Carbonyl-bridged heterocyclic compounds, and compositions and uses thereof

Abstract

Carbonyl-bridged heterocyclic compounds having a structure represented by formula (I), their stereoisomers or pharma- ceutically acceptable salts, pharmaceutical compositions containing these compounds, and the use of these compounds or compositions in the preparation of medicaments are provided. The compounds, their stereoisomers, pharma-ceutically acceptable salts, etc., can be used to treat or prevent autoimmune diseases, tumors, and neurodegenerative diseases associated with RIPK1 (RIPK1). [C1] TIFF2025501347000078.tif57156

Description

[Technical Field]

[0001] The present disclosure is in the field of medicinal chemistry, and in particular relates to a class of carbonyl-bridged heterocyclic compounds, their stereoisomers, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, and their use in the manufacture of medicaments for treating autoimmune diseases, tumors, inflammatory diseases, and neurodegenerative diseases associated with receptor-interacting protein 1 kinase (RIPK1). [Background technology]

[0002] Initially, cell death was thought to occur primarily through two modes: apoptosis and necrosis. Apoptosis is the autonomous and orderly death of cells, controlled by genes to maintain the stability of the internal environment. Apoptosis plays an important role in the evolution of organisms, the stability of the internal environment, and the development of systems. Necrosis is a pathological process in which cells undergo cell death in response to physical, chemical, and other environmental factors, such as mechanical damage, toxins, microorganisms, and radiation. In 2005, Degterev et al. first discovered and reported an orderly process of cell necrosis controlled by a series of biochemical molecules, which they named necroptosis (also known as programmed necrosis). This process is a type of programmed cell necrosis that occurs when death receptors are stimulated by TNF-α, FasL, or TRAIL. Morphological manifestations include cell swelling, increased cell volume, organelle dysfunction, damaged cell membrane integrity, release of cellular contents, and the production of large amounts of reactive oxygen species (ROS). Cell necroptosis was initially thought to be a defense mechanism evolved by the host to combat anti-apoptotic viruses, but it was later discovered that necroptosis can lead to an imbalance of inflammatory factors, potentially leading to acute or chronic inflammatory diseases.

[0003] Receptor-interacting protein 1 kinase (RIPK1) belongs to the TKL family of serine / threonine protein kinases. Members of the RIPK serine / threonine kinase family share the same N-terminal kinase domain but have distinct binding domains. Studies have shown that receptor-interacting protein 1 can regulate the process of cell apoptosis. The death domain of RIPK-1 binds to death receptors such as TNFR1, Fas, TRAILR1, and TRAILR2. Death receptors can also bind to other proteins containing death domains, such as TRADD and FADD. Binding to the latter is a prerequisite for activating caspase-8 and inducing apoptosis. The intermediate structure of RIPK-1 is a RIPK isotype interaction target, through which RIPK-1 can interact with RIPK-3. Kelliher et al. found that congenital RIPK-1-deficient mice died within 3 days of birth due to massive cell apoptosis, indicating that RIPK-1 is also involved in regulating cell apoptosis. Furthermore, cells with a congenital RIPK-1 deficiency are highly sensitive to TNF-induced cell death, presumably because such cells are unable to effectively activate NF-κB.

[0004] Meanwhile, research has also shown that RIPK-1 and RIPK-3 are also involved in the process of cell necroptosis. In most cell types, the death receptors TNFR1, Fas, and TRAILR mediate cell apoptosis. Activation of TNFR1 can induce ubiquitination of RIPK-1 via cIAP1 and cIAP2, and the ubiquitinated RIPK-1 determines the next step in the cell's life or death. When the apoptosis pathway is inhibited by the pan-caspase inhibitor z-VAD-fmk, cell death progresses to necroptosis. In this process, RIPK-1 activity is a key factor, which is regulated by FasL, TNF, and TRAIL death receptors.

[0005] Recent studies have shown that the process of necroptosis is associated with various diseases, including tumors, autoimmune diseases, neurodegenerative diseases, and inflammatory diseases, indicating that RIP family kinases are closely related to the development of such diseases.

[0006] For example, in their study of Alzheimer's disease, Claudia Balducci et al. discovered that activated microglia play an important role in the progression of Alzheimer's disease (Pharmacological Research. 2018;130:402-413). At the same time, microglia highly express RIPK-1. RIPK-1 inhibitors can prevent Aβ-induced neuronal cell death and suppress microglial proliferation in vitro. Furthermore, in an Alzheimer's disease-like rat model, RIPK-1 inhibitors can improve learning and memory abilities in rats. RIPK-1 inhibitors are expected to be applicable not only to Alzheimer's disease but also to various neurodegenerative diseases such as Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.

[0007] At present, there are few studies on RIPK-1 inhibitors, and only a few studies are in the clinical stage. Research and development of further drugs based on RIPK-1 inhibitors is urgently needed. Meanwhile, there is even less research on RIPK-1 inhibitors that can cross the blood-brain barrier. In the aforementioned Alzheimer's disease and many other neurodegenerative diseases, the ability of a drug to cross the blood-brain barrier is crucial for therapeutic efficacy.

[0008] Furthermore, preclinical animal testing plays a crucial role in modern drug development, typically using rats or mice for early-stage testing. From the perspective of translational medicine, animal models and their results should be consistent with and applicable to the pathophysiology and treatment of the corresponding human disease. Therefore, it is desirable for the compounds developed to have minimal species differences in biological activity between humans and mice. While GSK has disclosed a number of compounds with specific RIPK-1 inhibitory activity in patent application WO018 / 092089, these compounds have low inhibitory activity against mouse cells, making them unsuitable for drug development through animal testing.

[0009] This application provides a class of carbonyl-bridged heterocyclic compounds that exhibit good RIPK-1 inhibitory activity and blood-brain barrier penetration. It is worth emphasizing that this class of compounds exhibits extremely strong inhibitory activity not only against human RIPK-1 but also against mouse RIPK-1. Therefore, the compounds of this application show a certain degree of similarity and applicability when extrapolating the results of animal experiments to human diseases, making them useful for drug discovery through animal experiments. The compounds of this application are expected to be used as RIPK-1 inhibitors in the manufacture of pharmaceuticals for treating tumors, autoimmune diseases, neurodegenerative diseases, and inflammatory diseases. Summary of the Invention [Means for solving the problem]

[0010] The present disclosure provides a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which can be used to prepare a medicament for treating or preventing a RIPK1-associated disease. [ka]

[0011] In formula (I),

[0012] In formula (I), X is CH or N;

[0013] L is O, S, NH, carbonyl, sulfonyl, or sulfinyl;

[0014] R1 is C1-C 10 Alkyl, C3-C8 cycloalkyl, 4-8 membered heteroalicyclyl, or C1-C substituted with 1-3 substituents 10 alkyl, and the 1 to 3 substituents are hydroxyl, C1-C6 alkoxy, cyano, -NR a R b , C3-C8 cycloalkyloxy, -CONH-R5, C3-C8 cycloalkyl, hydroxyl-substituted and / or C1-C4 alkyl-substituted C3-C8 cycloalkyl, carboxyl, halogen, C1-C6 haloalkoxy, -SO2-R5, -SO-R5, -CO-R5, C2-C6 alkynyl, C2-C6 alkenyl, C1-C4 alkoxyC1-C6 alkoxy, 4-8 membered heteroalicyclyl, oxo-substituted 4-8 membered heteroalicyclyl, hydroxyl-substituted and / or C1-C4 alkyl-substituted 4-8 membered heteroalicyclyl, and C1-C6 alkylthio;

[0015] The 4- to 8-membered heteroalicyclyl is a 4- to 8-membered heteroalicyclyl containing 1 to 2 atoms selected from N, O, and S as ring atoms,

[0016] R5 is hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyC1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heteroalicyclyl-substituted C1-C6 alkyl;

[0017] R a and R bare each independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl, 4- to 8-membered heteroalicyclyl-substituted C1-C6 alkyl, C1-C3 alkylthio-substituted C1-C6 alkyl, mono- or di-C1-C3 alkyl-substituted or unsubstituted amino-substituted C1-C6 alkyl;

[0018] R2 is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, or halogen;

[0019] R3 and R4 are each independently hydrogen, halogen, or methyl.

[0020] In some embodiments, the compound alternatively has the structure of formula (II): [ka]

[0021] In formula (II),

[0022] R1 is C1-C 10 Alkyl, C3-C8 cycloalkyl, 4-8 membered heteroalicyclyl, or C1-C substituted with 1-3 substituents 10 alkyl, and the 1 to 3 substituents are hydroxyl, C1-C6 alkoxy, cyano, -NR a R b , C3-C8 cycloalkyloxy, -CONH-R5, C3-C8 cycloalkyl, hydroxyl-substituted and / or C1-C4 alkyl-substituted C3-C8 cycloalkyl, carboxyl, halogen, C1-C6 haloalkoxy, -SO2-R5, -SO-R5, -CO-R5, C2-C6 alkynyl, C2-C6 alkenyl, C1-C4 alkoxyC1-C6 alkoxy, 4-8 membered heteroalicyclyl, oxo-substituted 4-8 membered heteroalicyclyl, hydroxyl-substituted and / or C1-C4 alkyl-substituted 4-8 membered heteroalicyclyl, and C1-C6 alkylthio;

[0023] The 4- to 8-membered heteroalicyclyl is a 4- to 8-membered heteroalicyclyl containing 1 to 2 atoms selected from N, O, and S as ring atoms,

[0024] R5 is hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyC1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heteroalicyclyl-substituted C1-C6 alkyl;

[0025] R a and R b are each independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl, 4- to 8-membered heteroalicyclyl-substituted C1-C6 alkyl, C1-C3 alkylthio-substituted C1-C6 alkyl, mono- or di-C1-C3 alkyl-substituted or unsubstituted amino-substituted C1-C6 alkyl;

[0026] R2 is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, or halogen;

[0027] R3 and R4 are each independently hydrogen, halogen, or methyl.

[0028] In some embodiments, alternatively, R1 is C1-C8 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heteroalicyclyl, or C1-C8 alkyl substituted with 1-3 substituents, wherein the 1-3 substituents are selected from hydroxyl, C1-C3 alkoxy, cyano, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl, hydroxyl- and / or C1-C4 alkyl-substituted C3-C6 cycloalkyl, halogen, 4- to 6-membered heteroalicyclyl, oxo-substituted 4- to 6-membered heteroalicyclyl, hydroxyl- and / or C1-C4 alkyl-substituted 4- to 6-membered heteroalicyclyl, and C1-C3 alkylthio;

[0029] The above 4- to 6-membered heteroalicyclyl is a 4- to 6-membered heteroalicyclyl containing 1 or 2 atoms selected from N, O, and S as ring atoms.

[0030] In some embodiments, alternatively, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, octyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, or C1-C8 alkyl substituted with 1 to 3 substituents, wherein the 1 to 3 substituents are hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, cyano, cyclobutyloxy, cyclopentyloxy, cyclohex ... Selected from siloxy, cyclobutyl, cyclopentyl, cyclohexyl, 4-hydroxylcyclohexyl, 4-hydroxyl-4-methylcyclohexyl, fluorine, chlorine, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, morpholinyl, thiomorpholinyl, 1-methyl-pyrrolidin-2-yl, 1-methyl-piperidin-4-yl, methylthio, ethylthio, propylthio, and isopropylthio.

[0031] In some embodiments, R1 is further alternatively methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, tetrahydropyran-4-yl, 4-methyl-4-hydroxypentyl, tetrahydropyran-4-ylethyl, tetrahydropyran-4-ylmethyl, tetrahydropyran-4-ylpropyl, tetrahydropyran-4-ylbutyl, 3-methyl-3-hydroxylbutyl, 2-methyl-2-hydroxylpropyl, 5-methyl-5-hydroxyhexyl, fluoropropyl, fluoroethyl, 2,2-difluoro-3-hydroxylpropyl.

[0032] In some embodiments, R1 is C1-C8 alkyl substituted with 1-hydroxycyclopropyl, 1-hydroxycyclobutyl, 1-hydroxycyclopentyl, or 1-hydroxycyclohexyl.

[0033] Further alternatively, R1 is 1-hydroxycyclopropylmethyl or 1-hydroxycyclobutylmethyl.

[0034] In some embodiments, further alternatively, R1 is hydroxyl-substituted and / or halogen-substituted C1-C6 alkyl, and even further alternatively, R1 is hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, 2-methyl-2-hydroxypropyl, 3-methyl-3-hydroxybutyl, 4-methyl-4-hydroxypentyl, 5-methyl-5-hydroxyhexyl, fluoropropyl, fluoroethyl, or 2,2-difluoro-3-hydroxypropyl.

[0035] In some embodiments, R2 is alternatively hydrogen, methyl, methoxy, fluorine, chlorine, or bromine.

[0036] Further alternatively, R2 is fluorine.

[0037] In some embodiments, alternatively, R3 and R4 are each independently hydrogen, fluorine, chlorine, or methyl.

[0038] Further alternatively, R3 and R4 are each independently fluorine.

[0039] In some embodiments, the compound alternatively has the structure of formula (III): [ka]

[0040] wherein X is CH or N;

[0041] L is O, S, NH, carbonyl, sulfonyl, or sulfinyl;

[0042] R1 is C1-C 10 Alkyl, C3-C8 cycloalkyl, 4-8 membered heteroalicyclyl, or C1-C substituted with 1-3 substituents 10 alkyl, and the 1 to 3 substituents are hydroxyl, C1-C6 alkoxy, cyano, -NR a R b , C3-C8 cycloalkyloxy, -CONH-R5, C3-C8 cycloalkyl, hydroxyl-substituted and / or C1-C4 alkyl-substituted C3-C8 cycloalkyl, carboxyl, halogen, C1-C6 haloalkoxy, -SO2-R5, -SO-R5, -CO-R5, C2-C6 alkynyl, C2-C6 alkenyl, C1-C4 alkoxyC1-C6 alkoxy, 4-8 membered heteroalicyclyl, oxo-substituted 4-8 membered heteroalicyclyl, hydroxyl-substituted and / or C1-C4 alkyl-substituted 4-8 membered heteroalicyclyl, and C1-C6 alkylthio;

[0043] The 4- to 8-membered heteroalicyclyl is a 4- to 8-membered heteroalicyclyl containing 1 to 2 atoms selected from N, O, and S as ring atoms,

[0044] R5 is hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyC1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heteroalicyclyl-substituted C1-C6 alkyl;

[0045] R a and R b are each independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl, 4- to 8-membered heteroalicyclyl-substituted C1-C6 alkyl, C1-C3 alkylthio-substituted C1-C6 alkyl, or mono- or di-C1-C3 alkyl-substituted or unsubstituted amino-substituted C1-C6 alkyl;

[0046] R2 is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, or halogen;

[0047] R3 and R4 are each independently hydrogen, halogen, or methyl.

[0048] In some embodiments, the compound alternatively has the structure of formula (IV): [ka]

[0049] In the formula, R1 is C1-C 10 Alkyl, C3-C8 cycloalkyl, 4-8 membered heteroalicyclyl, or C1-C substituted with 1-3 substituents 10 alkyl, and the 1 to 3 substituents are hydroxyl, C1-C6 alkoxy, cyano, -NR a R b, C3-C8 cycloalkyloxy, -CONH-R5, C3-C8 cycloalkyl, hydroxyl-substituted and / or C1-C4 alkyl-substituted C3-C8 cycloalkyl, carboxyl, halogen, C1-C6 haloalkoxy, -SO2-R5, -SO-R5, -CO-R5, C2-C6 alkynyl, C2-C6 alkenyl, C1-C4 alkoxyC1-C6 alkoxy, 4-8 membered heteroalicyclyl, oxo-substituted 4-8 membered heteroalicyclyl, hydroxyl-substituted and / or C1-C4 alkyl-substituted 4-8 membered heteroalicyclyl, and C1-C6 alkylthio;

[0050] The 4- to 8-membered heteroalicyclyl is a 4- to 8-membered heteroalicyclyl containing 1 to 2 atoms selected from N, O, and S as ring atoms,

[0051] R5 is hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyC1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heteroalicyclyl-substituted C1-C6 alkyl;

[0052] R a and R b are each independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl, 4- to 8-membered heteroalicyclyl-substituted C1-C6 alkyl, C1-C3 alkylthio-substituted C1-C6 alkyl, or mono- or di-C1-C3 alkyl-substituted or unsubstituted amino-substituted C1-C6 alkyl;

[0053] R2 is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, or halogen;

[0054] R3 and R4 are each independently hydrogen, halogen, or methyl.

[0055] In some embodiments, alternatively, R1 is C1-C8 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heteroalicyclyl, or C1-C8 alkyl substituted with 1-3 substituents, wherein the 1-3 substituents are selected from hydroxyl, C1-C3 alkoxy, cyano, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl, hydroxyl- and / or C1-C4 alkyl-substituted C3-C6 cycloalkyl, halogen, 4- to 6-membered heteroalicyclyl, oxo-substituted 4- to 6-membered heteroalicyclyl, hydroxyl- and / or C1-C4 alkyl-substituted 4- to 6-membered heteroalicyclyl, and C1-C3 alkylthio;

[0056] The above 4- to 6-membered heteroalicyclyl is a 4- to 6-membered heteroalicyclyl containing 1 or 2 atoms selected from N, O, and S as ring atoms.

[0057] In some embodiments, alternatively, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, octyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, or C1-C8 alkyl substituted with 1 to 3 substituents, wherein the 1 to 3 substituents are hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, cyano, cyclobutyloxy, cyclopentyloxy, cyclohex ... Selected from siloxy, cyclobutyl, cyclopentyl, cyclohexyl, 4-hydroxylcyclohexyl, 4-hydroxyl-4-methylcyclohexyl, fluorine, chlorine, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, morpholinyl, thiomorpholinyl, 1-methyl-pyrrolidin-2-yl, 1-methyl-piperidin-4-yl, methylthio, ethylthio, propylthio, and isopropylthio.

[0058] In some embodiments, R1 is further alternatively methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, tetrahydropyran-4-yl, 4-methyl-4-hydroxypentyl, tetrahydropyran-4-ylethyl, tetrahydropyran-4-ylmethyl, tetrahydropyran-4-ylpropyl, tetrahydropyran-4-ylbutyl, 3-methyl-3-hydroxylbutyl, 2-methyl-2-hydroxylpropyl, 5-methyl-5-hydroxyhexyl, fluoropropyl, fluoroethyl, or 2,2-difluoro-3-hydroxylpropyl.

[0059] In some embodiments, R1 is C1-C8 alkyl substituted with 1-hydroxycyclopropyl, 1-hydroxycyclobutyl, 1-hydroxycyclopentyl, or 1-hydroxycyclohexyl.

[0060] Further alternatively, R1 is 1-hydroxycyclopropylmethyl or 1-hydroxycyclobutylmethyl.

[0061] In some embodiments, further alternatively, R1 is hydroxyl-substituted and / or halogen-substituted C1-C6 alkyl, and even further alternatively, R1 is hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, 2-methyl-2-hydroxypropyl, 3-methyl-3-hydroxybutyl, 4-methyl-4-hydroxypentyl, 5-methyl-5-hydroxyhexyl, fluoropropyl, fluoroethyl, or 2,2-difluoro-3-hydroxypropyl.

[0062] In some embodiments, R2 is alternatively hydrogen, methyl, methoxy, fluorine, chlorine, or bromine.

[0063] Further alternatively, R2 is fluorine.

[0064] In some embodiments, alternatively, R3 and R4 are each independently hydrogen, fluorine, chlorine, or methyl.

[0065] Further alternatively, R3 and R4 are each independently fluorine.

[0066] In some embodiments, the compounds of the present application are deuterated compounds of the above-described compounds, or alternatively, compounds in which the 5-position of the pyrazolyl in any one of the above-described structural formulas (I) to (IV) is deuterated.

[0067] Exemplary compounds of the present application are shown below. [ka] [ka] [ka] [ka]

[0068] According to some embodiments of the present disclosure, the pharmaceutically acceptable salt of the compound is selected from one or more of hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, nitrate, phosphate, formate, acetate, propionate, glycolate, lactate, succinate, maleate, tartrate, malate, citrate, fumarate, gluconate, benzoate, mandelate, methanesulfonate, isethionate, benzenesulfonate, oxalate, palmitate, 2-naphthalenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, salicylate, hexonate, trifluoroacetate, aluminum salt, calcium salt, chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, lithium salt, magnesium salt, potassium salt, sodium salt, and zinc salt.

[0069] Another aspect of the present disclosure relates to use of the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate, or deuterated derivative thereof, in the manufacture of a medicament for treating a RIPK1-associated disease, the RIPK1-associated disease being selected from the group consisting of ocular fundus disease, xerophthalmia, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, arteriosclerosis, pulmonary fibrosis, liver fibrosis, Myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic granulocytic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary tract carcinoma and sarcoma , cholangiocarcinoma, inflammatory bowel disease, ulcerative colitis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, spondyloarthritis, gout, SoJIA, Sjögren's syndrome, systemic sclerosis, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, atopic dermatitis, multiple sclerosis, type 1 diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converting enzyme-associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, and periodontitis.

[0070] Another aspect of the present disclosure is the carbonyl Pharmaceutical compositions are provided that contain a bridged heterocyclic compound, or a stereoisomer, solvate, pharmaceutically acceptable salt, or deuterated derivative thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0071] According to some embodiments of the present application, the pharmaceutical composition may further contain one or more other therapeutic agents.

[0072] The present disclosure also relates to a method for treating a RIPK1 kinase-mediated disease or disorder, comprising administering a therapeutically effective amount of a compound of formula (I) or a salt thereof to a patient (human or other mammal, particularly human) in need thereof. The RIPK1 kinase-mediated disease or disorder includes those described above. [Brief explanation of the drawings]

[0073] [Figure 1] 1 shows a Western blot photograph of the inhibition of RIPK1 phosphorylation by the compound of Example 40.

[0074] [Figure 2] 1 shows the ratio of RIPK1 phosphorylation to total RIPK1 protein expression in the presence of the compound of Example 40. DETAILED DESCRIPTION OF THE INVENTION

[0075] Unless otherwise stated, the following terms used in this application (including the specification and claims) have the following definitions: In this application, the use of "or" or "and" means "and / or" unless specifically stated otherwise. Furthermore, the use of the term "comprising" and other forms such as "including," "containing," and "having" is not limiting. Subheadings used herein are for organizational purposes only and should not be construed as limiting the topics described.

[0076] Unless otherwise specified, alkyl groups refer to saturated, straight-chain and branched hydrocarbon groups having the specified number of carbon atoms, C1-C 10The term alkyl refers to an alkyl moiety containing 1 to 10 carbon atoms. Similarly, C1-C3 alkyl refers to an alkyl moiety containing 1 to 3 carbon atoms. For example, C1-C6 alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3- Methi Lube Examples of alkyl groups include butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl.

[0077] "C1-C3 alkoxy C1-C6 alkylthio" or "hydroxy-substituted C1-C 10 When a substituent term such as "alkyl" is used in combination with another substituent term, such as the term "alkyl," the linking substituent term (e.g., alkyl or alkylthio) is intended to encompass a divalent moiety whose point of attachment is through the linking substituent. Examples of "C1-C3 alkoxyC1-C6 alkylthio" include, but are not limited to, methoxymethylthio, methoxyethylthio, and ethoxypropylthio. "Hydroxy-substituted C1-C 10 Examples of "alkyl" include, but are not limited to, hydroxymethyl, hydroxyethyl, and hydroxyisopropyl.

[0078] The alkoxy group is an alkyl-O- group formed by a linear or branched alkyl group as described above and -O-, such as methoxy, ethoxy, etc. Similarly, the alkylthio group is an alkyl-S- group formed by a linear or branched alkyl group as described above and -S-, such as methylthio, ethylthio, etc.

[0079] Alkenyl and alkynyl groups include straight-chain or branched alkenyl or alkynyl groups, and the terms C2-C6 alkenyl or C2-C6 alkynyl refer to straight-chain or branched hydrocarbon groups having at least one alkenyl or alkynyl group.

[0080] "C1-C 10 The term "haloalkyl" refers to a group having one or more halogen atoms, which may be the same or different, on one or more carbon atoms of an alkyl portion containing 1 to 10 carbon atoms. 10 Examples of "haloalkyl" include, but are not limited to, -CF3 (trifluoromethyl), -CCl3 (trichloromethyl), 1,1-difluoroethyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl. Similarly, "C1-C 10 The term "haloalkoxy" refers to any of the C1-C 10 It refers to a haloalkyl-O- group formed by haloalkyl and -O-, which can be, for example, trifluoromethoxy, trichloromethoxy, and the like.

[0081] The term "C1-C3 acyl" includes formyl (-CHO), acetyl (CH3CO-), and Propionyl Contains (C2H5CO-).

[0082] The terms "-CO-R5, -SO2-R5, -SO-R5, -CONH-R5" respectively mean " [ka] " represents.

[0083] The term "cycloalkyl" refers to a non-aromatic saturated cyclic hydrocarbon group containing the specified number of carbon atoms. For example, the term "(C3-C6)cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from 3 to 6 ring carbon atoms. Exemplary "(C3-C6)cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0084] The term "aryl" refers to a group or moiety containing an aromatic monocyclic or bicyclic hydrocarbon radical containing 6 to 12 carbon ring atoms and having at least one aromatic ring. Examples of "aryl" include phenyl, naphthyl, indenyl, and dihydroindenyl (indanyl). Typically, in the compounds of this disclosure, aryl is phenyl.

[0085] Unless otherwise specified, the term "heteroalicyclyl," as used herein, refers to an unsubstituted or substituted, stable, 4- to 8-membered, non-aromatic, monocyclic, saturated ring system consisting of one to three heteroatoms selected from N, O, and S (wherein the N or S heteroatom may optionally be oxidized, and the N heteroatom may further optionally be quaternized) and carbon atoms. Examples of such heterocycles include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, 1,4-oxathiolanyl, 1,4-oxathianyl, 1,4-dithianyl, morpholinyl, and thiomorpholinyl.

[0086] As used herein, the term "heteroaryl" refers to a group or moiety comprising an aromatic monocyclic or bicyclic radical (containing 5 to 10 ring atoms) containing one to three heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term also includes bicyclic heteroaryls containing an aryl ring moiety fused to a heterocycloalkyl ring moiety or a heteroaryl ring moiety fused to a cycloalkyl ring moiety. Unless otherwise specified, the term "heteroaryl" refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system, and may also refer to an unsubstituted or substituted benzo-fused heteroaromatic ring system or bicyclic heteroaromatic ring system containing 9 or 10 ring atoms, composed of one to three heteroatoms selected from N, O, and S (wherein the N and S heteroatoms can be oxidized and the N heteroatom can be further quaternized) and carbon atoms. The heteroaryl group can be attached to any heteroatom or carbon atom to create a stable structure. Representative examples of heteroaryl groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, oxo-pyridyl (pyridyl-N-oxide), pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indazinyl, indolyl, isoindolyl, indolinyl, and benzimidazolyl. , dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzothiazolyl, benzisothiazolyl, dihydrobenzisothiazolyl, indazolyl, imidazopyridyl, pyrazolopyridyl, benzotriazolyl, triazolopyridyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridyl.

[0087] The term "carbonyl" refers to the group -C(O)-. The terms "halogen" and "halo" refer to chlorine, fluorine, bromine, or iodine substituents. "Oxo" refers to an oxygen moiety containing a double bond, e.g., "oxo" may be directly attached to a carbon atom to form a carbonyl moiety (C=O). "Hydroxy" is intended to refer to the radical -OH. As used herein, the term "cyano" refers to the group -CN.

[0088] The term "independently at each occurrence" means that when multiple substituents are selected from a number of possible substituents, the substituents may be the same or different.

[0089] It is clear that the compound of formula I, or its isomer, crystalline form, or prodrug, and its pharmaceutically acceptable salt may exist in a solvated or non-solvated form. For example, the solvated form may be a water-soluble form. The present disclosure includes all solvated and non-solvated forms.

[0090] The compounds of the present disclosure may have asymmetric carbon atoms. Depending on their physical and chemical differences, diastereomeric mixtures can be separated into single diastereomers by well-known, technically mature methods, such as chromatography or fractional crystallization. Separation of enantiomers can be achieved by first converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound, separating the diastereomers, and then converting the single diastereomer into the corresponding pure enantiomer (hydrolysis). All such isomers, including diastereomeric mixtures and pure enantiomers, are considered part of the present disclosure.

[0091] The compounds of the present disclosure as active ingredients and their preparation methods are both included in the present disclosure.In addition, the crystalline forms of some compounds may exist as crystalline polymorphs, and such forms are also included in the present disclosure.In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included in the scope of the present disclosure.

[0092] The compounds of the present disclosure may be used in therapy in free form or, where appropriate, as pharmaceutically acceptable salts or other derivatives. As used herein, the term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present disclosure that are suitable for use in humans and lower animals and have a reasonable benefit / risk ratio without undue toxicity, irritation, allergic reactions, etc. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art. Salts can be formed by reacting the compounds of the present disclosure with a suitable free base or acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid. Alternatively, salts can be obtained by methods well known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, per-3-phenylpropionate, phosphate, picrate, propionate, stearate, sulfate, thiocyanate, p-toluenesulfonate, undecanoate, and the like. Representative alkali or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include suitable non-toxic salts of ammonium, quaternary ammonium, and amine cations formed from halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0093] The pharmaceutical compositions of the present disclosure contain a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof; an additional active agent selected from a kinase inhibitor (such as a small molecule, polypeptide, antibody), an immunosuppressant, an anti-cancer agent, an anti-viral agent, an anti-inflammatory agent, an anti-fungal agent, an antibiotic, and an anti-vascular hyperproliferation compound; and any pharmaceutically acceptable carrier, adjuvant, or excipient.

[0094] The compounds of the present disclosure may be used alone or in combination with one or more other compounds of the present disclosure or one or more other drugs. When administered in combination, the therapeutic agents can be formulated for simultaneous administration, sequential administration at different times, or administered as a single composition. "Combination therapy" refers to the use of a compound of the present disclosure with another drug, either simultaneously or sequentially, with the goal of achieving optimal efficacy of the drugs. Simultaneous administration includes both simultaneous delivery dosage forms and separate dosage forms for each compound. Thus, the administration of a compound of the present disclosure can be combined with other therapies known in the art, such as radiation therapy, cytostatic agents, cytotoxic agents, or other anti-cancer agents used in cancer treatment, to ameliorate cancer symptoms. The present disclosure does not limit the order of administration. The compounds of the present disclosure may be administered before, simultaneously with, or after the other anti-cancer or cytotoxic agent.

[0095] To prepare the pharmaceutical composition of the present disclosure, one or more compounds of formula (I) or their salts as active ingredients can be intimately mixed with pharmaceutical carriers, which can be carried out according to conventional pharmaceutical formulation techniques.Carriers can be used in a wide variety of forms depending on the formulations designed for various modes of administration (e.g., oral administration or parenteral administration).Suitable pharmaceutically acceptable carriers are well known in the art.Descriptions of some of these pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical Excipients, jointly published by the American Pharmaceutical Association and the British Pharmaceutical Society.

[0096] The pharmaceutical compositions of the present disclosure may be in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release forms, solutions, or suspensions; in a form for parenteral injection, such as a clear solution, suspension, or emulsion; in a form for topical application, such as an ointment or cream; or in the form of a suppository for rectal administration. The pharmaceutical composition may also be provided in a unit dosage form for single administration of a precise dosage. The pharmaceutical composition includes a conventional pharmaceutical carrier or excipient and a compound as an active ingredient prepared according to the present disclosure, and may also include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0097] Therapeutic compounds can also be administered to mammals other than humans. The dosage of a drug to a mammal depends on the species of the animal and its disease state or disorder state. Therapeutic compounds can be administered to animals in the form of capsules, boluses, tablets, or liquids. Therapeutic compounds can also be introduced into animals by injection or infusion. These pharmaceutical forms are prepared in traditional ways according to standard veterinary practice. Alternatively, pharmaceutical compound drugs can be mixed with animal feed and fed to animals, so that concentrated feed additives or premixes can be prepared by mixing with normal animal feed.

[0098] It is a further object of the present disclosure to provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition containing a compound of the present disclosure.

[0099] The present disclosure relates to the use of a compound of the present disclosure, or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for treating a RIPK1-associated disease, including ocular fundus disease, xerophthalmia, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, arteriosclerosis, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic granulocytic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary tract carcinoma and sarcoma, cholangiocarcinoma, inflammatory bowel disease, These include ulcerative colitis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, spondyloarthritis, gout, SoJIA, Sjögren's syndrome, systemic sclerosis, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, atopic dermatitis, multiple sclerosis, type 1 diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converting enzyme-associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, and periodontitis.

[0100] The present disclosure also provides methods for preparing the corresponding compounds. Various synthetic methods can be used to prepare the compounds described herein, including the following methods involved in the Examples. The compounds of the present disclosure, or their pharmaceutically acceptable salts, isomers, or hydrates, can be synthesized using the methods described below, synthetic methods known in the art of organic chemical synthesis, or modifications of these methods that would be understood by those skilled in the art. Alternative methods include, but are not limited to, the methods described below.

[0101] The present disclosure will be described in more detail below with specific examples to clarify the objectives, technical solutions, and advantages of the present disclosure. It should be understood that the specific examples described herein are used only to illustrate the present disclosure and are not intended to limit the present disclosure. If specific techniques or conditions are not specified in the examples, the techniques or conditions described in the literature or product specifications in the art shall be followed. If the manufacturer of the reagents or equipment used is not specified, the reagents or equipment are all commercially available conventional products. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. The following examples are provided to better illustrate the present disclosure, and all temperatures refer to °C unless otherwise specified. The names of some compounds in the present disclosure are generated by Chemdraw.

[0102] Abbreviation HATU N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate

[0103] DIEA N,N-Diisopropylethylamine

[0104] DMF N,N-dimethylformamide

[0105] DMSO dimethyl sulfoxide

[0106] PE Petroleum ether (boiling point 60-90°C)

[0107] EA Ethyl acetate

[0108] Compound synthesis Preparation of Intermediate A

[0109] Synthesis of intermediate A-1 [ka]

[0110] Step 1): 3,5-Difluorobenzaldehyde (30 g, 211.1 mmol) was dissolved in DMF, and (triphenylphosphoranylidene)acetaldehyde (CAS No. 2136-75-6) (70.7 g, 232.2 mmol) was added in several portions at room temperature with stirring. The mixture was heated at 80 °C for 15 hours, and the reaction solution was cooled to room temperature and extracted with water and ethyl acetate. The organic phase was washed with saturated brine, dried, and concentrated. The residue was purified by column chromatography (eluent: PE / EtOAc = 100:0 to 100:10) to give 25.1 g of 3-(3,5-difluorophenyl)propenal. The yield was 71%. MS:169[M+H] + ;

[0111] Step 2): N2H4.H2O (7.15 g, 223.03 mmol) was added to ethanol (300 mL), and acetic acid (14.5 mL, 252 mmol) was added while stirring. The mixture was heated to 40 °C, and a solution of 3-(3,5-difluorophenyl)propenal (25 g, 149 mmol) in ethanol (20 mL) was slowly added dropwise. The mixture was reacted at 80 °C overnight. The reaction solution was concentrated and purified by column chromatography (eluent: PE / EtOAc = 100:0 to 3:1) to obtain 20 g of product. The yield was 74%. MS: 183[M+H] + ;

[0112] The following intermediates A-2 and A-3 were synthesized in the same manner.

[0113] [Table 1]

[0114] Synthesis of intermediate B-1: 2-(2-fluoro-5-(3-methoxypropoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0115] Step 1): 3-Bromo-4-fluorophenol (330 mg, 1.73 mmol), potassium carbonate (718.98 mg, 5.20 mmol), and 1-bromo-3-methoxypropane (540 mg, 3.50 mmol) were added to DMF (5 mL). The mixture was reacted at 80 °C for 2 hours. Water was added to the reaction solution, and the mixture was extracted three times with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by thin-layer chromatography (PE:EA = 5:1 as the mobile phase) to give 2-bromo-1-fluoro-(4-methoxypropyl)phenyl ether (421 mg, 93% yield).

[0116] Step 2: 2-Bromo-1-fluoro-(4-methoxypropyl)phenyl ether (421 mg, 1.60 mmol), pinacol ester (815 mg, 3.21 mmol), KOAc (472 mg, 4.81 mmol), and Pd(dppf)Cl2 (235 mg, 321 μmol) were added to 1,4-dioxane (10 mL). The mixture was reacted at 100 °C for 16 hours under argon protection. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 5:1 as the mobile phase) to give 395 mg of 2-(2-fluoro-5-(3-methoxypropoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The yield was 80%.

[0117] The following intermediates B-2 to B-30 were synthesized in the same manner.

[0118] [Table 2] [Table 3] [Table 4] [Example]

[0119] Example 1: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(3-(2-methoxyethoxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone [ka]

[0120] Step 1: 1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (24 g, 105 mmol), Intermediate A-1 (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole) (21.9 g, 120 mmol), HATU (39.9 g, 105 mmol), and DIEA (27.1 g, 210 mmol) were added to DMF (150 mL). The mixture was reacted at 25 °C under argon protection for 1 hour. The reaction solution was diluted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting product was further purified by column chromatography to finally obtain 33.0 g. The yield was 80%. MS:394[M+H] + ;

[0121] Step 2): tert-Butyl 4-[3-(3,5-difluorophenyl)-3,4-dihydropyrazole-2-carbonyl]piperidine-1-carboxylate (26 g, 66.09 mmol) was dissolved in 1,4-dioxane (60 mL), and then hydrochloric acid solution (4 M solution in 1,4-dioxane, 82.61 mL) was added. The mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was suction filtered. The solid was dissolved in methanol, followed by the addition of solid sodium carbonate. The mixture was adjusted to pH 8, stirred for 30 minutes, and then diluted with ethyl acetate. The mixture was suction filtered, and the solid was washed twice with ethyl acetate. The filtrate was rotary evaporated to dryness and purified by column chromatography (dichloromethane / methanol / triethylamine = 500 / 100 / 5) to give 15.5 g. The yield was 80%. MS: 294[M+H] + ;

[0122] Step 3): A solution of (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperidin-4-yl)methanone (3.0 g, 10 mmol), 2-fluoro-4-bromopyridine (3.5 g, 20 mmol), and triethylamine (3.05 g, 30 mmol) in DMSO (20 ml) was heated to 80° C. and reacted for 16 hours. The mixture was cooled and diluted with ethyl acetate. The mixture was washed with water, dried, and concentrated. The residue was purified by column chromatography to give 3.93 g of a yellow solid product. The yield was 88%. MS: 449, 451[M+H] + ;

[0123] Step 4: (1-(4-Bromopyridin-2-yl)piperidin-4-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (450 mg, 1 mmol), Intermediate B-2 (2-(3-(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (250 mg, 1 mmol), potassium carbonate (210 mg, 2 mmol), and Pd(PPh3)4 (58 mg, 0.05 mmol) were dissolved in a mixture of 1,4-dioxane (8 mL) and water (0.8 mL). The mixture was heated to 80 °C under argon protection and stirred for 5 hours. The reaction solution was filtered, concentrated, and purified by column chromatography (mobile phase: PE / EtOAc) to finally obtain 130 mg of a yellow solid product. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 5.2 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.33 - 7.22 (m, 3H), 7.12 - 7.10 (m, 1H), 7.05 (s, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.93 - 6.80 (m, 3H), 5.34 (dd, J = 11.9, 4.9 Hz, 1H), 4.50 - 4.41 (m, 2H), 4.23 - 4.14 (m, 2H), 3.71 -3.68 (m, 2H), 3.57 - 3.42 (m, 2H), 3.32 (s, 3H), 3.00 - 2.87 (m, 2H), 2.74 (dd, J = 19.0, 5.0 Hz, 1H), 1.90 (d, J = 12.8 Hz, 1H), 1.76 (d, J = 13.0 Hz, 1H), 1.58 - 1.54 (m, 2H). MS: 521[M+H] + .

[0124] Example 2: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(3-(3-methoxypropoxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0125] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-4 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 5.2 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.27 (d, J = 19.0 Hz, 3H), 7.11 (t, J = 9.4 Hz, 1H), 7.06 - 6.96 (m, 2H), 6.92 - 6.80 (m, 3H), 5.34 (dd, J = 12.0, 5.0 Hz, 1H), 4.45 (d, J = 13.0 Hz, 2H), 4.10 (t, J = 6.4 Hz, 2H), 3.50 - 3.48 (m, 4H), 3.26 (s, 3H), 2.92 (dd, J = 12.7, 9.5 Hz, 2H), 2.74 (dd, J = 19.0, 5.1 Hz, 1H), 2.03 - 1.86 (m, 3H), 1.76 (d, J = 12.7 Hz, 1H), 1.65 - 1.48 (m, 2H). MS:535[M+H] + . [ka]

[0126] Example 3: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0127] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-8 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 5.2 Hz, 1H), 7.38 (dd, J = 8.9, 7.2 Hz, 1H), 7.32 - 7.22 (m, 3H), 7.16 - 7.00 (m, 3H), 6.92 - 6.79 (m, 3H), 5.34 (dd, J = 11.9, 4.9 Hz, 1H), 4.69 (dt, J = 8.7, 4.5 Hz, 1H), 4.45 (d, J = 11.8 Hz, 2H), 3.86 (dt, J = 11.6, 4.4 Hz, 2H), 3.55 - 3.39 (m, 4H), 2.93 (dt, J = 13.0, 10.3 Hz, 2H), 2.75 (dd, J = 19.1, 5.0 Hz, 1H), 2.00 - 1.98 (m, 3H), 1.90 (d, J = 12.5 Hz, 1H), 1.76 (d, J = 13.0 Hz, 1H), 1.67 - 1.43 (m, 3H). MS: 547 [M+H] + .

[0128] Example 4: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(5-(2-methoxyethoxy)-2-methylphenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0129] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-20 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 5.1 Hz, 1H), 7.27 - 7.07 (m, 3H), 6.92 - 6.72 (m, 5H), 6.59 (d, J = 5.1 Hz, 1H), 5.34 (dd, J = 12.1, 5.0 Hz, 1H), 4.43 - 4.34 (m, 2H), 4.13 - 4.05 (m, 2H), 3.68 - 3.60 (m, 2H), 3.51 - 3.49 (m, 2H), 3.30 (s, 3H), 3.00 - 2.86 (m, 2H), 2.80 - 2.68 (m, 1H), 2.16 (s, 3H), 1.88 (d, J = 12.9 Hz, 1H), 1.74 (d, J = 13.0 Hz, 1H), 1.53 - 1.50 (m, 2H). MS:535 [M+H] + . [ka]

[0130] Example 5: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(5-(3-methoxypropoxy)-2-methylphenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0131] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-21 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 5.1 Hz, 1H), 7.27 - 7.06 (m, 3H), 6.91 - 6.79 (m, 3H), 6.78 - 6.71 (m, 2H), 6.57 (dd, J = 5.1, 1.2 Hz, 1H), 5.34 (dd, J = 12.0, 5.0 Hz, 1H), 4.39 (d, J = 12.0 Hz, 2H), 4.01 (t, J = 6.4 Hz, 2H), 3.55 - 3.41 (m, 4H), 3.24 (s, 3H), 2.99 - 2.85 (m, 2H), 2.74 (dd, MS:549 [M+H] + .

[0132] Example 6: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-methyl-5-((tetrahydro-2H-pyran-4-yl) )O (oxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0133] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-23 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 5.1 Hz, 1H), 7.27 - 7.06 (m, 3H), 6.96 - 6.77 (m, 4H), 6.73 (s, 1H), 6.57 (dd, J = 5.1, 1.2 Hz, 1H), 5.34 (dd, J = 12.0, 5.0 Hz, 1H), 4.57 (dt, J = 8.7, 4.5 Hz, 1H), 4.39 (d, J = 13.0 Hz, 2H), 3.83 (dt, J = 11.6, 4.4 Hz, 2H), 3.55 - 3.41 (m, 4H), 2.92 (q, J = 11.2 Hz, 2H), 2.74 (dd, J = 19.0, 5.0 Hz, 1H), 2.15 (s, 3H), 2.02 - 1.84 (m, 4H), 1.73 (d, J = 13.0 Hz, 1H), 1.63 - 1.46 (m, 3H). MS:561 [M+H] + . [ka]

[0134] Example 7: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(3-(4-hydroxybutoxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0135] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-5 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 5.2 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.32 - 7.21 (m, 3H), 7.16 - 7.07 (m, 1H), 7.06 - 6.95 (m, 2H), 6.93 - 6.80 (m, 3H), 5.34 (dd, J = 12.0, 5.0 Hz, 1H), 4.51 - 4.41 (m, 3H), 4.06 (t, J = 6.5 Hz, 2H), 3.51 - 3.42 (m, 4H), 2.93 (q, J = 11.5 Hz, 2H), 2.74 (dd, J = 19.1, 5.1 Hz, 1H), 1.90 (d, J = 12.9 Hz, 1H), 1.83 - 1.71 (m, 3H), 1.65 - 1.45 (m, 4H). MS: 535 [M+H] + .

[0136] Example 8: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(3-((4-hydroxy-4-methylpentyl)oxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0137] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-7 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 5.2 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.31 - 7.20 (m, 3H), 7.12 (tt, J = 9.3, 2.3 Hz, 1H), 7.06 - 6.95 (m, 2H), 6.92 - 6.79 (m, 3H), 5.39 - 5.30 (m, 1H), 4.45 (d, J = 13.4 Hz, 2H), 4.20 (s, 1H), 4.04 (t, J = 6.5 Hz, 2H), 3.54 - 3.36 (m, 2H), 2.93 (td, J = 12.6, 9.4 Hz, 2H), 2.75 (dd, J = 19.0, 5.0 Hz, 1H), 2.06 - 1.84 (m, 2H), 1.84 - 1.72 (m, 3H), 1.64 - 1.46 (m, 3H), 1.11 (s, 6H). MS:563 [M+H] + . [ka]

[0138] Example 9: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(5-(4-hydroxybutoxy)-2-methylphenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0139] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-22 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 5.0 Hz, 1H), 7.27 - 7.07 (m, 3H), 6.86 - 6.84 (m, 3H), 6.78 - 6.70 (m, 2H), 6.57 (d, J = 5.1 Hz, 1H), 5.39 - 5.29 (m, 1H), 4.48 - 4.34 (m, 3H), 3.97 (t, J = 6.5 Hz, 2H), 3.54 - 3.39 (m, 4H), 2.92 (q, J = 11.0, 10.6 Hz, 2H), 2.81 - 2.68 (m, 1H), 2.15 (s, MS:549 [M+H] + .

[0140] Example 10: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(5-((4-hydroxy-4-methylpentyl)oxy)-2-methylphenyl) )Pi Lysin-2-yl)piperidin-4-yl)methanone

[0141] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-25 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 5.1 Hz, 1H), 7.27 - 7.06 (m, 3H), 6.87 - 6.84 (m, 3H), 6.77 - 6.70 (m, 2H), 6.57 (dd, J = 5.1 Hz, 1H), 5.34 (dd, J = 12.1, 4.9 Hz, 1H), 4.39 (d, J = 12.9 Hz, 2H), 4.17 (s, 1H), 3.95 (t, J = 6.6 Hz, 2H), 3.54 - 3.39 (m, 2H), 2.99 - 2.88 (m, 2H), 2.74 (dd, J = 19.1, 5.0 Hz, 1H), 2.15 (s, 3H), 2.05 - 1.99 (m, 1H), 1.88 (d, J = 12.9 Hz, 1H), 1.80 - 1.68 (m, 3H), 1.61 - 1.42 (m, 3H), 1.10 (s, 6H). MS: 577 [M+H] + . [ka]

[0142] Example 11: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-methylphenyl)-2-methyl-4-oxo-1H-pyrazol-1-yl)) Ru- 5-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0143] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-28 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 5.1 Hz, 1H), 7.27 - 7.06 (m, 3H), 6.91 - 6.79 (m, 3H), 6.79 - 6.71 (m, 2H), 6.58 (d, J = 5.1Hz, 1H), 5.34 (dd, J = 12.0, 5.0 Hz, 1H), 4.38 (d, J = 11.8 Hz, 2H), 4.01 (t, J = 6.3 Hz, 2H), 3.87 - 3.78 (m, 2H), 3.49 - 3.48 (m, 2H), 3.27 - 3.25 (m, 4H), 2.92 (q, J = 11.1, 10.6 Hz, 2H), 2.74 (dd, J = 19.1, 5.1 Hz, 1H), 2.15 (s, 3H), 1.99 (t, J = 7.4 Hz, 1H), 1.88 (d, J = 12.9 Hz, 1H), 1.78 - 1.43 (m, 7H). MS:589 [M+H] + .

[0144] Example 12: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(3-(3-hydroxypropoxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0145] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-3 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 5.2 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.32 - 7.22 (m, 3H), 7.12 (tt, J = 9.4, 2.3 Hz, 1H), 7.06 - 6.97 (m, 2H), 6.92 - 6.79 (m, 3H), 5.34 (dd, J = 11.9, 5.0 Hz, 1H), 4.57 (t, J = 5.1 Hz, 1H), 4.45 (d, J = 13.4 Hz, 2H), 4.11 (t, J = 6.4 Hz, 2H), 3.63 - 3.42 (m, 4H), 2.93 (dt, J = 13.2, 9.9 Hz, 2H), 2.74 (dd, J = 19.0, 5.0 Hz, 1H), 1.89 (p, J = 6.2 Hz, 3H), 1.76 (d, J = 13.2 Hz, 1H), 1.65 - 1.48 (m, 2H). MS:521 [M+H] + . [ka]

[0146] Example 13: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(3-(4-methoxybutoxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0147] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-6 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 5.2 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.32 - 7.21 (m, 3H), 7.11 (t, J = 9.4 Hz, 1H), 7.06 - 6.96 (m, 2H), 6.92 - 6.79 (m, 3H), 5.34 (dd, J = 11.9, 5.0 Hz, 1H), 4.49 - 4.40 (m, 2H), 4.06 (t, J = 6.3 Hz, 2H), 3.54 - 3.36 (m, 4H), 3.24 (s, 3H), 2.93 (dt, J = 12.9, 9.8 Hz, 2H), 2.74 (dd, J = 19.0, 5.0 Hz, 1H), 1.90 (d, J = 12.5 Hz, 1H), 1.81 - 1.64 (m, 5H), 1.55 (dt, J = 20.8, 12.2 Hz, 2H).MS:549 [M+H] + .

[0148] Example 14: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0149] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-9 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 5.2 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.32 - 7.21 (m, 3H), 7.12 (t, J = 9.3 Hz, 1H), 7.06 - 6.97 (m, 2H), 6.93 - 6.80 (m, 3H), 5.34 (dd, J = 11.9, 4.9 Hz, 1H), 4.49 - 4.41 (m, 2H), 3.95 - 3.84 (m, 4H), 3.55 - 3.40 (m, 4H), 2.93 (td, J = 12.6, 9.4 Hz, 2H), 2.75 (dd, J = 19.0, 4.9 Hz, 1H), 2.06 - 1.95 (m, 1H), 1.90 (d, J = 12.7 Hz, 1H), 1.80 - 1.66 (m, 3H), 1.55 (dd, J = 21.9, 12.5 Hz, 2H), 1.36 - 1.32 (m, 2H). MS: 561 [M+H] + . [ka]

[0150] Example 15: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(5-(3-hydroxypropoxy)-2-methylphenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0151] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-24 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 5.1 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.12 (t, J = 9.3 Hz, 1H), 6.91 - 6.80 (m, 3H), 6.78 - 6.70 (m, 2H), 6.57 (d, J = 5.1 Hz, 1H), 5.34 (dd, J = 11.9, 5.0 Hz, 1H), 4.53 (t, J = 5.2 Hz, 1H), 4.38 (dd, J = 13.2, 3.8 Hz, 2H), 4.02 (t, J = 6.4 Hz, 2H), 3.59 - 3.41 (m, 4H), 2.92 (dt, J = 12.8, 9.5 Hz, 2H), 2.74 (dd, J = 19.0, 5.0 Hz, 1H), 2.15 (s, 3H), 1.92 - 1.79 (m, 3H), 1.74 (d, J = 12.9 Hz, 1H), 1.64 - 1.44 (m, 2H). MS: 535 [M+H] + .

[0152] Example 16: (1-(4-(2-chloro-5-(2-methoxyethoxy)phenyl)pyridin-2-yl)piperidin-4-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone

[0153] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-10 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 5.1 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.25 (s, 1H), 7.17 - 7.07 (m, 1H), 7.06 - 6.95 (m, 2H), 6.88 - 6.80 (m, 3H), 6.66 (d, J = 5.1 Hz, 1H), 5.39 - 5.29 (m, 1H), 4.39 (d, J = 13.1 Hz, 2H), 4.18 - 4.10 (m, 2H), 3.69 - 3.62 (m, 2H), 3.50 - 3.48 (m, 2H), 3.30 (s, 3H), 2.95 - 2.92 (m, 2H), 2.74 (dd, J = 18.9, 5.0 Hz, 1H), 1.89 (d, J = 12.9 Hz, 1H), 1.74 (d, J = 13.0 Hz, 1H), 1.61 - 1.43 (m, 2H). MS:555 [M+H] + . [ka]

[0154] Example 17: (1-(4-(2-chloro-5-(3-hydroxypropoxy)phenyl)pyridin-2-yl)piperidin-4-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone

[0155] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-11 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 5.1 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.27 - 7.23 (m, 1H), 7.13 - 7.11 (m, 1H), 7.04 - 6.92 (m, 2H), 6.85 - 6.82 (m, 3H), 6.65 (d, J = 5.1 Hz, 1H), 5.39 - 5.29 (m, 2H), 4.38 (d, J = 12.2 Hz, 2H), 3.59 - 3.41 (m, 4H), 2.93 (d, J = 11.9 Hz, 2H), 2.74 (dd, J = MS: 555 [M+H] + .

[0156] Example 18: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-fluoro-5-(3-hydroxypropoxy)phenyl)pyridin-2-yl )Pi Peridine-4-ylmethanone

[0157] This was prepared in the same manner as in Example 1. However, in step 4, intermediate B-12 was used in place of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 5.1 Hz, 1H), 7.27 - 7.19 (m, 2H), 7.16 - 7.04 (m, 2H), 6.99 (d, J = 9.0 Hz, 1H), 6.93 (s, 1H), 6.86 - 6.82 (m, 2H), 6.76 (d, J = 5.1 Hz, 1H), 5.34 (dd, J = 12.0, 5.0 Hz, 1H), 4.56 (t, J = 5.2 Hz, 1H), 4.40 (d, J = 11.9 Hz, 2H), 4.06 (t, J = 6.4 Hz, 2H), 3.60 - 3.40 (m, 4H), 2.93 (q, J = 10.8 Hz, 2H), 2.74 (dd, J = 19.0, 5.0 Hz, 1H), 1.87 - 1.85 (m, 3H), 1.74 (d, J = 13.0 Hz, 1H), 1.63 - 1.42 (m, 2H). MS:539 [M+H] + . [ka]

[0158] Example 19: (5-(2-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(5-(2-methoxyethoxy)-2-methylphenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0159] This was prepared in the same manner as in Example 1, except that in step 1, intermediate A-2 was used instead of intermediate A-1, and in step 4, intermediate B-20 was used instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 5.0 Hz, 1H), 7.34 - 7.24 (m, 2H), 7.23 - 7.10 (m, 3H), 7.05 (t, J = 7.7 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.80 - 6.71 (m, 2H), 6.58 (d, J = 5.1 Hz, 1H), 5.45 (dd, J = 12.1, 5.1 Hz, 1H), 4.38 (d, J = 13.0 Hz, 2H), 4.12 - 4.05 (m, 2H), 3.67 - 3.60 (m, 2H), 3.54 - 3.50 (m, 2H), 3.30 (s, 3H), 2.92 (td, J = 12.9, 7.5 Hz, 2H), 2.71 (dd, J = 19.0, 5.2 Hz, 1H), 2.15 (s, 3H), 1.86 (d, J = 12.9 Hz, 1H), 1.73 (d, J = 12.5 Hz, 1H), 1.58 - 1.46 (m, 2H). MS: 517 [M+H] + .

[0160] Example 20: (5-(2-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(5-(3-hydroxypropoxy)-2-methylphenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0161] This was prepared in the same manner as in Example 1, except that in step 1, intermediate A-2 was used instead of intermediate A-1, and in step 4, intermediate B-24 was used instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 5.1 Hz, 1H), 7.34 - 7.25 (m, 2H), 7.22 - 7.12 (m, 3H), 7.05 (t, J = 7.7 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.75 (s, 1H), 6.72 (s, 1H), 6.57 (d, J = 5.1 Hz, 1H), 5.45 (dd, J = 12.0, 5.1 Hz, 1H), 4.53 (t, J = 5.2 Hz, 1H), 4.38 (d, J = 13.2 Hz, 2H), 4.02 (t, J = 6.4 Hz, 2H), 3.59 - 3.51 (m, 2H), 3.32 (br, 2H), 2.91 (q, J = 11.1, 10.6 Hz, 2H), 2.77 - 2.64 (m, 1H), 2.15 (s, 3H), 2.08 - 2.00 (m, 1H), 1.85 (q, J = 6.4 Hz, 2H), 1.73 (d, J = 13.0 Hz, 1H), 1.62 - 1.42 (m, 2H). MS: 517 [M+H] + . [ka]

[0162] Example 21: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-fluoro-5-(3-hydroxy-3-methylbutoxy)phenyl)pyridinyl) hmm- 2-yl)piperidin-4-yl)methanone

[0163] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-13 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 5.1 Hz, 1H), 7.30 - 7.19 (m, 2H), 7.18 - 7.03 (m, 2H), 7.00 (t, J = 9.0 Hz, 1H), 6.93 (s, 1H), 6.89 - 6.79 (m, 2H), 6.76 (d, J = 5.0 Hz, 1H), 5.34 (dd, J = 12.0, 4.9 Hz, 1H), 4.47 - 4.31 (m, 3H), 4.11 (t, J = 7.2 Hz, 2H), 3.48 - 3.40 (m, 2H), 2.93 (dt, J = 12.7, 10.3 Hz, 2H), 2.74 (dd, J = 19.0, 5.0 Hz, 1H), 1.95 - 1.80 (m, 3H), 1.75 (d, J = 12.7 Hz, 1H), 1.55 - 1.52 (m, 2H), 1.16 (s, 6H). MS: 567 [M+H] + .

[0164] Example 22: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-fluoro-5-(2-hydroxyethoxy)phenyl)pyridin-2-yl )Pi Peridine-4-ylmethanone

[0165] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-14 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 5.1 Hz, 1H), 7.29 - 7.19 (m, 2H), 7.18 - 6.96 (m, 3H), 6.93 (s, 1H), 6.89 - 6.73 (m, 3H), 5.34 (dd, J = 12.0, 4.9 Hz, 1H), 4.90 (br, 1H), 4.45 - 4.36 (m, 2H), 4.03 (t, J = 5.0 Hz, 2H), 3.72 (t, J = 4.9 Hz, 2H), 3.55 - 3.29 (m, 2H), 3.01 - 2.86 (m, 2H), 2.74 (dd, J = 19.0, 5.0 Hz, 1H), 1.89 (d, J = 12.2 Hz, 1H), 1.75 (d, J = 12.5 Hz, 1H), 1.56 - 1.53 (m, 2H). MS: 525 [M+H] + . [ka]

[0166] Example 23: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-fluoro-5-(2-hydroxy-2-methylpropoxy)phenyl)pyridinyl) hmm- 2-yl)piperidin-4-yl)methanone

[0167] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-15 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 5.1 Hz, 1H), 7.28 - 7.18 (m, 2H), 7.17 - 6.96 (m, 3H), 6.93 (s, 1H), 6.88 - 6.80 (m, 2H), 6.77 (dd, J = 5.2, 1.7 Hz, 1H), 5.34 (dd, J = 12.0, 4.9 Hz, 1H), 4.64 (s, 1H), 4.40 (d, J = 12.9 Hz, 2H), 3.76 (s, 2H), 3.48 - 3.40 (m, 2H), 2.94 (q, J = 10.7 Hz, 2H), 2.74 (dd, J = 19.0, 5.0 Hz, 1H), 1.89 (d, J = 12.8 Hz, 1H), 1.75 (d, J = 12.8 Hz, 1H), 1.63 - 1.43 (m, 2H), 1.20 (s, 6H). MS:553 [M+H] + .

[0168] Example 24: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-fluoro-5-((4-hydroxy-4-methylpentyl)oxy) )centre (phenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0169] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-16 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 5.2 Hz, 1H), 7.28 - 7.18 (m, 2H), 7.18 - 6.94 (m, 3H), 6.93 (s, 1H), 6.89 - 6.73 (m, 3H), 5.34 (dd, J = 12.0, 4.9 Hz, 1H), 4.45 - 4.36 (m, 2H), 4.20 (s, 1H), 3.99 (t, J = 6.5 Hz, 2H), 3.48 - 3.40 (m, 2H), 2.93 (dt, J = 13.4, 10.0 Hz, 2H), 2.74 (dd, J = MS:581 [M+H] + . [ka]

[0170] Example 25: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-fluoro-5-((5-hydroxypentyl)oxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0171] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-17 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 5.1 Hz, 1H), 7.28 - 7.18 (m, 2H), 7.18 - 6.95 (m, 3H), 6.93 (s, 1H), 6.89 - 6.73 (m, 3H), 5.34 (dd, J = 12.0, 4.9 Hz, 1H), 4.42 - 4.38 (m, 3H), 4.00 (t, J = 6.5 Hz, 2H), 3.55 - 3.30 (m, 4H), 2.93 (q, J = 11.4 Hz, 2H), 2.74 (dd, J = 19.0, 5.0Hz, 1H), 1.89 (d, J = 12.9 Hz, 1H), 1.76 - 1.70 (m, 3H), 1.62 - 1.39 (m, 6H). MS:567 [M+H] + .

[0172] Example 26: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-fluoro-5-((5-hydroxy-5-methylhexyl)oxy) )centre (phenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0173] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-18 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 5.1 Hz, 1H), 7.28 - 7.18 (m, 2H), 7.18 - 6.95 (m, 3H), 6.93 (s, 1H), 6.88 - 6.80 (m, 2H), 6.77 (d, J = 5.0 Hz, 1H), 5.34 (dd, J = 12.0, 5.0 Hz, 1H), 4.45 - 4.39 (m, 2H), 4.11 (s, 1H), 4.00 (t, J = 6.4 Hz, 2H), 3.48 - 3.40 (m, 2H), 2.93 (q, J = 11.2 Hz, 2H), 2.74 (dd, J = 19.0, 5.0 Hz, 1H), 1.94 - 1.85 (m, 1H), 1.79 - 1.65 (m, 3H), 1.62 - 1.34 (m, 6H), 1.07 (s, 6H). MS:595 [M+H] + . [ka]

[0174] Example 27: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-fluoro-5-(3-fluoropropoxy)phenyl)pyridin-2-yl )Pi Peridine-4-ylmethanone

[0175] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-19 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 5.2 Hz, 1H), 7.29 - 7.21 (m, 2H), 7.17 - 6.98 (m, 3H), 6.94 (s, 1H), 6.87 - 6.80 (m, 2H), 6.77 (dt, J = 5.1, 1.7 Hz, 1H), 5.34 (dd, J = 12.0, 5.0 Hz, 1H), 4.68 (t, J = 5.9 Hz, 1H), 4.56 (t, J = 5.9 Hz, 1H), 4.40 (dd, J = 13.3, 3.5 Hz, 2H), 4.12 (t, J = 6.2 Hz, 2H), 3.55 - 3.36 (m, 2H), 2.93 (dt, J = 12.9, 9.9 Hz, 2H), 2.74 (ddd, J = 19.0, 5.0, 1.8 Hz, 1H), 2.18 - 2.04 (m, 2H), 1.94 - 1.85 (m, 1H), 1.75 (d, J = 12.2 Hz, 1H), 1.64 - 1.43 (m, 2H). MS:541 [M+H] + .

[0176] Example 28: (1-(4-(5-(2-methoxyethoxy)-2-methylphenyl)pyridin-2-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methanone

[0177] This was prepared in the same manner as in Example 1, except that in step 1, intermediate A-3 was used instead of intermediate A-1, and in step 4, intermediate B-20 was used instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 5.1 Hz, 1H), 7.36 - 7.15 (m, 5H), 7.13 - 7.10 (m, 2H), 6.88 (d, J = 8.4 Hz, 1H), 6.80 - 6.70 (m, 2H), 6.58 (d, J = 5.0 Hz, 1H), 5.34 - 5.29 (m, 1H), 4.42 - 4.33 (m, 2H), 4.12 - 4.05 (m, 2H), 3.68 - 3.60 (m, 2H), 3.42 - 3.36 (m, 2H), 3.30 (s, 3H), 2.94 - 3.88 (m, 2H), 2.67 (dd, J = 18.9, 4.7 Hz, 1H), 2.15 (s, 3H), 1.91 - 1.82 (m, 1H), 1.73 (d, J = 13.0 Hz, 1H), 1.55 - 1.51 (m, 2H). MS: 499 [M+H] + . [ka]

[0178] Example 29: (5-(2-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(5-(3-hydroxypropoxy)-2-methylphenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0179] This was prepared in the same manner as in Example 1, except that in step 1, intermediate A-2 was used instead of intermediate A-1, and in step 4, intermediate B-24 was used instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 5.1 Hz, 1H), 7.34 - 7.24 (m, 2H), 7.22 - 7.12 (m, 3H), 7.10 - 7.01 (m, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.78 - 6.70 (m, 2H), 6.57 (d, J = 4.9 Hz, 1H), 5.43 - 5.38(m, 1H), 4.53 (s, 1H), 4.37 (d, J = 13.2 Hz, 2H), 4.02 (t, J = 6.4 Hz, 2H), 3.58 - 3.46 (m, 4H), 2.92 (d, J = 9.1 Hz, 2H), 2.71 (dd, J = 19.0, 5.1 Hz, 1H), 2.15 (s, 3H), 2.07 - 1.95 (m, 1H), 1.87-1.81 (m, 2H), 1.73 (d, J = 12.9 Hz, 1H), 1.63 - 1.45 (m, 2H). MS: 517 [M+H] + .

[0180] Example 30: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-fluoro-5-(3-methoxypropoxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0181] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-1 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 5.2 Hz, 1H), 7.29 - 7.19 (m, 2H), 7.17 - 7.04 (m, 2H), 7.00 (d, J = 9.0 Hz, 1H), 6.93 (s, 1H), 6.86 - 6.82 (m, 2H), 6.79 - 6.73 (m, 1H), 5.34 (dd, J = 12.0, 4.9 Hz, 1H), 4.40 (d, J = 13.0 Hz, 2H), 4.05 (t, J = 6.3 Hz, 2H), 3.55 - 3.41 (m, 4H), 3.24 (s, 3H), 2.93 (dt, J = 13.3, 10.5 Hz, 2H), 2.74 (dd, J = 19.1, 5.0 Hz, 1H), 2.01 - 1.84 (m, 3H), 1.75 (d, J = 13.1 Hz, 1H), 1.58 - 1.52 (m, 2H). MS: 553 [M+H] + . [ka]

[0182] Example 31: (1-(4-(5-(3-hydroxypropoxy)-2-methylphenyl)pyridin-2-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methanone

[0183] This was prepared in the same manner as in Example 1, except that in step 1, intermediate A-3 was used instead of intermediate A-1, and in step 4, intermediate B-24 was used instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 5.1 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.27 - 7.14 (m, 3H), 7.14 - 7.07 (m, 2H), 6.87 (dd, J = 8.4, 2.7 Hz, 1H), 6.78 - 6.69 (m, 2H), 6.57 (dd, J = 5.1, 1.3 Hz, 1H), 5.34 - 5.29 (m, 2H), 4.38 (d, J = 12.8 Hz, 2H), 4.02 (t, J = 6.4 Hz, 2H), 3.59 - 3.43 (m, 2H), 2.98 - 2.88 (m, 2H), 2.74 - 2.62 (m, 1H), 2.15 (s, 3H), 2.02 - 1.96 (m, 3H), 1.85 (q, J = 6.4 Hz, 2H), 1.73 (d, J = 12.7 Hz, 1H), 1.66 - 1.38 (m, 2H). MS: 499 [M+H] + .

[0184] Example 32: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(5-(4-methoxybutoxy)-2-methylphenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0185] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-26 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 5.1 Hz, 1H), 7.27 - 7.07 (m, 3H), 6.85 (dd, J = 11.4, 8.4 Hz, 3H), 6.78 - 6.71 (m, 2H), 6.58 (d, J = 5.3 Hz, 1H), 5.34 (dd, J = 12.0, 5.0 Hz, 1H), 4.38 (dd, J = 13.2, 3.6 Hz, 2H), 3.97 (t, J = 6.4 Hz, 2H), 3.60 - 3.41 (m, 4H), 3.22 (s, 3H), 3.00 - 2.85 (m, MS: 563 [M+H] + . [ka]

[0186] Example 33: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-methyl-5-((tetrahydro-2H-pyran-4-yl) )Me (2-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0187] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-27 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 5.1 Hz, 1H), 7.27 - 7.06 (m, 3H), 6.85 (dd, J = 15.5, 8.4 Hz, 3H), 6.78 - 6.70 (m, 2H), 6.57 (d, J = 5.1 Hz, 1H), 5.34 (dd, J = 12.0, 5.0 Hz, 1H), 4.38 (d, J = 12.5 Hz, 2H), 3.91 - 3.79 (m, 4H), 3.54 - 3.41 (m, 4H), 2.92 (q, J = 10.7 Hz, 2H), 2.74 (dd, J = 19.0, 5.0 Hz, 1H), 2.15 (s, 3H), 1.99 (br, 1H), 1.88 (d, J = 12.8 Hz, 1H), 1.70 (dd, J = 27.6, 12.7 Hz, 3H), 1.61 - 1.46 (m, 2H), 1.31 (qd, J = 12.2, 4.5 Hz, 2H). MS: 575 [M+H] + .

[0188] Example 34: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(5-(4-methoxybutoxy)-2-methylphenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0189] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-26 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 5.1 Hz, 1H), 7.27 - 7.06 (m, 3H), 6.88 - 6.82 (m, 3H), 6.78 - 6.70 (m, 2H), 6.57 (d, J = 5.0 Hz, 1H), 5.34 (dd, J = 12.0, 5.0 Hz, 1H), 4.43 - 4.34 (m, 2H), 3.97 (t, J = 6.3 Hz, 2H), 3.50 - 3.40 (m, 2H), 3.36 (t, J = 6.3 Hz, 2H), 3.22 (s, 3H), 2.92 (q, J = MS:563 [M+H] + . [ka]

[0190] Example 35: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(5-(4-hydroxybutoxy)-2-methylphenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0191] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-22 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 5.1 Hz, 1H), 7.27 - 7.07 (m, 3H), 6.88 - 6.81 (m, 3H), 6.77 - 6.70 (m, 2H), 6.57 (d, J = 5.2 Hz, 1H), 5.35 - 5.31 (m, 2H), 4.47 - 4.34 (m, 2H), 3.96 (t, J = 6.5 Hz, 2H), 3.56 - 3.46 (m, 2H), 2.92 (q, J = 11.0 Hz, 2H), 2.80 - 2.68 (m, 1H), 2.15 (s, 3H), 2.03-1.98 (m, 4H), 1.88 (d, J = 13.2 Hz, 1H), 1.75 - 1.69 (m, 2H), 1.58 - 1.50 (m, 3H). MS:549 [M+H] + .

[0192] Example 36: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-fluoro-5-(4-hydroxybutoxy)phenyl)pyridinyl) hmm- 2-yl)piperidin-4-yl)methanone

[0193] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-29 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 5.1 Hz, 1H), 7.28 - 7.18 (m, 2H), 7.17 - 6.95 (m, 3H), 6.93 (s, 1H), 6.89 - 6.73 (m, 3H), 5.34 (dd, J = 12.0, 5.0 Hz, 1H), 4.49 - 4.35 (m, 4H), 4.01 (t, J = 6.5 Hz, 2H), 3.55 - 3.42 (m, 3H), 3.01 - 2.86 (m, 2H), 2.74 (ddd, J = 19.1, 5.0, 1.8Hz, 1H), 1.94 - 1.85 (m, 1H), 1.78 - 1.71 (m, 3H), 1.64 - 1.43 (m, 4H). MS: 553 [M+H] + . [ka]

[0194] Example 37: (1-(4-(5-(2,2-difluoro-3-hydroxypropoxy)-2-fluorophenyl)pyridin hmm- 2-yl)piperidin-4-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone

[0195] This was prepared in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-30 instead of intermediate B-2. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 5.1 Hz, 1H), 7.33 - 7.05 (m, 5H), 6.95 (s, 1H), 6.89 - 6.75 (m, 3H), 5.67 (t, J = 6.2 Hz, 1H), 5.34 (dd, J = 12.0, 5.0 Hz, 1H), 4.39 (t, J = 12.9 Hz, 4H), 3.76 (td, J = 13.8, 6.2 Hz, 2H), 3.48 (m, 2H), 2.94 (dt, J = 12.7, 10.4 Hz, 2H), 2.74 (dd, J = 19.1, MS:575 [M+H] + .

[0196] Example 38: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-fluoro-5-(3-hydroxypropoxy)phenyl)pyrimidin-2-yl) )Pi Peridine-4-ylmethanone [ka]

[0197] Step 1): 2,4-Dichloropyrimidine (1.00 g, 6.71 mmol), Intermediate B-12 (3-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-1-ol) (2.58 g, 8.73 mmol), potassium carbonate (1.86 g, 13.4 mmol), and Pd[PPh3]4 (776 mg, 0.671 mmol) were added to a mixture of ethanol (12 mL) and toluene (6 mL). The mixture was heated to 55 °C under argon protection and reacted for 8 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by column chromatography to give 1.48 g of 3-(3-(2-chloropyrimidin-4-yl)-4-fluorophenoxy)propyl-1-ol, a yield of 78%.

[0198] Step 2): 3-(3-(2-chloropyrimidin-4-yl)-4-fluorophenoxy)propyl-1-ol (741 mg, 2.62 mmol), ethyl piperidine-4-carboxylate (412.35 mg, 2.62 mmol), and cesium carbonate (1.71 g, 5.25 mmol) were added to DMF (8 mL). The atmosphere was replaced with argon, and the mixture was reacted at 85 °C for 3 hours. The reaction solution was diluted with dichloromethane and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 907 mg of product. The yield was 85.71%. MS:404 [M+H] + ;

[0199] Step 3): Ethyl 1-(4-(2-fluoro-5-(3-hydroxypropoxy)phenyl)pyrimidin-2-yl)piperidine-4-carboxylate (650 mg, 1.61 mmol) and NaOH (321 mg, 8.03 mmol) were added to MeOH (10 mL) and HO (2 mL). The mixture was stirred and reacted at room temperature for 3 hours. The mixture was adjusted to pH 3 with hydrochloric acid (2N concentration) at 0°C. The reaction solution was diluted with dichloromethane and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to finally obtain 532 mg of 1-(4-(2-fluoro-5-(3-hydroxypropoxy)phenyl)pyrimidin-2-yl)piperidine-4-carboxylic acid. The yield was 87.92%. MS:376[M+H] + ;

[0200] Step 4: 1-(4-(2-Fluoro-5-(3-hydroxypropoxy)phenyl)pyrimidin-2-yl)piperidine-4-carboxylic acid (190 mg, 0.5 mmol), Intermediate A-1 (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole) (100 mg, 0.55 mmol), HATU (190 mg, 0.5 mmol), and DIEA (129 mg, 1 mmol) were added to DMF (3 mL). The mixture was reacted under argon protection at 25 °C for 2 hours. The reaction solution was diluted with dichloromethane and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting product was further purified by column chromatography to finally obtain 78 mg of product. The yield was 29%. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 5.1 Hz, 1H), 7.48 (d, J = 6.2 Hz, 1H), 7.32 - 7.19 (m, 2H), 7.18 - 7.05 (m, 2H), 7.00 (d, J = 5.1 Hz, 1H), 6.88 - 6.81 (m, 2H), 5.34 (dd, J = 12.0, 5.0 Hz, 1H), 4.75 (d, J = 13.1 Hz, 2H), 4.60(t, J = 5.0 Hz, 1H),4.08 (t, J = 6.3 Hz, 2H), 3.55 (q, J = 6.4 Hz, 2H), 3.51 - 3.35 (m, 2H), 3.04 (td, J = 12.5, 9.7 Hz, 2H), 2.75 (dd, J = 19.0, 5.0 Hz, 1H), 1.98 - 1.76 (m, 4H), 1.56 - 1.49 (m, 2H). MS: 540 [M+H] + .

[0201] Example 39: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-fluoro-5-(3-hydroxy-3-methylbutoxy)phenyl)pyrimidinyl) hmm- 2-yl)piperidin-4-yl)methanone [ka]

[0202] This was prepared in the same manner as in Example 38, except that in step 1, intermediate B-13 was used instead of intermediate B-12. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 5.1 Hz, 1H), 7.49 (d, J = 6.2 Hz, 1H), 7.31 - 7.21 (m, 2H), 7.17 - 7.04 (m, 2H), 7.00 (d, J = 5.1 Hz, 1H), 6.88 - 6.80 (m, 2H), 5.34 (dd, J = 12.0, 5.0 Hz, 1H), 4.79 - 4.71 (m, 2H), 4.41 (s, 1H), 4.13 (t, J = 7.2 Hz, 2H), 3.55 - 3.35 (m, 2H), 3.04 (td, J = MS:568[M+H] + .

[0203] Separation of stereoisomers

[0204] The racemates obtained in Examples 18, 21, 23, and 24 were separated and purified using a chiral column. Separation was carried out using a chromatograph (Shimadzu LC-20A) under the following separation conditions. [Table 5]

[0205] The peak with the longer retention time was collected and the solvent was removed by rotary evaporation to give the pure enantiomer. The absolute configuration of the active enantiomer was determined to be (S). [Table 6]

[0206] Example 44: [5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl]-[1-[4-[5-(2-ethyl-2-hydroxybutoxy)-2-fluorophenyl]pyridin-2-yl]piperidin-4-yl]methanone [ka]

[0207] Step 1): Methyl 2-bromoacetate (14.42 g, 94.24 mmol), 3-bromo-4-fluorophenol (6 g, 31.41 mmol), and potassium carbonate (13.03 g, 94.24 mmol) were added to DMF (30 mL). The mixture was reacted at 80 °C for 12 hours under argon protection. The reaction solution was diluted with ethyl acetate and then washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography to finally obtain 6 g of methyl 2-(3-bromo-4-fluoro-phenoxy)acetate. The yield was 73%.

[0208] Step 2): Methyl 2-(3-bromo-4-fluoro-phenoxy)acetate (1 g, 3.80 mmol) was dissolved in tetrahydrofuran. Ethyl magnesium bromide (2.0 M in tetrahydrofuran) (5.7 mL) was added dropwise at 0°C under argon protection. The mixture was reacted at this temperature for 2 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution. The reaction solution was suction filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate. The organic phase was washed with water and saturated brine, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain 800 mg of 3-[(3-bromo-4-fluoro-phenoxy)methyl]pentan-3-ol. The yield was 72%.

[0209] Step 3): 3-[(3-Bromo-4-fluoro-phenoxy)methyl]pentan-3-ol (800 mg, 2.75 mmol), pinacol ester (907.06 mg, 3.57 mmol), Pd(dppf)Cl (120.63 mg, 164.86 μmol), and potassium acetate (539.31 mg, 5.50 mmol) were dissolved in 1,4-dioxane (15 mL). Under argon protection, the mixture was slowly heated to 100 °C and reacted for 8 hours. The mixture was cooled to room temperature. The reaction solution was suction filtered through diatomaceous earth, diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography to give 800 mg of 3-[[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]pentan-3-ol in a yield of 90%.

[0210] Step 4: (1-(4-Bromopyridin-2-yl)piperidin-4-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (100 mg, 222.57 μmol), 3-[[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]pentan-3-ol (112.92 mg, 333.86 μmol), potassium carbonate (61.52 mg, 445.15 μmol), and Pd(dppf)Cl (16.29 mg, 22.26 μmol) were dissolved in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL). The mixture was slowly heated to 100 °C under argon protection and reacted for 8 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The product was purified by silica gel column chromatography to finally obtain 40 mg of [5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl]-[1-[4-[5-(2-ethyl-2-hydroxybutoxy)-2-fluorophenyl]pyridin-2-yl]piperidin-4-yl]methanone. The yield was 31%.

[0211] 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 5.1 Hz, 1H), 7.27 - 7.18 (m, 2H), 7.17 - 6.97 (m, 3H), 6.93 (s, 1H), 6.89 - 6.80 (m, 2H), 6.76 (d, J = 5.2 Hz, 1H), 5.34 (dd, J = 12.0, 4.9 Hz, 1H), 4.44 - 4.32 (m, 3H), 3.77 (s, 2H), 3.48 (dd, J = 18.8, 12.1 Hz, 1H), 3.37 (dd, J = 11.7, 3.9 Hz, 1H), 3.00 - 2.87 (m, 2H), 2.80 - 2.66 (m, 1H), 1.89 (d, J = 13.3 Hz, 1H), 1.75 (d, J = 12.8 Hz, 1H), 1.59 - 1.47 (m, 6H), 0.83 (t, J = 7.5 Hz, 6H). MS: 581[M+H] + .

[0212] Example 45: [5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl]-[1-[4-[2-fluoro-5-[(1-hydroxycyclopropyl)methoxy]phenyl]pyridin-2-yl]piperidin-4-yl]methanone [ka]

[0213] Step 1): Methyl 2-(3-bromo-4-fluoro-phenoxy)acetate (500 mg, 1.80 mmol) was dissolved in THF (8 mL). Ethyl magnesium bromide (2 M in tetrahydrofuran, 0.9 mL, 1.80 mmol) was added dropwise under argon protection at 0°C. The mixture was reacted at this temperature for 30 minutes, then slowly heated to 25°C and reacted for an additional 16 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution. The mixture was filtered. The filtrate was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to finally obtain 180 mg of 1-[(3-bromo-4-fluoro-phenoxy)methyl]cyclopropanol. The yield was 38%.

[0214] Step 2): 1-[(3-Bromo-4-fluoro-phenoxy)methyl]cyclopropanol (180 mg, 689.42 μmol), pinacol ester (370.63 mg, 1.46 mmol), potassium acetate (238.73 mg, 2.43 mmol), and Pd(dppf)Cl (88.99 mg, 121.63 μmol) were added to 1,4-dioxane (10 mL). The mixture was reacted at 100 °C under argon protection for 3 hours. The reaction solution was concentrated and purified by column chromatography to finally obtain 1-[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2-methyl-cyclopropan-2-ol (170 mg). The yield was 80%.

[0215] Step 3): (1-(4-Bromopyridin-2-yl)piperidin-4-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (80 mg, 178.06 μmol), 1-[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2-methyl-cyclopropan-2-ol (71.33 mg, 231.48 μmol), potassium carbonate (49.22 mg, 356.12 μmol), and Pd(dppf)Cl (13.03 mg, 17.81 μmol) were dissolved in a mixture of 1,4-dioxane (3 mL) and water (0.4 mL). Under argon protection, the mixture was slowly heated to 80 °C and reacted for 6 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography to finally obtain 28 mg of [5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl]-[1-[4-[2-fluoro-5-[(1-hydroxycyclopropyl)methoxy]phenyl]pyridin-2-yl]piperidin-4-yl]methanone. The yield was 29%. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 5.3 Hz, 1H), 7.30 - 7.20 (m, 2H), 7.18 - 7.05 (m, 2H), 7.03 - 6.94 (m, 2H), 6.89 - 6.76 (m, 3H), 5.34 (dd, J = 12.0, 5.0 Hz, 1H), 4.90 (s, 2H), 4.38 (d, J = 13.0 Hz, 2H), 3.55 - 3.32 (m, 2H), 2.99 (d, J = 12.0 Hz, 2H), 2.75 (dd, J = 19.0, 5.0Hz, 1H), 2.55 (d, J = 7.3 Hz, 1H), 1.91 (d, J = 12.9 Hz, 1H), 1.76 (d, J = 13.1 Hz, 1H), 1.63 - 1.46 (m, 2H), 0.97 (t, J = 7.3 Hz, 4H). MS: 551[M+H] + .

[0216] Example 46: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-fluoro-5-((1-hydroxycyclobutyl)methoxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone [ka]

[0217] Step 1): 1-Hydroxycyclobutanecarboxylic acid (500 mg, 4.31 mmol) was dissolved in THF (10 mL). Under argon protection, lithium aluminum hydride (490.25 mg, 12.92 mmol) was added in portions at room temperature. The mixture was heated to 80°C and reacted for another 1 hour. In an ice bath, 0.5 mL of water, 1.5 mL of 20% aqueous NaOH, and 0.5 mL of water were added sequentially. The reaction mixture was quenched and filtered. The filtrate was collected and concentrated under reduced pressure to finally obtain 400 mg of crude 1-(hydroxymethyl)cyclobutanol. The yield was 91%.

[0218] Step 2): 1-(Hydroxymethyl)cyclobutanol (400 mg, 3.92 mmol), p-toluenesulfonyl chloride (1.12 g, 5.87 mmol), triethylamine (1.19 g, 11.75 mmol, 1.64 mL), and DMAP (47.85 mg, 391.65 μmol) were added to dichloromethane (20 mL). The mixture was reacted at 25 °C for 16 hours under argon protection. Saturated aqueous sodium carbonate solution was added to the reaction solution. The mixture was stirred for 30 minutes and then extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography to give 430 mg of (1-hydroxycyclobutyl)methyl 4-p-toluenesulfonate. The yield was 43%.

[0219] Step 3): (1-Hydroxycyclobutyl)methyl 4-p-toluenesulfonate (430 mg, 1.68 mmol), 3-bromo-4-fluorophenol (106.81 mg, 559.20 μmol), and potassium carbonate (231.86 mg, 1.68 mmol) were added to DMF (10 mL). The mixture was heated to 80 °C, stirred, and reacted under argon protection for 16 hours. Water was added to the reaction system, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to finally obtain 150 mg of 1-[(3-bromo-4-fluorophenoxy)methyl]cyclobutanol. The yield was 98%.

[0220] Step 4): 1-[(3-Bromo-4-fluoro-phenoxy)methyl]cyclobutanol (150 mg, 545.23 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (179.99 mg, 708.80 μmol), Pd(dppf)Cl (23.94 mg, 32.71 μmol), and potassium acetate (107.02 mg, 1.09 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was slowly heated to 100 °C and reacted under argon protection for 8 hours. The reaction solution was cooled to room temperature and suction filtered through diatomaceous earth. The filtrate was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography (eluent: PE:EA = 3:1) to finally obtain 1-[[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]cyclobutanol (150 mg, 486.77 μmol, yield: 89.28%).

[0221] Step 5: (1-(4-Bromopyridin-2-yl)piperidin-4-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (100 mg, 222.57 μmol), 1-[[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]cyclobutanol (107.56 mg, 333.86 μmol), potassium carbonate (61.52 mg, 445.15 μmol), and Pd(dppf)Cl (16.29 mg, 22.26 μmol) were dissolved in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL). The mixture was slowly heated to 100 °C and reacted under argon protection for 8 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and purified by column chromatography to give (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-fluoro-5-((1-hydroxycyclobutyl)methoxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone (40 mg, 32% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 5.1 Hz, 1H), 7.29 - 7.19 (m, 2H), 7.17 - 7.00 (m, 3H), 6.94 (s, 1H), 6.88 - 6.74 (m, 3H), 5.34 (dd, J = 12.0, 5.0 Hz, 1H), 5.25 (s, 1H), 4.40 (dd, J = 13.4, 3.7 Hz, 2H), 3.95 (s, 2H), 3.48 (dd, J = 19.1, 12.0 Hz, 1H), 3.40 - 3.35 (m, 1H), 3.01 - 2.87 (m, 2H), 2.74 (dd, J = 18.9, 4.9 Hz, 1H), 2.11 (t, J = 9.1 Hz, 2H), 2.00 (dt, J = 12.5, 9.5 Hz, 2H), 1.89 (d, J = 13.0 Hz, 1H), 1.75 (d, J = 12.9 Hz, 1H), 1.66 - 1.49 (m, 4H). MS: 565[M+H] + .

[0222] Example 47: (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl-5-deutero)(1-(4-(2-fluoro-5-(2-hydroxy-2-methylpropoxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone [ka]

[0223] Step 1): 3,5-Difluorobenzaldehyde (800 mg, 5.63 mmol) was added to THF (18 mL). NaBH4 (354 mg) was added to the solution in portions at 0 °C, and the mixture was reacted at 0 °C for 2 hours. The reaction solution was quenched with 0.5 mL of acetone and concentrated under reduced pressure. The residue was purified on a silica gel column to finally obtain 800 mg of dideuterated-(3,5-difluorophenyl)methanol. The yield was 97.24%.

[0224] Step 2): Dideuterated-(3,5-difluorophenyl)methanol (800 mg, 5.47 mmol) was placed in dichloromethane (54 mL), and MnO (2.38 g) was added to the solution. The mixture was reacted at 25 °C for 20 hours. The reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to finally obtain 600 mg of crude deuterated 3,5-difluorobenzaldehyde. The yield was 77%.

[0225] Step 3): Deuterated 3,5-difluorobenzaldehyde (143 mg, 999.24 μmol) and acetaldehyde (66.03 mg, 1.50 mmol) were added to water. 1N aqueous NaOH solution (1.1 mL) was added dropwise to the reaction solution at 0°C under argon. The mixture was reacted at 25°C for 16 hours. TLC confirmed the absence of starting material. Water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA=20:1) to finally obtain 60 mg of (E)-3-deuterated-3-(3,5-difluorophenyl)propen-2-enal. The yield was 36%.

[0226] Step 4): Hydrazine hydrate (17.05 mg, 532.08 μmol) was added to ethanol (2 mL), and acetic acid (36.21 mg, 603.03 μmol, 34.49 μL) was added with stirring. The mixture was heated to 40°C, and (E)-3-deutero-3-(3,5-difluorophenyl)propen-2-enal (60 mg, 354.72 μmol) was slowly added dropwise. The mixture was sealed and heated at 80°C and reacted overnight. The reaction solution was concentrated and purified on a silica gel plate (PE / EtOAc = 3:1) to give the product, 5-deutero-5-(3,5-difluorophenyl)-4,5-dihydropyrazole (20 mg). The yield was 31%.

[0227] Step 5): 1-[4-[2-Fluoro-5-(2-hydroxy-2-methyl-propoxy)phenyl]-2-pyridinyl]piperidinyl-4-carboxylic acid (178.13 mg, 458.58 μmol), 5-deuterated-5-(3,5-difluorophenyl)-4,5-dihydropyrazole (70 mg, 382.15 μmol), HATU (174.36 mg, 458.58 μmol), and DIEA (148.17 mg, 1.15 mmol, 199.68 μL) were added to DMF (5 mL). The mixture was reacted under argon protection at 25 °C for 16 hours. The reaction solution was diluted with dichloromethane and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The product was further purified by preparative HPLC to finally obtain 50 mg of (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl-5-deutero)(1-(4-(2-fluoro-5-(2-hydroxy-2-methylpropoxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone in a yield of 24%.

[0228] 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 5.1 Hz, 1H), 7.28 - 7.18 (m, 2H), 7.17 - 6.97 (m, 3H), 6.93 (s, 1H), 6.88 - 6.80 (m, 2H), 6.85 - 6.73 (m, 1H), 4.63 (s, 1H), 4.44 - 4.36 (m, 2H), 3.76 (s, 2H), 3.48 (dd, J = 19.1, 1.7 Hz, 1H), 3.37 (dt, J = 7.5, 3.6 Hz, 1H), 3.01 - 2.87 (m, 2H), 2.74 (dd, MS: 554[M+H] + .

[0229] Synthesis of 1-[4-[2-fluoro-5-(2-hydroxy-2-methyl-propoxy)phenyl]-2-pyridyl]piperidinyl-4-carboxylic acid

[0230] (I) Synthesis of 1-[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2-methyl-propan-2-ol [ka]

[0231] Step 1: 3-Bromo-4-fluoro-phenol (5 g, 26.18 mmol), 2,2-dimethyloxirane (5.66 g, 78.54 mmol), and potassium carbonate (10.85 g, 78.54 mmol) were added to DMF (50 mL). The mixture was reacted at 100 °C for 16 hours under argon protection. The reaction solution was diluted with dichloromethane and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to finally obtain 1-(3-bromo-4-fluoro-phenoxy)-2-methyl-propan-2-ol (5 g, 19.00 mmol, 72.6% yield).

[0232] Step 2: 1-(3-Bromo-4-fluoro-phenoxy)-2-methyl-propan-2-ol (30 g, 114.02 mmol), pinacol ester (34.75 g, 136.83 mmol), potassium acetate (22.38 g, 228.05 mmol), and Pd(dppf)Cl (4.17 g, 5.70 mmol) were added to 1,4-dioxane (300 mL). The mixture was reacted at 90 °C under argon protection for 16 hours. The reaction solution was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography to finally obtain 1-[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2-methyl-propan-2-ol (25 g, 80.60 mmol, 70.7% yield).

[0233] (II) Synthesis of methyl 1-(4-bromo-2-pyridyl)piperidinyl-4-carboxylate [ka]

[0234] 2-Fluoro-4-bromo-pyridine (3.52 g, 20 mmol) and methyl piperidinyl-4-carboxylate (2.86 g, 20.00 mmol) were dissolved in DMF (50 mL), and triethylamine (4.05 g, 40.00 mmol, 5.58 mL) was added. The mixture was heated to 80 °C for 3 hours. The reaction solution was cooled to room temperature, diluted with water, and extracted twice with ethyl acetate. The combined organic phases were washed three times with saturated brine, then dried and concentrated. The residue was purified by silica gel column chromatography to give the product, methyl 1-(4-bromo-2-pyridinyl)piperidinyl-4-carboxylate (5.1 g, 17.05 mmol, 85.2% yield).

[0235] (III) Synthesis of 1-[4-[2-fluoro-5-(2-hydroxy-2-methyl-propoxy)phenyl]-2-pyridinyl]piperidinyl-4-carboxylic acid [ka]

[0236] Step 1: 1-[4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2-methyl-propan-2-ol (372.20 mg, 1.2 mmol) and methyl 1-(4-bromo-2-pyridyl)piperidinyl-4-carboxylate (299.16 mg, 1.00 mmol) were dissolved in 1,4-dioxane (10 mL). Pd(dppf)Cl2 (878.04 mg, 1.20 mmol) was added and the atmosphere was replaced with nitrogen. The mixture was heated to 80 °C and reacted for 1 hour. The mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated to give the crude product. The crude product was purified on silica gel plates to give methyl 1-[4-[2-fluoro-5-(2-hydroxy-2-methyl-propoxy)phenyl]-2-pyridinyl]piperidinyl-4-carboxylate (400 mg, 993.89 μmol, 82.8% yield).

[0237] Step 2: Methyl 1-[4-[2-fluoro-5-(2-hydroxy-2-methyl-propoxy)phenyl]-2-pyridinyl]piperidinyl-4-carboxylate (400 mg, 993.89 μmol) was dissolved in MeOH (5 mL). LiOH.HO (83.41 mg, 1.99 mmol) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated, and water was added. The mixture was adjusted to pH 6 using hydrochloric acid. The precipitated solid was collected and dried to give the product 1-[4-[2-fluoro-5-(2-hydroxy-2-methyl-propoxy)phenyl]-2-pyridinyl]piperidinyl-4-carboxylic acid (350 mg, 901.06 μmol, 90.66% yield).

[0238] Reference example With reference to the disclosure of WO2018 / 092089, the following two compounds were synthesized as controls. [ka]

[0239] Assay Example 1. Western blot detection of compounds inhibiting RIPK1 phosphorylation in HT29 cells

[0240] In this assay, the effects of test compounds on intracellular RIPK1 and its phosphorylation during the induction of programmed necrosis in HT29 cells were detected using Western blotting, and the inhibitory effect of the compounds on RIPK1 phosphorylation was verified.

[0241] I. Main Assay Reagents / Equipment

[0242] [Table 7]

[0243] II. Assay Procedure

[0244] 1. Cell Harvesting and Protein Sample Extraction

[0245] a) Healthy HT29 cells were harvested, resuspended in McCoy's 5A complete medium, and counted. Cells were plated in 12-well plates at a cell density of 1 x 10 6 The cells were seeded at 1 mL / well and placed in a cell culture incubator at 37°C overnight.

[0246] b) Z-VAD-FMK (final concentration: 20 μM) was added to the 12-well plate. After 30 minutes, inducers (TNF-α at a final concentration of 20 ng / mL, AT-406 at a final concentration of 100 nM) and test compounds at different concentrations were added, and the plate was incubated at 37°C for 7 hours in a cell incubator.

[0247] c) Preparation of complete lysate: Thaw the RIPA lysate tube and add phosphatase inhibitor and Roche protease inhibitor (phosphatase inhibitor:RIPA = 1:100, Roche protease inhibitor:RIPA = 4:100). Place the mixture on ice for later use.

[0248] d) The cell culture medium supernatant was discarded, and the cells were washed twice with PBS. 100 μL of the prepared complete lysate was added to each well, and the cells were lysed on ice for 15 minutes with intermittent shaking during lysis.

[0249] e) After lysis was complete, the lysate was transferred to a pre-labeled 1.5 mL centrifuge tube and centrifuged at 14,000 rpm at 4°C for 20 minutes.

[0250] f) The supernatant was transferred to a labeled 600 μL centrifuge tube and placed on ice.

[0251] g) Detected using a BCA kit and calculated protein concentration.

[0252] 2. Test protein samples or pre-stained two-color protein molecular weight standards were added to each well of the precast gel. The protein loading was 40-50 μg / well.

[0253] 3. Electrophoresis was carried out at a constant voltage of 100 V. Electrophoresis was stopped when the stained two-color protein molecular weight standard band on the gel ran out from the bottom of the lane.

[0254] 4. After electrophoresis was completed, the gel holder was removed. The short glass plate was gently peeled off with a spatula, and the top layer of the stacking gel was discarded. The separating gel was slowly peeled off and placed in transfer buffer.

[0255] 5. The NC membrane was cut to an appropriate size to fit the gel. The membrane was immersed in pure water, then immersed in pre-cooled transfer buffer, and at the same time, filter paper was immersed in the same transfer buffer.

[0256] 6. The transfer cartridge was assembled in the following order: filter paper, NC membrane, gel, and filter paper, and then set into the Trans-Blot (registered trademark) Turbo. The transfer was completed by calling up the "Standard SD" program built into the device.

[0257] 7. The NC membrane with attached protein was gently washed with deionized water. Based on the marker band indication, the membrane was cut according to the molecular weight of the protein to be detected. The membrane was submerged in blocking solution and blocked for 1 hour at room temperature while gently shaking on a shaker.

[0258] 8. After blocking, the NC membrane was placed in an antibody incubation box, diluted primary antibody was added, and the box was incubated at room temperature for 1 hour with gentle shaking on a shaker.

[0259] 9. After the incubation was completed, the membrane was washed three times with TBST for 10 minutes each.

[0260] 10. The secondary antibody was selected according to the source of the primary antibody. The secondary antibody was diluted in secondary antibody diluent at a ratio of 1:10,000 to 1:15,000. The secondary antibody was added to an antibody incubation box, and the membrane was immersed in it. The box was incubated at room temperature for 1 hour with gentle shaking on a shaker.

[0261] 11. After the incubation, the membrane was washed three times with TBST for 10 minutes each.

[0262] 12. The membrane was washed once with pure water and scanned using an Odyssey CLX infrared fluorescence scanning imaging system to obtain images. The fluorescent signal values ​​of the bands were read using the system's grayscale reading function.

[0263] III. Typical Assay Results and Analysis

[0264] The ratio of target protein phosphorylation to target protein expression was calculated according to the fluorescence intensity value. Then, the normalized expression fold of target protein phosphorylation in the drug-treated group was calculated based on the control group. The calculation method was as follows: Normalized fold expression of target protein phosphorylation = A / B A: Fluorescence intensity value of phosphorylation of target protein in drug administration group / Fluorescence intensity value of target protein in drug administration group B: Fluorescence intensity value of phosphorylation of target protein in drug-untreated group / Fluorescence intensity value of target protein in drug-untreated group

[0265] The compound of Example 40 was tested using the above method. The results are shown in Figures 1 and 2. Figure 1 shows Western blot images of RIPK1 total protein and phosphorylated protein at different compound concentrations. Figure 2 shows the ratio of RIPK1 phosphorylation to total RIPK1 protein expression, obtained by quantitative calculation based on the fluorescence intensity values ​​of the bands in Figure 1. The assay results show that the compound of Example 40 directly inhibits the phosphorylation activity of RIPK1 and exhibits a dose-dependent relationship, but has no obvious inhibitory effect on RIPK1.

[0266] Assay Example 2: Assay method for cell necrosis inhibitor compounds (CCK8 method)

[0267] In Assay Example 2, under conditions that induce programmed cell necrosis in HT29 and L929 cell lines, different concentrations of a test compound are added to measure the IC of the test compound's rescue effect on programmed necrosis. 50 was tested.

[0268] I. Main Assay Reagents, Equipment, and Materials

[0269] [Table 8]

[0270] Compounds: Dissolved in DMSO to make 10 mM solutions.

[0271] TNF-α: initial concentration 100μg / mL

[0272] Z-VAD-FMK: Dissolved in DMSO to prepare a 10 mM solution.

[0273] AT-406: Dissolved in DMSO to prepare a 10 mM solution.

[0274] Cell lines: HT29 cells were cultured in McCoy's 5A medium containing 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin, and L929 cells were cultured in MEM medium containing 10% horse serum, 100 U / mL penicillin, and 100 μg / mL streptomycin.

[0275] II. Specific Assay Methods

[0276] 1. Test compounds were dissolved in DMSO to make stock solutions, and gradient dilutions were performed. The solutions were then diluted with the corresponding culture media to obtain solutions at 10 times the working concentration.

[0277] 2. Logarithmic growth phase cells were diluted with culture medium to a specific cell concentration. 80 μL of cell suspension was added to a 96-well plate, and the cell density of HT29 and L929 was 1.2*10 4 cells / well and 2.0*10 4 The plate was incubated overnight in a 5% carbon dioxide incubator at 37°C.

[0278] 3. 10 μL of compound solution was added to each well of the 96-well plate containing the cells. The test compounds were serially diluted 4-fold starting from a maximum concentration of 10 μM to obtain 9 concentrations in duplicate. A control group without compound was also prepared.

[0279] 4. After culturing the cells for an additional 30 minutes, 10 μL of the inducer mixture was added to each well. The final concentrations of human TNF-α, AT-406, and Z-VAD-FMK in HT29 cells were 20 ng / mL, 1 μM, and 20 μM, respectively. The final concentrations of mouse TNF-α and Z-VAD-FMK in L929 cells were 20 ng / mL and 25 μM, respectively.

[0280] 5. The 96-well plate containing the compound and inducer was further cultured in a 5% CO2 incubator at 37°C. HT29 cells were cultured for 16 hours, and L929 cells for 4-8 hours. Cell viability was detected by CCK8. Dose-effect curves were generated using GraphPad Prism software, and IC values ​​were calculated. 50 was calculated.

[0281] Table 5 shows the results of measuring the inhibition of necrosis in HT29 and L929 cells for several compounds of the present disclosure. In the table, A is the IC 50 is 10nM or less, B is IC 50 is greater than 10 nM and less than 50 nM, and C is IC 50 is greater than 50nM and less than 100nM, and D is IC 50 is greater than 100nM and less than or equal to 400nM, and E is IC 50 is greater than 400nM and less than or equal to 4000nM, and F is IC 50 indicates that the concentration is greater than 4000 nM.

[0282] The results shown in the table below show that the compounds of the present application exhibit excellent inhibitory activity against both human HT29 cells and mouse L929 cells, and although the inhibitory activity against human HT29 cells is higher than that against mouse L929 cells, the difference is small. However, the inhibitory activity against human HT29 cells of the compounds of Reference Examples 1 and 2 is significantly inferior to that of the compounds of the present application. In addition, the compounds of Reference Examples 1 and 2 have almost no inhibitory activity against mouse L929 cells, and no meaningful test results were obtained.

[0283] [Table 9]

[0284] Assay Example 3: Pharmacokinetic Assay of Small Molecule Compounds

[0285] In this assay, several compounds of the present invention were administered to SD rats, CD-1 mice, or beagle dogs by single oral and intravenous administration, and the pharmacokinetic properties and ability to cross the blood-brain barrier were examined.

[0286] (i) Reagents, equipment, and animals used

[0287] [Table 10]

[0288] [Table 11]

[0289] [Table 12]

[0290] (ii) Preparation of sample formulations

[0291] 1. Intravenous (IV) injection group: The appropriate amount of assay compound was weighed and completely dissolved in the appropriate volume of vehicle. The mixture was stirred, vortexed, and / or sonicated. Once a solution was obtained, the vehicle was gradually added to the final volume to achieve the target concentration. The solution was vortexed and sonicated to obtain a homogeneous solution. The solution was filtered through a 0.22 μm PVDF membrane.

[0292] 2. Oral (PO) group: The appropriate amount of assay compound was weighed and completely dissolved in the appropriate volume of vehicle. The mixture was stirred, vortexed, and / or sonicated. Once a solution was obtained, vehicle was gradually added to the final volume to achieve the target concentration. The solution was vortexed and sonicated to obtain a homogeneous solution.

[0293] [Table 13]

[0294] (iii) Administration and sample collection

[0295] The animals were randomly assigned to groups according to their body weight. After group assignment, the animals in each group had similar body weights (not exceeding ±20% of the mean body weight). The IV group was not fasted, while the PO group was fasted overnight (>12 hours) and fed 2 hours after drug administration. All animals had free access to water. The dosing schedule and pharmacokinetic sample collection schedule are shown in Tables 10 and 11, respectively.

[0296] [Table 14]

[0297] [Table 15]

[0298] [Table 16]

[0299] [Table 17]

[0300] [Table 18]

[0301] Rats were dosed according to the above protocol, and blood and brain tissue samples were collected and processed at predetermined time points (collection and processing was performed according to conventional methods in the art).

[0302] [Table 19]

[0303] Mice were dosed according to the above protocol, and blood and brain tissue samples were collected and processed at the designated time points (collection and processing was performed according to conventional methods in the art).

[0304] [Table 20]

[0305] [Table 21]

[0306] (v) Sample analysis

[0307] The brains were weighed and homogenized by adding 4 volumes of ultrapure water. Six volumes of acetonitrile were added to the whole blood samples and brain homogenates (20 volumes of acetonitrile were added to the whole blood samples of mouse PK), and the mixtures were vortexed for 1 minute and centrifuged at 4500 rpm for 15 minutes at 4°C. The supernatants were diluted with diluent according to the instrument response, and the samples were analyzed by LC / MS.

[0308] (vi) Data analysis

[0309] Pharmacokinetic parameters were calculated using WinNonlin software. When adequate plasma / whole blood drug concentration-time data were available, the following pharmacokinetic parameters were calculated: CL (clearance); V d (apparent volume of distribution); T 1 / 2 (elimination half-life); C max (peak concentration); T max (time to peak); AUC (area under the plasma drug concentration-time curve); MRT (mean retention time); F% (bioavailability)

[0310] The test results are shown in Tables 12 to 14 below. Each table shows the blood drug concentrations and various pharmacokinetic parameter values ​​of Example Compounds 18, 40, and 42 of the present application at various time points. In addition, the concentrations and ratios of Example Compounds 18, 40, and 42 of the present application in the brain and blood of rats or mice are also shown. The above results demonstrate that the compounds of Examples 18, 40, and 42 of the present application have excellent pharmacokinetic properties and exhibit the ability to cross the blood-brain barrier.

[0311] [Table 22]

[0312] [Table 23]

[0313] [Table 24]

[0314] [Table 25]

[0315] [Table 26]

[0316] [Table 27]

[0317] [Table 28]

[0318] The biological data provided by the present disclosure indicates that the compounds of the present disclosure are useful for treating or preventing diseases caused by abnormal RIPK1 kinase. Thus, the compounds of the present disclosure are useful for treating RIPK1-associated diseases, including ocular fundus diseases, xerophthalmia, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, arteriosclerosis, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic granulocytic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary tract carcinoma and sarcoma, bile duct cancer, inflammatory bowel disease, ulcerative colitis, retinal detachment, retinal pigment epithelium, and the like. These include retinal degeneration, macular degeneration, pancreatitis, atopic dermatitis, spondyloarthritis, gout, SoJIA, Sjögren's syndrome, systemic sclerosis, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, atopic dermatitis, multiple sclerosis, type 1 diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converting enzyme-associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, and periodontitis. The compounds of the present disclosure can be used as a monotherapy or in combination therapy, and can be used in combination with more than one compound of the present disclosure or in combination with other agents other than the compounds of the present disclosure.

[0319] The above description is merely an alternative embodiment of the present disclosure and is not intended to limit the present disclosure. Any modifications, equivalent replacements, and improvements made within the spirit and principle of the present disclosure should be included in the protection scope of the present disclosure.

Claims

1. Formula (I): 【Chemistry 1】 In formula (I), X is CH or N; L is O; R １ is C １ -C １０ Alkyl, C ３ -C ８ Cycloalkyl, 4- to 8-membered heteroalicyclyl, or C substituted with 1 to 3 substituents １ -C １０ alkyl, and the 1 to 3 substituents are hydroxyl, C １ -C ６ Alkoxy, cyano, -NR ａ R ｂ , C ３ -C ８ Cycloalkyloxy, -CONH-R ５ , C ３ -C ８ Cycloalkyl, hydroxyl-substituted and / or C １ -C ４ Alkyl-substituted C ３ -C ８ Cycloalkyl, carboxyl, halogen, C １ -C ６ Haloalkoxy, —SO ２ -R ５ , -SO-R ５ , -CO-R ５ , C ２ -C ６ Alkynyl, C ２ -C ６ Alkenyl, C １ -C ４ Alkoxy C １ -C ６ Alkoxy, 4- to 8-membered heteroalicyclyl, oxo-substituted 4- to 8-membered heteroalicyclyl, hydroxyl-substituted and / or C １ -C ４ Alkyl-substituted 4- to 8-membered heteroalicyclyl, and C １ -C ６ alkylthio; The 4- to 8-membered heteroalicyclyl is a 4- to 8-membered heteroalicyclyl containing 1 to 2 atoms selected from N, O, and S as ring atoms, R ５ is hydrogen, hydroxyl, C １ -C ６ Alkyl, C １ -C ６ Alkoxy C １ -C ６ Alkyl, hydroxyl substituted C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl, or 4- to 8-membered heteroalicyclyl-substituted C １ -C ６ is alkyl, R ａ and R ｂ are each independently hydrogen, C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl, C １ -C ６ Alkoxy-substituted C １ -C ６ Alkyl, hydroxyl substituted C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl C １ -C ６ Alkyl, 4-8 membered heteroalicyclyl substituted C １ -C ６ Alkyl, C １ -C ３ Alkylthio-substituted C １ -C ６ Alkyl, mono or di C １ -C ３ Alkyl-substituted or unsubstituted amino-substituted C １ -C ６ is alkyl; R ２ is hydrogen, C １ -C ３ Alkyl, C １ -C ３ alkoxy, or halogen; R ３ and R ４ are each independently hydrogen, halogen, or methyl. or a stereoisomer, pharmaceutically acceptable salt, or deuterated derivative thereof.

2. The following formula (II): 【Chemistry 2】 (In formula (II), R １ is C １ -C １０ Alkyl, C ３ -C ８ Cycloalkyl, 4- to 8-membered heteroalicyclyl, or C substituted with 1 to 3 substituents １ -C １０ alkyl, and the 1 to 3 substituents are hydroxyl, C １ -C ６ Alkoxy, cyano, -NR ａ R ｂ , C ３ -C ８ Cycloalkyloxy, -CONH-R ５ , C ３ -C ８ Cycloalkyl, hydroxyl-substituted and / or C １ -C ４ Alkyl-substituted C ３ -C ８ Cycloalkyl, carboxyl, halogen, C １ -C ６ Haloalkoxy, —SO ２ -R ５ , -SO-R ５ , -CO-R ５ , C ２ -C ６ Alkynyl, C ２ -C ６ Alkenyl, C １ -C ４ Alkoxy C １ -C ６ Alkoxy, 4- to 8-membered heteroalicyclyl, oxo-substituted 4- to 8-membered heteroalicyclyl, hydroxyl-substituted and / or C １ -C ４ Alkyl-substituted 4- to 8-membered heteroalicyclyl, and C １ -C ６ alkylthio; The 4- to 8-membered heteroalicyclyl is a 4- to 8-membered heteroalicyclyl containing 1 to 2 atoms selected from N, O, and S as ring atoms, R ５ is hydrogen, hydroxyl, C １ -C ６ Alkyl, C １ -C ６ Alkoxy C １ -C ６ Alkyl, hydroxyl substituted C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl, or 4- to 8-membered heteroalicyclyl-substituted C １ -C ６ is alkyl, R ａ and R ｂ are each independently hydrogen, C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl, C １ -C ６ Alkoxy-substituted C １ -C ６ Alkyl, hydroxyl substituted C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl C １ -C ６ Alkyl, 4-8 membered heteroalicyclyl substituted C １ -C ６ Alkyl, C １ -C ３ Alkylthio-substituted C １ -C ６ Alkyl, or mono- or di-C １ -C ３ Alkyl-substituted or unsubstituted amino-substituted C １ -C ６ is alkyl; R ２ is hydrogen, C １ -C ３ Alkyl, C １ -C ３ alkoxy, or halogen; R ３ and R ４ are each independently hydrogen, halogen, or methyl.

2. The compound of claim 1 having the structure: or a stereoisomer or pharmaceutically acceptable salt thereof.

3. The following formula (III): 【Transformation 3】 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.

4. The following formula (IV): 【Chemistry 4】 3. The compound of claim 2 having the structure: or a pharmaceutically acceptable salt thereof.

5. R １ is C １ -C ８ Alkyl, C ３ -C ６ Cycloalkyl, 4- to 6-membered heteroalicyclyl, or C substituted with 1 to 3 substituents １ -C ８ alkyl, and the 1 to 3 substituents are hydroxyl, C １ -C ３ Alkoxy, cyano, C ３ -C ６ Cycloalkyloxy, C ３ -C ６ Cycloalkyl, hydroxyl-substituted and / or C １ -C ４ Alkyl-substituted C ３ -C ６ Cycloalkyl, halogen, 4- to 6-membered heteroalicyclyl, oxo-substituted 4- to 6-membered heteroalicyclyl, hydroxyl-substituted and / or C １ -C ４ Alkyl-substituted 4- to 6-membered heteroalicyclyl, and C １ -C ３ alkylthio; The 4- to 6-membered heteroalicyclyl is a 4- to 6-membered heteroalicyclyl containing 1 to 2 atoms selected from N, O, and S as ring atoms.

5. The compound according to any one of claims 1 to 4, or a stereoisomer or a pharmaceutically acceptable salt thereof.

6. R １ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, octyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, or C substituted by 1 to 3 substituents; １ -C ８ alkyl, wherein the 1 to 3 substituents are selected from hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, cyano, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclobutyl, cyclopentyl, cyclohexyl, 4-hydroxylcyclohexyl, 4-hydroxyl-4-methylcyclohexyl, fluorine, chlorine, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, morpholinyl, thiomorpholinyl, 1-methyl-pyrrolidin-2-yl, 1-methyl-piperidin-4-yl, methylthio, ethylthio, propylthio, and isopropylthio; 6. The compound of claim 5, or a stereoisomer or pharmaceutically acceptable salt thereof.

7. R 1 is methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, tetrahydropyran-4-yl, 4-methyl-4-hydroxypentyl, tetrahydropyran-4-ylethyl, tetrahydropyran-4-ylmethyl, tetrahydropyran-4-ylpropyl, tetrahydropyran-4-ylbutyl, 3-methyl-3-hydroxylbutyl, 2-methyl-2-hydroxylpropyl, 5-methyl-5-hydroxyhexyl, fluoropropyl, fluoroethyl, or 2,2-difluoro-3-hydroxylpropyl.

6. The compound of claim 5, or a stereoisomer or pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, wherein R 1 is C 1 -C 8 alkyl substituted with 1-hydroxycyclopropyl, 1-hydroxycyclobutyl, 1-hydroxycyclopentyl, or 1-hydroxycyclohexyl.

6. The compound of claim 5, or a stereoisomer or pharmaceutically acceptable salt thereof.

9. R 1 is 1-hydroxycyclopropylmethyl or 1-hydroxycyclobutylmethyl, 6. The compound of claim 5, or a stereoisomer or pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, wherein R 1 is a hydroxyl-substituted and / or halogen-substituted C 1 -C 6 alkyl.

6. The compound of claim 5, or a stereoisomer or pharmaceutically acceptable salt thereof.

11. R 1 is hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, 2-methyl-2-hydroxypropyl, 3-methyl-3-hydroxybutyl, 4-methyl-4-hydroxypentyl, 5-methyl-5-hydroxyhexyl, fluoropropyl, fluoroethyl, or 2,2-difluoro-3-hydroxypropyl.

6. The compound of claim 5, or a stereoisomer or pharmaceutically acceptable salt thereof.

12. R ２ is hydrogen, methyl, methoxy, fluorine, chlorine, or bromine; 2. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof.

13. R 2 is fluorine.

2. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof.

14. R ３ and R ４ are each independently hydrogen, fluorine, chlorine, or methyl; 2. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof.

15. R 3 and R 4 are each independently fluorine.

2. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof.

16. The following structure: 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 2. The compound of claim 1 selected from: or a stereoisomer or pharmaceutically acceptable salt thereof.

17. A deuterated derivative of the compound of claim 2.

18. A deuterated derivative of the compound according to claim 17, wherein the 5-position of the pyrazolyl in structural formula (II) is deuterated.

19. 10. A pharmaceutical composition comprising a compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt, or deuterated derivative thereof, and one or more pharmaceutically acceptable carriers or excipients, Optionally, the pharmaceutical composition further comprises one or more other therapeutic agents.

20. A pharmaceutical composition for treating a RIPK1-associated disease, comprising the compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt, or deuterated derivative thereof.

21. The RIPK1-related diseases include ocular fundus diseases, xerophthalmia, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, arteriosclerosis, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic granulocytic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary tract carcinoma sarcoma, bile duct cancer, inflammatory bowel disease, ulcerative colitis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, spinal cord cancer, and the like.

21. The pharmaceutical composition of claim 20, comprising arthritis, gout, SoJIA, Sjogren's syndrome, systemic sclerosis, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, atopic dermatitis, multiple sclerosis, type 1 diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme-associated febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, and periodontitis.

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