Compound for treating or preventing LRRK2 mediated diseases

Abstract

The invention relates to a novel compound as shown in a formula (I) and a pharmaceutically acceptable salt of the novel compound. The compound can be used for inhibiting leucine-rich repeat kinase 2 (LRRK2), and can be used for inhibiting leucine-rich repeat kinase 2 (LRRK2), leucine-rich repeat kinase 2 (LRRK2) and leucine-rich repeat kinase 2 (LRRK2). The invention also relates to pharmaceutical compositions thereof, processes for their preparation and therapeutic uses.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a novel compound that inhibits LRRK2. The invention provides the novel compound or a pharmaceutically acceptable salt thereof, as well as a pharmaceutically acceptable carrier, and its use in treating or preventing LRRK2-mediated conditions, including neurodegenerative diseases such as Parkinson's disease, immune-inflammatory diseases such as inflammatory bowel disease, and glaucoma. Background of the Invention

[0002] Leucine-rich repeatkinase 2 (LRRK2) is a protein kinase encoded by the PARK8 gene and a member of the ROCO protein family. It consists of 2527 amino acids (286 kDa) and contains multiple domains including ARM, ANK, LRR, Roc, COR, Kinase, and WD40. The Roc and COR domains together form the GTPase domain. LRRK2 is a large, multifunctional protein with both GTPase and serine-threonine kinase activities. Studies show that LRRK2 is expressed in various organs (including the brain, kidneys, lungs, liver, heart, and spleen), primarily in the cytoplasm and on various membrane structures such as mitochondria, endosomes, lysosomes, and the Golgi apparatus. It is associated with various cellular functions, including autophagy, cytoskeleton dynamics, intracellular membrane transport, synaptic vesicle circulation, and inflammatory responses. Abnormalities in the LRRK2 pathway are closely related to various diseases, including Parkinson's disease, glaucoma, and inflammatory bowel disease.

[0003] Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, affecting a large proportion of middle-aged and elderly people (1-2%), with over 8 million patients worldwide. The main pathological features of PD are the degeneration and loss of dopaminergic neurons in the substantia nigra of the midbrain and the formation of Lewy bodies. Clinical manifestations include motor symptoms such as resting tremor, bradykinesia, muscle rigidity, and postural instability, often accompanied by sleep disturbances, autonomic dysfunction, depression, and other psychiatric symptoms, as well as non-motor symptoms such as cognitive impairment, severely impacting patients' quality of life. Currently common treatments include compound dopamine preparations, dopamine receptor agonists, and monoamine oxidase inhibitors, which supplement the depleted dopamine system through exogenous supplementation, enhanced efficacy, and metabolic inhibition, effectively alleviating motor symptoms in the early stages of the disease. However, these drugs only treat the symptoms, not the root cause, and cannot stop the continuous progression of the disease. They are also largely ineffective for non-motor symptoms and have drawbacks such as gradually increasing side effects and diminishing efficacy. Therefore, there is an urgent clinical need for disease-modifying therapies that can halt or slow disease progression. Genome-wide association studies (GWAS) have shown that LRRK2 gene mutations are one of the most common causes of familial Parkinson's disease (PD), including major pathogenic mutations such as the G2019S mutation. These mutations lead to LRRK2 overactivation; for example, the G2019S mutation increases LRRK2 protein kinase activity by 2-3 times. Furthermore, multiple studies have also shown LRRK2 overactivation in patients with idiopathic Parkinson's disease (PD). Therefore, LRRK2 inhibitors are generally considered a promising disease-modifying therapy that can halt or slow disease progression in Parkinson's disease patients by inhibiting overactivated LRRK2 kinase function. Currently, one LRRK2 inhibitor is in phase II clinical trials for the treatment of Parkinson's disease.

[0004] Glaucoma is a collective term for a group of progressive optic nerve diseases that ultimately impair vision, primarily related to pathologically elevated intraocular pressure. It is the second leading cause of blindness worldwide, after cataracts, and the leading cause of irreversible blindness. The overall prevalence of glaucoma is approximately 1%, gradually increasing with age; in China alone, there are over 20 million glaucoma patients. Glaucoma-induced blindness results from optic nerve damage, which is closely related to elevated intraocular pressure. Therefore, lowering intraocular pressure is currently the primary goal of glaucoma treatment. LRRK2 is widely distributed in tegmental tumor cells (TM cells). LRRK2 inhibitors can regulate LRRK2 in TM cells and may lower intraocular pressure by inhibiting the contractile tension of the actin cytoskeleton, leading to TM relaxation. Currently, one LRRK2 inhibitor is in phase II clinical trials for the treatment of glaucoma.

[0005] Inflammatory bowel disease (IBD) is an idiopathic inflammatory bowel disease affecting the ileum, rectum, and colon. Its main clinical manifestations include diarrhea, abdominal pain, rectal bleeding, and weight loss. It includes Crohn's disease (CD) and ulcerative colitis (UC). Ulcerative colitis is a continuous inflammation of the colonic mucosa and submucosa, typically starting in the rectum and gradually spreading to the entire colon. Crohn's disease can affect the entire digestive tract, presenting as a discontinuous, full-thickness inflammation, most commonly affecting the terminal ileum, colon, and perianal region. The etiology of IBD is not fully understood. It is known that an abnormal intestinal mucosal immune system response plays a crucial role in its pathogenesis, currently believed to be caused by a multifactorial interaction, primarily including environmental, genetic, infectious, and immune factors. Genome-wide association studies have identified the LRRK2 gene as one of the key loci influencing genetic susceptibility to CD. Studies have confirmed that LRRK2 expression is upregulated in dendritic cells of Crohn's disease patients and in lymphoblastoid cell lines of patients carrying high-risk alleles. Analysis of mouse models shows that LRRK2 overexpression can exacerbate colitis, which is related to Dectin-1-induced pro-inflammatory cytokine responses and autophagy defects in intestinal dendritic cells. LRRK2 inhibitors can alleviate colitis, providing a new approach for the treatment of inflammatory bowel disease. Currently, some LRRK2 inhibitors are in the preclinical discovery stage for the treatment of inflammatory bowel disease.

[0006] In addition, LRRK2 inhibitors are potential treatments for a variety of diseases, including tuberculosis, leprosy, Alzheimer's disease, dementia, Pick's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, neuroinflammation, ischemic stroke, multiple sclerotic rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura, Evans syndrome, vasculitis, bullous skin diseases, type I diabetes, Sjögren's syndrome, Dervédex disease, inflammatory myopathy, ankylosing spondylitis, glioblastoma, lymphoma, acute myeloid leukemia, kidney cancer, breast cancer, lung cancer, prostate cancer, and thyroid cancer.

[0007] Therefore, LRRK2 inhibitors have broad application prospects and urgent clinical needs. Currently, some related literature and patent applications have disclosed small-molecule LRRK2 inhibitors, including WO2014001973A1, WO2015092592A1, WO2016036586A1, WO2017046675A1, and WO2020247298A3, but there is still a pressing need to develop more novel LRRK2 inhibitors with novel structures and better drug-like properties. This invention provides a novel LRRK2 inhibitor and discovers that such compounds have good LRRK2 inhibitory activity. Summary of the Invention

[0008] This invention provides an orally administered LRRK2 inhibitor with high activity and good pharmacokinetic properties. The LRRK2 inhibitor has high in vivo exposure, good absorption efficiency, and good brain penetration rate, resulting in higher drug concentration in the brain and thus better efficacy in the central nervous system.

[0009] This invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0010]

[0011] in:

[0012] A is a five-membered heteroaryl group containing 2 or 3 N atoms;

[0013] X is N or CH;

[0014] Y is selected from single bond, O, S, NH or NRy, and Ry is C. 1-6 alkyl;

[0015] R 1 Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic or 5-6 membered heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic or 5-6 membered heteroaryl groups are optionally coated with halogens, C 1-3 Alkyl, C 1-3 Alkoxy or di(C) 1-3 One or more substitutions in alkyl)oxyphosphine group;

[0016] R 2 Selected from C 1-6Alkyl, halogen, cyano, 3-7 membered alicyclic alkyl or 4-8 membered alicyclic heterocyclic group, wherein the alicyclic heterocycle contains 1, 2 or 3 heteroatoms selected from N, S or O, wherein the C 1-6 Alkyl, 3-7 membered aliphatic rings or 4-8 membered aliphatic heterocycles may be optionally surrounded by 1, 2 or 3 Rs. 5 replace;

[0017] R 3 Selected from cyano, C 1-6 Acyl group, C 1-6 alkylsulfonyl, -C(O)-NR a R b or

[0018] R a Or R b Each is independently H or C 1-3 alkyl;

[0019] R 3a Or R 3b Each is independently selected from H, cyano, hydroxyl, or C. 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted with one or more of halogen, cyano, hydroxyl, alkoxy, and amino groups; or R 3a and R 3b Together with the atoms they are connected to, they form a group that can optionally consist of 1, 2, or 3 R atoms. 6 The substituted ring is a 3-7 membered aliphatic ring or a 4-8 membered aliphatic heterocycle, the aliphatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, S or O;

[0020] R 3c Selected from H, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 2-6 Haloalkenyl, C 2-6 Halogenated alkynyl group, C 1-6 alkylsulfonyl, C 2-6 The ester group, 3-7 membered aliphatic ring, 4-6 membered aliphatic heterocycle, or 5-6 membered heteroaryl group, wherein the 4-6 membered aliphatic heterocycle or 5-6 membered heteroaryl group contains 1, 2, 3, or 4 heteroatoms selected from N, O, or S, and wherein the 3-7 membered aliphatic ring, 4-6 membered aliphatic heterocycle, or 5-6 membered heteroaryl group is optionally surrounded by 1, 2, or 3 R atoms. 7 replace;

[0021] R 4 Selected from halogen, cyano, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0022] R 5 Selected from halogens, hydroxyl groups, cyano groups, C 1-6 Acyl or C 1-6 alkylsulfonyl;

[0023] R 6 Selected from oxo, cyano, hydroxyl, halogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Ester group, -C(O)-NRaRb, C 1-6 Acyl or C 1-6 alkylsulfonyl;

[0024] R 7 Selected from cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halogen, or oxo;

[0025] The condition is that X is CH when A contains 3 N atoms;

[0026] When A contains 2 N atoms, X is N, R 3 yes And R 3a and R 3b Together with the atoms they are connected to, they form a group that can optionally consist of 1, 2, or 3 R atoms. 6 The substituted ring is a 3-7 membered aliphatic ring or a 4-8 membered aliphatic heterocycle, the aliphatic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, or O, and R 3c It is not H or cyano.

[0027] In some specific embodiments, the compound or a pharmaceutically acceptable salt thereof, wherein:

[0028] A is a five-membered heteroaryl group containing 2 or 3 N atoms;

[0029] X is N or CH;

[0030] Y is a single bond, O, S, NH, or NRy, and Ry is C. 1-6 alkyl;

[0031] R 1 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl or 5-6-membered heteroaryl, wherein C 3-6 Cycloalkyl or 5-6 heteroaryl groups are optionally halogenated or C 1-3 One or more substitutions in alkyl groups;

[0032] R 2 It is C 1-6Alkyl, halogen, cyano, 3-7 membered aliphatic ring or 4-8 membered aliphatic heterocycle, wherein the aliphatic heterocycle contains 1, 2 or 3 heteroatoms selected from N, S or O, and the 3-7 membered aliphatic ring or 4-8 membered aliphatic heterocycle is optionally surrounded by 1, 2 or 3 R atoms. 5 replace;

[0033] R 3 It is cyano, C 1-6 Acyl group, C 1-6 alkylsulfonyl, -C(O)-NRaRb or

[0034] Ra or Rb are each independently selected from H or C. 1-3 alkyl;

[0035] R 3a Or R 3b Each group is independently selected from H, cyano, hydroxyl, and C. 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted with one or more of halogen, cyano, hydroxyl, alkoxy, and amino groups; or R 3a and R 3b Together with the atoms they are connected to, they form a group that can optionally consist of 1, 2, or 3 R atoms. 6 The substituted ring is a 3-7 membered aliphatic ring or a 4-8 membered aliphatic heterocycle, the aliphatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, S or O;

[0036] R 3c It is H, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylsulfonyl, C 2-6 The ester group, 3-7 membered aliphatic ring, 4-6 membered aliphatic heterocycle, or 5-6 membered heteroaryl group, wherein the 4-6 membered aliphatic heterocycle or 5-6 membered heteroaryl group contains 1, 2, 3, or 4 heteroatoms selected from N, O, or S, and wherein the 3-7 membered aliphatic ring, 4-6 membered aliphatic heterocycle, or 5-6 membered heteroaryl group is optionally surrounded by 1, 2, or 3 R atoms. 7 replace;

[0037] R 4 It is halogen, cyano, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0038] R 5 It is halogen, hydroxyl, cyano, C 1-6 Acyl or C 1-6 alkylsulfonyl;

[0039] R 6 It is oxo, cyano, hydroxyl, halogen, amino, C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 Ester group, -C(O)-NRaRb, C 1-6 Acyl or C 1-6 alkylsulfonyl;

[0040] R 7 It is cyano, C 1-6 Alkyl or oxo;

[0041] The condition is that X is CH when A contains 3 N atoms;

[0042] When A contains 2 N atoms, X is N, R 3 yes And R 3a and R 3b Together with the atoms they are connected to, they form a group that can optionally consist of 1, 2, or 3 R atoms. 6 The substituted ring is a 3-7 membered aliphatic ring or a 4-8 membered aliphatic heterocycle, the aliphatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, S or O, and in this case R 3c It is not H or cyano.

[0043] In some specific embodiments, the compound or a pharmaceutically acceptable salt thereof, wherein:

[0044] Y is a single bond, O, S, or NH;

[0045] R 1 It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, the C 3-6 cycloalkyl groups may be halogenated or C 1-3 One or more substitutions in alkyl groups;

[0046] R 2 It is C 1-3 Alkyl, halogen, cyano, 3-6 membered aliphatic ring or 4-6 membered aliphatic heterocycle, wherein the aliphatic heterocycle contains one or two heteroatoms selected from N, S or O, and the 3-6 membered aliphatic ring or 4-6 membered aliphatic heterocycle is optionally surrounded by one, two or three R atoms. 5 replace;

[0047] R 3 yes

[0048] R 3a Or R 3b Each group is independently selected from H, cyano, hydroxyl, and C. 1-3 Alkyl, the C 1-3 The alkyl group may be optionally substituted with one or more of halogen, cyano, hydroxyl, alkoxy, and amino groups; or R 3a and R3b Together with the atoms they are connected to, they form a group that can optionally consist of 1, 2, or 3 R atoms. 6 The substituted ring is a 3-6 membered aliphatic ring or a 4-7 membered aliphatic heterocycle, the aliphatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, S or O;

[0049] R 3c It is H, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 alkylsulfonyl, C 2-3 The ester group, 3-5 membered aliphatic ring, 4-5 membered aliphatic heterocycle, or 5-6 membered heteroaryl group, wherein the 4-5 membered aliphatic heterocycle or 5-6 membered heteroaryl group contains 1, 2, 3, or 4 heteroatoms selected from N, O, or S, and wherein the 3-5 membered aliphatic ring, 4-5 membered aliphatic heterocycle, or 5-6 membered heteroaryl group is optionally surrounded by 1, 2, or 3 R atoms. 7 replace;

[0050] R 4 It is halogen, cyano, C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0051] R 5 It is a halogen, hydroxyl, cyano, formyl, acetyl, methanesulfonyl, or ethylsulfonyl group;

[0052] R 6 It is an oxo, cyano, hydroxyl, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, methyl ester, ethyl ester, formyl, acetyl, methylsulfonyl, or ethylsulfonyl;

[0053] R 7 It is cyano, C 1-3 Alkyl or oxo.

[0054] In some specific embodiments, the compounds of formulas (IIa) and (IIb) or their pharmaceutically acceptable salts are:

[0055]

[0056] Among them, R 1 R 2 R 3a R 3b R 3c R 4 As defined in claim 2;

[0057] More preferably, the compound or its salt has the structural formula (II):

[0058]

[0059] Among them, R 1 R 2 R 3a R 3b R 4 As defined in claim 2.

[0060] In some specific embodiments, the compound of formula (Ⅲa) or a pharmaceutically acceptable salt thereof:

[0061]

[0062] Among them, R 1 R 2 R 3a R 3b R 3c R 4 As defined in claim 2,

[0063] More preferably, the compound or its salt has the structural formula (III):

[0064]

[0065] Among them, R 1 R 2 R 3a R 3b R 4 As defined in claim 2.

[0066] In some specific embodiments, the compound or a pharmaceutically acceptable salt thereof, wherein:

[0067] Y is NH;

[0068] R 1 Selected from C 1-6 Alkyl, C 2-6 alkynyl or C 3-6 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkynyl or C 3-6 cycloalkyl groups are optionally coated with halogens, C 1-3 Alkyl, C 1-3 Alkoxy or di(C) 1-3 One or more substitutions in alkyl)oxyphosphine group;

[0069] The condition is that A contains 2 N atoms, X is N, and R... 1 It is an unsubstituted ethyl group, R 2 It is a cycloalkyl group, R 3 yes R 3c When it is a triazole group, R 3a Or R3b Not both are methyl, and R 3a and R 3b It does not form a ring.

[0070] In some specific embodiments, the compound or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (IV), formula (V) or formula (VI):

[0071]

[0072] Among them, Y and R 1 R 2 R 3a R 3b R 3c R 4 As defined in claim 1 or 6.

[0073] In some specific embodiments, the compound or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (IVa):

[0074]

[0075] in,

[0076] R 1 It is C 1-6 Alkyl; R 2 It is C 3-6 cycloalkyl; R 3a Or R 3b Each is C independently 1-6 Alkyl, or R 3a and R 3b Together with the atoms they are connected to, they form C 3-6 cycloalkyl; R 4 It is C 1-6 Halogenated alkyl groups;

[0077] Preferably, R 1 It is methyl or ethyl; R 2 It is cyclopropyl; R 3a Or R 3b It is methyl, or R 3a and R 3b Together with the atoms they are bonded to, they form a cyclopropyl group; R 4 It is trifluoromethyl.

[0078] In some specific embodiments, the compound or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (Va):

[0079]

[0080] Among them, R 1 R 2 R 3a R 3b R 3c R 4 As defined in claim 7.

[0081] In some specific embodiments, the compound or a pharmaceutically acceptable salt thereof, wherein:

[0082] R 1 Selected from C 1-6 Alkyl, C 2-6 alkynyl or C 3-6 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkynyl or C 3-6 cycloalkyl groups are optionally coated with halogens, C 1-3 Alkyl or C 1-3 One or more substitutions in the alkoxy group;

[0083] R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-8 membered aliphatic heterocyclic groups, wherein the aliphatic heterocycle contains 1, 2, or 3 heteroatoms selected from N, S, or O, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-8 membered aliphatic heterocyclic groups are optionally surrounded by 1, 2 or 3 R groups. 5 replace;

[0084] R 3a Or R 3b Each is independently H or C 1-6 Alkyl, or R 3a and R 3b Together with the atoms they are connected to, they form a group that can optionally consist of 1, 2, or 3 R atoms. 6 The replaced ring, the ring being C 3-6 Cycloalkyl or 4-8 membered aliphatic heterocycles, wherein the aliphatic heterocycle contains 1, 2 or 3 heteroatoms selected from N, S or O;

[0085] R 3c It is C 1-6 Alkyl or 5-6-membered heteroaryl, said heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, said heteroaryl being optionally surrounded by 1, 2 or 3 R atoms. 7 replace;

[0086] R 4 It is C 1-6 Halogenated alkyl groups;

[0087] R 5 It is either halogen or cyano;

[0088] R 6 It is oxygenation;

[0089] R 7 It is C 1-6 Alkyl or C 1-6 Alkylthio;

[0090] Preferably,

[0091] R 1 Selected from C 1-3 Alkyl, C 2-3 alkynyl or C 3-4 cycloalkyl, the C 1-3 Alkyl, C 2-3 alkynyl or C 3-4 The cycloalkyl group may optionally be substituted with one or more of a halogen or a methoxy group;

[0092] R 2 Selected from methyl, cyclopropyl, oxetane, or tetrahydrofuranyl, wherein the methyl group is optionally surrounded by one R 5 replace;

[0093] R 3a Or R 3b It is methyl, or R 3a and R 3b Together with the atoms they are connected to, they form an optional group of 2 R atoms. 6 The replaced ring, the ring being C 3-5 Cycloalkyl or tetrahydrothiophene group;

[0094] R 3c It is a methyl or 5-6-membered heteroaryl group, wherein the heteroaryl group contains 1, 2, 3 or 4 heteroatoms selected from N or S, and the heteroaryl group is optionally surrounded by one R 7 replace;

[0095] R 5 It is cyano;

[0096] R 6 It is oxygenation;

[0097] R 7 It is methyl or ethyl thio.

[0098] In some specific embodiments, the compound or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (Vb):

[0099]

[0100] in,

[0101] R 1 It is C 1-6 Alkyl or C 3-6cycloalkyl, the C 1-6 Alkyl or C 3-6 cycloalkyl groups are optionally C 1-3 Alkyl or C 1-3 One or more substitutions in the alkoxy group;

[0102] R 3a Or R 3b It is C 1-6 Alkyl, or R 3a and R 3b Together with the atoms they are connected to, they form C 3-5 cycloalkyl;

[0103] R 3c It is a 5-membered heteroaryl group, wherein the heteroaryl group contains 1, 2 or 3 heteroatoms selected from N or S;

[0104] Preferably,

[0105] R 1 It is ethyl or cyclobutyl, wherein the cyclobutyl group is optionally substituted with methyl or methoxy;

[0106] R 3a Or R 3b It is methyl, or R 3a and R 3b Together with the atoms they are connected to, they form a cyclopropyl group;

[0107] R 3c yes

[0108] In some specific embodiments, the compound or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (VIa):

[0109]

[0110] Among them, R 1 It is C 1-3 Alkyl; R 8 It is C 1-3 Halogenated alkyl groups;

[0111] Preferably, R 1 It is methyl or ethyl; R 8 It is trifluoromethyl or difluoromethyl.

[0112] In some specific embodiments, the compound or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (VII):

[0113]

[0114] in,

[0115] X or X 1 Each is either N or CH independently;

[0116] R 1 It is C 1-6 Alkyl or C 3-6 cycloalkyl, the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally halogenated or di(C) 1-3 One or more substitutions in alkyl)oxyphosphine group;

[0117] R 3a Or R 3b It is C 1-6 Alkyl, or R 3a and R 3b Together with the atoms they are connected to, they form C 3-5 cycloalkyl;

[0118] R 3c It can be chosen by 1 or 2 Rs. 7 Substituted triazole or tetraazole groups;

[0119] R 7 Each is C independently 1-3 alkyl;

[0120] Preferably, R 3c yes

[0121] In some specific embodiments, the compound or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (VIIa) or formula (VIIb):

[0122]

[0123] Among them, R 1 R 3a R 3b R 3c As defined in claim 13.

[0124] In some specific embodiments, the compound or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (VIIc) or formula (VIId):

[0125]

[0126] in,

[0127] R 1 It is C 1-6 Alkyl or C 3-6 cycloalkyl, the C 1-6 Alkyl or C 3-6The cycloalkyl group may optionally be substituted with one, two or three halogens;

[0128] R 3c It is optional to be one R 7 Substituted triazole or tetraazole groups;

[0129] R 7 It is C 1-3 alkyl;

[0130] Preferably,

[0131] R 1 C can be arbitrarily replaced by 1, 2, or 3 Fs. 1-3 Alkyl or cyclopropyl;

[0132] R 3c yes

[0133] R 7 It is a methyl group.

[0134] In some specific embodiments, the compound or a pharmaceutically acceptable salt thereof, wherein:

[0135] R1 is ethyl or cyclopropyl;

[0136] R 3a Or R 3b It is methyl, or R 3a and R 3b Together with the atoms they are connected to, they form a cyclopropyl group;

[0137] R 3c yes

[0138] On the other hand, the specific compounds provided by the present invention include, but are not limited to, the following compounds:

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145] This invention includes all pharmaceutically acceptable salt forms of the compounds. These salts can be prepared using commercially available reagents via conventional organic chemical methods, and specifically include hydrochlorides, hydrobroms, hydroiodates, phosphates, sulfates, nitrates, formates, acetates, succinates, benzenesulfonates, citrates, glucurons, lactates, methanesulfonates, toluenesulfonates, bis(hydroxynaphthyl) salts, and tartrates, etc.

[0146] This invention aims to include all isotopes of atoms in all compounds. The isotope-labeled compounds of this invention can generally be prepared using conventional techniques known in the art or by methods similar to those described in this application, and these compounds have the potential to improve pharmacological or pharmacokinetic properties.

[0147] For stereoisomers, the compounds of the present invention may have a chiral center and may exist as racemates, racemic mixtures, and individual enantiomers or diastereomers. All such isomeric forms, including mixtures thereof, are included within the scope of this invention.

[0148] Furthermore, certain crystalline forms of the compounds described in this invention may exist in polymorphic forms, which are also included in this invention. Additionally, some of the compounds may also form solvates with water or other organic solvents, and such solvates are similarly included within the scope of this invention.

[0149] On the other hand, the present invention provides a method for preparing compound of formula (I), wherein:

[0150] Compound (Ⅱa) can be synthesized using the scheme shown below.

[0151]

[0152] Among them, R 3a R 3b R 3c R 1 R 2 R 4 The definition is as described above.

[0153] Compound (Ⅱb) can be synthesized using the scheme shown below.

[0154]

[0155] Among them, R 3a R 3b R 3c R 1 R 2 R 4 The definition is as described above.

[0156] Compound (II) can be synthesized using the scheme shown below.

[0157]

[0158] Among them, R 3a R 3b R 1 R 2 R 4 The definition is as described above.

[0159] Compound (Ⅲa) can be synthesized using the scheme shown below.

[0160]

[0161] Among them, R 3a R 3b R 3c R 1 R 2 R 4 The definition is as described above.

[0162] Compound (Ⅲ) can be synthesized using the scheme shown below.

[0163]

[0164] Among them, R 3a R 3b R 1 R 2 R 4 The definition is as described above.

[0165] On the other hand, the present invention provides pharmaceutical formulations suitable for use in human patients, comprising any of the compounds shown above (e.g., compounds of the present invention, such as compounds having formula (I)) and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical formulations may be used to treat or prevent the conditions or diseases described herein.

[0166] On the other hand, this invention discloses the use of the compounds in the preparation of medicaments for treating LRRK2-related conditions. These conditions include, but are not limited to, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar atrophy, Friedreich ataxia, Pick's disease, Lewy body dementia, dystonia, amyotrophic lateral sclerosis, neuroinflammation, progressive supranuclear palsy, and frontotemporal dementia; immune-inflammatory diseases such as inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, ankylosing spondylitis, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura, Evans syndrome, vasculitis, bullous skin diseases, type I diabetes, Sjögren's syndrome, Dervé disease, and inflammatory myopathy; as well as malignant tumors and glaucoma.

[0167] The compounds involved in this invention possess LRRK2 inhibitory activity. According to the assay methods described below, in some embodiments, the IC50 value of the compounds of this invention against LRRK2 kinase is less than 500 nM; in some embodiments, the IC50 value of the compounds of this invention against LRRK2 kinase is less than 400 nM; in some embodiments, the IC50 value of the compounds of this invention against LRRK2 kinase is less than 300 nM; in some embodiments, the IC50 value of the compounds of this invention against LRRK2 kinase is less than 200 nM; in some embodiments, the IC50 value of the compounds of this invention against LRRK2 kinase is less than 100 nM; in some embodiments, the IC50 value of the compounds of this invention against LRRK2 kinase is less than 50 nM; in some embodiments, the IC50 value of the compounds of this invention against LRRK2 kinase is less than 20 nM; in some embodiments, the IC50 value of the compounds of this invention against LRRK2 kinase is less than 10 nM; and in some embodiments, the IC50 value of the compounds of this invention against LRRK2 kinase is less than 1 nM.

[0168] The compounds of this invention also exhibit good in vitro liver microsomal stability and plasma and brain pharmacokinetic characteristics. Those skilled in the art can use relevant experiments known for determining such parameters. In some embodiments, for example, according to the in vitro microsomal stability assay method described below, the compounds of this invention exhibit low clearance (CL) and favorable half-life (T1 / 2); in some embodiments, according to in vivo PK assays commonly used in the art, the compounds of this invention have favorable AUC and C0. max This demonstrates better in vivo exposure; in some embodiments, as detected by the commonly used animal CNS-PK assay, the compounds of the present invention have better brain penetration, are more likely to cross the blood-brain barrier, and have higher cerebral blood drug concentrations.

[0169] Terminology Explanation

[0170] Alkyl or alkane are fully saturated straight-chain or branched non-aromatic hydrocarbons. Generally, unless otherwise defined, straight-chain or branched alkyl groups have 1 to about 20 carbon atoms, preferably 1 to about 10 carbon atoms. Examples of straight-chain and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl. C1-C6 straight-chain or branched alkyl groups are also called "lower alkyl groups".

[0171] Furthermore, as used throughout the specification, examples, and claims, the term "alkyl" (or "lower alkyl") is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter referring to an alkyl moiety having a substituent that replaces hydrogen on one or more carbons of the hydrocarbon backbone. Unless otherwise specified, such substituents may include, for example, halogens, hydroxyl groups, carbonyl groups (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (such as thioesters, thioacetate, or thioformate), alkoxy groups, phosphoryl groups, phosphate groups, phosphonates, phosphonites, amino groups, amide groups, amidines, imines, cyano groups, nitro groups, azides, mercapto groups, alkylthio groups, sulfate groups, sulfonates, aminosulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, aralkyl groups, or aromatic or heteroaromatic moiety components. Those skilled in the art will understand that, where appropriate, the substituted portion on the hydrocarbon chain may itself be substituted. For example, the substituents of the substituted alkyl group may include amino, azide, imino, amide, phosphoryl (including phosphonate and phosphonite), sulfonyl (including sulfate, sulfonamide, aminosulfonyl and sulfonate), and silyl, as well as substituted and unsubstituted forms of ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylic esters and esters), -CF3, -CN, etc.

[0172] The cycloalkyl group preferably has 3-7 ring carbon atoms and can be in substituted or unsubstituted form. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, or methylcyclopentyl. The cycloalkyl group can be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, etc.

[0173] Aryl groups represent monocyclic or bicyclic fused aromatic groups having 5-10 carbon atoms, such as phenyl, 1-naphthyl or 2-naphthyl; or partially saturated bicyclic fused rings containing phenyl, such as indanyl, dihydro- or tetrahydronaphthyl.

[0174] A heteroaryl group is an aromatic group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, and is either monocyclic or bicyclic. Monocyclic heteroaryl groups include 5- to 8-membered heteroaryl groups containing 1, 2, 3, or 4 heteroatoms selected from nitrogen, sulfur, and oxygen. Bicyclic heteroaryl groups include 9- or 10-membered fused-ring heteroaryl groups. Examples of heteroaryl groups include pyrroleyl, thiopheneyl, furanyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and benzo[a]-fused derivatives of these monocyclic heteroaryl groups, such as indolyl, benzimidazolyl, or benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, or purineyl.

[0175] In the optionally substituted heteroaryl group, the substituent is preferably a lower alkyl group, a lower alkoxy group, a lower alkoxy-lower alkoxy group, an amino group, and is optionally substituted by one or two substituents selected from lower alkyl groups, lower alkenyl groups, and alkyl carbonyl groups, halogenated lower alkyl groups, lower alkoxy-lower alkyl groups, halogens, or nitro groups.

[0176] The alkenyl group contains one or more, for example two or three double bonds and is preferably a lower alkenyl group, such as 1- or 2-butenyl, 1-propenyl, allyl or vinyl.

[0177] The alkynyl group is preferably a lower alkynyl group, such as propynyl or ethynyl.

[0178] In the optionally substituted alkenyl or alkynyl group, the substituent is preferably a lower alkyl, lower alkoxy, halo, or di(lower alkyl)amino group and is attached to a saturated carbon atom of the alkenyl or alkynyl group or to an unsaturated carbon atom of the alkenyl group.

[0179] Heterocyclic groups preferably represent saturated, partially saturated, or unsaturated monocyclic or bicyclic rings containing 4-10 atoms, including 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, they can be carbon or nitrogen-linked, wherein the cyclic nitrogen atom may optionally be substituted by a group selected from lower alkyl, amino-lower alkyl, aryl, aryl-lower alkyl, and acyl groups, and the cyclic carbon atom may be substituted by lower alkyl, amino-lower alkyl, aryl, aryl-lower alkyl, heteroaryl, lower alkoxy, hydroxyl, or oxo-substituted groups. Examples of heterocyclic groups include pyrrolidinyl, oxazolyl, thiazolyl, piperidinyl, morpholinyl, piperazine, dioxopentyl, or tetrahydropyranyl.

[0180] Acyl groups, for example, represent alkyl carbonyl groups, cyclohexyl carbonyl groups, aryl carbonyl groups, aryl-lower alkyl carbonyl groups, or heteroaryl carbonyl groups. Lower acyl groups are preferably lower alkyl carbonyl groups, especially propionyl or acetyl groups.

[0181] Hydroxyalkyl refers to an alkyl group that is substituted with at least one hydroxyl group, preferably a hydroxy-lower alkyl group, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-n-propyl, and hydroxyisopropyl.

[0182] Cyanoalkyl refers to an alkyl group that is substituted with at least one cyano group, preferably a cyano-lower alkyl group, such as cyanomethyl or cyanoethyl.

[0183] A haloalkyl group refers to an alkyl group that is substituted with at least one halogen, preferably a halogen-lower alkyl group, such as monofluoromethyl, difluoromethyl, trifluoromethyl, 3,3,3-trifluoroethyl or pentafluoroethyl.

[0184] Halogens are fluorine, chlorine, bromine or iodine.

[0185] Lower alkoxy groups, especially methoxy, ethoxy, isopropoxy, or tert-butoxy.

[0186] Arylalkyl groups include aryl and alkyl groups as defined above, and are, for example, benzyl, 1-phenylethyl, or 2-phenylethyl.

[0187] Heteroarylalkyl groups include heteroaryl and alkyl groups as defined above, and are, for example, 2-, 3- or 4-pyridylmethyl, 1- or 2-pyrrolithylmethyl, 1-pyrazolylmethyl, 1-imidazolylmethyl, 2-(1-imidazolyl)ethyl or 3-(1-imidazolyl)propyl.

[0188] Two adjacent substituents that can form a 5- or 6-membered carbon ring or heterocycle with the atoms of an aryl or heteroaryl group are, for example, propylene, 1- or 2-oxopropylene, 1- or 2-oxapropylene, 1-oxapropylidene, methylenedioxy, difluoro-methylenedioxy, 1- or 2-azapropylene, 1- or 2-azapropylidene, 1,2- or 1,3-diaza-2-oxopropylene, butylene, 1- or 2-oxabutene, ethylenedioxy, 1- or 2-azabutene, or 1- or 2-azabutadiene, or such groups carrying other substituents as defined above.

[0189] Alicyclic compounds refer to monocyclic or polycyclic alkanes with saturated or unsaturated bonds, with saturated monocyclic alkanes being preferred, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane. Polycyclic alkanes can be classified into spirocyclic and bridged rings according to their bonding mechanisms.

[0190] Aliphatic heterocycles refer to monocyclic or polycyclic alkanes with saturated or unsaturated bonds containing one or more heteroatoms in addition to carbon atoms. Heteroatoms include, for example, nitrogen, oxygen, or sulfur. Detailed Implementation

[0191] Synthesis Examples

[0192] To make the objectives and technical solutions of this invention clearer, the invention is further described below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, specific experimental methods not mentioned in the following embodiments were performed according to conventional experimental methods.

[0193] The abbreviations used in this article have the following meanings:

[0194] Abbreviation meaning

[0195] LCMS (Liquid Chromatography-Mass Spectrometry)

[0196] Preparative High Performance Liquid Chromatography (Pre-HPLC)

[0197] N,N-Dimethylformamide

[0198] PE petroleum ether

[0199] EA (ethyl acetate)

[0200] DOX Tetrahydrofuran

[0201] MeOH (methanol)

[0202] EtOH (ethanol)

[0203] ACN Acetonitrile

[0204] DCM dichloromethane

[0205] DMSO (dimethyl sulfoxide)

[0206] t BuOK Potassium tert-Butoxide

[0207] LiOH (Lithium hydroxide)

[0208] (COCl)2 oxalyl chloride

[0209] BINAP 1,1'-Binaphthyl-2,2'-bis(diphenylphosphine)

[0210] Brettphos Pd G3 Methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)

[0211] Xantphos 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene

[0212] Cs2CO3 (cesium carbonate)

[0213] SFC Supercritical Fluid Chromatography

[0214] TLC (Thin Layer Chromatography)

[0215] HPLC (High Performance Liquid Chromatography)

[0216] The structures of the compounds described in the following examples were obtained by nuclear magnetic resonance spectroscopy (NMR spectroscopy). 1 Confirmation can be made using 1H-NMR or mass spectrometry (MS).

[0217] 1 H-NMR measurements were performed using a Bruker 400MHz NMR spectrometer. The solvents used were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6), with tetramethylsilane (TMS) as the internal standard. Chemical shifts (δ) are given in parts per million (ppm).

[0218] The mass spectrometry (MS) instrument used was an Agilent (ESI) mass spectrometer, model Agilent 6120B.

[0219] Thin-layer chromatography (TLC) was performed using Merck aluminum plates (20×20cm), while preparative TLC was performed using GF254 silica gel plates (0.4–0.5 mm).

[0220] The reaction was monitored using thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS). The developing solvent systems used included dichloromethane and methanol, n-hexane and ethyl acetate, and petroleum ether and ethyl acetate. The developing solvent system was adjusted according to the polarity of the compounds to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc.).

[0221] Unless otherwise specified, the reaction temperature is room temperature (20℃~30℃).

[0222] The reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, Shanghai Teber Chemical Technology Co., Ltd., etc.

[0223] Preparation of common intermediates

[0224] Synthesis of intermediate 1 (INT1):

[0225]

[0226] Step 1: In a sealed tube, add INT1-1 (500 mg, 1.62 mmol) and methanol (10 mL), then add a tetrahydrofuran solution of ethylamine (1.6 mL, 3.25 mmol, 2 mol / L). After sealing the tube, heat to 80 °C and stir overnight. Cool the reaction solution to room temperature, remove the solvent under reduced pressure to obtain the crude product, which is then purified by silica gel column chromatography [eluent: petroleum ether-ethyl acetate (100:0-100:10)]. Collect the eluent, remove the solvent under reduced pressure to obtain a colorless oily compound INT1 (130 mg, yield: 35.6%). LC-MS (ESI, m / z): 225.3 [M+1] + .

[0227] Synthesis of intermediate 2 (INT2):

[0228]

[0229] Step 1: In an ice bath, add ethylamine (457.1 mg, 10.139 mmol) to a tetrahydrofuran (20 mL) solution of compound INT2-1 (2 g, 9.217 mmol) and stir at room temperature for 30 minutes. After the reaction is complete, dilute with water (20 mL), extract with ethyl acetate (30 mL x 3), wash the organic phase with saturated brine (30 mL x 3), dry with anhydrous sodium sulfate, filter, concentrate, and purify the crude product by normal-phase column chromatography (petroleum ether:ethyl acetate = 10:1) to give a colorless oil P1 (294 mg, yield 14.43%). 1 HNMR (400MHz, CDCl3) δ8.35 (d, J = 38.1Hz, 1H), 5.52 (s, 1H), 3.52-3.37 (m, 2H), 1.18 (d, J = 7.2Hz, 3H).

[0230] Synthesis of intermediate 3 (INT3):

[0231]

[0232] Step 1: In a sealed tube, add compound INT3-1 (2 g, 9.22 mmol) and tetrahydrofuran (40 mL). Add a tetrahydrofuran solution of methylamine (9.22 mL, 18.44 mmol, 2 mol / L) under ice bath conditions and stir overnight at room temperature. After the reaction is complete, remove the solvent under reduced pressure to obtain the crude product. Purify by silica gel column chromatography [eluent: petroleum ether–tetrahydrofuran (100:0–100:5)]. Collect the eluent and remove the solvent under reduced pressure to obtain a white solid compound INT3 (800 mg, yield: 41.2%). LC-MS (ESI, m / z): 212.1 [M+H] + . 1HNMR (400MHz, DMSO-d6) δ: 8.38 (s, 1H), 7.94 (br, 1H), 2.89 (d, J = 4.4Hz, 3H).

[0233] Comparative Example 1: Synthesis of N2-(3-(2-(2H-1,2,3-triazol-2-yl)propyl-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyridine-2,4-diamine (Compound A)

[0234]

[0235] Step 1: Under ice bath conditions, potassium tert-butoxide (12.2 g, 108.59 mmol) and A-1 (21.2 g, 108.59 mmol) were added to a solution of 1,2,3-triazole (5 g, 72.39 mmol) in N,N-dimethylformamide (100 mL). The mixture was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was complete, the mixture was quenched with saturated ammonium chloride aqueous solution (200 mL), extracted with ethyl acetate (300 mL x 3), washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by reverse-phase column chromatography to give a pale yellow oily compound A-2 (1.44 g, yield: 10.6%). 1 HNMR(400MHz, DMSO-d6)δ7.94-7.69(m,2H),4.17-4.04(m,2H),1.97-1.84(m,6H),1.12(dd,J=14.7,7.6Hz,3H).LC-MS(ESI,m / z):184[M+H] + .

[0236] Step 2: At -78°C, n-butyllithium (2.5M, 4.6mL, 11.43mmol) was slowly added to a tetrahydrofuran (10mL) solution of acetonitrile (469.2mg, 11.43mmol). After reacting for 1 hour, compound A-2 (1g, 5.72mmol) dissolved in tetrahydrofuran (1mL) was added to the reaction system, and the mixture was stirred for 1 hour. After the reaction was complete, the mixture was quenched with saturated ammonium chloride aqueous solution (20mL), extracted with ethyl acetate (20mL x 3), washed with saturated brine (30 x 3mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain a light yellow powder solid compound A-3 (456mg, yield: 46.9%). 1 H NMR(400MHz, DMSO-d6)δ9.09(s,1H),4.33(s,2H),1.95(s,6H).LCMS(ESI,m / z):179.2[M+H] + .

[0237] Step 3: Hydrochloric acid (12M, 0.34mL, 4.125mmol) and compound B (448mg, 4.125mmol) were added to a 4mL ethanol solution of compound A-3 (245mg, 1.375mmol), and the mixture was stirred overnight at 70°C. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate (10mL), extracted with ethyl acetate (10mL x 3), washed with saturated brine (10 x 3mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to give a pale yellow oily compound A-4 (189mg, yield: 59.2%). LCMS (ESI, m / z): 233.2 [M+H] + .

[0238] Step 4: To a solution of compound A-4 (50 mg, 0.129 mmol) in dioxane (4 mL), intermediate INT1 (48.3 mg, 0.215 mmol), cesium carbonate (140 mg, 0.43 mmol), palladium acetate (5 mg, 0.022 mmol), and XantPhos (25 mg, 0.043 mmol) were added. The mixture was stirred at 110 °C for 3 hours under nitrogen protection. After the reaction was complete, the mixture was filtered, washed with ethyl acetate, concentrated, and the crude product was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 3:1) followed by preparative high-performance liquid chromatography to obtain a white powder, compound A. 1 H NMR (400MHz, DMSO-d6) δ8.72(s,1H),7.97(s,1H),7.74(s,2H),6.05(t,J=5.5Hz,1H),5.96(s,1H),5.86(s,1H),3.39-3.3 5(m,1H),3.13(dd,J=12.9,6.8Hz,2H),1.95(s,6H),1.10(t,J=7.1Hz,3H),0.96-0.87(m,4H).LCMS(ESI,m / z):421.1[M+H] + .

[0239] Comparative Example 2: Synthesis of N2-(3-(2-(2H-1,2,3-triazol-2-yl)propyl-2-yl)-1-cyclopropyl-1H-1,2,4-triazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound B)

[0240]

[0241] Step 1: In a reaction flask, add 1,2,3-triazole (5 g, 72.5 mmol) and N,N-dimethylformamide (50 mL), add potassium tert-butoxide (16.3 g, 145.0 mmol) under ice bath conditions, stir for 1 hour, then add compound B-1 (28 g, 145.0 mmol), and stir overnight at room temperature. After the reaction is complete, dilute with water (250 mL), extract with ethyl acetate (50 mL x 3), combine the organic phases, wash twice with saturated brine, dry to anhydrous sodium sulfate, remove solvent by vacuum distillation to obtain the crude product, and purify by silica gel column chromatography to obtain a colorless oily liquid compound B-2 (3.9 g, yield: 29%). 1 HNMR(400MHz, DMSO-d6)δ7.84(s,2H),4.09(q,J=7.2Hz,2H),1.85(s,6H),1.10(t,J=6.8Hz,1H).LC-MS(ESI,m / z):184.1[M+1] + .

[0242] Step 2: In a reaction flask, compound B-2 (3g, 1.64mmol), methanol (30mL), and water (5mL) were added, followed by lithium hydroxide (78mg, 3.27mmol). The mixture was stirred overnight at 40°C. After the reaction was complete, the pH was adjusted to 6-7 with dilute hydrochloric acid. The solvent was removed by vacuum distillation, and the mixture was dissolved in dichloromethane (30mL). The solution was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to obtain a colorless oily liquid compound B-3 (2g, yield: 80%). 1 H NMR(400MHz, DMSO-d6)δ7.68(s,2H),1.74(s,6H).LC-MS(ESI,m / z):156.3[M+1] + .

[0243] Step 3: In a reaction flask, add compound B-3 (300 mg, 1.93 mmol) and ultra-dry dichloromethane (10 mL), 1 drop of N,N-dimethylformamide, and under argon protection, add oxalyl chloride (491 mg, 3.87 mmol) dropwise in an ice bath. Stir at room temperature for 1 hour, concentrate under reduced pressure to remove the solvent, and obtain crude acyl chloride, which can be used directly in the next step.

[0244] The crude acyl chloride was added to ultra-dry dichloromethane (20 mL) under argon protection. Sodium cyanamide solid (247 mg, 3.87 mmol) was added under ice bath. After stirring at room temperature for 1 hour, the reaction was complete. The reaction solution was directly mixed and purified by silica gel column chromatography to obtain a colorless oily liquid compound B-4 (300 mg, two-step yield: 86.7%). 1H NMR(400MHz, DMSO-d6)δ7.65(s,2H),1.70(s,6H).LC-MS(ESI,m / z):180.1[M+1] + .

[0245] Step 4: In a reaction flask, add B-4 (200 mg, 1.12 mmol) and n-BuOH (5 mL), and finally add cyclopropylhydrazine hydrochloride (364 mg, 3.35 mmol). Stir overnight at 110 °C. After the reaction is complete, dilute with water (5 mL) and adjust the pH of the system to 7-8 with sodium carbonate aqueous solution. Extract with ethyl acetate (10 mL x 3). Dry the organic phase with anhydrous sodium sulfate, remove the solvent under reduced pressure, and obtain the crude product. Purify by silica gel column chromatography to obtain a yellow oily liquid compound B-5 (75 mg, yield: 28.8%). 1 H NMR(400MHz, DMSO-d6)δ7.70(s,2H),6.18(s,2H),3.15-3.09(m,1H),1.88(s,6H),0.94-0.91(m,2H),0.88-0.85(m,2H).LC-MS(ESI,m / z):234.3[M+1] + .

[0246] Step 5: In a reaction flask, compound B-5 (50 mg, 0.21 mmol) and ultra-dry tetrahydrofuran (3 mL) were added. The mixture was cooled to 0°C in an ice-water bath. NaH (35 mg, 0.86 mmol, 60% wt) was added, and the mixture was stirred in an ice bath for 1 hour. Then, the intermediate N-benzyl-2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (68 mg, 0.21 mmol) was added. The mixture was stirred at room temperature for 1 hour until the reaction was complete. The solvent was removed by concentration under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to give a yellow oily liquid compound B-6 (45 mg, yield: 41.3%). LC-MS (ESI, m / z): 513.3 [M+1] + .

[0247] Step 6: Add compound B-6 (40 mg, 0.078 mmol), Pd / C (10% wt, 10 mg), Pd(OH)2 (10% wt, 10 mg), ClCH2CHCl2 (10 mg, 0.078 mmol), and tetrahydrofuran (5 mL) to the reaction flask. Stir overnight at room temperature under a hydrogen atmosphere. After the reaction is complete, filter the solution. Concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product using a C18 reversed-phase column (eluent: water-acetonitrile). Collect the eluent, remove acetonitrile under reduced pressure, and freeze-dry to obtain a white solid compound B. 1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.15(s,1H),7.73(s,2H),7.20(t,J=5.6Hz,1H),3.43-3.38(m,1H) ,3.30-3.26(m,2H),1.96(s,6H),0.98(t,J=6.8Hz,3H),0.93-0.89(m,4H).LC-MS(ESI,m / z):423.2[M+1] + .

[0248] Comparative Example 3: Synthesis of 2-methyl-2-(4-methyl-3-((4-(methylamino)-5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazol-1-yl)propionitrile (compound C)

[0249]

[0250] Step 1: 4-Methyl-3-nitro-1H-pyrazole (1.98 g, 15.58 mmol) was dissolved in N,N-dimethylformamide (33 mL), and cesium carbonate (10.11 g, 31.16 mmol) and methyl 2-bromo-2-methylpropionate (2.84 g, 15.58 mmol) were added. The mixture was heated to 50 °C and stirred overnight. The reaction solution was poured into water, extracted three times with ethyl acetate, and the organic phase was washed once with saturated brine. The solution was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to give compound C-2 (1.00 g, yield: 28.2%). LC-MS (ESI, m / z): 228 [M+1] + .

[0251] Step 2: Compound C-2 (1.00 g, 4.40 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium hydroxide aqueous solution (4 M, 10 mL) was added. The mixture was then stirred at room temperature for one hour. The pH of the reaction solution was adjusted to acidic with 2 N dilute hydrochloric acid. The mixture was extracted three times with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a white solid compound C-3 (0.80 g, yield: 85.2%). LC-MS (ESI, m / z): 214 [M+1] + .

[0252] Step 3: Compound C-3 (0.80 g, 3.75 mmol) was dissolved in dichloromethane (16 ml), and one drop of N,N-dimethylformamide was added. Oxaloyl chloride (4 ml) was added dropwise under ice bath conditions, and the mixture was stirred at room temperature for 45 minutes. The reaction solution was then concentrated for later use. Ammonia water (10 ml) and tetrahydrofuran (10 ml) were dissolved in tetrahydrofuran (10 ml) and slowly added dropwise to the reaction solution under stirring at room temperature. The mixture was stirred at room temperature for half an hour. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain solid compound C-4 (0.85 g, yield: 100.0%). LC-MS (ESI, m / z): 213 [M+1] + .

[0253] Step 4: Compound C-4 (0.85 g, 4.01 mmol) was added to a single-necked flask, followed by phosphorus oxychloride (13 ml). The mixture was stirred in an oil bath at 90 °C for two hours. The reaction solution was then slowly added dropwise to warm water (150 ml). The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give a brown solid, compound C-5 (0.70 g, yield: 89.8%). LC-MS (ESI, m / z): 195 [M+1] + .

[0254] Step 5: Compound C-5 (0.70 g, 3.60 mmol) was placed in a single-necked flask, and iron powder (1120 mg) and ammonium chloride (1000 mg) were added. The mixture was dissolved in methanol (6 ml), tetrahydrofuran (6 ml), and water (3 ml). The mixture was stirred at room temperature for two hours. The reaction solution was then diluted with methanol, filtered through diatomaceous earth, and the filtrate was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to obtain compound C-6 (600 mg, yield: 67.8%). LC-MS (ESI, m / z): 165 [M+1] + .

[0255] Step 6: Compound C-6 (50 mg, 0.30 mmol), (2-chloro-5-trifluoromethyl-pyridin-4-yl)-methylamine (64 mg, 0.30 mmol), palladium acetate (7 mg, 0.03 mmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (35 mg, 0.06 mmol), and cesium carbonate (199 mg, 0.60 mmol) were placed in a single-necked flask. Dioxane (2 ml) was added, and the mixture was purged with nitrogen. The mixture was then stirred in an oil bath at 100 °C for two hours. The reaction mixture was directly filtered, and the filtrate was purified by thin-layer chromatography to obtain compound C. 1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),7.97(s,1H),7.71(s,1H),6.85(s,1H),6.21(q,J= 4.0Hz,1H),2.76(d,J=4.0Hz,3H),1.96(s,3H),1.93(s,6H).LC-MS(ESI,m / z):339[M+1] + .

[0256] Example 1: Synthesis of N2-(3-(2-(2H-1,2,3-triazol-2-yl)propyl-2-yl)-1-cyclopropyl-1H-1,2,4-triazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyridine-2,4-diamine (Compound 1)

[0257]

[0258] Step 1: In a reaction flask, add 1,2,3-triazole (5g, 72.5mmol) and N,N-dimethylformamide (50mL), and add under ice bath conditions. t Buok (16.3 g, 145.0 mmol), stirred for 1 hour. Compound 1-1 (28 g, 145.0 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water (250 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to give a colorless oily liquid compound 1-2 (3.9 g, yield: 29%). LC-MS (ESI, m / z): 184.1 [M+1] + .

[0259] Step 2: In a reaction flask, add compound 1-2 (3g, 1.64mmol), methanol (30mL), water (5mL), and finally LiOH (78mg, 3.27mmol). Stir overnight at 40°C. After the reaction is complete, adjust the pH to 6-7 with dilute hydrochloric acid. After removing the solvent under reduced pressure, dissolve the mixture in dichloromethane (30mL), dry with anhydrous sodium sulfate, filter, and concentrate the organic phase under reduced pressure to obtain a colorless oily liquid compound 1-3 (2g, yield: 80%). LC-MS (ESI, m / z): 156.3 [M+1] + .

[0260] Step 3: In a reaction flask, add compound 1-3 (300 mg, 1.93 mmol) and ultra-dry dichloromethane (10 mL), 1 drop of N,N-dimethylformamide, and under argon protection, add oxalyl chloride (491 mg, 3.87 mmol) dropwise in an ice bath. Stir at room temperature for 1 hour, concentrate under reduced pressure to remove the solvent, and obtain crude acyl chloride, which can be used directly in the next step.

[0261] The crude acyl chloride was added to ultra-dry dichloromethane (20 mL) under argon protection. Sodium cyanamide solid (247 mg, 3.87 mmol) was added in an ice bath. After stirring at room temperature for 1 hour, the reaction was complete. The reaction solution was directly mixed and purified by silica gel column chromatography to give a colorless oily liquid compound 1-4 (300 mg, two-step yield: 86.7%). LC-MS (ESI, m / z): 180.1 [M+1] + .

[0262] Step 4: In a reaction flask, add compounds 1-4 (300 mg, 1.67 mmol) and ethanol (10 mL), and finally add cyclopropylhydrazine hydrochloride (55 mg, 5.02 mmol). Stir overnight at 90°C under argon protection. After the reaction is complete, dilute with water (5 mL) and adjust the pH to 7-8 with sodium carbonate aqueous solution. Extract with ethyl acetate (10 mL x 3). Dry the organic phase with anhydrous sodium sulfate, remove the solvent under reduced pressure, and obtain the crude product. Purify by silica gel column chromatography to give a yellow oily liquid compound 1-5 (70 mg, yield: 18%). LC-MS (ESI, m / z): 234.1 [M+1] + .

[0263] Step 5: Add 1-5 (70 mg, 0.3 mmol), INT-1 (67 mg, 0.3 mmol), Brettphos Pd G3 (27 mg, 0.03 mmol), Xantphos (17 mg, 0.03 mmol), Cs₂CO₃ (196 mg, 0.6 mmol), and dioxane (5 mL) to the reaction flask. Heat to 105 °C and stir overnight under argon protection. After the reaction is complete, dilute with water (10 mL), extract with ethyl acetate (10 mL x 3), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure to obtain crude product, purify by silica gel column chromatography, collect the eluent, remove the solvent under reduced pressure, and obtain crude product. Purify the crude product by C18 reversed-phase column chromatography, collect the eluent, remove acetonitrile under reduced pressure, lyophilize to obtain compound 1. 1 H NMR (400MHz, DMSO-d6) δ8.04(s,1H),7.74(s,2H),7.12(s,1H),6.33(dd,J=5.2Hz,1H),3.56-3.52(m,1H) ,3.13-3.10(m,2H),1.98(s,6H),1.08(t,J=6.8Hz,3H),1.00-0.97(m,4H).LC-MS(ESI,m / z):421.9[M+1] + .

[0264] Example 2: Synthesis of N2-(3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (compound 2)

[0265]

[0266] Step 1: Triazole (13.80 g, 200 mmol) was dissolved in N,N-dimethylformamide (250 mL), and potassium carbonate (41.40 g, 300 mmol) and methyl bromoacetate (15.30 g, 100 mmol) were added. The reaction mixture was reacted at 25 °C for 15 hours. The reaction solution was poured into water, extracted three times with EA, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography to give compound 2-2 (4.53 g, 32.13 mmol), with a yield of 16.06%. LC-MS (ESI, m / z): 142 [M+1] + .

[0267] Step 2: [1,2,3]triazol-2-yl-acetate methyl ester 2-2 (1.41 g, 10.00 mmol) was dissolved in tetrahydrofuran (20 mL). Under nitrogen protection, the mixture was cooled to -78°C, and LDA (5.0 mL, 10.00 mmol) was slowly added dropwise. After 10 minutes of addition, 1,3,2-dioxazolthiophene-2,2-dioxide (1.30 g, 10.50 mmol) was added dropwise. After 10 minutes of addition, the mixture was heated to 0°C and reacted for 1 hour. The mixture was then cooled to -70°C, and diisopropylaminolithium (5.0 mL, 10.00 mmol) was slowly added dropwise. After 10 minutes of addition, the mixture was heated to 0°C and reacted for 1 hour. The reaction mixture was poured into water, extracted three times with ethyl acetate, and the organic phase was washed once with saturated brine. After drying with anhydrous sodium sulfate, the solution was concentrated and then subjected to column chromatography to obtain compound 2-3 (0.34 g, 2.04 mmol), with a yield of 20.36%. LC-MS (ESI, m / z): 168 [M+1] + .

[0268] Step 3: Anhydrous acetonitrile (0.23 g, 5.61 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Under nitrogen protection, the mixture was cooled to -78°C, and tert-butyllithium (1.12 mL, 2.80 mmol) was slowly added dropwise. After 5 minutes of addition, a tetrahydrofuran solution of compound 2-3 (0.24 g, 1.44 mmol) (2 mL) was slowly added, and the reaction was allowed to continue for 1 hour. The reaction solution was poured into water, and the aqueous phase was adjusted to pH 2 with dilute hydrochloric acid. The mixture was extracted twice with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a brown oily compound 2-4 (0.24 g, 1.36 mmol), with a yield of 96%. LC-MS (ESI, m / z): 177 [M+1]+ .

[0269] Step 4: Compound 2-4 (0.08 g, 0.45 mmol) and cyclopropylhydrazine hydrochloride (0.20 g, 1.85 mmol) were dissolved in ethanol (10 mL), and concentrated hydrochloric acid (0.2 mL) was added. The mixture was reacted at 85°C for 15 hours. The reaction solution was directly concentrated and column chromatography was performed to obtain compound 2-5 (56 mg, 0.24 mmol), with a yield of 53.33%. LC-MS (ESI, m / z): 231 [M+1] + .

[0270] Step 5: Compound 2-5 (50 mg, 0.22 mmol), (2-chloro-5-trifluoromethyl-pyrimidin-4-yl)-ethylamine (59 mg, 0.26 mmol), Pd2(dba)3 (40 mg, 0.044 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (40 mg, 0.064 mmol), and sodium tert-butoxide (45 mg, 0.47 mmol) were dissolved in dioxane (5 ml), purged three times with nitrogen, and heated to 100°C for 6 hours. The reaction solution was then directly concentrated and stirred into a column chromatography to obtain compound 2. 1 H NMR(400MHz, CDCl3)δ8.09(s,1H),7.62(s,2H),6.05(s,1H),5.22(s,1H),3.37(qd,J=7.2,5.2Hz,2H),3.27- 3.16(m,1H),1.75(s,4H),1.26(s,1H),1.20(d,J=7.3Hz,3H),1.15-1.08(m,4H).LC-MS(ESI,m / z):420[M+1] + .

[0271] Example 3: Synthesis of N2-(3-(1-(2H-1,2,3-triazol-2-yl)cyclobutyl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (compound 3)

[0272]

[0273] Step 1: Triazole 3-1 (3.33 g, 48.21 mmol) was dissolved in N,N-dimethylformamide (20 mL), potassium carbonate (1.38 g, 100 mmol) and ethyl 1-bromocyclobutane carboxylate (9.98 g, 48.21 mmol) were added, and the mixture was heated to 60°C and reacted for 15 hours. The reaction solution was poured into water, extracted three times with ethyl acetate, the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography to give compound 3-2 (1.20 g, 6.16 mmol), in a yield of 12.8%.1 H NMR (400MHz, CDCl3) δ7.67 (s, 2H), 4.16 (q, J = 7.1Hz, 2H), 3.05-2.92 (m, 4H), 2.27-1.98 (m, 2H), 1.17 (t, J = 7.1Hz, 3H). LC-MS (ESI, m / z): 196 [M+1] + .

[0274] Step 2: Anhydrous acetonitrile (0.967 g, 23.59 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Under nitrogen protection, the mixture was cooled to -78°C, and tert-butyllithium (4.7 mL, 11.75 mmol) was slowly added dropwise. After 10 minutes of addition, a tetrahydrofuran solution of compound 3-2 (1.15 g, 5.89 mmol) was slowly added. After 1 hour of addition, the reaction mixture was poured into water and extracted twice with ethyl acetate. The aqueous phase was adjusted to pH 2 with dilute hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a brown solid compound 3-3 (1.022 g, 5.37 mmol), with a yield of 91.2%. LC-MS (ESI, m / z): 191 [M+1] + .

[0275] Step 3: 3-oxo-3-(1-[1,2,3]triazol-2-yl-cyclobutyl)-propionitrile 3-3 (500 mg, 2.63 mmol) and cyclopropylhydrazine hydrochloride (568 mg, 5.26 mmol) were dissolved in ethanol (10 mL), and concentrated hydrochloric acid (2 mL) was added. The mixture was reacted at 80°C for 15 hours. The reaction solution was directly concentrated and stirred for column chromatography to obtain compound 3-4 (348 mg, 1.42 mmol), with a yield of 54.1%. LC-MS (ESI, m / z): 245 [M+1] + .

[0276] Step 4: 2-Cyclopropyl-5-(1-[1,2,3]triazol-2-yl-cyclobutyl)-2H-pyrazole-3-ylamine 3-4 (348 mg, 1.42 mmol), (2-chloro-5-trifluoromethyl-pyrimidin-4-yl)-ethylamine (385 mg, 1.71 mmol), Pd2(dba)3 (0.261 mg, 0.28 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.266 mg, 0.43 mmol), and sodium tert-butoxide (274 mg, 2.85 mmol) were dissolved in dioxane (10 ml), purged three times with nitrogen, and heated to 100°C for 5 hours. The reaction solution was directly concentrated and mixed, and purified by column chromatography to obtain compound 3. 1HNMR(400MHz, CDCl3)δ8.10(d,J=1.0Hz,1H),7.62(s,2H),6.08(s,1H),5.18(s,1H),3.40(qd,J=7.2,5.2Hz,2H),3 .24(tt,J=7.0,3.7Hz,1H),3.13-2.98(m,4H),2.11-1.98(m,2H),1.22(t,J=7.2Hz,6H).LC-MS(ESI,m / z):434[M+1] + .

[0277] Example 4: Synthesis of N2-(3-(1-(2H-1,2,3-triazol-2-yl)cyclopentyl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (compound 4)

[0278]

[0279] Step 1: Methyl cyclopentanecarbamate (10.00 g, 78.12 mmol), N-bromosuccinimide (16.89 g, 94.83 mmol), and benzoyl peroxide (1.89 g, 7.81 mmol) were dissolved in carbon tetrachloride (100 ml) and reacted at 85 °C for 2 hours. After cooling to room temperature, the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure at 45 °C to give compound 4-2 (14.54 g, 70.21 mmol), with a yield of 90%. This compound was used directly in the next step without further testing.

[0280] Step 2: Triazole (1.60 g, 23.19 mmol) was dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (6.40 g, 46.37 mmol) and methyl 1-bromocyclopentanecarboxylate (4.50 g, 21.63 mmol) were added. The mixture was heated to 60°C and reacted for 15 hours. The reaction solution was poured into water, extracted three times with ethyl acetate, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography to give compound 4-3 (0.64 g, 3.28 mmol), in a yield of 14.15%. 1 H NMR (400MHz, CDCl3) δ7.64 (s, 2H), 3.64 (d, J = 0.5Hz, 3H), 3.02-2.92 (m, 2H), 2.47 (dddd, J = 16.2, 8.5, 4.3, 1.7Hz, 2H),

[0281] 1.94-1.81(m,2H),1.70-1.58(m,2H).LC-MS(ESI,m / z):196[M+1] + .

[0282] Step 3: Anhydrous acetonitrile (0.26 g, 6.34 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL). Under nitrogen protection, the mixture was cooled to -78°C, and n-BuLi (1.30 mL, 3.25 mmol) was slowly added dropwise. After 10 minutes of addition, a solution of methyl 1-[1,2,3]triazol-2-yl-cyclopentanecarboxylate 4-3 (0.31 g, 1.59 mmol) in tetrahydrofuran (5 mL) was slowly added. After 1 hour of addition, the reaction mixture was poured into water and extracted twice with ethyl acetate. The aqueous phase was adjusted to pH 2 with dilute hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a brown oily compound 4-4 (0.58 g, 2.84 mmol), in a yield of 91.7%. LC-MS (ESI, m / z): 205 [M+1] + .

[0283] Step 4: 3-O-3-(1-[1,2,3]triazol-2-yl-cyclopentyl)-propionitrile 4-4 (0.47 g, 2.30 mmol) and cyclopropylhydrazine hydrochloride (1.08 g, 10.00 mmol) were dissolved in ethanol (50 mL), and concentrated hydrochloric acid (1 mL) was added. The mixture was reacted at 80°C for 7 hours. The reaction solution was directly concentrated and stirred by column chromatography to obtain compound 4-5 (0.27 mg, 1.05 mmol), with a yield of 45.50%. LC-MS (ESI, m / z): 259 [M+1] + .

[0284] Step 5: Compounds 4-5 (50 mg, 0.19 mmol), (2-chloro-5-trifluoromethyl-pyrimidin-4-yl)-ethylamine (52 mg, 0.23 mmol), Pd2(dba)3 (35 mg, 0.038 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (36 mg, 0.058 mmol), and sodium tert-butoxide (37 mg, 0.38 mmol) were dissolved in dioxane (5 ml), purged three times with nitrogen, and heated to 100°C for 5 hours. The reaction solution was then directly concentrated and stirred into a column chromatography solution to obtain compound 4. 1 H NMR (400MHz, CDCl3) δ8.07(s,1H),7.61(s,2H),5.99(s,1H),3.40(dd,J=7.3,5.3Hz,2H),3.24(t,J=3.6Hz,1H),3.06(td,J=7.8,4.6Hz ,2H),2.63-2.48(m,2H),1.92-1.80(m,2H),1.69-1.57(m,3H),1.24(d,J=3.0Hz,4H),1.16(d,J=1.9Hz,4H).LC-MS(ESI,m / z):448[M+1]+ .

[0285] Example 5: Synthesis of N2-(3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1-cyclopropyl-1H-1,2,4-triazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyridine-2,4-diamine (compound 5)

[0286]

[0287] Step 1: Take a reaction flask and add compound 2-3 (1.44 g, 2.0 eq) dissolved in methanol (10 mL). Replace the solution three times with a nitrogen balloon. Stir at 0 °C for 10 min. Slowly add 30% NaOMe in methanol (8 mL) and react at 0 °C for 20 min. Then add aminoguanidine (1.12 g, 1.0 eq), stir at 0 °C for 15 min, and then raise the temperature to 80 °C and react for 5 h. Thin-layer chromatography (TLC) confirmed the reaction was complete. Add silica gel directly and stir. The crude product was purified by normal-phase flash chromatography to obtain compound 5-2 (0.60 g, yield: 45.45%, purity: 96.33%). LC-MS (ESI, m / z): 191.94 [M+H] + .

[0288] Step 2: Take a reaction flask and add compound 5-2 (0.60 g, 1.0 eq), cyclopropylboronic acid (1.26 g, 4.0 eq), Cu(OAc)2 (0.22 g, 0.2 eq), 2,2'-bipyridine (0.19 g, 0.2 eq), and dichloroethane (40 mL) sequentially. The mixture is then exposed to the open container at 75°C for 12 h. Thin-layer chromatography is used to monitor the completeness of the reaction. The mixture is filtered, and the filter cake is washed with dichloromethane / methanol = 10 / 1 (30 mL). The filtrate is mixed with silica gel, and the crude product is purified by normal-phase flash chromatography to obtain compound 5-3 (0.33 g, yield: 45.8%). LC-MS (ESI, m / z): 231.98 [M+H] + .

[0289] Step 3: Take a reaction flask and add compound 5-3 (0.10 g, 1.0 eq), intermediate INT1 (0.10 g, 1.0 eq), Cs2CO3 (0.28 g, 2.0 eq), Pd2(dba)3 (0.04 g, 0.1 eq), Xantphos (0.03 g, 0.1 eq), and dioxane (5 mL) sequentially. Replace the mixture with a nitrogen balloon three times and react in a microwave at 90 °C for 2 h. Monitor the reaction for completeness using LCMS. Cool to room temperature and purify by thin-layer chromatography to obtain 0.1 g of crude product. The crude product is then purified by reversed-phase flash chromatography to obtain compound 5. 1H NMR(400MHz, CDCl3)δ:9.58(s,1H),8.01(s,1H),7.79(s,2H),7.07(s,1H),6.32(t,1H),3.43(m,1 H),3.14(q,2H),1.66(m,4H),1.10-1.07(t,3H),0.92-0.84(m,4H).LC-MS(ESI,m / z):419.97[M+H] + .

[0290] Example 6: Synthesis of (2-(3-(2-(2H-1,2,3-triazol-2-yl)propyl-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)aminoethyl)dimethylphosphine oxide (compound 6)

[0291]

[0292] Step 1: Under ice bath conditions, potassium tert-butoxide (12.2 g, 108.59 mmol) and compound 6-1 (21.2 g, 108.59 mmol) were added to a solution of 1,2,3-triazole (5 g, 72.39 mmol) in N,N-dimethylformamide (100 mL). The mixture was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was complete, the mixture was quenched with saturated ammonium chloride aqueous solution (200 mL), extracted with ethyl acetate (300 mL x 3), washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by reversed-phase column chromatography (FA) (ACN:H2O = 30%, 50%) to give compound 6-2 (1.44 g, 10.6%). 1 HNMR(400MHz,DMSO-d6)δ7.94-7.69(m,2H),4.17-4.04(m,2H),1.97-1.84(m,6H),1.12(dd,J=14.7,7.6Hz,3H).LCMS(ESI,m / z):184[M+H] + .

[0293] Step 2: At -78°C, n-butyllithium (2.5M, 4.6mL, 11.43mmol) was slowly added to a tetrahydrofuran (10mL) solution of acetonitrile (469.2mg, 11.43mmol). After reacting for 1 hour, compound 6-2 (1g, 5.72mmol) dissolved in tetrahydrofuran (1mL) was added to the reaction system, and the mixture was stirred for 1 hour. After the reaction was complete, the mixture was quenched with saturated ammonium chloride aqueous solution (20mL), extracted with ethyl acetate (20mL x 3), washed with saturated brine (30 x 3mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by normal-phase column chromatography (petroleum ether:tetrahydrofuran = 5:1) to give compound 6-3 (456mg, yield 46.9%). LCMS (ESI, m / z): 179.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.09(s,1H),4.33(s,2H),1.95(s,6H).

[0294] Step 3: Hydrochloric acid (12M, 0.34mL, 4.125mmol) and cyclopropylhydrazine hydrochloride (448mg, 4.125mmol) were added to a 4mL ethanol solution of compound 6-3 (245mg, 1.375mmol), and the mixture was stirred overnight at 70°C. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate (10mL), extracted with ethyl acetate (10mL x 3), washed with saturated brine (10 x 3mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to give compound 6-4 (189mg, yield 59.2%). LCMS (ESI, m / z): 233.2 [M+H] + .

[0295] Step 4: Take a reaction flask and add compound 6-4 (0.40 g, 1.0 eq), 1,3-dicyclohexylcarbodiimide (0.53 g, 1.5 eq), and dichloromethane (10 mL) sequentially. Then add HCOOH (0.20 g, 2.0 eq). Stir the reaction at room temperature for 12 hours. Monitor the reaction for completeness by thin-layer chromatography. Dilute the reaction solution with dichloromethane (20 mL), wash with saturated Na2CO3 aqueous solution (30 mL), dry with anhydrous Na2SO4, filter, and concentrate to obtain compound 6-5 (0.36 g, yield: 80%).

[0296] Step 5: Take a reaction flask and add 2-chloro-4-(methylthio)-5-(trifluoromethyl)pyrimidine (0.30 g, 1.0 eq), compound 6-5 (0.34 g, 1.0 eq), dimethyl sulfoxide (5 mL), and Cs₂CO₃ (0.86 g, 2.0 eq) sequentially. Place the reaction flask in a 50°C oil bath and stir for 2 min, then heat to 90°C and stir for 2 h. Monitor the reaction by LCMS until complete. Cool to room temperature, add 20 mL of water, extract with 20 mL of ethyl acetate (20 mL x 2), wash with saturated NaCl solution, dry with anhydrous Na₂SO₄, filter, and concentrate to obtain compound 6-6 (0.48 g, yield: 74.8%). LCMS (ESI, m / z): 425.05 [M+H] + .

[0297] Step 6: Take the reaction flask, add compound 6-6 (0.26 g, 1.0 eq), dissolve in dimethyl sulfoxide (5 mL), stir at 0 °C for 5 min, then add m-chloroperoxybenzoic acid (0.19 g, 1.5 eq), allow to return to room temperature naturally, and stir for 12 h. Thin-layer chromatography showed that the starting material had reacted completely. Add silica gel directly to the sample, and the crude product was purified by normal-phase flash chromatography to obtain compound 6-7 (0.21 g, yield: 78.0%). LCMS (ESI, m / z): 462.94 [M+Na] + .

[0298] Step 7: Take a reaction flask and add compounds 6-7 (20 mg, 1.0 eq), 2-aminoethyldimethylphosphine oxide (9 mg, 1.0 eq), and tetrahydrofuran (2 mL) sequentially. Add triethylamine (30 mg, 5.0 eq) while stirring at room temperature, and stir for 2 hours at room temperature. Thin-layer chromatography (TLC) confirms the complete reaction of the starting materials. Compound 6 is obtained by preparative TLC purification. 1 HNMR(400MHz,CD3OD)δ:9.25(s,1H),8.12(s,1H),7.71(s,2H),7.29(m,1H),5.79(s,1H),3.60-3.44(m,2H),3.41-3.3 3(m,1H),1.91(s,6H),1.88-1.80(m,2H),1.34-1.30(d,J=16Hz,6H),0.85-0.82(m,4H).LCMS(ESI,m / z):498.08[M+H] + .

[0299] Examples 7-8:

[0300] Refer to Examples 2 and 6, and Synthetic Examples 7 and 8.

[0301]

[0302] Example 9: Synthesis of 2-(1-cyclopropyl-5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-3-yl)-2-methyltetrahydrothiophene 1,1-dioxide (compound 9)

[0303]

[0304] Step 1: In a reaction flask, compound 9-1 (5 g, 41.67 mmol) and tetrahydrofuran (50 mL) were added. Under argon protection, a tetrahydrofuran solution of LiHMDS (20.8 mL, 41.67 mmol, 2 mol / L) was added at -78 °C. After stirring for 1 hour, benzyl chloroformate (7.08 g, 41.67 mmol) was added, and the reaction was stirred at -78 °C for 1 hour. After the reaction was complete, the mixture was quenched with water (150 mL), extracted with ethyl acetate (50 mL x 3), and the organic phases were combined. The mixture was washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography [eluent: petroleum ether-tetrahydrofuran (100:0-100:10)]. The eluent was collected, and the solvent was removed under reduced pressure to obtain compound 9-2 (5 g, yield: 47.26%). LCMS (ESI, m / z): 272.2 [M+18] + ; 1 HNMR(400MHz,DMSO-d6)δ:7.40-7.34(m,5H),5.22(s,2H),4.28(t,J=8.4Hz,1H),3.30-3 .24(m,1H),3.18-3.10(m,1H),3.00-2.98(m,1H),2.36-2.31(m,1H),2.19-2.05(m,2H).

[0305] Step 2: In a reaction flask, compound 9-2 (1 g, 3.94 mmol), Cs₂CO₃ (2.57 g, 7.88 mmol), and N,N-dimethylformamide (15 mL) were added, followed by CH₃I (1.12 g, 7.88 mmol). The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water (60 mL), and the system was extracted three times with ethyl acetate (20 mL). The organic phases were combined and backwashed three times with saturated brine. After drying the organic phase and removing the solvent under reduced pressure, the crude product was obtained. The crude product was purified by silica gel column chromatography [eluent: petroleum ether-tetrahydrofuran (100:0-100:30)]. The eluent was collected, and the solvent was removed under reduced pressure to obtain compound 9-3 (1 g, yield: 95%). LCMS (ESI, m / z): 286.3 [M+18] + ; 1HNMR(400MHz, DMSO-d6)δ:7.40-7.34(m,5H),5.23-5.15(m,2H),3.27-3.22(m,2H),2.72-2.69(m,1H),2.10-1.99(m,3H),1.52(s,3H).

[0306] Step 3: In a reaction flask, acetonitrile (245 mg, 5.97 mmol) and ultra-dry tetrahydrofuran (10 mL) were added. Under argon protection, n-BuLi (5.38 mL, 5.39 mmol, 1 mol / L) was added dropwise at -78 °C. After stirring for 1 hour, compound 9-3 (800 mg, 2.98 mmol) was added, and the mixture was stirred for 2 hours. The reaction was completed, quenched with water (30 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography [eluent: dichloromethane-methanol (100:0-100:10)]. The eluent was collected, and the solvent was removed under reduced pressure to obtain compound 9-4 (420 mg, yield: 70%). LCMS (ESI, m / z): 219.2 [M+18] + .

[0307] Step 4: In a reaction flask, add compound 9-4 (300 mg, 1.49 mmol) and ethanol (10 mL), then add cyclopropylhydrazine hydrochloride (488 mg, 4.48 mmol). Stir overnight at 90 °C until the reaction is complete. Adjust the pH of the reaction solution to approximately 8 with sodium bicarbonate aqueous solution, extract with water and ethyl acetate, dry the organic phase, add silica gel and stir. Purify by silica gel column chromatography [eluent: dichloromethane-methanol (100:0-100:5)]. Collect the eluent, remove the solvent under reduced pressure, and obtain compound 9-5 (330 mg, yield: 86%). LCMS (ESI, m / z): 256.3 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ:5.29(s,1H),5.26(s,2H),3.19-3.12(m,2H),3.06-3. 02(m,1H),2.63-2.59(m,1H),2.17-1.92(m,3H),1.48(s,3H),0.91-0.89(m,4H).

[0308] Step 5: In a reaction flask, add 007-3 (100 mg, 0.39 mmol) and dioxane (10 mL), then add compound 9-5 (88 mg, 0.39 mmol) and p-toluenesulfonic acid (34 mg, 0.19 mmol). Stir overnight at 90 °C. After the reaction is complete, remove the solvent under reduced pressure to obtain the crude product. Purify the crude product using a silica gel column [eluent: dichloromethane-methanol (100:0-100:8)]. Collect the eluent, remove the solvent under reduced pressure to obtain the crude product. Purify the crude product using a C18 reversed-phase column. Collect the eluent, remove the solvent under reduced pressure, and lyophilize to obtain compound 9. LCMS (ESI, m / z): 445.0 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ:9.46(br,1H),8.18(s,1H),7.21(br,1H),6.40(s,1H),3.54-3.48(m,1H),3.44-3.38(m,2H),3.23- 3.18(m,1H),3.12-3.04(m,1H),2.69-2.64(m,1H),2.20-2.02(m,3H),1.56(s,3H),1.09(t,J=7.2Hz,3H),0.97-0.92(m,4H).

[0309] Example 10: Synthesis of N2-(3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4-isopropyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (compound 10)

[0310]

[0311] Step 1: Take a reaction flask and first add compound 10-1 (40.0 g, 1.0 eq), N,N-dimethylformamide (250 mL), and methyl 2,4-dibromobutyrate (150.0 g, 1.0 eq). Replace the solution three times with a nitrogen balloon. Add CS2CO3 (376.1 g, 2.0 eq) in batches under an ice-water bath and react overnight. Monitor the reaction by LC-MS until complete. Add 2 L of water to the reaction mixture, then separate the layers. Extract the aqueous phase with ethyl acetate (3 x 1 L). Combine the organic phases and wash with saturated NaCl solution (3 x 500 mL). Dry, filter, and evaporate to dryness. Purify the crude product by normal-phase flash to obtain compound 10-2 (54 g, yield: 56%). LC-MS (ESI, m / z): 167.87 [M+H] + .

[0312] Step 2: Take a reaction flask and add compound 10⁻² (50 g, 1.0 eq), MeCN (25.8 g, 2.1 eq), and tetrahydrofuran (100 mL) sequentially. Then, add t-BuOK / tetrahydrofuran solution (1 mol / L) (600 mL, 2.0 eq) under ice bath conditions and react overnight. Monitor the reaction for completeness using LC-MS. Add 50 mL of water to the reaction system and extract once with 100 mL of ethyl acetate. After separation, adjust the pH of the aqueous phase to 1–2 with HCl, and extract again with ethyl acetate. Wash the organic phase with saturated NaCl solution (3 x 50 mL), dry, filter, and evaporate to dryness to obtain compound 10⁻³ (32 g, yield: 58%). LC-MS (ESI, m / z): 176.88 [M + H] + .

[0313] Step 3: Take the sealed tube and add compound 10⁻³ (10.0 g, 1.0 eq), cyclopropylhydrazine hydrochloride (7.4 g, 2.0 eq), ethanol (100 mL), and 6M HCl (28 mL) sequentially. React overnight at 60°C. Monitor the reaction for completeness using LC-MS. Add 50 mL of water to the reaction mixture, then separate the layers. Extract the aqueous phase with ethyl acetate (3 x 15 mL). Combine the organic phases and wash with saturated NaCl solution (3 x 20 mL). Dry, filter, and evaporate to dryness. Purify the crude product by normal-phase column chromatography to obtain compound 10⁻⁴ (4.45 g, yield: 34%). LC-MS (ESI, m / z): 230.91 [M + H⁺] + .

[0314] Step 4: Take a reaction flask and add compound 10⁻⁴ (2.3 g, 1.0 eq) and 2,4-dichloro-5-trifluoromethylpyrimidine (2.4 g, 5 mL) sequentially, dissolving them in 40 mL of tert-butanol. Then add N,N-diisopropylethylamine (3.9 g, 2.0 eq), and continue stirring at room temperature for 3 hours. Monitor the reaction for completeness using LC-MS. Pass the reaction solution through a column, concentrate, and obtain compound 10⁻⁵ (1.0 g, yield: 24%). LC-MS (ESI, m / z): 410.83 [M+H] + .

[0315] Step 5: Take the sealed tube, add compound 10-5 (30 mg, 1.0 eq) and isopropylamine (30 mg, 5.0 eq) sequentially, dissolve in 3 mL of 1,4-dioxane, then add N,N-diisopropylethylamine (94 mg, 10 eq), and react overnight at 60 °C. Monitor the reaction for completeness by LCMS, and directly prepare compound 10 by high performance liquid chromatography, followed by lyophilization. 1HNMR(400MHz,DMSO-d6)δ:9.38(s,1H),8.12(s,1H),7.80(s,2H),7.36(d,J=8.0Hz,1H),5.71(s,1H),4.10(s,1H),3 .43-3.41(m,1H),1.61-1.51(m,4H),1.08-1.06(d,J=6.4Hz,6H),0.92-0.87(m,4H).LC-MS(ESI,m / z):433.91[M+H] + .

[0316] Examples 11-26

[0317] Refer to Examples 2 and 10, and Synthetic Examples 11-26.

[0318]

[0319]

[0320]

[0321]

[0322] Example 27: Synthesis of N4-methyl-N2-(3-methyl-1-(5,5,5-trifluoro-2-methylpentan-3-yn-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (compound 27)

[0323]

[0324] Step 1: In a reaction flask, compound 27-1 (5 g, 39.3 mmol), ethyl 2-bromo-2-methylpropionate (11.51 g, 59.0 mmol), potassium carbonate (8.16 g, 59.0 mmol), and N,N-dimethylformamide (50 mL) were added and stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water (250 mL), extracted with ethyl acetate (50 mL x 3), and the organic phases were combined. The mixture was washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography [eluent: petroleum ether-ethyl acetate (100:0-80:20)]. The eluent was collected, and the solvent was removed under reduced pressure to obtain compound 27-2 (9.2 g, yield: 96.9%). LC-MS (ESI, m / z): 242.1 [M+H] + .

[0325] Step 2: In a reaction flask, compound 27-2 (9.0 g, 37.3 mmol) and methanol (100 mL) were added. The reaction flask was cooled to 0 °C in an ice bath, and sodium borohydride (2.82 g, 74.6 mmol) was added in portions below 5 °C. The mixture was stirred at 0 °C for 2 hours. After the reaction was complete, the methanol was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), and the organic phase was washed with water (50 mL) and saturated brine (50 mL), respectively. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 27-3 (7.0 g, yield: 94.2%). LC-MS (ESI, m / z): 200.2 [M+H] + .

[0326] Step 3: In a reaction flask, compound 27-3 (6.8 g, 34.1 mmol) and dichloromethane (100 mL) were added. Dess-Martin oxidant (28.96 g, 68.3 mmol) was added under ice bath conditions, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was quenched with sodium thiosulfate solution (50 mL). The organic phase was washed with sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography [eluent: petroleum ether-ethyl acetate (100:0-80:20)] to give compound 27-4 (4.9 g, yield: 72.8%). LC-MS (ESI, m / z): 198.1 [M+H] + .

[0327] Step 4: In a reaction flask, compound 27-4 (4.9 g, 24.8 mmol), potassium carbonate (6.87 g, 49.7 mmol), and methanol (50 mL) were added. Dimethyl (1-diazo-2-oxopropyl)phosphonate (7.16 g, 37.3 mmol) was slowly added to the reaction solution, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was directly mixed and purified by silica gel column chromatography [eluent: petroleum ether-ethyl acetate (100:0-90:10)]. The eluent was collected, and the solvent was removed under reduced pressure to give compound 27-5 (3.8 g, yield: 79.2%). LC-MS (ESI, m / z): 194.1 [M+H] + .

[0328] Step 5: In a reaction flask, add potassium carbonate (439 mg, 3.18 mmol), cuprous iodide (303 mg, 1.59 mmol), TMEDA (185 mg, 1.59 mmol), and dried N,N-dimethylformamide (5 mL). Stir the reaction mixture at room temperature for 20 minutes. Add TMSCF3 (301 mg, 2.12 mmol) to the reaction mixture and stir at room temperature for 20 minutes. Cool the reaction mixture to 0°C using an ice bath. Dissolve TMSCF3 (301 mg, 2.12 mmol) and compound 27-5 (301 mg, 2.12 mmol) in N,N-dimethylformamide (5 mL) and slowly add the solution dropwise to the reaction mixture. Then slowly heat to room temperature and stir overnight at room temperature. After the reaction was complete, the mixture was diluted with water (30 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The mixture was washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography [eluent: petroleum ether-ethyl acetate (100:0-80:20)]. The eluent was collected, and the solvent was removed under reduced pressure to give compound 27-6 (120 mg, yield: 43.4%). LC-MS (ESI, m / z): 262.2 [M+H] + .

[0329] Step 6: Add compound 27-6 (123 mg, 0.47 mmol), NH4Cl (126 mg, 2.36 mmol), EtOH (6 mL), and water (3 mL) to the reaction flask. Add iron powder (132 mg, 2.36 mmol) while stirring vigorously. Heat to 80°C and stir for 2 hours under argon protection. After the reaction is complete, filter. Extract the filtrate three times with ethyl acetate. Combine the organic phases, dry, and remove the solvent under reduced pressure to obtain the crude product. Purify by silica gel column chromatography [eluent: petroleum ether-ethyl acetate (100:0-100:50)]. Collect the eluent and remove the solvent under reduced pressure to obtain compound 27-7 (67 mg, yield: 61.7%). LC-MS (ESI, m / z): 232.1 [M+H] + .

[0330] Step 7: In a reaction flask, add compound 27-7 (30 mg, 0.13 mmol) and dioxane (5 mL), then add intermediate INT3 (27 mg, 0.13 mmol) and p-toluenesulfonic acid (2 mg, 0.01 mmol). Stir overnight at 90 °C. After the reaction is complete, dilute with ethyl acetate, wash the organic phase with saturated sodium bicarbonate, dry, and remove the solvent under reduced pressure to obtain the crude product. Purify the crude product using a C18 reverse-phase column, collect the eluent, remove the solvent under reduced pressure, and lyophilize to obtain compound 27. LC-MS (ESI, m / z): 407.3 [M+H] + . 1H NMR (400MHz, DMSO-d6)δ:9.06(brs,1H),8.08(s,1H),7.95(s,1H),7.00(s,1H),2.84-2.79(m,3H),2.18(s,3H),1.95(s,6H).

[0331] Examples 28-29

[0332] Refer to Example 27, and Synthesis Examples 28-29.

[0333]

[0334] Example 30: Synthesis of N2-(1-cyclopropyl-3-(2-(5-(ethylthio)-2H-tetrazol-2-yl)propyl-2-yl)-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (compound 30)

[0335]

[0336] Step 1: Take a reaction flask, add 5-ethylthiotetrazole (1.302 g, 1.0 eq) and N,N-dimethylformamide (20 mL), TEA (2.024 g, 2.0 eq), then slowly add compound 30-1 (3.621 g, 2.0 eq) and KI (0.166 g, 0.1 eq), and react overnight at 60 °C. The reaction was confirmed to be complete by LC-MS. Then, 100 mL of water was added to the reaction solution, and the mixture was separated. The aqueous phase was extracted with EA (3 x 50 mL), and the organic phases were combined and washed with saturated NaCl solution (3 x 30 mL). After drying and filtration, the mixture was evaporated to dryness. The crude product was purified by normal-phase column chromatography to obtain compound 30-2 (1.3 g, yield: 56%). LC-MS (ESI, m / z): 230.95 [M+H] + .

[0337] Step 2: Take a three-necked flask and add compound 30-2 (1.200 g, 1.0 eq), ultra-dry acetonitrile (0.450 g, 2.1 eq), and tetrahydrofuran (20 mL) sequentially. Stir for ten minutes in an ice bath under a nitrogen atmosphere. Then add 1N potassium tert-butoxide tetrahydrofuran solution (10.5 mL, 2.0 eq). After the addition is complete, allow the mixture to naturally warm to room temperature and react overnight. Monitor the reaction for completeness using LC-MS. Add the reaction solution directly to water (50 mL), then extract with ethyl acetate (50 mL). Separate the aqueous phase, adjust the pH to approximately 3 using 6N hydrochloric acid aqueous solution, and extract again with ethyl acetate (50 mL). Separate the organic phase, dry and concentrate to obtain compound 30-3 (1.2 g, yield: 96%). LC-MS (ESI, m / z): 239.96 [M+H]+ .

[0338] Step 3: Take the sealed tube and add compound 30-3 (0.100 g, 1.0 eq), cyclopropylhydrazine (0.114 g, 1.05 eq), 6N hydrochloric acid aqueous solution (0.2 mL, 3.0 eq), and ethanol (4 mL) sequentially. React overnight at 60 °C. Monitor the reaction for completeness using LC-MS. Dilute the reaction solution with ethanol, dry it with anhydrous sodium sulfate, and then directly filter and concentrate to obtain compound 30-4 (0.080 g, yield: 63%). LC-MS (ESI, m / z): 164.02.

[0339] Step 4: Take a reaction flask and add compound 30-4 (0.080 g, 1.0 eq), intermediate INT2 (0.061 g, 1.0 eq), Pd(OAc)2 (0.012 g, 0.2 eq), Xantphos (0.063 g, 0.4 eq), Cs2CO3 (0.266 g, 3.0 eq), and dioxane (5 ml) sequentially. Then, purge the mixture three times with nitrogen and react at 100 °C for 5 hours. Monitor the reaction for completeness using LC-MS. After washing the reaction solution with water, extract with ethyl acetate, dry and concentrate the organic phase, and send it to the preparation section. After lyophilization, compound 30 is obtained. LC-MS (ESI, m / z): 483.13 [M+H] + . 1 H NMR(400MHz,CD3OD)δ:8.10(s,1H),6.22(s,1H),3.44-3.38(m,2H),3.37-3.33(m,1H),3.15(dd,J =12.0Hz, 8.0Hz, 2H), 2.09 (s, 6H), 1.35 (t, J = 4.0Hz, 3H), 1.12 (t, J = 8.0Hz, 3H), 1.08-0.99 (m, 4H).

[0340] Example 31: Synthesis of N2-(1-cyclopropyl-3-(2-(thiazo-4-yl)propyl-2-yl)-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (compound 31)

[0341]

[0342] Step 1: Add thionyl chloride (833 mg, 7.00 mmol) to a 20.5 mL ethanol solution of compound 31-1 (505 mg, 3.53 mmol). After the addition is complete, stir overnight at room temperature. Once the reaction is complete as monitored by LC-MS, remove the solvent by vacuum distillation, dilute with ethyl acetate, wash with saturated sodium bicarbonate, dry the organic phase with anhydrous sodium sulfate, and evaporate to dryness to obtain compound 31-2 (540 mg, yield: 89.4%). LC-MS (ESI, m / z): 172.2 [M+H] + .

[0343] Step 2: At 0°C, NaH (60% w / w, 192 mg, 4.80 mmol) was added in portions to a solution of compound 31-2 (270 mg, 1.58 mmol) in N,N-dimethylformamide (5.3 mL). The mixture was stirred at 0°C for 5 minutes, and then MeI (897 mg, 6.32 mmol) was added. After the addition was complete, the mixture was stirred overnight at room temperature. Once the reaction was complete as monitored by LC-MS, the reaction was quenched with ice water, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate solution, and evaporated to dryness. The extract was then collected by silica gel column chromatography [eluent: petroleum ether-ethyl acetate (100:0-100:17)]. The solvent was removed under reduced pressure to give compound 31-3 (140 mg, yield: 44.6%). LC-MS (ESI, m / z): 200.2 [M+H] + .

[0344] Step 3: At -78℃, n-butyllithium (2.5M, 0.4mL, 1.22mmol) was added to a tetrahydrofuran (13.0mL) solution of acetonitrile (50mg, 0.60mmol), and the mixture was stirred for 5 minutes. Then, compound 31-3 (119mg, 0.60mmol) was added, and the mixture was stirred at -78℃ for 3 hours after the addition was complete. After the reaction was monitored by LC-MS to be complete, the reaction was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was dried over sodium sulfate. The crude product was subjected to silica gel column chromatography [eluent: petroleum ether-tetrahydrofuran (100:0-100:25)]. The eluent was collected, and the solvent was removed under reduced pressure to obtain compound 31-4 (120mg, yield: >99.9%). LC-MS (ESI, m / z): 195.2 [M+H] + .

[0345] Step 4: Cyclopropylhydrazine hydrochloride (26 mg, 0.24 mmol) was added to a solution of compound 31-4 (39 mg, 0.20 mmol) in isopropanol (4.5 mL), and the mixture was heated to 80 °C and stirred for 6 h. After the reaction was complete as monitored by LC-MS, the reaction solution was directly evaporated to dryness. The crude product was subjected to silica gel column chromatography [eluent: petroleum ether-tetrahydrofuran (100:0-100:75)]. The eluent was collected, and the solvent was removed under reduced pressure to obtain compound 31-5 (20 mg, yield: 40.1%). LC-MS (ESI, m / z): 249.2 [M+H] + .

[0346] Step 5: To a solution of compound 31-5 (10 mg, 0.040 mmol) in 1,4-dioxane (3.0 mL), intermediate INT2 (11 mg, 0.049 mmol) and p-toluenesulfonic acid (8 mg, 0.46 mmol) were added, and the mixture was heated to 90 °C and stirred overnight. After the reaction was complete as monitored by LC-MS, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried over sodium sulfate. The crude product was purified by silica gel column chromatography and preparative high-performance liquid chromatography to obtain compound 31. LC-MS (ESI, m / z): 438.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ:9.27(br,1H),8.97(d,J=2.0Hz,1H),8.14(s,1H),7.21(d,J=1.6Hz,1H),7.18-7.05(m,1H),6.0 7(s,1H),3.50-3.38(m,1H),3.31-3.18(m,2H),1.62(s,6H),1.02(t,J=6.8Hz,3H),0.98-0.91(m,2H),0.90-0.80(m,2H).

[0347] Examples 32-34

[0348] Refer to Examples 30 and 31, and Synthetic Examples 32-34.

[0349]

[0350]

[0351] Example 35: Synthesis of N2-(3-(2-(2H-1,2,3-triazol-2-yl)propyl-2-yl)-1-(oxetane-3-yl)-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (compound 35)

[0352]

[0353] Step 1: Take a sealed tube and add compound 6-3 (0.521 g, 1.0 eq), hydrazine hydrate (0.264 g, 1.5 eq), 6N hydrochloric acid aqueous solution (1.3 mL, 3.0 eq), and ethanol (10 mL) sequentially. React overnight at 60 °C. Monitor the reaction for completeness using LC-MS. Dilute the reaction solution with ethanol, dry it with anhydrous sodium sulfate, and then filter directly. Concentrate to obtain crude compound 35-2 (1.102 g, yield: 100%). LC-MS (ESI, m / z): 193.05 [M+H] + .

[0354] Step 2: Take a sealed tube and add compound 35-2 (0.948 g, 1.0 eq), N,N-dimethylformamide-DMA (2.350 g, 4.0 eq), and dioxane (15 mL) sequentially. Seal the tube and react for 2 hours at 100°C. Monitor the reaction for completeness using LC-MS. Purify the reaction solution directly by dry loading onto a column to obtain a white solid compound 35-3 (420 mg, yield: 35%). LC-MS (ESI, m / z): 248.09 [M+H] + .

[0355] Step 3: Take a reaction flask and add compound 35-3 (0.216 g, 1.0 eq) and N,N-dimethylformamide (4 ml) sequentially. Stir for ten minutes under a nitrogen atmosphere and ice bath. Add sodium hydride (0.081 g, 2.0 eq) and continue stirring for 15 minutes. Then add 3-iodooxetine (0.241 g, 1.5 eq). First, return to room temperature and stir for ten minutes, then react at 60°C for 5 hours. Monitor the reaction for completeness using LC-MS. Pour the reaction solution into water (50 ml) and extract with ethyl acetate (50 ml). After drying and concentrating the organic phase, perform thin-layer chromatography to obtain compound 35-4 (102 mg, yield: 38.4%). LC-MS (ESI, m / z): 304.01 [M+H] + .

[0356] Step 4: Take a sealed tube and add compound 35-4 (0.102 g, 1.0 eq), sodium hydroxide aqueous solution (4 M, 5 ml), and methanol (5 ml) sequentially. Seal the tube at 80°C and react for 2 hours. Then add sodium hydroxide (0.800 g) and continue reacting at 80°C for another 3 hours. Monitor the reaction for completeness using LC-MS. Then perform preparative thin-layer chromatography to obtain compound 35-5 (51 mg, yield: 61%). LC-MS (ESI, m / z): 249.02 [M+H] + .

[0357] Step 5: Take a reaction flask and add compound 35-5 (0.030 g, 1.0 eq), intermediate INT2 (0.033 g, 1.0 eq), Pd2(dba)3 (0.022 g, 0.2 eq), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.022 g, 0.2 eq), sodium tert-butoxide (0.024 g, 2.0 eq), and dioxane (3 ml) sequentially. Then, purge with nitrogen three times and react at 100 °C for 5 hours. Monitor the reaction for completeness using LC-MS. After washing the reaction solution with water, extract with ethyl acetate, dry and concentrate the organic phase, and then separate by preparative high-performance liquid chromatography to obtain compound 35. LC-MS (ESI, m / z): 438.10 [M+H] + . 1 H NMR (400MHz, CDCl3) δ: 8.11 (s, 1H), 8.00 (d, J = 1.2Hz, 1H), 7.62 (s, 2H), 6.01 (s, 1H), 5.49 (p, J = 6.8Hz, 1H), 5.3 5(s,1H),5.24-5.20(m,2H),4.95(dd,J=8.0,6.8Hz,2H),3.40-3.33(m,2H),2.13(s,6H),1.19(t,J=7.2Hz,3H).

[0358] Examples 36-37

[0359] Refer to Example 35, and synthesize Examples 36-37.

[0360]

[0361] Biological evaluation

[0362] Test Example 1: LRRK2 kinase inhibitory activity assay

[0363] Experimental Objective

[0364] The phosphate groups of phosphorylated Fluorescein-ERM (LRRKtide) petroleum ether ptide were detected by time-resolved fluorescence resonance energy transfer (TR-FRET) technique. Energy transfer (520 nM / 485 nM fluorescence signal ratio) following binding of Tb-petroleum ether RM(pLRRKtide) antibody antibody. Calculate the IC50 of the test compound against LRRK2 kinase. 50 value.

[0365] Experimental Principle

[0366] This protocol describes an in vitro method for measuring peptide substrate phosphorylation using the WT-LRRK2 enzyme. The kinase reaction is performed by incubating a fluorescein-labeled substrate with recombinant human kinase and ATP. Lantha Screen was used. TM Kinase activity was determined using a kinase activity assay. (Lantha Screen) TM In the kinase reaction, a terbium-labeled antibody (used to detect phosphorylation products) binds to a phosphorylated fluorescein-labeled substrate, leading to an increase in the TR-FRET value. The TR-FRET value is determined by the ratio of the FRET-specific signal measured by a 520 nm filter to the signal measured by a 495 nm filter. The amount of antibody bound to the tracer is proportional to the amount of phosphorylated substrate present. Therefore, kinase activity can be measured by the increase in the TR-FRET value.

[0367] Material:

[0368] Reagents:

[0369]

[0370] Consumables:

[0371]

[0372] instrument:

[0373]

[0374] Experimental steps:

[0375] 1. The dimethyl sulfoxide solution of the analyte was added to a 384 microplate using an Echo655 non-contact nano-ultrasonic dispensing system; the maximum concentration was 10 μM, with 3-fold serial dilutions and 11 concentration gradients.

[0376] 2. Prepare a mixed enzyme and peptide solution using freshly prepared reaction solution (final concentration: 2 nM enzyme + 0.4 μM luorescein-ERM (LRRKtide) petroleum ether ptide), add 5 μL to a 384 microplate containing the existing compound, and centrifuge at 1000 rpm / min for 1 min. Incubate at room temperature for 15 min;

[0377] 3. Add 5 μL of ATP (final concentration: 38 μM), centrifuge at 1000 rpm for 1 min. Incubate at room temperature for 120 min.

[0378] 4. Add 10 μL of detection reagent: Tb-petroleum ether RM(pLRRKtide) Antibody (final concentration: 0.25 nM and EDTA (final concentration: 10 mM), centrifuged at 1000 rpm / min for 1 min. Reacted at room temperature for 30 min;

[0379] 5. Envison detected TR-TRET fluorescence signals using mirror 447 (D400 / D505), filters 275 (520nm) and 102 (485nm);

[0380] 6. The inhibitory effect of the compound on enzyme activity was calculated using the signal ratio (520nm / 485nm), and the IC50 was calculated using the XLfit5 software to fit the curve. 50 value.

[0381] Experimental results:

[0382] The calculated inhibitory activity of some of the compounds in the examples against LRRK2 is shown in the table below.

[0383] Table 1

[0384] Compound numbering <![CDATA[IC 50 (nM)]]> Compound numbering <![CDATA[IC 50 (nM)]]> Compound numbering <![CDATA[IC 50 (nM)]]> Compound A 83.9 Compound B 4044.7 Compound C 36.96 Compound 1 15.2 Compound 13 3.06 Compound 26 7.23 Compound 2 1.36 Compound 14 4.61 Compound 27 1.28 Compound 3 2.17 Compound 15 5.58 Compound 28 0.49 Compound 4 3.87 Compound 16 1.01 Compound 29 0.29 Compound 5 14.41 Compound 17 3.42 Compound 30 7.60 Compound 6 19.15 Compound 18 6.03 Compound 31 1.0 Compound 7 1.76 Compound 19 3.29 Compound 32 13.8 Compound 8 30.47 Compound 20 3.0 Compound 33 2.75 Compound 9 4.33 Compound 21 6.1 Compound 34 2.8 Compound 10 2.88 Compound 22 8.1 Compound 35 2.60 Compound 11 11.16 Compound 24 1.1 Compound 36 7.12 Compound 12 3.07 Compound 25 4.3 Compound 37 10.16

[0385] Test Example 2: In vitro microparticle stability experiment

[0386] Material:

[0387] Liver microsomes: Human and animal microsomes were purchased from Corning or Xenotech and stored at -80°C.

[0388] Reduced nicotinamide adenine dinucleotide phosphate (NADPH), supplier: BONTAC, item number: BT04

[0389] Control compounds: testosterone, diclofenac, propafenone

[0390] Experimental steps:

[0391] 1. Preparation of working solution

[0392] Stock solution: 10 mM dimethyl sulfoxide solution

[0393] Preparation of working concentration: Dilute 100% acetonitrile to 100 μM (organic phase content: 99% ACN, 1% dimethyl sulfoxide)

[0394] 2. Experimental Procedure

[0395] Prepare two 96-well incubation plates, and name them T60 incubation plate and NCF60 incubation plate respectively.

[0396] Add 445 μL of microsomal working solution (liver microsomal protein concentration of 0.56 mg / mL) to both T60 and NCF60 incubation plates, and then place the incubation plates in a 37°C water bath for pre-incubation for about 10 minutes.

[0397] After pre-incubation, add 5 μL of the working solution of the test sample or control compound to both the T60 and NCF60 incubation plates and mix well. Add 50 μL of potassium phosphate buffer to each well of the NCF60 incubation plate to initiate the reaction.

[0398] Add 180 μL of stop solution (containing 200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) and 6 μL of NADPH regeneration working solution to the T0 stop plate. Transfer 54 μL of sample from the T60 incubation plate to the T0 stop plate (T0 sample generation). Add only 54 μL of microparticle working solution, 6 μL of NADPH regeneration working solution, and 180 μL of stop solution to the Blank plate.

[0399] The reaction was initiated by adding 44 μL of NADPH regeneration working solution to each well of a T60 incubation plate. Therefore, in the sample of the test or control compound, the final reaction concentrations of the compound, testosterone, diclofenac, and propafenone were 1 μM, the concentration of liver microsomes was 0.5 mg / mL, and the final concentrations of dimethyl sulfoxide and acetonitrile in the reaction system were 0.01% (v / v) and 0.99% (v / v), respectively.

[0400] After incubation for appropriate times (e.g., 5, 15, 30, 45, and 60 minutes), add 180 μL of stop solution (acetonitrile solution containing 250 nM tolbutamide and 250 nM labetalol) to the sample well of each stop plate, and then remove 60 μL of sample from the T60 or NCF60 incubation plate to terminate the reaction.

[0401] Shake all sample plates well and centrifuge at 3220×g for 20 minutes. Then, take 80 μL of the supernatant from each well and dilute it into 240 μL of pure water for liquid chromatography-tandem mass spectrometry analysis.

[0402] Liquid chromatography-tandem mass spectrometry analysis: analysis of all sample injections.

[0403] 1. Sample Analysis

[0404] In this study, the test and control compounds testosterone, diclofenac, and propafenone were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0405] 2. Data Analysis

[0406] The in vitro elimination rate constant k of the test and control compounds can be obtained by converting the ratio of the peak area of ​​the compound to that of the internal standard into the residual percentage using the following formula. e :

[0407]

[0408] when

[0409]

[0410] In vitro intrinsic clearance of liver microsomes (CLint(mic)) and intrinsic liver clearance (CLint(liver)) were calculated using ke.

[0411] CLint(mic) = 0.693 / T1 / 2 / microsomal protein content (microsomal concentration during incubation, mg / mL)

[0412] CLint(liver) = CLint(mic) × amount of microsomal protein in the liver (mg / g) × liver weight to body weight ratio

[0413] The parameters used in the formula are shown in the table below.

[0414]

[0415] The results of the in vitro microsomal stability of some of the compound examples in humans (HLM) and rats (RLM) are shown in the table below.

[0416] Table 2

[0417]

[0418] Test Example 3: Pharmacokinetic Evaluation of Compounds

[0419] Control drug 1 Synthesized according to compound 78 on page 73 of specification WO2017218843A1. Test Example 3-1:

[0420] Experimental materials

[0421] SD rats (male, 6 weeks old, weighing 180-210g).

[0422] Experimental Operation

[0423] The pharmacokinetic characteristics of the compound after oral administration in rodents were tested using a standard protocol. In this experiment, the candidate compound was prepared as a 1 mg / mL clear solution and administered to rats via a single oral dose. The oral solvent was a 60% polyethylene glycol 400 / 40% aqueous solution. Male SD rats were used in this project, and the compound was administered orally by gavage at a dose of 5 mg / kg. Plasma samples were collected at 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-administration. First, 10 μL of plasma sample was transferred to a 96-well plate, and 800 μL of acetonitrile solution containing an internal standard was added to precipitate proteins. The mixture was vortexed at 800 rpm for 10 minutes and then centrifuged at 3220 g, 4°C for 15 minutes. Next, 50 μL of the supernatant was transferred to another clean 96-well plate and centrifuged at 3220 g, 4°C for 5 minutes. Finally, the plasma drug concentration was quantitatively analyzed using LC-MS / MS, and pharmacokinetic parameters, such as peak concentration (C0.05), were calculated. max Half-life (T) 1 / 2 Peak time (T) max ), Area under the curve (AUC) 0-last )wait.

[0424] The results for some of the compounds in the examples are shown in the table below.

[0425] Table 3-1

[0426] Pharmacokinetic parameters Control drug 1 Compound 1 Compound 13 <![CDATA[C max (ng / mL)]]> 340 818 1066 <![CDATA[T max (h)]]> 1.83 0.667 2.00 <![CDATA[T 1 / 2 (h)]]> 3.35 3.48 2.49 <![CDATA[AUC 0-last (ng.h / mL)]]> 2448 5819 6049

[0427] Test Example 3-2:

[0428] Experimental materials

[0429] C57BL / 6J mice (male, 7 weeks old, weighing 20.0-24.0g)

[0430] Experimental Operation

[0431] The pharmacokinetic characteristics of the compound after oral administration in rodents were tested using a standard protocol. In the experiment, the candidate compound was prepared as a 1 mg / mL clear solution and administered to mice via a single oral dose. The solvent was 10% dimethyl sulfoxide / 10% Tween 80 / 20% petroleum ether G400 in water. Male C57BL / 6J mice were used in this project, and the compound was administered orally by gavage at a dose of 10 mg / kg. Plasma samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after drug administration. 5 μL of plasma sample was transferred to a 96-well plate, and 200 μL of acetonitrile solution containing an internal standard was added to precipitate proteins. The mixture was vortexed at 1000 rpm for 5 minutes and then centrifuged at 3220 g and 4 °C for 10 minutes. The supernatant was collected, and the blood drug concentration was quantitatively analyzed using LC-MS / MS. Pharmacokinetic parameters such as clearance (Cl), peak concentration (Cmax), half-life (T1 / 2), time to peak concentration (Tmax), and area under the curve (AUC0-last) were calculated.

[0432] The results for some of the compounds in the examples are shown in the table below.

[0433] Table 3-2

[0434] Pharmacokinetic parameters Control drug 1 Compound 2 Compound 12 Compound 13 Compound 32 Cmax (ng / mL) 2690 4012 12626 4724 5266 Tmax(h) 0.833 1.00 1.00 1.00 1.50 T1 / 2(h) 4.48 6.61 2.26 5.84 3.34 AUC0-last(ng.h / mL),po 13811 25284 56627 27602 37436

[0435] Test Example 4: Pharmacokinetic Evaluation of Compounds: Drug Concentration Ratio in Brain Tissue and Plasma

[0436] Experimental materials

[0437] SD rats (male, 6 weeks old, weighing 180-210g).

[0438] Experimental Operation

[0439] The pharmacokinetic characteristics of the compound after oral administration in rodents were tested using a standard protocol. In this experiment, the candidate compound was prepared as a 1 mg / mL clear solution and administered to rats via a single oral dose. The oral solvent was a 20% HP-β-CD aqueous solution. Male SD rats were used in this project, and the compound was administered orally by gavage at a dose of 5 mg / kg. Whole brain samples were collected at 0.5, 2, and 4 hours after administration. Tissue samples were homogenized with a 5-fold homogenate. Finally, LC-MS / MS was used to quantitatively analyze the sample concentrations, calculating the brain tissue to plasma drug concentration ratio (B / P) and the ratio of unbound drug concentration in brain tissue to unbound drug concentration in plasma (Kp,uu). Kp,uu is a key parameter for evaluating the distribution balance of compounds between blood and brain, and it comprehensively reflects the role of passive diffusion and transporters: when Kp,uu is close to 1, it is a relatively ideal compound characteristic, with good permeability and non-transporter substrate; when Kp,uu is much less than 1, it indicates that the compound may be a transporter substrate or has poor permeability; when Kp,uu is greater than 1, there may be active transporters involved in its transmembrane transport process.

[0440] The results for some of the compounds in the examples are shown in the table below.

[0441] Table 4

[0442] Pharmacokinetic parameters Control drug 1 Compound 13 <![CDATA[C brain,2h (of / of)]]> 415 1176 B / PRatio (AUC) 0.849 1.02 Kp,uu 0.366 0.710

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof: ###0001### wherein: A is a five-membered heteroaryl group containing 2 or 3 N atoms; X is N or CH; with the proviso that when A contains 3 N atoms, X is CH; and Y is a single bond, O, S, or NH.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: A is a five-membered heteroaryl group containing 2 or 3 N atoms; X is N or CH; with the proviso that when A contains 3 N atoms, X is CH; and Y is a single bond, O, S, or NH.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein: Y is a single bond, O, S, or NH.

4. A compound of Formula (IIa) and Formula (IIb) or a pharmaceutically acceptable salt thereof: ###0002### (IIa) (IIb) more preferably, the compound or salt thereof has the structural formula of Formula (II): ###0003### Y is selected from a single bond, O, S, NH or NRy, Ryis C 1-6 alkyl; R 1 selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, or 5-6 membered heteroaryl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, or 5-6 membered heteroaryl is optionally substituted with one or more of halo, hydroxyl, cyano, C 1-3 alkyl, C 1-6 haloalkyl, C 1-3 alkoxy, or di(C 1-3 alkyl)phosphinyl; R 2 selected from C 1-6 alkyl, halo, cyano, 3-7 membered aliphatic cycloalkyl, or 4-8 membered aliphatic heterocyclyl, said aliphatic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, or O, said C 1-6 alkyl, 3-7 membered aliphatic ring, or 4-8 membered aliphatic heterocycle, optionally substituted with 0, 1, 2, or 3 R 5 substituents; R 3 selected from cyano, C 1-6 acyl, C 1-6 alkylsulfonyl, -C(O)-NR a R b or R a or R b each independently is H or C 1-3 alkyl; R 3a or R 3b each independently is selected from H, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with one or more of halo, cyano, hydroxy, alkoxy, amino; or R 3a and R 3b together with the atom to which they are both attached form a ring optionally substituted with 1, 2 or 3 R 6 substituents, said ring is a 3-7 membered aliphatic ring or a 4-8 membered aliphatic heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S or O; R 3c selected from H, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, C 1-6 alkylsulfonyl, C 2-6 ester, a 3-7 membered aliphatic ring, a 4-6 membered aliphatic heterocyclic ring, or a 5-6 membered heteroaryl group, said 4-6 membered aliphatic heterocyclic ring or 5-6 membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms selected from N, O, or S, said 3-7 membered aliphatic ring, 4-6 membered aliphatic heterocyclic ring, or 5-6 membered heteroaryl group optionally substituted with 1, 2, or 3 R 7 substituents; R 4 selected from halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl; R 5 selected from halogen, hydroxy, cyano, C 1-6 acyl or C 1-6 alkylsulfonyl; R 6 selected from oxo, cyano, hydroxy, halogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 ester, -C(O)-NRaRb, C 1-6 acyl or C 1-6 alkylsulfonyl; R 7 selected from cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halogen or oxo; 5. A compound of Formula (IIIa) or a pharmaceutically acceptable salt thereof: ###0004### (IIIa) more preferably, the compound or salt thereof has the structural formula of Formula (III): ###0005### X is N, R 3 is and R 3a and R 3b together with the atom to which they are attached form a ring which is optionally substituted with 1, 2 or 3 R 6 is a 3-7 membered aliphatic ring or a 4-8 membered aliphatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, S or O, and R 3c is not H or cyano.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Y is NH.

7. The compound according to claim 1 or 6 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (IV), Formula (V), or Formula (VI): ###0006### 8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (IVa): ###0007### (IVa) wherein: R1 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy; R2 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy; and R3 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy. Y is a single bond, O, S, NH or NRy, Ry being C 1-6 alkyl; R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 5-6 membered heteroaryl, said C 3-6 cycloalkyl or 5-6 membered heteroaryl is optionally substituted with one or more of halo or C 1-3 alkyl; R 2 is C 1-6 alkyl, halo, cyano, 3-7 membered aliphatic ring or 4-8 membered aliphatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, S or O, said 3-7 membered aliphatic ring or 4-8 membered aliphatic heterocycle optionally substituted with 1, 2 or 3 R 5 substituents; R 3 is cyano, C 1-6 acyl, C 1-6 alkylsulfonyl, -C(O)-NRaRb or Raor Rbare each independently selected from H or C 1-3 alkyl; R 3a or R 3b each independently is selected from H, cyano, hydroxy, C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more halogen, cyano, hydroxy, alkoxy, amino; or R 3a and R 3b together with the atoms to which they are attached form a ring, optionally substituted with 1, 2 or 3 R 6 substituents, said ring is a 3-7 membered aliphatic ring or a 4-8 membered aliphatic heterocyclic ring, said aliphatic heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, S or O; R 3c is H, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylsulfonyl, C 2-6 ester, 3-7 membered aliphatic ring, 4-6 membered aliphatic heterocyclic ring or 5-6 membered heteroaryl, said 4-6 membered aliphatic heterocyclic ring or 5-6 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, said 3-7 membered aliphatic ring, 4-6 membered aliphatic heterocyclic ring or 5-6 membered heteroaryl being optionally substituted by 1, 2 or 3 R 7 ; R 4 is halogen, cyano, C 1-6 alkyl or halogen-C 1-6 alkyl; R 5 is halogen, hydroxy, cyano, C 1-6 acyl or C 1-6 alkylsulfonyl; R 6 is oxo, cyano, hydroxy, halogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 ester, -C(O)-NRaRb, C 1-6 acyl or C 1-6 alkylsulfonyl; R 7 is cyano, C 1-6 alkyl or oxo; 9. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (Va): ###0008### (Va) wherein: R1 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy; R2 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy; and R3 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy. X is N, R 3 is and R 3a and R 3b together with the atom to which they are attached form a ring which is optionally substituted with 1, 2 or 3 R 6 , which ring is a 3-7 membered aliphatic ring or a 4-8 membered aliphatic heterocyclic ring, said aliphatic heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S or O, and in this case R 3c is not H or cyano.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein: R1 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy; R2 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy; and R3 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy.

11. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (Vb): ###0009### (Vb) wherein: R1 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy; R2 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy; and R3 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy. R 1 is C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, said C 3-6 cycloalkyl is optionally substituted with one or more of halo or C 1-3 alkyl; R 2 is C 1-3 alkyl, halo, cyano, 3-6 membered aliphatic ring or 4-6 membered aliphatic heterocycle containing 1 or 2 heteroatoms selected from N, S or O, said 3-6 membered aliphatic ring or 4-6 membered aliphatic heterocycle optionally substituted with 1, 2 or 3 R 5 substituents; R 3 is R 3a or R 3b each independently is selected from H, cyano, hydroxy, C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with one or more halogen, cyano, hydroxy, alkoxy, amino; or R 3a and R 3b together with the atoms to which they are attached form a ring, optionally substituted with 1, 2 or 3 R 6 , said ring is a 3-6 membered aliphatic ring or a 4-7 membered aliphatic heterocyclic ring, said aliphatic heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, S or O; R 3c is H, cyano, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkylsulfonyl, C 2-3 ester, 3-5 membered aliphatic ring, 4-5 membered aliphatic heterocycle, or 5-6 membered heteroaryl, said 4-5 membered aliphatic heterocycle or 5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, or S, said 3-5 membered aliphatic ring, 4-5 membered aliphatic heterocycle, or 5-6 membered heteroaryl optionally substituted with 1, 2, or 3 R 7 ; R 4 is halogen, cyano, C 1-3 alkyl or halogen-C 1-3 alkyl; R 5 is halogen, hydroxy, cyano, formyl, acetyl, methylsulfonyl or ethylsulfonyl; R 6 is oxo, cyano, hydroxy, halogen, C 1-3 alkyl, C 1-3 haloalkyl, carboxylate, carboxyl, formyl, acetyl, methylsulfonyl or ethylsulfonyl; R 7 is cyano, C 1-3 alkyl or oxo.

12. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (VIa): ###0010### (VIa) wherein: R1 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy; R2 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy; and R3 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy. wherein, R 1 , R 2 , R 3a , R 3b , R 3c , R 4 as defined in claim 2; 13. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (VII): ###0011### (VII) wherein: R1 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy; R2 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy; and R3 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy. wherein R 1 , R 2 , R 3a , R 3b , R 4 as defined in claim 2.

14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (VIIa) or Formula (VIIb): ###0012### (VIIa) (VIIb) wherein: R1 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy; R2 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy; and R3 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy. wherein, R 1 , R 2 , R 3a , R 3b , R 3c , R 4 as defined in claim 2, 15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (VIIc) or Formula (VIId): ###0013### (VIIc) (VIId) wherein: R1 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy; R2 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy; and R3 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy. wherein R 1 , R 2 , R 3a , R 3b , R 4 as defined in claim 2.

16. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein: R1 is ethyl or cyclopropyl; R2 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy; and R3 is H, alkyl, cycloalkyl, haloalkyl, haloalkoxy, or alkoxy.

17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: ###0014### ###0015### R 1 selected from C 1-6 alkyl, C 2-6 alkenyl or C 3-6 cycloalkyl, said C 1-6 alkyl, C 2-6 alkenyl or C 3-6 cycloalkyl is optionally substituted with one or more of halo, C 1-3 alkyl, C 1-3 alkoxy or di(C 1-3 alkyl)phosphinyl; provided that when A contains 2 N atoms, X is N, R 1 is unsubstituted ethyl, R 2 is cycloalkyl, R 3 is R 3c is triazolyl, R 3a or R 3b are not simultaneously methyl, and R 3a and R 3b do not form a ring.

18. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as claimed in any one of the preceding claims and a pharmaceutically acceptable carrier. wherein Y, R 1 Y, R 2 Y, R 3a Y, R 3b Y, R 3c Y, R 4 as defined in claim 1 or 6.

19. Use of a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 17, or a pharmaceutical composition of claim 18, for the manufacture of a medicament for the treatment of a LRRK2 receptor related disorder.

20. The use according to claim 19, wherein the disorder is a neurodegenerative disease, an immune inflammation related disease, a tumor, or glaucoma. R 1 is C 1-6 alkyl; R 2 is C 3-6 cycloalkyl; R 3a or R 3b each independently is C 1-6 alkyl, or R 3a and R 3b together with the atom to which they are both attached form C 3-6 cycloalkyl; R 4 is C 1-6 haloalkyl; R is preferably methyl or ethyl; R 1 is cyclopropyl; R 2 is cyclopropyl; R 3a or R 3b is methyl, or R 3a and R 3b together with the atom to which they are both attached form cyclopropyl; R 4 is trifluoromethyl. ​ wherein, R 1 , R 2 , R 3a , R 3b , R 3c , R 4 As defined in claim 7. ​ R 1 selected from C 1-6 alkyl, C 2-6 alkenyl or C 3-6 cycloalkyl, said C 1-6 alkyl, C 2-6 alkenyl or C 3-6 cycloalkyl is optionally substituted with one or more of halogen, C 1-3 alkyl or C 1-3 alkoxy; R 2 selected from C 1-6 alkyl, C 3-6 cycloalkyl or 4-8 membered aliphatic heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, S or O, said C 1-6 alkyl, C 3-6 cycloalkyl or 4-8 membered aliphatic heterocyclyl optionally substituted with 1, 2 or 3 R 5 substituents; R 3a or R 3b each independently is H or C 1-6 alkyl, or R 3a and R 3b together with the atom to which they are both attached form a ring optionally substituted with 1, 2 or 3 R 6 substituted ring that is C 3-6 cycloalkyl or a 4-8 membered aliphatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, S or O; R 3c is C 1-6 alkyl or 5-6 membered heteroaryl, which contains 1, 2, 3 or 4 heteroatoms selected from N, O or S, which is optionally substituted by 1, 2 or 3 R 7 substituents; R 4 is C 1-6 haloalkyl; R 5 is halogen or cyano; R 6 is oxo; R 7 is C 1-6 alkyl or C 1-6 alkylthio; ​ R 1 selected from C 1-3 alkyl, C 2-3 alkenyl or C 3-4 cycloalkyl, said C 1-3 alkyl, C 2-3 alkenyl or C 3-4 cycloalkyl is optionally substituted with one or more of halogen or methoxy; R 2 selected from methyl, cyclopropyl, oxetane or tetrahydrofuran, said methyl being optionally substituted with 1 R 5 substituent; R 3a or R 3b is methyl, or R 3a and R 3b together with the atoms to which they are attached form a ring optionally substituted with 2 R 6 substituents; said ring is C 3-5 cycloalkyl or tetrahydrothienyl; R 3c is methyl or 5-6 membered heteroaryl, said heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N or S, said heteroaryl being optionally substituted by 1 R 7 substituent; R 5 is cyano; R 6 is oxo; R 7 is methyl or ethylthio. ​ ​ R 1 is C 1-6 alkyl or C 3-6 cycloalkyl, said C 1-6 alkyl or C 3-6 cycloalkyl is optionally substituted by one or more of C 1-3 alkyl or C 1-3 alkoxy; R 3a or R 3b is C 1-6 alkyl, or R 3a and R 3b together with the atoms to which they are attached form a C 3-5 cycloalkyl; R 3c is 5-membered heteroaryl, which heteroaryl contains 1, 2 or 3 heteroatoms selected from N or S; ​ R 1 is ethyl or cyclobutyl, said cyclobutyl being optionally substituted by methyl or methoxy; R 3a or R 3b is methyl, or R 3a and R 3b together with the atoms to which they are attached form a cyclopropyl group; R 3c is ​ wherein, R 1 is C 1-3 alkyl; R 8 is C 1-3 haloalkyl; Preferably, R 1 is methyl or ethyl; R 8 is trifluoromethyl or difluoromethyl. ​ ​ X or X 1 each independently N or CH; R 1 is C 1-6 alkyl or C 3-6 cycloalkyl, said C 1-6 alkyl or C 3-6 cycloalkyl is optionally substituted with one or more of halo or di(C 1-3 alkyl)phosphinyl; R 3a or R 3b is C 1-6 alkyl, or R 3a and R 3b together with the atoms to which they are attached form a C 3-5 cycloalkyl; R 3c is triazolyl or tetrazolyl optionally substituted with 1 or 2 R 7 substituted with 1 or 2 R R 7 each independently is C 1-3 alkyl; Preferably, R 3c is ​ wherein R 1 , R 3a , R 3b , R 3c As defined in claim 13. ​ ​ R 1 is C 1-6 alkyl or C 3-6 cycloalkyl, said C 1-6 alkyl or C 3-6 cycloalkyl is optionally substituted with 1, 2 or 3 halogen; R 3c is triazolyl or tetrazolyl optionally substituted with 1 R 7 substituted with 1 R R 7 is C 1-3 alkyl; ​ R 1 is C 1-3 alkyl or cyclopropyl; R 3c is R 7 is methyl. ​ ​ R 3a or R 3b is methyl, or R 3a and R 3b together with the atoms to which they are attached form a cyclopropyl group; R 3c is ​ ​ ​ ​ 21. Use according to claim 19, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar ataxias, Friedreich's ataxia, Pick's disease, Lewy body dementia, dystonia, amyotrophic lateral sclerosis, neuroinflammation, progressive supranuclear palsy and frontotemporal dementia.

22. Use according to claim 19, wherein the immune inflammation-related disease is selected from the group consisting of inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, ankylosing spondylitis, autoimmune hemolytic anemia, pure red cell anemia, idiopathic thrombocytopenic purpura, Evans syndrome, vasculitis, bullous skin disorder, type I diabetes, Sjogren's syndrome, Devic's disease and inflammatory myopathy.

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