Isoxazolidine as a RIPK1 inhibitor and its use

Abstract

This disclosure relates to compounds of formula (I). [Formula 1] TIFF2026516095000076.tif42170 (wherein R1 represents a phenyl or monocyclic heteroaryl optionally substituted with 1, 2, or 3 R3s; R2 represents an optionally substituted aryl or heteroaryl; each R3 is independently selected from halogens, cyanos, (C1-C4)alkyl groups, or (C1-C4)alkoxy groups; R4 and R5 are halogens, (C1-C4)alkyl groups, or (C1-C4)alkoxy groups) The present invention relates to a group that is independently selected from the others, or R4 and R5 together form a (C1-C4)alkylene bridge; m and s are independently 0 or 1; p, q, r and t are independently 0 or 1; Y is a bond or a divalent group selected from -C(O)-NH-, -C(O)-NH-CH2-, -NH-, -CH2-NH-, -NH-CH2-, -O-, CH2-O- and -O-CH2), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. This further relates to pharmaceutical compositions containing the novel compound.

Description

Technical Field

[0001] The present disclosure relates to novel isoxazolidine derivatives useful as pharmaceuticals. The novel compounds are useful as kinase inhibitors, and more particularly as RIPK1 inhibitors. They are effective in treating and / or preventing acute and chronic neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS).

[0002] The present disclosure further relates to pharmaceutical compositions containing the novel compounds.

Background Art

[0003] Inflammation can be a protective mechanism in response to harmful stimuli such as pathogen invasion and tissue damage, but chronic inflammation is an important underlying factor in many human diseases such as neurodegeneration, rheumatoid arthritis, autoimmune diseases and inflammatory diseases, and cancer. Similarly, the activation of cell death pathways such as necrosis and apoptosis, which are useful for eliminating infected or damaged cells, is also an important underlying mechanism of human diseases including acute and chronic neurodegenerative diseases. Receptor-interacting protein kinase 1 (UniProtKB Q13546) is an important regulator of inflammation, apoptosis, and necrosis. Receptor-interacting protein kinase 1 plays an important role in the regulation of the inflammatory response mediated by the nuclear factor κ-light chain enhancer of activated B cells (NF-κB). More recent studies have shown that its kinase activity controls necrosis, a form of necrotic cell death that was traditionally thought to be passive and unregulated, and is characterized by a unique morphology. Furthermore, receptor-interacting protein kinase 1 is part of an apoptosis-promoting complex that exhibits its activity in regulating apoptosis.

[0004] Receptor-interacting protein kinase 1 (RIPK1) is subject to a complex and intricate regulatory mechanism that includes ubiquitination, deubiquitination, and phosphorylation. These regulatory events collectively determine whether cells survive, activate the inflammatory response, or die by apoptosis or necrosis. Dysregulation of RIPK1 signaling can lead to excessive inflammation or cell death. Conversely, studies have shown that inhibition of RIPK1 can be an effective treatment for diseases associated with inflammation or cell death.

[0005] RIPK1 inhibition has been identified as a promising principle for treating various diseases such as rheumatoid arthritis (RA), psoriasis, multiple sclerosis, Alzheimer's disease, inflammatory bowel disease, such as Crohn's disease, amyotrophic lateral sclerosis (ALS) or ulcerative colitis (UC). To treat some of these diseases, such as multiple sclerosis (MS) and Alzheimer's disease, access to the central nervous system (CNS) is required. In the case of other diseases, such as inflammatory bowel disease (IBD) like RA, psoriasis, Crohn's disease or UC, access to the CNS is not essentially required.

[0006] Various RIPK1 inhibitors have already been described in patent applications such as WO 2014 / 125444, WO 2016 / 185423 or WO 2016 / 027253 (GSK).

[0007] GSK2982772, a RIPK1 inhibitor (an oxazepinone derivative disclosed in WO 2014 / 125444), was evaluated in a Phase II clinical trial for RA, psoriasis, and UC.

[0008] Dihydropyrazole compounds having a phenyl substituent and a pyrimidine-piperidine moiety on the dihydropyrazole were disclosed as RIPK1 inhibitors by GSK in WO 2018 / 092089. Other dihydropyrazole compounds as RIPK1 inhibitors are disclosed in WO 2020224656.

[0009] Isoxazolidine compounds having a phenyl substituent and a pyrimidine-piperidine element on an isoxazolidine are disclosed by GSK in International Publication No. 2019 / 130230 as RIPK1 inhibitors. Similar isoxazolidine compounds are disclosed in Korean Patent Application Publication No. 2020-087922 (Voronoi) and International Publication No. 2020 / 043173.

[0010] Isoxazolidine compounds, which are RIPK1 inhibitors with reduced ability to cross the blood-brain barrier, are disclosed in International Publication No. 2021 / 245070.

[0011] Compounds containing a cycloalkyl element as RIPK1 inhibitors are disclosed in International Publication No. 2022 / 194259. [Overview of the project] [Means for solving the problem]

[0012] According to one of its objectives, this disclosure relates to compounds of formula (I). [ka] (In the formula, R1 represents a phenyl or monocyclic heteroaryl, which can be optionally substituted with one, two, or three R3s; R2 represents an aryl or heteroaryl that is optionally substituted with one, two, or three R6s; Each R3 is independently selected from halogen, cyano, (C1-C4) alkyl, or (C1-C4) alkoxy groups; R4 and R5 are independently selected from halogens, (C1-C4) alkyl groups, and (C1-C4) alkoxy groups, or R4 and R5 together form a (C1-C4) alkylene bridge; m and s are independently either 0 or 1; p, q, r, and t are independently either 0 or 1; Y is a bond, or a divalent group selected from -C(O)-NH-, -C(O)-NH-CH2-, -NH-, -CH2-NH-, -NH-CH2-, -O-, CH2-O- and -O-CH2-; Each R6 is independently selected from halogens, cyano, -OH, (C1~C4)-alkyl groups, -CF3, -C(O)NH2, -C(O)NH-(C1~C4)-alkyl groups, -C(O)OH, -C(O)O-(C1~C4)-alkyl groups, -SO2NH2, (C1~C4)-alkoxy groups, -O-(C1~C4)alkylene-(C3~C6)cycloalkyl groups, -O-(C3~C6)cycloalkyl groups, -O-(C3~C6) heterocycloalkyl groups, 5- or 6-membered heterocycloalkyl groups, monocyclic heteroaryl groups, and oxo groups, and the (C1~C4) alkyl groups, (C1~C4) alkoxy groups, -O-(C3~C6) cycloalkyl groups, (C1~C4) alkyl groups, 5- or 6-membered heterocycloalkyl groups, or monocyclic heteroaryl groups are optionally substituted with 1, 2, 3, or 4 R7s; Each R7 is independently a halogen, oxo, -OH, (C1-C4) alkyl group, or (C1-C4) alkoxy group. Or relating to pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

[0013] In related embodiments, pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient are provided herein.

[0014] In another embodiment, a process for producing the compound of formula (I) and its intermediates is provided herein.

[0015] In another embodiment, compounds of formula (I) or pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided herein for use as pharmaceuticals.

[0016] In another aspect, provided herein are compounds of formula (I) or pharmaceutically acceptable salts, solvates or stereoisomers thereof for use in the treatment and / or prevention of a disease, disorder or condition that is at least partially mediated by receptor interacting protein kinase 1.

[0017] In another aspect, provided herein are compounds of formula (I) or pharmaceutically acceptable salts, solvates or stereoisomers thereof for use in the treatment and / or prevention of a disease selected from Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS).

[0018] In another aspect, provided herein is a method of inhibiting receptor interacting protein kinase 1. Further provided is a method of treating a disease, disorder or condition that is at least partially mediated by receptor interacting protein kinase 1, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition described herein. The present disclosure also provides the use of a compound of formula (I) or a composition thereof in the manufacture of a medicament for treating a disease, disorder or condition that is at least partially mediated by receptor interacting protein kinase 1.

Mode for Carrying Out the Invention

[0019] <U+ Definition Unless otherwise specified, the following terms used herein and in the claims have the following meanings.

[0020] As used herein, the term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group having the indicated number of atoms. More specifically, a (C x ~C y )alkyl group (where x and y are integers and x < y) is a straight or branched chain saturated aliphatic group containing x to y carbon atoms. For example, (C1-C4)alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl groups.

[0021] The term "alkylene" includes both straight-chain and branched-chain divalent alkyl groups. For example, "(C1-C4) alkylene" includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), methylmethylene (-CH(CH3)-), propylene, and butylene.

[0022] The term "alkoxy" refers to an alkyl group singly bonded to oxygen. In particular, "(C x -C y ) alkoxy", as used herein, refers to -O-(C x -C y ) alkyl, where x and y are integers and x < y. For example, "(C1-C4) alkoxy" includes, but is not limited to, methoxy, ethoxy, isopropoxy, and t-butoxy.

[0023] "Cycloalkyl" refers to a saturated or partially unsaturated, optionally substituted cyclic hydrocarbon group having the indicated number of atoms. More specifically, a (C3-C z )-cycloalkyl group (z is an integer of 4 or more) contains 3 to z carbon atoms. For example, a (C3-C8)-cycloalkyl group contains 3 to 8 carbon atoms and is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

[0024] The term "halogen" refers to a chlorine, fluorine, bromine, or iodine atom, particularly a chlorine or fluorine atom.

[0025] The terms “heterocyclyl,” “heterocyclic,” or “heterocyclic” refer to non-aromatic, saturated or partially unsaturated, optionally substituted monocyclic, condensed, or bridging bicyclic ring systems in which 1 to 5 (appropriately 1 or 2) carbon atoms are substituted with heteroatoms such as oxygen, sulfur, or nitrogen. For example, “(C3-C6) heterocycloalkyl group,” as used herein, refers to a (C3-C6) cycloalkyl group in which 1 or 2 carbon atoms are substituted with heteroatoms, particularly oxygen or nitrogen. Examples of heterocyclic groups include, but are not limited to, oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Examples of nitrogen-containing heterocycles include azetidinyl, pyrrolidinyl, imidazolinyl, dihydroimidazolyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, and tetrahydropyrazolyl. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocycles include oxazolidinyl, tetrahydrooxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. Regarding sulfur-containing heterocycles, oxidized sulfur heterocycles containing SO or SO2 groups are also included. Partially unsaturated heterocyclyl rings contain at least one double bond, such as one or two double bonds. Examples of partially unsaturated heterocyclyl rings include 1,6-dihydropyridinyl, 1,6-dihydropyridazinyl, and 2,3-dihydropyrrolyl. As those skilled in the art will understand, any heterocycle can be linked to another group via any suitable atom, such as a carbon or nitrogen atom.

[0026] A "bridged ring system" refers to a ring system in which two rings share three or more atoms. For example, see Jerry March, Advanced Organic Chemistry, 4th Edition, Wiley Interscience, pp. 131-133, 1992. In particular, "bridged (C6~C) 10 As used herein, the "cycloalkyl" group refers to a bicyclic or tricyclic compound, where the ring is cycloalkyl, the ring shares three or more atoms, and the bridge contains at least one atom, e.g., one atom, also called a C1-alkylene bridge, two atoms, or three atoms, also called a C2-alkylene bridge. Such a bridged cycloalkyl group may be substituted with one or more C1-C3 alkyl groups. Examples include, but are not limited to, norbornyl or bicyclo[2.2.2]octanyl.

[0027] The term "heteroaryl" refers to an aromatic monocyclic, bicyclic, or polycyclic ring incorporating one or more heteroatoms (e.g., 1 to 4, particularly 1, 2, or 3) selected from nitrogen, oxygen, or sulfur. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more commonly 5 to 10 ring members. Heteroaryl groups can be, for example, 5 or 6-membered monocyclic rings (or monocyclic heteroaryls) or 9 or 10-membered bicyclic rings, such as bicyclic structures formed from fused 5 and 6-membered rings or two fused 6-membered rings. Each ring can typically contain up to about 4 heteroatoms selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring contains up to 3 heteroatoms, more commonly up to 2, for example, 1 heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. Nitrogen atoms in a heteroaryl ring can be basic, as in the case of imidazole or pyridine, or they can be essentially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl group containing any amino group substituent of the ring is less than five. Heteroaryl groups containing nitrogen atoms can exist as corresponding N-oxides.

[0028] Non-restrictive examples of heteroaryl groups include furanil, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl (pyridinyl), pyridadinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranil, indolyl, isoindolyl, isoindlinyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, prinyl, benzoflazanil, quinolyl, isoquinolyl, quinazolinyl, quinoxalini Lu, cinnolinyl, pteridinyl, naphthilidinyl, carbazolyl, phenadinyl, benzisoquinolinyl, pyridopyradinyl, imidazolidinyl, triazolopyridinyl, e.g., [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, pyrrolopyridinyl, e.g., 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl or 1H-pyrrolo[3,2-c]pyridinyl, imidazopyridinyl, e.g., imidazo[1,2-a]pyridinyl, imidazopyridadinyl, e.g., imidazo[1,2-b]pyridadinyl, thieno[2,3 Examples include [b]furanil, 2H-flof[3,2b]pyranil, 5H-pyrido[2,3d]oxazinyl, 1H-pyrazolo[4,3d]oxazolyl, 4H-imidazo[4,5d]thiazolyl, pyrazino[2,3d]pyridazinyl, imidazo[2,1b]thiazolyl, imidazo[1,2b][1,2,4]triazinyl group, pyrazolopyridinyl, e.g., pyrazolo[4,3-b]pyridinyl, and triazolopyridazinyl, e.g., [1,2,4]triazolo[1,5-b]pyridazinyl, and benzimidazolyl, e.g., 1H-benzo[d]imidazolyl.

[0029] Non-exclusive examples of five-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0030] Non-exclusive examples of six-membered heteroaryl groups include, but are not limited to, pyridinyl, pyridyl, pyridazinyl, pyrimidinyl, and triazinyl groups.

[0031] Non-limiting examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include triazolopyridinyl, e.g., [1,2,4]triazolo[1,5-a]pyridinyl or [1,2,4]triazolo[4,3-a]pyridinyl; pyrrolopyridinyl, e.g., 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl or 1H-pyrrolo[3,2-c]pyridinyl; pyrrolopyridinyl; benzimidazolyl, e.g., 1H-benzo[d]imidazolyl; and benzoxazolyl, e.g., oxoben. Examples include zo[d]oxazole-3(2H)-yl, imidazopyridinyl, e.g., imidazo[1,2-a]pyridinyl, imidazopyridazinyl, e.g., imidazo[1,2-b]pyridazinyl, imidazolyl, indazolyl, e.g., indazole-1-yl or indazole-2-yl, indolyl, e.g., indole-1-yl, isoindolinyl, pyrazolopyridinyl, e.g., pyrazolo[4,3-b]pyridinyl, and triazolopyridazinyl, e.g., [1,2,4]triazolo[1,5-b]pyridazinyl. Certain non-limiting examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, clomenyl, isochromanyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzooxazinyl, benzodiadinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthilidinyl, and pteridinyl groups.

[0032] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent forms. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. More precisely, the aryl group is phenyl.

[0033] This specification may also use a plurality of compound terms to describe groups containing two or more functionalities. Such terms will be understood by those skilled in the art. For example, heterocyclyl C 1~4 alkyl is C substituted by heterocyclyl 1~4 alkyl and contains.

[0034] The term "optionally substituted" refers to either the substituted group, structure or molecule and the unsubstituted one.

[0035] When an optional substituent is selected from "one or more" groups, it should be understood that this definition includes all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups. When there are multiple substituents, it is understood that the selected substituents can be the same or different.

[0036] When a numerical range is given, the range is understood to include the endpoints.

[0037] The phrase "compounds of the present disclosure" generally and specifically means the compounds disclosed in this specification.

[0038] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0039] In this regard, the term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic acid addition salts of the compounds of the present disclosure. These salts can be prepared in situ in an administration excipient or dosage form manufacturing process, or by separately reacting the purified compound of the present disclosure in free base form with a suitable organic or inorganic acid and then isolating the salt thus formed during subsequent purification.

[0040] As used herein, the term “pharmaceutically acceptable excipient” refers to a substance that helps administer an activator to a subject. “pharmaceutically acceptable” means that the excipient is compatible with the other components of the formulation and is not harmful to its recipient. Useful pharmaceutical excipients in this disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, flow enhancers, coatings, sweeteners, flavors, and colorants.

[0041] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulant, that is involved in transporting or delivering the compound of interest from one organ or part of the body to another organ or part of the body.

[0042] References to “treating” or “treatment” should be understood to include the prevention and mitigation of established symptoms of a condition. Therefore, “treating” or “treating” a condition, disorder, or pathology includes (1) preventing or delaying the onset of clinical symptoms of a condition, disorder, or pathology in a person who has or is susceptible to the condition, disorder, or pathology but has not yet experienced or shown any clinical or asymptomatic symptoms of the condition, disorder, or pathology; (2) inhibiting the condition, disorder, or pathology, i.e., stopping, reducing, or delaying the onset or recurrence of the disease (in the case of maintenance therapy) or at least one clinical or asymptomatic symptom thereof; or (3) reducing or attenuating the disease, i.e., causing the regression of at least one of the condition, disorder, or clinical or asymptomatic symptoms thereof.

[0043] "Prevention" or "prevention" means any treatment of a disease or condition that prevents the development of the clinical symptoms of the disease or condition. In some embodiments, the compound may be administered to subjects (including humans) who are at risk of developing the disease or condition or who have a family history of the disease or condition.

[0044] "Subject" refers to a human being who has been or will be the subject of treatment, observation, or treatment. The methods described herein may be useful for human treatment.

[0045] The "therapeutic dose" refers to the amount of a compound sufficient to have such an effect on treating a disease when administered to a mammal. The "therapeutic dose" varies depending on the compound, the disease and its severity, as well as the age and weight of the mammal being treated, and this can be easily determined by those skilled in the art. As used herein, chemical nomenclature, unless otherwise defined, has the meanings used in the Art of this invention.

[0046] compound In this specification, formula (I): [ka] compounds (In the formula, R1 represents a phenyl or monocyclic heteroaryl molecule that is optionally substituted with one, two, or three R3 molecules; R2 represents an aryl or heteroaryl that is optionally substituted with one, two, or three R6s; Each R3 is independently selected from halogen, cyano, (C1-C4) alkyl, or (C1-C4) alkoxy groups; R4 and R5 are independently selected from halogens, (C1-C4) alkyl groups, and (C1-C4) alkoxy groups, or R4 and R5 together form a (C1-C4) alkylene bridge; m and s are independently either 0 or 1; p, q, r, and t are independently either 0 or 1; Y is a bond, or a divalent group selected from -C(O)-NH-, -C(O)-NH-CH2-, -NH-, -CH2-NH-, -NH-CH2-, -O-, CH2-O- and -O-CH2-; Each R6 is independently selected from halogens, cyano, -OH, (C1~C4)-alkyl groups, -CF3, -C(O)NH2, -C(O)NH-(C1~C4)-alkyl groups, -C(O)OH, -C(O)O-(C1~C4)-alkyl groups, -SO2NH2, (C1~C4)-alkoxy groups, -O-(C1~C4)alkylene-(C3~C6)cycloalkyl groups, -O-(C3~C6)cycloalkyl groups, -O-(C3~C6) heterocycloalkyl groups, 5- or 6-membered heterocycloalkyl groups, monocyclic heteroaryl groups, and oxo groups, and the (C1~C4) alkyl groups, (C1~C4) alkoxy groups, -O-(C3~C6) cycloalkyl groups, (C1~C4) alkyl groups, 5- or 6-membered heterocycloalkyl groups, or monocyclic heteroaryl groups are optionally substituted with 1, 2, 3, or 4 R7s; Each R7 is independently a halogen, oxo, -OH, (C1-C4) alkyl group, or (C1-C4) alkoxy group. Alternatively, pharmaceutically acceptable salts, solvates, or stereoisomers thereof are disclosed.

[0047] According to one embodiment, R1 in formula (I) is a phenyl, thiazolyl, pyridinyl, or pyrazinyl which is optionally substituted with one or two groups independently selected from halogens, cyanos, (C1-C2)-alkyl groups, or (C1-C2)-alkoxy groups. In particular, R1 is (i) a phenyl which is optionally substituted with one or two groups independently selected from halogens, cyanos, (C1-C2)-alkyl groups, or (ii) a monocyclic heteroaryl selected from thiazolyl, pyridinyl, and pyrazinyl, wherein the heteroaryl is optionally substituted with one or two groups independently selected from halogens, cyanos, (C1-C2)-alkyl groups, or (C1-C2)-alkoxy groups.

[0048] According to one embodiment, R1 in formula (I) is a phenyl molecule optionally substituted with one or two groups independently selected from fluorine, chlorine, cyano, methyl, or methoxy groups.

[0049] According to one embodiment, R1 in formula (I) is a thiazolyl, pyridinyl, or pyrazinyl which is optionally substituted with one or two groups independently selected from fluorine, chlorine, cyano, methyl, or methoxy groups.

[0050] According to another embodiment, R2 in formula (I) is a phenyl, pyrimidinyl, pyridinyl, pyrrolopyrimidinyl, benzimidazolyl, indazolyl, or indolyl which is optionally substituted with one or two groups independently selected from halogens, cyanos, (C1-C2)-alkyl groups, -C(O)NH2, -C(O)O-(C1-C2)-alkyl groups, -SO2NH2, 5-membered or 6-membered heterocycloalkyl groups, and 5-membered heteroaryl groups, wherein the 5-membered or 6-membered heterocycloalkyl groups and 5-membered heteroaryl groups are optionally substituted with one, two, three, or four groups independently selected from (C1-C2)-alkyl groups and oxos.

[0051] According to another embodiment, R2 in formula (I) is a phenyl, pyrimidinyl, pyridinyl, pyrrolopyrimidinyl, benzimidazolyl, indazolyl, or indolyl, which is optionally substituted with one or two groups independently selected from halogens, cyanos, (C1-C2)-alkyl groups, -C(O)NH2, -C(O)O-(C1-C2)-alkyl groups, -SO2NH2, five-membered or six-membered heterocycloalkyl groups (particularly selected from oxazolidinyl, pyrrolidinyl, imidazolinyl, or dihydroimidazolyl), and five-membered heteroaryl groups, particularly pyrazolyl or triazolyl, wherein the five-membered or six-membered heterocycloalkyl groups and five-membered heteroaryl groups are optionally substituted with one, two, three, or four groups independently selected from (C1-C2) alkyl groups and oxo groups.

[0052] According to another embodiment, Y is a bond, or a divalent group selected from -NH-, -NH-CH2-, -O-, and -O-CH2-, particularly a group selected from -NH-, -NH-CH2-, and -O-CH2-.

[0053] According to one embodiment, R4 and R5 in formula (I) are independently selected from (C1-C2) alkyl groups.

[0054] According to another embodiment of the compound of formula (I), m is 0 and s is 0.

[0055] According to one embodiment, the compound according to the present disclosure is of formula (I), instead of: - p, q, r, and t are all equal to 0. - r, q, and t are all equal to 0, and p is equal to 1. - r and t are both equal to 0, q and p are both equal to 1, Or, - q, t, and p are all equal to 1, and r is equal to 0.

[0056] According to one embodiment, this specification provides a compound of formula (I) as defined above, wherein R1 is: - Phenyl substituted with 1, 2, or 3 R3 as defined above, or - Represents a monocyclic heteroaryl substituted with one, two, or three R3s as defined above.

[0057] According to one embodiment, the Specified herein provides a compound of formula (I) as defined above, where Y is a divalent group selected from -C(O)-NH-, -C(O)-NH-CH2-, -NH-, -CH2-NH-, -NH-CH2-, CH2-O-, and -O-CH2-.

[0058] According to one embodiment, the Specified herein provides a compound of formula (I) as defined above, wherein when p, q, r, and t are 0, R4 and R5 do not form a (C1-C4) alkylene crosslink together.

[0059] According to one embodiment, the compound according to this disclosure is of formula (Ia). [ka] (In the formula, Y, R1, R2, R4, R5, m, and s are defined as in equation (I). or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0060] According to another embodiment, the compound according to the present disclosure is of formula (Ia) (wherein, Y is either -NH-, -O-, or a bond; R1 is a phenyl or pyridinyl compound that is optionally substituted with one or two R3s; R2 is phenyl, pyrimidinyl, indazolyl, indolyl, or benzimidazolyl, either by choice or substituted with two R6s; Each R3 is independently selected from halogen or cyanoacrylate; m and s are independently either 0 or 1; Each R6 is a halogen, particularly fluorine, -C(O)NH2, cyano, or -C(O)O-(C1~C2)alkyl. or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0061] According to this embodiment, the compound of formula (I) is, more specifically, the compound of formula (Ib). [ka] (In the formula, Y, R1, R2, R4, R5, m, and s are as defined in formula (I)) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0062] According to another embodiment, the compound of formula (I) is, more specifically, the compound of formula (Ib) (wherein, Y is a bond or -O-CH2-; R1 is a phenyl compound that is optionally substituted with one or two R3s; R2 is a pyridinyl or pyrimidinyl that is optionally substituted with -C(O)NH2; Each R3 is independently selected from halogen or cyanoacrylate; (m and s are 0) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0063] According to this embodiment, the compound of formula (I) is, more specifically, the compound of formula (Ic). [ka] (In the formula, Y, R1, R2, R4, R5, m, and s are as defined in formula (I)) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0064] According to this embodiment, the compound of formula (I) is, more specifically, the compound of formula (Ic) (wherein, Y is -NH-, -NH-CH2-, bond, -O-, or -O-CH2-; R1 is a phenyl, pyrazinyl, triazolyl, or pyridinyl which is optionally substituted with one or two R3s; R2 is a pyridinyl, phenyl, pyrimidinyl, or pyrrolopyrimidinyl which is optionally substituted with one or two R6s; Each R3 is independently selected from halogen, -CH3, -OCH3, or cyanoacrylate; m and s are 0; R6 is a halogen, -C(O)NH 2、 A group independently selected from cyano, (C1-C2)-alkyl groups, -SO2NH2, 5-membered heterocycloalkyl groups (selected from imidazolidinyl, dihydroimidazolyl, pyrrolidinyl, and oxazolidinyl), or 5-membered heteroaryl groups (selected from pyrazolyl or triazolyl), wherein the heterocycloalkyl and heteroaryl groups are optionally substituted with one, two, three, or four groups independently selected from (C1-C2) alkyl groups and oxo groups. or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0065] According to this embodiment, the compound of formula (I) defined above is, more specifically, the compound of formula (Id). [ka] (In the formula, Y, R1, R2, R4, R5, m, and s are as defined in formula (I)) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0066] According to another embodiment, the compound of formula (I) is, more specifically, the compound of formula (Id) (wherein, Y is -O-CH2-; R1 is a phenyl compound that is optionally substituted with one or two R3s; R2 is a pyrimidinyl that is optionally substituted with -C(O)NH2; Each R3 is independently selected from halogen or cyanoacrylate; (m and s are 0) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0067] Among the compounds of formula (I), the following compounds may be specifically mentioned: (1) cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carboxamide, (2) cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitride, (3) Methyl cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carboxylate, (4) Trans-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carboxamide, (5) cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carbonitride, (6) cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxamide, (7) cis-2-((3-((S)-3-(5-cyanopyridine-3-yl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxamide, (8) Ethyl cis-6-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)-5-fluoropyrimidine-4-carboxylate, (9) Ethyl cis-6-chloro-5-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxylate, (10) cis-6-chloro-5-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxamide, (11) cis-6-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)-5-fluoropyrimidine-4-carboxamide, (12) cis-2-((4-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)amino)pyrimidine-4-carboxamide, (13) cis-6-((4-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)amino)pyrimidine-4-carboxamide, (14) Trans-2-(((4-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)amino)pyrimidine-4-carbonitrile, (15) Trans-6-(((4-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)amino)pyrimidine-4-carbonitrile, (16) cis-2-((3-((S)-3-(3-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile, (17) cis-6-((3-((S)-3-(3-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitri, (18) cis-6-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile, (19) cis-2-((3-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitride, (20) cis-6-((3-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitride, (21) cis-2-((3-((S)-3-(3,4-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile, (22) cis-6-((3-((S)-3-(3,4-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitride, (23) cis-6-((3-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitride, (24) cis-2-((3-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile, (25) cis-3-((3-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)-5-fluorobenzonitrile, (26) cis-3-fluoro-5-((3-((S)-3-(3-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)benzonitrile, (27) cis-3-((3-((S)-3-(3,4-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)-5-fluorobenzonitrile, (28) cis-6-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)amino)pyrimidine-4-carbonitride, (29) Trans-6-(((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)amino)pyrimidine-4-carboxamide, (30) Trans-6-(((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)amino)pyrimidine-4-carbonitride, (31) trans-3-fluoro-5-((S)-2-(4-(((7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)benzonitrile, (32) cis-5-((3-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)-2-fluorobenzonitrile, (33) cis-2-fluoro-5-((3-((S)-3-(5-fluoropyridine-3-yl)isoxazolidine-2-carbonyl)cyclobutyl)amino)benzonitrile, (34) trans-2-fluoro-5-(((4-((S)-3-(5-fluoropyridine-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)amino)benzonitrile, (35) trans-5-(((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)amino)-2-fluorobenzonitrile, (36) cis-3-fluoro-5-((3-((S)-3-(5-fluoropyridine-3-yl)isoxazolidine-2-carbonyl)cyclobutyl)amino)benzonitrile, (37) cis-3-((S)-2-(3-((3-cyano-5-fluorophenyl)amino)cyclobutan-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile, (38) trans-3-((S)-2-(4-(((3-cyano-5-fluorophenyl)amino)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile, (39) cis-3-((S)-2-(4-((3-cyano-5-fluorophenyl)amino)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile, (40) cis-3-((S)-2-(3-(1H-benzo[d]imidazole-1-yl)cyclobutan-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile, (41) cis-(3-(1H-benzo[d]imidazole-1-yl)cyclobutyl)((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)methanone, (42) cis-(3-(1H-benzo[d]imidazole-1-yl)cyclobutyl)((S)-3-(5-fluoropyridine-3-yl)isoxazolidine-2-yl)methanone, (43) trans-5-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-2-fluorobenzonitrile, (44) trans-5-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-2-fluorobenzonitrile, (45) trans-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)pyrimidine-4-carbonitrile, (46) trans-(4-(((6-chloropyrimidine-4-yl)oxy)methyl)cyclohexyl)((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)methanone, (47) Trans-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)pyrimidine-4-carboxamide, (48) trans-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-5-fluorobenzonitrile, (49) trans-3-((S)-2-(4-((3-cyano-5-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile, (50) trans-3-(3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutoxy)-5-fluorobenzonitrile, (51) trans-5-(3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutoxy)-2-fluorobenzonitrile, (52) cis-5-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-2-fluorobenzonitrile, (53) cis-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-5-fluorobenzonitrile, (54) cis-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)pyrimidine-4-carboxamide, (55) cis-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)pyrimidine-4-carbonitride, (56) cis-(4-(((6-chloropyrimidine-4-yl)oxy)methyl)cyclohexyl)((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)methanone, (57) Trans-3-(4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)phenyl)-5,5-dimethyloxazolidine-2,4-dione, (58) Trans-1-(4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)phenyl)pyrrolidine-2,5-dione, (59) Trans-3-(3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)4-fluorophenyl)-5,5-dimethyloxazolidine-2,4-dione, (60) Trans-1-(4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)phenyl)pyrrolidine-2-one, (61) cis-3-(3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutoxy)-5-fluorobenzonitrile, (62) trans-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)(4-((4-(3,5-dimethyl-1H-pyrazole-1-yl)-2-fluorophenoxy)methyl)cyclohexyl)methanone, (63) Trans-3-(4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)phenyl)-1-methylimidazolidin-2,4-dione, (64) trans-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)(4-((5-(3,5-dimethyl-4H-1,2,4-triazole-4-yl)-2-fluorophenoxy)methyl)cyclohexyl)methanone, (65) cis-5-(3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutoxy)-2-fluorobenzonitrile, (66) Trans-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)benzenesulfonamide, (67) trans-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)(4-((4-(3,5-dimethyl-4H-1,2,4-triazole-4-yl)-2-fluorophenoxy)methyl)cyclohexyl)methanone, (68) Trans-1-(4-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-3-fluorophenyl)-3-methyl-1,3-dihydro-2H-imidazole-2-one, (69) cis-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)(3-(5-fluoro-1H-benzo[d]imidazole-1-yl)cyclobutyl)methanone, (70) cis-3-fluoro-5-((S)-2-(3-(5-fluoro-1H-benzo[d]imidazole-1-yl)cyclobutan-1-carbonyl)isoxazolidine-3-yl)benzonitrile, (71) trans-5-((S)-2-(4-((3-cyanophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile, (72) trans-5-((S)-2-(4-((3-cyano-4-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile, (73) Trans-3-((4-((S)-3-(5-cyanopyridine-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)benzamide, (74) Trans-5-((4-((S)-3-(5-cyanopyridine-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-2-fluorobenzamide, (75) Trans-2-chloro-5-((4-((S)-3-(5-cyanopyridine-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)benzamide, (76) trans-3-((S)-2-(4-((4-(3,5-dimethyl-1H-pyrazole-1-yl)-2-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile, (77) Trans-3-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)benzenesulfonamide, (78) trans-3-fluoro-5-((S)-2-(4-((2-fluoro-4-(3-methyl-2-oxo-2,3-dihydro-1H-imidazole-1-yl)phenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)benzonitrile, (79) trans-3-((S)-2-(4-((5-(5,5-dimethyl-2,4-dioxoxazolidine-3-yl)-2-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile, (80) trans-3-((S)-2-(4-((2-chloro-5-(3-methyl-2,5-dioxoimidazolidine-1-yl)phenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile, (81) cis-3-((S)-2-(4-(5-(5,5-dimethyl-2,4-dioxoxazolidine-3-yl)-2-fluorophenoxy)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile, (82) cis-5-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)oxy)-2-fluorobenzonitrile, (83) trans-5-((S)-2-(4-((3-cyano-5-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile, (84) trans-(3-(5-fluoro-1H-benzo[d]imidazole-1-yl)cyclobutyl)((S)-3-(3-fluorophenyl)isoxazolidine-2-yl)methanone, (85) Trans-5-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-2-methylbenzamide, (86) Trans-5-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-2-methylbenzamide, (87) cis-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)(3-(6-fluoro-1H-benzo[d]imidazole-1-yl)cyclobutyl)methanone, (88) trans-5-((S)-2-(4-((2-chloro-5-(3-methyl-2,5-dioxoimidazolidine-1-yl)phenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile, (89) trans-5-((S)-2-(4-((2-fluoro-4-(3-methyl-2-oxo-2,3-dihydro-1H-imidazole-1-yl)phenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile, (90) trans-5-((S)-2-(4-((4-(3,5-dimethyl-1H-pyrazole-1-yl)-2-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile, (91) trans-2-[[4-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]pyridine-4-carbonitrile, (92) trans-5-((S)-2-(4-((5-(5,5-dimethyl-2,4-dioxoxazolidine-3-yl)-2-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile, (93) trans-4-[[4-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]pyridine-2-carbonitrile, (94) trans-5-((S)-2-(4-(((4-cyanopyridine-2-yl)oxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile, (95) trans-5-((S)-2-(4-(((5-cyanopyridine-2-yl)oxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile, (96) cis-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-[3-(5-fluoroindazole-1-yl)cyclobutyl]methanone, (97) trans-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-[3-(5-fluoroindazole-1-yl)cyclobutyl]methanone, (98) trans-3-fluoro-5-[(3S)-2-[3-(5-fluoroindazole-1-yl)cyclobutancarbonyl]isoxazolidine-3-yl]benzonitrile, (99) Trans-6-[[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]pyridine-3-carboxamide, (100) trans-3-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, (101) trans-2-fluoro-5-[[4-[(3S)-3-pyrazine-2-ylisooxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, (102) Trans-6-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]pyridine-3-carboxamide, (103) trans-6-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]pyridine-3-carbonitrile, (104) trans-3-fluoro-5-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzonitrile, (105) trans-3-fluoro-5-[(3S)-2-[3-(5-fluoroindole-1-yl)cyclobutancarbonyl]isoxazolidine-3-yl]benzonitrile, (106) trans-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-[3-(5-fluoroindole-1-yl)cyclobutyl]methanone, (107) cis-3-fluoro-5-[(3S)-2-[3-(5-fluoroindole-1-yl)cyclobutancarbonyl]isoxazolidine-3-yl]benzonitrile, (108) cis-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-[3-(5-fluoroindole-1-yl)cyclobutyl]methanone, (109) cis-3-fluoro-5-[(3S)-2-[3-(5-fluoroindazole-2-yl)cyclobutancarbonyl]isoxazolidine-3-yl]benzonitrile, (110) cis-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-[3-(5-fluoroindazole-2-yl)cyclobutyl]methanone, (111) trans-4-fluoro-3-[[4-[(3S)-3-pyrazine-2-ylisooxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, (112) trans-3-fluoro-5-[[4-[(3S)-3-pyrazine-2-ylisooxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, (113) trans-3-fluoro-4-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, (114) cis-2-[3-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl]cyclopentyl]pyridine-4-carboxamide, (115) cis-6-[[3-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide, (116) trans-6-[[3-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide stereoisomer 2, (117) trans-6-[[3-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide stereoisomer 3, (118) Trans-6-[[3-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide stereoisomer 1, (119) cis-6-[[3-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide stereoisomer 2, (120) Trans-6-[[3-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide stereoisomer 3, (121) cis-6-[[3-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide stereoisomer 4, (122) Trans-6-[[4-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide stereoisomer 1, (123) Trans-6-[[4-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide stereoisomer 2, (124) cis-6-[[4-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide stereoisomer 3, (125) cis-6-[[4-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide stereoisomer 4, (126) Trans-6-[[4-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide stereoisomer 1, (127) trans-6-[[4-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide stereoisomer 2, (128) cis-6-[[4-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide, (129) trans-3-[[4-[(3S)-3-(6-methoxypyrazine-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, (130) trans-3-[[4-[(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, and (131) Trans-3-[[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0068] According to one embodiment of the present disclosure, the compound of formula (I) is compound (1), (6), (32), (35), (37), (38), (43), (44), (45), (46), (47), (48), (49), (51), (52), (53), (57), (59), (62), (63), (65), (66), (68), (69), (71), (72), (73), (76), (77), (78), (79), (83), (85), (86), (89), (90), (91), (93), (95), (104), (112), (122), (123), (127), and (129), or selected from the group consisting of pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

[0069] According to another embodiment of the present disclosure, the compound of formula (I) is selected from the group consisting of compounds (6), (35), (43), (51), (52), (53), (68), (71), (72), (79), (86), (89), (90), (93), and (123), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

[0070] Some of the compounds described herein are shown in Table 1 along with their structures, but these are merely examples and do not limit the scope of this disclosure.

[0071] The NMR and LC / MS data in Table 1 were obtained according to the methods detailed in the experimental section provided for the detailed synthesis example.

[0072] [Table 1]

[0073] Table 2

[0074] Table 3

[0075] Table 4

[0076] Table 5

[0077] Table 6

[0078] Table 7

[0079] Table 8

[0080] Table 9

[0081] Table 10

[0082] Table 11

[0083] Table 12

[0084] Table 13

[0085] Table 14

[0086] Table 15

[0087] Table 16

[0088] Table 17

[0089] Table 18

[0090] Table 19

[0091] Table 20

[0092] Table 21

[0093] Table 22

[0094] Table 23

[0095] Table 24

[0096] Table 25

[0097] Table 26

[0098] Table 27

[0099] Table 28

[0100] Table 29

[0101] Table 30

[0102] Table 31

[0103] Table 32

[0104] Table 33

[0105] Table 34

[0106] Table 35

[0107] Table 36

[0108] Table 37

[0109] Table 38

[0110] Table 39

[0111] Table 40

[0112] Table 41

[0113] Table 42

[0114] [Table 43]

[0115] [Table 44]

[0116] [Table 45]

[0117] [Table 46]

[0118] [Table 47]

[0119] [Table 48]

[0120] [Table 49]

[0121] [Table 50]

[0122] [Table 51]

[0123] [Table 52]

[0124] Manufacturing process The compounds of formula (I) can be prepared using the methods disclosed herein and their routine modifications, which will be apparent in view of the disclosure herein and methods well known in the art.

[0125] Scheme 1: General synthesis of the compounds of formula (I)

Chemical formula

[0126] The substituted isoxazolidine of formula (A) can be synthesized by known procedures according to the literature, for example, International Publication No. WO2017096301 pamphlet, International Publication No. WO2019130230 pamphlet, and International Publication No. WO2021245070 pamphlet.

[0127] The compound of formula (IIb) can be synthesized by known procedures from the literature or as described herein.

[0128] Scheme 2: Synthesis of a compound of formula (III) in which R2 is a benzimidazolyl group substituted by choice and Y is a bond. [ka] Compounds of formula (I), in which R2 represents an optionally substituted imidazolyl group and Y is a bond, can be synthesized starting from optionally substituted orthofluoronitrobenzene (B) and compounds of formula (IVa). In scheme 2, R4, R5, R6, m, s, p, q, r, and t are as defined in formula (I), o is 0, 1, 2, or 3, R8 represents a hydrogen atom or an R6 group, and R9 represents a hydrogen atom or a group selected from halogen, cyano, -OH, (C1~C4)-alkyl group, -CF3, -C(O)NH2, -C(O)NH-(C1~C4)-alkyl group, -C(O)OH, -C(O)O-(C1~C4)-alkyl group, -SO2NH2, and (C1~C4)-alkoxy group.

[0129] Step 5 is carried out in a suitable solvent such as acetonitrile in the presence of a base such as diisopropylethylamine. N This is an Ar reaction. The resulting nitroaniline compound (Va) can then be converted to the corresponding aminoaniline compound (IVa) (step 4), which can be achieved, for example, by palladium-catalyzed reduction in a suitable solvent such as methanol under a hydrogen atmosphere. In step 3, compound (IIIa) can be obtained by condensation with a suitable orthoester or acid halide having an R9 group, such as acetyl chloride or trimethyl orthoformate. These types of reactions can be carried out in solvents such as methanol or dioxane, respectively.

[0130] Orthofluoronitrobenzene (B), which is optionally substituted, can be synthesized by known procedures from the literature or as described herein.

[0131] The compound of formula (VIa) can be synthesized by known procedures from the literature or as described herein.

[0132] The synthesis of the compound of formula (IIIa) via scheme 2 can be shown in Example 1 below.

[0133] Scheme 3: Synthesis of a compound of formula (III) in which R2 represents an aryl or heteroaryl group that is optionally substituted, unlike benzimidazolyl, and Y is bonded to -NH- or -NH-CH2. [ka] Compounds of general formula (IIIb), where R2 is defined as in formula (I), can be synthesized starting from compound (IVb).

[0134] When Y is -NH- or -NH-CH2-, compound (IIIb) can be obtained from compound (IVb), where X is a hydrogen atom, via step 6a. Step 6a may be a coupling reaction carried out in a polar solvent such as DMF, DMSO, DMA (dimethylacetamide), or NMP (N-methyl-2-pyrrolidone) in the presence of a metal catalyst, particularly a copper catalyst, such as copper(I) iodide, copper(I) bromide, or copper(I) oxide, and a base, such as Cs2CO3, K3PO4, or sodium acetate. Step 6a is shown in particular in Examples 2.1 and 2.2.

[0135] When Y is -NH- or -NH-CH2, compound (IIIb) can be obtained from compound (IVb) where X is a hydrogen atom via step 6b. Step 6b is carried out in a suitable solvent such as acetonitrile and DMSO in the presence of a base, such as diisopropylethylamine or K2CO3. N This may be an Ar reaction. Step 6b is shown in particular in Examples 2.3, 2.4, 2.5 and 3.1.

[0136] If Y is a bond, compound (IIIb) can be obtained from compound (IVb) where X is a detaching group via step 6c. If R2 represents an optionally substituted heteroaryl group containing an -NH group, compound (IIIb) can be obtained from compound (IVb) where X is a detaching group via alkylation step 6c. Compound (IVb) where X is a detaching group, particularly a halide or alkyl sulfonate, such as a mesylate, tosylate, or nosylate, can be reacted with a suitable heterocyclic aromatic compound containing an -NH group in an inert solvent, such as DMF or THF, in the presence of a base, such as Cs2CO3 or K2CO3. Step 6c is shown in particular in Examples 4.1 and 4.2.

[0137] The compound of formula (IVb) can be synthesized by known procedures from the literature or as described herein.

[0138] Scheme 4: General synthesis of compounds of formula (I) where Y is -O- or -O-CH2- and z is 0 or 1 [ka] According to the third synthesis method (SM3), represented by the arrow above in Scheme 4, the compound of formula (I) can be obtained from the amide of formula (IIc). This step may consist of a Mitsunobu reaction under well known conditions. This can be achieved by using the compound of formula (IIc) and the compound of formula R2OH (where R2 is as defined in formula (I), in particular an optionally substituted aryl group) in an azodicarboxylate reagent, such as DEAD, DIAD, ADDP (1,1'-(azodicarbonyl)dipiperidine), TMAD (N,N,N',N'-tetramethyldicarboxaamide), DCAD (di-4-chlorobenzylazodicarboxylate), or DNAD (di-4-nitrobenzylazodicarboxylate), together with a phosphine, such as triphenylphosphine, PH3, DPPE (1,2-bis(diphenylphosphino)ethane), PPh2Py (diphenyl-2-pyridylphosphine), or tris-DAP (tris(dimethylamino)phosphine), in an aprotic solvent such as THF, CH2Cl2, or Et2O, to form the compound of formula (I). The SM3 pathway is particularly shown in step 3a of Example 9, steps 2a and 2b of Example 12.2, and step 2 of Example 12.6.

[0139] According to the fourth synthesis method (SM4), represented by the central arrow in Scheme 4, the compound of formula (I) can be obtained from the amide of formula (IIc). This step may consist of nucleophilic substitution, particularly aromatic nucleophilic substitution under well known conditions. This can be achieved by forming the compound of formula (I) using a compound R2-leaving group (R2 is as defined in formula (I), in particular an optionally substituted aryl group, where the leaving group is a halogen, e.g., a chlorine atom or a cyano) in the presence of a base, e.g., diisopropylethylamine, K2CO3, NaH, KH, K3PO4, Na2CO3, tBuOK, in an aprotic solvent such as THF, acetonitrile, DMF, DMA, DMSO, NMP, or dioxane. The SM4 route is particularly shown in steps 2a and 2b of Example 12.1.

[0140] According to the third synthesis method (SM5) represented by the downward arrow in Scheme 4, the compound of formula (I) can be obtained from the amide of formula (IId) containing a leaving group. As an example, the compound of formula (IId) can be obtained by activating the hydroxyl group of the compound of formula (IIc) to form a leaving group, as represented by the dotted arrow in Figure 4. The activation can be carried out by nucleophilic substitution well-known in an aprotic solvent such as CH2Cl2, ethyl acetate, THF or DMF in the presence of a base, particularly an amine base such as triethylamine or diisopropylethylamine, on the hydroxyl group of the compound of formula (IIc) with a sulfonyl chloride, particularly a halide, particularly an iodide, or an arylsulfonyl chloride such as mesyl chloride, an arylsulfonyl chloride such as tosyl chloride or 4-nitrobenzenesulfonyl chloride to form the compound of formula (IId). The activation step is particularly shown in step 4a of Example 9.

[0141] The step of forming the compound of formula (I) using SM5 can consist of nucleophilic substitution under well-known conditions. This can be achieved by using the compound of formula (IId) and a R2-OH compound (where R2 is as defined in formula (I), particularly an optionally substituted aryl group, etc.) in an aprotic solvent such as DMF, acetonitrile, DMSO, NMP, or THF in the presence of a base such as Cs2CO3, NaH, potassium tert-butoxide to form the compound of formula (I). The SM5 route is particularly shown in steps 5a and 5b of Example 9.

[0142] Scheme 5: General synthesis of the compound of formula (I) where Y is -NH- or -NH-CH2- and z is 0 or 1

Chemical formula

[0143] Functional groups in a compound, such as acids, esters, amides, nitriles, and halogens, can be converted to other functional groups (interconversion of functional groups) by standard methods such as esterification, saponification, halogenation, and the Suzuki reaction, thereby producing further compounds of formula (I).

[0144] The synthesis of typical compounds described herein can be achieved as described in the following examples. Reagents, where available, can be commercially purchased from, for example, Sigma Aldrich or other chemical suppliers. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions may also be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through routine optimization procedures.

[0145] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, numerous protecting groups are described in Wuts, PGM, Greene, TW, & Greene, TW (2006), Greene's protective groups in organic synthesis, Hoboken, NJ, Wiley-Interscience, and the references cited therein.

[0146] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Therefore, if desired, such compounds may be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as concentrated mixtures of stereoisomers. All such stereoisomers (and concentrated mixtures) are included within the scope of this disclosure unless otherwise indicated. Pure stereoisomers (or concentrated mixtures) may be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds may be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0147] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof. The terms “solvent,” “inert organic solvent,” or “inert solvent” refer to solvents that are inert under the reaction conditions described herein (e.g., including benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane, "DCM"), diethyl ether, methanol, pyridine, etc.). Unless otherwise specified, the solvents used in the reactions of this disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably argon.

[0148] Pharmaceutical composition The compounds described herein are typically administered in the form of pharmaceutical compositions. Accordingly, pharmaceutical compositions are also provided herein that contain one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog, and one or more pharmaceutically acceptable media selected from carriers, adjuvants, and excipients.

[0149] In another embodiment, pharmaceutical compositions comprising the compounds described herein as active ingredients are disclosed. The compounds of this disclosure are typically, but not necessarily, formulated into pharmaceutical compositions before administration to a patient. These pharmaceutical compositions comprise at least one of the compounds of this disclosure as defined herein or a pharmaceutically acceptable salt thereof in an effective dose, and one or more pharmaceutically acceptable excipients.

[0150] The excipient is selected from conventional excipients known to those skilled in the art, according to the desired pharmaceutical form and method of administration.

[0151] In these pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, topical application, intratracheal, intranasal, transdermal, or rectal administration, the active ingredient is a compound of formula (I) or a salt thereof or, where appropriate, a solvate thereof, and may be administered in unit dose form to subjects such as humans in mixtures with conventional pharmaceutical excipients for the prevention or treatment of diseases, disorders, or conditions at least partially mediated by receptor-interacting protein kinase 1, particularly acute and chronic neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS).

[0152] Unit dose Appropriate unit dosage forms include oral forms such as tablets, soft or hard gel capsules, powders, granules, and oral solutions or suspensions; sublingual, buccal, tracheal, intraocular, and intranasal administration forms; intramuscular or intravenous administration forms; rectal administration forms; and implantable tablets.

[0153] When prepared in unit dose form, the pharmaceutical compositions of this disclosure typically contain 1 mg to 1000 mg of the active ingredient. The amount of the active ingredient combined with one or more excipients to produce a single dose form will inevitably vary depending on the host being treated and the specific route of administration. For example, formulations intended for oral administration to humans generally contain, for example, 0.5 mg to 0.5 g of the active ingredient, combined with an appropriate and convenient amount of excipients, which may vary in weight from about 5 to about 98 percent of the total composition.

[0154] As an example, a unit dose form of a compound described herein in tablet form may include the following components: Compound 50.0mg Mannitol 223.75 mg Croscarmellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg

[0155] When using the compounds of this disclosure for therapeutic or preventive purposes, they are generally administered in a daily dose that is acceptable, for example, in the range of 0.1 mg / kg to 75 mg / kg body weight, and are given in divided doses as needed.

[0156] Generally, when parenteral routes are used, lower doses are administered. Therefore, for example, for intravenous or intraperitoneal administration, doses in the range of 0.1 mg / kg to 30 mg / kg body weight are commonly used. Oral administration may also be particularly preferred in tablet form. Typically, a single dosage form contains approximately 0.5 mg to 0.5 g of the compound of this disclosure.

[0157] There may be specific cases where a higher or lower dose is appropriate. Such doses do not deviate from the scope of this disclosure. According to common practice, the appropriate dose for each patient is determined by a physician according to the mode of administration and the patient's weight and response.

[0158] Treatment method In other embodiments, methods for treating receptor-interacting protein kinase 1-mediated diseases or disorders are provided herein. These methods involve administering a therapeutically effective amount of a compound or pharmaceutical composition described herein to a subject in need thereof. In some embodiments, the receptor-interacting protein kinase 1-mediated disease or disorder is Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS).

[0159] Therefore, the receptor-interacting protein kinase 1 inhibitors of this disclosure are useful for treating receptor-interacting protein kinase 1-mediated diseases and conditions, including, but not limited to, neurodegenerative diseases and central nervous system (CNS) diseases.

[0160] Neurodegenerative diseases and CNS diseases The receptor-interacting protein kinase 1 inhibitors described herein may also be used to treat neurodegenerative diseases. Neurodegenerative diseases can affect many bodily activities, including balance, movement, speech, breathing, and cardiac function. Neurodegenerative diseases may be hereditary or may be caused by medical conditions such as alcoholism, tumors, stroke, toxins, chemicals, and viruses. Non-exclusive examples of neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease.

[0161] In certain embodiments, the compounds and compositions of the Disclosure are useful for treating Alzheimer's disease. In certain embodiments, the compounds and compositions of the Disclosure are useful for treating Parkinson's disease. In certain embodiments, the compounds and compositions of the Disclosure are useful for treating amyotrophic lateral sclerosis (ALS).

[0162] More generally, the receptor-interacting protein kinase 1 inhibitors described herein can be used to preserve neuronal viability and promote axonal growth and neuronal function within the central nervous system (CNS). Therefore, the compounds may be used to reduce or even restore cognitive, motor, and sensory function loss associated with disease or impairment of the CNS by maintaining neuronal viability and / or promoting axonal regeneration and / or neuronal function.

[0163] If desired, the effective daily dose of the active compound may be administered in unit dosage form as optional subdoses of 2, 3, 4, 5, 6 or more, administered separately at appropriate intervals throughout the day. In certain embodiments, the disclosure relates to a compound for inhibiting cell death, wherein the compound is represented by formula (I). In certain embodiments, the compound of the disclosure is an inhibitor of cell death. In any case, the compound of the disclosure in a different embodiment exerts its effect on inhibiting cell death at a concentration of less than about 50 micromoles, in yet another embodiment less than about 10 micromoles, and in the most recent embodiment less than 1 micromoles. The compound of the disclosure can be tested in standard animal models of stroke and in standard protocols such as those described by Hara, H., et al. Proc. Natl. Acad. Sci. USA, 1997. 94(5):2007-12.

[0164] When the compounds of this disclosure are administered to humans and animals as pharmaceuticals, they can be given either by themselves or as pharmaceutical compositions containing, for example, 0.1% to 99.5% (or, in yet another embodiment, 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0165] The compounds or compositions thereof of this disclosure may be administered once, twice, three times, or four times daily. Administration or treatment with the compounds may also be continued for several days; for example, treatment will generally last for at least 7, 14, or 28 days during one treatment cycle. Treatment cycles are well known, frequently alternating with rest periods of approximately 1 to 28 days, generally about 7 or 14 days, between cycles. In certain embodiments, treatment cycles may be continuous.

[0166] When administered orally, the total daily dose for human subjects may be 1 mg to 1,000 mg, approximately 1,000 to 2,000 mg / day, approximately 10 to 500 mg / day, approximately 50 to 300 mg / day, approximately 75 to 200 mg / day, or approximately 100 to 150 mg / day.

[0167] The daily dose may also be described as the total amount of the compound described herein administered per dose or per day. The daily dose of the compound may be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day. In certain embodiments, the method involves administering an initial daily dose of about 1 to 800 mg of the compound described herein and increasing the dose incrementally until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose may be increased daily, every other day, twice a week, or once a week.

[0168] In certain embodiments, the compound or pharmaceutical formulation is administered orally. In certain embodiments, the compound or pharmaceutical formulation is administered intravenously. Other routes of administration include sublingual, intramuscular, and transdermal administration.

[0169] The formulations of this disclosure may be administered orally, parenterally, topically, or rectally. They are, of course, provided in a form suitable for each route of administration. For example, they may be administered by injection, infusion, or inhalation in the form of tablets or capsules, by injection, inhalation, eye drops, ointment, suppository, etc.; topically by lotion or ointment; and rectally by suppository. In certain embodiments, administration is orally. [Examples]

[0170] The following examples illustrate the preparation of specific compounds. These examples are not limiting and are merely illustrative. Numerous variations and alternative compositions, methods, and systems can be envisioned by those skilled in the art without departing from the spirit and scope of this disclosure.

[0171] [Table 53]

[0172] [Table 54]

[0173] [Table 55]

[0174] Silica gel chromatography Silica gel chromatography was performed using either the CombiFlash® Rf (Teledyne ISCO), Biotage Isolera One automated flash purification system, or two Buch systems equipped with pre-filled cartridges (combinations of C-660, C-605, C-620, C-635 and C-660, C-605, C-615, C-630).

[0175] Preparative reverse-phase HPLC For preparative reverse-phase HPLC, we used an Agilent 1200 preparative HPLC system, a Gilson system (GX-271 liquid handler, 331 / 332 pump, UV / VIS-155), or a Waters automated purification LC preparative system.

[0176] Preparative RP-LC Reverse-phase liquid chromatography was performed using a Biotage apparatus with a C18 column and a water (0.1% formic acid) / acetonitrile gradient.

[0177] NMR 400MHz: 1 ¹H NMR spectra were recorded using a Bruker AVANCE II 400 spectrometer operating at a proton frequency of 400.23 MHz. The instrument was equipped with a 5 mm BBI room-temperature probe head. Alternatively, a Bruker AVANCE III HD 400 MHz or Bruker AVANCE NEO 400 MHz was used.

[0178] 600 MHz: NMR spectra were recorded using a Bruker AVANCE III 600 spectrometer operating at a proton frequency of 600.05 MHz. The instrument was equipped with a 5 mm BBI room-temperature probe head.

[0179] LC / MS instrument for analysis for Method A Retention time and mass detection were performed using a Waters Acquity UHPLC system combined with a Waters SQD mass detector. The injection volume was 1.0 μl. Molecular weight is given in grams / moles [g / mol], and detected mass is given in mass / charge [m / z].

[0180] LC / MS instrument for analysis for Methods B and C For retention time and mass detection, Agilent LC / MS systems (LC1200 series / MS6120 quadrupole LC / MS, LC1260 infinity / MS6120 quadrupole LC / MS, or LC1260 Infinity II / MSD Infinity Lab) were used. Molecular weight is given in grams / moles [g / mol], and detected mass is given in mass / charge [m / z].

[0181] LC / MS-Method A Gradient: 98% H2O (0.05% formic acid) / 2% acetonitrile (0.035% formic acid) for 0.2 minutes, then 98% H2O (0.05% formic acid) to 98% acetonitrile (0.035% formic acid) for 3.6 minutes, then 98% acetonitrile (0.035% formic acid) for 0.5 minutes, flow rate: 1.0 ml / min, column: 2.1 × 50 mm Waters ACQUITY UPLC BEH C18, 1.7 μm, 55℃. UV data: Retention time at λ=220nm (given in minutes) MS data: ES + ionization, [M + H] unless otherwise specified. + The given m / z

[0182] LC / MS method B Gradient: 0.8 min from 95% H2O (0.0375% TFA) / 5% acetonitrile (0.01875% TFA) to 5% H2O (0.0375% TFA) / 95% acetonitrile (0.01875% TFA), Flow rate: 1.5 ml / min, Column: Kinetex EVO C18 2.1 × 30 mm, 5 μm, 50°C UV data: Retention time at λ=220nm (given in minutes) MS data: ES + ionization, [M + H] unless otherwise specified. + The given m / z

[0183] LC / MS-Method C Gradient: 0.8 min from 100% H2O (0.0375% TFA) / 0% acetonitrile (0.01875% TFA) to 60% H2O (0.0375% TFA) / 40% acetonitrile (0.01875% TFA), Flow rate: 1.5 ml / min, Column: Kinetex EVO C18 2.1×30 mm, 5 μm, 50°C UV data: Retention time at λ=220nm (given in minutes) MS data: ES + ionization, [M + H] unless otherwise specified. + The given m / z

[0184] salt For compounds listed as HCl-, TFA-, or other salts, the exact amount of each salt is usually not determined. Therefore, the amount of salt can range from as low as 0.01 equivalents to a maximum of 5.0 equivalents, depending on the chemical structure (e.g., the number of basic centers).

[0185] Chiral purity If the enantiomer ratio exceeds 90:10, isolate the compound and name it as a single enantiomer. If the enantiomer ratio is less than 90:10, use the racemic mixture.

[0186] Example 1: Synthesis of compounds (40), (41), (42), (69), (70), (84), and (87) Example 1.0: Step 1: Synthesis of methyltrans-4-[(2-nitroanilino)methyl]cyclohexanecarboxylate NetiPR2 (3.71 ml, 21.26 mmol) was added at room temperature to a stirred suspension of 1-fluoro-2-nitrobenzene (749 μL, 7.09 mmol) and methyl 4-(aminomethyl)cyclohexanecarboxylehydrochloride (1.50 g, 7.09 mmol) in CH3cN (22 ml). The solution was heated under reflux for 2 hours. Volatile components were removed under reduced pressure, and the resulting residue was partitioned between EA and water. The aqueous layer was extracted with EA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. Crude 4-[(2-nitroanilino)methyl]cyclohexanecarboxylate was obtained. This was purified by column chromatography (SiO2; EA / heptane gradient) (860 mg, 2.95 mmol, yield 41%). 1 H NMR(600MHz,DMSO-d6):δ ppm 8.18(br t,J=5.41Hz,1H),8.06(m,1H),7.52(t,J=7.84Hz,1H),7.07(d,J=8.44Hz,1H),6.67(t,J=7.85Hz,1H),3 .58(s,3H),3.27(m,2H),2.27(m,1H),1.93(m,2H),1.82(m,2H),1.63(m,1H),1.32(m,2H),1.06(m,2H).

[0187] Step 2: Synthesis of methyltrans-4-[(2-aminoanilino)methyl]cyclohexanecarboxylate A stirred suspension of methyl trans-4-(((2-nitrophenyl)aminomethyl)cyclohexane-1-carboxylate (862 mg, 2.95 mmol) in MeOH (70 ml) and Pd / C (10%, 54% water, 470 mg, 442 μmol) in a round-bottom flask was evacuated under reduced pressure at 0°C and filled with H2. This process was repeated three times. The suspension was vigorously stirred at room temperature for 2 hours under an H2 atmosphere (H2 balloon). The suspension was filtered, the filter cake was rinsed with MeOH, and the filtrate was concentrated under reduced pressure. The title compound was obtained as a yellow solid and used in the next reaction without further purification (695 mg, 2.65 mmol, yield 90%). 1H NMR(400MHz,DMSO-d6):δ ppm 6.49(m,2H),6.38(m,2H),4.47(s,2H),4.32(t,J=5.62Hz,1H),3.58(s,3H),2.86( t,J=6.11Hz,2H),2.27(m,1H),1.92(m,4H),1.55(m,1H),1.31(m,2H),1.00(m,2H)

[0188] Step 3: Synthesis of methyltrans-4-(95-enezimidazole-1-ylmethyl)cyclohexanecarboxylate A stirred solution of methyl trans-4-(((2-aminophenyl)amino)methyl)cyclohexane-1-carboxylate (694 mg, 2.65 mmol) and trimethyl orthoformate (15 ml, 137 mmol) in MeOH (15 ml) was mixed with concentrated hydrochloric acid (1.54 ml) at room temperature. The solution was stirred at room temperature for 1 hour. Volatile components were removed under reduced pressure, and the resulting residue was partitioned between saturated NaHCO3 aqueous solution and EA. The aqueous layer was extracted with EA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain methyl trans-4-benzimidazole-1-ylmethyl)cyclohexanecarboxylate. This was used in the next reaction without further purification (700 mg, 2.57 mmol, 97% yield). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.18(s,1H),7.64(m,2H),7.22(m,2H),4.10(d,J=7.09Hz,2H),3.56(s ,3H),2.24(m,1H),1.85(m,3H),1.58(m,2H),1.25(m,2H),1.07(m,2H).

[0189] Step 4: Synthesis of trans-4-(benzimidazole-1-ylmethyl)cyclohexanecarboxylic acid - hydrolysis as shown in Step 2 of Scheme 1 A solution of methyl trans-4-(benzimidazole-1-ylmethyl)cyclohexanecarboxylate (700 mg, 2.57 mmol) in MeOH (12 ml) and tetrahydrofuran (12 ml) was added to lithium hydroxide (185 mg, 7.71 mmol) in water (12 ml). The resulting solution was stirred at room temperature for 3 hours. Volatile components were removed under reduced pressure, and the remaining aqueous solution was acidified with 1N HCl (10.0 ml, 10.0 mmol). The resulting solution was freeze-dried. The title compound was obtained as a white solid (2 × LiCl mixture), which was used in the next reaction without further purification (1.05 g, quantified). 1 H NMR(400MHz,DMSO-d6):δ ppm 12.04(br s,1H),9.14(s,1H),7.90(d,J=7.21Hz,1H),7.80(d,J=7.27Hz,1H),7.48(m,2H),4.2 7(d,J=7.21Hz,2H),2.14(m,1H),1.91(m,3H),1.61(m,2H),1.24(m,2H),1.09(m,2H).

[0190] Step 5: Synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)-6-fluoro-1H-benzo[d]imidazole-5-carbonitrile HATU (151 mg, 398 μmol) was added at room temperature to a stirred solution of trans-4-[(5-cyano-6-fluoro-benzimidazole-1-yl)methyl]cyclohexanecarboxylic acid (100 mg, 331 μmol), NetiPr2 (174 μl, 995 μmol), and 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride (98.7 mg, 431 μmol) in DMF (2 ml). The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and subjected to preparative reverse-phase HPLC (70 mg, 147 μmol, yield 44%).

[0191] Example 1.1: Synthesis of compounds (40), (41), and (42) Step 1: The synthesis of methyl cis-3-(2-nitroanilino)cyclobutane carboxylate, the compound corresponding to formula (Va) as defined in Scheme 2, is carried out in the same manner as in Example 1.0, but methyl cis-3-(amino)cyclobutane carboxylate is used instead of methyl 4-(aminomethyl)cyclohexane carboxylate.

[0192] Step 2: The synthesis of methyl cis-3-(2-aminoanilino)cyclobutanecarboxylate, which is the compound corresponding to formula (VIa) defined in Scheme 2, is carried out in the same manner as in Example 1.0, but starting from cis-3-(2-nitroanilino)cyclobutanecarboxylate.

[0193] Step 3: The synthesis of methyl cis-3-(benzimidazole-1-yl)cyclobutanecarboxylate, which is the compound corresponding to formula (VIa) defined in Scheme 2, is carried out in the same manner as in Example 1.0, but starting from methyl cis-3-(2-aminoanilino)cyclobutanecarboxylate.

[0194] Step 4: The synthesis of cis-3-(benzimidazole-1-yl)cyclobutanecarboxylic acid, which is the compound corresponding to formula (IIa) of Scheme 1, is carried out in the same manner as in Example 1.0, but starting from methylcis-3-(benzimidazole-1-yl)cyclobutanecarboxylate.

[0195] Step 5a: The synthesis of cis-3-((S)-2-(3-(1H-benzo[d]imidazole-1-l)cyclobutan-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile (compound (40)) is carried out in the same manner as in Step 5 of Example 1.0, but starting with cis-3-(benzimidazole-1-yl)cyclobutancarboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazole-1-yl)methyl]cyclobutancarboxylic acid.

[0196] Step 5b: The synthesis of cis-(3-(1H-benzo[d]imidazole-1-yl)cyclobutyl)((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)methanone (compound (41)) is carried out in the same manner as in Step 5 of Example 1.0, but starting from cis-3-(benzoimidazole-1-yl)cyclobutanecarboxylic acid and (S)-3-(3,5-difluorophenyl)isoxazolidine.

[0197] Step 5c: The synthesis of cis-(3-(1H-benzo[d]imidazole-1-yl)cyclobutyl)((S)-3-(5-fluoropyridine-3-yl)isoxazolidine-2-yl)methanone (compound (42)) is carried out in the same manner as in Step 5 of Example 1.0, but starting from cis-3-(benzoimidazole-1-yl)cyclobutanecarboxylic acid and (S)-3-(5-fluoroxazolidine-3-yl)isoxazolidine.

[0198] Example 1.2: Synthesis of compounds (69) and (70) Step 1: The synthesis of methylcis-3-(4-fluoro-2-nitro-anilino)cyclobutanecarboxylate, the compound corresponding to formula (Va) as defined in Scheme 2, is carried out in the same manner as detailed in Step 1 of Example 1.0.

[0199] Step 2: The synthesis of methylcis-3-(2-amino-4-fluoro-anilino)cyclobutanecarboxylate, which is the compound corresponding to formula (IVa) as defined in Scheme 2, is carried out in the same manner as the method detailed in Step 2 of Example 1.0, but starting from methylcis-3-(4-fluoro-2-nitro-anilino)cyclobutanecarboxylate.

[0200] Step 3: The synthesis of methylcis-3-(5-fluorobenzimidazole-1-yl)cyclobutanecarboxylate, which corresponds to compound (IIIa) of Scheme 2, is carried out in the same manner as detailed in Step 3 of Example 1.0, but starting from methylcis-3-(2-amino-4-fluoroanilino)cyclobutanecarboxylate.

[0201] Step 4: The synthesis of cis-3-(5-fluorobenzimidazole-1-yl)cyclobutanecarboxylic acid is carried out in the same manner as detailed in Step 4 of Example 1.0 (Step 2 of Scheme 1), but starting from methylcis-3-(5-fluorobenzimidazole-1-yl)cyclobutanecarboxylate.

[0202] Step 5a: The synthesis of cis-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)(3-(5-fluoro-1H-benzo[d]imidazole-1-yl)cyclobutyl)methanone (compound (69)) is carried out in the same manner as in Step 5 of Example 1.0, but starting from cis-3-(5-fluorobenzimidazole-1-yl)cyclobutanecarboxylic acid and (S)-3-(3,5-difluorophenyl)isoxazolidine.

[0203] Step 5b: The synthesis of cis-3-fluoro-5-((S)-2-(3-(5-fluoro-1H-benzo[d]imidazole-1-yl)cyclobutan-1-carbonyl)isoxazolidine-3-yl)benzonitrile (compound (70)) is carried out in the same manner as in Step 5a of Example 1.0, but starting with cis-3-(5-fluorobenzimidazole-1-yl)cyclobutanecarboxylic acid and 3-fluoro-5-[(3S)-isoxazolidine-3-yl]benzonitrile hydrochloride.

[0204] Example 1.3: Synthesis of compound (84) Step 1: The synthesis of methyltrans-3-(4-fluoro-2-nitro-anilino)cyclobutanecarboxylate, which is the compound corresponding to formula (Va) defined in Scheme 2, is carried out in the same manner as detailed in Step 1 of Example 1.0, but starting from methyltrans-3-(amino)cyclobutanecarboxylate.

[0205] Step 2: The synthesis of methyltrans-3-(2-amino-4-fluoro-anilino)cyclobutanecarboxylate, which is the compound corresponding to formula (VIa) defined in Scheme 2, is carried out in the same manner as detailed in Step 2 of Example 1.0, but starting from methyltrans-3-(4-fluoro-2-nitro-anilino)cyclobutanecarboxylate.

[0206] Step 3: The synthesis of methyltrans-3-(5-fluorobenzimidazole-1-yl)cyclobutanecarboxylate, which corresponds to compound (IIIa) of Scheme 2, is carried out in the same manner as detailed in Step 3 of Example 1.0, but starting from trans-3-(2-amino-4-fluoro-anilino)cyclobutanecarboxylate.

[0207] Step 4: The synthesis of trans-3-(5-fluorobenzimidazole-1-yl)cyclobutanecarboxylic acid, which is the compound corresponding to formula (IIa) of Scheme 1, is carried out in the same manner as the method detailed in Step 4 of Example 1.0, but starting from methyltrans-3-(5-fluorobenzimidazole-1-yl)cyclobutanecarboxylate.

[0208] Step 5: The synthesis of trans-(3-(5-fluoro-1H-benzo[d]imidazole-1-yl)cyclobutyl)((S)-3-(3-fluorophenyl)isoxazolidine-2-yl)methanone (compound (84)) is carried out in the same manner as in Step 5 of Example 1.0, but starting with trans-3-(5-fluorobenzimidazole-1-yl)cyclobutanecarboxylic acid.

[0209] Example 1.4: Synthesis of compound (87) Step 1: The synthesis of methylcis-3-(5-fluoro-2-nitro-anilino)cyclobutanecarboxylate, which is the compound corresponding to formula (Va) defined in Scheme 2, is carried out in the same manner as the method detailed in Step 1 of Example 1.1, but starting from 1,3-difluoro-4-nitrobenzene.

[0210] Step 2: The synthesis of methylcis-3-(2-amino-5-fluoro-anilino)cyclobutanecarboxylate, which is the compound corresponding to formula (VIa) defined in Scheme 2, is carried out in the same manner as the method detailed in Step 2 of Example 1.1, but starting from methylcis-3-(5-fluoro-2-nitro-anilino)cyclobutanecarboxylate.

[0211] Step 3: The synthesis of methylcis-3-(6-fluorobenzimidazole-1-yl)cyclobutanecarboxylate, which corresponds to compound (IIIa) of Scheme 2, is carried out in the same manner as detailed in Step 3 of Example 1.1, but starting from methylcis-3-(2-amino-5-fluoro-anilino)cyclobutanecarboxylate.

[0212] Step 4: The synthesis of cis-3-(6-fluorobenzimidazole-1-yl)cyclobutanecarboxylic acid is carried out in the same manner as detailed in Step 4 of Example 1.1, but starting from methylcis-3-(6-fluorobenzimidazole-1-yl)cyclobutanecarboxylate.

[0213] Step 5: The synthesis of cis-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)(3-(6-fluoro-1H-benzo[d]imidazole-1-yl)cyclobutyl)methanone (compound (87)) is carried out in the same manner as in Step 5b of Example 1.1, but starting with cis-3-(6-fluorobenzimidazole-1-yl)cyclobutanecarboxylic acid.

[0214] Example 2: Synthesis of compounds (32), (33), (34), (35), (25), (26), (27), (36), (37), (38), (39) Example 2.1: Synthesis of compounds (32) and (33) Step 1: Synthesis of methyl cis-3-(3-cyano-4-fluoro-anilino)cyclobutanecarboxylate - Reaction in Step 6a of Scheme 3 2-Fluoro-5-iodobenzonitrile (500 mg, 1.98 mmol) was added to a stirred suspension of cis-3-aminocyclobutane-1-carboxylate hydrochloride (361.4 mg, 2.18 mmol), Cs2CO3 (1.29 g, 3.97 mmol), CuI (75.6 mg, 396.8 μmol), and 2-(2-methylpropanoyl)cyclohexanone (276 μl, 1.59 mmol) in DMF (4.06 ml, 5.11 mmol) at room temperature. Stirring was continued for 5 hours, the mixture was quenched with water and the aqueous layer extracted with EA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain the crude title compound, which was purified by column chromatography (SiO2; EA / heptane gradient) (183 mg, 735 μmol, yield 37%). 1 H NMR(600MHz,DMSO-d6):δ ppm 7.21(t,J=9.17Hz,1H),6.86(m,1H),6.80(dd,J=5.04,3.03Hz,1H),6.40(d,J= 7.15Hz,1H),3.79(m,1H),3.60(s,3H),2.86(m,1H),2.62(m,2H),1.96(m,2H).

[0215] Step 2: The synthesis of cis-3-(3-cyano-4-fluoro-anilino)cyclobutanecarboxylic acid is carried out in the same manner as detailed in Step 4 of Example 1.1, but starting from methylcis-3-(3-cyano-4-fluoro-anilino)cyclobutanecarboxylate.

[0216] Step 4a: The synthesis of cis-5-((3-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)-2-fluorobenzonitrile (compound (32)) is carried out in the same manner as in Step 5a of Example 1.1, but starting from cis-3-(3-cyano-4-fluoro-anilino)cyclobutanecarboxylic acid.

[0217] Step 4b: The synthesis of cis-2-fluoro-5-((3-((S)-3-(5-fluoropyridine-3-yl)isoxazolidine-2-carbonyl)cyclobutyl)amino)benzonitrile (compound (33)) is carried out in the same manner as in Step 5b of Example 1.1, but starting from cis-3-(3-cyano-4-fluoroanilino)cyclobutanecarboxylic acid.

[0218] Example 2.2: Synthesis of compounds (34) and (35) Step 1: The synthesis of methyltrans-4-[(3-cyano-4-fluoro-anilino)methyl]cyclohexanecarboxylate is carried out in the same manner as in Step 1 of Example 2.1, but starting from trans-4-[aminomethyl]cyclohexanecarboxylate.

[0219] Step 2: The synthesis of trans-4-[(3-cyano-4-fluoro-anilino)methyl]cyclohexanecarboxylic acid is carried out in the same manner as in Step 1 of Example 2.1, but starting from methyltrans-4-[(3-cyano-4-fluoro-anilino)methyl]cyclohexanecarboxylate.

[0220] Step 4a: The synthesis of trans-2-fluoro-5-(((4-((S)-3-(5-fluoropyridine-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)amino)benzonitrile (compound (34))) is carried out in the same manner as in Step 5c of Example 1, but starting from trans-4-[(3-cyano-4-fluoro-anilino)methyl]cyclohexanecarboxylic acid.

[0221] Step 4b: The synthesis of trans-5-(((4-(S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)amino)-2-fluorobenzonitrile (compound (35))) is carried out in the same manner as in Step 5a of Example 1.1, but starting from trans-4-[(3-cyano-4-fluoro-anilino)methyl]cyclohexanecarboxylic acid.

[0222] Example 2.3: Synthesis of compound (38) Step 1: Synthesis of methyltrans-4-(3-cyano-5-fluoro-anilino)methyl]cyclohexanecarboxylate - reaction in step 6b of scheme 3 To a stirred suspension of 3,5-difluorobenzonitrile (140 mg, 1.01 mmol) and methyl trans-4-(aminomethyl)cyclohexane-1-carboxylate hydrochloride (313.6 mg, 1.51 mmol) in DMSO (2 ml), K2CO3 (281.0 mg, 2.01 mmol) was added, and the resulting suspension was heated at 80°C for 16 hours. The mixture was cooled to room temperature and poured into water (50 ml). The suspension was stirred for 10 minutes, filtered, and the filter cake was washed with a small amount of water. The solid was dried under reduced pressure. The title compound was obtained as a white solid and used in the next reaction without further purification (34 mg, 117 μmol, yield 12%). 1 H NMR(400MHz,DMSO-d6):δ ppm 6.76(s,1H),6.76(d,J=11.17Hz,1H),6.65(m,1H),6.52(br t,J=5.50Hz,1H),3.58(s,3H),2.89(t,J=6.14Hz,2H),2.26(m,1H),1.92(br d,J=10.45Hz,2H),1.84(br d,J=10.45Hz,2H),1.49(m,1H),1.31(m,2H),0.99(m,2H).

[0223] Step 2: The synthesis of trans-4-[(3-cyano-5-fluoro-anilino)methyl]cyclobutanecarboxylic acid is carried out in the same manner as detailed in Step 4 of Example 1.1, but starting from methyltrans-4-[(3-cyano-5-fluoro-anilino)methyl]cyclohexanecarboxylate.

[0224] Step 4a: The synthesis of trans-3-((S)-2-(4-(((3-cyano-5-fluorophenyl)amino)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile (compound (38))) is carried out in the same manner as in Step 5a of Example 1.1, but starting from trans-4-[(3-cyano-5-fluoroanilino)methyl]cyclohexanecarboxylic acid.

[0225] Example 2.4: Synthesis of intermediates of compounds (36) and (37) Step 1: The synthesis of methyl cis-3-(3-cyano-5-fluoro-anilino)cyclobutanecarboxylate is carried out in the same manner as in Step 1 of Example 2.3, but starting from cis-3-aminocyclobutane-1-carboxylate.

[0226] Step 2: The synthesis of cis-3-(3-cyano-5-fluoro-anilino)cyclobutanecarboxylic acid is carried out in the same manner as detailed in Step 4 of Example 1.1, but starting from methylcis-3-(3-cyano-5-fluoro-anilino)cyclobutanecarboxylate.

[0227] Example 2.5: Synthesis of compound (39) Step 1: The synthesis of methyl cis-4-(3-cyano-5-fluoro-anilino)cyclohexanecarboxylate is carried out in the same manner as in Step 1 of Example 2.3, but starting from cis-4-aminocyclohexanecarboxylate.

[0228] Step 2: The synthesis of cis-4-(3-cyano-5-fluoro-anilino)cyclohexanecarboxylic acid, which is the compound corresponding to formula (IIa) of Scheme 1, is carried out in the same manner as detailed in Step 4 of Example 1.1, but starting from methyl cis-4-(3-cyano-5-fluoro-anilino)cyclohexanecarboxylate.

[0229] Step 4: The synthesis of cis-3-((S)-2-(4-((3-cyano-5-fluorophenyl)amino)cyclohexane-1-carbonyl)isoxazolin-3-yl)-5-fluorobenzonitrile (compound (39)) is carried out in the same manner as in Step 5a of Example 1.1.

[0230] Example 3: Synthesis of compounds (5), (6), (7), (8), (9), (10), and (11) Synthesis of methylcis-3-amino-1-methylcyclobutane-1-carboxylate trifluoroacetate To a stirred solution of methyl cis-3-(tert-butoxycarbonylamino)-1-methylcyclobutane carboxylate (300 mg, 1.23 mmol) in CH2Cl2 (9.0 ml), TFA (2.50 ml) was added, and stirring was continued at room temperature for 2 hours. The solution was concentrated under reduced pressure. The resulting crude material was redissolved in CH3CN and water and lyophilized (374 mg, 1.39 mmol, quantitative yield). 1 H NMR (400MHz, DMSO-d6): δ ppm 7.96 (br s, 3H), 3.78 (m, 1H), 3.64 (s, 3H), 2.44 (m, 2H), 2.14 (m, 2H), 1.36 (s, 3H).

[0231] (cis-3-amino-1-methyl-cyclobutyl)-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]methanone trifluoroacetate is synthesized by a similar method, starting from (3S)-3-(3,5-difluorophenyl)isoxazolidine.

[0232] The synthesis of cis-3-(tert-butoxycarbonylamino)-1-methylcyclobutanecarboxylic acid, which corresponds to formula (IIa) of Scheme 1, is carried out in the same manner as detailed in step 4 of Example 1.1, but starting from methylcis-3-(tert-butoxycarbonylamino)-1-methylcyclobutanecarboxylate.

[0233] Example 3.1: Synthesis of compounds (5), (6), and (7) Step 1: Synthesis of methyl cis-3-[(4-cyanopyrimidine-2-yl)amino]-1-methylcyclobutanecarboxylate, the compound corresponding to formula (III) in Scheme 1 - reaction in step 6b of Scheme 3 NetiPr2 (957 μl, 5.49 mmol) was added at room temperature to a stirred suspension of 2-chloropyrimidine-4-carbonitride (215 mg, 1.51 mmol) and methylcis-3-amino-1-methylcyclobutane-1-carboxylate-trifluoroacetate (353 mg, 1.37 mmol) in CH3CN (3.5 ml) in a microwave vial. The vial was sealed and the solution was heated to 80°C for 2 hours in a microwave reactor. Volatile components were removed under reduced pressure, and the resulting residue was purified by column chromatography (SiO2;CH2Cl2 / EtOH gradient). The resulting product was dissolved in CH3CN / water and lyophilized (221 mg, 900 μmol, 65% yield).

[0234] Step 2: Synthesis of cis-3-[(4-cyanopyrimidine-2-yl)amino]-1-methylcyclobutanecarboxylate trifluoroacetate and cis-3-[(4-carbamoylpyrimidine-2-yl)amino]-1-methylcyclobutanecarboxylate trifluoroacetate, which are compounds corresponding to formula (IIa) of Scheme 1. A solution of methyl cis-3-[(4-cyanopyrimidine-2-yl)amino]-1-methylcyclobutane carboxylate (220 mg, 893 μmol) in THF (15 ml) was mixed with a solution of lithium hydroxide (44 mg, 1.80 mmol) in water (1.5 ml). The resulting solution was stirred at room temperature for 4 hours. Volatile components were removed under reduced pressure, and the remaining aqueous solution was acidified with 1 N HCl. The aqueous layer was extracted with CH2Cl2, the combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain a mixture (158 mg) of cis-3-[(4-cyanopyrimidine-2-yl)amino]-1-methylcyclobutanecarboxylic acid and cis-3-[(4-carbamoyl-1-pyrimidine-2-yl)amino]-1-methylcyclobutanecarboxylic acid. 100 mg of the mixture was subjected to preparative reverse-phase chromatography to obtain cis-3-[(4-cyanopyrimidine-2-yl)amino]-1-methyl-cyclobutanecarboxylic acid trifluoroacetate (37 mg, 107 μmol, yield 12%) and cis-3-[(4-carbamoylpyrimidine-2-yl)amino]-1-methyl-cyclobutanecarboxylic acid trifluoroacetate (45 mg, 123 μmol, yield 14%). The remaining 58 mg was used in the next reaction without further purification. cis-3-[(4-cyanopyrimidine-2-yl)amino]-1-methylcyclobutanecarboxylate trifluoroacetate: 1 H NMR(400MHz,DMSO-d6):δ ppm 12.18(br s,1H),8.55(br s,1H),8.14(br d,J=6.97Hz,1H),7.10(d,J=4.65Hz,1H),4.35(br s,1H),2.35(m,2H),2.17(m,2H),1.37(s,3H). cis-3-[(4-carbamoylpyrimidine-2-yl)amino]-1-methylcyclobutanecarboxylate trifluoroacetate: 1H NMR(400MHz,DMSO-d6):δ ppm 12.18(br s,1H),8.46(br d,J=3.91Hz,1H),8.08(br s,1H),7.74(br s,1H),7.64(br s,1H),7.05(d,J=4.77Hz,1H),4.57(br s,1H),2.36(m,2H),2.18(m,2H),1.40(s,3H).

[0235] Step 3a: Synthesis of cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carbonitride (compound (5)) and cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxamide (compound (6)) A mixture of cis-3-[(4-cyanopyrimidine-2-yl)amino]-1-methylcyclobutanecarboxylic acid and cis-3-[(4-carbamoylpyrimidine-2-yl)amino]-1-methylcyclobutanecarboxylic acid (35 mg) was dissolved in DMF (4.5 ml). Under stirring, iPrNEt2 (100 μl, 0.58 mmol) and (S)-3-(3,5-difluorophenyl)isoxazolidine (30 mg, 160 μmol) dissolved in dry DMF (0.5 ml) were added, and after 15 minutes, HATU (113 mg, 290 μmol) was added. After stirring for 1 hour, the mixture was allowed to stand overnight. The mixture was then purified directly by preparative reverse-phase chromatography.

[0236] Step 3b: The synthesis of cis-2-((3-((S)-3-(5-cyanopyridine-3-yl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxamide (compound (7)) is carried out in the same manner as in Step 3a, but starting with (S)-3-(5-cyanopyridine-3-yl)isoxazolidine.

[0237] Example 3.2: Synthesis of compounds (8) and (9) NetiPr2 (75 μl, 428 μmol) was added at room temperature to a stirred suspension of ethyl 6-chloro-5-fluoropyrimidine-4-carboxylate (25 mg, 134 μmol) and (cis-3-amino-1-methyl-cyclobutyl)-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]methanonetrifluoroacetate (55 mg, 134 μmol) in CH3CN (1.5 ml) in a microwave reaction vial. The vial was sealed and the solution was heated to 80°C for 30 minutes in a microwave reaction reactor. Volatile components were removed under reduced pressure, and the resulting residue was purified by column chromatography (SiO2; heptane / EA gradient) to obtain compound (8) (30 mg, 65 μmol, yield 53%) and compound (9) (20 mg, 42 μmol, yield 34%).

[0238] Example 3.3: Synthesis of compounds (1), (3), and (4) cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carboxamide (compound (1)), methylcis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carboxylate (compound (3)) and trans-2-((3-((S)-3-(3,5-difluorophenyl)isoxazol Phosphorus-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carboxamide (compound (4)) is synthesized in the same manner as compounds (8) and (9) in Example 3.2, starting from (cis-3-amino-cyclobutyl)-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]methanone and (trans-3-aminocyclobutyl)-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]methanone, respectively.

[0239] Example 3.4: Synthesis of cis-6-chloro-5-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxamide (compound (10)) Ethyl 6-chloro-5-[[cis-3-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl]-3-methylcyclobutyl]amino]pyrimidine-4-carboxylate (3 mg, 10 μmol) was dissolved in a solution of 7 M NH3 in methanol (0.3 ml). After stirring for 1 hour, the solvent mixture was removed under vacuum. The residue was freeze-dried to obtain the title compound in quantitative yield.

[0240] Example 3.5: Synthesis of cis-6-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)-5-fluoropyrimidine-4-carboxamide (compound (11)) Ethyl 6-[[cis-3-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl]-3-methyl-cyclobutyl]amino]-5-fluoropyrimidine-4-carboxylate (26 mg, 60 μmol) was dissolved in a solution of 7 M NH3 in methanol (2.3 ml). After stirring for 1 hour, the solvent mixture was removed under vacuum. The residue was purified by reverse-phase chromatography, and after lyophilization, 15.9 mg (36.5 μmol, yield 61%) of the title compound was obtained.

[0241] Example 4: Synthesis of compounds (96), (97), (98), (109), and (110) Example 4.0: Synthesis of methyltrans-4-(methylsulfonyloxymethyl)cyclohexanecarboxylate To a stirred solution of methyl trans-4-(hydroxymethyl)cyclohexanecarboxylate (4 g, 22.5 mmol) and Net3 (8.79 ml, 63.1 mmol) in THF (100 ml), methanesulfonyl chloride (2.67 ml, 33.8 mmol) was added dropwise at 0°C. The resulting suspension was stirred at room temperature for 2 hours. The reaction mixture was filtered, the filter cake was rinsed with THF, and the filtrate was concentrated under reduced pressure. The title compound was obtained as a pale yellow solid, which was used in the next reaction without further purification (5.64 g, 22.5 mmol, quantitative yield). 1 H NMR(400MHz,CDCl3):δ ppm 4.05(d,J=7.21Hz,2H),3.67(s,3H),3.01(s,3H)2.28(m,1H),2.05(m,2H),1.89(m,2H),1.75(m,1H),1.42(m,2H),1.09(m,2H)

[0242] The synthesis of methyl 3-methylsulfonyloxycyclobutane carboxylate is carried out in the same manner as described in detail for methyl trans-4-(methylsulfonyloxymethyl)cyclohexane carboxylate in Example 4.0, but starting from methyl 3-hydroxycyclobutane carboxylate.

[0243] Example 4.1: Synthesis of compounds (96), (97), (98), (109), and (110) Step 1: Synthesis of methyltrans-3-(5-fluoroindazole-1-yl)cyclobutanecarboxylate, methyltrans-3-(5-fluoroindazole-2-yl)cyclobutanecarboxylate, methylcis-3-(5-fluoroindazole-1-yl)cyclobutanecarboxylate, and methylcis-3-(5-fluoroindazole-2-yl)cyclobutanecarboxylate - Reaction in Step 6c of Scheme 3 A solution of methyl 3-methylsulfonyloxycyclobutane carboxylate (3.21 g, 15.43 mmol, 1.4 equivalents), 5-fluoro-1H-indazole (1.5 g, 11.02 mmol, 1 equivalent), and Cs2CO3 (7.18 g, 22.04 mmol, 2 equivalents) in DMF (10 ml) was stirred at 80°C for 16 hours. A saturated NH4Cl solution was added at 25°C to adjust the pH to 7-8, and the mixture was extracted with 150 ml of EA (50 ml x 3). The combined organic phase was washed with 100 ml of saturated brine (50 ml x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was then subjected to preparative HPLC (column: Phenomenex Luna). Purified using C18 (250 × 70 mm, 10 μm); mobile phase: [water (0.1% TFA)-ACN]; ACN 32%~62%, 25 min), the title compound methyltrans-3-(5-fluoroindazole-1-yl)cyclobutanecarboxylate (0.413 g, 1.66 mmol, yield 15%) was obtained as a yellow solid, and methyltrans-3-(5-fluoroindazole-2-yl)cyclobutanecarboxylate was obtained. Silate (0.95 g, 3.83 mmol, yield 35%) was obtained as a yellow oily substance, methyl cis-3-(5-fluoroindazole-1-yl)cyclobutane carboxylate (0.218 g, 878.14 μmol, yield 8%) was obtained as a yellow solid, and methyl cis-3-(5-fluoroindazole-2-yl)cyclobutane carboxylate (0.44 g, 1.77 mmol, yield 16%) was obtained as a yellow oily substance. Methyltrans-3-(5-fluoroindazole-1-yl)cyclobutanecarboxylate: 1 H NMR(400MHz,CDCl3):δ ppm 8.03(s,1H),7.71(dd,J=4.6,9.3Hz,1H),7.24(dd,J=2.1,9.0Hz,1H),5.04(t,J=8.3Hz,1H),3.77(s,3H),3.15-3.03(m,1H),3.03-2.85(m,4H). Methyltrans-3-(5-fluoroindazole-2-yl)cyclobutanecarboxylate: 1H NMR(400MHz,CDCl3):δ ppm 7.92(s,1H),7.72(dd,J=4.6,9.3Hz,1H),7.23(dd,J=2.0,9.0Hz,1H),7.12(dt,J=2.4,9.3Hz,1 H),5.32(t,J=8.1Hz,1H),3.80(s,3H),3.40-3.27(m,1H),3.17-3.03(m,2H),2.94-2.81(m,2H). Methylcis-3-(5-fluoroindazole-1-yl)cyclobutanecarboxylate: 1 H NMR(400MHz,CDCl3):δ ppm 7.91(s,1H),7.39(dd,J=4.1,9.1Hz,1H),7.27(dd,J=2.3,8.6Hz,1H),7.09(dt,J=2. 4,9.0Hz,1H),4.99-4.83(m,1H),3.68(s,3H),3.09-2.91(m,3H),2.80-2.66(m,2H). Methylcis-3-(5-fluoroindazole-2-yl)cyclobutanecarboxylate: 1 H NMR(400MHz,CDCl3):δ ppm 8.03(s,1H),7.44-7.32(m,2H),7.17(dt,J=2.4,9.0Hz,1H),5.37(quin,J=8.0 Hz,1H),3.81(s,3H),3.37-3.24(m,1H),3.16-3.00(m,2H),2.90-2.73(m,2H).

[0244] Step 2: The synthesis of cis-3-(5-fluoroindazole-2-yl)cyclobutanecarboxylic acid, cis-3-(5-fluoroindazole-1-yl)cyclobutanecarboxylic acid, and trans-3-(5-fluoroindazole-1-yl)cyclobutanecarboxylic acid, which are compounds corresponding to formula (IIa) of Scheme 1, is carried out in the same manner as detailed in Step 4 of Example 1.1, starting from their respective methyl esters.

[0245] Step 3a: The synthesis of cis-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-[3-(5-fluoroindazole-1-yl)cyclobutyl]methanone (compound (96)) is carried out in the same manner as in Step 5b of Example 1.1.

[0246] Step 3b: The synthesis of trans-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-[3-(5-fluoroindazole-1-yl)cyclobutyl]methanone (compound (97)) is carried out in the same manner as in Step 5b of Example 1.1.

[0247] Step 3c: The synthesis of trans-3-fluoro-5-[(3S)-2-[3-(5-fluoroindazole-1-yl)cyclobutanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (98)) is carried out in the same manner as in step 5a of Example 1.1.

[0248] Step 3d: The synthesis of cis-3-fluoro-5-[(3S)-2-[3-(5-fluoroindazole-2-yl)cyclobutanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (109)) is carried out in the same manner as in step 5a of Example 1.1.

[0249] Step 3e: The synthesis of cis-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-[3-(5-fluoroindazole-2-yl)cyclobutyl]methanone (compound (110)) is carried out in the same manner as in step 5b of Example 1.1.

[0250] Example 4.2: Synthesis of compounds (105), (106), (107), and (108) Step 1: Synthesis of methyl 3-(5-fluoroindole-1-yl)cyclobutanecarboxylate, the compound corresponding to formula (III) in Scheme 1 - reaction in step 6c of Scheme 3 To a solution of 5-fluoro-1H-indole (1.5 g, 11.10 mmol, 1 equivalent) in DMF (15 ml), Cs2CO3 (7.23 g, 22.20 mmol, 2 equivalents) and methyl 3-methylsulfonyloxycyclobutane carboxylate (3.47 g, 16.65 mmol, 1.5 equivalents) were added. The mixture was stirred at 80°C for 12 hours. The reaction mixture was adjusted to pH 3-4 with 1N HCl. The precipitate was collected by filtration and dried under reduced pressure to obtain the desired compound. The aqueous phase was extracted with EA (100 ml x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reverse-phase HPLC (under 0.1% formic acid conditions) to obtain methyl 3-(5-fluoroindole-1-yl)cyclobutane carboxylate (823 mg, 3.33 mmol, 30% yield).

[0251] Step 2: Synthesis of trans-3-(5-fluoroindole-1-yl)cyclobutanecarboxylic acid and cis-3-(5-fluoroindole-1-yl)cyclobutanecarboxylic acid - Compounds corresponding to formula (IIa) of Scheme 1 LiOH·H2O (290.18 mg, 6.92 mmol, 1 equivalent) was added to a solution of methyl 3-(5-fluoroindole-1-yl)cyclobutanecarboxylate (1.71 g, 6.92 mmol, 1 equivalent) in THF (9 ml) and water (9 ml). The mixture was stirred at 25°C for 1 hour. Several novel peaks were observed by LC / MS, and approximately 81% of the desired compound was detected. The reaction mixture was concentrated. The crude product was purified by reverse-phase HPLC (under 0.1% formic acid conditions), and then by preparative HPLC (column: Phenomenex luna C18 150×40 mm, 15 μm; mobile phase: [water (0.225% formic acid)-ACN]; gradient: 38%~48% ACN in 10 minutes) to obtain a cis / trans mixture of 3-(5-fluoroindole-1-yl)cyclobutanecarboxylic acid (1.3 g, yield 76%) as a white solid.

[0252] A cis / trans mixture of 3-(5-fluoroindole-1-yl)cyclobutanecarboxylic acid (1.54 g, 6.58 mmol, 1 equivalent) was separated by SFC (column: DAIEL CHIRALPAK AD, 250 × 30 mm, 10 μm; mobile phase: 20% MeOH [+0.1% NH3H2O] in supercritical CO2, single batch cycle process with a delay time of 6.1 minutes between two consecutive injections; total duration 400 minutes) to obtain trans-3-(5-fluoroindole-1-yl)cyclobutanecarboxylic acid (375 mg, >99.9% ee) as a yellow solid and cis-3-(5-fluoroindole-1-yl)cyclobutanecarboxylic acid (1.1 g, >99.9% ee) as a yellow oil. trans-3-(5-fluoroindole-1-yl)cyclobutancarboxylic acid: 1 H NMR(400MHz,DMSO-d6):δ ppm 7.70(d,J=3.2Hz,1H),7.43(dd,J=4.5,8.9Hz,1H),7.30(dd,J=2.6,9.9Hz,1H),6.95(dt,J=2.6,9 .2Hz,1H),6.47(d,J=3.1Hz,1H),5.10(quin,J=8.3Hz,1H),3.11-3.01(m,1H),2.77-2.59(m,4H). cis-3-(5-fluoroindole-1-yl)cyclobutancarboxylic acid: 1 H NMR(400MHz,DMSO-d6):δ ppm 7.57(d,J=3.2Hz,1H),7.53(dd,J=4.5,9.0Hz,1H),7.30(dd,J=2.5,9.8Hz,1H),6.97(dt,J=2.6,9.2Hz,1H),6.45( d,J=3.2Hz,1H),4.96-4.78(m,1H),4.03(q,J=7.2Hz,1H),2.96-2.79(m,1H),2.76-2.65(m,2H),2.57-2.51(m,2H).

[0253] Step 3a: The synthesis of trans-3-fluoro-5-[(3S)-2-[3-(5-fluoroindol-1-yl)cyclobutanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (105)) is carried out in the same manner as in Step 5a of Example 1.1.

[0254] Step 3b: The synthesis of trans-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-[3-(5-fluoroindole-1-yl)cyclobutyl]methanone (compound (106)) is carried out in the same manner as in Step 5b of Example 1.1.

[0255] Step 3c: The synthesis of cis-3-fluoro-5-[(3S)-2-[3-(5-fluoroindol-1-yl)cyclobutanecarbonyl]isoxazolidine-3-yl]benzonitrile (compound (107)) is carried out in the same manner as in step 5a of Example 1.1.

[0256] Step 3d: The synthesis of cis-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-[3-(5-fluoroindole-1-yl)cyclobutyl]methanone (compound (108)) is carried out in the same manner as in step 5b of Example 1.1.

[0257] Example 5: Synthesis of compound (114) Step 1: Synthesis of methyl cis-3-(4-carbamoyl-2-pyridyl)cyclopentanecarboxylate, the compound corresponding to formula (III) in Scheme 1. Step a: Synthesis of 2-bromopyridine-4-carboxamide A mixture of 2-bromopyridine-4-carboxylic acid (8.6 g, 42.57 mmol, 1 equivalent), NH4Cl (3.42 g, 63.86 mmol, 1.5 equivalents), NetiPr2 (22.01 g, 170.29 mmol, 29.66 ml, 4 equivalents), and CDI (8.28 g, 51.09 mmol, 1.2 equivalents) in DMF (80 ml) was degassed, purged three times with N2, and stirred at 20°C for 3 hours under an N2 atmosphere. The mixture was diluted with water (500 ml), extracted with EA (300 ml x 4), dried over Na2SO4, filtered, and concentrated. The residue was ground together with DCM (30 ml) to obtain the title compound (5.7 g, yield 67%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ ppm 8.53(d,J=5.0Hz,1H),8.31(br s,1H),8.00(s,1H),7.91-7.76(m,2H).

[0258] Step b: Synthesis of methyl 3-(trifluoromethylsulfonyloxy)cyclopenta-2-ene-1-carboxylate To a solution of methyl 3-oxocyclopentane carboxylate (19 g, 133.66 mmol, 1 equivalent) and NetiPr2 (25.91 g, 200.49 mmol, 34.92 ml, 1.5 equivalents) in toluene (500 ml), Tf2O (56.57 g, 200.49 mmol, 33.08 ml, 1.5 equivalents) was added dropwise at 45°C. After addition, the mixture was stirred at 45°C for 1 hour. The mixture was diluted with water (300 ml) and extracted with EA (300 ml x 2). The combined organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, petroleum ether / EA = 10 / 1 to 3 / 1) to obtain the title compound (29.3 g, yield 80%) as a black oil.

[0259] Step c: Synthesis of methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopenta-2-ene-1-carboxylate A mixture of methyl 3-(trifluoromethylsulfonyloxy)cyclopenta-2-ene-1-carboxylate (29 g, 105.76 mmol, 1 equivalent), KOAc (10.38 g, 105.76 mmol, 1 equivalent), BPD (26.86 g, 105.76 mmol, 1 equivalent), KOAc (10.38 g, 105.76 mmol, 1 equivalent), and DPPF (2.93 g, 5.29 mmol, 0.05 equivalent) in 300 ml of dioxane was degassed, purged three times with N2, and stirred at 20°C for 0.5 hours. Pd(dppf)Cl2·CH2Cl2 (4.32 g, 5.29 mmol, 0.05 equivalent) was added, and the mixture was stirred at 90°C for 12 hours under an N2 atmosphere. The mixture was concentrated, diluted with water (200 ml), extracted with EA (150 ml x 3), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash silica gel chromatography (petroleum ether / EA = 5 / 1) to obtain the title compound (25 g, yield 94%) as a yellow oily substance. 1 H NMR:(400MHz,CDCl3):δ ppm 6.52-6.36(m,1H),3.69(d,J=1.0Hz,3H),3.67-3.60(m,1H),3.20-3.08(m,1H),2.87 -2.70(m,2H),2.68-2.55(m,1H),2.53-2.40(m,1H),2.21-2.11(m,1H),1.27(s,12H).

[0260] Step d: Synthesis of methyl 3-(4-carbamoyl-2-pyridyl)cyclopenta-2-ene-1-carboxylate A mixture of methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopenta-2-ene-1-carboxylate (4.52 g, 17.91 mmol, 1.2 equivalents), 2-bromopyridine-4-carboxamide (3 g, 14.92 mmol, 1 equivalent), Na2CO3 (3.16 g, 29.85 mmol, 2 equivalents), X-PHOS (1.07 g, 2.24 mmol, 0.15 equivalents), and Pd(PPh3)4 (1.72 g, 1.49 mmol, 0.1 equivalent) in dioxane (40 ml) and water (10 ml) was degassed, purged three times with N2, and stirred at 80°C for 12 hours under an N2 atmosphere. The mixture was cooled to 20°C, diluted with EA (300 ml), washed with water (50 ml x 2), dried over Na2SO4, filtered, concentrated, and purified by preparative RP-LC (column: Welch Ultimate XB C18, 120 Å, ID 72 x 300 mm, 20-40 μm, mobile phase: water (0.1% formic acid) and ACN; gradient: 10%-35% ACN over 30 mins; 35% acetonitrile over 5 mins; flow rate: 200 ml / min) to obtain the title compound (1.1 g, yield 30%) as a yellow solid. LC / MS: m / z 247.2[M+H] +

[0261] Step e: Synthesis of methyl cis-3-(4-carbamoyl-2-pyridyl)cyclopentanecarboxylate To a solution of methyl 3-(4-carbamoyl-2-pyridyl)cyclopenta-2-ene-1-carboxylate (1.1 g, 4.47 mmol, 1 equivalent) in MeOH (10 ml), Pd / C (13 mg, 4.47 mmol, 10% purity, 1.00 equivalent) was added under an N2 atmosphere. The suspension was degassed, purged three times with H2, and stirred at 20°C for 1 hour under H2 (15 Psi). The reaction mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, DCM:MeOH = 10:1) to obtain the title compound (1 g, 88% yield) as a yellow solid. LC / MS: m / z 249.1[M+H] + 1H NMR(400MHz,DMSO-d6):δ ppm 8.61(d,J=5.0Hz,1H),8.21(br s,1H),7.66(s,2H),7.58(dd,J=1.4,5.1Hz,1H),3.65-3.59(m,3H),3.17(d,J=5.3H) z,1H),3.05-2.90(m,1H),2.35-2.24(m,1H),2.14-1.92(m,4H),1.89-1.76(m,1H).

[0262] Step 2: The synthesis of cis-3-(4-carbamoyl-2-pyridyl)cyclopentanecarboxylic acid, which is the compound corresponding to formula (IIa) of Scheme 1, is carried out in the same manner as detailed in Step 4 of Example 1.1, starting from methyl cis-3-(4-carbamoyl-2-pyridyl)cyclopentanecarboxylate.

[0263] Step 3: Synthesis of cis-2-[3-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl]cyclopentyl]pyridine-4-carboxamide (compound (114)). (3S)-3-(3,5-difluorophenyl)isoxazolidine (198.69 mg, 896.48 μmol, 1.05 equivalents, HCl) was added to a solution of cis-3-(4-carbamoyl-2-pyridyl)cyclopentancarboxylic acid (200.00 mg, 853.79 μmol, 1 equivalent), NetiPr2 (331.03 mg, 2.56 mmol, 446.13 μl, 3 equivalents), and T3P (651.98 mg, 1.02 mmol, 609.33 μl, 50% purity, 1.2 equivalents) in DMF (2 ml). The mixture was stirred at 20°C for 3 hours, diluted with water (20 ml), extracted with EA (10 ml x 3), washed with brine (10 ml), dried over Na2SO4, filtered, concentrated under reduced pressure, and the title compound (150 mg, crude) was obtained as a yellow oil.

[0264] A racemic mixture (150 mg) of cis-2-[3-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl]cyclopentyl]pyridine-4-carboxamide was separated by SFC (column: DAIEL CHIRALPAK AD, 250 × 30 mm, 10 μm; mobile phase: 45% MeOH (0.1% NH3·H2O) in supercritical CO2, single batch cycle process with a delay time of 5.2 minutes between two consecutive injections; total duration 30 minutes) to obtain stereoisomer 1 of cis-2-[3-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl]cyclopentyl]pyridine-4-carboxamide (peak 1, 77 mg) and stereoisomer 2 of compound 114 (peak 2, 42 mg) as off-white solids. cis-2-[3-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl]cyclopentyl]pyridine-4-carboxamide stereoisomer 1, peak 1: LC / MS: m / z 402.2[M+H] + , Rt=0.788 min (LC / MS method B) SFC (column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; mobile phase: CO2 and MeOH (0.05% DEA), gradient: 5% to 40% MeOH (0.05% DEA); flow rate: 3 ml / min; column temperature: 35 °C; 100 bar): Rt = 1.93 min (100%). 1H NMR(400MHz,CDCl3):δ ppm 8.67(d,J=5.0Hz,1H),7.69(s,1H),7.48(dd,J=1.5,5.0Hz,1H),6.90-6.81(m,2H),6.71(tt,J=2.1,8.9Hz,1H),6.27(br dd,J=4.0,6.9Hz,1H),5.82-5.51(m,1H),5.39(dd,J=6.1,8.8Hz,1H),4.26(dt,J=3.1,7.9Hz,1H),3.94-3.83(m,1H), 3.51-3.35(m,2H),2.86(dddd,J=3.0,6.5,9.2,12.3Hz,1H),2.44-2.27(m,2H),2.24-2.09(m,4H),2.04-1.91(m,1H).

[0265] Example 6: Synthesis of compounds (122), (123), (124), (125), (126), (127), and (128) Example 6.0: Synthesis of trans-4-[(6-carbamoyl-5-fluorobenzimidazole-1-yl)methyl]cyclohexanecarboxylic acid To a solution of trans-4-[(6-cyano-5-fluoro-benzimidazole-1-yl)methyl]cyclohexanecarboxylic acid (100 mg, 332 μmol) in THF (4 ml), hydrogen peroxide (50%, 40 μl, 663 μmol) was added at room temperature, followed by the addition of a solution of lithium hydroxide (19 mg, 797 μmol) in water (4 ml). The resulting solution was stirred at room temperature for 30 minutes, after which the same amount of hydrogen peroxide was added. The volatile components were removed under reduced pressure, and the remaining aqueous solution was diluted with approximately 3 ml of water and acidified with 1 N HCl (796 μL, 796 μmol). The resulting suspension was stirred for 10 minutes and filtered. The title compound was obtained as a white solid, which was used in the next reaction without further purification (76 mg, 72%).

[0266] Example 6.1 Step 1: Synthesis of methyl 4-[(6-cyanopyrimidine-4-yl)oxymethyl]cycloheptanecarboxylate, the compound corresponding to formula (III) in Scheme 1. Step a: Synthesis of 2-(3-oxo-3-phenyl-propyl)cyclopentanone To a solution of 3-(dimethylamino)-1-phenyl-propane-1-one hydrochloride (15.00 g, 70.19 mmol, 1 equivalent) in dioxane (150 ml), 4-(cyclopenten-1-yl)morpholine (10.75 g, 70.19 mmol, 11.23 ml, 1 equivalent) was added, and the mixture was stirred at 110°C for 12 hours. The reaction mixture was concentrated, diluted with EA (150 ml), washed with 1 N HCl (30 ml), the aqueous layer was extracted with EA (20 ml x 3), the combined organic layers were washed with brine (100 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / EA = 10 / 1) to obtain the title compound (8 g, yield 53%) as a white solid. LC / MS: m / z 217.1[M+H] + 1 H NMR(400MHz,CDCl3):δ ppm 7.98(d,J=7.3Hz,2H),7.64-7.52(m,1H),7.52-7.43(m,2H),3.14(ddd,J=4.7,6.6,8. 0Hz,2H),2.41-2.08(m,5H),2.04-1.98(m,1H),1.90-1.75(m,2H),1.68-1.52(m,2H).

[0267] Step b: Synthesis of 4-phenylcyclohepta-3-ene-1-carboxylic acid To a solution of 2-(3-oxo-3-phenylpropyl)cyclopentanone (8 g, 36.99 mmol, 1 equivalent) in AcOH (65 ml), HCl (12 M, 15 ml, 4.87 equivalents) was added, and the mixture was stirred at 110°C for 4 hours. The mixture was concentrated, poured into 1 N NaOH (10 ml), washed with DCM (10 ml), and the pH was adjusted to 1 by adding 1 N HCl. Extraction was performed with EA (30 ml x 2) to obtain the title compound (6.2 g, crude) as a yellow oily substance. LC / MS: m / z 217.2[M+H] 1H NMR(400MHz,DMSO-d6):δ ppm 12.05-11.98(m,1H),7.32-7.29(m,4H),7.27-7.23(m,1H),6.24-5.84(m,1H),2.71 -2.62(m,2H),2.36-2.30(m,2H),2.23(s,1H),2.15-1.79(m,6H),1.63-1.42(m,2H).

[0268] Step c: Synthesis of methyl 4-phenylcyclohepta-3-ene-1-carbonxylate To a solution of 4-phenylcyclohepta-3-ene-1-carboxylic acid (6.2 g, 28.67 mmol, 1 equivalent) in MeOH (60 ml), H2SO4 (562.33 mg, 5.73 mmol, 305.61 μl, 0.2 equivalents) was added, and the mixture was stirred at 70°C for 12 hours. The mixture was concentrated, diluted with EA (50 ml), washed with water (20 ml x 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the title compound (6 g, crude) as a yellow oil. LC / MS: m / z 231.2[M+H] +

[0269] Step d: Synthesis of 4-methoxycarbonylcycloheptanecarboxylic acid To a solution of methyl 4-phenylcyclohepta-3-ene-1-carboxylate (5.8 g, 24.97 mmol, 1 equivalent) and NaIO4 (96.12 g, 449.39 mmol, 24.90 ml, 18 equivalents) in ACN (60 ml) and water (120 ml), CCl4 (60 ml) and RuCl3 (103.57 mg, 499.32 μmol, 33.30 μl, 0.02 equivalents) were added, and the mixture was stirred at 20°C for 12 hours. The mixture was filtered and concentrated, the pH was adjusted to pH 8 with saturated sodium bicarbonate solution, washed with DCM (40 ml), acidified to pH 1 with 1N HCl, extracted with EA (80 ml x 2), dried over Na2SO4, filtered, and concentrated to obtain the title compound (3 g, crude) as a yellow oil. 1H NMR (400MHz, CD3OD): δ ppm 4.88(br s,3H),2.64-2.41(m,2H),2.10-2.05(m,1H),2.00-1.81(m,5H),1.79-1.58(m,4H),1.53-1.38(m,1H).

[0270] Step e: Synthesis of methyl 4-(hydroxymethyl)cycloheptane carboxylate To a solution of 4-methoxycarbonylcycloheptancarboxylic acid (3 g, 14.98 mmol, 1 equivalent) in THF (30 ml), BH3·Me2S (10 M, 1.95 ml, 1.3 equivalents) was added at 0°C under a N2 atmosphere, and the mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, DCM / MeOH = 5 / 1) to obtain the title compound (1.8 g, yield 65%) as a yellow oil. 1 H NMR(400MHz,CD3OD):δ ppm 3.64(s,3H),3.38-3.32(m,1H),2.61-2.43(m,1H),2.07-2.02(m,1H),2.01-1.93(m,1H),1.93-1.80( m,3H),1.79-1.67(m,2H),1.67-1.52(m,3H),1.49-1.34(m,1H),1.32-1.17(m,1H),1.16-1.00(m,1H).

[0271] Step f: Synthesis of methyl 4-[(6-chloropyrimidine-4-yl)oxymethyl]cycloheptane carboxylate To a solution of 4,6-dichloropyrimidine (1.12 g, 7.52 mmol, 1 equivalent) and methyl 4-(hydroxymethyl)cycloheptane carboxylate (1.4 g, 7.52 mmol, 1 equivalent) in DMF (14 ml), NaH (450.97 mg, 11.28 mmol, 60% purity, 1.5 equivalents) was added at 0°C, and the mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with water (100 ml), extracted with EA (30 ml x 3), washed with brine (50 ml), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, DCM / MeOH=5 / 1) to obtain the title compound (1.5 g, 64% yield) as a yellow oil. LC / MS: m / z 299.1[M+H] + 1 H NMR(400MHz,CDCl3):δ ppm 8.56(s,1H),6.77(s,1H),4.24-4.15(m,2H),3.68(s,3H),2.61-2.45(m,1H),2.13-1.97(m,2H),1.96-1. 84(m,3H),1.82-1.73(m,1H),1.72-1.60(m,2H),1.56-1.49(m,1H),1.48-1.31(m,1H),1.30-1.16(m,1H).

[0272] Step g: Synthesis of methyl 4-[(6-cyanopyrimidine-4-yl)oxymethyl]cycloheptanecarboxylate, which is the compound corresponding to formula (III) in Scheme 1. A mixture of methyl 4-[(6-chloropyrimidine-4-yl)oxymethyl]cycloheptanecarboxylate (1.5 g, 5.02 mmol, 1 equivalent), Zn(CN)2 (2.36 g, 20.08 mmol, 1.27 ml, 4 equivalents), and Pd(PPh3)4 (1.16 g, 1.00 mmol, 0.2 equivalents) in DMF (15 ml) was purged three times with N2 and stirred at 100°C for 16 hours under an N2 atmosphere. The reaction product was diluted with water (200 ml), extracted with EA (80 ml x 3), washed with brine (100 ml x 2), dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and purified by flash silica gel chromatography (SiO2, DCM:MeOH = 10:1) to obtain the title compound (1.2 g, yield 79%) as a yellow solid. LC / MS: m / z 290.1[M+H] + 1 H NMR(400MHz,CDCl3):δ ppm 8.82(s,1H),7.09(s,1H),4.23(br d,J=6.6Hz,2H),3.68(s,3H),2.63-2.46(m,1H),2.14-1.98(m,2H),1.98-1.84(m ,3H),1.83-1.73(m,1H),1.73-1.62(m,2H),1.49-1.31(m,1H),1.30-1.18(m,1H).

[0273] Step 2: The synthesis of 4-[(6-carbamoylpyrimidine-4-yl)oxymethyl]cycloheptanecarboxylic acid, which corresponds to formula (IIa) of Scheme 1, is carried out in the same manner as in Example 6.1.

[0274] Step 3a: The synthesis of the diastereomer mixture of 6-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide is carried out in the same manner as in Step 5b of Example 1.1, but starting with (3S)-3-(3,5-difluorophenyl)isoxazolidine.

[0275] A diastereomer mixture of 6-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide is used in a single batch cycle process with SFC (Column: DAISEL CHIRALPAK AD, 250×30mm, 10μm; Mobile phase: 60% IPA (0.1% NH3·H2O) in CO2, delay time between two consecutive injections is 4.3 minutes; Total duration 30 minutes; Column: DAISEL CHIRALPAK OJ, 250×30mm, 10μm; Mobile phase: 25% MeOH (0.1% NH3·H2O) in CO2, delay time between two consecutive injections is 2.4 minutes; Total duration 30 minutes; Column: DAISEL CHIRALPAK Separation was performed by a single batch cycle process (AD, 250 × 30 mm, 10 μm; mobile phase: 55% IPA (0.1% NH3·H2O) in CO2; delay time between two consecutive injections was 3.0 minutes; total duration 30 minutes), yielding stereoisomer 1 of compound (122) (peak 1, 47 mg, 102.07 μmol, yield 12%), stereoisomer 2 of compound (123) (peak 2, 71 mg, 154.19 μmol, yield 19%), stereoisomer 3 of compound (124) (peak 3, 73 mg, 158.53 μmol, yield 19%), and stereoisomer 4 of compound (125) (peak 4, 75 mg, 162.88 μmol, yield 20%) as white solids.

[0276] Step 3b: The synthesis of the diastereomer mixture of 6-[[4-[3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cycloheptyl]-methoxy]pyrimidine-4-carboxamide is carried out in the same manner as in Step 5a of Example 1.1.

[0277] A diastereomer mixture of 6-[[4-[3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cycloheptyl]-methoxy]pyrimidine-4-carboxamide is available in SFC (column: DAIEL CHIRALPAK). Separation was performed by a single batch cycle process (AD, 250 × 30 mm, 10 μm; mobile phase: 70% IPA (0.1% NH3·H2O) in CO2, with a delay time of 6.5 minutes between two consecutive injections; total duration 30 minutes), yielding a mixture of stereoisomer 1 of compound (126) and stereoisomer 2 of compound (127) (peaks 1 and 2, 80 mg) as a white solid, stereoisomer 3 of compound (128) (peak 3, 50 mg, 106.95 μmol, yield 18%) as a white solid, and stereoisomer 4 of cis-6-[[4-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide (peak 4, 55 mg, 117.65 μmol, yield 20%) as a yellow solid. Next, a mixture of peak 1 and peak 2 (80 mg) was separated by SFC (column: DAIEL CHIRALCEL OJ, 250 × 30 mm, 10 μm; mobile phase: 30% MeOH (0.1% NH3·H2O) in CO2, single batch cycle process with a delay time of 2.8 minutes between two consecutive injections; total duration 25 minutes) to obtain stereoisomer 1 of compound (126) (peak 1, 30 mg, 64.17 μmol, yield 11%) as a white solid and stereoisomer 2 of compound (127) (peak 2, 39 mg, 83.42 μmol, yield 14%) as a white solid.

[0278] Example 7: Synthesis of compounds (85) and (86) Step 1: Synthesis of methyl(1R,4R)-4-(iodomethyl)cyclohexane-1-carboxylate A solution of methyl(1R,4R)-4-(hydroxymethyl)cyclohexane-1-carboxylate (25 g, 145.16 mmol, 1 equivalent), imidazole (14.82 g, 217.74 mmol, 1.5 equivalents), and I2 (55.27 g, 217.74 mmol, 43.86 mL, 1.5 equivalents) was added to a solution of PPh3 (57.11 g, 217.74 mmol, 1.5 equivalents) under N2 conditions. The reaction mixture was stirred at 25°C for 4 hours. TLC showed that no starting material remained and new, large, highly polar spots were detected. The reaction mixture was poured into H2O (1000 mL) and extracted with EA (200 mL x 3). The combined organic layer was washed with valine (200 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). Methyl (1R,4R)-4-(iodomethyl)cyclohexane-1-carboxylate (28 g, 97.26 mmol, yield 67.00%, purity 98%) was obtained as a yellow oily substance. 1 H NMR(400MHz,CHLOROFORM-d)δ=3.67(s,3H),3.11(d,J=6.4Hz,2H).

[0279] Step 2: Synthesis of methyl(1R,4R)-4-((3-carbamoyl-4-methylphenoxy)methyl)cyclohexane-1-carboxylate, which is the compound corresponding to formula (III) in Scheme 1. To a solution of 5-hydroxy-2-methylbenzamide (200 mg, 1.32 mmol) in DMF (3.7 mL), NaH (60% in mineral oil, 32 mg, 1.32 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. Next, methyl(1R,4R)-4-(iodomethyl)cyclohexane-1-carboxylate (0.75 g, 2.65 mmol) in DMF (3.7 mL) was added, and the mixture was stirred at room temperature for 1 hour. An equal volume of NaH (60% in mineral oil, 32 mg, 1.32 mmol) was added, and the mixture was stirred at 50°C for 3 hours, and then at room temperature overnight. The mixture was diluted with EA, washed with 0.1 M NaOH, and the organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel to obtain methyl(1R,4R)-4-((3-carbamoyl-4-methylphenoxy)methyl)cyclohexane-1-carboxylate (90 mg, 22%). LCMS, m / z 306.2[M+H]+; RT 1.88 min (Method A). 1 H NMR(DMSO-d6,400MHz)δ ppm 4.63(s,2H),3.60(s,3H),3.58(s,1H),3.20(d,J=6.24Hz,1H),2.24(m,3H),2.04(m,2H),1.91(m,3H),1.40(m,3H),1.18(m,1H),1.04(m,1H)

[0280] Step 3: The synthesis of trans-4-[(3-carbamoyl-4-methylphenoxy)methyl]cyclohexanecarboxylic acid is carried out in the same manner as detailed in Step 4 of Example 1.1, but starting from methyl(1R,4R)-4-((3-carbamoyl-4-methylphenoxy)methyl)cyclohexane-1-carboxylate. LCMS, m / z 292.2 [M+H]+; RT 1.50 min (Method A). 1H NMR(DMSO-d6,400MHz)δ ppm 12.00(br s,1H),7.65(br s,1H),7.29(br s,1H),7.10(d,J=8.31Hz,1H),6.89(s,1H),6.87(d,J=8.67Hz,1H),3.77(d,J=6.36Hz,2H),2.27(s,3H) ),2.16(m,1H),1.90(m,4H),1.70(m,1H),1.32(m,2H),1.07(dtd,J=12.75,12.58,12.58,3.06Hz,2H).

[0281] Step 4a: The synthesis of trans-5-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-2-methylbenzamide (compound (85)) is carried out in the same manner as in Step 5a of Example 1.1, but starting from (1R,4R)-4-((3-carbamoyl-4-methylphenoxy)methyl)cyclohexane-1-carboxylic acid.

[0282] Step 4b: The synthesis of trans-5-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-2-methylbenzamide (compound (86))) is carried out in the same manner as in Step 5a of Example 1.1, but starting from (S)-3-(3,5-difluorophenyl)isoxazolidine.

[0283] Example 8: Synthesis of compounds (115), (116), (117), (118), (119), (120), and (121) Step 1: Synthesis of 3-[(6-carbamoylpyrimidine-4-yl)oxymethyl]cyclopentanecarboxylic acid Step a: Synthesis of dimethyltrans-cyclopentane-1,3-dicarboxylate A solution of trans-cyclopentane-1,3-dicarboxylate (9.5 g, 60.07 mmol, 1 equivalent) and H2SO4 (5.89 g, 60.07 mmol, 3.20 ml, 1 equivalent) in MeOH (95 ml) was stirred at 80°C for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, NaHCO3 was added to adjust the pH to 7-8, and the mixture was extracted with EA (100 ml x 3). The combined organic layer was washed with brine (100 ml x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (9.8 g, 52.63 mmol, yield 88%) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ ppm 3.61(s,6H),2.81-2.64(m,2H),2.17(td,J=7.9,13.0Hz,1H),2.09-1.97(m,1H),1.95-1.79(m,4H).

[0284] Step b: Synthesis of trans-3-ethoxycarbonylcyclopentanecarboxylic acid A mixture of dimethyl trans-cyclopentane-1,3-dicarboxylate (5.8 g, 31.15 mmol, 1 equivalent) in EtOH (60 ml) and NaOH (1.25 g, 31.15 mmol, 1 equivalent) was stirred at 80°C for 5 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, adjusted to pH 5-6 with 1 M HCl, and extracted with EA (100 ml x 2). The aqueous phase was adjusted to pH 5-6 with 1 M HCl, extracted with EA (50 ml x 3), and washed with brine (50 ml x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (3.9 g, crude) as a colorless oil.

[0285] Step c: Synthesis of ethyl trans-3-(hydroxymethyl)cyclopentanecarboxylate A solution of trans-3-ethoxycarbonylcyclopentanecarboxylic acid (3.9 g, 20.94 mmol, 1 equivalent) in THF (40 ml) and BH3·Me2S (10 M, 3.14 ml, 1.5 equivalents) was stirred at 0°C for 5 hours. Water (5 ml) and HCl (5 ml) were added, the mixture was stirred for 10 minutes, and extracted with EA (50 ml x 2). The combined organic layer was separated, washed with brine (50 ml x 2), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, petroleum ether / EA = 5 / 1 to 4 / 1) to obtain the title compound (2.7 g, 15.68 mmol, yield 75%) as a colorless oil. 1 H NMR(400MHz,CDCl3):δ ppm 4.14(q,J=7.1Hz,2H),3.63-3.57(m,1H),3.57-3.49(m,1H),2.88-2.69(m,1H),2.24-2 .03(m,2H),1.99-1.87(m,2H),1.86-1.69(m,2H),1.65-1.40(m,2H),1.29-1.24(m,3H).

[0286] Step d: Synthesis of ethyltrans-3-[(6-chloropyrimidine-4-yl)oxymethyl]cyclopentanecarboxylate, which is the compound corresponding to formula (III) in Scheme 1. Ethyl trans-3-(hydroxymethyl)cyclopentanecarboxylate (1.6 g, 9.29 mmol, 1 equivalent) and 4,6-dichloropyrimidine (1.38 g, 9.29 mmol, 1 equivalent) in DMF (16 ml) were stirred at 0°C for 5 minutes. Next, NaH (445.90 mg, 11.15 mmol, 60% purity, 1.2 equivalents) was added, and the mixture was stirred at 0°C for 2 hours under an N2 atmosphere. The reaction mixture was quenched at 0°C with saturated NH4Cl (20 ml) and extracted with EA (30 ml x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, petroleum ether / EA = 20 / 1) to obtain the title compound (1.71 g, 6.01 mmol, yield 65%) as a colorless oil. LC / MS: m / z 285.1[M+H]+ 1 H NMR(400MHz,CDCl3):δ ppm 8.57(s,1H),6.84-6.69(m,1H),4.40-4.32(m,1H),4.31-4.25(m,1H),4.15(q,J=7.1Hz,2H),2.93-2.77(m,1 H),2.62-2.36(m,1H),2.24-2.08(m,1H),2.02-1.88(m,2H),1.67-1.55(m,2H),1.28(dt,J=1.4,7.1Hz,3H).

[0287] Step e: Synthesis of ethyltrans-3-[(6-cyanopyrimidine-4-yl)oxymethyl]cyclopentanecarboxylate A solution of ethyl trans-3-[(6-chloropyrimidine-4-yl)oxymethyl]cyclopentanecarboxylate (1.8 g, 6.32 mmol, 1 equivalent), Pd(PPh3)4 (1.46 g, 1.26 mmol, 0.2 equivalents), and Zn(CN)2 (2.23 g, 18.96 mmol, 1.20 ml, 3 equivalents) in DMF (18 ml) was degassed, purged three times with N2, and stirred at 100°C under an N2 atmosphere for 15 hours. The reaction mixture was filtered, concentrated under reduced pressure, and purified by preparative TLC (SiO2, petroleum ether / EA=5 / 1) to obtain the title compound (1.1 g, 4.00 mmol, yield 63%) as a yellow oily substance. LC / MS: m / z 276.2[M+H] + 1 H NMR(400MHz,CDCl3):δ ppm 8.83(d,J=0.7Hz,1H),7.15-7.05(m,1H),4.45-4.28(m,2H),4.15(q,J=7.1Hz,2H),2.96-2.79(m,1H),2 .66-2.37(m,1H),2.25-2.11(m,1H),2.06-1.85(m,3H),1.76-1.52(m,2H),1.28(dt,J=1.3,7.1Hz,3H).

[0288] Step f: Synthesis of 3-[(6-carbamoylpyrimidine-4-yl)oxymethyl]cyclopentanecarboxylic acid To a mixture of ethyl trans-3-[(6-cyanopyrimidine-4-yl)oxymethyl]cyclopentanecarboxylate (1.3 g, 4.25 mmol, 90% purity, 1 equivalent) in THF (13 ml), a mixture of H2O2 (963.59 mg, 8.50 mmol, 816.60 μl, 30% purity, 2 equivalents) and LiOH·H2O (1 M, 4.25 ml, 1 equivalent) was added, the mixture was degassed, purged three times with N2, and stirred at 25°C for 30 minutes. LiOH·H2O (1 M, 1.49 ml, 0.35 equivalents) was added, and the mixture was stirred at 25°C under an N2 atmosphere for 12 hours. The reaction mixture was quenched by adding Na2SO3 solution, the pH was adjusted to 5-6 with 1 M HCl, and the mixture was filtered. The precipitate was ground in petroleum ether / EA=1 / 1 at 25°C for 30 minutes to obtain the title compound (0.57 g, 2.15 mmol, yield 51%) as a white solid. Analytical data indicated that cis-trans isomerization occurred. LC / MS: m / z 266.2[M+H] + SFC (Column: Chiralpak IG-3 50×4.6mm ID, 3μm; Gradient elution: IPA in CO2 (0.05% DEA), from 5% to 40%, flow rate: 3ml / min; Column temperature: 35℃, 100bar): Rt = 1.97 min (Peak 1, 28.4%), 2.02 min (Peak 2, 22.0%), 2.12 min (Peak 3, 18.0%) and 2.20 min (Peak 4, 31.6%). 1 H NMR(400MHz,DMSO-d6):δ ppm 12.09(br s,1H),8.86(d,J=0.7Hz,1H),8.23(br s,1H),7.93(br s,1H),7.37-7.25(m,1H),4.35-4.27(m,1H),4.39-4.18(m,1H),2.86-2.66(m,1 H),2.43-2.30(m,1H),2.12-1.88(m,2H),1.87-1.73(m,2H),1.59-1.31(m,2H).

[0289] Step 2a: The synthesis of the diastereomer mixture of 6-[[3-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide is carried out in the same manner as in Step 5a of Example 1.1, but starting with (3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine.

[0290] A diastereomer mixture of 6-[[3-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide was injected using SFC (Conditions: Column: DAISEL CHIRALPAK AD, 250×30mm, 10μm; Mobile phase: 55% EtOH (0.1% NH3·H2O) in CO2, Single batch cycle process with a delay time of 3.5 minutes between two consecutive injections; Total duration 70 minutes; and Column: DAISEL CHIRALPAK Separation was performed by a single batch cycle process (AS, 250×30mm, 10μm; mobile phase: 65% MeOH (0.1% NH3·H2O) in CO2, with a delay time of 4.4 minutes between two consecutive injections; total duration 25 minutes), yielding stereoisomer 1 of compound (115) (peak 1, 96 mg, 204.98 μmol, yield 18%), and stereoisomer 2 of compound (116) (peak 2, 57 mg, 126.36 μmol, yield 18%). 11%), stereoisomer 3 of compound (117) (peak 3, 41 mg, 89.95 μmol, yield 8%), and stereoisomer 4 of cis-6-[[3-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide (peak 4, 80 mg, 180.85 μmol, yield 16%) were all obtained as yellow solids. Stereoisomer 4 (peak 4) of cis-6-[[3-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide: LC / MS: m / z 440.3 [M+H] + ; SFC (Column: Chiralpak AS-3 50×4.6mm ID, 3μm; Mobile phase: CO2 and MeOH (0.05% DEA), Gradient: 5%~40% MeOH (0.05% DEA); Flow rate: 3ml / min, Column temperature: 35℃; 100bar): Rt=2.40min (100%); 1 H NMR(400MHz,CDCl3):δ ppm 8.74(d,J=1.0Hz,1H),7.76(br s,1H),7.51(d,J=1.0Hz,1H),7.42(s,1H),7.29-7.26(m,2H),5.72(br s,1H),5.41(dd,J=6.4,8.7Hz,1H),4.41-4.27(m,3H),3.87(ddd,J=6.7,8.2,9.6Hz,1H),3.31(quin,J=8.3Hz,1H),2.90( dddd,J=2.9,6.5,9.2,12.3Hz,1H),2.51(td,J=7.8,16.0Hz,1H),2.36-2.24(m,1H),2.14-1.90(m,4H),1.65-1.57(m,2H).

[0291] Step 2b: The synthesis of the diastereomer mixture of 6-[[3-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide is carried out in the same manner as in Step 5a of Example 1.1, but starting with (3S)-3-(3,5-difluorophenyl)isoxazolidine.

[0292] A diastereomer mixture of 6-[[3-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide is used in SFC (Conditions: Column: DAISEL CHIRALPAK AS, 250×30mm, 10μm; Mobile phase: 70% EtOH (0.1% NH3·H2O) in CO2, Single batch cycle process with a delay time of 10.0 minutes between two consecutive injections; Total duration 50 minutes; Column: DAISEL CHIRALPAK AS, 250×30mm, 10μm; Mobile phase: 40% EtOH (0.1% NH3·H2O) in CO2, Single batch cycle process with a delay time of 2.1 minutes between two consecutive injections; Total duration 40 minutes, and Column: DAISEL CHIRALPAK The compounds were separated by a single batch cycle process (AS, 250 × 30 mm, 10 μm; mobile phase: 65% MeOH (0.1% NH3·H2O) in CO2; delay time between two consecutive injections: 5.2 minutes; total duration: 40 minutes), yielding stereoisomer 1 of compound (118) (peak 1, 44 mg, 99.15 μmol, yield 6%), stereoisomer 2 of compound (119) (peak 2, 164 mg, 377.58 μmol, yield 22%), and stereoisomer 3 of compound (120) (peak 3, 37 mg, 84.75 μmol, yield 5%) as yellow solids, and stereoisomer 4 of compound (121) (peak 4, 154 mg, 356.14 μmol, yield 20%) as a white solid.

[0293] Example 9: Synthesis of compounds (71), (72), (73), (74), (75), (83), (88), (89), (90), (92), (94), (95), (99), (100), (101), (102), (103), (104), (111), (112), (113), (129), (130), and (131) Synthesis of trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexanecarboxylic acid A mixture of trans-4-(hydroxymethyl)cyclohexanecarboxylic acid (1.00 g, 6.32 mmol) and DMF (40 ml) was mixed with TBDMS-Cl (2.10 mg, 13.9 mmol) and TEA (2.4 ml, 17.2 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was diluted with water. HCl (aqueous solution, 1 M) was added until a weakly acidic pH was reached. The mixture was extracted with MTBE (twice). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue (2.9 g) was dissolved in DMF / water (20:1, 35 ml) and heated at 70°C for 2 hours. The mixture was diluted with MTBE at room temperature. The organic layers were separated, washed with NH4Cl (saturated aqueous solution) and brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography (SiO2; EA / heptane gradient 1 / 4 to 1 / 2) to obtain the title compound (1.22 g, 4.48 mmol, yield 71%). 1 H NMR(400MHz,DMSO-d6):δ ppm 11.95(br s,1H),3.32(m,2H),2.07(tt,J=12.12,12.12,3.53,3.53Hz,1H),1.87( m,2H),1.72(m,2H),1.29(m,3H),0.91(m,2H),0.85(s,9H),0.00(s,6H).

[0294] Step 1a: Synthesis of 5-[(3S)-2-[trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexanecarbonyl]isoxazolidine-3-yl]pyridine-3-carbonitrile To a mixture of trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexanecarboxylic acid (500 mg, 1.84 mmol) and DMF (20 ml), Oxyma (770 mg, 5.2 mmol) and NaHCO3 (1.43 g, 17.02 mmol) were added at 0°C. The mixture was stirred at room temperature for 1 hour. 5-[(3S)-isoxazolidine-3-yl]pyridine-3-carbonitrile (320 mg, 1.83 mmol) in DMF (10 ml) was added. The mixture was heated at 40°C for 2 hours. At room temperature, the mixture was diluted with EA and washed with water. The organic layer was separated, washed with NH4Cl (saturated aqueous solution), NaHCO3 (saturated aqueous solution) and brine, dried, filtered, and concentrated. The resulting crude compound (770 mg, 1.79 mmol, crude yield 98%) was used directly in the next step.

[0295] Step 1b: [Trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone, [Trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-[(3S)-3-(6-methoxypyrazine-2-yl)isoxazolidine-2-yl]methanone, [Trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-[(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-yl]methanone and [Trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-[(3S)-3-(2-pyridyl)isoxazolidine-2-yl]methanone are prepared as detailed in Step 1a of Example 9.

[0296] Step 2a: Synthesis of 5-((S)-2-(trans-4-(hydroxymethyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile, which is the compound corresponding to formula (IIc) of Scheme 4. 5-[(3S)-2-[trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexane-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonitrile (770 mg, 1.79 mmol) and DCM (30 ml) were mixed with TFA (2 ml). The mixture was stirred for 15 minutes. The reaction was quenched by adding NaHCO3 (saturated aqueous solution) and diluted with EA. The organic layer was separated, washed with brine, dried with (Na2SO4), filtered, and concentrated. The crude product was purified by preparative HPLC to obtain the title compound (340 mg, 1.08 mmol, 60% yield). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.94(d,J=1.83Hz,1H),8.77(d,J=2.08Hz,1H),8.19(t,J=1.96,1.96Hz,1H),5.41(dd,J=8.62,6.54Hz,1H),4.36(br s,1H),4.29(td,J=7.70,7.70,3.06Hz,1H),3.91(m,1H),3.21(br d,J=5.50Hz,2H),2.89(m,1H),2.66(br t,J=11.92,11.92Hz,1H),2.29(m,1H),1.90(br d,J=11.74Hz,1H),1.76(m,3H),1.31(m,3H),0.94(m,2H).

[0297] Step 2b: [Trans-4-(hydroxymethyl)cyclohexyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone, [Trans-4-(hydroxymethyl)cyclohexyl]-[(3S)-3-(6-methoxypyrazine-2-yl)isoxazolidine-2-yl]methanone, [Trans-4-(hydroxymethyl)cyclohexyl]-[(3S)-3-(2-pyridyl)isoxazolidine-2-yl]methanone, and [Trans-4-(hydroxymethyl)cyclohexyl]-[(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-yl]methanone are synthesized in the same manner as in Step 2a of Example 9.

[0298] Step 3a: Synthesis of trans-5-((S)-2-(4-((3-cyanophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile (compound (71)) via route SM3 of scheme 4. A mixture of 5-((S)-2-(trans-4-(hydroxymethyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile (50 mg, 159 μmol), 3-hydroxybenzonitrile (40 mg, 336 μmol), and THF (2 ml) was mixed with PPh3 (polymerized, 100 mg) and DIAD (70 μl, 0.36 mmol). The mixture was stirred at room temperature for 2 hours, diluted with THF (15 ml), and filtered. The filtrate was concentrated and purified by preparative HPLC to obtain the title compound (20 mg, 48.0 μmol, 30% yield).

[0299] Step 3b: Trans-5-((S)-2-(4-((3-cyano-4-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile (compound (72)), trans-3-((4-((S)-3-(5-cyanopyridine-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)benzamide (compound (73)), trans-5-((4-((S)-3-(5-cyanopyridine-3-yl)isoxazolidine-2-carbonyl)cyclohexyl The compounds (74) and (75) are prepared in the same manner as described in detail in step 3a of Example 9, starting from 3-hydroxy-5-fluorobenzonitrile, 3-hydroxybenzamide, 5-hydroxy-2-fluorobenzamide, and 2-chloro-5-hydroxybenzamide, respectively.

[0300] Step 4a: Synthesis of [trans-4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl-4-nitrobenzenesulfonate, corresponding to the compound of formula (IId) in Scheme 4 - Activation step before SM5 in Scheme 4 Trans-5-[(3S)-2-[4-(hydroxymethyl)cyclohexanecarbonyl]isoxazolidine-3-yl]pyridine-3-carbonitrile (50 mg, 159 μmol) and DCM (2 ml) were mixed with TEA (40 μl, 287 μmol) and 4-nitrobenzenesulfonyl chloride (50 mg, 221 μmol). The mixture was stirred for 14 hours, diluted with EA, and washed with water. The organic layer was concentrated, redissolved in EA, and filtered through a short silica pad. The filtrate was concentrated to obtain the title compound (53 mg, 106 μmol, 67% yield). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.93(d,J=1.96Hz,1H),8.76(d,J=2.20Hz,1H),8.46(d,J=8.06Hz,2H),8.19(m,3H),5.39(m,1H),4.27(td,J=7.64,7.64,2.93 Hz,1H),3.99(d,J=5.99Hz,2H),3.90(m,1H),2.89(dddd,J=12.13,9.14,6.42,3.12Hz,1H),2.64(m,1H),2.28(m,1H),1.88(br d,J=11.98Hz,1H),1.68(br d,J=12.10Hz,3H),1.63(br d,J=3.30Hz,1H),1.29(m,2H),1.00(m,2H).

[0301] Step 4b: [Trans-4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl-4-nitrobenzenesulfonate, [Trans-4-[(3S)-3-(6-methoxypyrazine-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl-4-nitrobenzenesulfonate, [Trans-4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl)cyclohexyl]methyl-4-nitrobenzenesulfonate, and [Trans-4-[(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-carbonyl)cyclohexyl]methyl-4-nitrobenzenesulfonate were synthesized in the same manner as in Step 4a of Example 9.

[0302] Step 5a: Synthesis of (Compound (83)) - Route SM5 of Scheme 4 [Trans-4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl 4-nitrobenzene sulfonate (23 mg, 46.0 μmol), 3-fluoro-5-hydroxy-benzo-nitrile (10 mg, 73 μmol), and DMF (2 ml) were mixed with Cs2CO3 (40 mg, 123 μmol). The mixture was stirred at 50°C for 2.5 hours. The mixture was filtered at room temperature, and the filtrate was purified by preparative HPLC to obtain the title compound (12 mg, 27.6 μmol, 60% yield).

[0303] Step 5b: The synthesis of trans-5-((S)-2-(4-((2-chloro-5-(3-methyl-2,5-dioxoimidazolidine-1-yl)phenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile (88) is carried out in the same manner as in Step 5a of Example 9, but each starts from 2-chloro-5-(3-methyl-2,5-dioxoimidazolidine-1-yl)phenol.

[0304] Step 5c: The synthesis of trans-5-((S)-2-(4-((2-fluoro-4-(3-methyl-2-oxo-2,3-dihydro-1H-imidazole-1-yl)phenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile (89) is carried out in the same manner as in Step 5a of Example 9, but each starts from 2-fluoro-4-(3-methyl-2-oxo-2,3-dihydro-1H-imidazole-1-yl)phenol.

[0305] Step 5d: The synthesis of trans-5-((S)-2-(4-((4-(3,5-dimethyl-1H-pyrazole-1-yl)-2-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile (90) is carried out in the same manner as in Step 5a of Example 9, but each starts from 4-(3,5-dimethyl-1H-pyrazole-1-yl)-2-fluorophenol.

[0306] Step 5e: The synthesis of trans-5-((S)-2-(4-((5-(5,5-dimethyl-2,4-dioxoxazolidine-3-yl)-2-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile (92) is carried out in the same manner as in Step 5a of Example 9, but each starts from 5-(5,5-dimethyl-2,4-dioxoxazolidine-3-yl)-2-fluorophenol.

[0307] Step 5f: The synthesis of trans-5-((S)-2-(4-(((4-cyanopyridine-2-yl)oxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile (94) is carried out in the same manner as in Step 5a of Example 9, but starting from 2-hydroxypyridine-4-carbonitrile.

[0308] Step 5g: The synthesis of trans-5-((S)-2-(4-(((5-cyanopyridine-2-yl)oxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile (95) is carried out in the same manner as in Step 5a of Example 9, but starting from 3-cyano-6-hydroxypyridine in each case.

[0309] Step 5h: The synthesis of trans-6-[[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]pyridine-3-carboxamide (99) is carried out in the same manner as in Step 5a of Example 9, but starting from 6-hydroxypyridine-3-carboxamide.

[0310] Step 5i: The synthesis of trans-3-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide (100) is carried out in the same manner as in Step 5a of Example 9, but starting from 3-hydroxybenzamide in each case.

[0311] Step 5j: The synthesis of trans-2-fluoro-5-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide (101) is carried out in the same manner as in Step 5a of Example 9, but starting from 2-fluoro-5-hydroxybenzamide in each case.

[0312] Step 5k: The synthesis of trans-6-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]pyridine-3-carboxamide (102) is carried out in the same manner as in Step 5a of Example 9, but starting from 6-hydroxypyridine-3-carboxamide.

[0313] Step 5l: The synthesis of trans-6-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]pyridine-3-carbonitrile (103) is carried out in the same manner as in Step 5a of Example 9, but starting from 6-hydroxynicotinonitrile.

[0314] Step 5m: The synthesis of trans-3-fluoro-5-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzonitrile (104) is carried out in the same manner as in Step 5a of Example 9, but starting from 3-fluoro-5-hydroxybenzonitrile.

[0315] Step 5n: The synthesis of trans-4-fluoro-3-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide (111) is carried out in the same manner as in Step 5a of Example 9, but starting from 4-fluoro-3-hydroxybenzamide.

[0316] Step 5o: The synthesis of trans-3-fluoro-5-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide (112) is carried out in the same manner as in Step 5a of Example 9, but starting from 3-fluoro-5-hydroxybenzamide in each case.

[0317] Step 5p: The synthesis of trans-3-fluoro-4-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide (113) is carried out in the same manner as in Step 5a of Example 9, but starting from 3-fluoro-4-hydroxybenzamide in each case.

[0318] Step 5q: The synthesis of trans-3-[[4-[(3S)-3-(6-methoxypyrazine-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide (129) is carried out in the same manner as in Step 5a of Example 9, but starting from 3-hydroxybenzamide in each case.

[0319] Step 5r: The synthesis of trans-3-[[4-[(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide (130) is carried out in the same manner as in Step 5a of Example 9, but starting with 3-hydroxybenzamide in each case.

[0320] Step 5s: The synthesis of trans-3-[[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide (131) is carried out in the same manner as in Step 5a of Example 9, but starting from 3-hydroxybenzamide in each case.

[0321] Example 10: Synthesis of compound (93) Example 10.1: Synthesis of compound (93) Step 1: Synthesis of methyltrans-4-[(2-cyano-4-pyridyl)oxymethyl]cyclohexanecarboxylate To a solution of 4-nitropyridine-2-carbonitride (300 mg, 2.01 mmol, 1 equivalent) in DMF (3 mL), NaH (120.71 mg, 3.02 mmol, 60% purity, 1.5 equivalents) and methyl (1R,4R)-4-(hydroxymethyl)cyclohexane-1-carboxylate (381.16 mg, 2.21 mmol, 1.1 equivalents) were added. The mixture was stirred at 25°C for 1 hour. TLC showed that no starting material remained and new spots were detected. The reaction mixture was concentrated under reduced pressure, and the DMF was removed. The residue was diluted with 20 mL of H2O, extracted with 20 mL of EA (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 5 / 1) to obtain methyl 4-[(2-cyano-4-pyridyl)oxymethyl]cyclohexanecarboxylate (532 mg, 1.51 mmol, yield 75.19%, purity 78%) as a white solid. LC / MS m / z 275.2[M+H]+; RT 0.905 min (Method B). 1 H NMR(CDCl3;400MHz)δ 8.50(d,J=5.9Hz,1H),7.21(d,J=2.5Hz,1H),6.98(dd,J=2.5,5.9Hz,1H),3.86(d,J=6.3Hz,2H),3.69(s,3H),2. 36-2.26(m,1H),2.17-2.04(m,3H),2.03-1.93(m,3H),1.91-1.79(m,2H),1.57-1.42(m,4H),1.20-1.08(m,4H).

[0322] Step 2: Synthesis of 4-[(2-cyano-4-pyridyl)oxymethyl]cyclohexanecarboxylic acid To a solution of methyl 4-[(2-cyano-4-pyridyl)oxymethyl]cyclohexanecarboxylate (732 mg, 2.67 mmol, 1 equivalent) in THF (7 mL), LiOH·H2O (1 M, 3.20 mL, 1.2 equivalents) was added. The mixture was stirred at 25°C for 1 hour. LC-MS showed that no starting material remained. Multiple novel peaks were observed on LC-MS, indicating the detection of the desired compound. The reaction mixture was concentrated. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25mm×10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 23%~56%, 10 min) to obtain 4-[(2-cyano-4-pyridyl)oxymethyl]cyclohexanecarboxylic acid (218 mg, 837.53 μmol, yield 31.39%, purity 100%) as a white solid. LC / MS m / z 261.2[M+H]+; RT 0.814 min (Method B). 1 H NMR(CDCl3;400MHz)δ 8.51(d,J=5.7Hz,1H),7.21(d,J=2.3Hz,1H),6.99(dd,J=2.5,5.8Hz,1H),3.87(d,J=6.2Hz,2H),2.36(tt,J=3. 5,12.2Hz,1H),2.20-2.09(m,2H),2.05-1.95(m,2H),1.91-1.81(m,1H),1.54-1.47(m,2H),1.23-1.10(m,2H).

[0323] Step 3: The synthesis of (trans-4-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]pyridine-2-carbonitrile (compound (93)) is carried out in the same manner as in Step 5a of Example 1.1, but starting from 4-[(2-cyano-4-pyridyl)oxymethyl]cyclohexanecarboxylic acid.

[0324] Example 11: Synthesis of compounds (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (28), (29), and (30) Example 11.1: Synthesis of compounds (12) and (13) Step 1: Synthesis of cis-(4-aminocyclohexyl)-[(3S)-3-(4-chlorophenyl)isoxazolidine-2-yl]methanone hydrochloride, corresponding to the compound of formula (IIe) in Scheme 5. To a stirred solution of tert-butyl N-[cis-4-[(3S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl]cyclohexyl]carbamate (260 mg, 635.8 μmol) in CH2Cl2 (2.7 ml), TFA (1.35 ml, 17.5 mmol) was added, and stirring was continued at room temperature for 1 hour. The solution was diluted with toluene and concentrated under reduced pressure. The resulting crude material was redissolved in toluene and concentrated again. Finally, the resulting material was dissolved in a 0.1 N aqueous HCl solution and freeze-dried. The title compound was obtained as a pale yellow oily substance and used in the next reaction without further purification (230 mg, 660 μmol, quantitative yield). 1 H NMR(600MHz,DMSO-d6):δ ppm 7.87(br s,3H),7.41(d,J=8.44Hz,2H),7.30(d,J=8.44Hz,2H),5.31(m,1H),4.24(m,1H),3.88(m, 1H),3.85(s,1H),3.12(m,1H),2.86(m,2H),2.14(m,1H),1.95-1.70(m,5H),1.51(m,2H).

[0325] Step 2: The synthesis of the compound cis-2-((4-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)amino)pyrimidine-4-carboxamide (12) is carried out in the same manner as in Step 2 of Example 11.2, but starting from 2-chloropyrimidine-4-carboxamide in each case.

[0326] Step 2a: The synthesis of cis-6-((4-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)amino)pyrimidine-4-carboxamide (13) is carried out in the same manner as in Step 2 of Example 11.2, but starting from 6-chloropyrimidine-4-carboxamide.

[0327] Example 11.2: Synthesis of compound (28) Step 1: The synthesis of cis-3-[(3S)-2-(4-aminocyclohexanecarbonyl)isoxazolidine-3-yl]-5-fluorobenzonitrile hydrochloride, which corresponds to the compound of formula (IIe) in Scheme 5, is carried out in the same manner as in Step 1 of Example 11.1, but starting from tert-butyl N-[cis-4-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cyclohexyl]carbamate.

[0328] Step 2: Synthesis of cis-6-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)amino)pyrimidine-4-carbonitrile compound (28) - Route of Scheme 5 NetiPr2 (75 μl, 428 μmol) was added at room temperature to a stirred solution of 6-chloropyrimidine-4-carbonitrile (28 mg, 198 μmol) and cis-3-[(3S)-2-(4-aminocyclohexanecarbonyl)isoxazolidine-3-yl]-5-fluoro-benzonitrile hydrochloride (70 mg, 198 μmol) in CH3CN (2 ml). The solution was heated under reflux for 2.5 hours. Volatile components were removed under reduced pressure, and the resulting residue was dissolved in DMF, filtered, and subjected to preparative reverse-phase HPLC (33 mg, 79 μmol, 40% yield).

[0329] Example 11.3: Synthesis of compounds (14) and (15) Step 1: The synthesis of trans-[4-(aminomethyl)cyclohexyl]-[(3S)-3-(4-chlorophenyl)isoxazolidine-2-yl]methanone hydrochloride, which corresponds to the compound of formula (IIe) in Scheme 5, is carried out in the same manner as in Step 1 of Example 11.1, but starting from tert-butyl N-[trans-4-[(3S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl]cyclohexyl]carbamate.

[0330] Step 2: The synthesis of trans-2-(((4-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)amino)pyrimidine-4-carbonitrile (compound (14)) is carried out in the same manner as in Step 2 of Example 11.2, but starting from 2-chloropyrimidine-4-carbonitrile in each case.

[0331] Step 2a: The synthesis of trans-6-(((4-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)amino)pyrimidine-4-carbonitrile (compound (15)) is carried out in the same manner as in Step 2 of Example 11.2, but starting from 6-chloropyrimidine-4-carbonitrile in each case.

[0332] Example 11.4: Synthesis of compounds (16) and (17) Step 1: The synthesis of cis-(3-aminocyclobutyl)-[(3S)-3-(3-fluorophenyl)isoxazolidine-2-yl]methanone hydrochloride is carried out in the same manner as in Step 1 of Example 11.1, but starting from tert-butyl N-[cis-3-[(3S)-3-(3-fluorophenyl)isoxazolidine-2-carbonyl]cyclobutyl]carbamate.

[0333] Step 2: The synthesis of cis-2-((3-((S)-3-(3-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile (compound (16)) is carried out in the same manner as in Step 2 of Example 11.2, but starting from 2-chloropyrimidine-4-carbonitrile in each case.

[0334] Step 2a: The synthesis of cis-6-((3-((S)-3-(3-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile (compound (17)) is carried out in the same manner as in Step 2 of Example 11.2, but starting from 6-chloropyrimidine-4-carbonitrile in each case.

[0335] Example 11.5: Synthesis of compound (18) Step 1: The synthesis of cis-(3-aminocyclobutyl)-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]methanone hydrochloride is carried out in the same manner as in Step 1 of Example 11.1, but starting from tert-butyl N-[cis-3-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl]cyclobutyl]carbamate.

[0336] Step 2: The synthesis of cis-6-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile (compound (18)) is carried out in the same manner as in Step 2 of Example 11.2, but starting from 6-chloropyrimidine-4-carbonitrile in each case.

[0337] Example 11.6: Synthesis of compounds (19) and (20) Step 1: The synthesis of cis-3-[(3S)-2-(3-aminocyclobutanecarbonyl)isoxazolidine-3-yl]-5-fluorobenzonitrile hydrochloride is carried out in the same manner as in Step 1 of Example 11.1, but starting from N-[cis-3-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cyclobutyl]carbamate.

[0338] Step 2: The synthesis of cis-2-((3-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile (compound (19)) is carried out in the same manner as in Step 2 of Example 11.2, but starting from 2-chloropyrimidine-4-carbonitrile.

[0339] Step 2a: The synthesis of cis-6-((3-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile (20)) is carried out in the same manner as in Step 2 of Example 11.2, but starting from 6-chloropyrimidine-4-carbonitrile in each case.

[0340] Example 11.7: Synthesis of compounds (21) and (22) Step 1: The synthesis of cis-(3-aminocyclobutyl)-[(3S)-3-(3,4-difluorophenyl)isoxazolidine-2-yl]methanone hydrochloride is carried out in the same manner as in Step 1 of Example 11.1, but starting from tert-butyl N-[cis-3-[(3S)-3-(3,4-difluorophenyl)isoxazolidine-2-carbonyl]cyclobutyl]carbamate.

[0341] Step 2: The synthesis of cis-2-((3-((S)-3-(3,4-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile (compound (21)) is carried out in the same manner as in Step 2 of Example 11.2, but starting from 2-chloropyrimidine-4-carbonitrile.

[0342] Step 2a: The synthesis of cis-6-((3-((S)-3-(3,4-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile (compound (22)) is carried out in the same manner as in Step 2 of Example 11.2, but starting from 6-chloropyrimidine-4-carbonitrile.

[0343] Example 11.8: Synthesis of compounds (23) and (24) Step 1: The synthesis of cis-(3-aminocyclobutyl)-[(3S)-3-(4-chlorophenyl)isoxazolidine-2-yl]methanone hydrochloride is carried out in the same manner as in Step 1 of Example 11.1, but starting from tert-butyl N-[cis-3-[(3S)-3-(4-fluorophenyl)isoxazolidine-2-carbonyl]cyclobutyl]carbamate.

[0344] Step 2: The synthesis of cis-6-((3-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile (compound (23)) is carried out in the same manner as in Step 2 of Example 11.2, but starting from 6-chloropyrimidine-4-carbonitrile in each case.

[0345] Step 2a: Synthesis of cis-2-((3-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile (compound (24)) is carried out in the same manner as in Step 2 of Example 11.2, but starting from 2-chloropyrimidine-4-carbonitrile in each case.

[0346] Example 11.9: Synthesis of compounds (29), (30), and (31) Step 1: The synthesis of trans-3-[(3S)-2-[4-(aminomethyl)cyclohexanecarbonyl]isoxazolidine-3-yl]-5-fluorobenzonitrile hydrochloride, which is the compound corresponding to formula (IIe) of Scheme 5, is carried out in the same manner as in Step 1 of Example 11.1, but starting from tert-butyl N-[trans-4-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]methylcyclohexyl]carbamate.

[0347] Step 2a: The synthesis of trans-6-(((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)amino)pyrimidine-4-carboxamide (compound (29)) is carried out in the same manner as in Step 2 of Example 11.2, but starting from 6-chloropyrimidine-4-carboxamide.

[0348] Step 2b: The synthesis of trans-6-(((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)amino)pyrimidine-4-carbonitrile (compound (30)) is carried out in the same manner as in Step 2 of Example 11.2, but starting from 6-chloropyrimidine-4-carbonitrile in each case.

[0349] Step 2c: Synthesis of trans-3-fluoro-5-((S)-2-(4-(((7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)benzonitrile compound (31) - Route of Scheme 5 A suspension of 4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine (26 mg, 150.7 μmol), NetiPr2 (131.5 μl, 753.7 μmol), and 3-((S)-2-(trans-4-(aminomethyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile hydrochloride (55.5 mg, 150.7 μmol) in CH3CN (3 ml) was heated to 120°C and stirred for 1.5 hours. K2CO3 (52.1 mg, 376.9 μmol) was added, and the reaction mixture was stirred again at 120°C for 10 hours. Volatile components were removed under reduced pressure, and the resulting residue was dissolved in DMF, filtered, and subjected to preparative reverse-phase HPLC (12 mg, yield 17%).

[0350] Example 11.10: Synthesis of compounds (25), (26), (27), (36), and (37) Synthesis of cis-3-((3-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)-5-fluorobenzonitrile (compound (25)) To a stirred suspension of ((cis-3-aminocyclobutyl)((S)-3-(4-chlorophenyl)isoxazolidine-2-yl)methanone hydrochloride (50 mg, 158 μmol) and 3,5-difluorobenzonitrile (44 mg, 315 μmol) in DMSO (1 ml), K2CO3 (44 mg, 315 μmol) was added, and the suspension was heated at 80°C for 16 hours. Water was added at room temperature, the aqueous layer was extracted with EA, the combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated to obtain the crude target compound, which was subjected to preparative reverse-phase HPLC (4 mg, 9 μmol, yield 6%).

[0351] The synthesis of cis-3-fluoro-5-((3-((S)-3-(3-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)benzonitrile (compound (26)) and cis-3-((3-((S)-3-(3,4-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)-5-fluorobenzonitrile (compound (27)) is carried out in the same manner as in Example 11.10, starting from ((cis-3-aminocyclobutyl)((S)-3-(2-fluorophenyl)isoxazolidine-2-yl)methanone and ((cis-3-aminocyclobutyl)((S)-3-(2,4-difluorophenyl)isoxazolidine-2-yl)methanone, respectively.

[0352] The synthesis of cis-3-fluoro-5-((3-((S)-3-(5-fluoropyridine-3-yl)isoxazolidine-2-carbonyl)cyclobutyl)amino)benzonitrile (compound (36)) is carried out in the same manner as in Example 11.10, but starting from ((cis-3-aminocyclobutyl)((S)-3-(5-fluoropyridine-3-yl)isoxazolidine-2-yl)methanone.

[0353] The synthesis of cis-3-((S)-2-(3-((3-cyano-5-fluorophenyl)amino)cyclobutan-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile (compound (37)) is carried out in the same manner as in Example 11.10, but starting from cis-3-((S)-2-((3-amino)cyclobutan-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile.

[0354] Example 12: Synthesis of compounds (45), (46), (47), (54), (55), and (56) Example 12.1: Synthesis of compounds (43), (45), (46), (47), (48), (54), (55), (56), (57), (58), (59), (60), (62), (63), (64), (66), (67), and (68) Step 1: Synthesis of [(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-[trans-4-(hydroxymethyl)cyclohexyl]methanone HATU (3.17 g, 8.34 mmol) was added at room temperature to a stirred solution of trans-4-(hydroxymethyl)cyclohexane-1-carboxylic acid (1.1 g, 6.95 mmol), NetiPr2 (3.64 ml, 20.9 mmol), and (S)-3-(3,5-difluorophenyl)isoxazolidine hydrochloride (2.00 g, 9.04 mmol) in DMF (26 ml). Stirring was continued at room temperature for 2 hours. The reaction mixture was diluted with water, and the aqueous layer was extracted with anhydrous EA. The combined organic layers were washed with 0.1 N aqueous NaOH solution and 0.1 N aqueous HCl solution, dried over Na2SO4, filtered, and concentrated to obtain the crude target compound, which was purified by column chromatography (SiO2; EA / heptane gradient) (1.75 g, 5.38 mmol, yield 77%).

[0355] Step 2a: Synthesis of trans-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)pyrimidine-4-carbonitrile (compound (45) and trans-(4-(((6-chloropyrimidine-4-yl)oxy)methyl)cyclohexyl)((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)methanone (46) - Route SM4 of Scheme 4 To a stirred solution of 6-chloropyrimidine-4-carbonitride (44 mg, 307 μmol) and [(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-[trans-4-(hydroxymethyl)cyclohexyl]methanone (100 mg, 307 μmol) in THF (1.2 ml), KotBu (41 mg, 368 μmol) was added at 0°C. The solution was stirred at 0°C for 1.5 hours. Water was added at 0°C, and the aqueous layer was extracted with EA. The combined organic layers were dried over Na2SO4, filtered, concentrated to obtain the crude target product, which was subjected to preparative reverse-phase HPLC.

[0356] Step 2b: Trans-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)pyrimidine-4-carboxamide (compound (47)), cis-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)pyrimidine-4-carboxamide (compound (54)), cis-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)pyrim Zin-4-carbonitride (compound (55)) and cis-(4-(((6-chloropyrimidine-4-yl)oxy)methyl)cyclohexyl)((S)-3-(3,5-difluorophenylisoxazolidine-2-yl)methanone (compound (56)) are synthesized in the same manner as described in detail in step 2a of Example 12.1 for compounds (45) and (46), starting with 6-chloropyrimidine-4-carboxamide (47), (54), 6-chloropyrimidine-4-carbonitride (55), and 4,6-dichloropyrimidine (56).

[0357] Step 2c: trans-5-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-2-fluorobenzonitrile (compound (43)), trans-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-5-fluorobenzonitrile (compound (48)), trans-3-(4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl) Cyclohexyl)methoxy)phenyl)-5,5-dimethyloxazolidine-2,4-dione (compound (57)), trans-1-(4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)phenyl)pyrrolidine-2,5-dione (compound (58)), trans-3-(3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-4-fluorophenyl)-5,5-dimethyl Xazolidine-2,4-dione (compound (59)), trans-1-(4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)phenyl)pyrrolidine-2-one (compound (60)), trans-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)(4-((4-(3,5-dimethyl-1H-pyrazole-1-yl)-2-fluorophenoxy)methyl)cyclohexyl)methanone (compound (62)), trans-3- (4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)phenyl)-1-methylimidazolidin-2,4-dione (compound (63)), trans-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)(4-((5-(3,5-dimethyl-4H-1,2,4-triazole-4-yl)-2-fluorophenoxy)methyl)cyclohexyl)methanone (compound (64)), trans-3-((4-((S)-3-(3,5-Difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)benzenesulfonamide (compound (66)), trans-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)(4-((4-(3,5-dimethyl-4H-1,2,4-triazole-4-yl)-2-fluorophenoxy)methyl)cyclohexyl)methanone (compound (67)), and trans-1-(4-(( The synthesis of 4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-3-fluorophenyl)-3-methyl-1,3-dihydro-2H-imidazole-2-one (compound (68)) is carried out in the same manner as detailed in step 2a of Example 12.1, but with 5-chloro-2-fluorobenzonitrile (43), 3-chloro-5-fluorobenzonitrile (48), and (3,4 -Dichlorophenyl)-5,5-dimethyloxazolidine-2,4-dione (57), 1-(3,4-dichlorophenyl)pyrrolidine-2,5-dione (58), 3-(3-chloro-4-fluorophenyl)-5,5-dimethyloxazolidine-2,4-dione (59), 1-(3,4-dichlorophenyl)pyrrolidine-2-one (60), 4-(3,5-dimethyl-1H-pyrazole-1-yl)-2-fluorochlorophenyl (62 Starting from ), 4-((5-(3,5-dimethyl-4H-1,2,4-triazole-4-yl)-2-fluoro)-chlorophenyl (64), 3-chlorobenzenesulfonamide (66), 4-(3,5-dimethyl-4H-1,2,4-triazole-4-yl)-2-fluoro-chlorophenyl (67), and 1-(4-chloro-3-fluorophenyl)-3-methyl-1,3-dihydro-2H-imidazole-2-one (68).

[0358] Example 12.2: Synthesis of compounds (61) and (65) Step 1: The synthesis of [(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-(cis-3-hydroxycyclobutyl)methanone is carried out in the same manner as in Step 1 of Example 12.1, but starting from (3S)-3-(3,5-difluorophenyl)isoxazolidine.

[0359] Step 2a: Synthesis of cis-3-(3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutoxy)-5-fluorobenzonitrile (compound (61)) - Route SM3 of Scheme 4 To a stirred solution of [(3S)-trans-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-(3-hydroxycyclobutyl)methanone (50 mg, 177 μmol), PPh3 (56 mg, 212 μmol), and 3-fluoro-5-hydroxybenzonitrile (24.2 mg, 177 μmol) in THF (1 ml), a 1 M solution of DIAD in THF (212 μl, 212 μmol) was added at room temperature, and stirring was continued at room temperature for 2 hours. A further 0.6 equivalents of a 1 M solution of DIAD in THF was added, and the mixture was stirred at room temperature for 1.5 hours. Volatile components were removed under reduced pressure, and the resulting residue was dissolved in DMF, filtered, and subjected to preparative reverse-phase HPLC to obtain 41 mg (102 μmol, yield 58%) of the title compound.

[0360] Step 2b: The synthesis of cis-5-(3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutoxy)-2-fluorobenzonitrile (compound (65)) is carried out in the same manner as detailed in Step 2a of Example 12.2, but starting from 2-fluoro-5-hydroxybenzonitrile.

[0361] Example 12.3: Synthesis of compounds (44), (49), (76), (77), (78), (79), (80), and (91) Step 1: The synthesis of 3-fluoro-5-[(3S)-2-[trans-4-(hydroxymethyl)cyclohexanecarbonyl]isoxazolidine-3-yl]benzonitrile is carried out in the same manner as detailed in Step 1 of Example 12.1, but starting from (3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine.

[0362] Step 2: Synthesis of trans-5-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-2-fluorobenzonitrile (compound (44)), trans-3-((S)-2-(4-((3-cyano-5-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile (compound (49)), trans-3-((S)-2-(4-((4-(3,5 -dimethyl-1H-pyrazole-1-yl)-2-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile (compound (76)), trans-3-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)benzenesulfonamide (compound (77)), trans-3-fluoro-5-((S)-2-(4-((2-fluoro-4-(3-methyl) Tyl-2-oxo-2,3-dihydro-1H-imidazole-1-yl)phenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)benzonitrile (compound (78)), trans-3-((S)-2-(4-((5-(5,5-dimethyl-2,4-dioxoxazolidine-3-yl)-2-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile (compound (79)), trans The synthesis of -3-((S)-2-(4-((2-chloro-5-(3-methyl-2,5-dioxoimidazolidine-1-yl)phenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile (compound (80)) and trans-2-[[4-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]pyridine-4-carbonile (compound (91)) was carried out in Example 12.The process is carried out in the same manner as detailed in step 2a of section 2, starting with 5-chloro-2-fluorobenzonitrile (44), 3-chloro-5-fluorobenzonitrile ((49), (50), (76)), 3-chlorobenzenesulfonamide (77), 2-fluoro-4-(3-methyl-2-oxo-2,3-dihydro-1H-imidazole-1-yl)chlorophenyl (78), 4-(5,5-dimethyl-2,4-dioxoxazolidine-3-yl)-2-fluorochlorophenyl (79), -1,2-dichloro-5-(3-methyl-2,5-dioxoimidazolidine-1-yl)phenyl (80), and 2-chloropyridine-4-carbonitrile (91).

[0363] Example 12.4: Synthesis of compounds (50) and (51) Step 1: The synthesis of [(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-(trans-3-hydroxycyclobutyl)methanone is carried out in the same manner as detailed in Step 1 of Example 12.1, but starting from (3S)-3-(3,5-difluorophenyl)isoxazolidine.

[0364] Step 2: The synthesis of trans-3-(3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutoxy)-5-fluorobenzonitrile (compound (50)) and trans-5-(3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutoxy)-2-fluorobenzonitrile (compound (51)) is carried out in the same manner as described in detail in Step 2a of Example 12.2, starting from 3-chloro-5-fluorobenzonitrile and 5-chloro-2-fluorobenzonitrile, respectively.

[0365] Example 12.5: Synthesis of compounds (52) and (53) Step 1: The synthesis of [(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-[cis-4-(hydroxymethyl)cyclohexyl]methanone is carried out in the same manner as the method detailed in Step 1 of Example 12.1, but starting from (3S)-3-(3,5-difluorophenyl)isoxazolidine.

[0366] Step 2: The synthesis of cis-3-((4-((S)3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-5-fluorobenzonitrile (compound (52)) and cis-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-5-fluorobenzonitrile (compound (53)) is carried out in the same manner as detailed in Step 2a of Example 12.2, starting from 5-chloro-2-fluorobenzonitrile and 3-chloro-5-fluorobenzonitrile, respectively.

[0367] Example 12.6: Synthesis of compounds (81) and (82) Step 1: The synthesis of 3-fluoro-5-[(3S)-2-[cis-4-(hydroxy)cyclohexanecarbonyl]isoxazolidine-3-yl]benzonitrile is carried out in the same manner as detailed in Step 1 of Example 12.1, but starting from (S)-3-(3-cyano-5-fluorophenyl)isoxazolidine.

[0368] Step 2: The synthesis of cis-3-((S)-2-(4-(5-(5,5-dimethyl-2,4-dioxoxazolidine-3-yl)-2-fluorophenoxy)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile (compound (81)) and cis-5-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)oxy)-2-fluorobenzonitrile (compound (82)) is carried out in the same manner as detailed in Step 2a of Example 12.2, but starting from 5-(5,5-dimethyl-2,4-dioxoxazolidine-3-yl)-2-fluorochlorophenyl (81) and 5-chloro-2-fluorobenzonitrile.

[0369] Example 13: Biological activity Evaluation of receptor-interacting protein kinase 1 inhibition The catalytic activity of RIPK1 was measured by monitoring the conversion of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) via autophosphorylation using the ADP-Glo ​​kinase kit (Promega, catalog number V9104).

[0370] In detail, 2 μl of recombinant hRIPK1(aa1-375) fusion protein (final concentration 3.6 μg / ml) and 2 μl of the compound (final concentration 33300-1.69 nM; DMSO final concentration 1%) were incubated at room temperature for 30 minutes, followed by the addition of 2 μl of ATP (ADP Glo kit, final concentration 50 μM). After further incubation at room temperature for 240 minutes, the reaction was quenched by adding 5 μl of Promega ADP-Glo ​​reagent I to deplete any unused ATP. After 30 minutes of incubation, 10 μl of Promega ADP-Glo ​​detection reagent II was added, causing ADP to be converted to ATP and a photoreaction to occur between luciferase and luciferin. After 30 minutes, luminescence was quantified using Pherastar FS (BMG LABTECH, Ortenberg).

[0371] For dose-response experiments, use ICs with a 95% confidence interval.50 The values ​​were calculated using a four-parameter logistic model according to Ratkowsky and Reedy, with constraints on asymptotic values ​​below and above 0% and 100%. Adjustments were obtained by nonlinear regression using the Levenberg Marquardt algorithm.

[0372] A cell assay in U937 cells to measure the activity of RIPK1 inhibitors against cell death (necroptosis). During TNF receptor I ligation, the Ser / Thr kinase RIPK1 is recruited to transient receptor complex I. Modification of RIPK1 promotes RIPK1 activation, which can lead to the formation of complex Iib, which is involved in the recruitment of RIPK3 and MLKL (mixed-series kinase domain-like protein), and subsequently translocates from the cytosol to the plasma membrane to carry out cell death (Cai, Z. et al, Nat. Cell Biol. (2014) 16:55-65).

[0373] Cell death in 96-well plates was quantified by determining the number of viable cells using the CellTiter 96 Aqueous reagent (Promega), a calorimetry method that measures the amount of viable cells by reducing the tetrazolium compound [3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, internal salt; MTS] to formazan. The absorbance of formazan was read at 490 nm. The inhibitory activity of the test compound was quantified by concentration-response curve (CRC) experiments.

[0374] The compound was obtained as a 10 mM stock solution and diluted with DMSO to 1 to 10 volumes to obtain a 1 mM solution. 2 μl of this solution was diluted with 998 μl of growth medium. 100 μl of the 2 μM compound solution was further diluted sequentially with a dilution factor of 2.5 by adding 150 μl of growth medium. A total of 10 concentrations in the range of 10 μM to 0.26 nM or 1 μM to 0.07 nM were tested.

[0375] U937 cells were cultured in RPMI 1640 Glutamax and 10% thermally inactivated FBS. 50 μl of cell suspension containing 1 × 10⁶ cells / ml supplemented with 50 μM zVAD.fmk (benzyloxycarbonyl-Val-Ala-Asp(Ome) fluoromethyl ketone) and 100 ng / ml recombinant human TNFα was dispensed into each well of a 96-well plate. 50 μl of compound dilution (as described in the cell assay for U937 cells) was added, and the cell suspension was incubated overnight (18-24 hours) at 37°C and 5% CO₂ in a humidified atmosphere (95% rH). High control (no compound) and low control (no TNFα or zVAD.fmk) were tested in 7-row sets, and all compound concentrations were tested in 2-row sets in each experimental plate.

[0376] CellTiter96 aqueous reagent was mixed (100 μl of PMS (phenazine methosulfate) solution / 2 ml of MTS (3-(4,5-dimethyldiazole-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, internal salt) solution), and 20 μl was added per well. After incubation at 37°C (5% CO2 95% rH) for 4 hours, the optical density was measured at 490 nm using a microplate reader (Tecan Infinite M1000).

[0377] The inhibition percentage is expressed as the percentage of the maximum inhibition value obtained in the absence of TNFα / zVAD.fmc. For each dose-response experiment, the IC with a 95% confidence interval is used. 50 The values ​​were calculated using a four-parameter logistic model according to Ratkowsky and Reedy without constraints, using an internal application (Biost@t-Speed ​​LTS V2.3).

[0378] The results of the biological activity are shown in Table 2 (ADP-Glo ​​IC). 50 (μM) and U937 IC 50 (μM)).

[0379] [Table 56]

[0380] [Table 57]

[0381] [Table 58]

[0382] All compounds described herein are potent RIPK1 inhibitors that reduce the catalytic activity of RIPK1, as evidenced by the ADP Glo assay. 50 It is less than 400 nM. Even most compounds have an IC of less than 200 nM. 50 The values ​​are shown. Advantageously, most compounds have ICs below 150 nM, and even below 100 nM. 50 Show the value.

[0383] All compounds described herein induce cell death (necroptosis) in U937 cells, and their IC 50 Since the IC50 value is less than 1000 nM, it is a potent RIPK1 inhibitor. Most compounds have an IC50 value of less than 500 nM, and even less than 200 nM. 50 The values ​​are shown. Advantageously, most compounds have ICs of less than 100 nM, and even less than 50 nM. 50 Show the value.

Claims

1. Compound of formula (I) 【Chemistry 1】 (In the formula, R1 represents a phenyl or monocyclic heteroaryl molecule optionally substituted with one, two, or three R3 molecules; R2 represents an aryl or heteroaryl that is optionally substituted with one, two, or three R6s; Each R3 is halogen, cyanoacrylate, (C １ ~C ４ ) alkyl group or (C １ ~C ４ ) independently selected from the alkoxy group; R4 and R5 are independently selected from halogen, (C １ ~C ４ )-alkyl group, (C １ ~C ４ )-alkoxy group, or R4 and R5 together form a (C １ ~C ４ )-alkylene bridge; m and s are independently either 0 or 1; p, q, r, and t are independently either 0 or 1; Y is a bond, -C(O)-NH-, -C(O)-NH-CH ２ -, -NH-, -CH ２ -NH-, -NH-CH ２ -, -O-, CH ２ -O- and -O-CH ２ - is a divalent group selected from; Each R6 is a halogen, cyano, -OH, (C １ ~C ４ )-alkyl group, -CF ３ , -C(O)NH ２ , -C(O)NH-(C １ ~C ４ )-alkyl group, -C(O)OH, -C(O)O-(C １ ~C ４ )-alkyl group,-SO ２ NH ２ , (C １ ~C ４ )-alkoxy group, -O-(C １ ~C ４ ) Alkylene-(C ３ ~C ６ ) Cycloalkyl group, -O-(C ３ ~C ６ ) Cycloalkyl group, -O-(C ３ ~C ６ ) independently selected from heterocycloalkyl groups, 5-membered or 6-membered heterocycloalkyl groups, monocyclic heteroaryl groups and oxo, and the (C １ ~C ４ ) alkyl group, (C １ ~C ４ ) Alkoxy group, -O-(C ３ ~C ６ ) Cycloalkyl groups, (C １ ~C ４ ) The alkyl group, 5 or 6-membered heterocycloalkyl group, or monocyclic heteroaryl group is optionally substituted with 1, 2, 3, or 4 R7s; Each R7 independently controls halogen, oxo, -OH, (C １ ~C ４ ) alkyl group or (C １ ~C ４ (It is an alkoxy group.) or its pharmaceutically acceptable salts, solvates, or stereoisomers.

2. R1 is halogen, cyano, (C １ ~C ２ )-alkyl group or (C １ ~C ２ ) - Represents a phenyl, thiazolyl, pyridinyl, or pyrazinyl which is optionally substituted with one or two groups independently selected from the alkoxy group, in particular R1 is (i) halogen, cyano, (C １ ~C ２ )-alkyl group or (C １ ~C ２ )-alkoxy group, or (ii) monocyclic heteroaryl selected from thiazolyl, pyridinyl and pyrazinyl, wherein the heteroaryl is a halogen, cyano, (C １ ~C ２ )-alkyl group or (C １ ~C ２ A compound of formula (I) according to claim 1, representing a heteroaryl compound that is optionally substituted with one or two groups independently selected from the alkoxy group.

3. R2 is halogen, cyano, (C １ ~C ２ )-alkyl group, -C(O)NH ２ , -C(O)O-(C １ ~C ２ )-alkyl group,-SO ２ NH ２ , represents phenyl, pyrimidinyl, pyridinyl, pyrrolopyrimidinyl, benzimidazolyl, indazolyl, or indolyl, which are optionally substituted with one or two groups independently selected from a 5-membered or 6-membered heterocycloalkyl group, particularly oxazolidinyl, pyrrolidinyl, imidazolinyl, or dihydroimidazolyl, and a 5-membered heteroaryl group, particularly pyrazolyl or triazolyl, wherein the 5-membered or 6-membered heterocycloalkyl group and the 5-membered heteroaryl group are (C １ ~C ２ A compound of formula (I) according to claim 1 or 2, optionally substituted with one, two, three, or four groups independently selected from alkyl groups and oxos.

4. Y represents a bond, or -NH-, -NH-CH ２ -, -O- and -O-CH ２ A divalent group selected from -, particularly -NH-, -NH-CH ２ -, and -O-CH ２ A compound of formula (I) according to any one of claims 1 to 3, wherein the group is selected from -.

5. R4 and R5 are (C １ ~C ２ A compound of formula (I) according to any one of claims 1 to 4, independently selected from alkyl groups.

6. or: - p, q, r, and t are all equal to 0. - r, q and t are all equal to 0, and p is equal to 1. - r and t are both equal to 0, and q and p are both equal to 1. Or, - A compound of formula (I) according to any one of claims 1 to 5, wherein q, t, and p are all equal to 1, and r is equal to 0.

7. If p, q, r, and t are 0, then R4 and R5 are (C １ ~C ４ A compound of formula (I) according to any one of claims 1 to 6, which does not form an alkylene crosslink together.

8. The following equation (Ia): 【Chemistry 2】 (In the formula, Y, R1, R2, R4, R5 are as defined in any one of claims 1 to 5, and in another embodiment, Y is -NH-, -O-, or a bond; R1 is a phenyl or pyridinyl molecule that is optionally substituted with one or two R3 molecules; R2 is phenyl, pyrimidinyl, indazolyl, indolyl, or benzimidazolyl, which is optionally substituted with one or two R6s; Each R3 is independently selected from halogen or cyanoacrylate; m and s are independently either 0 or 1; Each R6 represents a halogen, especially fluorine, -C(O)NH ２ , cyano, or -C(O)O-(C １ ~C ２ A compound of formula (I) according to any one of claims 1 to 7, having (being alkyl) or its pharmaceutically acceptable salts, solvates, or stereoisomers.

9. The following formula (Ib): 【Transformation 3】 (wherein Y, R1, R2, R4, R5, m and s are as defined in any one of claims 1 to 5, In another embodiment, Y is a bond or -O-CH ２ - and; R1 is a phenyl molecule that is optionally substituted with one or two R3 molecules; R2 is optionally -C(O)NH ２ It is a pyridinyl or pyrimidinyl substituted with; Each R3 is independently selected from halogen or cyanoacrylate; A compound of formula (I) according to any one of claims 1 to 7, wherein m and s are 0. or its pharmaceutically acceptable salts, solvates, or stereoisomers.

10. The following formula (Ic): 【Chemistry 4】 (wherein Y, R1, R2, R4, R5, m and s are as defined in any one of claims 1 to 5, and in another embodiment, Y is -NH-, -NH-CH ２ -, bond, -O- or -O-CH ２ - and; R1 is a phenyl, pyrazinyl, triazolyl, or pyridinyl compound that is optionally substituted with one or two R3s; R2 is a pyridinyl, phenyl, pyrimidinyl, or pyrrolopyrimidinyl molecule that is optionally substituted with one or two R6 molecules; Each R3 is halogen, -CH ３ , -OCH ３ Or selected independently of Cyano; m and s are 0; R6 is halogen, -C(O)NH ２、 cyano, (C １ ~C ２ )-alkyl group, -SO ２ NH ２ , 5-membered heterocycloalkyl (selected from imidazolidinyl, dihydroimidazolyl, pyrrolidinyl and oxazolidinyl), or 5-membered heteroaryl (selected from pyrazolyl or triazolyl), independently selected, and said heterocycloalkyl and heteroaryl are optionally substituted by one, two, three or four groups independently selected from (C １ ~C ２ )alkyl group and oxo), a compound of formula (I) according to any one of claims 1 to 7 or its pharmaceutically acceptable salts, solvates, or stereoisomers.

11. The following formula (Id): 【Transformation 5】 (wherein R1, R2, R4, R5, m and s are as defined in any one of claims 1 to 5, and in another embodiment, Y is -O-CH ２ - and; R1 is a phenyl molecule that is optionally substituted with one or two R3 molecules; R2 is optionally -C(O)NH ２ It is a pyrimidinyl that is substituted with; Each R3 is independently selected from halogen or cyanoacrylate; A compound of formula (I) according to any one of claims 1 to 7, having m and s being 0. or its pharmaceutically acceptable salts, solvates, or stereoisomers.

12. (1) cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carboxamide, (2) cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile, (3) Methyl cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carboxylate, (4) trans-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carboxamide, (5) cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carbonitrile, (6) cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxamide, (7) cis-2-((3-((S)-3-(5-cyanopyridine-3-yl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxamide, (8) Ethyl cis-6-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)-5-fluoropyrimidine-4-carboxylate, (9) Ethyl cis-6-chloro-5-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxylate, (10) cis-6-chloro-5-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxamide, (11) cis-6-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)-3-methylcyclobutyl)amino)-5-fluoropyrimidine-4-carboxamide, (12) cis-2-((4-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)amino)pyrimidine-4-carboxamide, (13) cis-6-((4-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)amino)pyrimidine-4-carboxamide, (14) trans-2-(((4-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)amino)pyrimidine-4-carbonitrile, (15) trans-6-(((4-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)amino)pyrimidine-4-carbonitrile, (16) cis-2-((3-((S)-3-(3-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile, (17) cis-6-((3-((S)-3-(3-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile, (18) cis-6-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile, (19) cis-2-((3-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile, (20) cis-6-((3-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile, (21) cis-2-((3-((S)-3-(3,4-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile, (22) cis-6-((3-((S)-3-(3,4-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile, (23) cis-6-((3-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile, (24) cis-2-((3-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile, (25) cis-3-((3-((S)-3-(4-chlorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)-5-fluorobenzonitrile, (26) cis-3-fluoro-5-((3-((S)-3-(3-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)benzonitrile, (27) cis-3-((3-((S)-3-(3,4-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)-5-fluorobenzonitrile, (28) cis-6-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)amino)pyrimidine-4-carbonitrile, (29) trans-6-(((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)amino)pyrimidine-4-carboxamide, (30) trans-6-(((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)amino)pyrimidine-4-carbonitrile, (31) trans-3-fluoro-5-((S)-2-(4-(((7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)benzonitrile, (32) cis-5-((3-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)-2-fluorobenzonitrile, (33) cis-2-fluoro-5-((3-((S)-3-(5-fluoropyridine-3-yl)isoxazolidine-2-carbonyl)cyclobutyl)amino)benzonitrile, (34) trans-2-fluoro-5-(((4-((S)-3-(5-fluoropyridine-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)amino)benzonitrile, (35) trans-5-(((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methyl)amino)-2-fluorobenzonitrile, (36) cis-3-fluoro-5-((3-((S)-3-(5-fluoropyridine-3-yl)isoxazolidine-2-carbonyl)cyclobutyl)amino)benzonitrile, (37) cis-3-((S)-2-(3-((3-cyano-5-fluorophenyl)amino)cyclobutan-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile, (38) trans-3-((S)-2-(4-(((3-cyano-5-fluorophenyl)amino)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile, (39) cis-3-((S)-2-(4-((3-cyano-5-fluorophenyl)amino)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile, (40) cis-3-((S)-2-(3-(1H-benzo[d]imidazole-1-yl)cyclobutan-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile, (41) cis-(3-(1H-benzo[d]imidazole-1-yl)cyclobutyl)((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)methanone, (42) cis-(3-(1H-benzo[d]imidazole-1-yl)cyclobutyl)((S)-3-(5-fluoropyridine-3-yl)isoxazolidine-2-yl)methanone, (43) trans-5-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-2-fluorobenzonitrile, (44) trans-5-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-2-fluorobenzonitrile, (45) trans-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)pyrimidine-4-carbonitrile, (46) trans-(4-(((6-chloropyrimidine-4-yl)oxy)methyl)cyclohexyl)((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)methanone, (47) trans-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)pyrimidine-4-carboxamide, (48) trans-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-5-fluorobenzonitrile, (49) trans-3-((S)-2-(4-((3-cyano-5-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile, (50) trans-3-(3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutoxy)-5-fluorobenzonitrile, (51) trans-5-(3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutoxy)-2-fluorobenzonitrile, (52) cis-5-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-2-fluorobenzonitrile, (53) cis-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-5-fluorobenzonitrile, (54) cis-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)pyrimidine-4-carboxamide, (55) cis-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)pyrimidine-4-carbonitrile, (56) cis-(4-(((6-chloropyrimidine-4-yl)oxy)methyl)cyclohexyl)((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)methanone, (57) trans-3-(4-chloro-3-((4-(((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)phenyl)-5,5-dimethyloxazolidine-2,4-dione, (58) trans-1-(4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)phenyl)pyrrolidine-2,5-dione, (59) trans-3-(3-((4-(((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-4-fluorophenyl)-5,5-dimethyloxazolidine-2,4-dione, (60) trans-1-(4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)phenyl)pyrrolidine-2-one, (61) cis-3-(3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutoxy)-5-fluorobenzonitrile, (62) trans-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)(4-((4-(3,5-dimethyl-1H-pyrazole-1-yl)-2-fluorophenoxy)methyl)cyclohexyl)methanone, (63) trans-3-(4-chloro-3-((4-(((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)phenyl)-1-methylimidazolidin-2,4-dione, (64) trans-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)(4-((5-(3,5-dimethyl-4H-1,2,4-triazole-4-yl)-2-fluorophenoxy)methyl)cyclohexyl)methanone, (65) cis-5-(3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutoxy)-2-fluorobenzonitrile, (66) trans-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)benzenesulfonamide, (67) trans-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)(4-((4-(3,5-dimethyl-4H-1,2,4-triazole-4-yl)-2-fluorophenoxy)methyl)cyclohexyl)methanone, (68) trans-1-(4-((4-(((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-3-fluorophenyl)-3-methyl-1,3-dihydro-2H-imidazole-2-one, (69) cis-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)(3-(5-fluoro-1H-benzo[d]imidazole-1-yl)cyclobutyl)methanone, (70) cis-3-fluoro-5-((S)-2-(3-(5-fluoro-1H-benzo[d]imidazole-1-yl)cyclobutan-1-carbonyl)isoxazolidine-3-yl)benzonitrile, (71) trans-5-((S)-2-(4-((3-cyanophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile, (72) trans-5-((S)-2-(4-((3-cyano-4-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile, (73) trans-3-((4-((S)-3-(5-cyanopyridine-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)benzamide, (74) trans-5-((4-((S)-3-(5-cyanopyridine-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-2-fluorobenzamide, (75) trans-2-chloro-5-((4-((S)-3-(5-cyanopyridine-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)benzamide, (76) trans-3-((S)-2-(4-((4-(3,5-dimethyl-1H-pyrazole-1-yl)-2-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile, (77) trans-3-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)benzenesulfonamide, (78) trans-3-fluoro-5-((S)-2-(4-((2-fluoro-4-(3-methyl-2-oxo-2,3-dihydro-1H-imidazole-1-yl)phenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)benzonitrile, (79) trans-3-((S)-2-(4-((5-(5,5-dimethyl-2,4-dioxoxazolidine-3-yl)-2-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile, (80) trans-3-((S)-2-(4-((2-chloro-5-(3-methyl-2,5-dioxoimidazolidine-1-yl)phenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile, (81) cis-3-((S)-2-(4-(5-(5,5-dimethyl-2,4-dioxoxazolidine-3-yl)-2-fluorophenoxy)cyclohexane-1-carbonyl)isoxazolidine-3-yl)-5-fluorobenzonitrile, (82) cis-5-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)oxy)-2-fluorobenzonitrile, (83) trans-5-((S)-2-(4-((3-cyano-5-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile, (84) trans-(3-(5-fluoro-1H-benzo[d]imidazole-1-yl)cyclobutyl)((S)-3-(3-fluorophenyl)isoxazolidine-2-yl)methanone, (85) trans-5-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-2-methylbenzamide, (86) trans-5-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-2-methylbenzamide, (87) cis-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl)(3-(6-fluoro-1H-benzo[d]imidazole-1-yl)cyclobutyl)methanone, (88) trans-5-((S)-2-(4-((2-chloro-5-(3-methyl-2,5-dioxoimidazolidine-1-yl)phenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile, (89) trans-5-((S)-2-(4-((2-fluoro-4-(3-methyl-2-oxo-2,3-dihydro-1H-imidazole-1-yl)phenoxy)methyl)cyclohexane-1-carbonyl)isosazaridin-3-yl)nicotinonitrile, (90) trans-5-((S)-2-(4-((4-(3,5-dimethyl-1H-pyrazole-1-yl)-2-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile, (91) trans-2-[[4-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]pyridine-4-carbonitrile, (92) trans-5-((S)-2-(4-((5-(5,5-dimethyl-2,4-dioxoxazolidine-3-yl)-2-fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile, (93) trans-4-[[4-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]pyridine-2-carbonitrile, (94) trans-5-((S)-2-(4-(((4-cyanopyridine-2-yl)oxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile, (95) trans-5-((S)-2-(4-(((5-cyanopyridine-2-yl)oxy)methyl)cyclohexane-1-carbonyl)isoxazolidine-3-yl)nicotinonitrile, (96) cis-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-[3-(5-fluoroindazole-1-yl)cyclobutyl]methanone, (97) trans-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-[3-(5-fluoroindazole-1-yl)cyclobutyl]methanone, (98) trans-3-fluoro-5-[(3S)-2-[3-(5-fluoroindazole-1-yl)cyclobutancarbonyl]isoxazolidine-3-yl]benzonitrile, (99) trans-6-[[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]pyridine-3-carboxyamide, (100) trans-3-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, (101) trans-2-fluoro-5-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, (102) trans-6-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]pyridine-3-carboxyamide, (103) trans-6-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]pyridine-3-carbonitrile, (104) trans-3-fluoro-5-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzonitrile, (105) trans-3-fluoro-5-[(3S)-2-[3-(5-fluoroindole-1-yl)cyclobutancarbonyl]isoxazolidine-3-yl]benzonitrile, (106) trans-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-[3-(5-fluoroindole-1-yl)cyclobutyl]methanone, (107) cis-3-fluoro-5-[(3S)-2-[3-(5-fluoroindole-1-yl)cyclobutancarbonyl]isoxazolidine-3-yl]benzonitrile, (108) cis-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-[3-(5-fluoroindole-1-yl)cyclobutyl]methanone, (109) cis-3-fluoro-5-[(3S)-2-[3-(5-fluoroindazole-2-yl)cyclobutancarbonyl]isoxazolidine-3-yl]benzonitrile, (110) cis-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]-[3-(5-fluoroindazole-2-yl)cyclobutyl]methanone, (111) trans-4-fluoro-3-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, (112) trans-3-fluoro-5-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, (113) trans-3-fluoro-4-[[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, (114) cis-2-[3-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl]cyclopentyl]pyridine-4-carboxamide, (115) cis-6-[[3-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide, (116) trans-6-[[3-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide stereoisomer 2, (117) trans-6-[[3-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide stereoisomer 3, (118) trans-6-[[3-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide stereoisomer 1, (119) cis-6-[[3-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide stereoisomer 2, (120) trans-6-[[3-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide stereoisomer 3, (121) cis-6-[[3-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide stereoisomer 4, (122) trans-6-[[4-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide stereoisomer 1, (123) trans-6-[[4-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide stereoisomer 2, (124) cis-6-[[4-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide stereoisomer 3, (125) cis-6-[[4-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide stereoisomer 4, (126) trans-6-[[4-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide stereoisomer 1, (127) trans-6-[[4-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide stereoisomer 2, (128) cis-6-[[4-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide, (129) trans-3-[[4-[(3S)-3-(6-methoxypyrazine-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, (130) trans-3-[[4-[(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, and (131) trans-3-[[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide A compound or formula (I) according to any one of claims 1 to 9, selected from: or its pharmaceutically acceptable salts, solvates, or stereoisomers.

13. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 11, or a compound according to claim 12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

14. A pharmaceutical product comprising a compound of formula (I) according to any one of claims 1 to 11, or a compound according to claim 12, or a pharmaceutically acceptable salt thereof.

15. A compound of formula (I) according to any one of claims 1 to 11, or a compound according to claim 12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use as a pharmaceutical.

16. A compound of formula (I) according to any one of claims 1 to 11, or a compound according to claim 12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in the treatment and / or prevention of diseases, disorders, or conditions at least partially mediated by receptor-interacting protein kinase 1.

17. A compound of formula (I) according to any one of claims 1 to 11, or a compound according to claim 12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in the treatment and / or prevention of a disease selected from Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS).

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