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, pharma- ceutical acceptable salts, 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] In the early days, cell death was thought to occur mainly in two ways: cell apoptosis and cell necrosis. Cell apoptosis is an autonomous and orderly death of cells that is controlled by genes to maintain the stability of the internal environment. Cell apoptosis plays an important role in the evolution of organisms, the stability of the internal environment, and the development of systems. Cell necrosis is a pathological process in which cells undergo cell death under the influence of physical, chemical, and other environmental factors, such as mechanical damage, toxins, microorganisms, and radiation. In 2005, Degterev A et al. were the first to discover and report an orderly cell necrosis process controlled by a series of biochemical molecules, which they named necroptosis (also called programmed necrosis). This process is a type of programmed cell necrosis that occurs by stimulating cell death receptors by TNF-α, FasL, or TRAIL, etc. Morphologically, it appears as cell swelling, increased cell volume, dysfunction of cell organelles, damage to the integrity of the cell membrane, release of cellular contents, and massive production of 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 resulting in 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 have the same N-terminal kinase domain, but different binding domains. Studies have shown that receptor-interacting protein 1 can control the process of cell apoptosis. The death domain of RIPK-1 binds to cell death receptors, such as TNFR1, Fas, TRAILR1, and TRAILR2. Cell death receptors can also bind to other proteins that contain 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 a large number of cell apoptosis. This indicates that RIPK-1 is also involved in regulating cell apoptosis. Moreover, 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, studies have also found 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. Activating TNFR1 can induce the ubiquitination of RIPK-1 via cIAP1 and cIAP2, and the ubiquitinated RIPK-1 determines the next step of the cell: survival or death. When the apoptosis pathway is inhibited by the pan-caspase inhibitor z-VAD-fmk, cell death proceeds to necroptosis. In this process, the activity of RIPK-1 is a key factor, which is controlled 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, inflammatory diseases, etc. This indicates that RIP family kinases are closely related to the development of diseases such as tumors, autoimmune diseases, neurodegenerative diseases, and inflammatory diseases.

[0006] For example, in a study on Alzheimer's disease, Claudia Balducci et al. found 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 the learning and memory abilities of rats. RIPK-1 inhibitors are expected to be applied 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 not many studies on RIPK-1 inhibitors, and only a few are in the clinical stage. Research and development of further drugs based on RIPK-1 inhibitors is urgently needed. Meanwhile, there are even fewer studies on RIPK-1 inhibitors that can cross the blood-brain barrier. In the above-mentioned Alzheimer's disease and many other neurodegenerative diseases, the ability of drugs to cross the blood-brain barrier is crucial for therapeutic efficacy.

[0008] Moreover, in modern drug development, preclinical animal testing is a very important part, and rats or mice are usually used for testing in the early stages of research. From the perspective of translational medicine, animal models and their results should be compatible with and applicable to the pathophysiology and treatment of the corresponding human disease. Therefore, it is desirable that the compounds developed have small species differences in biological activity between humans and mice. GSK has disclosed a number of compounds with specific RIPK-1 inhibitory activity in patent application WO018 / 092089, but these compounds have low inhibitory activity against mouse cells and are not suitable for drug development through animal testing.

[0009] The present application provides a class of carbonyl-bridged heterocyclic compounds that exhibit good RIPK-1 inhibitory activity and blood-brain barrier crossing ability. It is worth emphasizing that this class of compounds has extremely strong inhibitory activity not only against human RIPK-1 but also against mouse RIPK-1. In other words, the compounds of the present application show a certain degree of similarity and adaptability when the results of animal experiments are used to extrapolate to human diseases, which is useful for drug discovery through animal experiments. The compounds of the present application are expected to be used as RIPK-1 inhibitors in the manufacture of medicines 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 pharma- ceutically 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] R 1 is C 1 -C 10 Alkyl, C 3 -C 8 Cycloalkyl, 4-8 membered heteroalicyclyl, or C substituted with 1-3 substituents 1 -C 10 alkyl, the 1 to 3 substituents being 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, 4-8 membered heteroalicyclyl, oxo-substituted 4-8 membered heteroalicyclyl, hydroxyl-substituted and / or C 1 -C 4 Alkyl-substituted 4-8 membered heteroalicyclyl, and C 1 -C 6 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] 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 4-8 membered heteroalicyclyl substituted C 1 -C 6 is alkyl,

[0017] 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- or unsubstituted amino-substituted C 1 -C 6 is alkyl;

[0018] R 2 is hydrogen, C 1 -C 3Alkyl, C 1 -C 3 alkoxy, or halogen;

[0019] R 3 and R 4 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] R 1 is C 1 -C 10 Alkyl, C 3 -C 8 Cycloalkyl, 4-8 membered heteroalicyclyl, or C substituted with 1-3 substituents 1 -C 10 alkyl, the 1 to 3 substituents being 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, C1 -C 4 Alkoxy C 1 -C 6 Alkoxy, 4-8 membered heteroalicyclyl, oxo-substituted 4-8 membered heteroalicyclyl, hydroxyl-substituted and / or C 1 -C 4 Alkyl-substituted 4-8 membered heteroalicyclyl, and C 1 -C 6 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] 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 4-8 membered heteroalicyclyl substituted C 1 -C 6 is alkyl,

[0025] 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, C1 -C 3 Alkylthio-substituted C 1 -C 6 Alkyl, mono or di C 1 -C 3 Alkyl- or unsubstituted amino-substituted C 1 -C 6 is alkyl;

[0026] R 2 is hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 alkoxy, or halogen;

[0027] R 3 and R 4 are each independently hydrogen, halogen, or methyl.

[0028] In some embodiments, R 1 is C 1 -C 8 Alkyl, C 3 -C 6 Cycloalkyl, 4-6 membered heteroalicyclyl, or C substituted with 1-3 substituents 1 -C 8 alkyl, the 1 to 3 substituents being 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, 4-6 membered heteroalicyclyl, oxo-substituted 4-6 membered heteroalicyclyl, hydroxyl-substituted and / or C 1 -C 4 Alkyl-substituted 4- to 6-membered heteroalicyclyl, and C 1 -C 3 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, 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 with 1 to 3 substituents. 1 -C 8 and alkyl, the one to three substituents being 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.

[0031] In some embodiments, R 1is 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-hydroxylhexyl, fluoropropyl, fluoroethyl, 2,2-difluoro-3-hydroxylpropyl.

[0032] In some embodiments, R 1 is C substituted with 1-hydroxycyclopropyl, 1-hydroxycyclobutyl, 1-hydroxycyclopentyl, or 1-hydroxycyclohexyl. 1 -C 8 It is an alkyl.

[0033] Alternatively, R 1 is 1-hydroxycyclopropylmethyl or 1-hydroxycyclobutylmethyl.

[0034] In some embodiments, R 1 is hydroxyl- and / or halogen-substituted C 1 -C 6 alkyl, and even more alternatively, 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.

[0035] In some embodiments, R 2is hydrogen, methyl, methoxy, fluorine, chlorine, or bromine.

[0036] Alternatively, R 2 is fluorine.

[0037] In some embodiments, R 3 and R 4 are each independently hydrogen, fluorine, chlorine, or methyl.

[0038] Alternatively, R 3 and R 4 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] R 1 is C 1 -C 10 Alkyl, C 3 -C 8 Cycloalkyl, 4-8 membered heteroalicyclyl, or C substituted with 1-3 substituents 1 -C 10 alkyl, the 1 to 3 substituents being 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 -C4 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, 4-8 membered heteroalicyclyl, oxo-substituted 4-8 membered heteroalicyclyl, hydroxyl-substituted and / or C 1 -C 4 Alkyl-substituted 4-8 membered heteroalicyclyl, and C 1 -C 6 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] 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 4-8 membered heteroalicyclyl substituted C 1 -C 6 is alkyl,

[0045] R a and R b are each independently hydrogen, C 1 -C 6 Alkyl, C 3 -C8 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- or unsubstituted amino-substituted C 1 -C 6 is alkyl;

[0046] R 2 is hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 alkoxy, or halogen;

[0047] R 3 and R 4 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, R 1 is C 1 -C 10 Alkyl, C 3 -C 8 Cycloalkyl, 4-8 membered heteroalicyclyl, or C substituted with 1-3 substituents 1 -C 10alkyl, the 1 to 3 substituents being 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, 4-8 membered heteroalicyclyl, oxo-substituted 4-8 membered heteroalicyclyl, hydroxyl-substituted and / or C 1 -C 4 Alkyl-substituted 4-8 membered heteroalicyclyl, and C 1 -C 6 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] 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, C3 -C 8 Cycloalkyl or 4-8 membered heteroalicyclyl substituted C 1 -C 6 is alkyl,

[0052] 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- or unsubstituted amino-substituted C 1 -C 6 is alkyl;

[0053] R 2 is hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 alkoxy, or halogen;

[0054] R 3 and R 4 are each independently hydrogen, halogen, or methyl.

[0055] In some embodiments, R 1 is C 1 -C 8 Alkyl, C 3 -C6 Cycloalkyl, 4-6 membered heteroalicyclyl, or C substituted with 1-3 substituents 1 -C 8 alkyl, the 1 to 3 substituents being 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, 4-6 membered heteroalicyclyl, oxo-substituted 4-6 membered heteroalicyclyl, hydroxyl-substituted and / or C 1 -C 4 Alkyl-substituted 4- to 6-membered heteroalicyclyl, and C 1 -C 3 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, 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 with 1 to 3 substituents. 1 -C 8and alkyl, the one to three substituents being 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.

[0058] In some embodiments, 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-hydroxylhexyl, fluoropropyl, fluoroethyl, or 2,2-difluoro-3-hydroxylpropyl.

[0059] In some embodiments, R 1 is C substituted with 1-hydroxycyclopropyl, 1-hydroxycyclobutyl, 1-hydroxycyclopentyl, or 1-hydroxycyclohexyl. 1 -C 8 It is an alkyl.

[0060] Alternatively, R 1is 1-hydroxycyclopropylmethyl or 1-hydroxycyclobutylmethyl.

[0061] In some embodiments, R 1 is hydroxyl- and / or halogen-substituted C 1 -C 6 alkyl, and even more alternatively, 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.

[0062] In some embodiments, R 2 is hydrogen, methyl, methoxy, fluorine, chlorine, or bromine.

[0063] Alternatively, R 2 is fluorine.

[0064] In some embodiments, R 3 and R 4 are each independently hydrogen, fluorine, chlorine, or methyl.

[0065] Alternatively, R 3 and R 4 are each independently fluorine.

[0066] In some embodiments, the compounds of the present application are deuterated compounds of the above-mentioned compounds, or alternatively, compounds in which the 5-position of the pyrazolyl in any one of the above-mentioned 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 pharma- ceutically 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 the use of the compound, or a pharma- ceutically 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 fundus disease, xerophthalmia, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, arteriosclerosis, pulmonary fibrosis, hepatic 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 provides pharmaceutical compositions containing an amide-bridged heterocyclic compound of the present disclosure, or a stereoisomer, solvate, pharma- ceutically acceptable salt, or deuterated derivative thereof, and one or more pharma- ceutically 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 disease or disorder mediated by RIPK1 kinase, 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 disease or disorder mediated by RIPK1 kinase includes those described above. [Brief description of the drawings]

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

[0074] [Diagram 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 PREFERRED EMBODIMENTS

[0075] Unless otherwise stated, the following terms used in this application (including the specification and claims) are defined as follows: In this application, the use of "or" or "and" means "and / or" unless otherwise stated. Furthermore, the use of the term "comprising" as well as other forms such as "including," "containing," and "having" are 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 group refers to saturated straight-chain and branched hydrocarbon groups having the specified number of carbon atoms, C 1 -C 10 The term alkyl refers to an alkyl moiety containing 1 to 10 carbon atoms. 1 -C 3 Alkyl refers to an alkyl moiety containing 1 to 3 carbon atoms. For example, C 1 -C 6Alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl.

[0077] "C 1 -C 3 Alkoxy C 1 -C 6 Alkylthio" or "hydroxy-substituted C 1 -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 include a divalent moiety whose point of attachment is through the linking substituent. 1 -C 3 Alkoxy C 1 -C 6 Examples of "alkylthio" include, but are not limited to, methoxymethylthio, methoxyethylthio, and ethoxypropylthio. 1 -C 10 Examples of "alkyl" include, but are not limited to, hydroxymethyl, hydroxyethyl, and hydroxyisopropyl.

[0078] Alkoxy groups are alkyl-O- groups formed by a linear or branched alkyl group as described above and -O-, such as methoxy, ethoxy, etc. Similarly, alkylthio groups are alkyl-S- groups formed by a linear or branched alkyl group as described above and -S-, such as methylthio, ethylthio, etc.

[0079] Alkenyl and alkynyl groups include linear or branched alkenyl or alkynyl groups, 2 -C 6 Alkenyl or C 2 -C 6The term alkynyl refers to a straight-chain or branched hydrocarbon group containing at least one alkenyl or alkynyl group.

[0080] "C 1 -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. 1 -C 10 An example of a "haloalkyl" is -CF 3 (trifluoromethyl), -CCl 3 (trichloromethyl), 1,1-difluoroethyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl. 1 -C 10 The term "haloalkoxy" refers to the C 1 -C 10 It refers to a haloalkyl-O- group formed by haloalkyl and -O- and can be, for example, trifluoromethoxy, trichloromethoxy, and the like.

[0081] "C 1 -C 3 The term "acyl" includes formyl (-CHO), acetyl (CH 3 CO-), and acetyl (C 2 H 5 CO-).

[0082] "-CO-R 5 , -SO 2 -R 5 , -SO-R 5 , -CONH-R 5 The terms " and " [ka] " represents.

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

[0084] The term "aryl" refers to a group or moiety that includes 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 indicated, the term "heteroalicyclyl" as used herein refers to an unsubstituted or substituted, stable, 4-8 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] The term "heteroaryl" as used herein refers to a group or moiety containing an aromatic monocyclic or bicyclic radical (containing 5-10 ring atoms) containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term also includes bicyclic heterocyclic aryls containing an aryl ring moiety fused to a heterocycloalkyl ring moiety or a heteroaryl ring moiety fused to a cycloalkyl ring moiety. Unless otherwise indicated, 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 1-3 heteroatoms selected from N, O, and S (wherein the N and S heteroatoms may be oxidized and the N heteroatom may be further quaternized) and carbon atoms. The heteroaryl group may be attached to any heteroatom or carbon atom to form 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 attached directly 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" 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 pharma- ceutically acceptable salt, may exist in solvated or nonsolvated form.For example, the solvated form may be a water-soluble form.The present disclosure includes all solvated and nonsolvated forms.

[0090] The compounds of the present disclosure may have asymmetric carbons. Depending on the physical and chemical differences, the diastereomeric mixture can be separated into single diastereomers by technically mature and known methods such as chromatography and fractional crystallization. Separation of enantiomers can be carried out by first converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable 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 as 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 with 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 pharma- ceutically acceptable salts or other derivatives. As used herein, the term "pharma-ceutically 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, perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, etc. Alternatively, salts can be obtained by methods well known in the art, such as ion exchange. Other pharma- ceutically 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 the salts of sodium, lithium, potassium, calcium, magnesium, etc. Other pharma-ceutically acceptable salts include suitable non-toxic salts of ammonium, quaternary ammonium, and amine cations formed from the halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0093] The pharmaceutical compositions of the present disclosure contain a compound of formula (I) as described herein, or a pharma- ceutical acceptable salt thereof; an additional active agent selected from a kinase inhibitor (such as a small molecule, polypeptide, antibody, etc.), 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 pharma- ceutical 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 may be formulated for simultaneous administration or sequential administration at different times, or may be administered as a single composition. "Combination therapy" refers to the use of a compound of the present disclosure with another drug, in a manner in which each drug is administered simultaneously or sequentially, in either case with the goal of achieving the optimal effect of the drug. Simultaneous administration includes separate dosage forms for each compound, as well as dosage forms for simultaneous delivery. Thus, administration of the compounds of the present disclosure may be combined with other therapies known in the art, such as radiation therapy, cytostatic agents, cytotoxic agents, and other anti-cancer agents, such as those used in the treatment of cancer, to improve the symptoms of cancer. The order of administration is not limited in the present disclosure. The compounds of the present disclosure may be administered before, simultaneously, 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 is carried out according to conventional pharmaceutical preparation techniques.Carriers can be used in a wide variety of forms, depending on the formulations designed for various modes of administration (e.g., oral 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 Handbook of Pharmaceutical Excipients, jointly published by the American Pharmaceutical Association and the British Pharmaceutical Society.

[0096] The pharmaceutical composition 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 clear solutions, suspensions, emulsions; or in a form for topical application, such as ointments, creams; or in a form as a suppository for rectal administration. The pharmaceutical composition may also be provided in a unit dosage form for single administration with 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 further include other medicinal or pharmaceutical preparations, carriers, adjuvants, etc.

[0097] The therapeutic compound can also be administered to mammals other than humans. The dosage of the drug to the mammal depends on the species of the animal and its disease state or disorder state. The therapeutic compound can be administered to the animal in the form of a capsule, bolus, tablet, or liquid. The therapeutic compound can also be introduced into the animal by injection or infusion. These drug forms are prepared in traditional ways according to standard veterinary practice. Alternatively, the pharmaceutical compound can be mixed with the animal's feed and fed to the animal, so that a concentrated feed additive or premix can be prepared by mixing with the 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 pharma- ceutical acceptable derivative thereof, in the manufacture of a medicament for treating a RIPK1-associated disease, including but not limited to ocular diseases, xerophthalmia, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, arteriosclerosis, pulmonary fibrosis, hepatic 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, cholangiocarcinoma, inflammatory bowel disease, These include ulcerative colitis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, spondyloarthritis, gout, SoJIA, Sjogren'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, Behcet's disease, interleukin-1 converting enzyme-associated febrile 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. To prepare the compounds described herein, various synthetic methods can be used, including the following methods involved in the Examples. The compounds of the present disclosure, or their pharma-ceutically 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 are understood by those skilled in the art. Alternative methods include, but are not limited to, the following methods.

[0101] In the following, the present disclosure will be described in more detail with specific examples to make the objectives, technical solutions and advantages of the present disclosure clearer. It should be understood that the specific examples described herein are only used to illustrate the present disclosure and are not intended to limit the present disclosure. If no specific techniques or conditions are shown in the examples, the techniques or conditions described in the literature or product specifications in the art shall be followed. If no manufacturer is shown for the reagents or equipment used, 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. Hereinafter, the 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℃)

[0107] EA Ethyl acetate

[0108] Synthesis of compounds 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 number 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, 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 obtain 25.1 g of 3-(3,5-difluorophenyl)propenal. The yield was 71%. MS:169[M+H] + ;

[0111] Process 2):N 2 H 4 .H 2 O (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 the product 20 g. 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 h. Water was added to the reaction solution, and the mixture was extracted with EA three times. 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 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)Cl 2 (235 mg, 321 μmol) was 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 mobile phase) to obtain 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 by the same method.

[0118] [Table 2] [Table 3] [Table 4] EXAMPLES

[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. for 1 h under argon protection. 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 obtained 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 completed, the mixture was suction filtered. The solid was dissolved in methanol, and then solid sodium carbonate was added. The mixture was adjusted to pH 8 and 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): (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) were 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(PPh 3 ) 4(58 mg, 0.05 mmol) was dissolved in a mixed solvent of 1,4-dioxane (8 mL) and water (0.8 mL). The mixture was heated to 80° C. under argon protection and reacted with stirring for 5 h. 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. 1 H NMR (400 MHz, DMSO-d 6 ) 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] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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 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] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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, J = 19.0, 5.0 Hz, 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))oxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0133] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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 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] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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, 3H), 2.06 - 1.95 (m, 1H), 1.88 (d, J = 12.9 Hz, 1H), 1.75 - 1.65 (mp, 3H), 1.63 - 1.43 (m, 3H). 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))pyridin-2-yl)piperidin-4-yl)methanone

[0141] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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-methyl)-5-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0143] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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 = 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] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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 = 19.0, 5.0 Hz, 1H), 2.0 - 1.97 (m, 2H), 1.88 - 1.85 (m, 3H), 1.74 (d, J = 13.0 Hz, 1H), 1.61 - 1.43 (m, 2H). 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))piperidin-4-yl)methanone

[0157] The preparation was carried out in the same manner as in Example 1. However, in step 4, the reaction was carried out using intermediate B-12 instead of intermediate B-2. 1 H NMR (400 MHz, DMSO-d 6) 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] The preparation was carried out in the same manner as in Example 1. However, 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. 1 H NMR (400 MHz, DMSO-d 6) 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] The preparation was carried out in the same manner as in Example 1. However, 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. 1 H NMR (400 MHz, DMSO-d 6) 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)pyridin)-2-yl)piperidin-4-yl)methanone

[0163] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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))piperidin-4-yl)methanone

[0165] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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 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)pyridin)-2-yl)piperidin-4-yl)methanone

[0167] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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, 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))phenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0169] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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 = 19.0, 5.0 Hz, 1H), 1.94 - 1.85 (m, 1H), 1.82 - 1.69 (m, 3H), 1.64 - 1.44 (m, 4H), 1.10 (s, 6H). 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] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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, 5.0 Hz, 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))phenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0173] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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, 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))piperidin-4-yl)methanone

[0175] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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 = 6.2Hz, 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] The preparation was carried out in the same manner as in Example 1. However, 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. 1 H NMR (400 MHz, DMSO-d 6) 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] The preparation was carried out in the same manner as in Example 1. However, 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. 1 H NMR (400 MHz, DMSO-d 6) 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] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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 = 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] The preparation was carried out in the same manner as in Example 1. However, 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. 1 H NMR (400 MHz, DMSO-d 6) 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] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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, 2H), 2.74 (dd, J = 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))methoxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone

[0187] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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 = 11.2 Hz, 2H), 2.74 (ddd, J = 18.9, 5.0, 1.8 Hz, 1H), 2.15 (s, 3H), 1.88 (d, J = 13.1 Hz, 1H), 1.78 - 1.46 (m, 7H). 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] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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)pyridin)-2-yl)piperidin-4-yl)methanone

[0193] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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, 1.8 Hz, 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)-2-yl)piperidin-4-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone

[0195] The preparation was carried out 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. 1 H NMR (400 MHz, DMSO-d 6) 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, 5.0Hz, 1H), 1.90 (d, J = 12.7 Hz, 1H), 1.76 (d, J = 12.9 Hz, 1H), 1.64 - 1.44 (m, 2H). 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))piperidin-4-yl)methanone [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[PPh 3 ] 4(776 mg, 0.671 mmol) was added to a mixed solvent 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 obtain 1.48 g of 3-(3-(2-chloropyrimidin-4-yl)-4-fluorophenoxy)propyl-1-ol. The yield was 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 dissolved in MeOH (10 mL) and H 2 2 mL of 1-(4-(2-fluoro-5-(3-hydroxypropoxy)phenyl)pyrimidin-2-yl)piperidine-4-carboxylic acid was added to 1H2O (2 mL). The mixture was stirred and reacted at room temperature for 3 hours. The mixture was adjusted to pH 3 at 0° C. using hydrochloric acid (2N concentration). 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 at 25° C. for 2 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. The obtained product was further purified by column chromatography to finally obtain 78 mg of product. The yield was 29%. 1 H NMR (400 MHz, DMSO-d 6 ) 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, 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)pyrimidin)-2-yl)piperidin-4-yl)methanone [ka]

[0202] It was prepared in the same manner as in Example 38, except that in step 1, intermediate B-12 was replaced with intermediate B-13. 1 H NMR (400 MHz, DMSO-d 6 ) 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 = 12.5, 8.5 Hz, 2H), 2.75 (dd, J = 19.1, 5.0 Hz, 1H), 1.97 - 1.75 (m, 4H), 1.51 (dd, J = 17.4, 12.0 Hz, 2H), 1.16 (s, 6H). 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 performed 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): 2-bromoacetate methyl (14.42g, 94.24mmol), 3-bromo-4-fluorophenol (6g, 31.41mmol), and potassium carbonate (13.03g, 94.24mmol) were added to DMF (30mL). 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 2-(3-bromo-4-fluoro-phenoxy)methyl acetate 6g. The yield was 73%.

[0208] Step 2): 2-(3-bromo-4-fluoro-phenoxy)methyl 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 stopped 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 2 (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 obtain 800 mg of 3-[[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]pentan-3-ol. The yield was 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 2(16.29 mg, 22.26 μmol) was dissolved in a mixed solvent 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-d 6 ) 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): 2-(3-bromo-4-fluoro-phenoxy)methyl acetate (500 mg, 1.80 mmol) was dissolved in THF (8 mL). Ethyl magnesium bromide (2M 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 for another 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 1-[(3-bromo-4-fluoro-phenoxy)methyl]cyclopropanol 180 mg. 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 2 (88.99 mg, 121.63 μmol) was placed in 1,4-dioxane (10 mL). The mixture was reacted at 100° C. for 3 hours under argon protection. 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 2 (13.03 mg, 17.81 μmol) was dissolved in a mixed solvent 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%. 1 H NMR (400 MHz, DMSO-d 6) 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, 5.0 Hz, 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 h. In an ice bath, 0.5 ml of water, 1.5 mL of 20% aqueous NaOH, and 0.5 mL of water were added in sequence. 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 placed in dichloromethane (20 mL). The mixture was reacted at 25 °C under argon protection for 16 h. Saturated aqueous sodium carbonate solution was added to the reaction solution. The mixture was stirred for 30 min 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 obtain 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-fluoro-phenol (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. and stirred under argon protection for 16 h. Water was added to the reaction system and the mixture was extracted with ethyl acetate three times. 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 1-[(3-bromo-4-fluoro-phenoxy)methyl]cyclobutanol 150 mg. 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 2(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 h. 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 2 (16.29 mg, 22.26 μmol) was dissolved in a mixed solvent 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). 1 H NMR (400 MHz, DMSO-d 6) 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 placed in THF (18 mL). The solution was diluted with NaBH 4 (354 mg) was added 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 by 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 the solution was diluted with MnO 2 (2.38 g) was added. 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 NaOH aqueous 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 raw materials. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate three times. The organic phase was washed with saturated salt water, 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)prop-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 while stirring. The mixture was heated to 40° C., and (E)-3-deutero-3-(3,5-difluorophenyl)prop-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-deutero-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 placed in DMF (5 mL). The mixture was reacted at 25° C. under argon protection 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 give 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. The yield was 24%.

[0228] 1 H NMR (400 MHz, DMSO-d 6 ) 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, J = 19.0, 1.8 Hz, 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 under argon protection 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 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 2 (4.17g, 5.70mmol) was placed in 1,4-dioxane (300mL). 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 (25g, 80.60mmol, yield 70.7%).

[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 h. The reaction solution was cooled to room temperature, diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed three times with saturated brine, and then dried and concentrated. The residue was purified by silica gel column chromatography to give the product 1-(4-bromo-2-pyridinyl)piperidinyl-4-carboxylate methyl (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 1-(4-bromo-2-pyridyl)piperidinyl-4-methyl carboxylate (299.16 mg, 1.00 mmol) were dissolved in 1,4-dioxane (10 mL). Pd(dppf)Cl 2(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 system was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated to obtain a crude product. The crude product was purified on a silica gel plate to obtain 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.H 2 O (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, yield 90.66%).

[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 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 × 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 (final concentration of TNF-α was 20 ng / mL, final concentration of AT-406 was 100 nM) and test compounds at different concentrations were added and incubated in a cell incubator at 37° C. for 7 hours.

[0247] c) Preparation of complete lysate: RIPA lysate was thawed and phosphatase inhibitor and Roche protease inhibitor were added (phosphatase inhibitor:RIPA=1:100, Roche protease inhibitor:RIPA=4:100). The mixture was placed 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 for 15 min on ice 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. Protein loading was 40-50ug / well.

[0253] 3. Electrophoresis was performed at a constant voltage of 100 V. Electrophoresis was stopped when the stained two-color protein molecular weight standard bands 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 peeling spatula, and the top layer of the stacking gel was discarded. The separating gel was slowly peeled off and placed in the transfer buffer.

[0255] 5. The NC membrane was cut to an appropriate size to fit the size of the gel. The membrane was soaked in pure water, then immersed in pre-cooled transfer buffer, and at the same time, a filter paper was soaked 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 the attached protein was lightly washed with deionized water. Based on the indication of the marker band, the membrane was cut according to the molecular weight of the protein to be detected. The membrane was submerged by adding blocking solution, and the membrane was blocked for 1 hour at room temperature while shaking slowly on a shaker.

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

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

[0260] 10. The secondary antibody was selected according to the primary antibody source. The secondary antibody was diluted with secondary antibody diluent at a ratio of 1:10000 to 1:15000. 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 was completed, the membrane was washed three times with TBST for 10 min each.

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

[0263] III. Typical Assay Results and Analysis

[0264] According to the fluorescence intensity value, the ratio of the phosphorylation of the target protein to the expression of the target protein was calculated.Then, the normalized expression fold of the phosphorylation of the target protein in the drug administration group was calculated based on the control group.The calculation method is as follows: Normalized expression fold of phosphorylation of target protein = 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 by the above method. The results are shown in Figure 1 and Figure 2. Figure 1 is a Western blot image of RIPK1 total protein and phosphorylated protein at different compound concentrations. Figure 2 is the ratio of RIPK1 phosphorylation to RIPK1 total protein expression obtained by quantitative calculation based on the fluorescence intensity value of the band in Figure 1. The assay results show that the compound of Example 40 directly inhibits the phosphorylation activity of RIPK1 and shows 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 inducing programmed cell necrosis in HT29 and L929 cell lines, different concentrations of a test compound were added to measure the IC of the rescue effect of the test compound against programmed necrosis. 50 was tested.

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

[0269] [Table 8]

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

[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 medium 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 to obtain a cell density of 1.2*10 for HT29 and L929, respectively. 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 inoculated with cells. The compounds to be tested were serially diluted 4-fold starting from a maximum concentration of 10 μM to obtain 9 concentrations in duplicate. At the same time, a control group without compound was also prepared.

[0279] 4. After the cells were incubated for another 30 min, 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, and 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 compounds and inducers was further cultured in a 5% carbon dioxide 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 50 was calculated.

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

[0282] From the results shown in the table below, the compounds of the present application show very good 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, the pharmacokinetic properties and ability to cross the blood-brain barrier of some of the compounds were examined after single oral and intravenous administration to SD rats, CD-1 mice, or beagle dogs.

[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, vehicle was gradually added to the final volume to achieve the target concentration. The solution was vortexed and sonicated to obtain a homogenous solution. The solution was filtered through a 0.22 μm PVDF membrane.

[0292] 2. Oral (PO) group: An appropriate amount of assay compound was weighed and completely dissolved in an 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 homogenous solution.

[0293] [Table 13]

[0294] (iii) Administration and sample collection

[0295] The animals were randomly assigned to groups according to body weight. After group assignment, the animals in each group had similar body weights (not exceeding ±20% of the mean body weight). In addition, the IV group was not fasted, and 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 below, 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 taken and processed at the designated time points (collection and processing were 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 taken and processed at the indicated time points (collection and processing were performed according to conventional methods in the art).

[0304] [Table 20]

[0305] [Table 21]

[0306] (v) Sample Analysis

[0307] Brains were weighed and homogenized by adding 4 volumes of ultrapure water. Six volumes of acetonitrile were added to whole blood samples and brain homogenates, respectively (20 volumes of acetonitrile were added to mouse PK whole blood samples), and the mixtures were vortexed for 1 min and centrifuged at 4500 rpm for 15 min 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. The tables show the blood drug concentrations and various pharmacokinetic parameter values ​​of Example Compounds 18, 40, and 42 of the present application at various time points, respectively. 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. From the above results, it can be seen that the compounds of Examples 18, 40, and 42 of the present application have excellent pharmacokinetic properties and exhibit the ability to pass through 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 but not limited to 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, colon 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, retinal pigment epithelium, and the like. These include: retinal degeneration, macular degeneration, pancreatitis, atopic dermatitis, spondyloarthritis, gout, SoJIA, Sjogren'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, Behcet's disease, interleukin-1 converting enzyme-associated febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, and periodontitis. The compounds of the present disclosure can be used as 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 only 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, S, NH, carbonyl, sulfonyl, or sulfinyl; 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, the 1 to 3 substituents being 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 4-8 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 4-8 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, pharma- ceutically 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, the 1 to 3 substituents being 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 4-8 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 4-8 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 a pharma- ceutically acceptable salt thereof.

3. 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, the 1 to 3 substituents being 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; 3. A compound according to claim 1 or 2, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

4. 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 with 1 to 3 substituents. １ -C ８ alkyl, wherein the one to three 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; Alternatively, 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-hydroxylhexyl, fluoropropyl, fluoroethyl, or 2,2-difluoro-3-hydroxylpropyl; 4. The compound of claim 3, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

5. R １ is a C substituted with 1-hydroxycyclopropyl, 1-hydroxycyclobutyl, 1-hydroxycyclopentyl, or 1-hydroxycyclohexyl; １ -C ８ Is it alkyl? Alternatively, R １ is 1-hydroxycyclopropylmethyl or 1-hydroxycyclobutylmethyl; 4. The compound of claim 3, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

6. R ２ is hydrogen, methyl, methoxy, fluorine, chlorine or bromine; 5. The compound according to any one of claims 1 to 4, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

7. R ３ and R ４ are each independently hydrogen, fluorine, chlorine, or methyl; 5. The compound according to any one of claims 1 to 4, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

8. The following formula (III): 【Chemistry 3】 2. The compound of claim 1 having the structure: or a pharma- ceutically acceptable salt thereof.

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

10. The structure: 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 2. The compound of claim 1, selected from:

11. A deuterated derivative of the compound according to any one of claims 2 to 10.

12. 12. Use of a compound according to any one of claims 1 to 11, or a stereoisomer, a pharma- ceutically acceptable salt, or a deuterated derivative thereof, in the manufacture of a medicament for treating a RIPK1-related disease.

13. The RIPK1-related disease includes 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, colon 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 osteoporosis.

13. The use according to claim 12, comprising spondyloarthritis, 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 convertase associated febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor associated periodic syndrome, and periodontitis.

14. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a stereoisomer, pharma- ceutically acceptable salt, or deuterated derivative thereof, and one or more pharma- ceutically acceptable carriers or excipients.

15. 15. The pharmaceutical composition of claim 14, further comprising one or more other therapeutic agents.

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