by SFC (chiral chromatography column chiralpak IC column, 4.6 mm × 250 mm, 5 μm, eluted with CO2-IPA (0.2% NH4OH)) to obtain compound 423 (50 mg), RT = 10.55 min and compound 439 (17 mg), RT = 7.90 min, which were white solids.

[0190] Compound 423: 1 HNMR (400 MHz, CD3OD) δ 7.86 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 6.9 Hz, 1H), 6.95-6.90 (m, 2H), 4.76-4.66 (m, 1H), 4.21-4.13 (m, 1H), 3.77-3.68 (m, 2H), 2.28-2.21 (m, 2H), 1.64 (d, J = 6.7 Hz, 6H), 1.44-1.33 (m, 2H), 1.29 (d, J = 6.2 Hz, 6H); m / z (ESI) + : 354.9 [M+H] + .

[0191] Compound 439: 1HNMR (400 MHz, CD3OD) δ 7.87 (d, J = 2.5 Hz, 1H), 7.70 (d, J = 6.4 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 6.76 (d, J = 6.4 Hz, 1H), 4.67-4.57 (m, 1H), 4.54-4.49 (m, 1H), 4.06-3.97 (m, 2H), 2.04-1.97 (m, 2H), 1.67-1.62 (m, 2H), 1.60 (d, J = 6.8 Hz, 6H), 1.23 (d, J = 6.2 Hz, 6H); m / z (ESI) + : 354.9 [M+H] + .

[0192] Referring to Examples 3 and 5, the compounds shown in Table 5 can be produced by using a suitable amine instead of amine 3-3 in step 4 of Example 3.

[0193] [Table 5]

[0194] Example 6: Preparation of Compound 523

[0195] [ka]

[0196] Step 1: Synthesis of 2-(6-chloropyrimidine-4-yl)-2-cyanoacetate tert-butyl(6-1) At 0°C under nitrogen gas, sodium hydride (60%, 6.71 g, 0.168 mol) was added to a solution of 4,6-dichloropyrimidine (10 g, 0.067 mol) and 2-tert-butyl cyanoacetate (23.7 g, 0.168 mol) in THF (100 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding saturated aqueous solution of NH4Cl to the mixture, and then the pH was adjusted to 2-3 with 1 M aqueous solution of HCl. After extraction twice with HCl, the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain compound 6-1 (16 g, 94%), a white solid. m / z(ESI)+: 253.9[m+H] + .

[0197] Step 2: Synthesis of 2-(6-chloropyrimidine-4-yl)acetonitrile (6-2) To a solution of intermediate 6-1 (11 g, 0.043 mol) in toluene (100 mL), p-toluenesulfonic acid monohydrate (0.82 g, 0.0043 mol) was added. The mixture was stirred at 100°C for 3 hours. After cooling to room temperature, it was diluted with SiO2, washed with saturated aqueous NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (PE / EA = 7:3) to obtain compound 6-2 (5.5 g, 84%), a yellow solid. m / z(ESI)+: 154.0[m+H] + .

[0198] Step 3: Synthesis of 1-(6-chloropyrimidine-4-yl)cyclobutan-1-carbonitrili (6-3) In an ice bath, a suspension of potassium carbonate (1.38 g, 10 mmol) in DMF (10 mL) was added dropwise to a solution of intermediate 6-2 (612 mg, 4 mmol) and 1,3-dibromopropane (965 mg, 4.8 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with SiO2, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (PE / EA=1:1) to obtain compound 6-3 (600 mg, 78%), a yellow solid. m / z(ESI)+: 194.0 [m+H] + .

[0199] Step 4: Synthesis of 1-(6-(trimethylstannyl)pyrimidine-4-yl)cyclobutan-1-carbonitrile (6-4) 1-(6-(trimethylstannyl)pyrimidine-4-yl)cyclobutan-1-carbonitrili (6-4) was synthesized from compound 6-3 by a method similar to step 2 of Example 1, and was a yellow solid. m / z(ESI)+: 323.9 [m+H] + .

[0200] Step 5: Synthesis of 3-iodo-1-(4-methoxybenzyl)-N-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine-4-amine(6-5) A suspension of intermediates 1-4 (30 g, 0.075 mol), 2,2,2-trifluoroethylamine hydrochloride (30.5 g, 0.225 mol), and DBU (23 g, 0.15 mmol) in xylene (250 mL) was sealed and heated in an oil bath to 190°C, stirring for 3 hours. The mixture was cooled to room temperature, diluted with pharmaceutically acceptable ammonium compounds (SiO₂), washed with brine, dried over anhydrous sodium 2SO₄, filtered, and concentrated to obtain the residue. The residue was stirred over MTBE for 30 minutes at room temperature, filtered, and compound 6-5 (24 g, 69%) was obtained as a white solid. m / z(ESI)+: 463.1 [m+H] + .

[0201] Step 6: Synthesis of 1-(6-(1-(4-methoxybenzyl)-4-(2,2,2-trifluoroethyl)amino)-1H-pyrazolo[4,3-c]pyridin-3-yl)pyrimidine-4-yl)cyclobutan-1-carbonitrili (6-6) 1-(6-(1-(4-methoxybenzyl)-4-(2,2,2-trifluoroethyl)amino)-1H-pyrazolo[4,3-c]pyridin-3-yl)pyrimidine-4-yl)cyclobutan-1-carbonitrili (6-6) was synthesized from compounds 6-4 and 6-5 by a method similar to step 5 of Example 3, and was a yellow solid. m / z(ESI)+: 493.9[m+H]+.

[0202] Step 7: Synthesis of 1-(6-(4-((2,2,2-trifluoroethyl)amino)-1H-pyrazolo[4,3-c]pyridin-3-yl)pyrimidine-4-yl)cyclobutan-1-carbonitrile (523) 1-(6-(4-((2,2,2-trifluoroethyl)amino)-1H-pyrazolo[4,3-c]pyridin-3-yl)pyrimidine-4-yl)cyclobutan-1-carbonitrile (523) was synthesized from compound 6-6 by a method similar to step 6 of Example 3, and was a yellow solid. 1 HNMR (400 MHz, DMSO-d6) δ 13.65 (s, 1H), 10.26 (s, 1H), 8.08 (s, 1H), 7.80 (d, J = 6.0 Hz, 1H), 7.32 (s, 1H), 6.80 (d, J = 6.0 Hz, 1H), 4.48-4.35 (m, 2H), 3.92-3.81 (m, 2H), 2.34-2.27 (m, 2H), 1.90-1.80 (m, 2H); m / z (ESI) + : 373.8 [M+H] + .

[0203] Referring to Example 6, the compounds shown in Table 6 were prepared by using a suitable halogenated hydrocarbon instead of 1,3-dibromopropane in step 2, or by using a suitable amine instead of 2,2,2-trifluoroethylamine in step 5.

[0204] [Table 6]

[0205] Example 7: Preparation of Compounds 521 and 509

[0206] [ka]

[0207] Step 1: Synthesis of 2-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-1H-pyrazole-1-yl)acetonitrile (7-1) Sodium hydride (60%, 4.12 g, 0.103 mol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)-1H pyrazole (10 g, 0.052 mol) in DMF (150 mL) while stirring at 0°C. After stirring for 30 minutes, 2-bromoacetonitrile (12.35 g, 0.103 mol) was added. The mixture was stirred overnight at room temperature. The reaction was quenched by adding saturated aqueous solution of NH4Cl to the mixture, and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (DCM / MeOH = 97:3) to obtain compound 7-1 (2.0 g, 17%), a grayish-white solid. m / z (ESI)+: 234.0[m+H] + .

[0208] Step 2: Synthesis of 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-1H-pyrazole-1-yl)spiro[2.3]hexane-5-carbonitrile(7-2) Under nitrogen gas protection, a solution of LiHMDS (1 M, 43 mL, 43 mmol) in THF (150 mL) was added dropwise to a solution of intermediate 7-1 (2.05 g, 8.8 mmol) and 1,1-bis(bromomethyl)cyclopropane (2.0 g, 8.8 mmol) in THF (50 mL) at -5°C to 0°C. The mixture was stirred at this temperature for 10 minutes, and then the reaction was quenched with formic acid. The mixture was concentrated to obtain the residue. The residue was purified by silica gel column chromatography (DCM / MeOH = 99:1) to obtain compound 7-2 (170 mg, 26%), a colorless oil. m / z (ESI)+: 300.0 [m+H] + .

[0209] Step 3: Synthesis of 5-(4-(1-(4-methoxybenzyl)-4-(2,2,2-trifluoroethyl)amino)-1H-pyrazolo[4,3-c]pyridine-3-yl)-1H-pyrazole-1-yl)spiro[2,3]hexane-5-carbonitrile(7-3) 5-(4-(1-(4-methoxybenzyl)-4-(2,2,2-trifluoroethyl)amino)-1H-pyrazolo[4,3-c]pyridine-3-yl)-1H-pyrazole-1-yl)spiro[2.3]hexane-5-carbonitrile (7-3) was synthesized from compounds 7-2 and 6-5 by a method similar to step 4 of Example 2, and was a yellow solid. 1 HNMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.96 (s, 1H), 7.87 (d, J = 6.1 Hz, 1H), 7.20-7.15 (m, 2H), 6.86-6.79 (m, 2H), 6.68 (d, J = 6.1 Hz, 1H), 5.43 (s, 2H), 5.16 (t, J = 6.3 Hz, 1H), 4.37-4.24 (m, 2H), 3.76 (s, 3H), 3.34-3.26 (m, 2H), 3.03-2.95 (m, 2H), 0.85-0.77 (m, 2H), 0.67-0.59 (m, 2H); m / z (ESI) + : 507.7 [M+H] + .

[0210] Step 4: Synthesis of 3-ethylidene-1-(4-(4-((2,2,2-trifluoroethyl)amino)-1H-pyrazolo[4,3-c]pyridine-3-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile (521) and 5-(4-((2,2,2,2-trifluoroethyl)amino)-1H-pyrazolo[4,3-c]pyridine-3-yl)-1H-pyrazole-1-yl)spiro[2.3]hexane-5-carbonitrile (509) 1-(6-(4-((2,2,2-trifluoroethyl)amino)-1H-pyrazolo[4,3-c]pyridin-3-yl)pyrimidine-4-yl)cyclobutan-1-carbonitrile (521) and 5-(4-(4-((2,2,2-trifluoroethyl)amino)-1H-pyrazolo[4,3-c]pyridin-3-yl)-1H-pyrazole-1-yl)spiro[2.3]hexane-5-carbonitrile (509) were synthesized from compound 7-3 by a method similar to step 7 of Example 1, and were white solids.

[0211] Compound 521: RT = 8.3 min (preparative HPLC (GILSON, Gemini 5 μm, C18 150 x 21.2 mm, 20 mL / min, ACN / H2O (0.05%NH4OH) = 35%:65%~60%:40%, within 10 min)); 1 HNMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 7.99 (s, 1H), 7.84 (d, J = 6.2 Hz, 1H), 6.89 (d, J = 6.2 Hz, 1H), 5.60-5.52 (m, 1H), 4.28 (q, J = 9.5 Hz, 2H), 3.79-3.64 (m, 4H), 1.66-1.60 (m, 3H); m / z (ESI) + : 387.8 [M+H] + .

[0212] Compound 509: RT = 7.7 min (preparative HPLC (GILSON, Gemini 5 μm, C18 150 x 21.2 mm, 20 mL / min, ACN / H2O (0.05%NH4OH) = 35%:65%~60%:40%, within 10 min)); 1 HNMR (400 MHz, CD3OD) δ 8.30 (s, 1H), 7.99 (s, 1H), 7.84 (d, J = 6.2 Hz, 1H), 6.89 (d, J = 6.2 Hz, 1H), 5.60-5.52 (m, 1H), 4.29 (q, J = 3.30-3.26 (m, 2H), 3.04-2.98 (m, 2H), 0.83-0.77 (m, 2H), 0.66-0.59 (m, 2H); m / z (ESI) + : 387.9 [M+H] + .

[0213] Example 8: Preparation of Compound 526

[0214] [ka]

[0215] Step 1: Synthesis of 3-(6-((1R,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)pyrimidine-4-yl)-1-(4-methoxybenzyl)-N-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine-4-amine(8-1) Using a method similar to that of Example 1, and employing appropriate reagents in appropriate steps, 3-(6-((1R,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)pyrimidine-4-yl)-1-(4-methoxybenzyl)-N-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine-4-amine(8-1) was synthesized from 4,6-dichloropyrimidine.

[0216] Step 2: Synthesis of (3S,5R)-1-(6-(4-((2,2,2-trifluoroethyl)amino)-1H-pyrazolo[4,3-c]pyridin-3-yl)pyrimidine-4-yl)piperidine-3,5-diol (526) To a solution of compound 8-1 (90 mg, 0.176 mmol) in TFA (10 mL), TfOH (0.5 mL) was added. The resulting mixture was stirred at room temperature for 1 hour, then concentrated, diluted with DCM, and washed with 1 M NaOH aqueous solution and brine. The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by preparative TLC (DCM / MeOH = 5:1) and preparative HPLC (Gilson, Gemini 5 μm, C18 150 × 21.2 mm, 20 mL / min, ACN / H2O (0.1% FA) = 35%:65%~50%:50% in 10 min) to obtain compound 526 (20 mg), a white solid. 1 HNMR (400 MHz, CD3OD) δ 8.58 (d, J = 1.0 Hz, 1H), 7.77 (d, J = 6.3 Hz, 1H), 7.71 (d, J = 1.0 Hz, 1H), 6.87 (d, J = 6.3 Hz, 1H), 4.39 (q, J = m / z (ESI) + : 410.0 [M+H] + .

[0217] Example 9: Preparation of Compound 522

[0218] [ka]

[0219] Step 1: Synthesis of (2R,6S)-4-(2-bromopyridine-4-yl)-2,6-dimethylmorpholine (9-1) Under a nitrogen atmosphere, cuprous iodide (70 mg, 0.352 mmol) and L-proline (80 mg, 0.704 mmol) were added to a DMSO (20 mL) suspension of 2-bromo-4-iodopyridine (1.0 g, 3.52 mmol), (2R,6S)-2,6-dimethylmorpholine (400 mg, 3.52 mmol), and K2CO3 (1.5 g, 10.5 mmol). The resulting mixture was degassed, purged three times with nitrogen gas, and then stirred at 60°C for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine. The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (DCM / MeOH = 99:1) to obtain compound 9-1 (400 mg, 42%), a white solid. m / z (ESI)+: 270.8, 272.8 [m+H] + .

[0220] Step 2: Synthesis of 3-(4-((2S,6R)-2,6-dimethylmorpholino)pyridine-2-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine-4-amine (522) 3-(4-((2S,6R)-2,6-dimethylmorpholino)pyridine-2-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine-4-amine(522) was synthesized from compound 9-1 using appropriate reagents in appropriate steps, similar to the method in Example 1. 1 HNMR (400 MHz, CDCl3) δ 8.25 (d, J = 6.1 Hz, 1H), 7.87 (d, J = 6.1 Hz, 1H), 7.76 (d, J = 2.6 Hz, 1H), 6.71 (dd, J = 6.1, 2.6 Hz, 2H), 4.50-4.36 (m, 2H), 3.81-3.71 (m, 4H), 2.66-2.58 (m, 2H), 1.30 (d, J = 6.2 Hz, 6H. m / z (ESI) + : 406.8 [M+H] + .

[0221] Manufacturing example: Synthesis of a control compound

[0222] [ka]

[0223] Referring to the method of Example 1, the above control compound was synthesized, the difference being that step 1 was omitted, step 2 was performed using 2-chloropyridine, compounds 1-2 of Example 1 were replaced with the produced 2-(trimethylstannyl)pyridine, and CF3CH2NH2 was used instead of cyclopropanamine in step 5 to obtain the control compound.

[0224] Example 10 Measurement of kinase inhibition material The kinase LRRK2 G2019S protein is derived from Carna, LRRKtide from Signalchem, ATP from Promega, and DMSO from Sigma.

[0225] Kinase testing methods All measurements were performed at room temperature. Compounds awaiting measurement were dissolved and diluted, then added to a 384-well plate. 2.5 μL of 2× kinase reaction buffer was added, the mixture was centrifuged, 2.5 μL of 2× substrate and ATP mixture was added, the mixture was centrifuged again, 4 μL of ADP-Glo ​​reagent was added, and the mixture was incubated at room temperature for 40 minutes. 8 μL of LRRKtide was added, the mixture was incubated at room temperature for 40 minutes, and the data was then read using an Envision 2104 multi-label reader.

[0226] result IC of the compounds of the examples of this disclosure against LRRK2 G2019S inhibition 50 The values ​​are shown in Table 3 below.

[0227] [Table 7]

[0228] Example 11: Measurement of HEK293 cell kinase inhibition HEK293 cells were cultured, pancreatin was added to collect the cells, and then culture medium was added to increase the cell density to 2 × 10⁶. 5 The solution was adjusted to / mL. Liposome-DNA complexes were constructed, mixed with HEK293 cells at a ratio of 1:20, added to a 384-well plate, and incubated at 37°C for 20–30 hours. A mixed solution of enzyme substrate and compound awaiting measurement was added, incubated at room temperature for 2–3 minutes, NanoBRET reagent (Promega) was added, and within 10 minutes, the bioluminescence of the donor ciferase protein (donor) at 450 nm and the acceptor fluorescent group (acceptor) at 610 nm was read using a microplate reader (Envision 2104). The BRET ratio of the test product, including background correction options, was calculated according to the following formula.

[0229]

number

[0230] The inhibitory activity of the compounds awaiting measurement against the cellular LRRK2 enzyme was calculated using the following formula.

[0231] Percentage inhibition rate = 100 - (Test product BRET ratio - Mean BRET ratio of all microplate-positive controls) / (Mean BRET ratio of all microplate-negative controls - Mean BRET ratio of all microplate-positive controls) × 100.

[0232] Compound ICs awaiting measurement against the cellular LRRK2 enzyme 50 Calculation: Using Graphpad software, nonlinear regression fitting (dose-response gradient method) was performed on the percentage inhibition rate and the logarithmic concentration curve of the compound. Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)×Hill Slope)) X: Logarithmic inhibitor concentration, Y: Percentage inhibition rate, Bottom: Minimum value, Top: Maximum value, Hill Slope: Hill gradient.

[0233] result IC50 of compounds from some examples of this disclosure for inhibition of HEK293 intracellular LRRK2, LRRK2-2019S, and LRRK2-R1441C 50 The values ​​are summarized in the table below.

[0234] [Table 8]

[0235] Example 12: Study of in vivo drug efficacy by oral administration to mice 1. Experimental Objective: The in vivo efficacy of compound 527 was measured by observing its inhibitory effect on LRRK2 phosphorylation levels in the brain of mice in which the G2019S mutant LRRK2 gene was knocked in, following oral administration of compound 527.

[0236] 2. Experimental method: (1) Animals: B6.Cg-Tg(Lrrk2*G2019S)2Yue / J transgenic mice were purchased from Jackson Laboratory and crossed with C57BL / 6J mice to obtain LRRK2 heterozygous mice (LRRK2-G2019S mice) carrying the G2019S mutation. The mice were roughly half male and half female, weighed 16-20 g, and were 15-17 weeks old.

[0237] (2) Grouping and administration: Each group consisted of 8 animals, 4 female mice and 4 male mice, which were randomly divided into 5 experimental groups based on body weight. The specific administration for each experimental group is shown in Table 1 below. Of these, group G1 was the solvent control group, and groups G2 to G5 were administered 527 compounds at doses of 1 mg / kg, 3 mg / kg, 10 mg / kg, and 30 mg / kg, respectively.

[0238] [Table 9]

[0239] (3) Measurement of LRRK2 activity in the brain: Animals were euthanized with CO2 1 hour after administration, brain tissue was collected, rapidly frozen with liquid nitrogen, and then cryopreserved at -80C until the next experiment. TM Brain tissue was homogenized in RIPA buffer containing a protease inhibitor mixture (Roche, 04693124001) and a phosphatase enzyme inhibitor mixture 2 (sigma, R0278), and proteins were quantified using the BCA method. By Western blot, the level of phosphorylated LRRK2 at position pS935 (primary antibody Anti-LRRK2(phospho S935)antibody, abcam, ab133450) and the total LRRK2 level (primary antibody Anti-LRRK2 antibody, Abcam, ab133518) in the homogenized tissue were detected. Brain LRRK2 activity levels were expressed as the phosphorylation level at position S935 of LRRK2, i.e., the ratio of pS935-LRRK2 to total LRRK2 (pS935-LRRK2 / LRRK2).

[0240] (4) Results and conclusions: Typical results from brain tissue Western Blot are shown in Figure 1, and the inhibitory effect of compound 527 on the phosphorylation of brain tissue LRRK2 is shown in Figure 2.

[0241] The results showed that the effective dose of compound 527 for inhibiting LRRK2 phosphorylation in brain tissue by oral administration was 10 mg / kg, the maximum effective dose (defined as inhibiting 60% of LRRK2 phosphorylation levels) was 30 mg / kg, and the corresponding human equivalent doses (calculated for a body weight of 70 kg) were 57 mg and 171 mg, respectively.

[0242] The above describes exemplary embodiments of the present disclosure. However, the claims of this disclosure are not limited to the embodiments described above. Any modifications, equivalent substitutions or improvements made by a person skilled in the art that do not depart from the essence and principles of this disclosure are included within the claims of this disclosure. [Brief explanation of the drawing]

[0243] [Figure 1]This is an exemplary figure of the Western blot results for LRRK2 expression levels in LRRK2-G2019S mouse brain tissue from Example 12. [Figure 2] This diagram shows the effect of compound 527 from Example 12 on the phosphorylation level of LRRK2 in LRRK2-G2019S mouse brain tissue. The data are mean ± sample standard deviation (mean ± SE), n=8, * represents p<0.05 relative to the solvent control group, and *** represents p<0.001 relative to the solvent control group. Single-way ANOVA was employed.

Claims

1. A compound represented by formula (I), its racemic mixture, stereoisomer, tautomer, isotope-labeled compound, N-oxide, hydrate, solvate, crystalline polymorph, or pharmaceutically acceptable salt thereof, 【Chemistry 1】 Eventually, W is N, R １ C is a C substituted with one, two or more halogens. １－６ It is an alkyl group, R ２ H is, X is, 【Chemistry 2】 And, R ３ teeth, 【Transformation 3】 And, Eventually, 【Chemistry 4】 is one, two or more R ４ It has been replaced with, Each R ４ These are homologous or different, and each has a hydroxyl group or C １－６ Selected from alkyl groups, Compounds represented by formula (I), their racemates, stereoisomers, tautomers, isotope-labeled compounds, N-oxides, hydrates, solvates, crystalline polymorphs, or pharmaceutically acceptable salts.

2. R １ is selected from -CH ２ CF ３ , -CH(CH ３ )CF ３ and R ３ teeth, 【Transformation 5】 Selected from, A compound according to claim 1, characterized by the following: a racemic mixture thereof, a stereoisomer, a tautomer, an isotope-labeled compound, an N-oxide, a hydrate, a solvate, a crystalline polymorph, or a pharmaceutically acceptable salt thereof.

3. The compound represented by formula (I) has the structure shown in formula (II) below, 【Transformation 6】 Eventually, R ５ It is a trifluoromethyl group, R ６ It is a methyl group, R ７ 、 R １０ H is, R ８ , R ９ These are homologous or different, and are independent of each other C １－６ Selected from alkyl groups, R １１ , R １２ H is A compound according to claim 1, characterized by the following: a racemic mixture thereof, a stereoisomer, a tautomer, an isotope-labeled compound, an N-oxide, a hydrate, a solvate, a crystalline polymorph, or a pharmaceutically acceptable salt thereof.

4. The compound represented by formula (I) includes the compound represented by formula (III) below, 【Transformation 7】 Eventually, R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ has the definition described in claim 3, The compound according to claim 3, characterized by the racemic mixture thereof, stereoisomers, tautomers, isotope-labeled compounds, N-oxides, hydrates, solvates, crystalline polymorphs, or pharmaceutically acceptable salts thereof.

5. The compound represented by formula (I) is the following compound 【Transformation 8】 Selected from, A compound according to claim 1, characterized by the following: a racemic mixture thereof, a stereoisomer, a tautomer, an isotope-labeled compound, an N-oxide, a hydrate, a solvate, a crystalline polymorph, or a pharmaceutically acceptable salt thereof.

6. A method for producing a compound according to any one of claims 1 to 5, a racemic mixture thereof, a stereoisomer, a tautomer, an isotope-labeled compound, an N-oxide, a hydrate, a solvate, a crystalline polymorph, or a pharmaceutically acceptable salt thereof, The above manufacturing method includes the following reaction: 【Chemistry 9】 Eventually, R １ , R ２ W and X have the definitions described above, P １ It is selected from amino protecting groups, A manufacturing method characterized by the following features.

7. The above manufacturing method further includes the following reaction: 【Chemistry 10】 Eventually, R １ , R ２ , W, X and P １ It has the definition described above, L １ It is selected from halogens, L ２ This is selected from alkyltin groups or borate ester groups. The manufacturing method according to claim 6, characterized in that

8. A pharmaceutical composition, The pharmaceutical composition comprises at least one of the compounds described in any one of claims 1 to 5, their racemic mixtures, stereoisomers, tautomers, isotope-labeled compounds, N-oxides, hydrates, solvates, crystalline polymorphs, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable adjuvants. A pharmaceutical composition characterized by the following features.

9. The use of at least one of the compounds described in any one of claims 1 to 5, their racemic mixtures, stereoisomers, tautomers, isotope-labeled compounds, N-oxides, hydrates, solvates, crystalline polymorphs, or pharmaceutically acceptable salts in the manufacture of a drug, The aforementioned drug is used for diseases or conditions related to LRRK kinase activity. A use characterized by the following:

10. The diseases or conditions associated with LRRK kinase activity are selected from neurodegenerative diseases, proliferative disorders, protein kinase-related diseases, lysosomal disorders, tau diseases, and diseases resulting from decreased dopamine levels. The use according to claim 9, characterized by the features described herein.

11. Diseases or conditions associated with LRRK kinase activity are selected from cancer, Parkinson's disease (PD) associated with GBA mutations, other alpha-synucleinopathy, tauopathy, Alzheimer's disease, Gaucher disease, Niemann-Pick disease type C (NPC), argyrophilic granulopathy, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, hereditary frontotemporal dementia and Parkinson's disease associated with chromosome 17 (FTDP-17), and withdrawal symptoms / relapses associated with drug addiction. The use according to claim 9, characterized by the features described herein.

12. The use of at least one of the compounds described in any one of claims 1 to 5, their racemic mixtures, stereoisomers, tautomers, isotope-labeled compounds, N-oxides, hydrates, solvates, crystalline polymorphs, or pharmaceutically acceptable salts in the preparation of reagents for analytical measurement, The aforementioned analytical measurements were used to identify compounds that can inhibit LRRK2 kinase. The aforementioned analytical measurement is a competitive binding activity measurement. use.

13. The use of at least one of the compounds described in any one of claims 1 to 5, a racemic mixture thereof, a stereoisomer, a tautomer, an isotope-labeled compound thereof, an N-oxide, a hydrate, a solvate, a crystalline polymorph, or a pharmaceutically acceptable salt, in the preparation of a reagent for detecting the binding of a compound to LRRK2 kinase, (i) In the presence of the kinase and a known substrate, the step of contacting at least one of the compounds described in any one of claims 1 to 5, its racemic mixture, stereoisomer, tautomer, isotope-labeled compound, N-oxide, hydrate, solvate, crystalline polymorph, or pharmaceutically acceptable salt with the LRRK2 kinase, (ii) The step of detecting any change in the interaction between the LRRK2 kinase and the known substrate, use.

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