Isoxazolidines as RIPK1 inhibitors and uses thereof

Abstract

The present disclosure relates to compounds of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof wherein R1 represents phenyl or monocyclic heteroaryl, optionally substituted by one, two or three R3; r2 represents an optionally substituted aryl or heteroaryl group; each R3 is independently selected from the group consisting of halogen, cyano, (C1-C4) alkyl, or (C1-C4) alkoxy; r4 and R5 are independently selected from halogen, (C1-C4) alkyl, (C1-C4) alkoxy, 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 the group consisting of-C (O)-NH-,-C (O)-NH-CH2-,-NH-,-CH2-NH-,-NH-CH2-,-O-, CH2-O-and-O-CH2. The invention further relates to pharmaceutical compositions containing said novel compounds. (I)

Description

TECHNICAL FIELD

[0001] The present disclosure relates to new isoxazolidine derivatives useful as medicaments. The new compounds are particularly useful as kinase inhibitors and even particularly as RIPK1 inhibitors. They are effective in the treatment and / or prevention of acute and chronic neurodegenerative diseases like 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 new compounds. BACKGROUND

[0003] While inflammation can be a protective mechanism in response to harmful stimuli, such as pathogen invasion and tissue damage, chronic inflammation is an important underlying factor in many human diseases, such as neurodegeneration, rheumatoid arthritis, autoimmune and inflammatory diseases, and cancer. Likewise, activation of cell death pathways, such as necrosis and apoptosis, that help eliminate infected or damaged cells are also important underlying mechanisms of human diseases, including acute and chronic neurodegenerative diseases. Receptor-interacting protein kinase 1 (UniProtKB Q13546) is a key regulator of inflammation, apoptosis, and necroptosis. Receptor-interacting protein kinase 1 plays an important role in regulating the activation of nuclear factor kappa-light chain enhancer of activated B cells (NF-κΒ)-mediated inflammatory responses. Recent studies have shown that its kinase activity controls necroptosis, a form of necrotic cell death that was traditionally considered passive and unregulated, and is characterized by a distinct morphology. In addition, receptor-interacting protein kinase 1 is part of a pro-apoptotic complex, suggesting that it has activity in regulating apoptosis.

[0004] Receptor-interacting protein kinase 1 is influenced by a complex array of regulatory mechanisms, including ubiquitination, deubiquitination, and phosphorylation. These regulatory events collectively determine whether a cell will survive and activate an inflammatory response or die through apoptosis or necroptosis. Dysregulation of receptor-interacting protein kinase 1 signaling can result in excessive inflammation or cell death, and conversely, studies have shown that inhibition of receptor-interacting protein kinase 1 can be effective in treating diseases involving inflammation or cell death.

[0005] RIPK1 inhibition has been considered as a promising principle to treat different diseases, like rheumatoid arthritis (RA), psoriasis, multiple sclerosis, Alzheimer’s disease, inflammatory bowel disease (e.g. Crohn’s disease, amyotrophic lateral sclerosis (ALS) or ulcerative colitis (UC)). For the treatment of some of these diseases, like multiple sclerosis (MS) and Alzheimer’s disease, entry into the central nervous system (CNS) is required, while for other diseases, like rheumatoid arthritis, psoriasis, inflammatory bowel disease (IBD) (e.g. Crohn’s disease or UC), entry into the CNS is not necessarily required.

[0006] Different RIPK1 inhibitors have been described, e.g. in patent applications WO 2014 / 125444, WO 2016 / 185423 or WO 2016 / 027253 (GSK).

[0007] The RIPK1 inhibitor GSK2982772 (oxazepinone derivative disclosed in WO 2014 / 125444) was evaluated in phase II clinical trials against RA, psoriasis and UC.

[0008] GSK disclosed in WO 2018 / 092089 dihydropyrazole compounds with a phenyl substituent on the dihydropyrazole and a pyrimidine-piperidine element as RIPK1 inhibitors. Other dihydropyrazole compounds as RIPK1 inhibitors are disclosed in WO2020224656.

[0009] GSK disclosed in WO 2019 / 130230 isoxazolidine compounds with a phenyl substituent on the isoxazolidine and a pyrimidine-piperidine element as RIPK1 inhibitors. Similar isoxazolidine compounds are disclosed in KR 2020-087922 (Voronoi) and WO 2020 / 043173.

[0010] Isosxazolidine compounds with reduced ability to cross the blood brain barrier as RIPK1 inhibitors are disclosed in WO 2021 / 245070.

[0011] Compounds with a cycloalkyl element as RIPK1 inhibitors are disclosed in WO 2022 / 194259. SUMMARY

[0012] According to one of its objects, the present disclosure relates to a compound of formula (I): (I) wherein R1represents phenyl or monocyclic heteroaryl, optionally substituted by one, two or three R3; R2represents aryl or heteroaryl, which is optionally substituted with one, two or three R6; each R3is independently selected from halogen, cyano, (Ci-C4)alkyl or (Ci-C4)alkoxy; R4and R5are independently selected from halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, or R4and R5together form a (Ci-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-; each R6is independently selected from halogen, cyano, -OH, (Ci-C4)-alkyl, -CF3, -C(O)NH2, -C(O)NH-(Ci-C4)-alkyl, -C(O)OH, -C(O)O-(Ci-C4)-alkyl, -SO2NH2, (Ci-C4)-alkoxy, -O-(Ci-C4)alkylene-(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -O-(C3-C6)heterocycloalkyl, 5- or 6-membered heterocycloalkyl, monocyclic heteroaryl and oxo, wherein said (Ci-C4)alkyl, (Ci-C4)alkoxy, -O-(C3-C6)cycloalkyl, (Ci-C4)alkyl, 5- or 6-membered heterocycloalkyl or monocyclic heteroaryl is optionally substituted with one, two, three or four R7; each R7is independently halogen, oxo, -OH, (Ci-C4)alkyl or (Ci-C4)alkoxy, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0013] In a related aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

[0014] In another aspect, provided herein is a method for manufacturing a compound of Formula (I) and intermediates thereof.

[0015] In another aspect, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, for use as a medicament.

[0016] In another aspect, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in treating and / or preventing a disease, disorder, or condition mediated at least in part by receptor-interacting protein kinase 1.

[0017] In another aspect, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in treating and / or preventing 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 are methods for treating a disease, disorder, or condition mediated at least in part by receptor-interacting protein kinase 1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutical composition as described herein. The present disclosure also provides use of a compound of Formula (I) or a composition thereof in the manufacture of a medicament for treating a disease, disorder, or condition mediated at least in part by receptor-interacting protein kinase 1. DETAILED DESCRIPTION DEFINITIONS

[0019] The following terms as used in the specification and claims have the following meanings unless otherwise indicated.

[0020] In the present specification, the term “alkyl” refers to straight-chain or branched-chain saturated aliphatic hydrocarbon groups having the indicated number of atoms. More particularly, (C x -C y )alkyl (where x and y are integers, x < y) is a straight-chain or branched-chain saturated aliphatic group comprising from x to y carbon atoms. For example, (C1-C4)alkyl includes, but is not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl, and the like.

[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” denotes an alkyl group monobonded to oxygen. In particular, as used herein, “(C x -C y )alkoxy” refers to -O-(C x -C y)alkyl (wherein x and y are integers, x < y). For example, "(C1-C4)alkoxy" includes, but is not limited to, methoxy, ethoxy, isopropoxy, and tert-butoxy.

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

[0024] The term "halogen" means a chlorine, fluorine, bromine, or iodine atom, and particularly denotes a chlorine or fluorine atom.

[0025] The term "heterocyclyl," "heterocyclic," or "heterocycle" means one or more non-aromatic saturated or partially unsaturated, optionally substituted monocyclic, fused or bridged bicyclic ring systems in which one to five (suitably one or two) of the carbon atoms are replaced by heteroatoms such as oxygen, sulfur, or nitrogen atoms. For example, as used herein, "(C3-C6)heterocycloalkyl" means a (C3-C6)cycloalkyl group in which one or two of the carbon atoms are replaced by a heteroatom, particularly an oxygen or nitrogen atom. Examples of heterocyclyl groups include, but are not limited to, cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, imidazolinyl, dihydroimidazolyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur-containing heterocycles include tetrahydrothiophenyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiopyran. Other heterocycles include oxazolidinyl, tetrahydrooxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazinyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For sulfur-containing heterocycles, oxidized sulfur-containing heterocycles containing SO or SO2 groups are also included. Partially unsaturated heterocyclyl rings contain at least one double bond, such as 1 or 2 double bonds. Examples of partially unsaturated heterocyclyl rings include 1,6-dihydropyridinyl, 1,6-dihydropyridazinyl, and 2,3-dihydropyrrolyl. Those skilled in the art will appreciate that any heterocycle can be attached to another group via any suitable atom, such as via a carbon or nitrogen atom.

[0026] “Bridged ring system” means a ring system in which two rings share more than two atoms, see, e.g., Advanced Organic Chemistry, Jerry March, 4thEdition, Wiley Interscience, pages 131-133, 1992. In particular, as used herein, “bridged (C6-C10) cycloalkyl” groups refer to bicyclic or tricyclic compounds in which the rings are cycloalkyl, the rings share three or more atoms and the bridge contains at least one atom, e.g., 1 (also referred to as a C1-alkylene bridge), 2 (also referred to as a C2-alkylene bridge) or 3 atoms. Such bridged cycloalkyl groups can be substituted with one or more C1-C3 alkyl groups. Examples are, but are not limited to, norbornyl or bicyclo[2.2.2]octanyl. 10 ) cycloalkyl” groups refer to bicyclic or tricyclic compounds in which the rings are cycloalkyl, the rings share three or more atoms and the bridge contains at least one atom, e.g., 1 (also referred to as a C1-alkylene bridge), 2 (also referred to as a C2-alkylene bridge) or 3 atoms. Such bridged cycloalkyl groups can be substituted with one or more C1-C3 alkyl groups. Examples are, but are not limited to, norbornyl or bicyclo[2.2.2]octanyl.

[0027] The term “heteroaryl” means an aromatic monocyclic, bicyclic, or polycyclic ring incorporating one or more (e.g., 1 to 4, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. Examples of heteroaryl groups are monocyclic and bicyclic groups containing five to twelve ring members, and more typically five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic (or monocyclic heteroaryl) or a 9- or 10-membered bicyclic, such as a bicyclic structure formed from a fused five- and six-membered ring or two fused six-membered rings. Each ring can contain up to about four heteroatoms typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain up to 3 heteroatoms, more typically up to 2, e.g., a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or essentially non-basic, as in the case of indole or pyrrole nitrogen. Typically, the number of basic nitrogen atoms present in the heteroaryl group (including any amino substituents of the ring) will be fewer than five. Heteroaryl groups containing nitrogen atoms can exist as the corresponding N-oxides.

[0028] Non-limiting examples of heteroaryl groups include furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5 triazene, benzofuranyl, indolyl, isoindolyl, isoindolinyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenoxazinyl, benzoisoquinolinyl, pyridopyrazinyl, imidazolidinyl, triazolopyridinyl (such as [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl), pyrrolopyridinyl (such as 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, or 1H-pyrrolo[3,2-c]pyridinyl), imidazopyridinyl (such as imidazo[1,2-a]pyridinyl), imidazopyridazinyl (such as imidazo[1,2-b]pyridazinyl), thieno[2,3 b]furanyl, 2Hfuro[3,2 b]pyranyl, 5Hpyrido[2,3 d]oxazinyl, 1Hpyrazolo[4,3 d]oxazolyl, 4Himidazo[4,5 d]thiazolyl, pyrazolo[2,3 d]pyridazinyl, imidazo[2,1 b]thiazolyl, imidazo[1,2 b][1,2,4]triazinyl, pyrazolopyridinyl (such as pyrazolo[4,3-b]pyridinyl), and triazolopyridazinyl (such as [1,2,4]triazolo[1,5-b]pyridazinyl), benzimidazolyl (such as 1H-benzo[d]imidazolyl).

[0029] Non-limiting 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.

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

[0031] Non-limiting examples of bicyclic heteroaryls containing a six-membered ring fused to a five-membered ring include, but are not limited to, triazolopyridinyl (such as [1,2,4]triazolo[1,5-a]pyridinyl or [1,2,4]triazolo[4,3-a]pyridinyl), pyrrolopyridinyl (such as 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, or 1H-pyrrolo[3,2-c]pyridinyl), pyrrolopyrimidinyl, benzimidazolyl (such as 1H-benzo[d]imidazolyl), benzoxazolyl (such as oxobenzo[d]oxazol-3(2H)-yl), imidazopyridinyl (such as imidazo[1,2-a]pyridinyl), imidazopyridazinyl (such as imidazo[1,2-b]pyridazinyl), imidazolyl, indazolyl (such as indazol-1-yl or indazol-2-yl), indolyl (such as indol-1-yl), isoindolinyl, pyrazolopyridinyl (such as pyrazolo[4,3-b]pyridinyl), and triazolopyridazinyl (such as [1,2,4]triazolo[1,5-b]pyridazinyl). Particular non-limiting examples of bicyclic heteroaryls containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnoline, phthalazinyl, naphthyridinyl, and pteridinyl.

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

[0033] The specification can also use several composite terms to describe groups containing more than one functional group. Those of skill in the art will understand such terms. For example, heterocyclylC1-C4alkyl includes C1-C4alkyl substituted with a heterocyclyl group.

[0034] The term "optionally substituted" means both substituted and unsubstituted groups, structures, or molecules.

[0035] Where the optional substituents are selected from "one or more" groups, it is understood that this definition includes substitution with one or substitution with two or more of the indicated groups. It is understood that where there are multiple substituents, the selected substituents can be the same or different.

[0036] Where numerical ranges are given, it is understood that these ranges include the endpoints.

[0037] The phrase "compounds of the disclosure" means those compounds generally and specifically disclosed herein.

[0038] The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

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

[0040] As used herein, the term "pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to a subject. "Pharmaceutically acceptable" means that the excipient is compatible with the other ingredients of the formulation and is not deleterious to the recipient thereof. Pharmaceutical excipients useful in the disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, glidants, coating agents, sweeteners, flavoring agents, and coloring agents.

[0041] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.

[0042] It is understood that references to "treating" or "treatment" include prophylaxis as well as the alleviation of established symptoms of a condition. "Treating" or "treatment" of a state, disorder or condition includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in an individual who can be predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or its clinical or subclinical symptoms, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0043] "Prevention" or "preventing" means any treatment of a disease or condition that results in the clinical symptoms of the disease or condition not developing. In some embodiments, a compound can be administered to a subject (including a human) who is at risk of developing a disease or condition or who has a family history thereof.

[0044] A "subject" refers to a human who has been or will be the object of treatment, observation or experiment. The methods described herein can be used for human therapy.

[0045] A "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc. of the mammal to be treated, as can be determined by one of ordinary skill in the art.

[0046] As used herein, chemical nomenclature, if not otherwise defined, has the meaning as used in the art. Compounds

[0047] Disclosed herein is a compound of Formula (I): (I) wherein R1represents phenyl or monocyclic heteroaryl, optionally substituted with one, two or three R3; R2represents aryl or heteroaryl, optionally substituted with one, two or three R6; each R3is independently selected from halogen, cyano, (C1-C4)alkyl or (C1-C4)alkoxy; R4and R5are independently selected from halogen, (C1-C4)alkyl, (C1-C4)alkoxy, or R4and R5together 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-; each R6is independently selected from halogen, cyano, -OH, (C1-C4)-alkyl, -CF3, -C(O)NH2, -C(O)NH-(C1-C4)-alkyl, -C(O)OH, -C(O)O-(C1-C4)-alkyl, -SO2NH2, (C1-C4)-alkoxy, -O-(C1-C4)alkylene-(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -O-(C3-C6)heterocycloalkyl, 5- or 6-membered heterocycloalkyl, monocyclic heteroaryl and oxo, wherein said (C1-C4)alkyl, (C1-C4)alkoxy, -O-(C3-C6)cycloalkyl, (C1-C4)alkyl, 5- or 6-membered heterocycloalkyl or monocyclic heteroaryl are optionally substituted with one, two, three or four R7; each R7is independently halogen, oxo, -OH, (Ci-C4)alkyl, or (Ci-C4)alkoxy, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0048] According to one embodiment, R1in formula (I) is phenyl, thiazolyl, pyridinyl, or pyrazinyl, optionally substituted with one or two groups independently selected from halogen, cyano, (Ci-C2)-alkyl, or (Ci-C2)-alkoxy, in particular wherein R1represents (i) phenyl substituted with one or two groups independently selected from halogen, cyano, (Ci-C2)-alkyl, or (Ci-C2)-alkoxy, or (ii) monocyclic heteroaryl selected from thiazolyl, pyridinyl, and pyrazinyl, said heteroaryl optionally substituted with one or two groups independently selected from halogen, cyano, (Ci-C2)-alkyl, or (Ci-C2)-alkoxy.

[0049] According to one embodiment, R1in formula (I) is phenyl, optionally substituted with one or two groups independently selected from fluorine, chlorine, cyano, methyl, or methoxy.

[0050] According to one embodiment, R1in formula (I) is thiazolyl, pyridinyl, or pyrazinyl, optionally substituted with one or two groups independently selected from fluorine, chlorine, cyano, methyl, or methoxy.

[0051] According to another embodiment, R2in formula (I) is phenyl, pyrimidinyl, pyridinyl, pyrrolopyrimidinyl, benzimidazolyl, indazolyl, or indolyl, optionally substituted with one or two groups independently selected from halogen, cyano, (Ci-C2)-alkyl, -C(O)NH2, -C(O)O-(Ci-C2)-alkyl, -SO2NH2, 5- or 6-membered heterocycloalkyl, and 5-membered heteroaryl, said 5- or 6-membered heterocycloalkyl and 5-membered heteroaryl optionally substituted with one, two, three, or four groups independently selected from (Ci-C2)alkyl and oxo.

[0052] According to another embodiment, R2in formula (I) is phenyl, pyrimidinyl, pyridinyl, pyrrolopyrimidinyl, benzimidazolyl, indazolyl, or indolyl, optionally substituted with one or two groups independently selected from halogen, cyano, (Ci-C2)-alkyl, -C(O)NH2, -C(O)O-(Ci-C2)-alkyl, -SO2NH2, 5- or 6-membered heterocycloalkyl in particular selected from oxazolidinyl, pyrrolidinyl, imidazolinyl, or dihydroimidazolyl, and 5-membered heteroaryl in particular pyrazolyl or triazolyl, said 5- or 6-membered heterocycloalkyl and 5-membered heteroaryl optionally substituted with one, two, three, or four groups independently selected from (Ci-C2)alkyl and oxo.

[0053] According to another embodiment, Y is a bond or a divalent group selected from -NH-, -NH-CH2-, -0-, and -0-CH2-, in particular a group selected from -NH-, -NH-CH2-, and -0-CH2-.

[0054] According to one embodiment, R4and R5in formula (I) are independently selected from (Ci-C2)alkyl.

[0055] According to another embodiment of the compound of formula (I), m is 0 and s is 0.

[0056] According to one embodiment, the compound according to the disclosure has formula (I), wherein alternatively: - 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 all equal to 0 and q and p are both equal to 1, or - q, t and p are all equal to 1 and r is equal to 0.

[0057] According to one embodiment, there is provided a compound of formula (I) as defined above, wherein R1represents: - phenyl substituted with one, two or three R3as defined above, or - monocyclic heteroaryl optionally substituted with one, two or three R3as defined above.

[0058] According to one embodiment, there is provided a compound of formula (I) as defined above, wherein Y is a divalent group selected from -C(O)-NH-, -C(O)-NH-CH2-, -NH-, -CH2-NH-, -NH-CH2-, CH2-O-, and -0-CH2-.

[0059] According to one embodiment, there is provided a compound of formula (I) as defined above, wherein if p, q, r and t are 0, R4and R5do not form together a (Ci-C4)alkylene bridge.

[0060] According to one embodiment, the compound according to the disclosure has formula (la), wherein: (Ia) wherein: Y, R1, R2, R4, R5, m and s are as defined in formula (I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0061] According to another embodiment, the compounds according to the disclosure have formula (Ia), wherein: Y is -NH-, -0- or a bond; R1is phenyl or pyridyl, optionally substituted with one or two R3; R2is phenyl, pyrimidinyl, indazolyl, indolyl or benzimidazolyl, optionally substituted with one or two R6; each R3is independently selected from halogen or cyano; m and s are independently 0 or 1 ; each R6is halogen, in particular fluoro, -C(0)NH2, cyano or -C(0)0-(Ci-C2)alkyl; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0062] According to this embodiment, the compounds of formula (I) more particularly have the following formula (Ib): (Ib) wherein Y, R1, R2, R4, R5, m and s are as defined in formula (I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0063] According to another embodiment, the compounds of formula (I) more particularly have formula (Ib), wherein: Y is a bond or -0-CH2-; R1is phenyl, optionally substituted with one or two R3; R2is pyridyl or pyrimidinyl, optionally substituted with -C(0)NH2; each R3is independently selected from halogen or cyano; m and s are 0; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0064] According to this embodiment, the compounds of formula (I) more particularly have the following formula (Ic): (Ic) wherein Y, R1, R2, R4, R5, m and s are as defined in formula (I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0065] According to this embodiment, the compounds of formula (I) more particularly have formula (Ic), wherein Y is -NH-, -NH-CH2-, a bond, -0- or -0-CH2-; R1is phenyl, pyrazinyl, triazolyl or pyridinyl, optionally substituted with one or two R3; R2is pyridinyl, phenyl, pyrimidinyl, pyrrolopyrimidinyl, optionally substituted with one or two R6; each R3is independently selected from halogen, -CH3, -OCH3, or cyano; m and s are 0; each R6is independently selected from halogen, -C(O)NH2, cyano, (C1-C2)-alkyl, -SO2NH2, a 5-membered heterocycloalkyl selected from imidazolidinyl, dihydroimidazolyl, pyrrolidinyl and oxazolidinyl, or a 5-membered heteroaryl selected from pyrazolyl or triazolyl, said heterocycloalkyl and heteroaryl being optionally substituted with one, two, three or four groups independently selected from (C1-C2)alkyl and oxo, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0066] According to this embodiment, the compounds of formula (I) more particularly have the following formula (Id): (Id) wherein Y, R1, R2, R4, R5, m and s are as defined in formula (I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0067] According to another embodiment, the compounds of formula (I) more particularly have formula (Id) wherein: Y is -O-CH2-; R1is phenyl, pyrazinyl, triazolyl or pyridinyl, optionally substituted with one or two R3; R2is pyrimidinyl, optionally substituted with -C(O)NH2; each R3is independently selected from halogen or cyano; m and s are 0; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0068] Among the compounds of formula (I), the following can be particularly mentioned: (1) cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclobutyl)amino)pyrimidine-4-carboxamide, (2) cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile, (3) cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclobutyl)amino)pyrimidine-4-carboxylic acid methyl ester, (4) Trans-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)cyclobutyl)amino)pyrimidine-4-carboxamide, (5) Cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carbonitrile, (6) Cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxamide, (7) Cis-2-((3-((S)-3-(5-cyanopyridin-3-yl)isoxazolidin-2- carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxamide, (8) Cis-6-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)-3-methylcyclobutyl)amino)-5-fluoropyrimidine-4-carboxylic acid ethyl ester, (9) Cis-6-chloro-5-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxylic acid ethyl ester, (10) Cis-6-chloro-5-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxamide, (11) Cis-6-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)-3-methylcyclobutyl)amino)-5-fluoropyrimidine-4-carboxamide, (12) Cis-2-((4-((S)-3-(4-chlorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)amino)pyrimidine-4-carboxamide, (13) Cis-6-((4-((S)-3-(4-chlorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)amino)pyrimidine-4-carboxamide, (14) Trans-2-(((4-((S)-3-(4-chlorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)methyl)amino)pyrimidine-4-carbonitrile, (15) Trans-6-(((4-((S)-3-(4-chlorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)methyl)amino)pyrimidine-4-carbonitrile, (16) Cis-2-((3-((S)-3-(3-fluorophenyl)isoxazolidin-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]pyrimidin-4- yl)amino)methyl)cyclohexan-1 -carbonyl)isoxazolidin-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-fluoropyridin-3-yl)isoxazolidine-2-carbonyl)cyclobutyl)amino)benzonitrile, (34) Trans-2-fluoro-5-(((4-((S)-3-(5-fluoropyridin-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-fluoropyridin-3-yl)isoxazolidine-2-carbonyl)cyclobutyl)amino)benzonitrile, (37) Cis-3-((S)-2-(3-((3-cyano-5-fluorophenyl)amino)cyclobutane-1-carbonyl)isoxazolidin-3-yl)-5- fluorobenzonitrile, (38) Trans-3-((S)-2-(4-(((3-cyano-5-fluorophenyl)amino)methyl)cyclohexan-1-carbonyl)isoxazolidin-3-yl)-5- fluorobenzonitrile, (39) Cis-3-((S)-2-(4-((3-cyano-5-fluorophenyl)amino)cyclohexan-1-carbonyl)isoxazolidin-3-yl)-5- fluorobenzonitrile, (40) Cis-3-((S)-2-(3-(1 H-benzo[d]imidazol-1 -yl)cyclobutane-1 -carbonyl)isoxazolidin-3-yl)-5- fluorobenzonitrile, (41) Cis-(3-(1 H-benzo[d]imidazol-1 -yl)cyclobutyl)((S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)methanone, (42) Cis-(3-(1 H-benzo[d]imidazol-1 -yl)cyclobutyl)((S)-3-(5-fluoropyridin-3-yl)isoxazolidin-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)isoxazolidin-2- carbonyl)cyclohexyl)methoxy)-2-fluorobenzonitrile, (45) Trans-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)methoxy)pyrimidine-4-carbonitrile, (46) Trans-(4-(((6-chloropyrimidin-4-yl)oxy)methyl)cyclohexyl)((S)-3-(3,5- difluorophenyl)isoxazolidin-2-yl)methanone, (47) Trans-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)methoxy)pyrimidine-4-carboxamide, (48) Trans-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)methoxy)-5-fluorobenzonitrile, (49) Trans-3-((S)-2-(4-((3-cyano-5-fluorophenoxy)methyl)cyclohexane-1- carbonyl)isoxazolidin-3-yl)-5-fluorobenzonitrile, (50) Trans-3-(3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)cyclobutoxy)-5-fluorobenzonitrile, (51) Trans-5-(3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)cyclobutoxy)-2-fluorobenzonitrile, (52) Cis-5-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)methoxy)-2-fluorobenzonitrile, (53) Cis-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)methoxy)-5-fluorobenzonitrile, (54) Cis-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)methoxy)pyrimidine-4-carboxamide, (55) Cis-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)methoxy)pyrimidine-4-carbonitrile, (56) Cis-(4-(((6-chloropyrimidin-4-yl)oxy)methyl)cyclohexyl)((S)-3-(3,5- difluorophenyl)isoxazolidin-2-yl)methanone, (57) Trans-3-(4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)methoxy)phenyl)-5,5-dimethyl oxazolidine-2,4-dione, (58) Trans-1-(4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)methoxy)phenyl)pyrrolidine-2,5-dione, (59) Trans-3-(3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-carbonyl)cyclohexyl)methoxy)-4-fluorophenyl)-5,5-dimethyl oxazolidine-2,4-dione, (60) Trans-1-(4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)methoxy)phenyl)pyrrolidine-2-one, (61) Cis-3-(3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-carbonyl)cyclobutoxy)-5- fluorobenzonitrile, (62) Trans-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)(4-((4-(3,5-dimethyl-1H- pyrazol-1-yl)-2-fluorophenoxy)methyl)cyclohexyl)methanone, (63) Trans-3-(4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)methoxy)phenyl)-1-methylimidazolidine-2,4-dione, (64) Trans-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)(4-((5-(3,5-dimethyl-4H-1,2,4- triazol-4-yl)-2-fluorophenoxy)methyl)cyclohexyl)methanone, (65) Cis-5-(3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-carbonyl)cyclobutoxy)-2- fluorobenzonitrile, (66) Trans-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-carbonyl)cyclohexyl)methoxy) benzenesulfonamide, (67) Trans-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)(4-((4-(3,5-dimethyl-4H-1,2,4- triazol-4-yl)-2-fluorophenoxy)methyl)cyclohexyl)methanone, (68) Trans-1-(4-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-carbonyl)cyclohexyl)methoxy)-3- fluorophenyl)-3-methyl-1,3-dihydro-2H-imidazol-2-one, (69) cis-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)(3-(5-fluoro-lH- benzo[d]imidazol-l-yl)cyclobutyl)methanone, (70) cis-3-fluoro-5-((S)-2-(3-(5-fluoro-lH-benzo[d]imidazol-l-yl)cyclobutane-l- carbonyl)isoxazolidin-3-yl)benzonitrile, (71) trans-5-((S)-2-(4-((3-cyanophenoxy)methyl)cyclohexane-l-carbonyl)isoxazolidin- 3-yl)nicotinonitrile, (72) trans-5-((S)-2-(4-((3-cyano-4-fluorophenoxy)methyl)cyclohexane-l- carbonyl)isoxazolidin-3-yl)nicotinonitrile, (73) trans-3-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl) methoxy)benzamide, (74) trans-5-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl) methoxy)-2-fluorobenzamide, (75) trans-2-chloro-5-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl) cyclohexyl)methoxy)benzamide, (76) trans-3-((S)-2-(4-((4-(3,5-dimethyl-lH-pyrazol-l-yl)-2-fluorophenoxy)methyl) cyclohexane-l-carbonyl)isoxazolidin-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-lH- imidazol-l-yl)phenoxy)methyl)cyclohexane-l-carbonyl)isoxazolidin-3-yl)benzonitrile, (79) trans-3-((S)-2-(4-((5-(5,5-dimethyl-2,4-dioxooxazolidin-3-yl)-2- fluorophenoxy)methyl)cyclohexane-l-carbonyl)isoxazolidin-3-yl)-5- fluorobenzonitrile, (80) trans-3-((S)-2-(4-((2-chloro-5-(3-methyl-2,5-dioxoimidazolidin-l-yl)phenoxy) methyl)cyclohexane-l-carbonyl)isoxazolidin-3-yl)-5-fluorobenzonitrile, (81) cis-3-((S)-2-(4-(5-(5,5-dimethyl-2,4-dioxo-oxazolidin-3-yl)-2- fluorophenoxy)cyclohexane-l-carbonyl)isoxazolidin-3-yl)-5-fluorobenzonitrile, (82) cis-5-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)oxy)-2-fluorobenzonitrile, (83) trans-5-((S)-2-(4-((3-cyano-5-fluorophenoxy)methyl)cyclohexane-l- carbonyl)isoxazolidin-3-yl)nicotinonitrile, (84) trans-(3-(5-fluoro-lH-benzo[d]imidazol-l-yl)cyclobutyl)((S)-3-(3- fluorophenyl)isoxazolidin-2-yl)methanone, (85) trans-5-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)methoxy)-2-methylbenzamide, (86) trans-5-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-carbonyl)cyclohexyl)methoxy)-2- methylbenzamide, (87) cis-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)(3-(6-fluoro-lH- benzo[d]imidazol-l-yl)cyclobutyl)methanone, (88) trans-5-((S)-2-(4-((2-chloro-5-(3-methyl-2,5-dioxoimidazolidin-l- yl)phenoxy)methyl)cyclohexane-l-carbonyl)isoxazolidin-3-yl)nicotinonitrile, (89) trans-5-((S)-2-(4-((2-fluoro-4-(3-methyl-2-oxo-2,3-dihydro-lH- imidazol-l-yl)phenoxy)methyl)cyclohexane-l-carbonyl)isoxazolidin-3-yl)nicotinonitrile, (90) trans-5-((S)-2-(4-((4-(3,5-dimethyl-lH-pyrazol-l-yl)-2-fluorophenoxy)methyl)cyclohexane-l- carbonyl)isoxazolidin-3-yl)nicotinonitrile, (91) trans-2-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidin-2-carbonyl]cyclohexyl]methoxy]pyridine-4-carbonitrile, (92) trans-5-((S)-2-(4-((5-(5,5-dimethyl-2,4-dioxo-oxazolidin-3-yl)-2- fluorophenoxy)methyl)cyclohexane-l-carbonyl)isoxazolidin-3-yl)nicotinonitrile, (93) Trans-4-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidin-2- carbonyl]cyclohexyl]methoxy]pyridine-2-carbonitrile, (94) Trans-5-((S)-2-(4-(((4-cyanopyridin-2-yl)oxy)methyl)cyclohexane-1- carbonyl)isoxazolidin-3-yl)nicotinonitrile, (95) Trans-5-((S)-2-(4-(((5-cyanopyridin-2-yl)oxy)methyl)cyclohexane-1- carbonyl)isoxazolidin-3-yl)nicotinonitrile, (96) Cis-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[3-(5-fluoroindazol-1- yl)cyclobutyl]methanone, (97) Trans-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[3-(5-fluoroindazol-1- yl)cyclobutyl]methanone, (98) Trans-3-fluoro-5-[(3S)-2-[3-(5-fluoroindazol-1-yl)cyclobutane- carbonyl]isoxazolidin-3-yl]benzonitrile, (99) Trans-6-[[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidin-2-carbonyl]cyclohexyl] methoxy]pyridine-3-carboxamide, (100) Trans-3-[[4-[(3S)-3-pyrazin-2-ylisoxazolidin-2-carbonyl]cyclohexyl] methoxy]benzamide, (101) Trans-2-fluoro-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidin-2-carbonyl]cyclohexyl] methoxy]benzamide, (102) Trans-6-[[4-[(3S)-3-pyrazin-2-ylisoxazolidin-2-carbonyl]cyclohexyl] methoxy]pyridine-3-carboxamide, (103) Trans-6-[[4-[(3S)-3-pyrazin-2-ylisoxazolidin-2-carbonyl]cyclohexyl] methoxy]pyridine-3-carbonitrile, (104) Trans-3-fluoro-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidin-2-carbonyl]cyclohexyl] methoxy]benzonitrile, (105) Trans-3-fluoro-5-[(3S)-2-[3-(5-fluoroindol-1-yl)cyclobutane- carbonyl]isoxazolidin-3-yl]benzonitrile, (106) Trans-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[3-(5-fluoroindol-1- yl)cyclobutyl]methanone, (107) cis-3-fluoro-5-[(3S)-2-[3-(5-fluoroindol-l-yl)cyclobutanecarbonyl]isoxazolidin-3- yl]benzonitrile, (108) cis-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[3-(5-fluoroindol-l- yl)cyclobutyl]methanone, (109) cis-3-fluoro-5-[(3S)-2-[3-(5-fluoroindazol-2-yl)cyclobutanecarbonyl]isoxazolidin- 3-yl]benzonitrile, (110) cis-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[3-(5-fluoroindazol-2- yl)cyclobutyl]methanone, (111) trans-4-fluoro-3-[[4-[(3S)-3-pyrazin-2-ylisoxazolidin-2-carbonyl]cyclohexyl]methyloxy] benzamide, (112) trans-3-fluoro-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidin-2-carbonyl]cyclohexyl]methyloxy] benzamide, (113) trans-3-fluoro-4-[[4-[(3S)-3-pyrazin-2-ylisoxazolidin-2-carbonyl]cyclohexyl]methyloxy] benzamide, (114) cis-2-[3-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-carbonyl]cyclopentyl]pyridine-4- carboxamide, (115) cis-6-[[3-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidin-2-carbonyl]cyclopentyl]methyloxy] pyrimidine-4-carboxamide, (116) trans-6-[[3-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidin-2-carbonyl]cyclopentyl]methyloxy] pyrimidine-4-carboxamide stereoisomer 2, (117) trans-6-[[3-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidin-2-carbonyl]cyclopentyl]methyloxy] pyrimidine-4-carboxamide stereoisomer 3, (118) trans-6-[[3-[(3S)-3-(3,5-difluorophenyl)-l,2-oxazolidin-2-carbonyl]cyclopentyl]methyloxy] pyrimidine-4-carboxamide stereoisomer 1, (119) cis-6-[[3-[(3S)-3-(3,5-difluorophenyl)-l,2-oxazolidin-2-carbonyl]cyclopentyl]methyloxy] pyrimidine-4-carboxamide stereoisomer 2, (120) Trans-6-[[3-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cyclopentyl]methyloxy]pyrimidine-4-carboxamide stereoisomer 3, (121) Cis-6-[[3-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cyclopentyl]methyloxy]pyrimidine-4-carboxamide stereoisomer 4, (122) Trans-6-[[4-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cycloheptyl]methyloxy]pyrimidine-4-carboxamide stereoisomer 1, (123) Trans-6-[[4-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cycloheptyl]methyloxy]pyrimidine-4-carboxamide stereoisomer 2, (124) Cis-6-[[4-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cycloheptyl]methyloxy]pyrimidine-4-carboxamide stereoisomer 3, (125) Cis-6-[[4-[(3S)-3-(3,5-difluorophenyl)-1,2-oxazolidine-2-carbonyl]cycloheptyl]methyloxy]pyrimidine-4-carboxamide stereoisomer 4, (126) Trans-6-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cycloheptyl]methyloxy]pyrimidine-4-carboxamide stereoisomer 1, (127) Trans-6-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cycloheptyl]methyloxy]pyrimidine-4-carboxamide stereoisomer 2, (128) Cis-6-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cycloheptyl]methyloxy]pyrimidine-4-carboxamide, (129) Trans-3-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyloxy]benzamide, (130) Trans-3-[[4-[(3S)-3-(2-methylthiazol-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyloxy]benzamide, and (131) Trans-3-[[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyloxy]benzamide, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0069] According to one embodiment of the disclosure, the compound of Formula (I) is selected from the group consisting of compounds (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 a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0070] According to another embodiment of the 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 a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0071] Some of the compounds of the disclosure are described in Table 1 by their structure, which is illustrative only and does not limit the scope of the disclosure.

[0072] The NMR and LC / MS data in Table 1 were obtained according to the methods detailed in the Experimental Section provided for the synthesis of detailed examples. Table 1. Structures and analytical characterization of compounds (1) to (131) Preparation methods

[0073] Compounds of formula (I) can be prepared using the methods disclosed herein and routine modifications thereof, as will be apparent in view of the disclosure herein and methods well known in the art. Scheme 1: General synthesis of compounds of formula (I)

[0074] According to a first synthesis method (SM1), compounds of formula (I) can be obtained from alkyl esters of formula (III). Step 2 can comprise hydrolysis of alkyl esters of formula (III) to form compounds of formula (IIa) and can be achieved under well-known conditions using, for example, lithium hydroxide or sodium hydroxide in water or in a solvent mixture like THF / water or THF / water / MeOH. Step 2 is in particular illustrated in step 4 of Example 1. Step 1 is an amide coupling between a suitably substituted isoxazolidine compound of formula (A) and a compound of formula (IIa). It can be achieved by standard acid activation methods under basic conditions, for example using oxyma, acid chlorides, HOBt, HATU, HBTU, PyBOP or 1-propanephosphonic anhydride (T3P) in the presence of a base such as triethylamine, diisopropylethylamine, and the like, in an aprotic solvent like DMF, DMSO, acetonitrile, and the like, to form compounds of formula (I). Step 1 is in particular illustrated in step 3a of Example 3.1, step 3 of Example 5 and step 5 of Example 1.

[0075] Substituted isoxazolidines of formula (A) can be synthesized by known procedures from the literature, for example WO 2017096301, WO 2019130230 and WO 2021245070.

[0076] Compounds of formula (IIb) can be synthesized by known procedures from the literature or as described herein. Scheme 2: Synthesis of compounds of formula (III), wherein R2is an optionally substituted benzimidazolyl group and Y is a bond.

[0077] Compounds of formula (I) wherein R2represents an optionally substituted imidazolyl group and Y is a bond can be synthesized starting from an optionally substituted o-fluoronitrobenzene (B) and a compound 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, R8represents a hydrogen atom or a R6group, and R9represents a hydrogen atom or a group selected from halogen, cyano, -OH, (Ci-C4)-alkyl, -CF3, -C(0)NH2, -C(0)NH-(Ci-C4)-alkyl, -C(0)OH, -C(0)0-(Ci-C4)-alkyl, -SO2NH2, (Ci-C4)-alkoxy.

[0078] Step 5 is a S N Ar reaction. The obtained nitroaniline compound (Va) can then be converted (step 4) into the corresponding aminoaniline compound (IVa), which can be achieved by, for example, palladium catalyzed hydrogenolysis under a hydrogen atmosphere in a suitable solvent such as methanol. Step 3 allows to obtain compound (Ilia) via condensation with a suitable orthoester or acyl halide bearing a R9group such as acetyl chloride or trimethyl orthoformate, respectively. This type of reaction can be performed in solvents such as methanol or dioxane, respectively.

[0079] An optionally substituted o-fluoronitrobenzene (B) can be synthesized by known procedures from the literature or as described herein.

[0080] A compound of formula (Via) can be synthesized by known procedures from the literature or as described herein.

[0081] The synthesis of compounds of formula (Ilia) via scheme 2 can be illustrated in example 1 hereafter. Scheme 3: Synthesis of compounds of formula (III) wherein R2represents an optionally substituted aryl group or a heteroaryl group different from a benzimidazolyl group and Y is a bond, -NH- or -NH-CH2.

[0082] Compounds of general formula (IlIb) wherein R2is as defined in formula (I) can be synthesized starting from compound (IVb).

[0083] In case Y is -NH- or -NH-CH2-, compound (IIIb) can be obtained from compound (IVb) (wherein X is a hydrogen atom) via step 6a. Step 6a can be a coupling reaction performed in the presence of a metal catalyst, in particular a copper catalyst (such as copper (I) iodide, copper (I) bromide or copper (I) oxide) and a base (such as Cs2C03, K3P04or sodium acetate) in a polar solvent (such as DMF, DMSO, DMA (dimethylacetamide) or NMP (N-methyl-2-pyrrolidone)). Step 6a is in particular illustrated in examples 2.1 and 2.2.

[0084] In case Y is -NH- or -NH-CH2-, compound (IIIb) can be obtained from compound (IVb) (wherein X is a hydrogen atom) via step 6b. Step 6b can be a SNAr reaction performed in the presence of a base (such as diisopropylethylamine or K2C03) in a suitable solvent (such as acetonitrile and DMSO). N Ar reaction. Step 6b is in particular illustrated in examples 2.3, 2.4, 2.5 and 3.1.

[0085] In case Y is a bond, compound (IIIb) can be obtained from compound (IVb) (wherein X is a leaving group) via step 6c. In case R2represents an optionally substituted heteroaryl group containing a -NH group, compound (IIIb) can be obtained from compound (IVb) (wherein X is a leaving group) via an alkylation step 6c. Compound (IVb) (wherein X is a leaving group, in particular a halide or an alkylsulfonate such as a mesylate, a tosylate or a nosylate) can be reacted with a suitable heteroaromatic compound containing a -NH group in the presence of a base (such as Cs2C03or K2C03) in an inert solvent (such as for example DMF or THF). Step 6c is in particular illustrated in examples 4.1 and 4.2.

[0086] Compounds of formula (IVb) can be synthesized by known procedures from the literature or as described herein. Scheme 4: General synthesis of compounds of formula (I) wherein Y is -O- or -O-CH2- and z is 0 or 1.

[0087] According to a third synthetic method (SM3) indicated by the upper arrow in Scheme 4, compounds of formula (I) can be obtained from amides of formula (lie). This step can involve a Mitsunobu reaction under well-known conditions. It can be achieved by using compounds of formula (lie) and compounds of formula R2OH (R2 is as defined in formula (I) and in particular optionally substituted aryl) in the presence of an azodicarboxylate reagent (such as DEAD, DIAD, ADDP (1,1'-(azodicarbonyl)dipiperidine), TMAD (N,N,N',N'-tetramethyladipimidamide), DCAD (di-4-chlorobenzyl azodicarboxylate), DNAD (di-4-nitrobenzyl azodicarboxylate)), with a phosphine (such as triphenylphosphine, PH3, DPPE (1,2-bis(diphenylphosphino)ethane), PPh2Py (diphenyl-2-pyridylphosphine), Tris-DAP (tris(dimethylamino)phosphine)) in an aprotic solvent (such as THF, CH2CI2 or Et20, etc.) under anhydrous conditions to form compounds of formula (I). The SM3 approach is in particular illustrated in step 3a of Example 9, steps 2a and 2b of Example 12.2, and step 2 of Example 12.6.

[0088] According to a fourth synthetic method (SM4) indicated by the middle arrow in Scheme 4, compounds of formula (I) can be obtained from amides of formula (lie). This step can involve a nucleophilic substitution, in particular an aromatic nucleophilic substitution under well-known conditions. It can be achieved by using compounds of formula R2-leaving group (R2 is as defined in formula (I) and in particular optionally substituted aryl, etc., the leaving group being a halogen such as a chlorine atom or a cyano group) in the presence of a base (such as diisopropylethylamine, K2CO3, NaH, KH, K3PO4, Na2CO3, tBuOK) in an aprotic solvent (such as THF, acetonitrile, DMF, DMA, DMSO, NMP, dioxane, etc.) to form compounds of formula (I). The SM4 approach is in particular illustrated in steps 2a and 2b of Example 12.1.

[0089] According to the third synthetic method (SM5) indicated by the down arrow in Scheme 4, compounds having formula (I) can be obtained from amides having formula (IId) containing a leaving group. As an example, compounds having formula (IId) can be obtained from compounds having formula (IIc) by activating a hydroxyl group to form a leaving group, indicated by a dashed arrow in Scheme 4. This activation can be carried out in the presence of a base, particularly an amine base (such as triethylamine or diisopropylethylamine), in an aprotic solvent (such as CH2Cl2, ethyl acetate, THF, or DMF) via well-known nucleophilic substitution of the hydroxyl group of the compound having formula (IIc) with a sulfonyl chloride, particularly a halide (particularly an iodide), or an alkylsulfonyl chloride (such as methanesulfonyl chloride), or an arylsulfonyl chloride (such as toluenesulfonyl chloride or 4-nitrobenzenesulfonyl chloride) to form a compound having formula (IId). The activation step is specifically described in step 4a of Example 9.

[0090] The steps for forming compounds of formula (I) using SM5 may include nucleophilic substitution under well-known conditions. This can be achieved by using a compound of formula (IId) and an R2-OH compound (R2 being an aryl group as defined in formula (I) and preferably optionally substituted) in an aprotic solvent (such as DMF, acetonitrile, DMSO, NMP, or THF) in the presence of a base (e.g., Cs2CO3, NaH, potassium tert-butoxide, etc.) to form a compound of formula (I). The SM5 pathway is specifically illustrated in steps 5a and 5b of Example 9. Scheme 5: General synthesis of compounds having formula (I), wherein Y is -NH- or -NH-CH2- and z is 0 or 1.

[0091] Compounds having the general formula (I) (where R2 represents an optionally substituted phenyl or heteroaryl group) can be derived from compound (IIe) via aromatic nucleophilic substitution, particularly aromatic nucleophilic substitution (S). N Ar) synthesis. It can be achieved by reacting compound (IIe) with a compound having the chemical formula R2-Hal (R2 is an aryl or heteroaryl group as defined in formula (I) and particularly substituted with a Hal leaving group, where Hal is a halogen, such as a chlorine atom) in the presence of a base (e.g., diisopropylethylamine, K2CO3, NaH, KH, K3PO4, Na2CO3, or tBuOK) in an aprotic solvent (such as THF, DMSO, acetonitrile, DMF, NMP, or DMA, etc.) to form a compound having formula (I). This route is specifically illustrated in Example 2 of 11.2, Step 2b of Example 11.9, and Step 3 of Example 11.10.

[0092] Functional groups in compounds, such as acids, esters, amides, nitriles, halogens, can be transformed (functional group interconversion) into other functional groups using standard methods (like esterification, saponification, halogenation, Suzuki reaction) to produce additional compounds of Formula (I).

[0093] The synthesis of exemplary compounds described herein can be accomplished as described in the following examples. Reagents can be purchased commercially, if available, for example from Sigma Aldrich or other chemical suppliers. It will be recognized that, unless otherwise specified, where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can be used unless otherwise specified. Optimum reaction conditions can vary depending on the particular reactants or solvent used, but such conditions can be determined by those skilled in the art by routine optimization procedures.

[0094] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups can be necessary to protect certain functional groups from undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups, are well known in the art. For example, many protecting groups are described in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006), Greene’s protective groups in organic synthesis, Hoboken, N.J., Wiley-Interscience and references cited therein.

[0095] In addition, the compounds of the present disclosure can contain one or more chiral centers. Accordingly, such compounds can be prepared or isolated as pure stereoisomers, that is, as individual enantiomers or diastereomers, or as a mixture of stereoisomers, enriched in one or more stereoisomer, if desired. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

[0096] The starting materials for the following reactions are either 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). Other materials can be prepared by procedures described in standard reference texts or obvious modifications thereof, such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons [John Wiley, and Sons], 1991), Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers [Elsevier Science Publishers], 1989) Organic Reactions, Volumes 1-40 (John Wiley, and Sons [John Wiley, and Sons], 1991), March’s Advanced Organic Chemistry, (John Wiley, and Sons [John Wiley, and Sons], 5th Edition, 2001), and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc. [VCH Publishers Inc.], 1989). The terms “solvent,” “inert organic solvent,” or “inert solvent” mean a solvent that is inert under the conditions of the reaction in which it is used (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride or dichloromethane (“DCM”), diethyl ether, methanol, pyridine, and the like). Unless otherwise stated, the solvents used in the reactions of the present disclosure are inert organic solvents, and the reactions are conducted under an inert gas, preferably argon. Pharmaceutical compositions

[0097] The compounds provided herein are generally administered in the form of pharmaceutical compositions. Thus, also provided herein are pharmaceutical compositions comprising one or more compounds described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients.

[0098] According to another aspect, pharmaceutical compositions comprising as active ingredient a compound described herein are disclosed. The compounds of the present disclosure are typically, but not necessarily, formulated into pharmaceutical compositions before administration to a patient. These pharmaceutical compositions comprise an effective dose of at least one compound of the present disclosure, as defined herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0099] The excipients are selected from conventional excipients known to those skilled in the art, depending on the desired pharmaceutical form and method of administration.

[0100] In these pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient is a compound of formula (I) or a salt or solvate thereof, where appropriate, which can be administered to a subject, like a human, in unit administration form in admixture with conventional pharmaceutical excipients for the prevention or treatment of a disease or disorder or condition mediated at least in part by receptor-interacting protein kinase 1, and in particular acute and chronic neurodegenerative diseases, like Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). Unit administration

[0101] Suitable unit administration forms include oral forms, such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, intramuscular or intravenous administration, rectal administration forms and implants.

[0102] When prepared in unit administration form, the pharmaceutical compositions of the present disclosure typically contain from 1 mg to 1000 mg of active ingredient. The amount of active ingredient combined with one or more excipients to produce a single unit administration form will have to be varied depending on the host treated and particular administration route. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent compounded with an appropriate and convenient amount of excipients, which can vary from about 5 to about 98 percent of the total composition weight.

[0103] As an example, a unitary administration form of a compound described herein in tablet form can include the following components: Compound 50.0 mg Mannitol 223.75 mg Croscarmellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg

[0104] When the compounds of the disclosure are used for therapeutic or prophylactic purposes, the compounds of the disclosure will generally be administered to impart a daily dose in the range of, for example, 0.1 mg / kg to 75 mg / kg body weight, given in divided doses if needed.

[0105] Generally, lower doses will be administered when the parenteral route is employed. Thus, for intravenous or intraperitoneal administration, for example, a dose in the range of, for example, 0.1 mg / kg to 30 mg / kg body weight will generally be used. Oral administration can also be appropriate, especially in tablet form. Typically, unit dosage forms will contain between about 0.5 mg and 0.5 g of a compound of the disclosure.

[0106] There can be specific instances in which a higher or lower dose is appropriate; such dosages would not depart from the scope of the disclosure. The determination of an appropriate dosage for each patient, according to the mode of administration and the body weight and response of the patient, is within the skill of the attending physician. Methods of treatment

[0107] In other embodiments, provided herein are methods of treating a receptor-interacting protein kinase 1 -mediated disease or disorder. The method includes administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition described herein. 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).

[0108] Accordingly, the receptor-interacting protein kinase 1 inhibitors of the disclosure are useful in the treatment of diseases and conditions mediated by receptor-interacting protein kinase 1, including but not limited to neurodegenerative diseases, central nervous system (CNS) diseases. Neurodegenerative diseases and CNS diseases

[0109] The receptor-interacting protein kinase 1 inhibitors described herein can also be used to treat neurodegenerative diseases. Neurodegenerative diseases can affect many activities of the body, such as balance, movement, speech, breathing, and heart function. Neurodegenerative diseases can be inherited or can be caused by medical conditions such as alcoholism, tumors, stroke, toxins, chemicals, and viruses. Non-limiting examples of neurodegenerative diseases include Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and Parkinson’s disease.

[0110] In certain embodiments, the compounds and compositions of the present disclosure can be used to treat Alzheimer’s disease. In certain embodiments, the compounds and compositions of the present disclosure can be used to treat Parkinson’s disease. In certain embodiments, the compounds and compositions of the present disclosure can be used to treat amyotrophic lateral sclerosis (ALS).

[0111] More generally, the receptor-interacting protein kinase 1 inhibitors described herein can be used to preserve neuronal viability and promote axonal growth and neural function within the central nervous system (CNS). Thus, these compounds can be used to reduce or even reverse the loss of cognitive, motor, and sensory function associated with CNS diseases or disorders by preserving neuronal viability and / or promoting axonal regeneration and / or neural function.

[0112] If desired, the effective daily dose of the active compound can be administered as two, three, four, five, six, or more sub-doses administered at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments, the present disclosure relates to compounds for inhibiting cell death, wherein the compounds are represented by formula (I). In certain embodiments, the compounds of the present disclosure are inhibitors of cell death. In any case, the compounds of the present disclosure exert their cell death-inhibiting effect at a concentration of less than about 50 micromolar, more at a concentration of less than about 10 micromolar, and most at a concentration of less than 1 micromolar, in another embodiment. The compounds of the present disclosure can be tested in standard animal models of stroke and standard protocols such as those described in Hara, H., et al. Proc. Natl. Acad. Sci. USA, 1997. 94(5): 2007-12.

[0113] When the compounds of the present disclosure are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more at another embodiment 0.5% to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0114] The compounds of the disclosure, or compositions thereof, can be administered once, twice, three times, or four times per day. In addition, administration of the compound or treatment can continue for several days; for example, typically the treatment will continue for at least 7 days, 14 days, or 28 days, for a treatment cycle. Treatment cycles are well known and are often alternated with a rest period (between cycles) of about 1 to 28 days, typically about 7 days, or about 14 days. In certain embodiments, the treatment cycle can also be continuous.

[0115] When administered orally, the total daily dose for a human subject can be between 1 mg and 1,000 mg, between about 1,000-2,000 mg / day, between about 10-500 mg / day, between about 50-300 mg / day, between about 75-200 mg / day, or between about 100-150 mg / day.

[0116] The daily dose can also be described as the total amount of a compound described herein administered per dose or per day. The daily dose of the compound can be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg / day, between about 1 to 2,000 mg / day, between about 1 to 1,000 mg / day, between about 10 to 500 mg / day, between about 20 to 500 mg / day, between about 50 to 300 mg / day, between about 75 to 200 mg / day, or between about 15 to 150 mg / day. In certain embodiments, the method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased daily, every other day, twice a week, or once a week.

[0117] In certain embodiments, the compound or pharmaceutical formulation is administered orally. In certain embodiments, the compound or pharmaceutical formulation is administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

[0118] The formulations of the disclosure can be administered orally, parenterally, topically, or rectally. They are, of course, given in forms suitable to the chosen route of administration. For example, they are given in the form of tablets or capsules, by injection, inhalation, eye lotion, ointment, suppositories, etc., by injection, infusion, or inhalation; topically in the form of lotions or ointments; and rectally in the form of suppositories. In certain embodiments, the administration is oral. [Examples] The following examples describe the preparation of certain compounds. These examples are non-limiting and are merely illustrative. Numerous modifications and alternative compositions, methods, and systems can be devised by those skilled in the art without departing from the spirit and scope of the present disclosure. Abbreviations: silica gel chromatography

[0119] Silica gel chromatography was performed using a CombiFlash® Rf (Teledyne ISCO) with pre-packed cartridges, a Biotage Isolera One automated flash purification system or two Bϋchi systems (C-660, C-605, C-620, C-635 combination and C-660, C-605, C-615, C-630 combination). preparative reverse phase HPLC

[0120] For preparative reverse phase HPLC Agilent 1200 preparative HPLC machine, Gilson equipment (GX-271 liquid handler, 331 / 332-pumps, UV / VIS-155) or Waters Autopurification LC Prep system were used. preparative RP-LC

[0121] Reversed phase liquid chromatography was performed with Biotage equipment using C18 columns and water (0.1 % formic acid) / acetonitrile gradients. NMR

[0122] 400 MHz: recorded on a Bruker AVANCE II 400 spectrometer 1 H NMR spectra were operated at a proton frequency of 400.23 MHz. The instrument was equipped with a 5 mm BBI room temperature probehead. Alternatively, a Bruker AVANCE III HD 400 MHz or a Bruker AVANCE NEO 400 MHz was used.

[0123] 600 MHz: recorded on a Bruker AVANCE III 600 spectrometer 1 H NMR spectra were operated at a proton frequency of 600.05 MHz. The instrument was equipped with a 5 mm BBI room temperature probehead. analytical LC / MS equipment for method A

[0124] Retention times and mass detection were performed on a Waters Acquity UHPLC system equipped with a Waters SQD mass detector. The injection volume was 1.0 μΐ. Molecular weights are given in grams per mole [g / mol], detected masses in mass per charge [m / z]. Analytical LC / MS equipment for method B and method C

[0125] For the retention time and mass detection, an LC / MS-system from Agilent (LC 1200 series / MS 6120 quadrupole LC / MS, LC 1260 infinity / MS 6120 quadrupole LC / MS or LC 1260 Infinity II / MSD Infinity Lab) from Agilent was used. The molecular weight is given in gram per mole [g / mol], the detected mass in mass per charge [m / z]. LC / MS-method A

[0126] Gradient: 98% H2O (0.05% formic acid) / 2% acetonitrile (0.035% formic acid) for 0.2 min, then from 98% H2O (0.05% formic acid) to 98% acetonitrile (0.035% formic acid) in 3.6 min, then 98% acetonitrile (0.035% formic acid) for 0.5 min, flow: 1.0 ml / min, column: 2.1 x 50 mm Waters ACQUITY UPLC BEH C18, 1.7 µm, 55 °C. UV data: retention time ad λ = 220 nm, given in min MS data: ES+ ionization, m / z in [M+H] + given, unless otherwise indicated. LC / MS-method B

[0127] Gradient: from 95% H2O (0.0375% TFA) / 5% acetonitrile (0.01875% TFA) to 5% H2O (0.0375% TFA) / 95% acetonitrile (0.01875% TFA) in 0.8 min, flow: 1.5 ml / min, column: Kinetex EVO C18 2.1 x 30 mm, 5 µm, 50 °C UV data: retention time ad λ = 220 nm, given in min MS data: ES+ ionization, m / z in [M+H] + given, unless otherwise indicated. LC / MS-method C

[0128] Gradient: from 100% H2O (0.0375% TFA) / 0% acetonitrile (0.01875% TFA) to 60% H2O (0.0375% TFA) / 40% acetonitrile (0.01875% TFA) in 0.8 min, flow rate: 1.5 ml / min, column: Kinetex EVO C18 2.1 x 30 mm, 5 µm, 50 °C UV data: retention time ad λ = 220 nm, given in min MS data: ES+ ionization, m / z given in [M+H] + are given, unless otherwise stated. salt

[0129] In case a compound is described as HC1-, TFA- or another salt, it is not always possible to determine the exact amount of the corresponding salt. Therefore, the amount of salt can range from as low as 0.01 equivalent to 5.0 equivalents, depending on the chemical structure (e.g. number of basic centers). chiral purity

[0130] If the enantiomeric ratio exceeds 90 : 10, the compound is drawn and named as single enantiomer. For enantiomeric ratios below 90 : 10, the racemic form is used. Example 1 : Synthesis of compounds (40), (41), (42), (69), (70), (84) and (87) Example 1.0: Step 1: Synthesis of methyl trans-4-[(2-nitroanilino)methyl]cyclohexanecarboxylate

[0131] To a stirred suspension of 1-fluoro-2-nitrobenzene (749 μΐ, 7.09 mmol) and methyl 4-(aminomethyl)cyclohexanecarboxylate hydrochloride (1.50 g, 7.09 mmol) in CH3CN (22 ml) was added NetiPr2 (3.71 ml, 21.26 mmol) at room temperature. The solution was heated under reflux for 2 h. The volatile components were removed under reduced pressure and the resulting residue was partitioned between EA and water. The aqueous layer was extracted with EA, the combined organic layers were dried over Na2S04, filtered and concentrated to give crude 4-[(2-nitroanilino)methyl]cyclohexanecarboxylate which was purified by column chromatography (Si02; EA / heptane gradient) (860 mg, 2.95 mmol, 41% yield). 1H NMR (600 MHz, DMSO-d6): δ ppm 8.18 (br t, J=5.41 Hz, 1 H), 8.06 (m, 1 H), 7.52 (t, J=7.84 Hz, 1 H), 7.07 (d, J=8.44 Hz, 1 H), 6.67 (t, J=7.85 Hz, 1 H), 3.58 (s, 3 H), 3.27 (m, 2 H), 2.27 (m, 1 H), 1.93 (m, 2 H), 1.82 (m, 2H), 1.63 (m, 1 H), 1.32 (m, 2 H), 1.06 (m, 2 H). Step 2: Synthesis of trans-methyl 4-[(2-aminophenylamino)methyl]cyclohexanecarboxylate

[0132] A stirred suspension of trans-methyl 4-(((2-nitrophenyl)amino)methyl)cyclohexane-1- carboxylate (862 mg, 2.95 mmol) in MeOH (70 ml) and Pd / C (10%, 54% water, 470 mg, 442 pmol) in a round bottom flask was evacuated and backfilled with H2. This process was repeated 3 times. The suspension was stirred vigorously under an atmosphere of H2(gas balloon) at room temperature for 2 h. 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 without further purification for the next reaction (695 mg, 2.65 mmol, 90% yield). 1 H NMR (400 MHz, DMSO-d6): δ ppm 6.49 (m, 2 H), 6.38 (m, 2 H), 4.47(s, 2 H), 4.32 (t, J=5.62 Hz, 1 H), 3.58 (s, 3 H), 2.86 (t, J=6.11 Hz, 2 H),2.27 (m, 1 H), 1.92 (m, 4 H), 1.55 (m, 1 H), 1.31 (m, 2 H), 1.00 (m, 2 H) Step 3: Synthesis of trans-methyl 4-(benzimidazol-1-ylmethyl)cyclohexanecarboxylate

[0133] To a stirred solution of trans-4-(((2-aminophenyl)amino)methyl)cyclohexane-1- carboxylate (694 mg, 2.65 mmol) and orthoformic acid trimethyl ester (15 ml, 137 mmol) in MeOH (15 ml) was added concentrated HC1 (1.54 ml) at room temperature. The solution was stirred at room temperature for 1 h. The volatile components were removed under reduced pressure and the resulting residue was partitioned between saturated aqueous NaHC03and EA. The aqueous layer was extracted with EA, the combined organic layers were dried over Na2S04, filtered and concentrated to give trans-4- (benzimidazol-1-ylmethyl)cyclohexane carboxylic acid methyl ester which was used in the next reaction without further purification (700 mg, 2.57 mmol, 97% yield). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.18 (s, 1 H), 7.64 (m, 2 H), 7.22(m, 2 H), 4.10 (d, J=7.09 Hz, 2 H), 3.56 (s, 3 H), 2.24 (m, 1 H), 1.85 (m, 3H), 1.58 (m, 2 H), 1.25 (m, 2 H), 1.07 (m, 2 H). Step 4: Synthesis of trans-4-(benzimidazol-1-ylmethyl)cyclohexane carboxylic acid - hydrolysis was performed as described in step 2 of scheme 1.

[0134] To a solution of trans-4-(benzimidazol-1-ylmethyl)cyclohexane carboxylic acid methyl ester (700 mg, 2.57 mmol) in MeOH (12 ml) and THF (12 ml) was added a solution of lithium hydroxide (185 mg, 7.71 mmol) in water (12 ml). The resulting solution was stirred at room temperature for 3 h. The volatile components were removed under reduced pressure and the remaining aqueous solution was acidified with 1 N HC1 (10.0 ml, 10.0 mmol). The resulting solution was lyophilized. The title compound was obtained as a white solid (2 x LiCl mixture) which was used in the next reaction without further purification (1.05 g, quantitative). 1H NMR (400 MHz, DMSO-d6): δ ppm 12.04 (br s, 1 H), 9.14 (s, 1 H), 7.90 (d, J=7.21 Hz, 1 H), 7.80 (d, J=7.27 Hz, 1 H), 7.48 (m, 2 H), 4.27 (d, J=7.21 Hz, 2 H), 2.14 (m, 1 H), 1.91 (m, 3 H), 1.61 (m, 2 H), 1.24 (m, 2 H), 1.09 (m, 2 H). Step 5: Synthesis of trans-1-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidin-2- yl) cyclohexyl)methyl)-6-fluoro-1H-benzo[d]imidazole-5-carbonitrile

[0135] To a stirred solution of trans-4-[(5-cyano-6-fluoro-benzimidazol-1-yl)methyl] cyclohexanecarboxylic acid (100 mg, 331 µmol), NetiPr2 (174 µl, 995 µmol) and 3-fluoro-5-[(3S)-isoxazolidin-3-yl]benzonitrile hydrochloride (98.7 mg, 431 µmol) in DMF (2 ml) was added HATU (151 mg, 398 µmol) at room temperature. Stirring was continued at room temperature for 2 h. The reaction mixture was filtered and subjected to preparative reverse phase HPLC (70 mg, 147 µmol, 44% yield). Example 1.1: Synthesis of compounds (40), (41) and (42)

[0136] Step 1: Synthesis of cis-3-(2-nitroanilino)cyclobutane carboxylate - a compound corresponding to formula (Va) as defined in Scheme 2 was carried out in a similar manner as in Example 1.0, but using cis-3-(amino)cyclobutane carboxylate methyl ester instead of 4-(aminomethyl)cyclohexane carboxylic acid methyl ester.

[0137] Step 2: Synthesis of cis-3-(2-aminoanilino)cyclobutane carboxylate methyl ester - a compound corresponding to formula (Via) as defined in Scheme 2 was carried out in a similar manner as in Example 1.0, but starting from cis-3-(2-nitroanilino)cyclobutane carboxylate

[0138] Step 3: Synthesis of cis-3-(benzimidazol-1-yl)cyclobutane carboxylate methyl ester - a compound corresponding to formula (Via) as defined in Scheme 2 was carried out in a similar manner as in Example 1.0, but starting from cis-3-(2-aminoanilino)cyclobutane carboxylate methyl ester

[0139] Step 4: cis-3-(benzimidazol-l-yl)cyclobutane carboxylic acid - synthesis of a compound corresponding to Formula (IIa) in Scheme 1 was carried out in a similar manner as in Example 1.0, but starting from cis-3-(benzimidazol-l-yl)cyclobutane carboxylic acid methyl ester

[0140] Step 5a: synthesis of cis-3-((S)-2-(3-(lH-benzo[d]imidazol-l- yl)cyclobutane-l-carbonyl)isoxazolidin-3-yl)-5-fluorobenzonitrile (Compound (40)) was carried out as in Step 5 of Example 1.0, but starting from cis-3-(benzimidazol-l- yl)cyclobutane carboxylic acid instead of trans-4-[(5-cyano-6-fluoro-benzimidazol-l- yl)methyl]cyclohexanecarboxylic acid.

[0141] Step 5b: synthesis of cis-(3-(lH-benzo[d]imidazol-l-yl)cyclobutyl)((S)-3-(3,5- difluorophenyl)isoxazolidin-2-yl)methanone (Compound (41)) was carried out in a similar manner as in Step 5 of Example 1.0, but starting from cis-3-(benzimidazol-l- yl)cyclobutane carboxylic acid and (S)-3-(3,5-difluorophenyl)isoxazolidine.

[0142] Step 5c: synthesis of cis-(3-(lH-benzo[d]imidazol-l-yl)cyclobutyl)((S)-3-(5- fluoropyridin-3-yl)isoxazolidin-2-yl)methanone (Compound (42)) was carried out in a similar manner as in Step 5 of Example 1.0, but starting from cis-3-(benzimidazol-l- yl)cyclobutane carboxylic acid and (S)-3-(5-fluoropyridin-3-yl)isoxazolidine. Example 1.2: synthesis of Compounds (69) and (70)

[0143] Step 1: cis-3-(4-fluoro-2-nitro-anilino)cyclobutane carboxylic acid methyl ester - synthesis of a compound corresponding to Formula (Va) as defined in Scheme 2 - was carried out in a similar manner as detailed in Step 1 of Example 1.0.

[0144] Step 2: cis-3-(2-amino-4-fluoro-anilino)cyclobutane carboxylic acid methyl ester - synthesis of a compound corresponding to Formula (IVa) as defined in Scheme 2 - was carried out in a similar manner as detailed in Step 2 of Example 1.0, but starting from cis-3-(4-fluoro-2-nitro-anilino)cyclobutane carboxylic acid methyl ester

[0145] Step 3: Synthesis of cis-3-(5-fluorobenzimidazol-l-yl)cyclobutane carboxylic acid methyl ester - corresponding to compound (Ilia) - in analogy to the procedure detailed in Step 3 of Example 1.0, but starting from cis-3-(2-amino-4-fluoro- anilino)cyclobutane carboxylic acid methyl ester

[0146] Step 4: Synthesis of cis-3-(5-fluorobenzimidazol-l-yl)cyclobutane carboxylic acid in analogy to the procedure detailed in Step 4 of Step 2 - Scheme 1 of Example 1.0, but starting from cis-3-(5-fluorobenzimidazol-l-yl)cyclobutane carboxylic acid methyl ester

[0147] Step 5a: Synthesis of cis-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)(3-(5-fluoro-lH- benzo[d]imidazol-l-yl)cyclobutyl)methanone (compound (69)) in analogy to Step 5 of Example 1.0, but starting from cis-3-(5-fluorobenzimidazol-l-yl)cyclobutane carboxylic acid and (S)-3-(3,5-difluorophenyl)isoxazolidine.

[0148] Step 5b: Synthesis of cis-3-fluoro-5-((S)-2-(3-(5-fluoro-lH-benzo[d]imidazol-l-yl)cyclobutane-l- carboxylato)isoxazolidin-3-yl)benzonitrile (compound (70)) in analogy to Step 5 of Example 1.0, but starting from cis-3-(5-fluorobenzimidazol-l-yl)cyclobutane carboxylic acid and 3-fluoro-5-[(3S)-isoxazolidin-3-yl]benzonitrile hydrochloride. a Example 1.3: Synthesis of compound (84)

[0149] Step 1: Synthesis of trans-3-(4-fluoro-2-nitro-anilino)cyclobutane carboxylic acid methyl ester - corresponding to compound of formula (Va) as defined in Scheme 2 - in analogy to the procedure detailed in Step 1 of Example 1.0, but starting from trans-3-(amino)cyclobutane carboxylic acid methyl ester.

[0150] Step 2: Synthesis of trans-3-(2-amino-4-fluoro-anilino)cyclobutane carboxylic acid methyl ester - corresponding to compound of formula (VIa) as defined in Scheme 2 - in analogy to the procedure detailed in Step 2 of Example 1.0, but starting from trans-3-(4-fluoro-2-nitro-anilino)cyclobutane carboxylic acid methyl ester

[0151] ​Step 3: Synthesis of trans-3-(5-fluorobenzimidazol-l-yl)cyclobutane carboxylic acid methyl ester - corresponding to compound (Ilia) in Scheme 2 - was carried out in a similar manner as detailed in Step 3 of Example 1.0, but starting from trans-3-(2-amino-4-fluoro- anilino)cyclobutane carboxylate

[0152] Step 4: Synthesis of trans-3-(5-fluorobenzimidazol-l-yl)cyclobutane carboxylic acid - corresponding to compound of formula (IIa) in Scheme 1 - was carried out in a similar manner as detailed in Step 4 of Example 1.0, but starting from trans-3-(5-fluorobenzimidazol-l-yl)cyclobutane carboxylic acid methyl ester

[0153] Step 5: Synthesis of trans-(3-(5-fluoro-lH-benzo[d]imidazol-l-yl)cyclobutyl)((S)-3-(3- fluorophenyl)isoxazolidin-2-yl)methanone (compound (84)) was carried out in a similar manner as in Step 5 of Example 1.0, but starting from trans-3-(5-fluorobenzimidazol-l- yl)cyclobutane carboxylic acid Example 1.4: Synthesis of compound (87)

[0154] Step 1: Synthesis of cis-3-(5-fluoro-2-nitro-anilino)cyclobutane carboxylic acid methyl ester - corresponding to compound of formula (Va) as defined in Scheme 2 - was carried out in a similar manner as detailed in Step 1 of Example 1.1, but starting from 1,3-difluoro-4-nitrobenzene.

[0155] Step 2: Synthesis of cis-3-(2-amino-5-fluoro-anilino)cyclobutane carboxylic acid methyl ester - corresponding to compound of formula (Via) as defined in Scheme 2 - was carried out in a similar manner as detailed in Step 2 of Example 1.1, but starting from cis-3-(5-fluoro-2-nitro- anilino)cyclobutane carboxylic acid methyl ester

[0156] Step 3: Synthesis of cis-3-(6-fluorobenzimidazol-l-yl)cyclobutane carboxylic acid methyl ester - corresponding to compound (Ilia) in Scheme 2 - was carried out in a similar manner as detailed in Step 3 of Example 1.1, but starting from cis-3-(2-amino-5-fluoro-anilino)cyclobutane carboxylic acid methyl ester

[0157] Step 4: Synthesis of cis-3-(6-fluorobenzimidazol-l-yl)cyclobutane carboxylic acid was carried out in a similar manner as detailed in Step 4 of Example 1.1, but starting from cis-3-(6-fluorobenzimidazol-l-yl)cyclobutane carboxylic acid methyl ester

[0158] Step 5: Synthesis of cis-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)(3-(6-fluoro- lH-benzo[d]imidazol-l-yl)cyclobutyl)methanone (compound (87)) was performed in a similar manner as in Step 5b of Example 1.1, but starting from cis-3-(6-fluorobenzimidazol-l- yl)cyclobutane carboxylic acid 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 cis-methyl 3-(3-cyano-4-fluoro-anilino)cyclobutane carboxylate - reaction under step 6a of Scheme 3

[0159] To a stirred suspension of cis-3-aminocyclobutane-l-carboxylate hydrochloride (361.4 mg, 2.18 mmol), Cs2CO3(1.29 g, 3.97 mmol), CuI (75.6 mg, 396.8 pmol) and 2-(2-methylpropanoyl)cyclohexanone (276 mΐ, 1.59 mmol) in DMF (4.06 ml, 5.11 mmol) was added 2-fluoro-5-iodobenzonitrile (500 mg, 1.98 mmol) at rt. Stirring was continued for 5 h, quenched with water and the aqueous layer was extracted with EA, the combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude title compound which was purified by column chromatography (SiO2; EA / heptane gradient) (183 mg, 735 pmol, 37% yield). 1 H NMR (600 MHz, DMSO-d6): δ ppm 7.21 (t, J=9.17 Hz, 1 H), 6.86 (m, 1H), 6.80 (dd, J=5.04, 3.03 Hz, 1 H), 6.40 (d, J=7.15 Hz, 1 H), 3.79 (m, 1 H),3.60 (s, 3 H), 2.86 (m, 1 H), 2.62 (m, 2 H), 1.96 (m, 2 H).

[0160] Step 2: Synthesis of cis-3-(3-cyano-4-fluoro-anilino)cyclobutane carboxylic acid was performed in a similar manner as detailed in Step 4 of Example 1.1, but starting from cis-methyl 3-(3-cyano-4-fluoro-anilino)cyclobutane carboxylate

[0161] Step 4a: Synthesis of cis-5-((3-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2- carboxyl)cyclobutyl)amino)-2-fluorobenzonitrile (Compound (32)) was performed in a similar manner as in Step 5a of Example 1.1, but starting from cis-3-(3-cyano-4- fluoro-phenylamino)cyclobutane carboxylic acid

[0162] Step 4b: Synthesis of cis-2-fluoro-5-((3-((S)-3-(5-fluoropyridin-3-yl)isoxazolidine-2- carboxyl)cyclobutyl)amino)benzonitrile (Compound (33)) was performed in a similar manner as in Step 5b of Example 1.1, but starting from cis-3-(3-cyano-4-fluoro- phenylamino)cyclobutane carboxylic acid Example 2.2: Synthesis of Compounds (34) and (35)

[0163] Step 1: Synthesis of trans-methyl 4-[(3-cyano-4-fluoro-phenylamino)methyl]cyclohexane carboxylate was performed in a similar manner as in Step 1 of Example 2.1, but starting from trans-4-[aminomethyl]cyclohexane carboxylate

[0164] Step 2: Synthesis of trans-4-[(3-cyano-4-fluoro-phenylamino)methyl]cyclohexane carboxylic acid was performed in a similar manner as in Step 1 of Example 2.1, but starting from trans-methyl 4-[(3-cyano-4-fluoro-phenylamino)methyl]cyclohexane carboxylate

[0165] Step 4a: Synthesis of trans-2-fluoro-5-(((4-((S)-3-(5-fluoropyridin-3-yl)isoxazolidine-2- carboxyl)cyclohexyl)methyl)amino)benzonitrile (Compound (34)) was performed in a similar manner as in Step 5c of Example 1, but starting from trans-4-[(3-cyano-4-fluoro- phenylamino)methyl]cyclohexane carboxylic acid.

[0166] Step 4b: Synthesis of trans-5-(((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2- carboxyl)cyclohexyl)methyl)amino)-2-fluorobenzonitrile (Compound (35)) was performed in a similar manner as in Step 5a of Example 1.1, but starting from trans-4-[(3- cyano-4-fluoro-phenylamino)methyl]cyclohexane carboxylic acid Example 2.3: Synthesis of Compound (38) Step 1: Synthesis of trans-methyl 4-[(3-cyano-5-fluoro-phenylamino)methyl]cyclohexane carboxylate - reaction under Step 6b of Scheme 3

[0167] To a stirred suspension of 3,5-difluorobenzonitrile (140 mg, 1.01 mmol) and trans-4-(aminomethyl)cyclohexane-1 -carboxylic acid methyl ester hydrochloride (313.6 mg, 1.51 mmol) in DMSO (2 ml) was added K2CO3 (281.0 mg, 2.01 mmol) and the resulting suspension heated to 80 °C for 16 h. The mixture was allowed to reach room temperature and poured into water (50 ml). The suspension was stirred for 10 min, filtered and the filter cake 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 without further purification for the next reaction (34 mg, 117 pmol, 12% yield). 1 H NMR (400 MHz, DMSO-d6): δ ppm 6.76 (s, 1 H), 6.76 (d, J=11.17 Hz, 1H), 6.65 (m, 1 H), 6.52 (br t, J=5.50 Hz, 1 H), 3.58 (s, 3 H), 2.89 (t, J=6.14 Hz, 2 H), 2.26 (m, 1 H), 1.92 (br d, J=10.45 Hz, 2 H), 1.84 (br d, J=10.45 Hz, 2 H), 1.49 (m, 1 H), 1.31 (m, 2 H), 0.99 (m, 2 H).

[0168] Step 2: Synthesis of trans-4-[(3-cyano-5-fluoro-phenylamino)methyl]cyclohexanecarboxylic acid was performed in a similar manner as detailed in Step 4 of Example 1.1, but starting from trans-4-[(3-cyano-5-fluoro-phenylamino)methyl]cyclohexanecarboxylic acid methyl ester

[0169] Step 4a: Synthesis of trans-3-((S)-2-(4-(((3-cyano-5-fluorophenyl)amino)methyl)cyclohexane-1 -carbonyl)isoxazolidin-3-yl)-5-fluorobenzonitrile (Compound (38)) was performed in a similar manner as in Step 5a of Example 1.1, but starting from trans-4-[(3-cyano-5-fluoro-phenylamino)methyl]cyclohexanecarboxylic acid Example 2.4: Synthesis of intermediates for compounds (36) and (37)

[0170] Step 1: Synthesis of cis-3-(3-cyano-5-fluoro-phenylamino)cyclobutanecarboxylic acid methyl ester was performed in a similar manner as in Step 1 of Example 2.3, but starting from cis-3-aminocyclobutane-1 -carboxylic acid ester

[0171] Step 2: Synthesis of cis-3-(3-cyano-5-fluoro-anilino)cyclobutane carboxylic acid was performed in a similar manner as detailed in Step 4 of Example 1.1, but starting from cis-3-(3-cyano-5-fluoro-anilino)cyclobutane carboxylic acid methyl ester Example 2.5: Synthesis of compound (39)

[0172] Step 1: Synthesis of cis-4-(3-cyano-5-fluoro-anilino)cyclohexane carboxylic acid methyl ester was performed in a similar manner as in Step 1 of Example 2.3, but starting from cis-4- aminocyclohexane carboxylate

[0173] Step 2: Synthesis of cis-4-(3-cyano-5-fluoro-anilino)cyclohexane carboxylic acid - the compound corresponding to formula (IIa) in Scheme 1 was performed in a similar manner as detailed in Step 4 of Example 1.1, but starting from cis-4-(3-cyano-5-fluoro-anilino)cyclohexane carboxylic acid methyl ester

[0174] Step 4: Synthesis of cis-3-((S)-2-(4-((3-cyano-5-fluorophenyl)amino)cyclohexane-1- carboxylate)isoxazolidin-3-yl)-5-fluorobenzonitrile (compound (39)) was performed in a similar manner as in Step 5a of Example 1.1. Example 3: Synthesis of compounds (5), (6), (7), (8), (9), (10), (11) Synthesis of cis-3-amino-1-methylcyclobutane-1-carboxylic acid methyl ester trifluoroacetate salt

[0175] To a stirred solution of cis-3-(tert-butoxycarbonylamino)-1-methyl-cyclobutane carboxylic acid methyl ester (300 mg, 1.23 mmol) in CH2Cl2(9.0 ml) was added TFA (2.50 ml) and stirring was continued at room temperature for 2 h. The solution was concentrated under reduced pressure. The resulting crude material was re-dissolved in CH3CN and water and lyophilized (374 mg, 1.39 mmol, quantitative yield). 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.96 (br s, 3 H), 3.78 (m, 1 H), 3.64(s, 3 H), 2.44 (m, 2 H), 2.14 (m, 2 H), 1.36 (s, 3 H).

[0176] (cis-3-amino-l-methyl-cyclobutyl)-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2- yl]methanone trifluoroacetate was synthesized analogously, but starting from (3S)-3-(3,5- difluorophenyl)isoxazolidine.

[0177] cis-3-(tert-butoxycarbonylamino)-l-methyl-cyclobutane carboxylic acid - synthesis of a compound corresponding to formula (IIa) in Scheme 1 was carried out in a similar manner as detailed in step 4 of Example 1.1, but starting from cis-3-(tert- butoxycarbonylamino)-l-methyl-cyclobutane carboxylic acid methyl ester Example 3.1: Synthesis of compounds (5), (6) and (7) Step 1: cis-3-[(4-cyanopyrimidin-2-yl)amino]-l-methyl-cyclobutane carboxylic acid methyl ester - synthesis of a compound corresponding to formula (III) in Scheme 1 - reaction under step 6b of Scheme 3

[0178] To a stirred suspension of 2-chloropyrimidine-4-carbonitrile (215 mg, 1.51 mmol) and cis-3-amino-l-methylcyclobutane-l-carboxylic acid methyl ester-trifluoroacetate (353 mg, 1.37 mmol) in CH3CN (3.5 ml) in a microwave vial was added NetiPr2 (957 μΐ, 5.49 mmol) at room temperature. The vial was capped and the solution was heated to 80 °C in a microwave reactor for 2 h. The volatile components were removed under reduced pressure and the resulting residue was purified by column chromatography (Si02; CH2Cl2 / EtOH gradient). The obtained product was dissolved in CH3CN / water and lyophilized (221 mg, 900 μmol, 65% yield). Step 2: cis-3-[(4-cyanopyrimidin-2-yl)amino]-l-methyl-cyclobutane carboxylic acid trifluoroacetate and cis-3-[(4-carbamoylpyrimidin-2-yl)amino]-l-methyl-cyclobutane carboxylic acid trifluoroacetate - synthesis of a compound corresponding to formula (IIa) in Scheme 1

[0179] To a solution of cis-3-[(4-cyanopyrimidin-2-yl)amino]-1-methyl-cyclobutane-carboxylic acid methyl ester (220 mg, 893 µmol) in THF (15 ml) was added 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 h. The volatile components were removed under reduced pressure and the remaining aqueous solution was acidified with 1 N HC1. The aqueous layer was extracted with CH2Cl2, the combined organic layers were dried over Na2SO4, filtered and concentrated to give a mixture of cis-3-[(4-cyanopyrimidin-2-yl)amino]-1-methyl-cyclobutane carboxylic acid and cis-3-[(4-carbamoyl-pyrimidin-2-yl)amino]-1-methyl-cyclobutane carboxylic acid (158 mg). 100 mg of the mixture was subjected to preparative reverse phase chromatography to give cis-3-[(4-cyanopyrimidin-2-yl)amino]-1-methyl-cyclobutane carboxylic acid trifluoroacetic acid salt (37 mg, 107 µmol, 12% yield) and cis-3-[(4-carbamoylpyrimidin-2-yl)amino]-1-methyl-cyclobutane carboxylic acid trifluoroacetic acid salt (45 mg, 123 µmol, 14% yield). The remaining 58 mg was used in the next reaction without further purification. cis-3-[(4-Cyanopyrimidin-2-yl)amino]-1-methyl-cyclobutane carboxylic acid trifluoroacetic acid salt: 1 H NMR (400 MHz, DMSO-d6): δ ppm 12.18 (br s, 1 H), 8.55 (br s, 1 H), 8.14 (br d, J=6.97 Hz, 1 H), 7.10 (d, J=4.65 Hz, 1 H), 4.35 (br s, 1 H), 2.35 (m, 2 H),2.17 (m, 2 H), 1.37 (s, 3 H). cis-3-[(4-Carbamoylpyrimidin-2-yl)amino]-1-methyl-cyclobutane carboxylic acid trifluoroacetic acid salt: 1 H NMR (400 MHz, DMSO-d6): δ ppm 12.18 (br s, 1 H), 8.46 (br d, J=3.91 Hz, 1 H),8.08 (br s, 1 H), 7.74 (br s, 1 H), 7.64 (br s, 1 H), 7.05 (d, J=4.77 Hz, 1H), 4.57 (br s, 1 H), 2.36 (m, 2 H), 2.18 (m, 2 H), 1.40 (s, 3 H). Step 3a: Synthesis of cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2- carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carbonitrile (Compound (5)) and cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)-3- methylcyclobutyl)amino)pyrimidine-4-carboxamide (Compound (6))

[0180] A mixture of cis-3-[(4-cyanopyrimidin-2-yl)amino]-1-methyl-cyclobutanecarboxylic acid and cis-3-[(4-carbamoylpyrimidin-2-yl)amino]-1-methyl-cyclobutanecarboxylic acid (35 mg) was dissolved in DMF (4.5 ml). With 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, followed by HATU (113 mg, 290 µmol) after 15 min. After stirring for 1 h, the mixture was left overnight. The mixture was then purified directly by preparative reverse-phase chromatography. Step 3b: Synthesis of cis-2-((3-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2- carbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxamide (Compound (7)) was performed analogously to Step 3a, but starting from (S)-3-(5-cyanopyridin-3- yl)isoxazolidine. Example 3.2: Synthesis of Compounds (8) and (9)

[0181] To a stirred suspension of ethyl 6-chloro-5-fluoro-pyrimidine-4-carboxylate (25 mg, 134 µmol) and (cis-3-amino-1-methyl-cyclobutyl)-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2- yl]methanone trifluoroacetate (55 mg, 134 µmol) in CH3CN (1.5 ml) in a microwave vial was added NetiPr2 (75 µl, 428 µmol) at rt. The vial was capped and the solution was heated to 80 °C in a microwave reactor for 30 min. The volatile components were removed under reduced pressure and the resulting residue was purified by column chromatography (SiO2; heptane / EA gradient) to give Compound (8) (30 mg, 65 µmol, 53% yield) and Compound (9) (20 mg, 42 µmol, 34% yield). Example 3.3: Synthesis of Compounds (1), (3) and (4)

[0182] Cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclobutyl)amino)pyrimidine-4-carboxamide (compound (1)), cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclobutyl)amino)methyl pyrimidine-4-carboxylate (compound (3)) and trans-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclobutyl)amino)pyrimidine-4-carboxamide (compound (4)) were synthesized analogously to compounds (8) and (9) in Example 3.2, but starting from (cis-3-amino-cyclobutyl)-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]methanone and (trans-3-amino-cyclobutyl)-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]methanone, respectively. Example 3.4: Synthesis of cis-6-chloro-5-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- ylcarbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxamide (compound (10))

[0183] Ethyl 6-chloro-5-[[cis-3-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl]-3- methyl-cyclobutyl]amino]pyrimidine-4-carboxylate (3 mg, 10 µmol) was dissolved in a 7 M NH3 solution in methanol (0.3 ml). After stirring for 1 h, the solvent mixture was removed in vacuo. The residue was lyophilized to give the title compound in quantitative yield. Example 3.5: Synthesis of cis-6-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)-3- methylcyclobutyl)amino)-5-fluoropyrimidine-4-carboxamide (compound (11))

[0184] Ethyl 6-[[cis-3-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl]-3-methyl- cyclobutyl]amino]-5-fluoro-pyrimidine-4-carboxylate (26 mg, 60 µmol) was dissolved in a 7 M NH3 solution in methanol (2.3 ml). After stirring for 1 h, the solvent mixture was removed in vacuo. The residue was purified by reverse phase chromatography to give 15.9 mg (36.5 µmol, 61% yield) of the title compound after lyophilization. Example 4: Synthesis of compounds (96), (97), (98), (109), (110) Example 4.0: Synthesis of methyl trans-4-(methylsulfonyloxymethyl)cyclohexanecarboxylate

[0185] 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) was added dropwise methanesulfonyl chloride (2.67 ml, 33.8 mmol) at 0°C. The resulting suspension was stirred at room temperature for 2 h. 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 light yellow solid which was used in the next reaction without further purification (5.64 g, 22.5 mmol, quantitative yield). 1 H NMR (400 MHz, CDCl3): δ ppm 4.05 (d, J=7.21 Hz, 2 H), 3.67 (s, 3H), 3.01 (s, 3 H) 2.28 (m, 1 H), 2.05 (m, 2 H), 1.89 (m, 2 H), 1.75 (m, 1 H),1.42 (m, 2 H), 1.09 (m, 2 H) The synthesis of methyl 3-methylsulfonyloxy cyclobutane carboxylate was carried out in a similar way as detailed for methyl trans-4-(methylsulfonyloxymethyl)cyclohexane carboxylate in Example 4.0, but starting from methyl 3-hydroxycyclobutane carboxylate Example 4.1 : Synthesis of compounds (96), (97), (98), (109) and (110) Step 1 : Synthesis of methyl trans-3-(5-fluoroindazol-1-yl)cyclobutane carboxylate, methyl trans-3-(5-fluoroindazol-2-yl)cyclobutane carboxylate, methyl cis-3-(5-fluoroindazol-1- yl)cyclobutane carboxylate and methyl cis-3-(5-fluoroindazol-2-yl)cyclobutane carboxylate - the reaction under step 6c of scheme 3

[0186] A solution of methyl 3-methylsulfonyloxy cyclobutane carboxylate (3.21 g, 15.43 mmol, 1.4 eq), 5-fluoro-1H-indazole (1.5 g, 11.02 mmol, 1 eq) and Cs2CO3(7.18 g, 22.04 mmol, 2 eq) in DMF (10 ml) was stirred at 80 °C for 16 h. A saturated NH4CI solution was added at 25 °C to adjust pH = 7~8 and extracted with EA 150 ml (50 ml x 3). The combined organic layers were washed with saturated brine 100 ml (50 ml x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex luna C18 (250 70 mm, 10 µm); mobile phase: [water (0.1% TFA) - ACN]; ACN 32% - 62%, 25 min) purification to give the title compound: trans-methyl 3-(5-fluoroindazol-l-yl)cyclobutanecarboxylate as a yellow solid (0.413 g, 1.66 mmol, 15% yield), trans-methyl 3-(5-fluoroindazol-2-yl)cyclobutanecarboxylate as a yellow oil (0.95 g, 3.83 mmol, 35% yield), cis-methyl 3-(5-fluoroindazol-l-yl)cyclobutanecarboxylate as a yellow solid (0.218 g, 878.14 µmol, 8% yield) and cis-methyl 3-(5-fluoroindazol-2-yl)cyclobutanecarboxylate as a yellow oil (0.44 g, 1.77 mmol, 16% yield). trans-methyl 3-(5-fluoroindazol-l-yl)cyclobutanecarboxylate: 1 H NMR (400 MHz, CDCl3): δ ppm 8.03 (s, 1 H), 7.71 (dd, J=4.6, 9.3 Hz, 1 H), 7.24 (dd, J=2.1, 9.0 Hz, 1 H), 5.04 (t, J=8.3 Hz, 1 H), 3.77 (s, 3 H), 3.15-3.03 (m, 1 H), 3.03-2.85 (m, 4H). trans-methyl 3-(5-fluoroindazol-l-yl)cyclobutanecarboxylate: 1 H NMR (400 MHz, CDCl3): δ ppm 8.03 (s, 1 H), 7.71 (dd, J=4.6, 9.3 Hz, 1 H), 7.24 (dd, J=2.1, 9.0 Hz, 1 H), 5.04 (t, J=8.3 Hz, 1 H), 3.77 (s, 3 H), 3.15-3.03 (m, 1 H), 3.03-2.85 (m, 4H). cis-methyl 3-(5-fluoroindazol-l-yl)cyclobutanecarboxylate: 1H NMR (400 MHz, CDCl3): δ ppm 7.91 (s, 1 H), 7.39 (dd, J=4.1, 9.1 Hz, 1 H), 7.27 (dd, J=2.3, 8.6 Hz, 1 H), 7.09 (dt, J=2.4, 9.0 Hz, 1 H), 4.99-4.83 (m, 1 H), 3.68 (s, 3 H), 3.09-2.91 (m, 3 H), 2.80-2.66 (m, 2 H). cis-3-(5-Fluoroindazol-2-yl)cyclobutanecarboxylic acid methyl ester: 1 H NMR (400 MHz, CDCl3): δ ppm 8.03 (s, 1 H), 7.44-7.32 (m, 2 H), 7.17 (dt, J=2.4, 9.0 Hz, 1 H), 5.37 (quin, J=8.0 Hz, 1 H), 3.81 (s, 3 H), 3.37-3.24 (m, 1 H), 3.16-3.00 (m, 2 H), 2.90-2.73 (m, 2 H).

[0187] Step 2: Synthesis of cis-3-(5-fluoroindazol-2-yl)cyclobutanecarboxylic acid, cis-3-(5-fluoroindazol-l-yl)cyclobutanecarboxylic acid and trans-3-(5-fluoroindazol-l- yl)cyclobutanecarboxylic acid - the synthesis of compounds corresponding to Formula (IIa) in Scheme 1 was performed from their corresponding methyl esters in a similar manner as detailed in Step 4 of Example 1.1

[0188] Step 3a: Synthesis of cis-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[3-(5-fluoroindazol-l- yl)cyclobutyl]methanone (Compound (96)) was performed in a similar manner as in Step 5b of Example 1.1.

[0189] Step 3b: Synthesis of trans-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[3-(5-fluoroindazol-l- yl)cyclobutyl]methanone (Compound (97)) was performed in a similar manner as in Step 5b of Example 1.1.

[0190] Step 3c: Synthesis of trans-3-fluoro-5-[(3S)-2-[3-(5-fluoroindazol-l-yl)cyclobutane- carbonyl]isoxazolidin-3-yl]benzonitrile (Compound (98)) was performed in a similar manner as in Step 5a of Example 1.1.

[0191] Step 3d: Synthesis of cis-3-fluoro-5-[(3S)-2-[3-(5-fluoroindazol-2-yl)cyclobutyl]isoxazolidin-3-yl]benzonitrile (Compound (109)) was carried out in a similar manner as in Step 5a of Example 1.1.

[0192] Step 3e: Synthesis of cis-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[3-(5-fluoroindazol-2-yl)cyclobutyl]methanone (Compound (110)) was carried out in a similar manner as in Step 5b of Example 1.1. Example 4.2: Synthesis of Compound (105), (106), (107) and (108) Step 1: Synthesis of methyl 3-(5-fluoroindol-1-yl)cyclobutane carboxylate - corresponding to the compound of formula (III) in Scheme 1 - reaction under Step 6c of Scheme 3

[0193] To a solution of 5-fluoro-1H-indole (1.5 g, 11.10 mmol, 1 eq) in DMF (15 ml) was added Cs2CO3(7.23 g, 22.20 mmol, 2 eq) and methyl 3-methylsulfonyloxy cyclobutane-carboxylate (3.47 g, 16.65 mmol, 1.5 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was adjusted to pH 3~4 with 1 N HCI. The precipitate was collected by filtration, dried under reduced pressure to give the desired compound. The aqueous phase was extracted with EA (100 ml x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (0.1% formic acid condition) to give methyl 3-(5-fluoroindol-1-yl)cyclobutane carboxylate (823 mg, 3.33 mmol, 30% yield). Step 2: Trans-3-(5-fluoroindol-1-yl)cyclobutane carboxylic acid and cis-3-(5-fluoroindol-1-yl)cyclobutane carboxylic acid - corresponding to the synthesis of the compound of formula (IIa) in Scheme 1

[0194] To a solution of methyl 3-(5-fluoroindol-1-yl)cyclobutanecarboxylate (1.71 g, 6.92 mmol, 1 equiv) in THF (9 ml) and water (9 ml) was added LiOH H2O (290.18 mg, 6.92 mmol, 1 equiv). The mixture was stirred at 25 °C for 1 h. Several new peaks were shown on LC / MS and about 81% of the desired compound was detected. The reaction mixture was concentrated. The crude product was purified by reverse phase HPLC (0.1% formic acid condition) and 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 min) to give a cis / trans mixture of 3-(5-fluoroindol-1-yl)cyclobutanecarboxylic acid as a white solid (1.3 g, 76% yield). The cis / trans mixture of 3-(5-fluoroindol-1-yl)cyclobutanecarboxylic acid (1.54 g, 6.58 mmol, 1 equiv) was separated by SFC (column: DAICEL CHIRALPAK AD (250 30 mm, 10 µm); mobile phase: 20% MeOH in supercritical CO2 [+ 0.1% NH3H2O], single batch process with a lag time of 6.1 min between two consecutive injections; total duration 400 min) to give trans-3-(5-fluoroindol-1-yl)cyclobutanecarboxylic acid as a yellow solid (375 mg, >99.9% e.e.) and cis-3-(5-fluoroindol-1-yl)cyclobutanecarboxylic acid as a yellow oil (1.1 g, >99.9% e.e.). trans-3-(5-Fluoroindol-1-yl)cyclobutanecarboxylic acid: 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.70 (d, J=3.2 Hz, 1 H), 7.43 (dd, J=4.5, 8.9 Hz, 1 H), 7.30 (dd, J=2.6, 9.9 Hz, 1 H), 6.95 (dt, J=2.6, 9.2 Hz, 1 H), 6.47 (d, J=3.1 Hz, 1 H), 5.10 (quin, J=8.3 Hz, 1 H), 3.11-3.01 (m, 1 H), 2.77-2.59 (m, 4 H). cis-3-(5-Fluoroindol-1-yl)cyclobutanecarboxylic acid: 1H NMR (400 MHz, DMSO-d6): δ ppm 7.57(d, J=3.2 Hz, 1 H), 7.53 (dd, J=4.5, 9.0 Hz, 1 H), 7.30 (dd, J=2.5, 9.8 Hz, 1H), 6.97 (dt, J=2.6, 9.2 Hz, 1 H), 6.45 (d, J=3.2 Hz, 1 H), 4.96-4.78 (m, 1H), 4.03 (q, J=7.2 Hz, 1 H), 2.96-2.79 (m, 1 H), 2.76-2.65 (m, 2 H), 2.57-2.51 (m, 2 H)。

[0195] Step 3a: Synthesis of trans-3-fluoro-5-[(3S)-2-[3-(5-fluoroindol-1- yl)cyclobutanecarbonyl]isoxazolidin-3-yl]benzonitrile (Compound (105)) was performed in a similar manner as in Step 5a of Example 1.1.

[0196] Step 3b: Synthesis of trans-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]- [3-(5-fluoroindol-1-yl)cyclobutyl]methanone (Compound (106)) was performed in a similar manner as in Step 5b of Example 1.1.

[0197] Step 3c: Synthesis of cis-3-fluoro-5-[(3S)-2-[3-(5-fluoroindol-1- yl)cyclobutanecarbonyl]isoxazolidin-3-yl]benzonitrile (Compound (107)) was performed in a similar manner as in Step 5a of Example 1.1.

[0198] Step 3d: Synthesis of cis-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]- [3-(5-fluoroindol-1-yl)cyclobutyl]methanone (Compound (108)) was performed in a similar manner as in Step 5b of Example 1.1. Example 5: Synthesis of Compound (114) Step 1: Synthesis of cis-3-(4-carbamoyl-2-pyridyl)cyclopentanecarboxylic acid methyl ester - a compound corresponding to Formula (III) in Scheme 1 Step a: Synthesis of 2-bromopyridine-4-carboxamide

[0199] A mixture of 2-bromopyridine-4-carboxylic acid (8.6 g, 42.57 mmol, 1 eq), NH4CI (3.42 g, 63.86 mmol, 1.5 eq), NetiPr2(22.01 g, 170.29 mmol, 29.66 ml, 4 eq) and CDI (8.28 g, 51.09 mmol, 1.2 eq) in DMF (80 ml) was degassed, purged with N2three times and stirred at 20 °C under N2atmosphere for 3 h. The mixture was diluted with water (500 ml), extracted with EA (300 ml x 4), dried over Na2S04, filtered and concentrated. The residue was triturated with DCM (30 ml) to give the title compound as a white solid (5.7 g, 67% yield). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.53 (d, J=5.0 Hz, 1 H), 8.31 (br s,1 H), 8.00 (s, 1 H), 7.91-7.76 (m, 2 H). Step b: synthesis of methyl 3-(trifluoromethylsulfinyl)oxycyclopent-2-ene-1- carboxylate

[0200] To a solution of methyl 3-oxocyclopentanecarboxylate (19 g, 133.66 mmol, 1 eq) and NetiPr2(25.91 g, 200.49 mmol, 34.92 ml, 1.5 eq) in toluene (500 ml) was added Tf20 (56.57 g, 200.49 mmol, 33.08 ml, 1.5 eq) dropwise at 45 °C. After the addition, the mixture was stirred at 45 °C for 1 h. The mixture was diluted with water (300 ml) and extracted with EA (300 ml x 2). The combined organic layers were dried over Na2S04, filtered, concentrated under reduced pressure and purified by column chromatography (Si02, petroleum ether / EA = 10 / 1 to 3 / 1) to give the title compound as a black oil (29.3 g, 80% yield). Step c: synthesis of methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2- ene-1-carboxylate

[0201] A mixture of 3-(trifluoromethylsulfonyloxy)cyclopent-2-en-1 -carboxylic acid methyl ester (29 g, 105.76 mmol, 1 equiv), KOAc (10.38 g, 105.76 mmol, 1 equiv), BPD (26.86 g, 105.76 mmol, 1 equiv), KOAc (10.38 g, 105.76 mmol, 1 equiv) and DPPF (2.93 g, 5.29 mmol, 0.05 equiv) in dioxane (300 ml) was degassed and purged with N2 three times and stirred at 20 °C for 0.5 h. Pd(dppf)Cl2.CH2Cl2(4.32 g, 5.29 mmol, 0.05 equiv) was added and the mixture was stirred at 90 °C under N2atmosphere for 12 h. The mixture was concentrated and 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 give the title compound (25 g, 94% yield) as a yellow oil. 1 H NMR: (400 MHz, CDCI3): δ ppm 6.52-6.36 (m, 1 H), 3.69 (d, J=1.0 Hz, 3H), 3.67-3.60 (m, 1 H), 3.20-3.08 (m, 1 H), 2.87-2.70 (m, 2 H), 2.68-2.55 (m, 1 H), 2.53-2.40 (m, 1 H), 2.21-2.11 (m, 1 H), 1.27 (s, 12 H). Step d: Synthesis of 3-(4-carbamoyl-2-pyridyl)cyclopent-2-en-1 -carboxylic acid methyl ester

[0202] A mixture of 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopent-2- ene-l-carboxylic acid methyl ester (4.52 g, 17.91 mmol, 1.2 eq), 2-bromopyridine-4- carboxamide (3 g, 14.92 mmol, 1 eq), Na2C03(3.16 g, 29.85 mmol, 2 eq), X-PHOS (1.07 g, 2.24 mmol, 0.15 eq) and Pd(PPh3)4(1.72 g, 1.49 mmol, 0.1 eq) in dioxane (40 ml) and water (10 ml) was degassed and purged with N2for 3 times and stirred at 80 °C under N2atmosphere for 12 h. The mixture was cooled to 20 °C and diluted with EA (300 ml), washed with water (50 ml x 2), dried over Na2S04, filtered, concentrated and purified by preparative RP-LC (column: Welch Ultimate XB C18, 120 Å, I.D. 72 x 300 mm, 20-40 μm, mobile phase: water (0.1% formic acid) and ACN; gradient: 10-35% ACN in 30 min; 35% ACN for 5 min; flow rate: 200 ml / min) to give the title compound (1.1 g, 30% yield) as a yellow solid. LC / MS: m / z 247.2 [M+H] + Step e: Synthesis of cis-3-(4-carbamoyl-2-pyridyl)cyclopentane carboxylic acid methyl ester

[0203] To a solution of 3-(4-carbamoyl-2-pyridyl)cyclopent-2-ene-l-carboxylic acid methyl ester (1.1 g, 4.47 mmol, 1 eq) in MeOH (10 ml) was added Pd / C (13 mg, 4.47 mmol, 10% purity, 1.00 eq) under N2atmosphere. The suspension was degassed and purged with H2for 3 times and stirred at 20 °C under H2(15 Psi) for 1 h. The reaction mixture was filtered, concentrated under reduced pressure and purified by column chromatography (Si02, DCM : MeOH = 10 : 1) to give the title compound (1 g, 88% yield) as a yellow solid. LC / MS: m / z 249.1 [M+H] + 1H NMR (400 MHz, DMSO-d6): δ ppm 8.61 (d, J=5.0 Hz, 1 H), 8.21 (br s,1 H), 7.66 (s, 2 H), 7.58 (dd, J=1.4, 5.1 Hz, 1 H), 3.65-3.59 (m, 3 H), 3.17(d, J=5.3 Hz, 1 H), 3.05-2.90 (m, 1 H), 2.35-2.24 (m, 1 H), 2.14-1.92 (m, 4H), 1.89-1.76 (m, 1 H)。

[0204] Step 2: Synthesis of cis-3-(4-carbamoyl-2-pyridyl)cyclopentanecarboxylic acid - The synthesis of the compound corresponding to formula (IIa) in Scheme 1 was performed in a similar manner as detailed in Step 4 of Example 1.1, but starting from cis-methyl 3-(4-carbamoyl-2-pyridyl)cyclopentanecarboxylate Step 3: Synthesis of cis-2-[3-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2- yl]cyclopentyl]pyridine-4-carboxamide (compound (114)).

[0205] To a solution of cis-3-(4-carbamoyl-2-pyridyl)cyclopentanecarboxylic acid (200.00 mg, 853.79 pmol, 1 eq), NetiPr2 (331.03 mg, 2.56 mmol, 446.13 pi, 3 eq) and T3P (651.98 mg, 1.02 mmol, 609.33 pi, 50% purity, 1.2 eq) in DMF (2 ml) was added (3S)-3-(3,5-difluorophenyl)isoxazolidine (198.69 mg, 896.48 pmol, 1.05 eq, HCI). The mixture was stirred at 20 °C for 3 h, diluted with water (20 ml), extracted with EA (10 ml x 3), washed with brine (10 ml), dried over Na2S04, filtered, concentrated under reduced pressure to give the title compound (150 mg, crude) as a yellow oil. A racemic mixture of cis-2-[3-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl]cyclopentyl]pyridine-4-carboxamide (150 mg) was separated by SFC (Column: DAICEL CHIRALPAK AD, 250 x 30 mm, 10 µm; Mobile phase: 45% MeOH (0.1% NH3•H2O) in supercritical CO2, single batch process with a lag time of 5.2 min between two consecutive injections; Total duration 30 min) to give cis-2-[3-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-carbonyl]cyclopentyl]pyridine-4-carboxamide stereoisomer 1 (peak 1, 77 mg) and compound 114 stereoisomer 2 (peak 2, 42 mg) as off-white solids. cis-2-[3-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-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 x 4.6 mm I.D., 3 µm; Mobile phase: CO2 and MeOH (0.05% DEA), gradient: 5-40% MeOH (0.05% DEA); Flow rate: 3 ml / min; Column temperature: 35 °C; 100 bar): Rt = 1.93 min (100%). 1H NMR (400 MHz, CDCl3): δ ppm 8.67 (d, J=5.0 Hz, 1 H), 7.69 (s, 1 H),7.48 (dd, J=1.5, 5.0 Hz, 1 H), 6.90-6.81 (m, 2 H), 6.71 (tt, J=2.1, 8.9 Hz, 1H), 6.27 (br dd, J=4.0, 6.9 Hz, 1 H), 5.82-5.51 (m, 1 H), 5.39 (dd, J=6.1,8.8 Hz, 1 H), 4.26 (dt, J=3.1, 7.9 Hz, 1 H), 3.94-3.83 (m, 1 H), 3.51-3.35(m, 2 H), 2.86 (dddd, J=3.0, 6.5, 9.2, 12.3 Hz, 1 H), 2.44-2.27 (m, 2 H),2.24-2.09 (m, 4 H), 2.04-1.91 (m, 1 H)。 Example 6: Synthesis of compounds (122), (123), (124), (125), (126), (127), (128) Example 6.0: Synthesis of trans-4-[(6-carbamoyl-5-fluoro-benzimidazol-l- yl)methyl]cyclohexanecarboxylic acid

[0206] To a solution of trans-4-[(6-cyano-5-fluoro-benzimidazol-l-yl)methyl]cyclohexanecarboxylic acid (100 mg, 332 µmol) in THF (4 ml) was added hydrogen peroxide (50%, 40 µl, 663 µmol) at room temperature, followed by a solution of lithium hydroxide (19 mg, 797 µmol) in water (4 ml). The resulting solution was stirred at room temperature for 30 min, after which another equivalent of hydrogen peroxide was added. The volatile components were removed under reduced pressure and the remaining aqueous solution was diluted with about 3 ml of water and acidified with 1 N HC1 (796 µl, 796 µmol). The obtained suspension was stirred for 10 min and filtered. The title compound was obtained as a white solid, which was used in the next reaction without further purification (76 mg, 72%). Example 6.1 Step 1: Synthesis of methyl 4-[(6-cyanopyrimidin-4-yl)oxymethyl]cycloheptanecarboxylate - compound corresponding to formula (III) in Scheme 1 Step a: Synthesis of 2-(3-oxo-3-phenyl-propyl)cyclopentanone

[0207] To a solution of 3-(dimethylamino)-1-phenyl-propan-1-one hydrochloride (15.00 g, 70.19 mmol, 1 eq) in dioxane (150 ml) was added 4-(cyclopenten-1-yl)morpholine (10.75 g, 70.19 mmol, 11.23 ml, 1 eq) and the mixture was stirred at 110 °C for 12 h. The reaction mixture was concentrated and diluted with EA (150 ml), washed with 1 N HC1 (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 Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si02, petroleum ether / EA = 10 / 1) to give the title compound (8 g, 53% yield) as a white solid. LC / MS: m / z 217.1 [M+H] + 1 H NMR (400 MHz, CDCl3): δ ppm 7.98 (d, J=7.3 Hz, 2 H), 7.64-7.52 (m,1 H), 7.52-7.43 (m, 2 H), 3.14 (ddd, J=4.7, 6.6, 8.0 Hz, 2 H), 2.41-2.08 (m,5 H), 2.04-1.98 (m, 1 H), 1.90-1.75 (m, 2 H), 1.68-1.52 (m, 2 H). Step b: synthesis of 4-phenylcyclohepta-3-ene-1-carboxylic acid

[0208] To a solution of 2-(3-oxo-3-phenyl-propyl)cyclopentanone (8 g, 36.99 mmol, 1 eq) in AcOH (65 ml) and HC1 (12 M, 15 ml, 4.87 eq) was added and the mixture was stirred at 110 °C for 4 h. The mixture was concentrated and poured into 1 N NaOH (10 ml), washed with DCM (10 ml), the pH was adjusted to pH 1 by adding 1 N HC1 and extracted with EA (30 ml x 2) to give the title compound (6.2 g, crude) as a yellow oil. LC / MS: m / z 217.2 [M+H] + 1H NMR (400 MHz, DMSO-d6): δ ppm 12.05-11.98 (m, 1 H), 7.32-7.29 (m, 4H), 7.27-7.23 (m, 1 H), 6.24-5.84 (m, 1 H), 2.71-2.62 (m, 2 H), 2.36-2.30 (m,2 H), 2.23 (s, 1 H), 2.15-1.79 (m, 6 H), 1.63-1.42 (m, 2 H). Step c: synthesis of methyl 4-phenylcyclohepta-3-ene-1-carboxylate

[0209] To a solution of methyl 4-phenylcyclohepta-3-ene-1-carboxylate (5.8 g, 24.97 mmol, 1 eq) and NaIO4(96.12 g, 449.39 mmol, 24.90 ml, 18 eq) in ACN (60 ml) and water (120 ml) was added CCl4(60 ml) and RuCl3(103.57 mg, 499.32 pmol, 33.30 pi, 0.02 eq) and the mixture was stirred at 20 °C for 12 h. The mixture was filtered and concentrated, the pH was adjusted to pH 8 by saturated sodium bicarbonate solution, washed with DCM (40 ml), acidified to pH 1 by 1 N HC1, extracted with EA (80 ml x 2), dried over Na2SO4, filtered and concentrated to give the title compound (3 g, crude) as a yellow oil. LC / MS: m / z 231.2 [M+H] + Step d: synthesis of 4-methoxycarbonylcycloheptanecarboxylic acid

[0210] To a solution of methyl 4-phenylcyclohepta-3-ene-1-carboxylate (5.8 g, 24.97 mmol, 1 eq) and NaIO4(96.12 g, 449.39 mmol, 24.90 ml, 18 eq) in ACN (60 ml) and water (120 ml) was added CCl4(60 ml) and RuCl3(103.57 mg, 499.32 pmol, 33.30 pi, 0.02 eq) and the mixture was stirred at 20 °C for 12 h. The mixture was filtered and concentrated, the pH was adjusted to pH 8 by saturated sodium bicarbonate solution, washed with DCM (40 ml), acidified to pH 1 by 1 N HC1, extracted with EA (80 ml x 2), dried over Na2SO4, filtered and concentrated to give the title compound (3 g, crude) as a yellow oil. 1H NMR (400 MHz, CD3OD): δ ppm 4.88 (br s, 3 H), 2.64-2.41 (m, 2 H),2.10-2.05 (m, 1 H), 2.00-1.81 (m, 5 H), 1.79-1.58 (m, 4 H), 1.53-1.38 (m, 1H). Step e: Synthesis of methyl 4-(hydroxymethyl)cycloheptanecarboxylate

[0211] To a solution of 4-methoxycarbonylcycloheptanecarboxylic acid (3 g, 14.98 mmol, 1 eq) in THF (30 ml) was added BH3.Me2S (10 M, 1.95 ml, 1.3 eq) at 0 °C under N2atmosphere and the mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, DCM / MeOH = 5 / 1) to give the title compound (1.8 g, 65% yield) as a yellow oil. 1 H NMR (400 MHz, CD3OD): δ ppm 3.64 (s, 3 H), 3.38-3.32 (m, 1 H),2.61-2.43 (m, 1 H), 2.07-2.02 (m, 1 H), 2.01-1.93 (m, 1 H), 1.93-1.80 (m, 3H), 1.79-1.67 (m, 2 H), 1.67-1.52 (m, 3 H), 1.49-1.34 (m, 1 H), 1.32-1.17 (m,1 H), 1.16-1.00 (m, 1 H). Step f: Synthesis of methyl 4-[(6-chloropyrimidin-4-yl)oxymethyl]cycloheptanecarboxylate

[0212] To a solution of 4,6-dichloropyrimidine (1.12 g, 7.52 mmol, 1 eq) and methyl 4- (hydroxymethyl)cycloheptanecarboxylate (1.4 g, 7.52 mmol, 1 eq) in DMF (14 ml) was added NaH (450.97 mg, 11.28 mmol, 60% purity, 1.5 eq) at 0 °C and the mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with water (100 ml), extracted with EA (30 ml x 3), washed with brine (50 ml), dried over anhydrous Na2S04, filtered, concentrated under reduced pressure and purified by column chromatography (Si02, DCM / MeOH = 5 / 1) to give the title compound (1.5 g, 64% yield) as a yellow oil. LC / MS: m / z 299.1 [M+H] + 1 H NMR (400 MHz, CDCl3): δ ppm 8.56 (s, 1 H), 6.77 (s, 1 H), 4.24-4.15(m, 2 H), 3.68 (s, 3 H), 2.61-2.45 (m, 1 H), 2.13-1.97 (m, 2 H), 1.96-1.84(m, 3 H), 1.82-1.73 (m, 1 H), 1.72-1.60 (m, 2 H), 1.56-1.49 (m, 1 H), 1.48-1.31 (m, 1 H), 1.30-1.16 (m, 1 H)。 Step g: Methyl 4-[(6-cyanopyrimidin-4-yl)oxymethyl]cycloheptanecarboxylate - synthesis of a compound corresponding to formula (III) in Scheme 1

[0213] A mixture of methyl 4-[(6-chloropyrimidin-4-yl)oxymethyl]cycloheptanecarboxylate (1.5 g, 5.02 mmol, 1 eq), Zn(CN)2(2.36 g, 20.08 mmol, 1.27 ml, 4 eq) and Pd(PPh3)4(1.16 g, 1.00 mmol, 0.2 eq) in DMF (15 ml) was purged with N2for 3 times and stirred at 100 °C under N2atmosphere for 16 h. The reaction was diluted with water (200 ml), extracted with EA (80 ml x 3), washed with brine (100 ml x 2), dried over anhydrous Na2S04, filtered, concentrated in vacuum and purified by flash silica gel chromatography (Si02, DCM:MeOH = 10:1) to give the title compound (1.2 g, 79% yield) as a yellow solid. LC / MS: m / z 290.1 [M+H] + 1 H NMR (400 MHz, CDCl3): δ ppm 8.82 (s, 1 H), 7.09 (s, 1 H), 4.23 (br d, J = 6.6 Hz, 2 H), 3.68 (s, 3 H), 2.63-2.46 (m, 1 H), 2.14-1.98 (m, 2 H), 1.98-1.84 (m, 3 H), 1.83-1.73 (m, 1 H), 1.73-1.62 (m, 2 H), 1.49-1.31 (m, 1 H), 1.30-1.18 (m, 1 H).

[0214] Step 2: Synthesis of 4-[(6-carbamoylpyrimidin-4-yl)oxymethyl]cycloheptanecarboxylic acid - The synthesis of the compound corresponding to formula (IIa) in Scheme 1 was carried out in a similar manner as in Example 6.1

[0215] Step 3a: Synthesis of a diastereomeric mixture of 6-[[4-[(3S)-3-(3,5- difluorophenyl)isoxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide was carried out in a similar manner as in Step 5b of Example 1.1, but starting from (3S)-3-(3,5-difluorophenyl)isoxazolidine. A diastereomeric mixture of 6-[[4-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2- ylcarbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide was separated by SFC (column: DAICEL CHIRALPAK AD, 250 x 30 mm, 10 µm, mobile phase: 60% IPA (0.1% NH3•H2O) in CO2, single batch cycle, lag time between consecutive injections 4.3 min, total duration 30 min; column: DAICEL CHIRALCEL OJ, 250 x 30 mm, 10 µm, mobile phase: 25% MeOH (0.1% NH3•H2O) in CO2, single batch cycle, lag time between consecutive injections 2.4 min, total duration 30 min; and column: DAICEL CHIRALPAK AD, 250 x 30 mm, 10 µm, mobile phase: 55% IPA (0.1% NH3•H2O) in CO2, single batch cycle, lag time between consecutive injections 3.0 min, total duration 30 min) to give compound (122) stereoisomer 1 (peak 1, 47 mg, 102.07 µmol, 12% yield), compound (123) stereoisomer 2 (peak 2, 71 mg, 154.19 µmol, 19% yield), compound (124) stereoisomer 3 (peak 3, 73 mg, 158.53 µmol, 19% yield) and compound (125) stereoisomer 4 (peak 4, 75 mg, 162.88 µmol, 20% yield) as white solids.

[0216] Step 3b: Synthesis of a diastereomeric mixture of 6-[[4-[3-(3-cyano-5-fluoro- phenyl)isoxazolidin-2-ylcarbonyl]cycloheptyl]-methoxy]pyrimidine-4-carboxamide was performed in a similar manner to Step 5a of Example 1.1. A mixture of diastereoisomers of 6-[[4-[3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2- carbonyl]cycloheptyl]-methoxy]pyrimidine-4-carboxamide was separated by SFC (Column: DAICEL CHIRALPAK AD, 250 x 30 mm, 10 µm, mobile phase: 70% IPA (0.1% NH3•H2O) in CO2, single batch cycle process, lag time between two consecutive injections 6.5 min, total duration 30 min) to give a mixture of compound (126) stereoisomer 1 and compound (127) stereoisomer 2 (peak 1 and peak 2, 80 mg) as a white solid, compound (128) stereoisomer 3 (peak 3, 50 mg, 106.95 µmol, 18% yield) as a white solid and cis-6-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide stereoisomer 4 (peak 4, 55 mg, 117.65 µmol, 20% yield) as a yellow solid. The mixture of peak 1 and peak 2 (80 mg) was then separated by SFC (Column: DAICEL CHIRALCEL OJ, 250 x 30 mm, 10 µm, mobile phase: 30% MeOH (0.1% NH3•H2O) in CO2, single batch cycle process, lag time between two consecutive injections 2.8 min; total duration 25 min) to give compound (126) stereoisomer 1 (peak 1, 30 mg, 64.17 µmol, 11% yield) as a white solid and compound (127) stereoisomer 2 (peak 2, 39 mg, 83.42 µmol, 14% yield) as a white solid. Example 7: Synthesis of compounds (85), (86) Step 1: Synthesis of (1R,4R)-methyl 4-(iodomethyl)cyclohexane-1-carboxylate

[0217] To a solution of (1R,4R)-methyl 4-(hydroxymethyl)cyclohexane-1-carboxylate (25 g, 145.16 mmol, 1 eq), imidazole (14.82 g, 217.74 mmol, 1.5 eq) and I2 (55.27 g, 217.74 mmol, 43.86 mL, 1.5 eq) in DCM (250 mL) was added a solution of PPh3 (57.11 g, 217.74 mmol, 1.5 eq) under N2. The reaction mixture was stirred at 25 °C for 4 h. TLC indicated no starting material remained and one major new spot with greater polarity was detected. The reaction mixture was poured into H2O (1000 mL) and EA (200 mL 3) Extraction. The combined organic layers were washed with brine (200 mL), dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (Si02, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). (1r,4r)-methyl 4-(iodomethyl)cyclohexane-1-carboxylate was obtained as a yellow oil (28 g, 97.26 mmol, 67.00% yield, 98% purity). 1 H NMR (400 MHz, chloroform-d) δ = 3.67 (s, 3H), 3.11 (d, J = 6.4 Hz, 2H). Step 2: Synthesis of (1r,4r)-methyl 4-((3-carbamoyl-4-methylphenoxy)methyl)cyclohexane-1- carboxylate - compound corresponding to formula (III) in Scheme 1

[0218] To a solution of 5-hydroxy-2-methylbenzamide (200 mg, 1.32 mmol) in DMF (3.7 mL) was added NaH (60% in mineral oil, 32 mg, 1.32 mmol) and the mixture was stirred at room temperature for 10 min. Then (1r,4r)-methyl 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 h. An additional equivalent of NaH (60% in mineral oil, 32 mg, 1.32 mmol) was added and the mixture was stirred at 50 °C for 3 h and then at room temperature overnight. The mixture was diluted with EA and washed with 0.1 M NaOH and the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography to give (1R,4R)-methyl 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, 400 MHz) δ ppm 4.63 (s, 2 H), 3.60 (s, 3 H), 3.58(s, 1 H), 3.20 (d, J=6.24 Hz, 1 H), 2.24 (m, 3 H), 2.04 (m, 2 H), 1.91 (m, 3H), 1.40 (m, 3 H), 1.18 (m, 1 H), 1.04 (m, 1 H)

[0219] Step 3: Synthesis of trans-4-[(3-carbamoyl-4-methyl-phenoxy)methyl]cyclohexanecarboxylic acid was performed in a similar manner as detailed in Step 4 of Example 1.1, but starting from (1r,4r)-4-((3-carbamoyl-4-methylphenoxy)methyl)cyclohexane-1- carboxylic acid methyl ester LCMS, m / z 292.2 [M+H]+; RT 1.50 min (Method A). 1 H NMR (DMSO-d6, 400 MHz) δ ppm 12.00 (br s, 1 H), 7.65 (br s, 1 H), 7.29 (br s, 1 H), 7.10 (d, J=8.31 Hz, 1 H), 6.89 (s, 1 H), 6.87 (d, J=8.67 Hz, 1 H), 3.77 (d, J=6.36 Hz, 2 H), 2.27 (s, 3 H), 2.16 (m, 1 H), 1.90 (m, 4H), 1.70 (m, 1 H), 1.32 (m, 2 H), 1.07 (dtd, J=12.75, 12.58, 12.58, 3.06 Hz, 2 H).

[0220] Step 4a: Synthesis of trans-5-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2- carbonyl)cyclohexyl)methoxy)-2-methylbenzamide (Compound (85)) was performed in a similar manner as in Step 5a of Example 1.1, but starting from (1r,4r)-4-((3- carbamoyl-4-methylphenoxy)methyl)cyclohexane-1-carboxylic acid.

[0221] Step 4b: Synthesis of trans-5-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine-2- carbonyl)cyclohexyl)methoxy)-2-methylbenzamide (Compound (86)) was performed in a similar manner as in Step 5a of Example 1.1, but starting from (S)-3-(3,5- difluorophenyl)isoxazolidine. Example 8: Synthesis of Compounds (115), (116), (117), (118), (119), (120), and (121)

[0222] Step 1: Synthesis of 3-[(6-carbamoylpyrimidin-4-yl)oxymethyl]cyclopentanecarboxylic acid Step a: Synthesis of trans-dimethyl cyclopentane-1,3-dicarboxylate

[0223] A solution of trans-cyclopentane-1,3-dicarboxylate (9.5 g, 60.07 mmol, 1 equiv) and H2SO4(5.89 g, 60.07 mmol, 3.20 ml, 1 equiv) in MeOH (95 ml) was stirred at 80 °C for 3 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, NaHCO3was added to adjust to pH = 7~8 and extracted with EA (100 ml x 3). The combined organic layers were washed with brine (100 ml x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (9.8 g, 52.63 mmol, 88% yield) as a brown oil. 1 H NMR (400 MHz, CDCl3): δ ppm 3.61 (s, 6 H), 2.81-2.64 (m, 2 H), 2.17(td, J=7.9, 13.0 Hz, 1 H), 2.09-1.97 (m, 1 H), 1.95-1.79 (m, 4 H). Step b: synthesis of trans-3-ethoxycarbonylcyclopentanecarboxylic acid

[0224] A mixture of trans-cyclopentane-1,3-dicarboxylic acid dimethyl ester (5.8 g, 31.15 mmol, 1 equiv) in EtOH (60 ml) and NaOH (1.25 g, 31.15 mmol, 1 equiv) was stirred at 80 °C for 5 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, adjusted to pH 5~6 with 1 M HC1 and extracted with EA (100 ml x 2). The aqueous phase was adjusted to pH 5~6 with 1 M HC1, 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 give the title compound (3.9 g, crude) as a colourless oil. Step c: synthesis of trans-3-(hydroxymethyl)cyclopentanecarboxylic acid ethyl ester

[0225] A solution of trans-3-ethoxycarbonylcyclopentanecarboxylic acid (3.9 g, 20.94 mmol, 1 eq) in THF (40 ml) and BH3.Me2S (10 M, 3.14 ml, 1.5 eq) was stirred at 0 °C for 5 h. Water (5 ml) and HC1 (5 ml) were added, the mixture was stirred for 10 min and extracted with EA (50 ml x 2). The combined organic layers were separated, washed with brine (50 ml x 2), dried over anhydrous Na2S04, filtered, concentrated under reduced pressure and purified by column chromatography (Si02, petroleum ether / EA = 5 / 1 to 4 / 1) to give the title compound (2.7 g, 15.68 mmol, 75% yield) as a colorless oil. 1 H NMR (400 MHz, CDC13): δ ppm 4.14 (q, J = 7.1 Hz, 2 H), 3.63-3.57 (m, 1 H), 3.57-3.49 (m, 1 H), 2.88-2.69 (m, 1 H), 2.24-2.03 (m, 2 H), 1.99-1.87 (m, 2 H), 1.86-1.69 (m, 2 H), 1.65-1.40 (m, 2 H), 1.29-1.24 (m, 3 H). Step d: Synthesis of trans-3-[(6-chloropyrimidin-4-yl)oxymethyl]cyclopentane carboxylic acid ethyl ester - a compound corresponding to formula (III) in Scheme 1

[0226] A solution of trans-3-(hydroxymethyl)cyclopentane carboxylic acid ethyl ester (1.6 g, 9.29 mmol, 1 eq), 4,6-dichloropyrimidine (1.38 g, 9.29 mmol, 1 eq) in DMF (16 ml) was stirred at 0 °C for 5 min. NaH (445.90 mg, 11.15 mmol, 60% purity, 1.2 eq) was then added and the mixture was stirred at 0 °C under N2atmosphere for 2 h. The reaction mixture was quenched by the addition of saturated NH4CI (20 ml) at 0 °C and extracted with EA (30 ml x 3). The combined organic layers were dried over anhydrous Na2S04, filtered, concentrated under reduced pressure and purified by column chromatography (Si02, petroleum ether / EA = 20 / 1) to give the title compound (1.71 g, 6.01 mmol, 65% yield) as a colorless oil. LC / MS: m / z 285.1 [M+H] + 1H NMR (400 MHz, CDC13): δ ppm 8.57 (s, 1 H), 6.84-6.69 (m, 1 H), 4.40-4.32 (m, 1 H), 4.31-4.25 (m, 1 H), 4.15 (q, J=7.1 Hz, 2 H), 2.93-2.77 (m, 1 H), 2.62-2.36 (m, 1 H), 2.24-2.08 (m, 1 H), 2.02-1.88 (m, 2 H), 1.67-1.55 (m, 2 H), 1.28 (dt, J=1.4, 7.1 Hz, 3 H). Step e: Synthesis of trans-3-[(6-cyanopyrimidin-4-yl)oxymethyl]cyclopentanecarboxylic acid ethyl ester

[0227] A solution of trans-3-[(6-chloropyrimidin-4-yl)oxymethyl]cyclopentanecarboxylic acid ethyl ester (1.8 g, 6.32 mmol, 1 equiv), Pd(PPh3)4(1.46 g, 1.26 mmol, 0.2 equiv), Zn(CN)2(2.23 g, 18.96 mmol, 1.20 ml, 3 equiv) in DMF (18 ml) was degassed and purged with N2three times and stirred at 100 °C under N2atmosphere for 15 h. The reaction mixture was filtered, concentrated under reduced pressure and purified by preparative TLC (SiO2, Petroleum ether / EA = 5 / 1) to give the title compound (1.1 g, 4.00 mmol, 63% yield) as a yellow oil. LC / MS: m / z 276.2 [M+H] + 1 H NMR (400 MHz, CDC13): δ ppm 8.83 (d, J=0.7 Hz, 1 H), 7.15-7.05 (m, 1 H), 4.45-4.28 (m, 2 H), 4.15 (q, J=7.1 Hz, 2 H), 2.96-2.79 (m, 1 H), 2.66-2.37 (m, 1 H), 2.25-2.11 (m, 1 H), 2.06-1.85 (m, 3 H), 1.76-1.52 (m, 2 H), 1.28 (dt, J=1.3, 7.1 Hz, 3 H). Step f: Synthesis of 3-[(6-carbamoylpyrimidin-4-yl)oxymethyl]cyclopentanecarboxylic acid

[0228] To a mixture of trans-3-[(6-cyanopyrimidin-4-yl)oxymethyl]cyclopentane carboxylic acid ethyl ester (1.3 g, 4.25 mmol, 90% purity, 1 eq) in THF (13 ml) was added a mixture of H2O2 (963.59 mg, 8.50 mmol, 816.60 µl, 30% purity, 2 eq) and LiOH•H2O (1 M, 4.25 ml, 1 eq), degassed and purged with N2 3 times and stirred at 25 °C for 30 min. LiOH•H2O (1 M, 1.49 ml, 0.35 eq) was added and the mixture was stirred at 25 °C under N2 atmosphere for 12 h. The reaction mixture was quenched by addition of Na2SO3 solution, adjusted to pH 5~6 with 1 M HC1 and filtered. The precipitate was triturated with petroleum ether / EA = 1 / 1 at 25 o C for 30 min to give the title compound (0.57 g, 2.15 mmol, 51% yield) as a white solid. Analytical data showed that cis-trans-isomerization had occurred. LC / MS: m / z 266.2 [M+H] + SFC (Column: Chiralpak IG-3 50 x 4.6 mm I.D., 3 µm; Gradient elution: IPA (0.05% DEA) in CO2, 5% to 40%, flow rate: 3 ml / min; Column temperature: 35 °C, 100 bar): 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 (400 MHz, DMSO-d6): δ ppm 12.09 (br s, 1 H), 8.86 (d, J=0.7 Hz,1 H), 8.23 (br s, 1 H), 7.93 (br s, 1 H), 7.37-7.25 (m, 1 H), 4.35-4.27 (m, 1H), 4.39-4.18 (m, 1 H), 2.86-2.66 (m, 1 H), 2.43-2.30 (m, 1 H), 2.12-1.88 (m,2 H), 1.87-1.73 (m, 2 H), 1.59-1.31 (m, 2 H).

[0229] Step 2a: Synthesis of diastereoisomer mixture of 6-[[3-[(3S)-3-(3-cyano-5- fluoro-phenyl)isoxazolidine-2-carbonyl]cyclopentyl]methoxy]-pyrimidine-4- carboxamide in a similar manner as in Step 5a of Example 1.1, but starting from (3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine The diastereoisomer mixture of 6-[[3-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cyclopentyl]methoxy]-pyrimidine-4-carboxamide was separated by SFC (conditions: Column: DAICEL CHIRALPAK AD, 250 x 30 mm, 10 µm; Mobile phase: 55% EtOH (0.1% NH3•H2O) in CO2, single batch cycle, lag time between two consecutive injections 3.5 min; total duration 70 min; and Column: DAICEL CHIRALPAK AS, 250 x 30 mm, 10 µm; Mobile phase: 65% MeOH (0.1% NH3•H2O) in CO2, single batch cycle, lag time between two consecutive injections 4.4 min; total duration 25 min) to give compound (115) stereoisomer 1 (peak 1, 96 mg, 204.98 µmol, 18% yield), compound (116) stereoisomer 2 (peak 2, 57 mg, 126.36 µmol, 11% yield), compound (117) stereoisomer 3 (peak 3, 41 mg, 89.95 µmol, 8% yield) and cis-6-[[3-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide stereoisomer 4 (peak 4, 80 mg, 180.85 µmol, 16% yield), all as yellow solids. cis-6-[[3-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide stereoisomer 4 (peak 4): LC / MS: m / z 440.3 [M+H] + ; SFC (Column: Chiralpak AS-3 50 x 4.6 mm I.D., 3 µm; Mobile phase: CO2 and MeOH (0.05% DEA), gradient: 5-40% MeOH (0.05% DEA); Flow rate: 3 ml / min; Column temperature: 35 °C; 100 bar): Rt = 2.40 min (100%); 1H NMR (400 MHz, CDC13): δ ppm 8.74 (d, J=1.0 Hz, 1 H), 7.76 (br s, 1H), 7.51 (d, J=1.0 Hz, 1 H), 7.42 (s, 1 H), 7.29-7.26 (m, 2 H), 5.72 (br s, 1H), 5.41 (dd, J=6.4, 8.7 Hz, 1 H), 4.41-4.27 (m, 3 H), 3.87 (ddd, J=6.7, 8.2,9.6 Hz, 1 H), 3.31 (quin, J=8.3 Hz, 1 H), 2.90 (dddd, J=2.9, 6.5, 9.2, 12.3Hz, 1 H), 2.51 (td, J=7.8, 16.0 Hz, 1 H), 2.36-2.24 (m, 1 H), 2.14-1.90 (m, 4H), 1.65-1.57 (m, 2 H).

[0230] Step 2b: Synthesis of a diastereomeric mixture of 6-[[3-[(3S)-3-(3,5- difluorophenyl)isoxazolidin-2-yl]carbonyl]cyclopentyl]methoxy]pyrimidine-4- carboxamide was performed in a similar manner as in Step 5a of Example 1.1, but starting from (3S)-3-(3,5-difluorophenyl)isoxazolidine A mixture of diastereoisomers of 6-[[3-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2- ylcarbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide was separated by SFC (conditions: Column: DAICEL CHIRALPAK AS, 250 x 30 mm, 10 µm; Mobile phase: 70% EtOH (0.1% NH3•H2O) in CO2, single batch cycle with a lag time of 10.0 min between consecutive injections; total duration 50 min, and Column: DAICEL CHIRALPAK AS, 250 x 30 mm, 10 µm; Mobile phase: 40% EtOH (0.1% NH3•H2O) in CO2, single batch cycle with a lag time of 2.1 min between consecutive injections; total duration 40 min, and Column: DAICEL CHIRALPAK AS, 250 x 30 mm, 10 µm; Mobile phase: 65% MeOH (0.1% NH3•H2O) in CO2, single batch cycle with a lag time of 5.2 min between consecutive injections; total duration 40 min) to give compound (118) stereoisomer 1 (peak 1, 44 mg, 99.15 µmol, 6% yield), compound (119) stereoisomer 2 (peak 2, 164 mg, 377.58 µmol, 22% yield), compound (120) stereoisomer 3 (peak 3, 37 mg, 84.75 µmol, 5% yield) as a yellow solid and compound (121) stereoisomer 4 (peak 4, 154 mg, 356.14 µmol, 20% yield) as a white solid. 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

[0231] To a mixture of trans-4-(hydroxymethyl)cyclohexanecarboxylic acid (1.00 g, 6.32 mmol) and DMF (40 ml) was added 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 h. The mixture was diluted with water. HC1 (aq, 1 M) was added until a slightly acidic pH was reached. The mixture was extracted with MTBE (2 x). The combined organic layers were washed with brine, dried (Na2S04), filtered and concentrated. The residue (2.9 g) was dissolved in DMF / water (20:1, 35 ml) and heated to 70 °C for 2 h. The mixture was diluted with MTBE at room temperature. The organic layer was separated, washed with NH4C1 (sat. aq.) and brine, dried (Na2S04), filtered and concentrated. The crude product was purified by column chromatography (Si02; EA / heptane gradient 1 / 4 to 1 / 2) to give the title compound (1.22 g, 4.48 mmol, 71% yield). 1 H NMR (400 MHz, DMSO-d6): δ ppm 11.95 (br s, 1 H), 3.32 (m, 2 H),2.07 (tt, J=12.12, 12.12, 3.53, 3.53 Hz, 1 H), 1.87 (m, 2 H), 1.72 (m, 2 H),1.29 (m, 3 H), 0.91 (m, 2 H), 0.85 (s, 9 H), 0.00 (s, 6 H). Step 1a: Synthesis of 5-[(3S)-2-[trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl] cyclohexanecarbonyl]isoxazolidin-3-yl]pyridine-3-carbonitrile

[0232] To a mixture of trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexanecarboxylic acid (500 mg, 1.84 mmol) and DMF (20 ml) was added Oxyma (770 mg, 5.2 mmol) and NaHC03(1.43 g, 17.02 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. 5-[(3S)-isoxazolidin-3-yl]pyridine-3-carbonitrile (320 mg, 1.83 mmol) in DMF (10 ml) was added. The mixture was warmed to 40 °C for 2 h. At room temperature, the mixture was diluted with EA and washed with water. The organic layer was separated, washed with NH4CI (saturated aqueous solution), NaHC03(saturated aqueous solution) and brine, dried (Na2S04), filtered and concentrated. The crude title compound (770 mg, 1.79 mmol, 98% crude yield) was used directly in the next step.

[0233] Step 1b: [trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-[(3S)-3- pyrazin-2-ylisoxazolidin-2-yl]methanone, [trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidin-2-yl]methanone, [trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-[(3S)-3-(2-methylthiazol-4-yl)isoxazolidin-2-yl]methanone and [trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-[(3S)-3-(2-pyridyl)isoxazolidin-2-yl]methanone were performed as detailed in Step 1a of Example 9. Step 2a: 5-((S)-2-(trans-4-(hydroxymethyl)cyclohexane-1-carbonyl)isoxazolidin-3- yl)nicotinonitrile - synthesis of a compound corresponding to formula (lie) in Scheme 4

[0234] To a mixture of 5-[(3S)-2-[trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexane- carbonyl]isoxazolidin-3-yl]pyridine-3-carbonitrile (770 mg, 1.79 mmol) and DCM (30 ml) was added TFA (2 ml). The mixture was stirred for 15 min. The reaction was quenched by the addition of NaHC03(saturated aqueous solution) and diluted with EA. The organic layer was separated, washed with brine, dried (Na2S04), filtered and concentrated. The crude product was purified by preparative HPLC to give the title compound (340 mg, 1.08 mmol, 60% yield). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.94 (d, J=1.83 Hz, 1 H), 8.77 (d, J=2.08 Hz, 1 H), 8.19 (t, J=1.96, 1.96 Hz, 1 H), 5.41 (dd, J=8.62, 6.54 Hz, 1H), 4.36 (br s, 1 H), 4.29 (td, J=7.70, 7.70, 3.06 Hz, 1 H), 3.91 (m, 1 H),3.21 (br d, J=5.50 Hz, 2 H), 2.89 (m, 1 H), 2.66 (br t, J=11.92, 11.92 Hz, 1H), 2.29 (m, 1 H), 1.90 (br d, J=11.74 Hz, 1 H), 1.76 (m, 3 H), 1.31 (m, 3H), 0.94 (m, 2 H)。

[0235] Step 2b: [trans-4-(hydroxymethyl)cyclohexyl]-[(3S)-3-pyrazin-2-ylisoxazolidin-2- yl]methanone, [trans-4-(hydroxymethyl)cyclohexyl]-[(3S)-3-(6-methoxypyrazin-2- yl)isoxazolidin-2-yl]methanone, [trans-4-(hydroxymethyl)cyclohexyl]-[(3S)-3-(2- pyridyl)isoxazolidin-2-yl]methanone and [trans-4-(hydroxymethyl)cyclohexyl]-[(3S)-3- (2-methylthiazol-4-yl)isoxazolidin-2-yl]methanone were synthesized in a similar manner as in Step 2a of Example 9. Step 3a: Synthesis of trans-5-((S)-2-(4-((3-cyanophenoxy)methyl)cyclohexane-l- carbonyl)isoxazolidin-3-yl)nicotinonitrile (Compound (71)) - according to the route SM3 in Scheme 4

[0236] To a mixture of 5-((S)-2-(trans-4-(hydroxymethyl)cyclohexane-l-carbonyl)isoxazolidin- 3-yl)nicotinonitrile (50 mg, 159 µmol), 3-hydroxybenzonitrile (40 mg, 336 µmol) and THF (2 ml) was added PPh3 (polymer bound, 100 mg) and DIAD (70 µl, 0.36 mmol). The mixture was stirred at room temperature for 2 h, diluted with THF (15 ml) and filtered. The filtrate was concentrated and purified by preparative HPLC to give the title compound (20 mg, 48.0 µmol, 30% yield).

[0237] Step 3b: Synthesis of trans-5-((S)-2-(4-((3-cyano-4-fluorophenoxy)methyl)cyclohexane-1- carbonyl)isoxazolidin-3-yl)nicotinonitrile (compound (72)), trans-3-((4-((S)-3-(5- cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)benzamide (compound (73)), trans-5-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-2- fluorobenzamide (compound (74)) and trans-2-chloro-5-((4-((S)-3-(5-cyanopyridin-3- yl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)benzamide (compound (75)) was carried out in a similar manner as detailed in Step 3a of Example 9, but starting from 3- hydroxy-5-fluorobenzonitrile, 3-hydroxybenzamide, 5-hydroxy-2-fluorobenzamide and 2- chloro-5-hydroxybenzamide, respectively. Step 4a: Synthesis of [trans-4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl 4-nitrobenzenesulfonate - a compound corresponding to formula (lid) in Scheme 4 - activation step prior to pathway SM5 of Scheme 4

[0238] To a mixture of trans-5-[(3S)-2-[4-(hydroxymethyl)cyclohexanecarbonyl]isoxazolidin-3-yl]pyridine-3- carbonitrile (50 mg, 159 µmol) and DCM (2 ml) was added TEA (40 µl, 287 µmol) and 4-nitrobenzenesulfonyl chloride (50 mg, 221 µmol). The mixture was stirred for 14 h, diluted with EA and washed with water. The organic layer was concentrated, re-dissolved in EA and filtered through a short silica pad. The filtrate was concentrated to give the title compound (53 mg, 106 µmol, 67% yield). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.93 (d, J=1.96 Hz, 1 H), 8.76 (d, J=2.20 Hz, 1 H), 8.46 (d, J=8.06 Hz, 2 H), 8.19 (m, 3 H), 5.39 (m, 1 H), 4.27(td, J=7.64, 7.64, 2.93 Hz, 1 H), 3.99 (d, J=5.99 Hz, 2 H), 3.90 (m, 1 H),2.89 (dddd, J=12.13, 9.14, 6.42, 3.12 Hz, 1 H), 2.64 (m, 1 H), 2.28 (m, 1 H),1.88 (br d, J=11.98 Hz, 1 H), 1.68 (br d, J=12.10 Hz, 3 H), 1.63 (br d, J=3.30 Hz, 1 H), 1.29 (m, 2 H), 1.00 (m, 2 H)。

[0239] Step 4b: [trans-4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methyl- 4-nitrobenzenesulfonate, [trans-4-[(3S)-3-(6-methoxypyrazin-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-methylthiazol-4-yl)isoxazolidine-2-carbonyl]cyclohexyl]methyl-4-nitrobenzenesulfonate were synthesized in a similar manner as in Step 4a of Example 9. Step 5a: synthesis of (compound (83)) - route SM5 of scheme 4

[0240] To a mixture of [trans-4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl]methyl 4-nitrobenzenesulfonate (23 mg, 46.0 µmol), 3-fluoro-5-hydroxy- benzonitrile (10 mg, 73 µmol) and DMF (2 ml) was added Cs2CO3(40 mg, 123 µmol). The mixture was stirred at 50 °C for 2.5 h. At room temperature, the mixture was filtered and the filtrate was purified by preparative HPLC to give the title compound (12 mg, 27.6 µmol, 60% yield).

[0241] Step 5b: Synthesis of trans-5-((S)-2-(4-((2-chloro-5-(3-methyl-2,5-dioxoimidazolidin- 1-yl)phenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidin-3-yl)nicotinonitrile (88) was performed in a similar manner as in Step 5a of Example 9, but starting from 2-chloro-5-(3-methyl-2,5-dioxoimidazolidin-1-yl)phenol, respectively.

[0242] Step 5c: Synthesis of trans-5-((S)-2-(4-((2-fluoro-4-(3-methyl-2-oxo-2,3-dihydro-1H- imidazol-1-yl)phenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidin-3-yl)nicotinonitrile (89) was performed in a similar manner as in Step 5a of Example 9, but starting from 2-fluoro-4-(3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)phenol, respectively.

[0243] Step 5d: Synthesis of trans-5-((S)-2-(4-((4-(3,5-dimethyl-1H-pyrazol-1-yl)-2- fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidin-3-yl)nicotinonitrile (90) was performed in a similar manner as in Step 5a of Example 9, but starting from 4-(3,5-dimethyl-1H-pyrazol-1-yl)-2-fluorophenol, respectively.

[0244] Step 5e: Synthesis of trans-5-((S)-2-(4-((5-(5,5-dimethyl-2,4-dioxooxazolidin-3-yl)-2- fluorophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidin-3-yl)nicotinonitrile (92) was performed in a similar manner as in Step 5 a of Example 9, but starting from 5-(5,5-dimethyl-2,4-dioxooxazolidin-3-yl)-2-fluorophenol, respectively.

[0245] Step 5f: Synthesis of trans-5-((S)-2-(4-(((4-cyanopyridin-2-yl)oxy)methyl)cyclohexane-1- carbonyl)isoxazolidin-3-yl)nicotinonitrile (94) was performed in a similar manner as in Step 5a of Example 9, but starting from 2-hydroxypyridine-4-carbonitrile, respectively.

[0246] Step 5g: Synthesis of trans-5-((S)-2-(4-(((5-cyanopyridin-2-yl)oxy)methyl)cyclohexane-1- carbonyl)isoxazolidin-3-yl)nicotinonitrile (95) was performed in a similar manner as in Step 5a of Example 9, but starting from 3-cyano-6-hydroxypyridine, respectively.

[0247] Step 5h: Synthesis of trans-6-[[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2- carbonyl]cyclohexyl]methoxy]pyridine-3-carboxamide (99) was performed in a similar manner as in Step 5a of Example 9, but starting from 6-hydroxypyridine-3- carboxamide, respectively.

[0248] Step 5i: Synthesis of trans-3-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl] methoxy]benzamide (100) was performed in a similar manner as in Step 5a of Example 9, but starting from 3-hydroxybenzamide, respectively.

[0249] Step 5j: Synthesis of trans-2-fluoro-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2- carbonyl]cyclohexyl]methoxy]benzamide (101) was performed in a similar manner as in Step 5a of Example 9, but starting from 2-fluoro-5-hydroxybenzamide, respectively.

[0250] Step 5k: Synthesis of trans-6-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl] methoxy]pyridine-3-carboxamide (102) was performed in a similar manner as in Step 5a of Example 9, but starting from 6-hydroxypyridine-3-carboxamide, respectively.

[0251] Step 5l: Synthesis of trans-6-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl] methoxy]pyridine-3-carbonitrile (103) was performed in a similar manner as in Step 5 a a of Example 9, but starting from 6-hydroxynicotinonitrile, respectively.

[0252] Step 5m: Synthesis of trans-3-fluoro-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2- carbonyl]cyclohexyl]methoxy]benzonitrile (104) was performed in a similar manner as in Step 5a of Example 9, but starting from 3-fluoro-5-hydroxybenzonitrile, respectively.

[0253] Step 5n: Synthesis of trans-4-fluoro-3-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2- carbonyl]cyclohexyl]methoxy]benzamide (111) was performed in a similar manner as in Step 5a of Example 9, but starting from 4-fluoro-3-hydroxybenzamide, respectively.

[0254] Step 5o: Synthesis of trans-3-fluoro-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2- carbonyl]cyclohexyl]methoxy]benzamide (112) was performed in a similar manner as in Step 5a of Example 9, but starting from 3-fluoro-5-hydroxybenzamide, respectively.

[0255] Step 5p: Synthesis of trans-3-fluoro-4-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2- carbonyl]cyclohexyl]methoxy]benzamide (113) was performed in a similar manner as in Step 5a of Example 9, but starting from 3-fluoro-4-hydroxybenzamide, respectively.

[0256] Step 5q: Synthesis of trans-3-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2- carbonyl]cyclohexyl]methoxy]benzamide (129) was performed in a similar manner as in Step 5a of Example 9, but starting from 3-hydroxybenzamide, respectively.

[0257] Step 5r: Synthesis of trans-3-[[4-[(3S)-3-(2-methylthiazol-4-yl)isoxazolidine-2- carbonyl]cyclohexyl]methoxy]benzamide (130) was performed in a similar manner as in Step 5a of Example 9, but starting from 3-hydroxybenzamide, respectively.

[0258] Step 5s: Synthesis of trans-3-[[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]cyclohexyl] methoxy]benzamide (131) was performed in a similar manner as in Step 5a of Example 9, but starting from 3-hydroxybenzamide, respectively. Example 10: Synthesis of compound (93) Example 10.1: Synthesis of compound (93) Step 1: Synthesis of trans-4-[(2-cyano-4-pyridyl)oxymethyl]cyclohexanecarboxylic acid methyl ester

[0259] To a solution of 4-nitropyridine-2-carbonitrile (300 mg, 2.01 mmol, 1 eq) in DMF (3 mL) was added NaH (120.71 mg, 3.02 mmol, 60% purity, 1.5 eq) and (1r,4r)-4- (hydroxymethyl)cyclohexane-1 -carboxylic acid methyl ester (381.16 mg, 2.21 mmol, 1.1 eq). The mixture was stirred at 25 °C for 1 h. TLC indicated no starting material remained and a new spot was detected. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was diluted with H2O 20 mL and extracted with EA 20 mL (20 mL 2) extraction, dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether / Ethyl acetate = 1 / 1 to 5 / 1) to give methyl 4-[(2-cyano-4-pyridyl)oxymethyl]cyclohexanecarboxylate (532 mg, 1.51 mmol, 75.19% yield, 78% purity) as a white solid. LC / MS m / z 275.2 [M+H]+; RT 0.905 min (Method B). 1 H NMR (CDC13; 400 MHz) δ 8.50 (d, J = 5.9 Hz, 1H), 7.21 (d, J = 2.5Hz, 1H), 6.98 (dd, J = 2.5, 5.9 Hz, 1H), 3.86 (d, J = 6.3 Hz, 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). Step 2: Synthesis of 4-[(2-cyano-4-pyridyl)oxymethyl]cyclohexanecarboxylic acid

[0260] To a solution of methyl 4-[(2-cyano-4-pyridyl)oxymethyl]cyclohexanecarboxylate (732 mg, 2.67 mmol, 1 eq) in THF (7 mL) was added LiOH H20 (1 M, 3.20 mL, 1.2 eq). The mixture was stirred at 25 °C for 1 h. LC-MS showed no starting material left. Several new peaks were shown on LC-MS and the desired compound was detected. The reaction mixture was concentrated. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150 25mm 10um; mobile phase: [water (0.225% FA) - ACN]; B%: 23%-56%, 10 min) to give 4-[(2-cyano-4-pyridyl)oxymethyl]cyclohexanecarboxylic acid (218 mg, 837.53 umol, 31.39% yield, 100% purity) as a white solid. LC / MS m / z 261.2 [M+H]+; RT 0.814 min (Method B). 1H NMR (CDC13; 400 MHz) δ 8.51 (d, J = 5.7 Hz, 1H), 7.21 (d, J = 2.3Hz, 1H), 6.99 (dd, J = 2.5, 5.8 Hz, 1H), 3.87 (d, J = 6.2 Hz, 2H), 2.36 (tt,J = 3.5, 12.2 Hz, 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). Step 3: Synthesis of (trans-4-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidin-2- yl]cyclohexyl]methoxy]pyridine-2-carbonitrile (compound (93)) was performed in a similar manner as in Step 5a of Example 1.1, but starting from 4-[(2-cyano-4-pyridyl)oxymethyl]cyclohexanecarboxylic acid 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)isoxazolidin-2- yl]methanone hydrochloride - compound of formula (lie) of Scheme 5

[0261] To a stirred solution of tert-butyl N-[cis-4-[(3S)-3-(4-chlorophenyl)isoxazolidin-2- yl]cyclohexyl]carbamate (260 mg, 635.8 µmol) in CH2Cl2(2.7 ml) was added TFA (1.35 ml, 17.5 mmol) and stirring was continued at room temperature for 1 h. The solution was diluted with toluene and concentrated under reduced pressure. The resulting crude material was re-dissolved in toluene and concentrated again. Finally, the obtained material was dissolved in 0.1 N aqueous HC1 solution and lyophilized. The title compound was obtained as a light yellow oil which was used without further purification for the next reaction (230 mg, 660 µmol, quantitative yield). 1H NMR (600 MHz, DMSO-d6): δ ppm 7.87 (br s, 3 H), 7.41 (d, J=8.44 Hz,2 H), 7.30 (d, J=8.44 Hz, 2 H), 5.31 (m, 1 H), 4.24 (m, 1 H), 3.88 (m, 1 H),3.85 (s, 1 H), 3.12 (m, 1 H), 2.86 (m, 2 H), 2.14 (m, 1 H), 1.95-1.70 (m, 5H), 1.51 (m, 2 H).

[0262] Step 2: Synthesis of compound cis-2-((4-((S)-3-(4-chlorophenyl)isoxazolidin-2- ylcarbonyl)cyclohexyl)amino)pyrimidine-4-carboxamide (12) was performed in a similar manner as in Step 2 of Example 11.2, but starting from 2-chloropyrimidine-4- carboxamide, respectively.

[0263] Step 2a: Synthesis of compound cis-6-((4-((S)-3-(4-chlorophenyl)isoxazolidin-2- ylcarbonyl)cyclohexyl)amino)pyrimidine-4-carboxamide (13) was performed in a similar manner as in Step 2 of Example 11.2, but starting from 6-chloropyrimidine-4- carboxamide, respectively. Example 11.2: Synthesis of compound (28)

[0264] Step 1: Synthesis of cis-3-[(3S)-2-(4-aminocyclohexanecarbonyl)isoxazolidin-3-yl]-5- fluoro-benzonitrile hydrochloride - corresponds to the compound of formula (lie) in Scheme 5 was performed as in Step 1 of Example 11.1, but starting from tert-butyl N-[cis-4-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidin-2-ylcarbonyl]cyclohexyl]carbamate Step 2: Synthesis of compound cis-6-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidin- 2-ylcarbonyl)cyclohexyl)amino)pyrimidine-4-carbonitrile (28) - route of Scheme 5

[0265] To a stirred solution of 6-chloropyrimidine-4-carbonitrile (28 mg, 198 µmol) and cis-3-[(3S)-2-(4-aminocyclohexanecarbonyl)isoxazolidin-3-yl]-5-fluoro- benzonitrile hydrochloride (70 mg, 198 µmol) in CH3CN (2 ml) was added NetiPr2 (75 µl, 428 µmol) at room temperature. The solution was heated to reflux for 2.5 h. The volatile components were removed under reduced pressure, the obtained residue was dissolved in DMF, filtered and subjected to preparative reverse-phase HPLC (33 mg, 79 µmol, 40% yield). Example 11.3: Synthesis of compounds (14) and (15)

[0266] Step 1: Synthesis of trans-[4-(aminomethyl)cyclohexyl]-[(3S)-3-(4-chlorophenyl)isoxazolidin-2- yl]methanone hydrochloride - corresponding to the compound of formula (lie) in Scheme 5 was carried out as in Step 1 of Example 11.1 but starting from tert-butyl N-[trans-4-[(3S)-3-(4- chlorophenyl)isoxazolidin-2-yl]cyclohexyl]carbamate

[0267] Step 2: Synthesis of trans-2-(((4-((S)-3-(4-chlorophenyl)isoxazolidin-2-yl) cyclohexyl)methyl)amino)pyrimidine-4-carbonitrile (compound (14)) was carried out in a similar manner as Step 2 of Example 11.2 but starting from 2-chloropyrimidine-4-carbonitrile, respectively.

[0268] Step 2a: Synthesis of trans-6-(((4-((S)-3-(4-chlorophenyl)isoxazolidin-2-yl)cyclohexyl)methyl)amino)pyrimidine-4-carbonitrile (compound (15)) was carried out in a similar manner as Step 2 of Example 11.2 but starting from 6-chloropyrimidine-4-carbonitrile, respectively. Example 11.4: Synthesis of compounds (16) and (17)

[0269] Step 1: Synthesis of cis-(3-aminocyclobutyl)-[(3S)-3-(3-fluorophenyl)isoxazolidin-2-yl]methanone; hydrochloride was carried out as in Step 1 of Example 11.1 but starting from tert-butyl N-[cis-3-[(3S)-3-(3- fluorophenyl)isoxazolidin-2-yl]cyclobutyl]carbamate

[0270] Step 2: Synthesis of cis-2-((3-((S)-3-(3-fluorophenyl)isoxazolidin-2-yl)cyclobutyl)amino)pyrimidine-4- carbonitrile (compound (16)) was carried out in a similar manner as Step 2 of Example 11.2 but starting from 2-chloropyrimidine-4-carbonitrile, respectively.

[0271] Step 2a: Synthesis of cis-6-((3-((S)-3-(3-fluorophenyl)isoxazolidine-2- carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile (Compound (17)) was performed in a similar manner as Step 2 of Example 11.2, but starting from 6-chloropyrimidine-4-carbonitrile, respectively. Example 11.5: Synthesis of Compound (18)

[0272] Step 1: Synthesis of cis-(3-aminocyclobutyl)-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2- yl]methanone hydrochloride was performed as in Step 1 of Example 11.1, but starting from N-[cis-3-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl]cyclobutyl] carbamic acid tert-butyl ester

[0273] Step 2: Synthesis of cis-6-((3-((S)-3-(3,5-difluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile (Compound (18)) was performed in a similar manner as Step 2 of Example 11.2, but starting from 6-chloropyrimidine-4-carbonitrile, respectively. Example 11.6: Synthesis of Compounds (19) and (20)

[0274] Step 1: Synthesis of cis-3-[(3S)-2-(3-aminocyclobutane carbonyl)isoxazolidin-3-yl]-5- fluoro-benzonitrile; hydrochloride was performed as in Step 1 of Example 11.1, but starting from N-[cis-3-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl]cyclobutyl] carbamic acid tert-butyl ester

[0275] Step 2: Synthesis of cis-2-((3-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile (Compound (19)) was performed in a similar manner as Step 2 of Example 11.2, but starting from 2-chloropyrimidine-4-carbonitrile, respectively.

[0276] Step 2a: Synthesis of cis-6-((3-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2-carbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile (20) was performed in a similar manner as Step 2 of Example 11.2, but starting from 6-chloropyrimidine-4-carbonitrile, respectively. Example 11.7: Synthesis of Compounds (21) and (22)

[0277] Step 1 : Synthesis of cis-(3-aminocyclobutyl)-[(3S)-3-(3,4-difluorophenyl)isoxazolidin-2- yl]methanone; hydrochloride was performed as in Step 1 of Example 11.1 but starting from tert-butyl N-[cis-3-[(3S)-3-(3,4-difluorophenyl)isoxazolidin-2-yl]cyclobutyl]carbamate

[0278] Step 2: Synthesis of cis-2-((3-((S)-3-(3,4-difluorophenyl)isoxazolidin-2- yl)cyclobutyl)amino)pyrimidine-4-carbonitrile (compound (21)) was performed in a similar manner as Step 2 of Example 11.2 but starting from 2-chloropyrimidine-4-carbonitrile, respectively.

[0279] Step 2a: Synthesis of cis-6-((3-((S)-3-(3,4-difluorophenyl)isoxazolidin-2- yl)cyclobutyl)amino)pyrimidine-4-carbonitrile (compound (22)) was performed in a similar manner as Step 2 of Example 11.2 but starting from 6-chloropyrimidine-4-carbonitrile, respectively. Example 11.8: Synthesis of compounds (23) and (24)

[0280] Step 1 : Synthesis of cis-(3-aminocyclobutyl)-[(3S)-3-(4-chlorophenyl)isoxazolidin-2- yl]methanone; hydrochloride was performed as in Step 1 of Example 11.1 but starting from tert-butyl N-[cis-3-[(3S)-3-(4-fluorophenyl)isoxazolidin-2-yl]cyclobutyl]carbamate

[0281] Step 2: Synthesis of cis-6-((3-((S)-3-(4-chlorophenyl)isoxazolidin-2- yl)cyclobutyl)amino)pyrimidine-4-carbonitrile (compound (23)) was performed in a similar manner as Step 2 of Example 11.2 but starting from 6-chloropyrimidine-4-carbonitrile, respectively.

[0282] Step 2a: Synthesis of cis-2-((3-((S)-3-(4-chlorophenyl)isoxazolidin-2- yl)cyclobutyl)amino)pyrimidine-4-carbonitrile (compound (24)) was performed in a similar manner as Step 2 of Example 11.2 but starting from 2-chloropyrimidine-4-carbonitrile, respectively. Example 11.9: Synthesis of compounds (29), (30) and (31)

[0283] Step 1 : trans-3-[(3S)-2-[4-(aminomethyl)cyclohexanecarbonyl]isoxazolidin-3-yl]-5- fluoro-benzonitrile; hydrochloride salt - the synthesis of a compound corresponding to formula (lie) of Scheme 5 was carried out as in Example 11.1, Step 1, but starting from i?rø-tørt-buty\ N-[trans-4-[(3S)-3-(3-cyano-5-fluorophenyl)isoxazolidin-2- yl]methylcyclohexyl]carbamate

[0284] Step 2a: synthesis of trans-6-(((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidin-2- yl)cyclohexyl)methyl)amino)pyrimidine-4-carboxamide (compound (29)) was carried out in a similar manner as Example 11.2, Step 2, but starting from 6-chloropyrimidine-4- carboxamide, respectively.

[0285] Step 2b: synthesis of trans-6-(((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidin-2- yl)cyclohexyl)methyl)amino)pyrimidine-4-carbonitrile (compound (30)) was carried out in a similar manner as Example 11.2, Step 2, but starting from 6-chloropyrimidine-4- carbonitrile, respectively. Step 2c: synthesis of trans-3-fluoro-5-((S)-2-(4-(((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)cyclohexan-1 -carbonyl)isoxazolidin-3-yl)benzonitrile compound (31 ) - route of Scheme 5

[0286] 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)cyclohexan-1 - carbonyl)isoxazolidin-3-yl)-5-fluorobenzonitrile hydrochloride salt (55.5 mg, 150.7 μmol) in CH3CN (3 ml) was heated to 120 °C in a microwave vial and stirred for 1.5 h. K2CO3 (52.1 mg, 376.9 μmol) was added and the reaction mixture was stirred again at 120 °C for 10 h. The volatile components were removed under reduced pressure, the obtained residue was dissolved in DMF, filtered and subjected to preparative reverse phase HPLC (12 mg, 17% yield). Example 11.10: synthesis of compounds (25), (26), (27), (36) and (37) Synthesis of cis-3-((3-((S)-3-(4-chlorophenyl)isoxazolidin-2-carbonyl)cyclobutyl)amino)-5- fluorobenzonitrile (compound (25))

[0287] To a stirred suspension of ((cis-3-aminocyclobutyl)((S)-3-(4- chlorophenyl)isoxazolidin-2-yl)methanone hydrochloride (50 mg, 158 µmol) and 3,5- difluorobenzonitrile (44 mg, 315 µmol) in DMSO (1 ml) was added K2CO3 (44 mg, 315 µmol) and the suspension was heated at 80 °C for 16 h. Water was added at room temperature and the aqueous layer was extracted with EA, the combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated to give the crude title compound which was subjected to preparative reverse phase HPLC (4 mg, 9 µmol, 6% yield).

[0288] 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)) was carried out in a similar manner as in Example 11.10, but starting from ((cis-3-aminocyclobutyl)((S)-3-(2-fluorophenyl)isoxazolidin-2-yl)methanone and ((cis-3-aminocyclobutyl)((S)-3-(2,4-difluorophenyl)isoxazolidin-2-yl)methanone, respectively.

[0289] The synthesis of cis-3-fluoro-5-((3-((S)-3-(5-fluoropyridin-3-yl)isoxazolidine-2- carbonyl)cyclobutyl)amino)benzonitrile (Compound (36)) was carried out in a similar manner as in Example 11.10, but starting from ((cis-3-aminocyclobutyl)((S)-3-(5- fluoropyridin-3-yl)isoxazolidin-2-yl)methanone.

[0290] The synthesis of cis-3-((S)-2-(3-((3-cyano-5-fluorophenyl)amino)cyclobutane-1- carbonyl)isoxazolidin-3-yl)-5-fluorobenzonitrile (Compound (37)) was carried out in a similar manner as in Example 11.10, but starting from cis-3-((S)-2-((3-amino)cyclobutane-1- carbonyl)isoxazolidin-3-yl)-5-fluorobenzonitrile. Example 12: Synthesis of Compounds (45), (46), (47), (54), (55), (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)isoxazolidin-2-yl]-[trans-4- (hydroxymethyl)cyclohexyl]methanone

[0291] To a stirred solution of trans-4-(hydroxymethyl)cyclohexane-l -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) was added HATU (3.17 g, 8.34 mmol) at rt. Stirring was continued at rt for 2 h. The reaction mixture was diluted with water and the aqueous layer was extracted with EA. The combined organic layers were washed with 0.1 N aq. NaOH and 0.1 N aq. HC1, dried over Na2S04, filtered and concentrated to give the crude title compound which was purified by column chromatography (Si02; EA / heptane gradient) (1.75 g, 5.38 mmol, 77% yield). Step 2a: Synthesis of trans-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- yl) cyclohexyl)methoxy)pyrimidine-4-carbonitrile (compound (45)) and trans-(4-(((6- chloropyrimidin-4-yl)oxy)methyl)cyclohexyl)((S)-3-(3,5-difluorophenyl)isoxazolidin-2- yl)methanone (46) - Route SM4 of Scheme 4

[0292] To a stirred solution of 6-chloropyrimidine-4-carbonitrile (44 mg, 307 pmol) and [(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[trans-4-(hydroxymethyl)cyclohexyl]methanone (100 mg, 307 pmol) in THF (1.2 ml) was added KotBu (41 mg, 368 pmol) at 0 °C. The solution was stirred at 0 °C for 1.5 h. Water was added at 0 °C and the aqueous layer was extracted with EA. The combined organic layers were dried over Na2S04, filtered and concentrated to give the crude title compound which was subjected to preparative reverse phase HPLC.

[0293] Step 2b: trans-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- ylcarbonyl)cyclohexyl)methoxy)pyrimidine-4-carboxamide (Compound (47)), cis-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclohexyl)methoxy)pyrimidine-4-carboxamide (Compound (54)), cis-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclohexyl)methoxy)pyrimidine-4-carbonitrile (Compound (55)), and cis-(4-(((6-chloropyrimidin-4-yl)oxy)methyl)cyclohexyl)((S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)methanone (Compound (56)) were synthesized analogously as detailed in Step 2a of Example 12.1 for Compounds (45) and (46), but starting from 6-chloro-pyrimidine-4-carboxamide (47), (54), 6-chloro-pyrimidine-4-carbonitrile (55), and 4,6-dichloropyrimidine (56)

[0294] Step 2c: Synthesis of 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-dimethyloxazolidine-2,4-dione (Compound (59)), trans-1-(4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidine- 2-carbonyl)cyclohexyl)methoxy)phenyl)pyrrolidin-2-one (Compound (60)), trans- ((S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)(4-((4-(3,5-dimethyl-1H-pyrazol-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-methylimidazolidine-2,4-dione (Compound (63)), trans-((S)-3-(3,5-in a similar manner as detailed in step 2a of example 1, but starting from 5-chloro-2- fluorobenzonitrile (43), 3-chloro-5-fluorobenzonitrile (48), (3,4-dichlorophenyl)-5,5- dimethyloxazolidine-2,4-dione (57), l-(3,4-dichlorophenyl)pyrrolidine-2,5-dione (58), 3- (3-chloro-4-fluorophenyl)-5,5-dimethyloxazolidine-2,4-dione (59), l-(3,4-dichlorophenyl) pyrrolidin-2-one (60), 4-(3,5-dimethyl-lH-pyrazol-l-yl)-2-fluoro-chlorophenyl (62), (4- ((5-(3,5-dimethyl-4H-l,2,4-triazol-4-yl)-2-fluoro-chlorophenyl (64), 3-chlorobenzenesulfonamide (66), 4-(3,5-dimethyl-4H-l,2,4-triazol-4-yl)-2-fluoro-chlorophenyl (67) and l-(4- chloro-3-fluorophenyl)-3-methyl-l,3-dihydro-2H-imidazol-2-one (68). Example 12.2: Synthesis of compounds (61), (65)

[0295] Step 1: Synthesis of [(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-(cis-3- hydroxycyclobutyl)methanone was performed in a similar manner as detailed in step 1 of example 12.1, but starting from (3S)-3-(3,5-difluorophenyl)isoxazolidine Step 2a: Synthesis of cis-3-(3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- ylcarbonyl)cyclobutoxy)-5-fluorobenzonitrile (compound (61)) - Route SM3 of Scheme 4

[0296] To a stirred solution of [(3S)-trans-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-(3- hydroxycyclobutyl)methanone (50 mg, 177 pmol), PPh3 (56 mg, 212 pmol) and 3- fluoro-5-hydroxybenzonitrile (24.2 mg, 177 pmol) in THF (1 ml) at room temperature was added a 1 M solution of DIAD (212 pi, 212 pmol) in THF and stirring was continued at room temperature for 2 h. An additional 0.6 equivalent of a 1 M solution of DIAD in THF was added followed by stirring at room temperature for 1.5 h. The volatile components were removed under reduced pressure, the resulting residue was dissolved in DMF, filtered and subjected to preparative reverse phase HPLC to give 41 mg (102 pmol, 58% yield) of the title compound.

[0297] Step 2b: Synthesis of cis-5-(3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- ylcarbonyl)cyclobutoxy)-2-fluorobenzonitrile (Compound (65)) was performed in a similar manner as detailed in Step 2a of Example 12.2, but starting from 2-fluoro-5- hydroxybenzonitrile. Example 12.3: Synthesis of compounds (44), (49), (76), (77), (78), (79), (80), (91)

[0298] Step 1: Synthesis of 3-fluoro-5-[(3S)-2-[trans-4-(hydroxymethyl)cyclohexanecarbonyl] isoxazolidin-3-yl]benzonitrile was performed in a similar manner as detailed in Step 1 of Example 12.1, but starting from (3S)-3-(3-cyano-5-fluorophenyl)isoxazolidine

[0299] Step 2: The synthesis of trans-5-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidine-2- carboxylate)cyclohexyl)methoxy)-2-fluorobenzonitrile (Compound (44)), trans-3-((S)-2-(4- ((3-cyano-5-fluorophenoxy)methyl)cyclohexane-l-carbonyl)isoxazolidin-3-yl)-5- fluorobenzonitrile (Compound (49)), trans-3-((S)-2-(4-((4-(3,5-dimethyl-lH-pyrazol-l-yl)- 2-fluorophenoxy)methyl)cyclohexane-l-carbonyl)isoxazolidin-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-2- oxo-2,3-dihydro-lH-imidazol-l-yl)phenoxy)methyl)cyclohexane-l-carbonyl)isoxazolidin-3- yl)benzonitrile (Compound (78)), trans-3-((S)-2-(4-((5-(5,5-dimethyl-2,4-dioxooxazolidin-3- yl)-2-fluorophenoxy)methyl)cyclohexane-l-carbonyl)isoxazolidin-3-yl)-5-fluorobenzonitrile (Compound (79)), trans-3-((S)-2-(4-((2-chloro-5-(3-methyl-2,5-dioxoimidazolidin-l- yl)phenoxy)methyl)cyclohexane-l-carbonyl)isoxazolidin-3-yl)-5-fluorobenzonitrile (Compound (80)), and trans-2-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cyclohexyl] methoxy]pyridine-4-carbonitrile (Compound (91)) were carried out in a similar manner as detailed in Step 2a of Example 12.2, starting from 5-chloro-2-fluorobenzonitrile (44), 3-chloro-5- fluorobenzonitrile ((49), (50), (76)), 3-chloro-benzenesulfonamide (77), 2-fluoro-4-(3-methyl-2- oxo-2,3-dihydro-lH-imidazol-l-yl)chlorobenzene (78), 4-(5,5-dimethyl-2,4-dioxooxazolidin-3- yl)-2-fluorochlorobenzene (79), -l,2-dichloro-5-(3-methyl-2,5-dioxoimidazolidin-l-yl)benzene (80), 2-chloropyridine-4-carbonitrile (91) Example 12.4: Synthesis of Compound (50), (51)

[0300] Step 1: Synthesis of [(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-(trans-3- hydroxycyclobutyl)methanone was performed in a similar manner as detailed in Step 1 of Example 12.1, but starting from (3S)-3-(3,5-difluorophenyl)isoxazolidine

[0301] Step 2: Synthesis of trans-3-(3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- yl)oxycyclobutyl)-5-fluorobenzonitrile (Compound (50)) and trans-5-(3-((S)-3-(3,5- difluorophenyl)isoxazolidin-2-yl)oxycyclobutyl)-2-fluorobenzonitrile (Compound (51)) was performed in a similar manner as detailed in Step 2a of Example 12.2, but starting from 3-chloro-5-fluorobenzonitrile and 5-chloro-2-fluorobenzonitrile, respectively Example 12.5: Synthesis of Compound (52), (53)

[0302] Step 1: Synthesis of [(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[cis-4- (hydroxymethyl)cyclohexyl]methanone was performed in a similar manner as detailed in Step 1 of Example 12.1, but starting from (3S)-3-(3,5-difluorophenyl)isoxazolidine

[0303] Step 2: Synthesis of cis-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- yl)cyclohexyl)methoxy)-5-fluorobenzonitrile (Compound (52)) and cis-3-((4-((S)-3- (3,5-difluorophenyl)isoxazolidin-2-yl)cyclohexyl)methoxy)-5-fluorobenzonitrile (Compound (53)) was performed in a similar manner as detailed in Step 2a of Example 12.2, but starting from 5-chloro-2-fluorobenzonitrile and 3-chloro-5-fluorobenzonitrile, respectively Example 12.6: Synthesis of Compound (81) and (82)

[0304] Step 1: Synthesis of 3-fluoro-5-[(3S)-2-[cis-4-(hydroxy)cyclohexanecarbonyl]isoxazolidin-3- yl]benzonitrile was performed in a similar manner as detailed in Step 1 of Example 12.1, but starting from (S)-3-(3-cyano-5-fluorophenyl)isoxazolidine

[0305] Step 2: Synthesis of cis-3-((S)-2-(4-(5-(5,5-dimethyl-2,4-dioxooxazolidin-3-yl)-2- fluoro phenyloxy)cyclohexane-1-carbonyl)isoxazolidin-3-yl)-5-fluorobenzonitrile (compound (81)) and cis-5-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)oxy)-2-fluorobenzonitrile (compound (82)) was carried out in a similar manner as detailed in step 2a of example 12.2, but starting from 5-(5,5-dimethyl-2,4- dioxooxazolidin-3-yl)-2-fluoro-chlorophenyl (81) and 5-chloro-2-fluorobenzonitrile Example 13: Biological activity Evaluation of receptor-interacting protein kinase 1 inhibition.

[0306] Catalytic activity of RIPK1 was measured by monitoring the conversion of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) resulting from autophosphorylation using the ADP-Glo kinase assay kit (Promega, cat. no. V9104).

[0307] In detail, 2 µl of recombinantly produced hRIPK1 (aa 1-375) fusion protein (final concentration 3.6 µg / ml) and 2 µl of compound (final concentration 33300 - 1.69 nM; final DMSO concentration 1%) were incubated for 30 min at room temperature and then 2 µl ATP (ADP Glo kit, final concentration 50 µM) were added. After an additional incubation period of 240 min at room temperature, 5 µl of ADP-Glo reagent I from Promega were added to quench the reaction and deplete the unspent ATP. After an incubation period of 30 min, 10 µl of ADP-Glo detection reagent II from Promega were added, resulting in a light reaction between luciferase and luciferin due to the conversion of ADP to ATP. After 30 min, luminescence was quantified with a Pherastar FS (BMG LABTECH, Ortenberg).

[0308] For the dose response experiments, IC 50 values with 95% confidence intervals were calculated according to Ratkowsky and Reedy using a 4-parameter logistic model with constraints of the lower and upper asymptote to 0% and 100%. Adjustments were obtained by non-linear regression using the Levenberg Marquardt algorithm. Cellular assays were performed in U937 cells to measure the activity of RIPK1 inhibitors on cell death (necroptosis).

[0309] Upon TNF-receptor I ligation, the Ser / Thr kinase RIPK1 is recruited to the transient receptor complex I. Modification of RIPK1 promotes activation of RIPK1, which can form complex Iib, involving recruitment of RIPK3 and MLKL (mixed lineage kinase domain-like protein), and then translocation from the cytoplasm to the plasma membrane to execute cell death (Cai, Z. et al., Nat. Cell Biol. (2014) 16:55-65).

[0310] Cell death in 96-well plates was quantified by determining the amount of viable cells using the CellTiter 96 Aqueous reagent (Promega), a calorimetric method for measuring the number of living cells by reduction of the tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; MTS] to formazan. The absorbance of formazan was read at 490 nm. Inhibition activity of test compounds was quantified in concentration response curve (CRC) experiments.

[0311] Compounds were obtained as 10 mM stock solutions and diluted with DMSO in 1 to 10 volumes to yield 1 mM solutions. 2 μΐ of this solution was diluted with 998 μΐ growth medium. A 100 μΐ solution of 2 μΜ compound was further serially diluted by adding 150 μΐ growth medium in 2.5 dilution steps. In total 10 concentrations were tested, ranging from 10 μΜ to 0.26 nM or from 1 μΜ to 0.07 nM.

[0312] U937 cells were cultured in RPMI1640 Glutamax and 10% heat inactivated FBS. 50 μΐ cell suspension containing 1 x 106cells / ml supplemented with 50 μΜ zVAD.fmk (benzyloxy carbonyl-Val-Ala-Asp(Ome) fluoromethyl ketone) and 100 ng / ml recombinant human TNFα were dispensed into each well of a 96-well plate. 50 μΐ of compound dilutions (described in cell assays in U937 cells) were added and the cell suspension was incubated overnight (18 to 24 h) at 37°C, 5% CO2, in a humidified atmosphere (95% rH). High control (no compound) and low control (no TNFα, zVAD.fmk) were tested in 7 replicates; all compound concentrations were tested in duplicate on each experimental plate.

[0313] CellTiter 96 Aqueous reagent mix (100 μΐ PMS (phenylmethane sulfonic acid) solution / 2 ml MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4- sulfophenyl)-2H-tetrazolium, inner salt) solution) was added and 20 μΐ per well. After 4 h incubation at 37 °C (5% CO2 95% rH), the optical density was measured at 490 nm on a microplate reader (Tecan Infinite M1000).

[0314] Inhibition is expressed as a percentage of the maximum inhibition obtained in the absence of TNFa / zVAD.fmc. IC 50 values with 95% confidence intervals were calculated for each dose response experiment using an in-house application (Biost-Speed LTS V2.3) using a 4 parameter logistic model according to Ratkowsky and Reedy (unconstrained).

[0315] Biological activity results are shown in Table 2 (ADP-Glo IC 50 (μΜ) and U937 IC 50 (μΜ)). Table 2: Activity data for all examples

[0316] All compounds according to the present disclosure are potent RIPK1 inhibitors as they exhibit reduced catalytic activity of RIPK1 highlighted by the ADP Glo assay with IC 50 values below 400 nM. Most compounds even exhibit IC 50 values below 200 nM. Advantageously, most compounds exhibit IC 50 values below 150 nM and even below 100 nM.

[0317] All compounds according to the present disclosure are potent RIPK1 inhibitors as they exhibit cell death (necroptosis) in U937 cells with IC 50 values below 1000 nM. Most compounds even exhibit IC 50 values below 500 nM and even below 200 nM. Advantageously, most compounds exhibit IC 50 values below 100 nM and even below or equal to 50 nM.

Claims

1. A compound of formula (I) ###0001### (I) wherein R1 represents phenyl or monocyclic heteroaryl, optionally substituted with one, two or three R3; (I) R2 represents aryl or heteroaryl, optionally substituted with one, two or three R6; each R3 is independently selected from halogen, cyano, (Ci-C4)alkyl or (Ci-C4)alkoxy; R4 and R5 are independently selected from halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, or R4 and R5 together form a (Ci-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-; each R6 is independently selected from halogen, cyano, -OH, (Ci-C4)-alkyl, -CF3, -C(O)NH2, -C(O)NH-(Ci-C4)-alkyl, -C(O)OH, -C(O)O-(Ci-C4)-alkyl, -SO2NH2, (Ci-C4)-alkoxy, -O-(Ci-C4)alkylene-(C3-C6)cycloalkyl, -O-(C3-C6)cycloalkyl, -O-(C3-C6)heterocycloalkyl, 5- or 6-membered heterocycloalkyl, monocyclic heteroaryl and oxo, wherein said (Ci-C4)alkyl, (Ci-C4)alkoxy, -O-(C3-C6)cycloalkyl, (Ci-C4)alkyl, 5- or 6-membered heterocycloalkyl or monocyclic heteroaryl is optionally substituted with one, two, three or four R7; each R7 is independently halogen, oxo, -OH, (Ci-C4)alkyl or (Ci-C4)alkoxy, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. R1 represents phenyl, thiazolyl, pyridinyl or pyrazinyl, optionally substituted with one or two groups independently selected from halogen, cyano, (Ci-C2)-alkyl or (Ci-C2)-alkoxy, in particular wherein R1 represents (i) phenyl substituted with one or two groups independently selected from halogen, cyano, (Ci-C2)-alkyl or (Ci-C2)-alkoxy, or (ii) monocyclic heteroaryl selected from thiazolyl, pyridinyl and pyrazinyl, said heteroaryl being optionally substituted with one or two groups independently selected from halogen, cyano, (Ci-C2)-alkyl or (Ci-C2)-alkoxy. ​ 2. The compound of claim 1, having formula (I), wherein, ​ 3. The compound of formula (I) as claimed in claim 1 or 2, wherein, R2represents phenyl, pyrimidinyl, pyridinyl, pyrrolopyrimidinyl, benzimidazolyl, indazolyl or indolyl, optionally substituted by one or two groups independently selected from halogen, cyano, (Ci-C2)-alkyl, -C(0)NH2, -C(0)0-(Ci-C2)-alkyl, -S02NH2, 5- or 6-membered heterocycloalkyl, in particular oxazolidinyl, pyrrolidinyl, imidazolinyl or dihydroimidazolyl, and 5-membered heteroaryl, in particular pyrazolyl or triazolyl, said 5- or 6-membered heterocycloalkyl and 5-membered heteroaryl being optionally substituted by one, two, three or four groups independently selected from (Ci-C2)alkyl and oxo.

4. The compound of any one of claims 1 to 3 of formula (I), wherein, Y is a bond or a bivalent radical selected from -NH-, -NH-CH2-, -0- and -0-CH2-, in particular a radical selected from -NH-, -NH-CH2-, and -0-CH2-.

5. The compound of any one of claims 1 to 4 of formula (I), wherein, R4and R5are independently selected from (Ci-C2)alkyl.

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

7. The compound of any one of claims 1 to 6 of formula (I), wherein, If p, q, r and t are 0, R4and R5do not form together a (Ci-C4)alkylene bridge.

8. The compound of formula (I) as claimed in any one of claims 1 to 7, having the following formula (la): (Ia) wherein: Y, R1, R2, R4, R5are as defined in any one of claims 1 to 5, in a further embodiment wherein: Y is -NH-, -0- or a bond; R1is phenyl or pyridinyl, optionally substituted by one or two R3; R2is phenyl, pyrimidinyl, indazolyl, indolyl or benzimidazolyl, optionally substituted by one or two R6; each R3is independently selected from halogen or cyano; m and s are independently 0 or 1 ; each R6is halogen, in particular fluorine, -C(0)NH2, cyano or -C(0)0-(Ci-C2)alkyl, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

9. The compound of formula (I) as claimed in any one of claims 1 to 7, having the following formula (lb): (Ib) wherein Y, R1, R2, R4, R5, m and s are as defined in any one of claims 1 to 5, in a further embodiment wherein: Y is a bond or -0-CH2-; R1is phenyl, optionally substituted by one or two R3; R2is pyridinyl or pyrimidinyl, optionally substituted by -C(0)NH2; each R3is independently selected from halogen or cyano; m and s are 0; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

10. The compound of formula (I) as claimed in any one of claims 1 to 7, having the following formula (Ic): (Ic) wherein Y, R1, R2, R4, R5, m and s are as defined in any one of claims 1 to 5, in a further embodiment wherein: Y is -NH-, -NH-CH2-, a bond, -0- or -0-CH2-; R1is phenyl, pyrazinyl, triazolyl or pyridinyl, optionally substituted with one or two R3; R2is pyridinyl, phenyl, pyrimidinyl, pyrrolopyrimidinyl, optionally substituted with one or two R6; each R3is independently selected from halogen, -CH3, -OCH3, or cyano; m and s are 0; each R6is independently selected from halogen, -C(O)NH2, cyano, (C1-C2)-alkyl, -SO2NH2, a 5-membered heterocycloalkyl selected from imidazolidinyl, dihydroimidazolyl, pyrrolidinyl and oxazolidinyl, or a 5-membered heteroaryl selected from pyrazolyl or triazolyl, said heterocycloalkyl and heteroaryl optionally substituted with one, two, three or four groups independently selected from (C1-C2)alkyl and oxo, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

11. The compound of Formula (I) as defined in any one of claims 1 to 7, having the following formula (Id): (Id) wherein R1, R2, R4, R5, m and s are as defined in any one of claims 1 to 5, and in another embodiment wherein: Y is -O-CH2-; R1is phenyl, pyrazinyl, triazolyl or pyridinyl, optionally substituted with one or two R3; R2is pyridinyl, phenyl, pyrimidinyl, pyrrolopyrimidinyl, optionally substituted with one or two R6; each R3is independently selected from halogen, -CH3, -OCH3, or cyano; m and s are 0; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

12. The compound of Formula (I) as defined in any one of claims 1 to 9, selected from: (1) cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclobutyl)amino)pyrimidine-4-carboxamide, (2) cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclobutyl)amino)pyrimidine-4-carbonitrile, (3) cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclobutyl)amino)pyrimidine-4-carboxylic acid methyl ester, (4) trans-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclobutyl)amino)pyrimidine-4-carboxamide, (5) cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carbonitrile, (6) cis-2-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxamide, (7) cis-2-((3-((S)-3-(5-cyanopyridin-3-yl)isoxazolidin-2-ylcarbonyl)-3-methylcyclobutyl)amino)pyrimidine-4-carboxamide, (8) cis-6-((3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)-3-methylcyclobutyl)amino)-5-fluoropyrimidine-4-carboxylic acid ethyl ester, (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]pyrimidin-4-yl)amino)methyl)cyclohexane-1-carbonyl)isoxazolidin-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-fluoropyridin-3-yl)isoxazolidine-2-carbonyl)cyclobutyl)amino)benzonitrile, (34) trans-2-fluoro-5-(((4-((S)-3-(5-fluoropyridin-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-fluoropyridin-3-yl)isoxazolidine-2-carbonyl)cyclobutyl)amino)benzonitrile, (37) cis-3-((S)-2-(3-((3-cyano-5-fluorophenyl)amino)cyclobutane-1-carbonyl)isoxazolidin-3-yl)-5- fluorobenzonitrile, (38) trans-3-((S)-2-(4-(((3-cyano-5-fluorophenyl)amino)methyl)cyclohexane-1-carbonyl)isoxazolidin-3-yl)-5-fluorobenzonitrile, (39) cis-3-((S)-2-(4-((3-cyano-5-fluorophenyl)amino)cyclohexane-1-carbonyl)isoxazolidin-3-yl)-5- fluorobenzonitrile, (40) cis-3-((S)-2-(3-(1H-benzo[d]imidazol-1-yl)cyclobutane-1-carbonyl)isoxazolidin-3-yl)-5- fluorobenzonitrile, (41) cis-(3-(1H-benzo[d]imidazol-1-yl)cyclobutyl)((S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)methanone, (42) cis-(3-(1H-benzo[d]imidazol-1-yl)cyclobutyl)((S)-3-(5-fluoropyridin-3-yl)isoxazolidin-2-yl)methanone, (43) trans-5-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclohexyl)methoxy)-2-fluorobenzonitrile, (44) trans-5-((4-((S)-3-(3-cyano-5-fluorophenyl)isoxazolidin-2-ylcarbonyl)cyclohexyl)methoxy)-2-fluorobenzonitrile, (45) trans-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclohexyl)methoxy)pyrimidine-4-carbonitrile, (46) trans-(4-(((6-chloropyrimidin-4-yl)oxy)methyl)cyclohexyl)((S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)methanone, (47) trans-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclohexyl)methoxy)pyrimidine-4-carboxamide, (48) trans-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclohexyl)methoxy)-5-fluorobenzonitrile, (49) trans-3-((S)-2-(4-((3-cyano-5-fluorophenoxy)methyl)cyclohexan-1-ylcarbonyl)isoxazolidin-3-yl)-5-fluorobenzonitrile, (50) trans-3-(3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclobutoxy)-5-fluorobenzonitrile, (51) trans-5-(3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclobutoxy)-2-fluorobenzonitrile, (52) cis-5-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclohexyl)methoxy)-2-fluorobenzonitrile, (53) cis-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclohexyl)methoxy)-5-fluorobenzonitrile, (54) cis-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclohexyl)methoxy)pyrimidine-4-carboxamide, (55) cis-6-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclohexyl)methoxy)pyrimidine-4-carbonitrile, (56) cis-(4-(((6-chloropyrimidin-4-yl)oxy)methyl)cyclohexyl)((S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)methanone, (57) trans-3-(4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-ylcarbonyl)cyclohexyl)methoxy)phenyl)-5,5-dimethyloxazolidine-2,4-dione, (58) Trans-1-(4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2- carbonyl)cyclohexyl)methoxy)phenyl)pyrrolidine-2,5-dione, (59) Trans-3-(3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-carbonyl)cyclohexyl)methoxy)-4- fluorophenyl)-5,5-dimethylisoxazolidine-2,4-dione, (60) Trans-1-(4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-carbonyl)cyclohexyl)methoxy) phenyl)pyrrolidin-2-one, (61) Cis-3-(3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-carbonyl)cyclobutoxy)-5-fluorobenzonitrile, (62) Trans-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)(4-((4-(3,5-dimethyl-1H-pyrazol-1-yl)-2- fluorophenoxy)methyl)cyclohexyl)methanone, (63) Trans-3-(4-chloro-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-carbonyl)cyclohexyl)methoxy) phenyl)-1-methylimidazolidine-2,4-dione, (64) Trans-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)(4-((5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-2- fluorophenoxy)methyl)cyclohexyl)methanone, (65) Cis-5-(3-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-carbonyl)cyclobutoxy)-2-fluorobenzonitrile, (66) Trans-3-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-carbonyl)cyclohexyl)methoxy)benzenesulfonamide, (67) Trans-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)(4-((4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-2- fluorophenoxy)methyl)cyclohexyl)methanone, (68) Trans-1-(4-((4-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-carbonyl)cyclohexyl)methoxy)-3- fluorophenyl)-3-methyl-1,3-dihydro-2H-imidazol-2-one, (69) Cis-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)(3-(5-fluoro-1H-benzo[d]imidazol-1-yl)cyclobutyl) methanone, (70) Cis-3-fluoro-5-((S)-2-(3-(5-fluoro-1H-benzo[d]imidazol-1-yl)cyclobutane-1-carbonyl)isoxazolidin-3- yl)benzonitrile, (71) Trans-5-((S)-2-(4-((3-cyanophenoxy)methyl)cyclohexane-1-carbonyl)isoxazolidin-3-yl)nicotinonitrile, (72) Trans-5-((S)-2-(4-((3-cyano-4-fluorophenoxy)methyl)cyclohexane-l- carbonyl)isoxazolidin-3-yl)nicotinonitrile, (73) Trans-3-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)benzamide, (74) Trans-5-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)-2- fluorobenzamide, (75) Trans-2-chloro-5-((4-((S)-3-(5-cyanopyridin-3-yl)isoxazolidine-2-carbonyl)cyclohexyl)methoxy)benzamide, (76) Trans-3-((S)-2-(4-((4-(3,5-dimethyl-lH-pyrazol-l-yl)-2-fluorophenoxy)methyl)cyclohexane-l- carbonyl)isoxazolidin-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-lH-imidazol-l- yl)phenoxy)methyl)cyclohexane-l-carbonyl)isoxazolidin-3-yl)benzonitrile, (79) Trans-3-((S)-2-(4-((5-(5,5-dimethyl-2,4-dioxooxazolidin-3-yl)-2-fluorophenoxy)methyl)cyclohexane-l- carbonyl)isoxazolidin-3-yl)-5-fluorobenzonitrile, (80) Trans-3-((S)-2-(4-((2-chloro-5-(3-methyl-2,5-dioxoimidazolidin-l-yl)phenoxy)methyl)cyclohexane-l- carbonyl)isoxazolidin-3-yl)-5-fluorobenzonitrile, (81) Cis-3-((S)-2-(4-(5-(5,5-dimethyl-2,4-dioxooxazolidin-3-yl)-2-fluorophenoxy)cyclohexane-l- carbonyl)isoxazolidin-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-l-carbonyl)isoxazolidin-3- yl)nicotinonitrile, (84) Trans-(3-(5-fluoro-lH-benzo[d]imidazol-l-yl)cyclobutyl)((S)-3-(3-fluorophenyl)isoxazolidin-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)isoxazolidin-2-carbonyl)cyclohexyl)methoxy)-2-methylbenzamide, (87) Cis-((S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl)(3-(6-fluoro-1H-benzo[d]imidazol-1- yl)cyclobutyl)methanone, (88) Trans-5-((S)-2-(4-((2-chloro-5-(3-methyl-2,5-dioxoimidazolidin-1-yl)phenoxy)methyl)cyclohexane-1- carbonyl)isoxazolidin-3-yl)nicotinonitrile, (89) Trans-5-((S)-2-(4-((2-fluoro-4-(3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)phenoxy)methyl)cyclohexane-1- carbonyl)isoxazolidin-3-yl)nicotinonitrile, (90) Trans-5-((S)-2-(4-((4-(3,5-dimethyl-1H-pyrazol-1-yl)-2-fluorophenoxy)methyl)cyclohexane-1- carbonyl)isoxazolidin-3-yl)nicotinonitrile, (91) Trans-2-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidin-2-carbonyl]cyclohexyl]methoxy]pyridine-4- carbonitrile, (92) Trans-5-((S)-2-(4-((5-(5,5-dimethyl-2,4-dioxooxazolidin-3-yl)-2-fluorophenoxy)methyl)cyclohexane-1- carbonyl)isoxazolidin-3-yl)nicotinonitrile, (93) Trans-4-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidin-2-carbonyl]cyclohexyl]methoxy]pyridine-2- carbonitrile, (94) Trans-5-((S)-2-(4-(((4-cyanopyridin-2-yl)oxy)methyl)cyclohexane-1-carbonyl)isoxazolidin-3-yl)nicotinonitrile, (95) Trans-5-((S)-2-(4-(((5-cyanopyridin-2-yl)oxy)methyl)cyclohexane-1-carbonyl)isoxazolidin-3-yl)nicotinonitrile, (96) Cis-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[3-(5-fluoroindazol-1-yl)cyclobutyl]methanone, (97) Trans-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[3-(5-fluoroindazol-1-yl)cyclobutyl]methanone, (98) Trans-3-fluoro-5-[(3S)-2-[3-(5-fluoroindazol-1-yl)cyclobutane carbonyl]isoxazolidin-3-yl]benzamide, (99) Trans-6-[[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidin-2-carbonyl]cyclohexyl]methoxy]pyridine-3- carboxamide, (100) Trans-3-[[4-[(3S)-3-pyrazin-2-ylisoxazolidin-2-carbonyl]cyclohexyl]methoxy]benzamide, (101) Trans-2-fluoro-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, (102) Trans-6-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]pyridine-3-carboxamide, (103) Trans-6-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]pyridine-3-carbonitrile, (104) Trans-3-fluoro-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzonitrile, (105) Trans-3-fluoro-5-[(3S)-2-[3-(5-fluoroindol-1-yl)cyclobutane-carbonyl]isoxazolidin-3-yl]benzonitrile, (106) Trans-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[3-(5-fluoroindol-1-yl)cyclobutyl]methanone, (107) Cis-3-fluoro-5-[(3S)-2-[3-(5-fluoroindol-1-yl)cyclobutane-carbonyl]isoxazolidin-3-yl]benzonitrile, (108) Cis-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[3-(5-fluoroindol-1-yl)cyclobutyl]methanone, (109) Cis-3-fluoro-5-[(3S)-2-[3-(5-fluoroindazol-2-yl)cyclobutane-carbonyl]isoxazolidin-3-yl]benzonitrile, (110) Cis-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[3-(5-fluoroindazol-2-yl)cyclobutyl]methanone, (111) Trans-4-fluoro-3-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, (112) Trans-3-fluoro-5-[[4-[(3S)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, (113) Trans-3-fluoro-4-[[4-[(3S)-3-pyrazin-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-fluoro-phenyl)isoxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide, (116) Trans-6-[[3-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cyclopentyl]methoxy]pyrimidine-4-carboxamide stereoisomer 2, (117) Trans-6-[[3-[(3S)-3-(3-cyano-5-fluoro-phenyl)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-fluoro-phenyl)isoxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide stereoisomer 1, (127) Trans-6-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide stereoisomer 2, (128) Cis-6-[[4-[(3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carbonyl]cycloheptyl]methoxy]pyrimidine-4-carboxamide, (129) Trans-3-[[4-[(3S)-3-(6-methoxypyrazin-2-yl)isoxazolidine-2-carbonyl]cyclohexyl]methoxy]benzamide, (130) Trans-3-[[4-[(3S)-3-(2-methylthiazol-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.

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

14. A medicament comprising a compound of Formula (I) or a compound of claim 12, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11.

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

16. A compound of Formula (I) or a compound of claim 12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, as claimed in any one of claims 1 to 11, for use in the treatment and / or prevention of a disease, disorder, or condition mediated at least in part by receptor-interacting protein kinase 1.

17. A compound of Formula (I) or a compound of claim 12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, as claimed in any one of claims 1 to 11, 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).

Images