Isoxazolidine and its use as a RIPKI inhibitor

Abstract

The present invention relates to isoxazolidines of formula I and their use as receptor-interacting protein kinase I inhibitors in the treatment of diseases and disorders mediated by RIP kinase (I), such as, for example, rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease (IBD), Crohn's disease, or ulcerative colitis. [Formula 1] TIFF2023527580000438.tif42104

Description

[Background technology]

[0001] While inflammation can be a defense mechanism in response to harmful stimuli such as pathogen invasion and tissue damage, chronic inflammation is a crucial underlying factor in numerous human diseases, including neurodegeneration, rheumatoid arthritis, autoimmune and inflammatory diseases, and cancer. Similarly, the activation of cell death pathways such as necrosis and apoptosis, which are useful in eliminating infected or damaged cells, is also a crucial underlying mechanism for 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 a vital role in modulating the inflammatory response mediated by the nuclear factor kappa light chain enhancer (NF-κB) of activated B cells. More recent studies have shown that the kinase activity of receptor-interacting protein kinase 1 regulates necroptosis, a form of necrotizing cell death that was previously thought to be passive and unregulated, and which is characterized by specific morphologies. Furthermore, one receptor-interacting protein kinase is part of a pro-apoptotic complex that exhibits activity in regulating apoptosis.

[0002] Receptor-interacting protein kinase 1 undergoes complex and intricate regulatory mechanisms, including ubiquitination, deubiquitination, and phosphorylation. These regulatory events collectively determine whether cells survive and activate an inflammatory response, or die through apoptosis or necroptosis. Dysregulation of receptor-interacting protein kinase 1 signaling can lead to excessive inflammation or cell death; conversely, studies have shown that inhibition of receptor-interacting protein kinase 1 may be an effective treatment for diseases involving inflammation or cell death.

[0003] RIPK1 inhibition has been identified as a promising principle for addressing a variety of diseases, including rheumatoid arthritis (RA), psoriasis, multiple sclerosis, Alzheimer's disease, and inflammatory bowel disease, such as Crohn's disease or ulcerative colitis (UC). Access to the central nervous system (CNS) is required to treat some of these diseases, such as multiple sclerosis (MS) and Alzheimer's disease, while access to the CNS is substantially unnecessary for other diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD), such as Crohn's disease or UC.

[0004] The most advanced RIPK1 inhibitor, GSK2982772 (an oxazepinone derivative disclosed in Patent Document 1), has been evaluated in Phase II clinical trials for rheumatoid arthritis (RA), psoriasis, and ulcerative colitis (UC). Interestingly, central nervous system side effects, such as irregular gait and clumsy movements, were reported at doses of ≥100 mg / kg during toxicological evaluations of GSK2982772 in monkeys (GSK2982772; Non-Patent Document 1).

[0005] [1-(6-methoxypyrimidine-4-yl)-4-piperidyl]-[(3S)-3-(3,5-difluorophenyl)isoxazolidine-2-yl]methanone (comparative compound K, see Examples section) is cerebral permeable and is an analogue close to the isoxazolidine derivatives claimed in Patent Documents 2 and 3. When applied to cynomolgus monkeys (1 mg / kg, iv), severe side effects (decreased activity, followed by pressure ulcers, decreased responsiveness, stiffness of the limbs, and hypotonia with a debilitating phase) were observed. Histopathological examination revealed bilateral and symmetrical lesions of cerebral necrosis (i.e., malacia) located in the basal ganglia (globus pallidus) and hypothalamic regions, consisting of nerve necrosis, cavernous state, cellular infiltration occupied by macrophage populations, and reactive capillary angiogenesis.

[0006] Regarding the comparative compound K, which is an isoxazolidine derivative, as mentioned above, it showed severe CNS-related side effects in monkeys, specifically at 68 Å. 2The cause was TPSA. In mice 15 minutes after application of iv3 mg / kg, a brain / blood ratio of 2.1 and a brain level of 1.58 μg / ml were observed, confirming good brain permeability with this type of compound. Two hours after oral application of 30 mg / kg to mice, a brain / plasma ratio of 1.6 was determined.

[0007] Therefore, in order to avoid possible CNS-related side effects, the present invention relates to RIPK1 inhibitor compounds with a low ability to cross the blood-brain barrier. The literature describes several compound properties that are associated with low blood-brain barrier permeability, such as topological polar surface area (TPSA) and the number of hydrogen bond donors (HBDs) (Non-Patent Literature 2). >75Å 2 Molecules possessing TPSA are thought to have impaired penetration into the brain.

[0008] Various RIPK1 inhibitors have already been described (for example, Patent Document 1 (GSK298772), Patent Document 4 (GSK963), Patent Document 5 (GSK), Patent Document 6 (GSK, piperidyl dihydropyrazole)).

[0009] Denali also discloses benzoxapine derivatives in Patent Documents 7 and 8. Other chemical classifications of RIPK1 inhibitors include bicyclic sulfones and sulfoxides (Patent Document 9, Roche), heterocyclic compounds (Patent Document 10, Takeda), and other benzoxazepinones (Patent Document 11, Genetech).

[0010] Interestingly, Patent Documents 12 (Zhang), 13 (Denali), 3 (Ningbo), and 2 (GSK, Ref. D) also relate to isoxazolidine derivatives as RIPK1 inhibitors, such as Example 4 of Patent Document 2 (Comparative Compound D), which has a maximum range of 102 Å. 2 A compound having a TPSA of 75 Å is described. 2While far exceeding that, it surprisingly still shows good brain penetration (brain / plasma ratio of 1.1 (2 hours after oral administration of 30 mg / kg in mice)). Therefore, TPSA penetrates approximately / up to 100 Å. 2 With respect to the compounds described in these applications having [the specified characteristic], at least reasonable CNS penetration can be expected.

[0011] To increase the likelihood of obtaining reduced brain levels, the present invention relates to TPSA > 90 Å. 2 Preferably >105Å 2 , most preferably >120Å 2 This relates to novel isoxazolidine derivatives as RIPK1 inhibitors possessing the following properties.

[0012] To obtain compounds that only insufficiently penetrate the CNS, polar heterocycles were implemented in a so-called deep pocket 1 (DP1). In the literature (Non-Patent Literature 3), the heterocycle substitution of extremely potent unsubstituted or halogen-substituted phenyl derivatives in DP1 with 2-,3- or 4-pyridyl, pyrazole-3-yl, imidazole-4-yl, or 4-oxazolyl derivatives resulted in a significant decrease in enzyme and cellular activity. [Prior art documents] [Patent Documents]

[0013] [Patent Document 1] WO2014 / 125444 [Patent Document 2] WO2019130230 [Patent Document 3] WO2020043173 [Patent Document 4] WO2016 / 185423 [Patent Document 5] WO2016027253 [Patent Document 6] WO2018 / 092089 [Patent Document 7] WO2017136727

Patent Document 8

Patent Document 9

Patent Document 10

Patent Document 11

Patent Document 12

Patent Document 13

Non-Patent Document

[0014]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0015] Surprisingly, the inventors were able to identify a compound having a heterocyclic group in DP1, which showed excellent potency in the enzyme ADP - glo and cell U937 assays, and had a TPSA > 90 Å 2 and showed no CNS - related side effects in monkeys.

Means for Solving the Problems

[0016] The present invention relates to a compound of formula I:

Chemical Formula

[0017] In another embodiment, a method for producing compounds and their intermediates is provided.

[0018] In related embodiments, pharmaceutical compositions comprising compounds described herein and pharmaceutically acceptable additives are provided herein.

[0019] In another embodiment, a method for inhibiting receptor-interacting protein kinase 1 is provided herein. Further provided is a method for treating a disease or disorder mediated by receptor-interacting protein kinase 1, comprising the step of administering a therapeutically effective amount of the compound or a pharmaceutical composition described herein to a subject requiring such treatment. The disclosure also provides the use of the compound or a composition thereof in the manufacture of a pharmaceutical for treating a disease, disorder or condition mediated by (or at least partially mediated by receptor-interacting protein kinase 1). [Modes for carrying out the invention]

[0020] definition As used herein, the term “alkyl” refers to a linear or branched saturated aliphatic radical having the specified number of carbon atoms, either by itself or as part of another substituent. 1~2 , C 1~3 , C 1~4 , C 1~5 , C 1~6 , C 1~7 , C 1~8 , C 1~9 , C 1~10 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 3~4 , C 3~5 , C 3~6 , C 4~5 , C 4~6 and C 5~6 Alkyl groups can contain any number of carbon atoms, such as (C1-4) alkyl groups, but are not limited to these. For example, alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. Alkyl groups can also refer to alkyl groups having up to 20 carbon atoms, such as, but are not limited to these, heptyl, octyl, nonyl, and decyl. Alkyl groups can be substituted or unsubstituted.

[0021] As used herein, the term "alkoxy" means a group having the formula -OR, either by itself or as part of another substituent, where R is alkyl.

[0022] As used herein, the term "cycloalkyl" means a saturated or partially unsaturated monocyclic, fused bicyclic, or bridging polycyclic ring assembly containing 3 to 12 ring atoms, or the number of atoms indicated, either by itself or as part of another substituent.

[0023] Cycloalkyl is C 3~6 , C 4~6 , C 5~6 , C 3~8 , C4~8 , C 5~8 , C 6~8 , C 3~9 , C 3~10 , C 3~11 and C 3~12 It can contain any number of carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups are partially unsaturated and have one or more double or triple bonds in the ring. Representative partially unsaturated cycloalkyl groups, but not limited to these, include cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and norbornadiene. 3~8 In the case of cycloalkyl groups, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0024] Cycloalkyls, saturated monocyclic C 3~6 In the case of cycloalkyl groups, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups may be substituted or unsubstituted.

[0025] As used herein, the term “heteroalkyl” refers to an alkyl group of any preferred length, either by itself or as part of another substituent, having one to three heteroatoms such as N, O, and S, provided that the substituents are bonded to carbon atoms. For example, heteroalkyls may include ethers, thioethers, and alkylamines. Heteroatoms can be oxidized to form moieties such as, but not limited to, -S(O)- and -S(O)2-. The heteroatomic moieties of a heteroalkyl can replace hydrogen atoms of the alkyl group to form a hydroxyl group, a thio group, or an amino group. Alternatively, the heteroatomic moieties may be inserted between two carbon atoms.

[0026] As used herein, the term “alkenyl” means a straight-chain or branched hydrocarbon having at least two carbon atoms and at least one double bond, either by itself or as part of another substituent. Alkenyls are C2, C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 2~7 , C 2~8 , C 2~9 , C 2~10 , C3, C 3~4 , C 3~5 , C 3~6 , C4, C 4~5 , C 4~6 , C5, C 5~6Alkenyl groups can contain any number of carbon atoms, such as C6. Alkenyl groups can have a preferred number of double bonds, including, but are not limited to, one, two, three, four, five, or more double bonds. Examples of alkenyl groups include, but are not limited to, vinyl(ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexadienyl. Alkenyl groups can be substituted or unsubstituted.

[0027] As used herein, the term "alkynyl" refers to either a linear or branched hydrocarbon having at least two carbon atoms and at least one triple bond, either by itself or as part of another substituent. Alkynnyl is C2, C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 2~7 , C 2~8 , C 2~9 , C 2~10 , C3, C 3~4 , C 3~5 , C 3~6 , C4, C 4~5 , C 4~6 , C5, C 5~6Alkynyl groups can contain any number of carbon atoms, such as C6. Examples of alkynyl groups, but not limited to these, include acetylenyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, sec-butynyl, butadiinyl, 1-pentynyl, 2-pentynyl, isopentinyl, 1,3-pentadinyl, 1,4-pentadinyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadinyl, 1,4-hexadinyl, 1,5-hexadinyl, 2,4-hexadinyl, or 1,3,5-hexadinyl. Alkynyl groups can be substituted or unsubstituted. Unless otherwise specified, a "substituted alkynyl" group is substituted with one or more of the halo, hydroxyl, amino, alkylamino, amide, acyl, nitro, cyano, and / or alkoxy groups.

[0028] As used herein, the terms “halo” and “halogen” refer to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, either by themselves or as part of another substituent.

[0029] As used herein, the term “haloalkyl” refers to an alkyl group in which some or all of its hydrogen atoms are replaced by halogen atoms, either by themselves or as part of another substituent. With respect to alkyl groups, haloalkyl groups are C 1~6 They can have any suitable number of carbon atoms, such as . For example, haloalkyls include trifluoromethyl and fluoromethyl. In some cases, the term “perfluoro” can be used to define a compound or radical in which all hydrogen atoms are replaced by fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0030] As used herein, the term “aryl” refers to an aromatic ring system having any preferred number of carbon ring atoms and any preferred number of rings, either by itself or as part of another substituent. The aryl group is C6, C7, C8, C9, C 10 , C 11 , C12 , C 13 , C 14 , C 15 or C 16 , and C 5~7 , C 5~10 , C 6~10 , C 6~12 or C 6~14 can include any suitable number of carbocyclic atoms such as those of C. The aryl group can be monocyclic, can form a fused bicyclic group (e.g., benzocyclohexyl) or a tricyclic group, or can be linked by bonds to form a biaryl group. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl having a methylene linking group. Some aryl groups have 6 to 12 ring members such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6 to 10 ring members such as phenyl or naphthyl. Some other aryl groups have 6 ring members such as phenyl. The aryl group can be substituted or unsubstituted. Unless otherwise specified, a "substituted aryl" group is substituted by one or more of halo, hydroxy, amino, alkylamino, amide, acyl, nitro, cyano, and / or alkoxy groups.

[0031] As used herein, the term "heteroaryl" refers to a monocyclic, or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, either by itself or as part of another substituent, wherein 1 to 5 of the ring atoms are heteroatoms such as N, O, or S.

[0032] The heteroatoms can be oxidized to form moieties such as, but not limited to, -S(O)- and -S(O)2-. The heteroaryl group is C 5~6 , C 3~8 , C 4~8 , C 5~7 , C 5~8 , C 6~8 , C 3~9 , C 3~10 , C 3~11 , C5~10 or C 3~12 and may contain any number of ring atoms such as, in which case at least one of the carbon atoms is replaced by a heteroatom. The heteroaryl group contains any suitable number of heteroatoms such as 1, 2, 3, 4; or 5, or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4 or 3-5.

[0033] For example, the heteroaryl group is C in which 1-4 carbocyclic atoms are replaced by heteroatoms 5~8 heteroaryl; C in which 1-3 carbocyclic atoms are replaced by heteroatoms 5~8 heteroaryl; or C in which 1-4 carbocyclic atoms are replaced by heteroatoms 5~6 heteroaryl; or C in which 1-3 carbocyclic atoms are replaced by heteroatoms 5~6Heteroaryl groups can be heteroaryl. Heteroaryl groups can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups can also condense to aromatic ring systems such as phenyl rings to form members including, but are not limited to, benzopyrrole such as indole and isoindole, benzopyridine such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazine such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by bonds such as bipyridine. Heteroaryl groups can be substituted or unsubstituted. Heteroaryl groups can be linked at any position on the ring.For example, pyrrole contains 1-, 2-, and 3-pyrrole; pyridine contains 2-, 3-, and 4-pyridine; imidazole contains 1-, 2-, 4-, and 5-imidazole; pyrazole contains 1-, 3-, 4-, and 5-pyrazole; triazole contains 1-, 4-, and 5-triazole; tetrazole contains 1- and 5-tetrazole; pyrimidine contains 2-, 4-, 5-, and 6-pyrimidine; pyridazine contains 3- and 4-pyridazine; 1,2,3-triazine contains 4- and 5-triazine; 1,2,4-triazine contains 3-, 5-, and 6-triazine; 1,3,5-triazine contains 2-triazine; thiophene contains 2- and 3-thiophene; and furan contains 2- and 3-furan. These include thiazoles containing 2-, 4-, and 5-thiazoles, isothiazoles containing 3-, 4-, and 5-isothiazoles, oxazoles containing 2-, 4-, and 5-oxazoles, isoxazoles containing 3-, 4-, and 5-isoxazoles, indoles containing 1-, 2-, and 3-indoles, isoindoles containing 1- and 2-isoindoles, quinolines containing 2-, 3-, and 4-quinolines, isoquinolines containing 1-, 3-, and 4-isoquinolines, quinazolines containing 2- and 4-quinoazolines, sinnolines containing 3- and 4-sinnolines, benzothiophenes containing 2- and 3-benzothiophenes, and benzofurans containing 2- and 3-benzofurans.

[0034] Some heteroaryl groups include those having 5 to 10 ring members and 1 to 3 ring atoms, including N, O, or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include those with 5 to 8 ring members and 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Some other heteroaryl groups include those with 9 to 12 ring members and 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran, and bipyridine. Other heteroaryl groups include those with 5-6 ring members and 1-2 ring atoms, including N, O, or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.

[0035] Some heteroaryl groups contain only 5 to 10 ring members and a nitrogen heteroatom, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, and cinnoline. Other heteroaryl groups contain only 5 to 10 ring members and an oxygen heteroatom, such as furan and benzofuran. Some other heteroaryl groups contain only 5 to 10 ring members and a sulfur heteroatom, such as thiophene and benzothiophene. Furthermore, other heteroaryl groups include imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine, and cinnoline, which contain 5 to 10 ring members and at least 2 heteroatoms.

[0036] As used herein, the term “heterocyclyl” refers to a saturated ring system having 3 to 12 ring members, and 1 to 4 heteroatoms consisting of N, O, and S, either by itself or as part of another substituent. The heteroatoms can be oxidized to form moieties such as, but are not limited to, -S(O)- and -S(O)2-. The heterocyclyl group is C 3~6 , C 4~6 , C 5~6 , C 3~8 , C 4~8 , C 5~8 , C 6~8 , C 3~9 , C 3~10 , C 3~11 or C 3~12It can contain any number of ring atoms, in which case at least one of the carbon atoms is replaced by a heteroatom. In the heterocyclyl group, any preferred number of carbon ring atoms, such as 1, 2, 3 or 4, or 1-2, 1-3, 1-4, 2-3, 2-4, or 3-4, are replaced by heteroatoms. Heterocyclyl groups can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thiethane, thiolane (tetrahydrothiophene), thian (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocyclyl groups can also condense to aromatic or non-aromatic ring systems to form members containing indoline, but are not limited to these. Heterocyclyl groups can be unsubstituted or substituted. Unless otherwise specified, a "substituted heterocyclyl" group is substituted with one or more of the following: halo, hydroxyl, amino, oxo (=O), alkylamino, amide, acyl, nitro, cyano, and / or alkoxy.

[0037] Heterocyclyl groups can be linked at any position on the ring. For example, aziridine can be 1- or 2-aziridine, azetidine can be 1- or 2-azetidine, pyrrolidine can be 1-, 2- or 3-pyrrolidine, piperidine can be 1-, 2-, 3- or 4-piperidine, pyrazolidine can be 1-, 2-, 3- or 4-pyrazolidine, imidazolidine can be 1-, 2-, 3- or 4-imidazolidine, and piperazine can be 1-, 2-, 3- or 4-piperazine. Tetrahydrofuran can be 1- or 2-tetrahydrofuran, oxazolidine can be 2-, 3-, 4- or 5-oxazolidine, isoxazolidine can be 2-, 3-, 4- or 5-isoxazolidine, thiazolidine can be 2-, 3-, 4- or 5-thiazolidine, isothiazolidine can be 2-, 3-, 4- or 5-isothiazolidine, and morpholine can be 2-, 3- or 4-morpholine.

[0038] When a heterocyclyl contains 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. Heterocyclyls can also form rings having 5 to 6 ring members and 1 to 2 heteroatoms, with representative members including, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.

[0039] As used herein, the term “carbonyl” means, either by itself or as part of another substituent, a carbon atom double-bonded to oxygen, i.e., oxygen, and two other groups in the carbonyl moiety.

[0040] As used herein, the term "amino" refers to the -NR2 moiety, where each R group is either H or alkyl. The amino moiety can be ionized to form the corresponding ammonium cation.

[0041] "Dialkylamino" refers to the amino portion in which each R group is alkyl. In this specification, the term "hydroxy" refers to the -OH portion.

[0042] As used herein, the term "cyano" refers to the carbon atom that is triple-bonded to a nitrogen atom (i.e., the -C≡N portion).

[0043] As used herein, the term "carboxyl" refers to the -C(O)OH moiety. The carboxyl moiety can be ionized to form the corresponding carboxylate anion.

[0044] As used herein, the term "amide" refers to the -NRC(O)R or -C(O)NR2 moiety, where the R group is either H or -(C1-C4)alkyl, respectively.

[0045] As used herein, the term "nitro" refers to the -NO2 portion.

[0046] As used herein, the term "oxo" refers to an oxygen atom (i.e., O=) that is double-bonded to a compound. As used herein, the term "pharmaceutically acceptable excipient" refers to a substance that assists in the administration of an activator to a subject. "pharmaceutically acceptable" means that the excipient is compatible with the other components of the formulation and is not harmful to its recipient. Pharmaceutical excipients useful in this disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, flow enhancers, coatings, sweeteners, flavorings, and colorants.

[0047] As used herein, the term “salt” refers to an acid acid or base salt of a compound disclosed herein. Exemplary examples of pharmaceutically acceptable salts include inorganic acid salts, organic acid salts, and quaternary ammonium salts. A pharmaceutically acceptable salt is understood to be non-toxic.

[0048] The pharmaceutically acceptable salts of the acidic compounds disclosed herein are salts formed with bases, i.e., cationic salts such as alkali metal salts and alkaline earth metal salts.

[0049] Similarly, acid addition salts of inorganic acids, organic carboxylic acids, and organic sulfonic acids, such as hydrochloric acid, methanesulfonic acid, and maleic acid, are also possible, provided that a basic group such as pyridyl constitutes a structural part.

[0050] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound by conventional methods. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents; otherwise, the salt is equivalent to the parent form of the compound for the purposes of this disclosure. In addition to the salt forms, prodrug forms of the compound are described herein. The prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions that result in the compounds of this disclosure. Furthermore, the prodrugs can be converted to the compounds of this disclosure in an ex vivo environment by chemical or biochemical methods. For example, a prodrug is slowly converted to the compounds of this disclosure when placed in a transdermal patch leather bar containing a suitable enzyme or chemical reagent.

[0051] "Treatment" or "to treat" is an approach to obtain beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes may include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition, and / or reducing the severity of the disease or condition); b) delaying or suppressing the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis)); and / or c) alleviating the disease, i.e., resulting in regression of clinical symptoms (e.g., restoring the condition, achieving partial or complete remission of the disease or condition, enhancing the effects of another medicine, slowing the progression of the disease, increasing quality of life, and / or extending survival).

[0052] "Prevention" or "prevention" means any treatment of a disease or condition that results in the absence of clinical symptoms of the disease or condition. In some embodiments, the compound may be administered to subjects (including humans) who are at risk of developing the disease or condition or who have a family history of the disease or condition.

[0053] "Subject" refers to an animal, such as a mammal (including humans), that has been or will be the subject of treatment, observation, or experimentation. The methods described herein may be useful in the therapeutic and / or veterinary use of humans. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0054] For any compound described herein, or any pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, the terms “therapeutic effective dose” or “effective dose” mean an amount sufficient to accomplish the treatment and achieve a therapeutic benefit, such as the recovery of symptoms or the delay of disease progression, when administered to a subject. For example, a therapeutic effective dose may be an amount sufficient to reduce the symptoms of a disease or condition as described herein. The therapeutic effective dose may vary depending on the subject, as well as the disease or condition being treated, the subject’s weight and age, the severity of the disease or condition, and the mode of administration, which can be readily determined by those skilled in the art.

[0055] This invention relates to a compound of formula I: [ka] (In the formula, R1 represents a 5-6 member heteroaryl group in which 1 to 4 ring atoms are independently selected from -N-, -O-, or -S-, and R1 is halogen, -(C1~C4) alkyl, -O(C1~C4) alkyl, -S(C1~C4) alkyl, -S(O)(C1~C4)alkyl, -S(O)2(C1-C4)alkyl, -O(C1-C4)alkyl-R4, -(CO)OH, -CN, -(CO)O(C1-C4)alkyl, -NRaRb, -(CO)NRaRb, and -(CO)NRcRd is optionally substituted by 1 to 4 substituents independently selected from; Ra and Rb are, independently of each other, H or (C1-C4)alkyl; Rc is H or (C1-C4)alkyl; Rd is -(CH2) x -(C3-C7)cycloalkyl or -(CH2) x -(C3-C7)heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by 1 to 3 substituents selected from (C1-C4)alkyl, (CO)OH, or (CO)O(C1-C4)alkyl; x is an integer of 0, 1, 2 or 3; R2 is a 5- to 10-membered heteroaryl or a 5- to 6-membered heterocycle, wherein 1 to 4 ring atoms are independently selected from -N-, -O-, or -S-, and the heteroaryl or heterocycle is optionally substituted by 1 to 4 substituents selected from halogen, CN, -(C1-C4)alkyl, -(C1-C4)alkyl-OH, -(CO)NReRf and -NReRf, wherein Re and Rf are independently selected from H, (C1-C4)alkyl, or -CO(C1-C4)alkyl; or Re and Rf together with the nitrogen atom to which they are attached form a 4- to 6-membered ring optionally substituted with oxo; R3 is halogen or (C1-C2)alkyl; m is an integer of 0, 1, 2, 3 or 4; R4 is OH, CN, -(CO)OH, -(CO)NRgRh, or -(CO)O(C1~C4)alkyl; Rg and Rh are independently selected from H or (C1-C4) alkyl groups. or relating to pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

[0056] According to another embodiment, the compound of formula I of the present invention is R1 represents a 5-6 member heteroaryl group in which 1-2 ring atoms are -N- atoms, and R1 is halogen, -(C1~C4) alkyl, -O(C1~C4) alkyl, -S(C1~C4) alkyl, -S(O)(C1~C4)alkyl, -S(O)2(C1~C4)alkyl, O(C1~C4)alkyl-R4, -(CO)OH, -CN, -(CO)O(C1~C4)alkyl, -NRaRb, -(CO)NRaRb, and -(CO)NRcRd may be optionally substituted with 1 to 3 substituents independently selected from the original; Ra and Rb are independently H or (C1-C4) alkyl groups; Rc is either H or (C1-C4) alkyl; Rd is -(CH2) x -Cycloalkyl or -(CH2) x -A heterocyclyl, where the cycloalkyl or heterocyclyl is optionally substituted with 1 to 3 substituents selected from (C1-C4)alkyl, COOH, or COO(C1-C4)alkyl; x is an integer, such as 0, 1, 2, or 3; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. That is the case.

[0057] According to another embodiment, the compound of formula I of the present invention is R1 is pyridyl, pyrazinyl, or pyrimidinyl, and R1 is halogen, -(C1~C4) alkyl, -O(C1~C4) alkyl, -S(C1~C4) alkyl, -S(O)(C1~C4)alkyl, -S(O)2(C1~C4)alkyl, -O(C1~C4)alkyl-R4, -(CO)OH, -CN, -(CO)O(C1~C4)alkyl, -NRaRb, -(CO)NRaRb, and -(CO)NRcRd It is optionally substituted by one or two substituents independently selected from; Ra and Rb are independently H or (C1-C4) alkyl groups; Rc is either H or (C1-C4) alkyl; Rd is -(CH2) x -Cycloalkyl or -(CH2) x -A heterocyclyl, where the cycloalkyl or heterocyclyl is optionally substituted with 1 to 3 substituents selected from (C1-C4)alkyl, (CO)OH, or (CO)O(C1-C4)alkyl; x is an integer, such as 0, 1, 2, or 3; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0058] According to another embodiment, the compound of formula I of the present invention is R1 is pyridyl, pyrazinyl, or pyrimidinyl, and R1 is F, Cl, Methyl, -O-methyl, -S-methyl, -S(O)methyl, -S(O)2 methyl, -O-CH2-R4, -(CO)OH, -CN, -(CO)O-CH3, -(CO)O-CH2-CH3, -NH2, -(CO)NH2, (CO)NHCH3, and -(CO)NRcRd, and is optionally substituted by one or two substituents independently selected from; Rc is H or methyl; Rd is -(CH2)-cycloalkyl or -(CH2)-heterocyclyl, and the cycloalkyl or heterocyclyl is optionally substituted by methyl, ethyl, (CO)OH, or (CO)O(C1-C4)alkyl, a compound; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0059] According to another embodiment, the compound of formula I of the present invention is R1 is pyridyl, pyrazinyl or pyrimidinyl, and R1 is -(CO)NRcRd substituted by; Rc is H or methyl; Rd is -(CH2)-cycloalkyl or -(CH2)-heterocyclyl, the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, the heterocyclyl is selected from aziridine, azetidine, pyrrolidine, and piperidine, and the cycloalkyl or heterocyclyl is optionally substituted by methyl, ethyl, (CO)OH, or (CO)O(C1-C4)alkyl, a compound; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0060] According to another embodiment, the compound of formula I of the present invention is R1 is pyridyl, pyrazinyl, or pyrimidinyl, and R1 -(CO)NRcRd It is replaced by Rc is H; Rd is -(CH2)-cyclopropyl, -(CH2)-azetidine, or -(CH2)-piperidine. Compounds in which the cyclic group is optionally substituted with methyl, ethyl, (CO)OH, or (CO)O(C1-C4)alkyl groups; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0061] According to another embodiment, the compound of formula I of the present invention is R1 is 6-ylpyrimidine-4-carboxamide 2-Il-pyrimidine-4-carboxamide, 6-Pyrimidine-4-Carbonitrile, 2-Pyrimidine-4-Carbonitrile, 2-Pyrimidine-4-carboxylic acid, Methyl 2-ylpyrimidine-4-carboxylate, Ethyl 2-yl-(5-fluoropyrimidine-4-yl-oxyacetate), 4-(cyanomethoxy)-5-fluoropyrimidine-2-yl, 5-Fluoropyrimidine-4-yloxyacetic acid, 5-Fluoropyrimidine-4-yloxyacetamide, 4-amino-5-fluoropyrimidine-2-yl, 4-Cyanopyrimidine-2-yl, 2-yl-5-methylpyrimidine-4-carboxamide, Ethyl 6-yl-5-fluoropyrimidine-4-carboxylate, 6-yl-5-fluoropyrimidine-4-carboxylic acid, 2-yl-5-fluoropyrimidine-4-carboxamide, 5-Fluoro2-ylpyrimidine-4-oxyacetonitrile, 5-Fluoro-4-methoxypyrimidine-2-yl, 6-yl-5-fluoropyrimidine-4-carboxamide, 5-Fluoro-2-ylpyrimidine-4-carboxamide, 2-yl-N-(1-methylazetidine-3-yl)pyrimidine-4-carboxamide, 2-yl-N-[2-(1-methylcyclopropyl)ethyl]pyrimidine-4-carboxamide, tert-butyl3-ylpyrimidine-4-carbonylaminoazetidine-1-carboxylate, 2-yl-N-[(1-ethyl-4-piperidyl)methyl]pyrimidine-4-carboxamide, N-(azetidine-3-yl)-2-ylpyrimidine-4-carboxamide, Ethyl 3-ylpyrimidine-4-carbonyl]amino]azetidine-1-carboxylate, 6-Ilpyrimidine-4-Carbonitrile, 5-methyl-2-ylpyrimidine-4-carboxamide, 5-methyl-2-ylpyrimidine-4-carboxylate, 2-yl-5-fluoropyrimidine-4-carboxamide, 2-Ilpyrimidine-4-carboxylic acid, 5-Fluoro-4-methylsulfanylpyrimidine-2-yl, 5-Fluoro-4-methylsulfinylpyrimidine-2-yl, 5-Fluoro-4-methylsulfonylpyrimidine-2-yl, 2-pyridine-4-carbonitride, 4-(cyanomethoxy)-5-fluoro-2-pyridyl, 2-pyridine-4-carboxamide, 5-pyrazine-2-carbonitrile, 6-pyrazine-2-carbonitrile, 6-Pyrazine-2-carboxamide, and 5-pyrazine-2-carboxamide, A compound selected from; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0062] According to another embodiment, the compound of formula I of the present invention is R2 The compound is a 5-10 membered heteroaryl or 5-6 membered heterocycle, where 1 to 3 ring atoms are independently selected from -N-, -O-, or -S-, and the heteroaryl or heterocycle is optionally substituted by 1 to 2 substituents selected from halogens, CN, -(C1-C4)alkyl, -(C1-C4)alkyl-OH, (CO)NReRf, and -NReRf, where Re and Rf are independently selected from H, (C1-C4)alkyl, or -CO(C1-C4)alkyl; or Re and Rf, together with the nitrogen atom to which they are bonded, form a 4-6 membered ring that is optionally substituted with an oxo; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0063] According to another embodiment, the compound of formula I of the present invention is R2 However, it is a 5-10 member heteroaryl in which 1 to 3 ring atoms are independently selected from -N- or -S-, or a 5-6 member heterocycle in which 1 to 2 ring atoms are independently selected from -N-, -O-, or -S-. Heteroaryl or heterocycles are Compounds optionally substituted with one or two substituents selected from halogens, CN, -(C1~C4)alkyl, -(C1~C4)alkyl-OH, (CO)NReRf, and -NReRf, where Re and Rf are independently selected from H, (C1~C4)alkyl, or -CO(C1~C4)alkyl; or compounds in which Re and Rf, together with the nitrogen atom to which they are bonded, optionally substituted oxo at positions adjacent to the nitrogen atom; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0064] According to another embodiment, the compound of formula I of the present invention is R2 However, a 5-10 member heteroaryl in which one or two ring atoms are -N- and up to one more ring atom is -S-; or It is a 5-6 member heterocycle in which 1 or 2 ring atoms are -O-. Heteroaryl or heterocycles are Compounds optionally substituted with one or two substituents selected from halogens, CN, -(C1~C4)alkyl, -(C1~C4)alkyl-OH, (CO)NReRf, and -NReRf, where Re and Rf are independently selected from H, (C1~C4)alkyl, or -CO(C1~C4)alkyl; or compounds in which Re and Rf, together with the nitrogen atom to which they are bonded, optionally substituted oxo at positions adjacent to the nitrogen atom; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0065] According to another embodiment, the compound of formula I of the present invention is R2 However, it is selected from pyrazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, imidazo[1,2a]pyridinyl, or tetrahydropyranil. Compounds optionally substituted with one or two substituents selected from halogens, CN, -(C1~C4)alkyl, -(C1~C4)alkyl-OH, (CO)NReRf, and -NReRf, where Re and Rf are independently selected from H, (C1~C4)alkyl, or -CO(C1~C4)alkyl; or compounds in which Re and Rf, together with the nitrogen atom to which they are bonded, optionally substituted oxo at positions adjacent to the nitrogen atom; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0066] According to another embodiment, the compound of formula I of the present invention is R2 However, it is selected from pyrazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, imidazo[1,2a]pyridinyl, or tetrahydropyranil. Compounds optionally substituted with one or two substituents selected from F, Cl, Br, CN, -methyl, -(CH)2-OH, NH2, NH(C1~C4)alkyl, NH(CO)-(C1~C4)alkyl, (CO)NH2, -(CO)NH(C1~C4)alkyl, -(CO)NH(CO)-(C1~C4)alkyl, 1-oxo-azilinyl, 1-oxo-azetidinyl, 1-oxo-pyrrolidinyl, and 1-oxo-piperidinyl; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0067] According to another embodiment, the compound of formula I of the present invention is R2 However, it is selected from pyrazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, imidazo[1,2a]pyridinyl, or tetrahydropyranil. Compounds optionally substituted with one or two substituents selected from F, Cl, Br, CN, -methyl, -(CH)2-OH, NH2, NHCH3, -(CO)NH2, -(CO)NHCH3, -(CO)NH(CO)CH3, 1-oxo-azilinyl, 1-oxo-azetidinyl, 1-oxo-pyrrolidinyl, and 1-oxo-piperidinyl; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0068] According to another embodiment, the compound of formula I of the present invention is R2 5-cyano-3-pyridyl, 5-pyridine-3-carbonitride, 5-(hydroxymethyl)-3-pyridyl, 5-Carbamoyl-3-pyridyl, 5-(hydroxymethyl)-3-pyridyl, 6-amino-3-pyridyl, 5-pyridine-3-carbonitride, 5-yl-(methylcarbamoyl)-3-pyridyl, 5-yl-N-methylpyridine-3-carboxamide, 5-acetamido-3-pyridyl, 5-fluoro-3-pyridyl, 5-(2-oxoazetidine-1-yl)-3-pyridyl, 5-(2-oxopyrrolidine-1-yl)-3-pyridyl, 5-cyano-3-pyridyl, 5-fluoro-3-pyridyl, 5-Cyano-6-methyl-3-pyridyl 5-Cyano-6-methyl-3-pyridyl 5-fluoro-3-pyridyl, 5-Carbamoyl-3-pyridyl, 5-ylpyridine-3-carbonitrile, 5-Cyano-2-pyridyl, 5-Chloro-2-pyridyl, 5-pyrimidyl, 1-Methylpyrazole-3-yl, 3-Imidazou[1,2-a]pyridine-6-yl, 3-tetrahydropyranyl, 1-Methylpyrazole-4-yl, Pyrazine-2-yl, 6-methylpyrazine-2-yl, 5-methylpyrazine-2-yl, and 5-methyl-1,3,4-thiadiazole-2-yl, A compound selected from; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0069] According to another embodiment, the compound of formula I of the present invention is R3 is F, Cl, methyl, or ethyl; It is a compound in which m is an integer of 0, 1, 2, or 3.

[0070] According to another embodiment, the compound of formula I of the present invention is R3 is either F or methyl; It is a compound in which m is an integer, either 0 or 1.

[0071] According to another embodiment, the compound of formula I of the present invention is It is a compound in which R3 is either F or methyl.

[0072] According to another embodiment, the compound of formula I of the present invention is It is a compound in which m is an integer, either 0, 1, or 2.

[0073] According to another embodiment, the compound of formula I of the present invention is It is a compound where m is an integer of 0.

[0074] According to another embodiment, the compound of formula I of the present invention is It is a compound in which m is an integer of 1.

[0075] According to another embodiment, the compound of formula I of the present invention is R3 is either F or methyl; It is a compound in which m is an integer of 1.

[0076] According to another embodiment, the compound of formula I of the present invention is Compounds in which R4 is OH, CN, -(CO)OH, -(CO)NH2, -(CO)NHCH3, or -(CO)O(C1~C4)alkyl; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. That is the case.

[0077] According to another embodiment, the compound of formula I of the present invention is Compounds in which R4 is OH, CN, -(CO)OH, -(CO)NH2, -(CO)NHCH3, -(CO)O-CH3, or -(CO)O-CH2-CH3; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. That is the case.

[0078] According to another embodiment, the compound of formula I of the present invention is R1 represents a 5-6 member heteroaryl group in which 1-2 ring atoms are -N- atoms, and R1 is halogen -(C1~C4) alkyl, -O(C1~C4) alkyl, -S(C1~C4) alkyl, -S(O)(C1~C4)alkyl, -S(O)2(C1~C4)alkyl, -O(C1~C4)alkyl-R4, -(CO)OH, -CN, -(CO)O(C1~C4)alkyl, -NRaRb, -(CO)NRaRb, and -(CO)NRcRd It is optionally substituted by one to three substituents independently selected from; Ra and Rb are independently H or (C1-C4) alkyl groups; Rc is either H or (C1-C4) alkyl; Rd is -(CH2) x -Cycloalkyl or -(CH2) x -A heterocyclyl, where the cycloalkyl or heterocyclyl is optionally substituted with 1 to 3 substituents selected from (C1-C4)alkyl, COOH, or COO(C1-C4)alkyl; x is an integer, either 0, 1, 2, or 3; R2 However, the heteroaryl or heterocycle is a 5-10 membered heteroaryl or a 5-6 membered heterocycle, where 1 to 3 ring atoms are independently selected from -N-, -O-, or -S-, and the heteroaryl or heterocycle is optionally substituted by 1 to 2 substituents selected from halogens, CN, -(C1-C4)alkyl, -(C1-C4)alkyl-OH, (CO)NReRf, and -NReRf, where Re and Rf are independently selected from H, (C1-C4)alkyl, or -CO(C1-C4)alkyl; or Re and Rf, together with the nitrogen atom to which they are bonded, form a 4-6 membered ring that is optionally substituted with an oxo; R3 is F, Cl, methyl, or ethyl; m is an integer, 0, 1, or 2. Compounds in which R4 is OH, CN, -(CO)OH, -(CO)NH2, -(CO)NHCH3, or -(CO)O(C1~C4)alkyl; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0079] According to another embodiment, the compound of formula I of the present invention is R1 is pyridyl, pyrazinyl, or pyrimidinyl, and R1 is -halogen, -(C1~C4) alkyl, -O(C1~C4) alkyl, -S(C1~C4) alkyl, -S(O)(C1~C4)alkyl, -S(O)2(C1~C4)alkyl, -O(C1~C4)alkyl-R4, -(CO)OH, -CN, -(CO)O(C1~C4)alkyl, -NRaRb, -(CO)NRaRb, and -(CO)NRcRd It is optionally substituted by one or two substituents independently selected from; Ra and Rb are independently H or (C1-C4) alkyl groups; Rc is either H or (C1-C4) alkyl; Rd is -(CH2) x -Cycloalkyl or -(CH2) x -A heterocyclyl, where the cycloalkyl or heterocyclyl is optionally substituted with 1 to 3 substituents selected from (C1-C4)alkyl, (CO)OH, or (CO)O(C1-C4)alkyl; x is an integer, either 0, 1, 2, or 3; R2 However, it is a 5-10 member heteroaryl in which 1 to 3 ring atoms are independently selected from -N- or -S-, or a 5-6 member heterocycle in which 1 to 2 ring atoms are independently selected from -N-, -O-, or -S-. Heteroaryl or heterocycles are They are optionally substituted with one or two substituents selected from halogens, CN, -(C1~C4)alkyl, -(C1~C4)alkyl-OH, (CO)NReRf and -NReRf, where Re and Rf are independently selected from H, (C1~C4)alkyl, or -CO(C1~C4)alkyl; or Re and Rf, together with the nitrogen atom to which they are bonded, form a 4 to 6-membered ring that is optionally substituted oxo at a position adjacent to the nitrogen atom; R3 is either F or methyl; m is an integer, either 0 or 1; Compounds in which R4 is OH, CN, -(CO)OH, -(CO)NH2, -(CO)NHCH3, or -(CO)O(C1~C4)alkyl; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0080] According to another embodiment, the compound of formula I of the present invention is R1 is pyridyl, pyrazinyl, or pyrimidinyl, and R1 is F, Cl, Methyl, -O-methyl, -S-methyl, -S(O)methyl, -S(O)2methyl, -O-CH2-R4, -(CO)OH, -CN, -(CO)O-CH3, -(CO)O-CH2-CH3, -NH2, -(CO)NH2, (CO)NHCH3, and -(CO)NRcRd It is optionally substituted by one or two substituents independently selected from; Rc is either H or methyl; Rd is a -(CH2)-cycloalkyl or -(CH2)-heterocyclyl, where the cycloalkyl or heterocyclyl is optionally substituted with methyl, ethyl, (CO)OH, or (CO)O(C1-C4)alkyl; R2 However, a 5-10 member heteroaryl in which one or two ring atoms are -N- and up to one more ring atom is -S-; or It is a 5-6 member heterocycle in which 1 or 2 ring atoms are -O-. Heteroaryl or heterocycles are They are optionally substituted with one or two substituents selected from halogens, CN, -(C1~C4)alkyl, -(C1~C4)alkyl-OH, (CO)NReRf and -NReRf, where Re and Rf are independently selected from H, (C1~C4)alkyl, or -CO(C1~C4)alkyl; or Re and Rf, together with the nitrogen atom to which they are bonded, form a 4 to 6-membered ring that is optionally substituted oxo at a position adjacent to the nitrogen atom; R3 is either F or methyl; m is an integer, either 0 or 1; Compounds in which R4 is OH, CN, -(CO)OH, -(CO)NH2, -(CO)NHCH3, or -(CO)O(C1~C4)alkyl; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0081] According to another embodiment, the compound of formula I of the present invention is R1 is pyridyl, pyrazinyl, or pyrimidinyl, and R1 -(CO)NRcRd It is replaced by; Rc is either H or methyl; Rd is a -(CH2)-cycloalkyl or -(CH2)-heterocyclyl, Cycloalkyls are selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Heterocyclines are selected from azirine, azetidine, pyrrolidine, and piperidine. A cycloalkyl or heterocyclyl is a compound that is optionally substituted with methyl, ethyl, (CO)OH, or (CO)O(C1-C4)alkyl groups; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0082] According to another embodiment, the compound of formula I of the present invention is R1 is pyridyl, pyrazinyl, or pyrimidinyl, and R1 -(CO)NRcRd It is replaced by Rc is H; Rd is -(CH2)-cyclopropyl, -(CH2)-azetidine, or -(CH2)-piperidine. Compounds in which the cyclic group is optionally substituted with methyl, ethyl, (CO)OH, or (CO)O(C1-C4)alkyl groups; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0083] According to another embodiment, the compound of formula I of the present invention is R2 However, it is selected from pyrazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, imidazo[1,2a]pyridinyl, or tetrahydropyranil. Optionally substituted with one or two substituents selected from F, Cl, Br, CN, -methyl, -(CH)2-OH, NH2, NH(C1~C4)alkyl, NH(CO)-(C1~C4)alkyl, (CO)NH2, -(CO)NH(C1~C4)alkyl, -(CO)NH(CO)-(C1~C4)alkyl, 1-oxo-azilinyl, 1-oxo-azetidinyl, 1-oxo-pyrrolidinyl, and 1-oxo-piperidinyl; R3 is either F or methyl; m is an integer, either 0 or 1; Compounds in which R4 is OH, CN, -(CO)OH, -(CO)NH2, -(CO)NHCH3, -(CO)O-CH3, or -(CO)O-CH2-CH3; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0084] Another embodiment is a compound of formula I as described above, R1 is not replaced with halogen; R2 is either not replaced or replaced with a halogen; Compounds where m is 0 or 1 It will be excluded.

[0085] In another embodiment of the present invention, the compound of formula I is 6-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 2-[4-[(3S)-3-pyrimidine-5-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 6-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carbonitrile 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxylic acid Methyl 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxylate 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carbonil 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyridine-4-carbonyl 5-[(3S)-2-[1-[4-(cyanomethoxy)-5-fluoro-2-pyridyl]-4-methyl-piperidine-4-carbonyl]isoxazolidine-3-yl]pyridin-3-carbonil 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-4-methyl-1-piperidyl]pyrimidine-4-carboxamide Methyl 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-4-methyl-1-piperidyl]pyrimidine-4-carboxylate 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-4-methyl-1-piperidyl]pyrimidine-4-carboxylic acid 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyridine-4-carboxamide Ethyl 2-[2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-4-methyl-1-piperidyl]-5-fluoropyrimidine-4-yl]oxyacetate 5-[(3S)-2-[1-[4-(cyanomethoxy)-5-fluoropyrimidine-2-yl]piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil 2-[2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-yl]oxyacetic acid 2-[2-[4-[(3S)-3-(5-carbamoyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-yl]oxyacetic acid 2-[2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-yl]oxyacetamide 5-[(3S)-2-[1-(4-amino-5-fluoropyrimidine-2-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil 2-[4-[(3S)-3-(5-acetamide-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 2-[4-[(3S)-3-(6-methylpyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 2-[4-[(3S)-3-(6-methylpyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carbonil 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-methylpyrimidine-4-carboxamide 2-[4-[(3S)-3-[5-(2-oxoazetidine-1-yl)-3-pyridyl]isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 2-[4-[(3S)-3-[5-(2-oxoazetidine-1-yl)-3-pyridyl]isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carbonil Ethyl 6-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxylate 6-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxylic acid 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-4-fluoro-1-piperidyl]-5-fluoropyrimidine-4-carboxamide 2-[4-[(3S)-3-[5-(2-oxopyrrolidine-1-yl)-3-pyridyl]isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 2-[4-methyl-4-[(3S)-3-pyrimidine-5-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 2-[5-fluoro-2-[4-methyl-4-[(3S)-3-pyrimidine-5-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-yl]oxyacetonitrile 2-[5-fluoro-2-[4-[(3S)-3-pyrimidine-5-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-yl]oxyacetonitrile [1-(5-fluoro-4-methoxypyrimidine-2-yl)-4-piperidyl]-[(3S)-3-pyrimidine-5-ylisoxazolidine-2-yl]methanone 2-[4-[(3S)-3-pyrimidine-5-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyridine-4-carbonil 5-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrazine-2-carbonil 6-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrazine-2-carbonitri 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide 2-[4-[(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 6-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrazine-2-carboxamide 5-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrazine-2-carboxamide 6-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide 2-[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 5-Fluoro-2-[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-N-(1-methylazetidine-3-yl)pyrimidine-4-carboxamide 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-N-[2-(1-methylcyclopropyl)ethyl]pyrimidine-4-carboxamide tert-butyl3-[[2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carbonyl]amino]azetidine-1-carboxylate 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-N-[(1-ethyl-4-piperidyl)methyl]pyrimidine-4-carboxamide 5-Fluoro-2-[4-[(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 2-[4-[(3S)-3-(5-cyano-6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 5-Fluoro-2-[4-[(3S)-3-(6-methylpyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 2-[4-[(3S)-3-(5-chloro-2-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 2-[4-[(3S)-3-(5-chloro-2-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide 2-[4-[(3S)-3-(5-cyano-6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide N-(azetidine-3-yl)-2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 2-[4-[(3S)-3-(5-methylpyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide Ethyl 3-[[2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carbonyl]amino]azetidine-1-carboxylate 5-Fluoro-2-[4-[(3S)-3-(5-methylpyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 6-[4-[(3S)-3-(5-methylpyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carbonil 2-[(3R,4R)-4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-fluoro-1-piperidyl]pyrimidine-4-carboxamide 2-[(3R,4R)-4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-fluoro-1-piperidyl]pyrimidine-4-carboxamide 2-[(3S,4S)-4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-fluoro-1-piperidyl]pyrimidine-4-carboxamide 2-[(3R,4S)-4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-fluoro-1-piperidyl]pyrimidine-4-carboxamide 2-[(3S,4R)-4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-fluoro-1-piperidyl]pyrimidine-4-carboxamide 5-Methyl-2-[4-[(3S)-3-(6-methylpyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 2-[4-[(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-methylpyrimidine-4-carboxamide 5-Methyl-2-[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide Methyl 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxylate 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxylic acid 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxylic acid 5-[(3S)-2-[1-(5-fluoro-4-methylsulfanylpyrimidine-2-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil 5-[(3S)-2-[1-(5-fluoro-4-methylsulfinylpyrimidine-2-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil 5-[(3S)-2-[1-(5-fluoro-4-methylsulfonylpyrimidine-2-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil 2-[4-[(3S)-3-(5-cyano-2-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide 6-[4-[(3S)-3-(5-cyano-2-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 2-[4-[(3S)-3-(5-cyano-2-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide (S)-6-(4-(3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide (S)-2-(4-(3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carbonil 2-[4-[(3S)-3-(5-cyano-2-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carbonil 5-[(3S)-2-[1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil 5-[(3S)-2-[1-(5-fluoro-4-methoxypyrimidine-2-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3,3,4-trifluoro-1-piperidyl]pyrimidine-4-carboxamide [1-(5-fluoro-4-methoxypyrimidine-2-yl)-4-piperidyl]-[(3S)-3-(6-methylpyrazine-2-yl)isoxazolidine-2-yl]methanone 6-[(3S)-2-[1-(5-fluoro-4-methoxypyrimidine-2-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil 2-[4-[(3S)-3-(6-cyanopyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 6-[(3S)-2-[1-(5-fluoro-4-methoxypyrimidine-2-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil 5-Fluoro-2-[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carbonil 2-Chloro-5-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxylic acid 2-[3,3,4-trifluoro-4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3,3,4-trifluoro-1-piperidyl]pyrimidine-4-carbonil 2-[3,3,4-trifluoro-4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carbonil 5-[(3S)-2-[1-(5-fluoro-4-hydroxypyrimidine-2-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil (S)-5-fluoro-2-(4-fluoro-4-(3-(5-fluoropyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide (S)-2-(4-(3-(6-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonil (S)-6-(4-(3-(6-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonil (S)-2-(4-(3-(6-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide 5-[(3S)-2-[1-(2-chloro-5-fluoropyrimidine-4-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil (S)-2-(4-(3-(5-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonil (S)-2-(4-(3-(5-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide (S)-6-(4-(3-(5-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonil (S)-6-(4-(3-(5-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide (S)-6-(4-(3-(6-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide (S)-2-(4-(3-(5-fluoro-6-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonil 2-[4-[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide (S)-6-(4-(3-(5-fluoro-6-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonil 6-[4-[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide (S)-2-(4-(3-(5-fluoro-4-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonil (S)-2-(4-(3-(5-fluoro-4-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide (S)-6-(4-(3-(5-fluoro-4-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide (S)-6-(4-(3-(5-fluoro-4-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonil 5-[(3S)-2-[1-(2-methoxypyrimidine-4-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil 4-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-2-carbonitrile 5-[(3S)-2-[1-(2-methylsulfanylpyrimidine-4-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil 5-[(3S)-2-[1-(2-chloropyrimidine-4-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil 5-[(3S)-2-[1-(2-aminopyrimidine-4-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil Ethyl 4-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-2-carboxylate (S)-2-(4-(3-(4-methylfuran-2-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonil (S)-2-(4-(3-(4-methylfuran-2-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide (S)-6-(4-(3-(4-methylfuran-2-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonitri (S)-6-(4-(3-(4-methylfuran-2-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide 2-[(3R,4R or 3S,4S)-4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-fluoro-1-piperidyl]-5-fluoropyrimidine-4-carboxamide 2-[(3S,4S or 3R,4R)-4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-fluoro-1-piperidyl]-5-fluoropyrimidine-4-carboxamide 4-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-2-carboxamide 5-[(3S)-2-[1-(2-bromopyrimidine-4-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil 5-[(3S)-2-[1-(4-chloropyrimidine-2-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil 5-[(3S)-2-[1-(6-chloropyrimidine-4-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil 5-[(3S)-2-[1-(4-bromopyrimidine-2-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil (S)-2-(4-(3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonil (S)-6-(4-(3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonitri 2-Chloro-5-[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxylic acid 5-[(3S)-2-[1-(6-bromopyrimidine-4-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil 2-[4-[(3S)-3-(5-cyano-3-thienyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide 2-[4-[(3S)-3-(5-cyano-3-furyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide 2-[4-[(3S)-3-(5-cyano-3-thienyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide (S)-5-(2-(1-(6-fluoropyrimidine-4-yl)piperidine-4-carbonyl)isoxazolidine-3-yl)nicotinonitrile 5-Fluoro-2-[4-[(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 2-[4-[(3S)-3-(5-cyano-3-furyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide [1-(4-chloro-1,3,5-triazine-2-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone 5-Fluoro-2-[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 6-[4-[(3S)-3-(5-methyl-2-thienyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 2-[4-[(3S)-3-(6-cyanopyridazine-4-yl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide 2-[4-[(3S)-3-(6-cyanopyridazine-4-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide [1-(4-chloro-6-methyl-1,3,5-triazine-2-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone [1-(4-chloro-6-methoxy-1,3,5-triazine-2-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone 5-methyl-2-[4-[(3S)-3-(5-methyl-2-thienyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide 5-Fluoro-2-[4-[(3S)-3-(5-methyl-2-thienyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide [1-(4-amino-6-chloro-1,3,5-triazine-2-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone 2-[(3R,4R or 3S,4S)-3-fluoro-4-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-methyl-pyrimidine-4-carboxamide 2-[(3S,4S or 3R,4R)-3-fluoro-4-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-methyl-pyrimidine-4-carboxamide 5-Fluoro-6-[4-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide; trifluoroacetic acid 2-[4-[(3S)-3-(2-cyanothiazole-4-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide and 2-[4-[(3S)-3-(2-cyanothiazole-4-yl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide Alternatively, a selection may be made from these pharmaceutically acceptable salts, solvates, or stereoisomers.

[0086] According to another embodiment, the compound of formula I of the present invention is R1 is pyrimidinyl, and R1 is Substituted with -(CO)NH2, and possibly further substituted with F; R2 However, they are selected from pyridyl and pyrazinyl and optionally substituted with -methyl, Compounds where m is an integer of 0; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0087] In another embodiment of the present invention, the compound of formula I is 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide, 2-[4-[(3S)-3-(6-methylpyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, and 5-Fluoro-2-[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide; Alternatively, it may be selected from a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0088] In another embodiment of the present invention, the compound of formula I is 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide, and 2-[4-[(3S)-3-(6-methylpyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide; Alternatively, it may be selected from a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0089] Further embodiments include an IC50 of 200 nM or less in the ADP Glo assay described in the example. 50 Compounds of formula I that show the value; Alternatively, these may be pharmaceutically acceptable salts, solvates, or stereoisomers.

[0090] Further embodiments include an IC of less than 50 nM in the ADP Glo assay described in the example.50 Compounds of formula I that show the value; Alternatively, these may be pharmaceutically acceptable salts, solvates, or stereoisomers.

[0091] Further embodiments include an IC of less than 20 nM in the ADP Glo assay described in the example. 50 Compounds of formula I that show the value; Alternatively, these may be pharmaceutically acceptable salts, solvates, or stereoisomers.

[0092] Further embodiments include cases where the TPSA value described in the example is 90 Å. 2 The compounds of formula I described above; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0093] Further embodiments include a TPSA value of 105 Å described in the example. 2 The compounds of formula I described above; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0094] Further embodiments include cases where the TPSA value described in the example is 120 Å. 2 The compounds of formula I described above; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0095] Compound synthesis The compounds may also be prepared using the methods disclosed herein and their respective modifications, which will become apparent from the given disclosures herein and from methods well known in the art.

[0096] Scheme 1: [ka]

[0097] Synthesis method a: The isoxazolidine of formula II, synthesized by well-known procedures from the literature, e.g., Denali's WO2017096301 and GSK's WO2019130230, is bonded to a 4-piperidyl-carboxylic acid of formula IX, which is optionally substituted with (R3)m and optionally has N protected by substitution, using a standard acid activation method such as hydrochloric acid, HOBt, HATU, HBTU, PyBOP, and 1-propanephosphonic anhydride, under basic conditions, e.g., diisopropylethylamine, in an aprotic solvent such as DMF, DMSO, or acetonitrile, or using a method for forming the compound of formula VIII optionally substituted with (R3)m as defined above. (wherein (R3)m is as defined above). (PG)BOC, benzoyl, or benzyl may be used as the protecting group. Cleavage of the protecting group under acidic or hydrogenation conditions yields a compound of formula VI optionally substituted with (R3)m, which may then be reacted, for example, under nucleophilic aromatic substitution or Hartwig-Buchwald coupling conditions with a 5-6 membered heterocyclic group of formula VI substituted with X representing a leaving group such as F, Cl, Br, or O-triflate to provide a compound of formula I optionally substituted with (R3)m.

[0098] Synthesis method b: The 4-piperidyl carboxylic acid ester of formula V, optionally substituted with (R3)m, may be reacted, for example, under nucleophilic aromatic substitution conditions or Hartwig-Buchwald coupling conditions with a 5- to 6-membered heterocyclic group of formula VI substituted with X representing a leaving group such as F, Cl, Br, or O-triflate, to obtain the compound of formula IV, optionally substituted with (R3)m. R' represents methyl, ethyl, or tert-butyl. Preferably, the 4-piperidinyl carboxylic acid of formula III, optionally substituted with (R3)m, is obtained by esterification of the methyl and ethyl esters under basic conditions such as LiOH, NaOH, or tert-butyl ester, and preferably under acidic conditions such as HCl, TFA, or p-toluenesulfonic acid. Isoxazolidine of formula II (wherein (R3)m is as defined above), synthesized by procedures known from the literature, e.g., Denali's WO2017096301 and GSK's WO2019130230, is bonded to 4-piperidyl-carboxylic acid of formula III, optionally substituted with (R3)m, by standard acid activation methods such as hydrochloric acid, HOBt, HATU, HBTU, PyBOP, and 1-propanephosphonic anhydride, in a non-protic solvent such as DMF, DMSO, acetonitrile, under basic conditions, e.g., diisopropylethylamine, or by methods for forming compounds of formula I optionally substituted with (R3)m as defined above.

[0099] Functional groups such as acids, esters, amides, nitriles, and halogens in the compounds of formula I may be converted to other functional groups (functional group interconversion) using standard methods such as esterification, saponification, halogenation, and the Suzuki reaction to obtain further compounds of formula I. Typical synthesis of the compounds described herein can be carried out as described in the following examples. Reagents, where available, can be commercially purchased from, for example, Sigma Aldrich or other chemical suppliers. Typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reagents, solvent, pressure, etc.) are given, and it will be understood that other process conditions may also be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reagents or solvents used, and such conditions can be determined by those skilled in the art by customary optimization procedures.

[0100] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, numerous protecting groups are described in Wuts, PGM, Greene, TW, & Greene, TW (2006), Greene's protective groups in organic synthesis, Hoboken, NJ, Wiley-Interscience, and the references cited therein.

[0101] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-rich mixtures. Unless otherwise specified, all such stereoisomers (and enriched mixtures) are included within the scope of this disclosure. Pure stereoisomers (or enriched mixtures) are prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0102] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Ernka-Chemce, or Sigma (St. Louis, Missouri, USA). Others can be manufactured by procedures or obvious modifications described in standard reference textbooks such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, 5th edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). The terms “solvent,” “inert organic solvent,” or “inert solvent” mean, for example, that the solvent is inert under the reaction conditions described in combination with them (including benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane, "DCM"), diethyl ether, methanol, pyridine, etc.). Conversely, unless otherwise specified, the solvents used in the reactions of this disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably argon.

[0103] Pharmaceutical composition The compounds provided herein are typically administered in the form of pharmaceutical compositions. Accordingly, pharmaceutical compositions are also provided that contain one or more of the compounds described herein or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof, as well as one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients.

[0104] Suitable pharmaceutically acceptable vehicles may include, for example, inert solid excipients and fillers, excipients including sterile aqueous solutions, and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Such compositions are manufactured by methods well known in the pharmaceutical field.

[0105] The pharmaceutical compositions of this disclosure may be formulated in particular for administration in solid or liquid form, including those adapted for: oral administration, e.g., aqueous drugs (aqueous solutions, non-aqueous solutions, or suspensions), tablets, e.g., those targeting oral buccal, sublingual, and systemic absorption, boluses, powders, granules, and pastes for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., by sterile solutions or suspensions or sustained-release formulations; topical application, e.g., by creams, ointments, or controlled-release patches or sprays applied to the skin; intravaginal or rectal, e.g., as pessaries, creams, or foams; sublingual; eye; transdermal; or transnasal, lung, and other mucosal surfaces.

[0106] The term "pharmaceutically acceptable" is used herein to mean, within the bounds of sound medical judgment, that the compounds, materials, compositions and / or dosage forms are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and that the benefit / risk ratio is reasonable.

[0107] The term “pharmaceutically acceptable carrier,” as used herein, means a pharmaceutically acceptable material, composition, or vehicle, e.g., liquid or solid fillers, excipients, additives, or solvent encapsulating materials, that are involved in carrying or transporting a compound of interest from one organ or body part to another. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; surfactants, e.g., polysorbate 80 (i.e., Tween 80); tragacanth powder; malt; gelatin; talc; additives, e.g., cocoa butter and suppository wax; oils, e.g., peanut oil, cottonseed oil, safflower oil, Sesame oil, olive oil, corn oil, and soybean oil; glycols, e.g., propylene glycol; polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; esters, e.g., ethyl oleate and ethyl laurate; agar; buffers, e.g., magnesium hydroxide and aluminum hydroxide; alginic acid; water free of pyrogens; isotonic saline; Ringer's solution; ethyl alcohol; pH buffer solutions; polyesters, polycarbonates, and / or polyacid anhydrides; and other non-toxic, suitable substances used in pharmaceutical formulations. Examples of such formulations, but not limited to these, include DMSO, 10 mM DMSO, 8% hydroxypropyl-beta-cyclodextrin in PBS, propylene glycol, and the like. For example, in a particular embodiment, the compounds of the Disclosure may be used as a 4 mM solution in 8% hydroxypropyl-beta-cyclodextrin in PBS for parenteral administration. In another particular embodiment, the compounds of the Disclosure may be used as a suspension in a 0.5% CMC aqueous solution containing 0.1% Tween 80.

[0108] As described herein, certain embodiments of the compounds may contain basic functional groups, such as amino or methylamino (NCH3), and thus can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term “pharmaceutically acceptable salt” in this regard refers to relatively non-toxic inorganic and organic acid addition salts of the compounds of the Disclosure. These salts can be produced in situ in a dosing vehicle or in a dosage form production process, or by separately reacting the purified compound of the Disclosure in the form of its free base with a suitable organic or inorganic acid and then isolating the salt thus formed during subsequent purification. Typical salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfonate.

[0109] pharmaceutically acceptable salts of the compound in question include, for example, ordinary non-toxic salts or quaternary ammonium salts of the compound from non-toxic organic or inorganic acids. For example, such ordinary non-toxic salts include those derived from inorganic acids, such as hydrochloride, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and salts produced from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, etc.

[0110] In other cases, the compounds of the Disclosure may contain one or more acidic functional groups, and thus can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term “pharmaceutically acceptable salt” refers to relatively non-toxic inorganic and organic base addition salts of the compounds of the Disclosure. These salts can also be produced in situ in a dosing vehicle or in a dosage form production process, or by separately reacting a purified compound in the form of its free acid with a suitable base, such as a pharmaceutically acceptable metal cation hydroxide, carbonate or bicarbonate, ammonia, or a pharmaceutically acceptable organic primary, secondary or tertiary amine. Typical alkali salts or alkaline earth salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, and aluminum salts. Typical organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine.

[0111] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents, and fragrances, preservatives, and antioxidants may also be present in the composition. Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfite, sodium metabisulfite, and sodium sulfite; oil-soluble antioxidants, such as ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0112] The formulations of this disclosure include those suitable for oral, nasal, topical (including oral buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may be conveniently presented in unit dosage forms and may be manufactured by any method well known in the pharmaceutical art. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form varies depending on the host being treated and the specific mode of administration. Generally, the amount of active ingredient that can be combined with a carrier material to produce a single dosage form is that amount of the compound that produces the therapeutic effect. Generally, this amount is in the range of about 1% to about 99% of the active ingredient, preferably about 5% to about 70%, and most preferably about 10% to about 30%. In certain embodiments, the formulations of this disclosure include cyclodextrins, liposomes, micellaring agents, e.g., bile acids, and polymer carriers, e.g., polyesters and polyacid anhydrides; and one or more of the compounds of this disclosure. In certain embodiments, the above formulations make the compounds of this disclosure orally bioavailable.

[0113] Methods for producing these formulations or compositions include the step of mixing the compound of the Disclosure with a carrier and, optionally, one or more auxiliary components. Generally, formulations are produced by homogeneously and closely mixing the compound of the Disclosure with a liquid carrier or a pulverized solid carrier or both, and then, if necessary, forming a product. Formulations of the Disclosure suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as flavored tablets (using an inert base, e.g., gelatin and glycerin or sucrose and acacia), and / or mouthwashes, each containing a predetermined amount of the compound of the Disclosure as an active ingredient. The compound of the Disclosure may also be administered as a bolus, lick, or paste.

[0114] In the solid dosage forms of the present disclosure for oral administration (capsules, tablets, pills, sugar-coated tablets, powders, granules, etc.), the active ingredient is contained in one or more pharmaceutically acceptable carriers, e.g., sodium citrate or dicalcium phosphate and / or any of the following: fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol and / or silicic acid; binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; humectants, e.g., glycerin; disintegrants, For example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; dissolution retarders, e.g., paraffin; absorption enhancers, e.g., quaternary ammonium compounds; wetting agents, e.g., cetyl alcohol, glyceryl monostearate and nonionic surfactants; absorbents, e.g., kaolin and bentonite clay; lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and colorants. In the case of capsules, tablets and pills, the pharmaceutical composition may also contain buffers. Similar types of solid compositions may also be used as fillers in soft-shell and hard-shell gelatin capsules, using additives such as lactose and high molecular weight polyethylene glycol.

[0115] Tablets may be prepared by compression or molding, sometimes with one or more auxiliary components. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert excipients, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked carboxymethylcellulose sodium), surfactants, or dispersants. Molded tablets may be prepared in a suitable machine in which a mixture of powdered compounds is moistened with an inert liquid excipient.

[0116] Tablets and other solid dosage forms of the pharmaceutical compositions of this disclosure, e.g., sugar-coated tablets, capsules, pills, and granules, may optionally be etched or manufactured with coatings and shells, e.g., enteric coatings and other coatings known in the art of pharmaceutical formulation. These may also be formulated to achieve sustained or controlled release of the active ingredient therein, for example, using a variable proportion of hydroxypropyl methylcellulose, other polymer matrices, liposomes, and / or microspheres to achieve a desired release profile. These may be formulated for rapid release and, for example, lyophilized. These may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifiers and may be compositions that release only or preferentially the active ingredient(s) in a delayed manner to a specific portion of the gastrointestinal tract. Examples of embedding compositions that can be used include polymer substances and waxes. The active ingredient may also be in a microencapsulated form, accompanied by one or more of the above-mentioned additives, where appropriate.

[0117] Liquid dosage forms for oral administration of the compounds of this disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredients, the liquid dosage forms may contain inert excipients commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, as well as mixtures thereof.

[0118] In addition to inert excipients, oral compositions may also contain adjuvants, such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, colorants, fragrances and preservatives.

[0119] The suspension may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0120] Formulations of the pharmaceutical compositions of the present disclosure for rectal or vaginal administration may be presented as suppositories that can be prepared by mixing one or more of the compounds of the present disclosure with one or more suitable non-irritating additives or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylate, which are solid at room temperature but liquid at body temperature, and therefore melt in the rectal or vaginal cavity to release the active compound.

[0121] Formulations of the present disclosure suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known in the art as suitable.

[0122] Dosage forms for topical or transdermal administration of the compounds of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compounds may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as needed.

[0123] In addition to the active compounds of this disclosure, ointments, pastes, creams, and gels may contain additives such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0124] The powders and sprays may contain, in addition to the compounds of the Disclosure, additives such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. The sprays may further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0125] Transdermal patches offer the added advantage of enabling controlled delivery of the compounds of this disclosure to the body. Such dosage forms can be prepared by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flow of the compounds through the skin. The rate of such flow can be controlled by providing a rate-limiting membrane or by dispersing the compounds in a polymer matrix or gel.

[0126] Ophthalmic preparations, ophthalmic ointments, powders, solutions, etc., are also intended to be within the scope of this disclosure. Pharmaceutical compositions of this disclosure suitable for parenteral administration include one or more compounds of this disclosure in combination with one or more pharmaceutically acceptable sterile and isotonic aqueous or non-aqueous solutions, dispersions, suspensions, emulsions, or sterile powders, which may contain sugars, alcohols, antioxidants, buffers, antibacterial agents, solutes isotonic with the blood of the recipient to whom the preparation is intended, or suspending agents or thickeners.

[0127] Suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of this disclosure include water, ethanol, polyols (e.g., glycerin, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). Appropriate fluidity can be maintained, for example, by the use of coating materials (e.g., lecithin), by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0128] These compositions may also contain adjuvants, such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action by the target compound can be ensured by including various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenyl, and sorbic acid. It is also desirable to include isotonic agents, such as sugars and sodium chloride, in the composition. Furthermore, sustained absorption of the injectable pharmaceutical form can be achieved by including absorption-delaying agents, such as aluminum monostearate and gelatin.

[0129] In some cases, it is desirable to slow down the absorption of a drug from subcutaneous or intramuscular injection in order to prolong its effects. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The rate of drug absorption is determined by its dissolution rate, which can be determined by the crystal size and crystalline form. Alternatively, delayed absorption of drug forms administered parenterally is achieved by dissolving or suspending the drug in an oil vehicle.

[0130] Injectable depot formulations are prepared by forming a microencapsulated matrix of the target compound in a biodegradable polymer, such as polylactide-polyglycolide. The rate of drug release can be controlled by the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoesters) and poly(acid anhydrides). Depot injection formulations are also prepared by capturing the drug in liposomes or microemulsions that are compatible with body tissues.

[0131] Treatment method In other embodiments, methods for treating receptor-interacting protein kinase 1-mediated diseases or disorders are provided herein. These methods include administering a therapeutically effective amount of a compound or pharmaceutical composition described herein to a subject in need thereof. In some embodiments, receptor-interacting protein kinase 1-mediated diseases or disorders include trauma, ischemia, stroke, myocardial infarction, infection, Gaucher disease, Krabbe disease, sepsis, systemic inflammatory response syndrome (SIRS), Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, HIV-related dementia, retinal degenerative diseases, glaucoma, age-related macular degeneration, rheumatoid arthritis, non-communicable inflammatory skin diseases (ncISDs) such as psoriasis or atopic dermatitis, psoriatic arthritis, or inflammatory bowel disease.

[0132] The term “trauma,” as used herein, refers to any physical injury to the body resulting from violence, an accident, a fracture, etc. The term “ischemia” refers to a cardiovascular disorder characterized by a hypoxic state, usually caused by obstruction of arterial blood supply or inadequate blood flow resulting in low oxygen in tissues. The term “stroke” refers to a cardiovascular disorder resulting from a blood clot or hemorrhage in the brain, most commonly caused by an interruption in blood flow in the brain, such as from a blood clot blocking a blood vessel, and in certain embodiments of this disclosure, the term stroke refers to ischemic stroke or hemorrhagic stroke. The term “myocardial infarction” refers to a cardiovascular disorder characterized by localized necrosis resulting from obstruction of blood supply.

[0133] The methods described herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living organism, such as in an animal or a human. In this context, the methods described herein may be used therapeutically in an organism. “Ex vivo” means outside a living organism. Examples of cell populations ex vivo include in vitro cell cultures and biological samples, including liquid or tissue samples obtained from an organism.

[0134] Such samples are obtained by methods well known in the art. Exemplary body fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine the optimal schedule and / or dosage of the compounds disclosed herein for a given indication, cell type, individual, and other parameters. Information gathered from such use may be used for experimental purposes or in a clinic to establish protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein are suitable are described below or will be obvious to those skilled in the art. Selected compounds may be further characterized to investigate their safety or tolerance in human or non-human subjects. Such properties may be investigated using methods generally known to those skilled in the art.

[0135] Experiments using knockout animal models and the receptor-interacting protein kinase 1 inhibitor necrostatin 1 have demonstrated the efficacy of receptor-interacting protein kinase 1 inhibition in protecting tissues from inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), non-communicable inflammatory skin diseases (ncISDs) such as psoriasis or atopic dermatitis, retinal detachment-induced photoreceptor necrosis, retinitis pigmentosa, cerulein-induced acute pancreatitis, and septic / systemic inflammatory response syndrome (SIRS), as well as mitigating ischemic brain injury, retinal ischemia / reperfusion injury, Huntington's disease, renal ischemia-reperfusion injury, cisplatin-induced kidney injury, traumatic brain injury, malignancies of the hematological and parenchymal organs, bacterial and viral infections (e.g., tuberculosis and influenza or SARS-coronavirus), and lysosomal storage disorders. Therefore, the receptor-interacting protein kinase 1 inhibitors of this disclosure demonstrate that both RIPK1 kinase-driven inflammation and cell death are key contributing factors in systemic inflammatory response syndrome (SIRS). There is also rationale for the fact that vascular permeability and endothelial dysfunction contribute to SIRS / shock and lethality. Therefore, the receptor-coupled protein kinase 1 inhibitors of this disclosure are useful in treating receptor-coupled protein kinase 1-mediated diseases and conditions, including, but not limited to, inflammatory diseases or disorders, necrotic cell diseases, neurodegenerative diseases, central nervous system (CNS) diseases, ocular diseases, infections, and malignancies. In certain embodiments, the receptor-coupled protein kinase 1 inhibitors described herein may inhibit inflammation, protect tissues or cells from damage or unwanted cell death (e.g., necrosis or apoptosis), restore symptoms, and improve immune responses or neurological function in patients suffering from any of the prescribed diseases or conditions. Furthermore, the compounds may be suitable for treating immune-mediated diseases such as allergic diseases and autoimmune diseases, and for preventing transplant rejection, but are not limited to these.

[0136] Provided herein are compounds and compositions for use in pharmaceuticals. In certain embodiments, the compounds and compositions are for use in the treatment of diseases or disorders mediated by receptor-coupled protein kinase 1. Also provided are methods for treating diseases or disorders mediated by receptor-coupled protein kinase 1, comprising administering a therapeutically effective amount of the compounds or pharmaceutical compositions disclosed herein to a subject in need. In certain embodiments, the disease or disorder is an inflammatory disease associated with A20 SNPs.

[0137] Various specific diseases and disorders are described below. In certain embodiments, a disease or disorder is necrotizing enterocolitis, tuberous sclerosis, Tangier disease, Wolmann syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, non-contagious inflammatory skin diseases (ncISDs) such as psoriasis or atopic dermatitis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis (e.g., acute pancreatitis), interfacial dermatitis (e.g., cutaneous lupus erythematosus, lichen planus, keratosis pilaris, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, graft-versus-host disease (GvHD), alopecia areata, vitiligo), atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis Inflammation, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular disease, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, atopic dermatitis, multiple sclerosis, type 1 diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converting enzyme-associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndromes, periodontitis, bacterial infections, Staphylococcus infections, Mycobacterium infections, retinitis pigmentosa, influenza, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), acute respiratory response syndrome (ARDS), transplant rejection, burns, or hypoxia. In certain embodiments, the disease or disorder is trauma, ischemia, stroke, myocardial infarction, infection, lysosomal storage disorder, Niemann-Pick disease, Gaucher disease, Krabbe disease, sepsis, systemic inflammatory response syndrome (SIRS), Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's disease), Huntington's disease, HIV-related dementia, encephalopathy, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, non-communicable inflammatory skin disease (ncISD) such as psoriasis or atopic dermatitis, psoriatic arthritis, or inflammatory bowel disease.In certain embodiments, the disease or disorder is Alzheimer's disease, ALS, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (PolyQ) disease, stroke, Fahl's disease, Menkes disease, Wilson's disease, cerebral ischemia, lysosomal storage disease, or prion disorder. In certain embodiments, the disease is ALS. In certain embodiments, the disease is Alzheimer's disease. In certain embodiments, the disease is lysosomal storage disease. In certain embodiments, the disease is Parkinson's disease. In certain embodiments, the disorder is ischemic disease of organs, including but not limited to the brain, heart, kidneys, and liver. In some different embodiments, the disorder is an ocular disorder such as retinal degenerative disease, glaucoma, or age-related macular degeneration. In some different embodiments, the disorder is a central nervous system (CNS) disorder.

[0138] In certain embodiments, a method is provided for treating rheumatoid arthritis (see Lawlor KE, Nat Commun. 2015, p. 6282; Lee SH, Sci Rep. 2017, p. 10133), systemic onset juvenile idiopathic arthritis (SoJIA), spondyloarthritis, osteoarthritis, non-communicable inflammatory skin diseases (ncISDs) such as psoriasis or atopic dermatitis, Crohn's disease, ulcerative colitis, or multiple sclerosis, comprising administering a therapeutically effective amount of a compound provided herein to a subject in need thereof. In certain embodiments, a method is provided for treating autoimmune hepatitis, atherosclerosis, neutrophilic dermatosis, or rare diseases driven by A20, NEMO, and / or LUBAC mutations, comprising administering a therapeutically effective amount of a compound provided herein to a subject in need thereof.

[0139] In certain embodiments, the compounds and compositions are useful for treating non-communicable inflammatory skin diseases (ncISDs) such as psoriasis or atopic dermatitis.

[0140] In certain embodiments, the disorder is an inflammatory bowel disease, e.g., Crohn's disease or ulcerative colitis (both commonly known together as inflammatory bowel disease, IBD). In certain embodiments, the mammal is a primate, dog, or cat subject. In certain embodiments, the mammal is a human subject. While not bound by theory, it is believed that inhibition of receptor-coupled protein kinase 1 by the currently disclosed compounds is at least partially involved in their anti-inflammatory activity. Accordingly, embodiments of the present disclosure also include methods for inhibiting receptor-coupled protein kinase 1 in vitro or in subjects where it is required, the methods comprising contacting receptor-coupled protein kinase 1 with the compounds disclosed herein. In some of these embodiments, inhibition of receptor-coupled protein kinase 1 is effective in blocking (partially or completely) the release of inflammatory mediators, e.g., TNF and / or IL-6.

[0141] Inflammatory diseases or disorders Inflammatory diseases and disorders can be treated using receptor-coupled protein kinase 1 inhibitors described herein. Inflammatory diseases and disorders typically exhibit high levels of inflammation or degeneration of connective tissue.

[0142] Non-exclusive examples of inflammatory diseases and disorders include Alzheimer's disease, ankylosing spondylitis, arthritis including osteoarthritis, rheumatoid arthritis (RA), non-communicable inflammatory skin diseases (ncISDs) such as psoriasis or atopic dermatitis, asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), nephritis, Parkinson's disease, and ulcerative colitis. In certain embodiments, the compounds and compositions of this disclosure are useful for treating autoimmune disorders, such as rheumatoid arthritis, psoriasis, psoriatic arthritis, encephalitis, allograft rejection, autoimmune thyroid diseases (e.g., Graves' disease and Hashimoto's thyroiditis), autoimmune uretinitis, giant cell arteritis, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, focal colitis, granulomatous colitis, distal ileitis, focal ileitis, and terminal ileitis), insulin-dependent diabetes mellitus, multiple sclerosis, pernicious anemia, sarcoidosis, scleroderma, and systemic lupus erythematosus. In one embodiment, the receptor-coupled protein kinase 1 inhibitors described herein are useful for treating autoimmune encephalitis. In certain embodiments, the compounds and compositions are useful for treating rheumatoid arthritis (RA). In certain embodiments, the compounds and compositions are useful for treating ulcerative colitis. In certain embodiments, the compounds and compositions are useful for treating non-communicable inflammatory skin diseases (ncISDs) such as psoriasis or atopic dermatitis.

[0143] In certain embodiments, the disorder is an inflammatory bowel disease such as Crohn's disease or ulcerative colitis (both commonly known together as inflammatory bowel disease). In certain embodiments, the mammal is a primate, canid, or feline subject. In certain embodiments, the mammal is a human subject. While we do not wish to be bound by theory, it is thought that the inhibition of receptor-interacting protein kinase 1 by the currently disclosed compounds is at least partially responsible for its anti-inflammatory activity.

[0144] Accordingly, embodiments of the present disclosure also include methods for inhibiting receptor-interacting protein kinase 1 either in vitro or in an object where such inhibition is required, comprising the step of contacting receptor-interacting protein kinase 1 with a compound disclosed herein. In some of these embodiments, inhibition of receptor-interacting protein kinase 1 is effective in blocking (partially or completely) the release of inflammatory mediators such as TNF and / or IL-6.

[0145] In another embodiment, the receptor-interacting protein kinase 1 inhibitors described herein may be used to treat inflammatory diseases and disorders such as rheumatoid arthritis (RA), psoriasis, Crohn's disease, or inflammatory bowel disease (IBD), such as ulcerative colitis.

[0146] In another embodiment, the receptor-interacting protein kinase 1 inhibitors described herein may be used to treat interfacial dermatitis such as cutaneous lupus erythematosus (CLE), lichen planus (LP), toxic epidermal necrolysis (TEN), or Stevens-Johnson syndrome (SJS).

[0147] In another embodiment, the receptor-interacting protein kinase 1 inhibitors described herein may be used to treat hyperinflammation during viral infections such as coronavirus disease 19 (COVID-19), acute respiratory distress syndrome (ARDS), and systemic inflammatory response syndrome (SIRS).

[0148] In another embodiment, the receptor-interacting protein kinase 1 inhibitors described herein may be used to treat coronavirus disease 19 (COVID-19).

[0149] In another embodiment, the receptor-interacting protein kinase 1 inhibitors described herein may be used to treat respiratory diseases such as influenza (e.g., swine influenza, H7N9), severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), respiratory syncytial virus (RSV), or bronchiolitis.

[0150] Necrotic cell disease The compounds described herein may be used to treat diseases / disorders caused by or otherwise related to cell necrosis. In particular, this disclosure provides a method for preventing or treating a disorder in a mammal that is related to cell necrosis, comprising the step of administering a therapeutically effective amount of the compound or composition described herein to the mammal. The term “necrotic cell disease” means a disease that is related to or caused by cell necrosis, for example, trauma, ischemia, stroke, myocardial infarction, infection, Gaucher disease, Krabbe disease, sepsis, systemic inflammatory response syndrome (SIRS), Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, HIV-related dementia, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, non-communicable inflammatory skin diseases (ncISDs) such as psoriasis or atopic dermatitis, psoriatic arthritis, or inflammatory bowel disease.

[0151] Necrotic cell diseases may also be acute conditions such as trauma, ischemia, stroke, myocardial infarction, anthrax lethal toxin-induced septic shock, sepsis, systemic respiratory response syndrome (SIRS), LPS-induced cell death, and HIV-induced T-cell death resulting in immunodeficiency. In certain embodiments, the disorder may be ischemic disease of organs including, but is not limited to, the brain, heart, kidneys, and liver.

[0152] Necrotic cell diseases also include chronic neurodegenerative diseases, such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, infectious encephalopathy, and dementia, such as HIV-associated dementia. In some different embodiments, the disorder is an eye disorder, such as retinal degenerative disease, glaucoma, or age-related macular degeneration. In some different embodiments, the disorder is a central nervous system (CNS) disorder.

[0153] Neurodegenerative and CNS diseases Neurodegenerative diseases can also be treated using receptor-coupled protein kinase 1 inhibitors described herein. Neurodegenerative diseases can affect many bodily functions, such as balance, movement, speech, respiration, and cardiac function. Neurodegenerative diseases can be genetic or caused by medical conditions, such as alcoholism, tumors, stroke, toxins, chemicals, and viruses. Non-limited examples of neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Lewy body dementia, Parkinson's disease, and spinal muscular atrophy. In certain embodiments, neurodegenerative diseases and CNS diseases include Niemann-Pick disease type C1 (NPC1), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Lewy body dementia, Parkinson's disease, and spinal muscular atrophy.

[0154] In certain embodiments, NPC1 can be treated by inhibiting necroptosis resulting in neuronal loss using receptor-coupled protein kinase 1 inhibitors described herein. In certain embodiments, the compounds and compositions of the Disclosure are useful for treating Alzheimer's disease. In certain embodiments, the compounds and compositions of the Disclosure are useful for treating Parkinson's disease. In certain embodiments, the compounds and compositions of the Disclosure are useful for treating amyotrophic lateral sclerosis (ALS).

[0155] More generally, receptor-coupled protein kinase 1 inhibitors described herein can be used to preserve neuronal viability and promote axonal growth and neuronal function within the central nervous system (CNS). Thus, by using these compounds to preserve neuronal viability and / or promote axonal regeneration and / or neuronal function, the loss of cognitive, motor, and sensory functions associated with CNS disease or impairment may be reduced, or even reversed.

[0156] The receptor-coupled protein kinase 1 inhibitors described herein can be used in methods to promote axonal regeneration in CNS neurons, such as CNS sensory neurons, motor neurons, cortical neurons, cerebellar neurons, hippocampal neurons, and midbrain neurons. Following injury to CNS neurons, the receptor-coupled protein kinase 1 inhibitors described herein can be used in methods to promote neuronal function or preserve viability. In another embodiment, these compounds can be used to promote axonal regeneration in degenerated CNS neurons in CNS disease or injury. RIP receptor-coupled protein kinase 1 inhibitors can be administered by any conventional means, for example, topically to neurons or applied ex vivo before reimplantation.

[0157] Accordingly, in one embodiment, the present disclosure provides a method for treating CNS disorder in a subject in need, where the symptoms of CNS disorder are degeneration or injury of axons within CNS neurons. The method comprises administering an effective amount of the compound or composition disclosed herein to a subject, thereby promoting axonal regeneration in CNS neurons affected by the CNS disorder. Following administration, neuronal function may be measured, for example, as an expression of axonal regeneration. It is also intended that, following administration of the compound or composition, the neuronal function of the CNS neurons is preserved or improved compared to the neuronal function prior to administration.

[0158] Non-limiting examples of CNS diseases or disorders include brain injury, spinal cord injury, dementia, stroke, Alzheimer's disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's disease), Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (PolyQ) disease, stroke, Fahl's disease, Menkes disease, Wilson's disease, cerebral ischemia, and prion diseases.

[0159] In exemplary embodiments, the CNS injury is either a brain injury or a spinal cord injury.

[0160] Also provided herein are methods for promoting neuronal survival and axonal regeneration in the CNS. CNS disorders, characterized by impaired or declining axonal growth or axonal degeneration, may result from CNS neuronal injury (e.g., trauma, surgery, nerve compression, nerve contusion, nerve transection, neurotoxicity, or other physical injury to the brain or spinal cord) or neurodegenerative CNS diseases, and symptoms of the disorder include axonal degeneration (e.g., Alzheimer's disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's disease), Parkinson's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (PolyQ) disease, stroke, Fahl's disease, Menkes disease, Wilson's disease, cerebral ischemia, and prion disorders (e.g., Creutzfeldt-Jakob disease). In certain embodiments, the CNS disorder is a brain injury (e.g., traumatic brain injury) or a spinal cord injury (e.g., chronic, acute, or traumatic spinal cord injury). In certain embodiments, a CNS disorder, such as an injury to the brainstem or an aneurysm in the brainstem, affects the subject's basic and vital vital functions, such as respiration, heart rate, and blood pressure. In certain embodiments, a CNS disorder or impairment affects the subject's cognitive abilities. In certain embodiments, a CNS disorder or impairment affects the subject's motor and / or strength. In certain embodiments, a CNS disorder or impairment affects the subject's coordination.

[0161] In certain embodiments, CNS disorders, such as brain damage to the cerebral cortex, or neurodegenerative CNS disorders, such as Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, and prion disorders, affect the cognitive abilities of the subject.

[0162] In certain embodiments, CNS disorders, such as injuries to the brain or spinal cord, or neurodegenerative CNS disorders, such as Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, Huntington's disease, multiple system atrophy, amyotrophic lateral sclerosis, and hereditary spastic paresis, affect the subject's movement and / or intensity.

[0163] In certain embodiments, CNS disorders, such as brain injury to the cerebellum or neurodegenerative CNS disorders, such as spinocerebellar atrophy, Friedreich's ataxia, and prion disorders, affect the coordination of the subject.

[0164] In each of the above methods, CNS disorders include, but are not limited to, brain injury, spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's disease), Parkinson's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (PolyQ) disorders, stroke, Fahl's disease, Menkes' disease, Wilson's disease, cerebral ischemia, prion disorders (e.g., Creutzfeldt-Jakob disease), dementia (e.g., frontotemporal dementia, dementia with Lewy bodies), corticobasal degeneration, progressive supranuclear palsy, multiple system atrophy, hereditary spastic paraplegia, and spinocerebellar atrophy.

[0165] Non-limited examples of neurodegenerative diseases include Alzheimer's disease, lysosomal storage disorders, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Lewy body dementia, Parkinson's disease, and spinal muscular atrophy.

[0166] In certain embodiments, the compounds and compositions of the Disclosure are useful for the treatment of Alzheimer's disease. In certain embodiments, the compounds and compositions of the Disclosure are useful for the treatment of Parkinson's disease. In certain embodiments, the compounds and compositions of the Disclosure are useful for the treatment of amyotrophic lateral sclerosis (ALS). In certain embodiments, the compounds and compositions of the Disclosure are useful for the treatment of lysosomal storage disorders.

[0167] In certain embodiments, the disorders are brain disorders such as, but are not limited to, Alzheimer's disease, ALS, frontotemporal dementia, vascular dementia, Huntington's disease, Parkinson's disease, Ruby body dementia, progressive supranuclear palsy, multiple sclerosis, neuromyelitis optica, ischemic brain injury (stroke), hypoxic brain injury, traumatic brain injury, spinal cord injury, sepsis-induced brain injury, CNS infection, CNS abscess, glioblastoma multiforme, epilepsy, neuropathic pain, major depressive disorder, bipolar disorder, schizophrenia, autism, Niemann-Pick disease, and neuro-Behçet's disease.

[0168] In certain embodiments, a method is provided for treating a CNS disease or disorder, comprising the step of administering a therapeutically effective amount of the compound provided herein to a subject in need thereof. In certain embodiments, the disease or disorder is Alzheimer's disease or amyotrophic lateral sclerosis (ALS).

[0169] Eye condition The receptor-coupled protein kinase 1 inhibitors described herein can also be used to treat eye conditions, for example, to reduce or prevent the loss of photoreceptor and / or retinal pigment epithelial cell viability.

[0170] In certain embodiments, the Disclosure provides a method for preserving the visual function of an eye having an eye condition, the symptom of which is a loss of viability of photoreceptor cells in the retina of the eye having the condition. The method comprises administering an effective amount of the compound or composition described herein to the eye of the subject, thereby preserving the viability of photoreceptor cells located in the retina of the eye. After administration, the visual function of the eye (e.g., visual acuity) may be preserved or improved compared to the visual function of the eye before administration.

[0171] The eye condition may be age-related macular degeneration (AMD), retinitis pigmentosa (RP), macular edema, diabetic retinopathy, central ring-spot choroidal dystrophy, Best's disease, adult yolk-like disease, pattern dystrophy, myopic degeneration, central serous retinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis, or photo-induced toxicity. AMD may be a neovascular or dry form of AMD. Retinal detachment may be rhegmatogenous, serous, or tractional retinal detachment. In certain embodiments, the eye condition may be geographic atrophy, glaucoma, or another ischemic eye disease. In certain embodiments, the disclosure provides a method for protecting the survival of retinal pigment epithelial (RPE) cells in the retina of a subject having an eye condition by administration of the compounds of the disclosure. The subject to be treated may have loss of retinal pigment epithelial cells in the retina of an eye having a condition, which may be age-related macular degeneration (AMD), Best's disease, myopic degeneration, Stargardt disease, uveitis, adult vitiligo macular degeneration, retinal macula, multiple disappearing white spot syndrome, creeping choroidopathy, acute posterior multiple plaque epithelial disease (AMPPE), or another uveitis disorder. In certain embodiments, the method includes administering an effective amount of the compound or composition described herein to the eye of the subject, thereby protecting the survival of retinal pigment epithelial cells. In another embodiment, a method is provided to protect the survival of photoreceptors located in the retina of a subject having age-related macular degeneration (AMD), retinitis pigmentosa (RP), macular edema, diabetic retinopathy, centrally serous chorioretinopathy, Best's disease, adult vitelliform disease, patterned macular dystrophy, myopic degeneration, central serous chorioretinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis, or photo-induced toxicity. Thus, in a particular embodiment, the method comprises administering an effective amount of the compound or composition described herein to the eye, thereby preserving the viability of photoreceptor cells located in the retina of a subject having the condition.In another embodiment, a method is provided for protecting the viability of photoreceptor cells in the retina of a mammalian eye after retinal detachment. Retinal detachment may be rhegmatogenous retinal detachment, tractional retinal detachment, or serous retinal detachment. In other embodiments, retinal detachment may occur as a result of a retinal tear, retinoblastoma, melanoma or other cancer, diabetic retinopathy, uveitis, choroidal neovascularization, retinal ischemia, pathological myopia, or trauma. In certain embodiments, the method involves administering a compound or composition described herein to an eye in which a region of the retina is detached in an amount sufficient to preserve the viability of photoreceptor cells located within the detached region of the retina. In another embodiment, the Disclosure provides a method for protecting the visual function of the eye of a subject having age-related macular degeneration (AMD), retinitis pigmentosa (RP), macular edema, centrally serous chorioretinopathy, retinal detachment, diabetic retinopathy, Best's disease, adult yolk-like disease, patterned macular dystrophy, myopic degeneration, central serous chorioretinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis, or photo-induced toxicity, wherein the symptoms of the eye condition are loss of photoreceptor cell viability in the retina of the eye, and the Method provides a method comprising the step of treating the subject with a compound or composition described herein to the subject. In another embodiment, the Disclosure provides a method for preserving the visual function of the eye of a subject having an eye condition, wherein the symptoms of the eye condition are loss of photoreceptor cell viability and / or RPE viability in the retina of the eye, and the Method comprises treating the subject with a compound or composition described herein to the subject.

[0172] In a particular embodiment, a method is provided for preserving the visual function of an eye having an eye condition, where the symptom of the eye condition is a loss of viability of retinal ganglion cells in the retina of the eye having the condition. The method comprises administering an effective amount of a compound or composition to the eye of the subject, thereby preserving the viability of retinal ganglion cells located within the retina of the eye. After administration of the compound or composition, the visual function of the eye may be preserved or improved compared to the visual function of the eye before administration. Furthermore, after administration, the preserved retinal ganglion cells can support axonal regeneration.

[0173] Non-limited examples of symptoms related to eye conditions include loss of survival of retinal ganglion cells in the retina of the eye, glaucoma, optic nerve injury, optic neuritis, optic neuropathy, diabetic retinopathy, central retinal artery occlusion, and central retinal vein occlusion. The compounds described herein may also be used to treat optic neuropathy such as ischemic neuropathy (e.g., arteritis or non-arteritic anterior and posterior ischemic optic neuropathy), compressive optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (e.g., Leber optic neuropathy), nutritional optic neuropathy, toxic optic neuropathy, and hereditary optic neuropathy (e.g., Leber optic neuropathy, dominant optic atrophy, Baer syndrome).

[0174] Also disclosed is a method for preserving the visual function of an eye in a subject having glaucoma, optic nerve injury, optic neuropathy, diabetic retinopathy, central retinal artery occlusion, or central retinal vein occlusion. This method comprises administering an effective amount of the compound or composition described herein to the eye of a subject, thereby preserving the viability of retinal ganglion cells located within the retina of the eye and the visual function of the eye.

[0175] In another embodiment, disclosed herein is a method for preserving the viability of retinal ganglion cells located within the retina of a mammalian eye affected by, for example, glaucoma, optic nerve injury, optic neuritis, optic neuropathy, diabetic retinopathy, central retinal artery occlusion, and central retinal vein occlusion. The method comprises administering a compound or composition described herein to an affected eye in an amount sufficient to preserve the viability of retinal ganglion cells located within the affected retinal region. The preserved retinal ganglion cells can support axonal regeneration and are effective against linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, malignancies of the hematological and parenchymal organs, bacterial and viral infections (e.g., tuberculosis and influenza or SARS coronavirus), and lysosomal storage disorders.

[0176] Non-exclusive examples of lysosomal storage disorders include Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosamiuria, cholesteryl ester storage, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Faber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic cerebral leukodea, mucopolysaccharidosis, multiple sulfatase deficiencies, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, concentrated dysostosis, Sandhoff disease, Schindler disease, sialic acid storage, Tay-Sachs disease, and Wolmann disease. In certain embodiments, compounds and compositions for use in pharmaceuticals are provided. In certain embodiments, the compounds and compositions are for use in the treatment of diseases or disorders mediated by receptor-coupled protein kinase 1. Also provided are methods for treating receptor-coupled protein kinase 1-mediated diseases or disorders, comprising administering a therapeutically effective amount of the compounds or pharmaceutical compositions disclosed herein to a subject in need. In other embodiments, the disclosure provides a method for inhibiting receptor-coupled protein kinase 1. The method comprises contacting receptor-coupled protein kinase 1 with an effective amount of the compounds described herein. Inhibition of receptor-coupled protein kinase 1 generally involves contacting receptor-coupled protein kinase 1 with an amount of the compound sufficient to reduce the activity of receptor-coupled protein kinase 1 compared to receptor-coupled protein kinase 1 in the absence of the compound. For example, contact of receptor-coupled protein kinase 1 with the compound can result in about 1% to about 99% inhibition of receptor-coupled protein kinase 1 (i.e., the activity of the inhibited enzyme ranges from 99% to 1% of the enzyme activity in the absence of the compound).The level of receptor-interacting protein kinase 1 inhibition can range from about 1% to about 10%, or about 10% to about 20%, or about 20% to about 30%, or about 30% to about 40%, or about 40% to about 50%, or about 50% to about 60%, or about 60% to about 70%, or about 70% to about 80%, or about 80% to about 90%, or about 90% to about 99%. The level of receptor-interacting protein kinase 1 inhibition can range from about 5% to about 95%, or about 10% to about 90%, or about 20% to about 80%, or about 30% to about 70%, or about 40% to about 60%. In some embodiments, contact of receptor-interacting protein kinase 1 with the compounds described herein results in complete (i.e., 100%) inhibition.

[0177] Combination therapy In certain embodiments, the compounds described herein may be administered in combination with at least one other therapeutically active agent. Two or more agents may be administered simultaneously, simultaneously formulated, or individually. In certain embodiments, other therapeutically active agents include thrombolytic agents, tissue plasminogen activators, anticoagulants, platelet aggregation inhibitors, antimicrobial agents (antibiotics, broad-spectrum antibiotics, lactams, antimycobacterial agents, bactericidal antibiotics, anti-MRSA agents), long-acting beta-agonists, combinations of inhaled corticosteroids and long-acting beta-agonists, short-acting beta-agonists, leukotriene modulators, anti-IgE, methylxanthine bronchodilators, mast cell inhibitors, protein tyrosine kinase inhibitors, CRTH2 / D prostanoid receptor antagonists, epinephrine inhalation aerosol, phosphodiesterase inhibitors, combinations of phosphodiesterase-3 and phosphodiesterase-4 inhibitors, long-acting inhaled anticholinergics, muscarinic antagonists, long-acting muscarinic antagonists, low-dose steroids, inhaled corticosteroids, oral corticosteroids, topical corticosteroids, antithymocyte globulin, thalidomide, chlorambushi The following are selected from: calcium channel blockers, topical emollients, ACE inhibitors, serotonin reuptake inhibitors, endothelin-I receptor inhibitors, antifibrotic agents, proton pump inhibitors, cystic fibrosis transmembrane conductance regulator enhancers, mucolytic agents, pancreatic enzymes, bronchodilators, intravitreous injections, antivascular endothelial growth factor inhibitors, ciliary neurotrophic growth factor agents, trivalent (IIV3) influenza inactivated vaccine, quadrivalent (IIV4) influenza inactivated vaccine, trivalent recombinant influenza vaccine, quadrivalent influenza attenuated live vaccine, antiviral agents, influenza inactivated vaccine, ciliary neurotrophic growth factor, gene transfer agents, topical immune modulators, calcineurin inhibitors, interferon gamma, antihistamines, monoclonal antibodies, polyclonal anti-T cell antibodies, anti-thymocyte gamma globulin-equine antibodies, anti-thymocyte globulin-rabbit antibodies, anti-CD40 antagonists, JAK inhibitors, and anti-TCR mouse mAbs.

[0178] Other exemplary therapeutically active agents include heparin, coumadin, clopidol gel, dipyridamole, ticlopidine HCl, eptifivatide, aspirin, vancomycin, cefeprime, combination of piperacillin and tazobactam, imipenem, meropenem, doripenem, ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, hydrocortisone, vedolizumab, aricahorsen, remestemcell-L, ixekizumab, tildrakizumab, secukinumab, chlorhexidine, doxycycline, minocycline, and fluticasone. Fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, triamcinolone acetonide, flunisolide, mometasone furoate, ciclesonide, alformoterol tartrate, formoterol fumarate, salmeterol xinafoate, albuterol (albuterol sulfate), revalbuterol tartrate, ipratropium bromide, montelukast sodium, zafirlukast, dileuton, omalizumab, theophylline, cromolyn sodium, nedocromil sodium, masitinib, AMG853, indacaterol Lu, E004, reslizumab, salbutamol, tiotropium bromide, VR506, lebrikizumab, RPL554, aflibercept, umeclidinium, indacaterol maleate, acridinium bromide, roflumilast, SCH527123, glycopyrronium bromide, olodaterol, combination of fluticasone furoate and vilanterol, combination of fluticasone propionate and salmeterol, combination of fluticasone furoate and fluticasone propionate, combination of fluticasone propionate and formoterol fumarate dihydrate, formoterol Combinations of ru and budesonide, combination of beclomethasone dipropionate and formoterol, combination of mometasone furoate and formoterol fumarate dihydrate, combination of umeclidinium and vilanterol, combination of ipratropium bromide and albuterol sulfate, combination of glycopyrronium bromide and indacaterol maleate, combination of glycopyrrolate and formoterol fumarate, combination of acridinium and formoterol, isoniazid, ethambutol, rifampin, pyrazinamide, rifabutin, rifapentin, capreomycin,Levofloxacin, Moxifloxacin, Ofloxacin, Ethionamide, Cycloserine, Kanamycin, Streptomycin, Biomycin, Bedaquiline Fumarate, PNU-100480, Delamanid, Imatinib, ARG201, Tocilizumab, Muromonab-CD3, Basiliximab, Daclizumab, Rituximab, Prednisolone, Antithymocyte Globulin, FK506 (Tacrolimus), Methotrexate, Cyclosporine, Sirolimus, Everolimus, Sodium Mycophenolate, Mofetil Mycophenolate, Cyclophosphamide Azathioprine, thalidomide, chlorambucil, nifedipine, nicardipine, nitroglycerin, lisinopril, diltiazem, fluoxetine, bosentan, epoprostenol, colchicine, para-aminobenzoic acid, dimethyl sulfoxide, D-penicillamine, interferon alpha, interferon gamma (INF-g), omeprazole, metoclopramide, lansoprazole, esomeprazole, pantoprazole, rabeprazole, imatinib, belimumab, ARG201, tocilizumab, ibaftol, dorunazeal Fa, pancrelipase, tobramycin, aztreonam, colistimethate sodium, cefadroxil monohydrate, cefazolin, cephalexin, cefazolin, moxifloxacin, levofloxacin, gemifloxacin, azithromycin, gentamicin, ceftazidime, combination of trimetaprim and sulfamethoxazole, chloramphenicol, combination of ibakhtol and lumakhtol, atallen, NT-501-CNTF, gene transdermal agent encoding myosin VIIA (MY07A), ranibizumab, pegaptanib sodium Um, NT501, humanized sphingomab, bevacizumab, oseltamivir, zanamivir, rimantadine, amantadine, nafcillin, sulfamethoxazole, trimetaprim, sulfasalazine, acetylsulfisoxazole, vancomycin, muromonab-CD3, ASKP-1240, ASP015K, TOL101, pimecrolimus, hydrocortisone, betamethasone, flurandrenolide, triamcinolone, fluocinonide, clobetasol, hydrocortisone, methylprednisolone, prednisolone,These include recombinant synthetic type I interferon, interferon alpha-2a, interferon alpha-2b, hydroxyzine, diphenhydramine, flucloxacillin, dicloxacillin, and erythromycin.

[0179] The compounds described herein may be administered orally or in combination with other anti-inflammatory biological agents for any of the above applications, including localized corticosteroids, anti-TNF agents, 5-aminosalicylic acid and mesalamine preparations, hydroxychloroquine, thiopurine, methotrexate, cyclophosphamide, cyclosporine, calcineurin inhibitors, mycophenolic acid, mTOR inhibitors, JAK inhibitors, Syk inhibitors, anti-IL6 biopharmaceuticals, anti-IL1 agents, anti-IL17 biopharmaceuticals, anti-CD22, anti-integrin agents, anti-IFNa, anti-CD20 or CD4 biopharmaceuticals, as well as other cytokine inhibitors or biopharmaceuticals against T cell or B cell receptors or interleukins.

[0180] In the treatment of ALS, the compounds described herein may be administered in combination with riluzole.

[0181] In the treatment of Parkinson's disease, the compounds described herein may be administered in combination with levodopa, carbidopa, or a combination thereof, pramipexole, ropinirole, rotigotine, selegiline, rasagiline, entacapone, tolcapone, benztropine, trihexyphenidyl, or amantadine.

[0182] In the treatment of Alzheimer's disease, the compounds described herein may be administered in combination with anti-ABeta (amyloid beta) therapies including donepezil, galantamine, memantine, rivastigmine, aducanumab, crenezumab, solanezumab, and gantenerumab; small molecule inhibitors of BACE1 including verbecestat, AZD3293 (LY3314814), elenbecestat (E2609), LY2886721, PF-05297909, JNJ-54861911, TAK-070, VTP-37948, HPP854, and CTS-21166; or anti-tau therapies such as LMTM (leucomethylthioninium-bis(hydromethanesulfonate®)).

[0183] In the treatment of rheumatoid arthritis, the compounds described herein may be administered in combination with ibuprofen, naproxen, prednisone, methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, tocilizumab, or tofacitinib.

[0184] In the treatment of CVA, the compounds described herein may be administered in combination with thrombolytic agents (e.g., tissue plasminogen activator), anticoagulants (e.g., heparin, coumadin, clopidol gel), and platelet aggregation inhibitors (e.g., dipyridamole, ticlopidine HCl, eptifbatide, and / or aspirin).

[0185] In the treatment of SIRS, the compounds described herein may be administered in combination with broad-spectrum antibiotics (e.g., vancomycin) or other anti-MRSA agents (cefeprime, piperacillin / tazobactam, carbapenems (imipenem, meropenem, doripenem), quinolones (ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, etc.)) and low-dose steroids such as hydrocortisone.

[0186] In the treatment of inflammatory bowel disease (particularly Crohn's disease and / or ulcerative colitis), any compound of any of the formulas described herein may be administered in combination with vedolizumab, alicahorsen, or remestemcell-L. In particular, in the treatment of inflammatory bowel disease (particularly Crohn's disease and / or ulcerative colitis), the compounds described herein may be administered in combination with alicahorsen, or remestemcell-L.

[0187] In the treatment of non-communicable inflammatory skin diseases (ncISDs) such as psoriasis or atopic dermatitis, the compounds described herein may be administered in combination with ixekizumab, tildrakizumab (MK-3222), or secukinumab (AIN457).

[0188] In particular, in the treatment of non-communicable inflammatory skin diseases (ncISDs) such as psoriasis or atopic dermatitis, the compounds described herein may be administered in combination with ixekizumab or tildrakizumab (MK-3222). In the treatment of periodontitis, any compound of any of the formulas described herein may be administered in combination with an antibacterial agent (e.g., chlorhexidine) or an antibiotic (e.g., doxycycline or minocycline).

[0189] In the treatment of asthma, any compound of any of the formulas described herein is an inhaled corticosteroid ((ICS), e.g., fluticasone propionate, beclomethasone dipropionate, budesonide (Pulmicort), triamcinolone acetonide, flunisolide, mometasone furoate, or ciclesonide), a long-acting beta-agonist ((LABA), e.g., formoterol fumarate, salmeterol xinafoate), a combination of ICS and LABA (e.g., fluticasone furoate and vilanterol, formoterol / budesonide inhalation, beclomethasone dipropionate / formoterol, and fluticasone propionate / salmeterol It may be administered in combination with (e.g., olol), short-acting beta-agonists ((SABA) e.g., albuterol sulfate, levalbuterol tartrate, ipratropium bromide / albuterol, ipratropium bromide), leukotriene modulators (e.g., montelukast sodium, zafirlukast, or dileuton), and anti-IgE (e.g., omalizumab), methylxanthine bronchodilators (e.g., theophylline), mast cell inhibitors (e.g., cromolyn sodium and nedocromil sodium), and long-acting muscarinic antagonists ((LAMA) e.g., mometasone furoate / formoterol fumarate dihydrate).

[0190] Other medications that may be suitable for use in combination therapy for the treatment of asthma include protein tyrosine kinase inhibitors (masitinib), CRTH2 / D-prostanoid receptor antagonists (AMG853), indacaterol, epinephrine inhalation aerosol (E004), fluticasone furoate / fluticasone propionate, vilanterol inhalation / fluticasone furoate powder, fluticasone propionate / formoterol fumarate dihydrate, reslizumab, salbutamol dry powder inhalation, tiotropium bromide, formoterol / budesonide, fluticasone furoate, Vectura VR506, lebrikizumab (RG3637), and combinations of phosphodiesterase (PDE)-3 and (PDE)-4 inhibitors (RPL554).

[0191] In the treatment of COPD, any compound of any of the formulas described herein is used as LABA (e.g., salmeterol xinafoate, umeclidinium / vilanterol, umeclidinium, alformoterol tartrate, formoterol fumarate inhalation powder, indacaterol maleate, or fluticasone propionate / formoterol fumarate anhydride), long-acting inhaled anticholinergics (or muscarinic antagonists, e.g., tiotropium bromide and acridinium bromide), phosphodiesterase (PDE-r) inhibitors (e.g., Lof It may be administered in combination with Lumilast (Darilesp), ICS / LABA combinations (e.g., fluticasone fluate and vilanterol, fluticasone propionate / salmeterol, budesonide / formoterol, mometasone / formoterol, ipratropium bromide / albuterol sulfate, albuterol / ipratropium), SABA (e.g., ipratropium bromide and albuterol sulfate), and ICS (e.g., budesonide and fluticasone propionate, beclomethasone dipropionate).

[0192] Other drugs that may be suitable for use in combination therapy for the treatment of COPD include SCH527123 (CXCR2 antagonist), glycopyrronium bromide (NVA237), glycopyrronium bromide and indacaterol maleate (QVA149), glycopyrrolate and formoterol fumarate (PT003), indacaterol maleate (QVA149), olodaterol, tiotropium / olodaterol, and acridinium / formoterol inhalation.

[0193] In the treatment of Mycobacterium infections (tuberculosis), any compound of any of the formulas described herein may be administered in combination with antimycobacterial agents (e.g., isoniazid (INH), ethambutol, rifampin, and pyrazinamide), bactericidal antibiotics (e.g., rifabutin or rifapentin, aminoglycosides (capreomycin), fluoroquinolones (levofloxacin, moxifloxacin, ofloxacin), thioamides (ethionamide), cyclosporine, para-aminosalicylic acid, cycloserine, kanamycin, streptomycin, biomycin, capreomycin, bedaquiline fumarate, oxazolidinone, or delamanid (OPC-67683)).

[0194] In particular, in the treatment of Mycobacterium infections (tuberculosis), the compounds described herein may be administered in combination with antimycobacterial agents (e.g., isoniazid (INH), ethambutol, rifampin, and pyrazinamide), bactericidal antibiotics (e.g., rifabutin or rifapentin, aminoglycosides (capreomycin), fluoroquinolones (levofloxacin, moxifloxacin, ofloxacin), thioamides (ethionamide), cycloserine, kanamycin, streptomycin, biomycin, capreomycin, bedaquiline fumarate, oxazolidinone, or delamanid (OPC-67683)).

[0195] In the treatment of systemic sclerosis, any compound of any of the formulas described herein is an oral corticosteroid (e.g., prednisolone), immunosuppressants (e.g., methotrexate, cyclosporine, antithymocyte globulin, mycophenolate mofetil, cyclophosphamide, FK506 (tacrolimus), thalidomide, chlorambucil, azathioprine), calcium channel blockers (e.g., nifedipine or nicardipine), topical emollients (nitroglycerin ointment), ACE inhibitors (e.g., lisinopril), serotonin reuptake inhibitors. It may be administered in combination with harmful agents (e.g., fluoxetine), endothelin-I receptor inhibitors (e.g., bosentan or epoprostenol), antifibrotic agents (e.g., colchicine, para-aminobenzoic acid (PABA), dimethyl sulfoxide (DMSO), and D-penicillamine, interferon alpha and interferon gamma (INF-g)), proton pump inhibitors (e.g., omeprazole, metoclopramide, lansoprazole, esomeprazole, pantoprazole, rabeprazole), or imatinib, ARG201 (arGentis Pharmaceutical), belimumab, or tocilizumab.

[0196] In particular, in the treatment of systemic sclerosis, any compound of any of the formulas described herein is used in conjunction with oral corticosteroids (e.g., prednisolone), antithymocyte globulin, FK506 (tacrolimus), thalidomide, chlorambucil, calcium channel blockers (e.g., nifedipine or nicardipine), topical emollients (nitroglycerin ointment), ACE inhibitors (e.g., lisinopril), diltiazem, serotonin reuptake inhibitors (e.g., fluoxetine), and endothelin-I receptor inhibitors. It may be administered in combination with harmful agents (e.g., bosentan or epoprostenol), antifibrotic agents (e.g., colchicine (Colcris), para-aminobenzoic acid (PABA), dimethyl sulfoxide (DMSO), and D-penicillamine, interferon alpha and interferon gamma (INF-g)), proton pump inhibitors (e.g., omeprazole, metoclopramide, lansoprazole, esomeprazole, pantoprazole, rabeprazole), or imatinib, ARG201 (arGentis Pharmaceutical), or tocilizumab.

[0197] In the treatment of cystic fibrosis, the compounds described herein include cystic fibrosis transmembrane conductance regulator (CFTR) enhancers (ibacaftol), mucolytics (e.g., dorunase alfa), pancreatic enzymes (e.g., pancrelipase), bronchodilators (e.g., albuterol), antibiotics (including inhaled, oral, or parenteral antibiotics such as tobramycin solution for inhalation, aztreonam inhalation, and colistimate sodium), and cephalosporins (cefadroxyl monohydrate, It may be administered in combination with cefazolin, cephalexin, cefazolin, fluoroquinolones (moxifloxacin, levofloxacin, gemifloxacin, etc.), azithromycin, gentamicin, piperacillin / tazobactam, cephalexin, ceftazidime, ciprofloxacin, trimaprim / sulfamethoxazole), or ibacaftol / lumakaftol (VX-809), or atallen, or in combination with tiotropium bromide in addition to standard treatment.

[0198] In the treatment of retinitis pigmentosa, the compounds described herein may be administered in combination with ciliary neurotrophic growth factor (NT-501-CNTF), a gene transdermal agent, or UshStat.

[0199] In the treatment of macular degeneration, any compound of any of the formulas described herein may be administered in combination with intravitreous injection (aflibercept) or with an anti-vascular endothelial growth factor (VEGF) inhibitor (e.g., ranibizumab or pegaptanib sodium, ciliary neurotrophic growth factor agent (NT501), iSONEP, or bevacizumab).

[0200] In the treatment of influenza, the compounds described herein may be administered in combination with trivalent (IIV3) inactivated influenza vaccines (e.g., Afluria, Fluarix, Flucelvax, FluLaval, Fluvirin, Fluzone), quadrivalent (IIV4) inactivated influenza vaccines (e.g., Fluarix Quadrivalent, Flulaval Quadrivalent, Fluzone Quadrivalent), trivalent recombinant influenza vaccines (e.g., FluBlok), quadrivalent attenuated live influenza vaccines (e.g., FluMist Quadrivalent), antiviral agents (e.g., oseltamivir, zanamivir, rimantadine, or amantadine), or Fluad, Fludase, FluNhance, Preflucel, or VaxiGrip.

[0201] In the treatment of Staphylococcus infections, any compound of any of the formulas described herein may be administered in combination with an antibiotic (e.g., α-lactam cephalosporin, nafcillin, sulfonamide (sulfamethoxazole and trimetaprim, sulfasalazine, acetylsulfisoxazole), or vancomycin).

[0202] In the treatment of transplant rejection, any compound of any of the formulas described herein may be administered in combination with a high-dose corticosteroid (e.g., prednisone, methylprednisolone), a calcineurin inhibitor (e.g., cyclosporine), tacrolimus, an mTor inhibitor (e.g., sirolimus or everolimus), an antiproliferative agent (e.g., azathioprine, mycophenolate mofetil, or sodium mycophenolate), a monoclonal antibody (e.g., muromonab-CD3, an interleukin-2 receptor antagonist, daclizumab, or rituximab), a polyclonal anti-T cell antibody (e.g., anti-thymocyte gamma globulin-equine, or anti-thymocyte globulin-rabbit), an anti-CD40 antagonist (ASKP-1240), a JAK inhibitor (ASP015K), or an anti-TCR mouse mAb (TOL101).

[0203] In particular, in the treatment of transplant rejection, any compound of any of the formulas described herein may be administered in combination with a monoclonal antibody (e.g., muromonab-CD3), a polyclonal anti-T cell antibody (e.g., anti-thymocyte gamma globulin-equine, or anti-thymocyte globulin-rabbit), an anti-CD40 antagonist (ASKP-1240), a JAK inhibitor (ASP015K), or an anti-TCR mouse mAb (TOL101).

[0204] In the treatment of atopic dermatitis, any compound of any of the formulas described herein is a topical immunomodulator or calcineurin inhibitor (e.g., pimecrolimus or tacrolimus ointment), a topical corticosteroid (e.g., hydrocortisone, betamethasone, flurandrenolide, fluticasone, triamcinolone, fluocinonide, and clobetasol), an oral corticosteroid (e.g., hydrocortisone, methylprednisolone, or prednisolone), or an immunosuppressant (e.g., cyclosporine or interferon gamma (Alferon)). It may be administered in combination with N, Infergen, IntronA, Roferon-A®, antihistamines (for itching, such as Atarax, Vistaril, Benadryl), antibiotics (e.g., penicillin derivatives flucloxacillin or dicloxacillin, erythromycin), nonsteroidal immunosuppressants (e.g., azathioprine), methotrexate, cyclosporine, or mycophenolate mofetil.

[0205] In particular, in the treatment of atopic dermatitis, any compound of any of the formulas described herein may be administered in combination with a topical immunomodulator or calcineurin inhibitor (e.g., pimecrolimus) or tacrolimus ointment, topical corticosteroids (e.g., hydrocortisone, betamethasone, flurandrenolide, fluticasone, triamcinolone, fluocinonide, and clobetasol), oral corticosteroids (e.g., hydrocortisone, methylprednisolone, or prednisolone), interferon-gamma (Alferon N, Infergen, Intron A, Roferon-A), antihistamines (for itching, such as Atarax, Vistaril, and Benadryl), or antibiotics (e.g., penicillin derivatives flucloxacillin or dicloxacillin, erythromycin).

[0206] In the treatment of burns, such as thermal injuries or thermal shock, any compound of any of the formulas described herein may be administered alone or in combination with an antimicrobial agent, typically a topical antibiotic (mafenide acetate cream, silver sulfadiazine cream) and / or an analgesic (opioid analgesic, e.g., morphine, oxycodone). Other therapeutic agents that may be useful in the treatment of burns include retinoids and pirfenidone.

[0207] In certain embodiments, at least one other therapeutically active agent is selected from thrombolytic agents, tissue plasminogen activators, anticoagulants, and platelet aggregation inhibitors.

[0208] In certain embodiments, at least one other therapeutically active agent is selected from heparin, coumadin, clopidrogen, dipyridamole, ticlopidine HCl, eptifivatide, and aspirin. In certain embodiments, the kinase-mediated disorder or impairment treated with these agents is a cerebrovascular disorder.

[0209] In certain embodiments, at least one other therapeutically active agent is selected from broad-spectrum antibiotics, anti-MRSA agents, and low-dose steroids. In certain embodiments, at least one other therapeutically active agent is selected from vancomycin, cefeprime, a combination of piperacillin and tazobactam, imipenem, meropenem, doripenem, ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, and hydrocortisone. In certain embodiments, the disease or disorder treated with these agents is a systemic inflammatory response syndrome.

[0210] In certain embodiments, at least one other therapeutically active agent is Arikahorsen or Remestemcell-L. In certain embodiments, the disease or disorder treated with these agents is Crohn's disease or ulcerative colitis.

[0211] In certain embodiments, at least one other therapeutically active agent is ixekizumab or tildrakizumab. In certain embodiments, the kinase-mediated disease or disorder treated with these agents is a non-communicable inflammatory skin disease (ncISD), such as psoriasis or atopic dermatitis.

[0212] In certain embodiments, at least one other therapeutically active agent is an antibacterial agent or antibiotic. In certain embodiments, at least one other therapeutically active agent is selected from chlorhexidine, doxycycline, and minocycline. In certain embodiments, the disease or disorder treated with these agents is periodontitis.

[0213] In certain embodiments, at least one other therapeutically active agent is selected from inhaled corticosteroids, long-acting beta-agonists, combinations of inhaled corticosteroids and long-acting beta-agonists, short-acting beta-agonists, leukotriene modulators, anti-IgE, methylxanthine bronchodilators, mast cell inhibitors, and long-acting muscarinic antagonists. In certain embodiments, at least one other therapeutically active agent is selected from fluticasone propionate, beclomethasone dipropionate, budesonide, triamcinolone acetonide, flunisolide, mometasone furoate, or ciclesonide, formoterol fumarate, salmeterol xinafoate, a combination of fluticasone furoate and vilanterol, a combination of formoterol and budesonide inhalation, a combination of beclomethasone dipropionate and formoterol, a combination of fluticasone propionate and salmeterol, albuterol sulfate, levalbuterol tartrate, a combination of ipratropium bromide and albuterol, ipratropium bromide, montelukast sodium, zafirlukast, dileuton, omalizumab theophylline, cromolyn sodium, nedocromyl sodium, and a combination of mometasone furoate and formoterol fumarate dihydrate.

[0214] In certain embodiments, at least one other therapeutically active agent is selected from protein tyrosine kinase inhibitors, CRTH2 / D-prostanoid receptor antagonists, epinephrine inhalation aerosols, and combinations of phosphodiesterase-3 inhibitors and phosphodiesterase-4 inhibitors. In certain embodiments, at least one other therapeutically active agent is selected from masitinib, AMG853, indacaterol, E004, combinations of fluticasone furoate and fluticasone propionate, combinations of vilanterol and fluticasone furoate, combinations of fluticasone propionate and formoterol fumarate dihydrate, reslizumab, salbutamol, tiotropium bromide, combinations of formoterol and budesonide, fluticasone furoate, VR506, lebrikizumab, and RPL554. In certain embodiments, the kinase-mediated disease or disorder treated with these agents is asthma.

[0215] In certain embodiments, at least one other therapeutically active agent is selected from long-acting beta-agonists, long-acting inhaled anticholinergics or muscarinic antagonists, phosphodiesterase inhibitors, and inhaled corticosteroids, as well as combinations of long-acting beta-agonists and short-acting beta-agonists and inhaled corticosteroids. In certain embodiments, at least one other therapeutically active agent is selected from salmeterol xinafoate, a combination of umeclidinium and vilanterol, umeclidinium, alformoterol tartrate, formoterol fumarate, indacaterol maleate, a combination of fluticasone propionate and formoterol fumarate dihydrate, tiotropium bromide, aclidinium bromide, roflumilast, a combination of fluticasone furoate and vilanterol, a combination of fluticasone propionate and salmeterol, a combination of budesonide and formoterol, a combination of mometasone and formoterol, a combination of ipratropium bromide and albuterol sulfate, a combination of albuterol and ipratropium, ipratropium bromide, albuterol sulfate, budesonide, fluticasone propionate, and beclomethasone dipropionate. In certain embodiments, at least one other therapeutically active agent is selected from SCH527123, glycopyrronium bromide, a combination of glycopyrronium bromide and indacaterol maleate, a combination of glycopyrrolate and formoterol fumarate, indacaterol maleate, olodaterol, tiotropium, olodaterol, and a combination of acridinium and formoterol. In certain embodiments, the disease or disorder treated with these agents is COPD.

[0216] In certain embodiments, at least one other therapeutically active agent is an antimycobacterial agent or a bactericidal antibiotic. In certain embodiments, at least one other therapeutically active agent is selected from isoniazid, ethambutol, rifampin, pyrazinamide, rifabutin, rifapentin, capreomycin, levofloxacin, moxifloxacin, ofloxacin, ethionamide, cycloserine, kanamycin, streptomycin, biomycin, bedaquiline fumarate, PNU-100480, and delamanid. In certain embodiments, the kinase-mediated disease or disorder treated with these agents is a Mycobacterium infection.

[0217] In certain embodiments, at least one other therapeutically active agent is selected from oral corticosteroids, antithymocyte globulins, thalidomide, chlorambucil, calcium channel blockers, topical emollients, ACE inhibitors, serotonin reuptake inhibitors, endothelin-I receptor inhibitors, antifibrotic agents, proton pump inhibitors, or imatinib, ARG201, and tocilizumab. In certain embodiments, at least one active agent is selected from prednisolone, antithymocyte globulin, FK506 (tacrolimus), thalidomide, chlorambucil, nifedipine, nicardipine, nitroglycerin ointment, lisinopril, diltiazem, fluoxetine, bosentan, epoprostenol, colchicine, para-aminobenzoic acid, dimethyl sulfoxide, D-penicillamine, interferon alpha, interferon gamma (INF-g), omeprazole, metoclopramide, lansoprazole, esomeprazole, pantoprazole, rabeprazole, imatinib, ARG201, and tocilizumab. In certain embodiments, the disease or disorder treated with these agents is systemic sclerosis.

[0218] In certain embodiments, at least one other therapeutically active agent is selected from cystic fibrosis transmembrane conductance regulator enhancers, mucolytics, pancreatic enzymes, bronchodilators, antibiotics, or ibacaftol / lumaftol, atallen, and tiotropium bromide. In certain embodiments, at least one other therapeutically active agent is selected from ibacaftol, dorunase alfa, pancrelipase, albuterol, tobramycin, aztreonam, colistimethate sodium, cefadroxil monohydrate, cefazolin, cephalexin, cefazolin, moxifloxacin, levofloxacin, gemifloxacin, azithromycin, gentamicin, piperacillin / tazobactam, ceftazidime, ciprofloxacin, trimetaprim / sulfamethoxazole, chloramphenicol, or ibacaftol / lumaftol, atallen, and tiotropium bromide. In certain embodiments, the disease or disorder treated with these agents is cystic fibrosis.

[0219] In certain embodiments, at least one other therapeutically active agent is ciliary neurotrophic growth factor or a gene transderm. In certain embodiments, at least one other therapeutically active agent is NT-501-CNTF or a gene transderm encoding myosin VIIA (MY07A).

[0220] In a particular embodiment, the disease or disorder treated with these agents is retinitis pigmentosa.

[0221] In certain embodiments, at least one other therapeutically active agent is selected from intravitreous injections, anti-vascular endothelial growth factor inhibitors, and ciliary neurotrophic growth factor agents. In certain embodiments, at least one other therapeutically active agent is selected from aflibercept, ranibizumab, pegaptanib sodium, NT501, humanized sphingomab, and bevacizumab. In certain embodiments, the disease or disorder treated with these agents is macular degeneration.

[0222] In certain embodiments, at least one other therapeutically active agent is selected from trivalent (IIV3) influenza inactivated vaccine, quadrivalent (IIV4) influenza inactivated vaccine, trivalent recombinant influenza vaccine, quadrivalent influenza attenuated live vaccine, antiviral agent, or influenza inactivated vaccine. In certain embodiments, at least one other therapeutically active agent is selected from oseltamivir, zanamivir, rimantadine, or amantadine. In certain embodiments, the kinase-mediated disease or disorder treated with these agents is influenza.

[0223] In certain embodiments, at least one other therapeutically active agent is selected from beta-lactams, nafcillin, sulfamethoxazole, trimetaprim, sulfasalazine, acetylsulfisoxazole, and vancomycin. In certain embodiments, the disease or disorder treated with these agents is a Staphylococcus infection.

[0224] In a particular embodiment, at least one other therapeutically active agent is selected from monoclonal antibodies, polyclonal anti-T cell antibodies, anti-thymocyte gamma globulin-equine antibodies, anti-thymocyte globulin-rabbit antibodies, anti-CD40 antagonists, JAK inhibitors, and anti-TCR mouse mAbs.

[0225] In certain embodiments, at least one other therapeutically active agent is selected from muromonab-CD3, ASKP-1240, ASP015K, and TOL101. In certain embodiments, the disease or disorder treated with these agents is transplant rejection.

[0226] In certain embodiments, at least one other therapeutically active agent is selected from topical immune modulators or calcineurin inhibitors, topical corticosteroids, oral corticosteroids, interferon gamma, antihistamines, or antibiotics. In certain embodiments, at least one other therapeutically active agent is selected from pimecrolimus, tacrolimus, hydrocortisone, betamethasone, flurandrenolide, fluticasone, triamcinolone, fluocinonide, clobetasol, hydrocortisone, methylprednisolone, prednisolone, interferon alpha protein, recombinant synthetic type I interferon, interferon alpha-2a, interferon alpha-2b, hydroxyzine, diphenhydramine, flucloxacillin, dicloxacillin, and erythromycin. In certain embodiments, the disease or disorder treated with these agents is atopic dermatitis.

[0227] dosage When used herein, the terms “parenteral administration” and “administering parenterally” typically mean, but are not limited to, methods of administration other than enteral and topical administration, by injection, including, but are not limited to, intravenous, intramuscular, intra-arterial, subarachnoid, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0228] The terms “systemic administration,” “administered systemically,” “peripheral administration,” and “peripherally administered,” as used herein, mean the administration of a compound, drug, or other material other than directly to the central nervous system, such as subcutaneous administration, in which the compound, drug, or other material enters the patient’s system and is thus subjected to metabolism and other similar processes. These compounds may be administered to humans and other animals for therapeutic purposes by any suitable route of administration, including oral, nasal (e.g., by spray), rectal, vaginal, parenteral, intracisional, and oral buccal and sublingual, as well as topically (e.g., by powder, ointment or drop).

[0229] Regardless of the chosen route of administration, the compounds of the Disclosure that can be used in an appropriate hydrated form and / or in a pharmaceutical composition of the Disclosure are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0230] The actual dose levels of the active ingredient in the pharmaceutical compositions of this disclosure may be varied to obtain an amount of the active ingredient effective in achieving a desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0231] The selected dosage level is determined by a variety of factors, including the activity of the specific compound used in this disclosure, or its ester, salt, or amide; the route of administration; the time of administration; the excretion rate or metabolism of the specific compound used; the duration of treatment; other drugs; compounds and / or materials used in combination with the specific compound used; the age, sex, weight, condition, overall health and medical history of the patient being treated; and similar factors well known in medicine. Daily, weekly, or monthly dosages (or other time intervals) may be used.

[0232] A physician or veterinarian with ordinary skill in the art can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian can start the dose of the compound of the present disclosure used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and then gradually increase the dose until the desired effect is achieved.

[0233] Generally, the appropriate daily dose of the compounds of this disclosure is the lowest dose of the compound that is effective in producing a therapeutic effect (e.g., inhibition of necrosis). Such an effective dose is generally determined by the factors described above.

[0234] Generally, the dosage of the compounds of this disclosure for patients, when used for the indicated effects, is in the range of about 0.0001 to about 100 mg per kg of body weight per day. Preferably, the daily dose is in the range of 0.001 to 50 mg of the compound per kg of body weight, and more preferably, 0.01 to 10 mg of the compound per kg of body weight.

[0235] If necessary, the effective daily dose of the active compound may be administered as two, three, four, five, six or more partial doses, each administered separately at appropriate intervals throughout the day in unit dosage form. In certain embodiments, the disclosure relates to a compound for inhibiting cell death, and the compound is represented by structure (I). In certain embodiments, the compound of the disclosure is a cell death inhibitor. In any case, the compounds of the disclosure exert these effects on inhibiting cell death preferably at concentrations of less than about 50 micromoles, more preferably at concentrations of less than about 10 micromoles, and most preferably at concentrations of less than 1 micromoles. The compounds of the disclosure can be tested in standard animal models and standard protocols of stroke, e.g., as described by Hara, H. et al., Proc. Natl. Acad. Sci. USA, 1997, 94(5):2007-12.

[0236] When the compounds of this disclosure are administered to humans and animals as pharmaceuticals, they can be given, either by themselves or in combination with a pharmaceutically acceptable carrier, as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient.

[0237] The compounds or compositions of this application may be administered once, twice, three times, or four times daily using any suitable mode described above. Furthermore, administration or treatment with the compounds may last for several days; for example, generally, treatment lasts for at least 7, 14, or 28 days for one treatment cycle. Treatment cycles are well known and frequently alternate with rest periods of about 1 to 28 days, generally about 7 or about 14 days. Treatment cycles may also be continuous in certain embodiments.

[0238] When administered orally, the total daily dose for human subjects may be 1 mg to 1,000 mg, approximately 1,000 to 2,000 mg / day, approximately 10 to 500 mg / day, approximately 50 to 300 mg / day, approximately 75 to 200 mg / day, or approximately 100 to 150 mg / day.

[0239] The daily dose may also be described as the total amount of the compound described herein administered per dose or per day. The daily dose of the compound may be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day. In certain embodiments, the method involves administering to a subject an initial daily dose of about 1 to 800 mg of the compound described herein and increasing the dose by a fixed amount until clinical efficacy is achieved. The dose may be increased using increases of about 5 mg, 10 mg, 25 mg, 50 mg, or 100 mg. The dose may be increased daily, every other day, twice a week, or once a week.

[0240] In certain embodiments, the compound or pharmaceutical product is administered orally. In certain embodiments, the compound or pharmaceutical product is administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

[0241] Products of the present disclosure may be administered orally, parenterally, topically, or rectally. These may, of course, be administered in a form suitable for each route of administration. For example, they may be administered by injection, infusion, or inhalation, such as in tablet or capsule form, by injection, by inhalation, by eye drops, ointment, or suppository; topically by lotion or ointment; and rectally by suppository. In certain embodiments, administration is orally. [Examples]

[0242] Abbreviation: ACN Acetonitrile aq. aqueous solution DEA (Diethylamine) DIPEA N,N-diisopropylethylamine DIAD Diisopropyl Azodicarboxylate DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) EA ethyl acetate eq. equivalent amount ESI Electrospray Ionization EtOH Ethanol FA Formic Acid h time HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-hexafluorophosphate) HOBt 1-hydroxybenzotriazole (RP)HPLC (Reverse Phase) High-Pressure Liquid Chromatography IBX 2-Iodoxybenzoic acid IPA Isopropylamine (RP)LC (Reverse-Phase) Liquid Chromatography LC / MS Liquid Chromatography / Mass Spectrometry M molar concentration m / z mass / charge ratio MeOH methanol min MsCl methanesulfonyl chloride (mesyl chloride) MTBE Methyl tertiary butyl ether N specified concentration NMR nuclear magnetic resonance PE (Petroleum Ether) prep. PyBOP Benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate RT room temperature sat. saturation SFC Supercritical Fluid Chromatography TEA (Triethylamine) TFA (Trifluoroacetic Acid) TFAA Trifluoroacetic anhydride THF (Tetrahydrofuran) TLC (Thin-Layer Chromatography) tR retention time UV ultraviolet light

[0243] Silica gel chromatography Silica gel chromatography was performed using either a CombiFlash® Rf (Teledyne ISCO) system with pre-packed cartridges, a Biotage Isolera One automated flash purification system, or two Buchi systems (combinations of C-660, C-605, C-620, C-635 and C-660, C-605, C-615, C-630).

[0244] Preparative RP-HPLC For preparative reverse-phase HPLC, we used either an Agilent 1200 preparative HPLC machine, Gilson instruments (GX-271 liquid handler, 331 / 332 pump, UV / VIS-155), or a Waters automated purification LC preparative system.

[0245] Preparative RP-LC Reverse-phase liquid chromatography was performed using a Biotage instrument with a C18 column and a water (0.1% FA) / ACN gradient.

[0246] NMR 400MHz: 1 ¹H NMR spectra were recorded using a Bruker AVANCE II 400 spectrophotometer operating at a proton frequency of 400.23 MHz. The instrument was equipped with a 5 mm BBI room-temperature probe head. Alternatively, a Bruker AVANCE III HD 400 MHz or Bruker AVANCE NEO 400 MHz was used. 600MHz: 1 The 1H NMR spectrum was recorded using a Bruker AVANCE III 600 spectrophotometer operating at a proton frequency of 600.05 MHz. The instrument was equipped with a 5 mm BBI room-temperature probe head.

[0247] LC / MS instrument for analysis of Method A Retention time and mass detection were performed on a Waters Acquity UHPLC system equipped with a Waters SQD mass detector. The injection volume was 1.0 μl. Molecular weight was obtained in grams per mole [g / mol], and the detected mass was obtained in mass per charge [m / z].

[0248] LC / MS instruments for analysis for methods B, C, and D For retention time and mass detection, LC / MS systems 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) were used. Molecular weight was obtained in grams per mole [g / mol], and detected mass was obtained in mass per charge [m / z].

[0249] LC / MS-Method A Gradient: 0.2 minutes 98% H2O (0.05% FA) / 2% ACN (0.035% FA); then 3.6 minutes 98% H2O (0.05% FA) to 98% ACN (0.035% FA), then 0.5 minutes 98% ACN (0.035% FA), flow rate: 1.0 ml / min, column: 2.1 × 50 mm Waters ACQUITY UPLC BEH C18, 1.7 μm, 55℃. UV data: Retention time at λ220nm was obtained in minutes. MS Data: ES + Ionization; unless otherwise noted, m / z is [M+H] + Obtained as

[0250] LC / MS-Method B Gradient: 99% H2O (0.05% TFA) / 1% ACN to 7% ACN in 0.3 minutes; then 7% ACN to 95% ACN in 1.3 minutes; flow rate: 1.1 ml / min; column: 2.0 × 10 mm Luna C18, 3 μm, 30°C; injection volume: 0.2 μl UV data: Retention time at λ220nm was obtained in minutes. MS Data: ES + Ionization; unless otherwise noted, m / z is [M+H] + Obtained as

[0251] LC / MS-Method C Gradient: 93% H2O (0.05% TFA) / 7% ACN to 95% ACN over 1.45 minutes; followed by 5% ACN over 0.05 minutes; flow rate: 1.1 ml / min; column: 2.0 × 10 mm Luna C18, 3 μm, 30°C; injection volume: 0.2 μl UV data: Retention time at λ220nm was obtained in minutes. MS Data: ES + Ionization; unless otherwise noted, m / z is [M+H] + Obtained as

[0252] LC / MS-Method D Gradient: 96% H2O (0.05% TFA) / 4% ACN to 5% H2O / 95% ACN over 2.0 minutes; followed by 5% H2O / 95% ACN over 0.4 minutes; flow rate: 1.0 ml / min; column: YMC J'Sphere ODS H80, 20 × 2.1 mm, 4 μm, 30℃; injection volume: 0.4 μl UV data: Retention time at λ220nm was obtained in minutes. MS Data: ES + Ionization; unless otherwise noted, m / z is [M+H] + Obtained as

[0253] LC / MS-Method E: Gradient: 0.8 min from 95% H2O (0.0375% TFA) / 5% ACN (0.01875% TFA) to 5% H2O (0.0375% TFA) / 95% ACN (0.01875% TFA); Flow rate: 1.5 ml / min, Column: Kinetex EVO C18 2.1×30 mm, 5 μm, 50℃ UV data: Retention time at λ220nm was obtained in minutes. MS Data: ES + Ionization; unless otherwise noted, m / z is [M+H] + Obtained as

[0254] LC / MS-Method F: Gradient: 0.8 min from 100% H2O (0.0375% TFA) / 0% ACN (0.01875% TFA) to 40% H2O (0.0375% TFA) / 60% ACN (0.01875% TFA); then 0.4 min of 40% H2O (0.0375% TFA) / 60% ACN (0.01875% TFA); flow rate: 1.5 ml / min, column: Kinetex EVO C18 2.1×30 mm, 5 μm, 50℃ UV data: Retention time at λ220nm was obtained in minutes. MS Data: ES + Ionization, unless otherwise noted, is obtained as [M+H]+ in m / z.

[0255] Chiral HPLC for analysis SFC: SHIMADZU LC-30AD sf system LC: Agilent 1100 Series System

[0256] salt In compounds described as HCl-, TFA-, or other salts, the exact amount of each acid is not usually determined. Therefore, the amount of acid can range from as low as 0.01 equivalents to 5.0 equivalents, depending on the chemical structure (e.g., the number of base centers).

[0257] Chiral purity If the enantiomer ratio exceeds 90:10, the compound is described and named as a single enantiomer. If the enantiomer ratio is less than 90:10, a racemic form is used.

[0258] Synthesis method: Intermediate: I-01: 3-Pyrimidine-5-ylisoxazolidine hydrochloride / TFA salt I-01a: (E)-3-(pyrimidine-5-yl)acrylaldehyde [ka] A mixture of 5-bromopyrimidine (30 g), propa-2-enal (31.74 g), Pd(OAc)2 (2.12 g), benzyl(triethyl)ammonium chloride (42.98 g), and TEA (57.28 g) in DMF (300 ml) was stirred at 80°C under N2 for 12 hours. The mixture was concentrated, the residue was diluted with water (800 ml), extracted with EA (500 ml x 4), washed with brine (1.5 l), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EA = 10:1 to 4:1) and grinding (PE / EA = 3:1, 50 mL) to obtain 4.2 g of the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 9.78 (1 H), 9.26 (1 H), 8.95 (2 H), 7.45 (1 H), 6.86 (1 H)

[0259] I-01b: tert-butyl(3S)-5-hydroxy-3-pyrimidine-5-yl-isoxazolidine-2-carboxylate [ka] To a solution of [diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]trimethylsilane (2.28 g) in CHCl3 (50 ml), (E)-3-(pyrimidine-5-yl)acrylaldehyde (4.7 g) and tert-butyl N-hydroxycarbamate (5.60 g) were added at 0°C. The mixture was smoothly heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated, and the residue was purified by preparative RP-LC to obtain 6.4 g of the title compound.

[0260] I-01c:tert-butylN-hydroxy-N-[(1S)-3-hydroxy-1-pyrimidine-5-yl-propyl]carbamate [ka] To a solution of tert-butyl(3S)-5-hydroxy-3-pyrimidine-5-yl-isoxazolidine-2-carboxylate (6.1 g) in MeOH (40 ml), NaBH4 (1.04 g) was added at 0°C. The mixture was stirred at 0°C under N2 for 2 hours. The mixture was quenched with saturated NH4Cl solution (200 ml), extracted with EA (200 ml x 3), dried over Na2SO4, filtered, and concentrated to obtain 5.4 g of the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 9.14 (1 H), 8.81 (2 H), 7.18 - 7.02 (1 H), 5.32 (1 H), 3.94 - 3.72 (2 H), 2.55 - 2.39 (1 H), 2.31 - 2.20 (1 H), 2.12 - 2.05 (1H), 1.49 (9H)

[0261] I-01d: tert-butyl(3S)-3-pyrimidine-5-ylisoxazolidine-2-carboxylate [ka] To a solution of tert-butyl N-hydroxy-N-[(1S)-3-hydroxy-1-pyrimidine-5-yl-propyl]carbamate (4.9 g) in THF (40 ml), tributylphosphan (8.84 g) and DIAD (7.36 g) were added at 0°C. The mixture was smoothly warmed to 20°C and stirred under N2 for 12 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography (PE:EA = 1:5 to 0:1), followed by preparative RP-LC (flow rate: 100 ml / min; gradient: 95% H2O (0.1% FA) / 5% ACN to 71% H2O (0.1% FA) / 29% ACN over 12 minutes; 71% H2O (0.1% FA) / 29% ACN over 4 minutes; 71% H2O (0.1% FA) / 29% ACN to 60% H2O (0.1% FA) / 40% ACN over 12 minutes; column: Agela C18, 20 μm, 100 Å, ID 60.6 mm × 187 mm) to obtain 1.4 g of the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 9.16 (1 H), 8.76 (2 H), 5.27 (1 H), 4.25 (1 H), 3.93 (1 H), 2.87 (1 H), 2.32 (1 H), 1.50 (9 H) Chiral HPLC: tR 1.98 min, 100%; 100% ee (chiralpak AD-3, 50 × 4.6 mm, 3 μm; Phase A: CO2, Phase B: MeOH (0.05% DEA); Gradient: MeOH (0.05% DEA) in CO2 from 5 to 40%; Flow rate 3 ml / min; T 35°C, p 100 bar)

[0262] I-01: (3S)-3-pyrimidine-5-ylisoxazolidineHCl / TFA salt [ka]

[0263] TFA salt: 25 mg of tert-butyl 3-pyrimidine-5-ylisoxazolidine-2-carboxylate was dissolved in 2.5 ml of dry dimethyl carboxylate (DCM) at room temperature in a 10 ml round-bottom flask with stirring. 0.3 ml of tallow-containing phosphate (TFA) was added, and the mixture was stirred for 1 hour. The DCM was then removed under vacuum, and the residue was dissolved in ACN / water and freeze-dried overnight. 23 mg of the title compound was obtained as its TFA salt. LC / MS: m / z = 152.2[M+H] + ;tR:0.37 min (LC / MS-Method A)

[0264] HCl salt: 17 mg of tert-butyl 3-pyrimidine-5-ylisoxazolidine-2-carboxylate was dissolved in 0.5 ml of dioxane, and 70 μl of 4 M HCl was added to the dioxane at room temperature while stirring. After 1 hour, 800 μl of HCl was added to the dioxane, and stirring was continued for 3 hours. The solvent was then removed under vacuum, and the residue was dissolved in ACN / water and freeze-dried overnight. 10 mg of the title compound was obtained as its HCl salt.

[0265] I-02-1:5-[(3S)-isoxazolidine-3-yl]pyridine-3-carbonilicate I-02a:1-(5-bromo-3-pyridyl)propa-2-en-1-ol [ka]

[0266] The two reactions were carried out in parallel: A mixture of 5-bromopyridine-3-carboaldehyde (100 g) in THF (500 ml) was degassed three times and purged with N2. Vinyl magnesium bromide (1 M, 645 ml) was added dropwise at a rate that maintained the internal temperature below -70°C. The mixture was stirred at -70°C for 1 hour, and then stirred at 25°C for 1 hour under an N2 atmosphere. The two solutions were then combined and poured into saturated NH4Cl (3.00 l), and extracted with MTBE (2.00 l, 1.00 l). The combined organic phase was washed with brine (1.00 l), dehydrated with Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (240 g, crude) as a brownish oily substance. 1 H NMR (400 MHz, CDCl3): δ 8.54 (1 H), 8.40 (1 H), 7.87 (1 H), 5.95-5.97 (1 H), 5.36 (1 H), 5.25-5.38 (1 H), 5.18-5.25 (1 H).

[0267] I-02b:1-(5-bromo-3-pyridyl)propa-2-en-1-one [ka]

[0268] The two reactions were carried out in parallel. To a solution of 1-(5-bromo-3-pyridyl)propa-2-en-1-ol (120 g) in ACN (1.20 l), IBX (235 g) was added in small increments at 20°C. The reaction mixture was then heated to 50°C and stirred for 12 hours. The two reaction suspensions were combined, cooled to 25°C, filtered, and the filtrate was concentrated under reduced pressure. The title compound (240 g, crude) was obtained as a yellow oily substance and used in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ 9.02 (1 H), 8.86 (1 H), 8.36 (1 H), 7.07 (1 H), 6.49 (1 H), 6.06 (1 H).

[0269] I-02c:1-(5-bromo-3-pyridyl)-3-chloro-propan-1-one [ka]

[0270] To a solution of 1-(5-bromo-3-pyridyl)propa-2-en-1-one (220 g) in DCM (200 ml), HCl / dioxane (4 M, 1.04 l) was added at 0°C. The solution was heated to 25°C and stirred for 48 hours. The solution was concentrated under reduced pressure to obtain a brown solid. The solid was diluted with saturated NaHCO3 solution (2.00 l) and extracted with DCM (1.50 l x 2). The combined organic layers were washed with brine (1.50 l), dehydrated with Na2SO4, filtered through a silica gel pad, and concentrated under reduced pressure to obtain the residue. The crude title compound (100 g, crude product) was used in the next step without further purification.

[0271] I-02d: 1-(5-bromo-3-pyridyl)-3-chloropropane-1-ol [ka] 100 g of 1-(5-bromo-3-pyridyl)-3-chloro-propan-1-one, degassed three times and purged with N2, was dissolved in MeOH (500 ml) and THF (250 ml) and NaBH4 (4.57 g) was added at 0°C. The suspension was stirred at 25°C under an N2 atmosphere for 0.5 hours. The reaction solutions were combined and poured into saturated NH4Cl (1.00 l), and extracted with EA (2.00 l, 1.00 l). The combined organic layer was washed with brine (1.00 l), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was dissolved in DCM (600 ml), filtered through a silica gel pad, eluted with MTBE / DCM (volume / volume = 1 / 1, 1.50 l), and the filtrate was concentrated under reduced pressure. The crude title compound (90.0 g) was used in the next step without further purification.

[0272] I-02e:tert-butyl N-[3-(5-bromo-3-pyridyl)-3-hydroxypropoxy]carbamate [ka]

[0273] The two reactions were carried out in parallel. To a solution of tert-butyl N-hydroxycarbamate (47.0 g) in DMF (200 ml), NaH (18.0 g, 60%) was added in small amounts at 0-5°C. A large amount of foam was generated. The reaction mixture was stirred at 0°C for 30 minutes. A solution of 1-(5-bromo-3-pyridyl)-3-chloro-propan-1-ol (45.0 g) in DMF (300 ml) was added dropwise to the reaction mixture at 0-5°C. After addition, the reaction mixture was heated to 20°C and stirred for 12 hours. The two reaction solutions were combined and poured into a cooled saturated NH4Cl solution (1.50 l), and extracted with ethyl acetate (2.00 l, 1.00 l). The combined organic layer was washed with brine (1.00 l), dehydrated with Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was subjected to column chromatography (SiO₂). 2、 The compound was purified using a PE / EA ratio of 100 / 1 to 0 / 1. The title compound (50.0 g) was obtained as a yellow solid. 1 H NMR (400 MHz, CDCl3): δ 8.56 (1 H), 8.52 (1 H), 7.97 (1 H), 7.32 (1 H), 5.09-5.11 (1 H), 4.58 (1 H), 4.06-4.14 (2 H), 2.02-2.08 (1 H), 1.88-1.91 (1H), 1.50 (9H).

[0274] I-02f:tert-butyl3-(5-bromo-3-pyridyl)isoxazolidine-2-carboxylate [ka]

[0275] The two reactions were carried out in parallel. A suspension of tert-butyl N-[3-(5-bromo-3-pyridyl)-3-hydroxypropoxy]carbamate (25.0 g) and Et3N (21.0 g) in DCM (250 ml) was cooled to 0°C. MsCl (9.90 g) was added dropwise to the reaction mixture and stirred at 0-5°C for 1 hour. An additional amount of Et3N (14.0 g) was added to the reaction mixture, and the solution was heated to 25°C and stirred for 16 hours. The reaction solution was poured into saturated NaHCO3 solution (100 ml) while stirring. The organic layer was separated, and the aqueous layer was extracted with DCM (300 ml, 200 ml). The combined organic layers were washed with brine (100 ml). The organic layers were separated, dehydrated with Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The two reactions were purified together. The residue was purified by column chromatography (SiO2, PE / EA = 50 / 1 to 0 / 1). The title compound (36.0 g) was obtained as a white solid. 1 H NMR (400 MHz, CDCl3): δ 8.58 (1 H), 8.50 (1 H), 7.87 (1 H), 5.21-5.25 (1 H), 4.18-4.23 (1 H), 3.86-3.92 (1H), 2.81-2.85 (1 H), 2.25-2.31 (1 H), 1.48 (9 H).

[0276] I-02g: tert-butyl 3-(5-cyano-3-pyridyl)isoxazolidine-2-carboxylate

[0277] The two reactions were carried out in parallel. To a solution of tert-butyl 3-(5-bromo-3-pyridyl)isoxazolidine-2-carboxylate (15.0 g) in DMF (75.0 ml), Zn(CN)2 (8.03 g) and Pd(PPh3)4 (6.32 g) were added under N2. The mixture was stirred at 110°C for 12 hours under a nitrogen atmosphere. The two reactions were combined and workd up. The reaction suspension was poured into water (500 ml) and extracted with EA (500 ml, 300 ml). The combined organic layer was washed with brine (200 ml), dehydrated with Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, PE / EA = 50 / 1 to 0 / 1) to obtain the title compound as a white solid (12 g). 1 H NMR (400 MHz, CDCl3): δ 8.79 (2 H), 7.99 (1 H), 5.29-5.33 (1 H), 4.21-4.24 (1 H), 3.87-3.93 (1 H), 2.87-2.91 (1 H), 2.25-2.30 (1 H), 1.50 (9 H).

[0278] I-02g-1 and I-02g-2: tert-butyl(3R)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carboxylate and tert-butyl(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carboxylate [ka]

[0279] The two enantiomers were separated by SFC (column: DAIEL CHIRALPAK AD (250 × 50 mm, 10 μm); mobile phase A: CO2, B: isopropanol (0.1 vol. % NH3 aqueous solution (25 wt / wt%)); no gradient, 15% B for 5 minutes) to obtain two enantiomers, I-02g-1 (5.1 g) and I-02g-2 (5.1 g), as white solids.

[0280] I-02g-1: tert-butyl(3R)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carboxylate 1 1H NMR (400 MHz, CDCl3): δ 8.79 (2 H), 8.00 (1 H), 5.29-5.33 (1 H), 4.20-4.25 (1 H), 3.87-3.93 (1 H), 2.85-2.92 (1 H), 2.25-2.31 (1 H), 1.50 (9 H). SFC:tR 1.50 min (Column: Chiralpak AD-3, 100 × 4.6 mm, ID, 3 μm, Mobile phase: A: CO2, B: Isopropanol (0.05% DEA), Gradient: Hold B from 5% to 40% for 2 mins and then at 40% for 1 min, then from 40% to 5% for 1 min, Flow rate: 3.4 ml / min, Column temperature: 35°C).

[0281] I-02g-2: tert-butyl(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carboxylate 1 1H NMR (400 MHz, CDCl3): δ 8.79 (2 H), 7.99 (1 H), 5.29-5.33 (1 H), 4.20-4.24 (1H), 3.87-3.93 (1 H), 2.87-2.92 (1 H), 2.25-2.30 (1 H), 1.49 (9 H). SFC:tR 1.72 min (Column: Chiralpak AD-3, 100 × 4.6 mm, ID, 3 μm, Mobile phase: A: CO2, B: Isopropanol (0.05% DEA), Gradient: Hold B from 5% to 40% for 2 mins and then at 40% for 1 min, then from 40% to 5% for 1 min, Flow rate: 3.4 ml / min, Column temperature: 35°C).

[0282] Alternative approaches to tert-butyl(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carboxylate (I-02g-2) I-02h:5-[(E)-3-oxopropa-1-enyl]pyridine-3-carbonitrile [ka] A mixture of 5-bromopyridine-3-carbonitride (23.4 g), propa-2-enal (21.51 g), Pd(OAc)2 (1.44 g), TEA (38.82 g), and benzyl(triethyl)ammonium chloride (29.12 g) in 230 ml of DMF was degassed three times, purged with N2, and then stirred at 80°C under an N2 atmosphere for 12 hours. The mixture was concentrated, diluted with water (500 ml), extracted with EA (300 ml x 5), washed with brine (500 ml), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (PE:EA = 1:1) to obtain 14.5 g of the title compound. 1 H NMR (400 MHz, CDCl3) δ = 9.79 (1 H), 8.99 (1 H), 8.92 (1 H), 8.14 (1 H), 7.48 (1 H), 6.84 (1 H)

[0283] I-02i:tert-butyl(3S)-3-(5-cyano-3-pyridyl)-5-hydroxyisoxazolidine-2-carboxylate [ka] To a solution of (S)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine (5.97 g) in CHCl3 (150 ml), 5-[(E)-3-oxopropa-1-enyl]pyridine-3-carbonitrile (14.5 g) and tert-butyl N-hydroxycarbamate (13.43 g) were added at 0°C. The mixture was degassed three times and purged with N2, then the mixture was gradually heated to 25°C and stirred at this temperature for 36 hours. The mixture was concentrated, and the residue was purified by preparative RP-LC (water (0.1% FA) / ACN) to obtain 18.1 g of the title compound. 1H NMR (400 MHz, CDCl3) δ = 8.82 (1 H), 8.79 (1 H), 7.99 (1 H), 5.90 (1 H), 5.41 (1 H), 4.95- 4.53 (1 H), 2.87 (1 H), 2.29 - 2.20 (1 H), 1.47 (9 H).

[0284] I-02j:tert-butyl N-[(1S)-1-(5-cyano-3-pyridyl)-3-hydroxy-propyl]-N-hydroxy-carbamate [ka] To a solution of tert-butyl(3S)-3-(5-cyano-3-pyridyl)-5-hydroxyisoxazolidine-2-carboxylate (18.1 g) in MeOH (150 ml), NaBH4 (2.43 g) was added at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (10 ml) and diluted with water (500 ml). The resulting solution was extracted with EA (300 ml x 4), and the combined organic layers were washed with brine (500 ml) and concentrated. The crude product was purified by RP-LC (flow rate: 200 ml / min; gradient: 50 minutes from 90% H2O (0.1% FA) / 10% ACN to 65% H2O (0.1% FA) / 35% ACN; then 17 minutes for 65% H2O (0.1% FA) / 35% ACN; column: Welch Ultimate XB_C18, 20-40 μm, 100 Å, ID 95 mm × H 365 mm) to obtain 16.4 g of the title compound. SFC: S-enantiomer: tR 1.03 min (94.7%), R-enantiomer: tR: 1.31 min (5.3%) [Column: Chiralpak AD-3, 50 × 4.6 mm, ID, 3 μm, Mobile phase: A: CO2, B: MeOH (0.05% DEA), Gradient: 5% to 40% B; Flow rate: 3 ml / min, Column temperature: 35°C]. 1H NMR (400 MHz, CDCl3) δ = 8.82 (2 H), 8.11 (1 H), 7.12 (1 H), 5.35 (1 H), 3.94 - 3.85 (1 H), 3.81 (1 H), 2.48 - 2.37 (1 H), 2.28 (1 H), 2.11 - 2.01 (1 H), 1.52 - 1.43 (9 H).

[0285] I-02g-2: tert-butyl(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carboxylate [ka] To a solution of tert-butyl N-[(1S)-1-(5-cyano-3-pyridyl)-3-hydroxypropyl]-N-hydroxycarbamate (15.4 g) in THF (160 ml), tributylphosphan (17.00 g) was added dropwise at 0°C, followed by DIAD (13.80 g) at 0°C. The mixture was then gradually heated to 20°C and stirred for 16 hours. The reaction mixture was concentrated. The crude product was purified by RP-LC (flow rate: 200 ml / min; gradient: 80 minutes from 90% H2O (0.1% FA) / 10% ACN to 63% H2O (0.1% FA) / 37% ACN; then 30 minutes for 63% H2O (0.1% FA) / 37% ACN; column: Welch Ultimate XB_C18, 20-40 μm, 100 Å, ID 95 mm × H 365 mm), and the residue was ground with PE:EA = 5:1 (80 ml) to obtain 6.6 g (>99.9% ee) of the title compound. 1 H NMR (400 MHz, CDCl3) δ = 8.84 - 8.76 (2 H), 8.04 - 7.98 (1 H), 5.32 (1 H), 4.27 - 4.20 (1 H), 3.95 - 3.87 (1 H), 2.95 - 2.85 (1 H), 2.28 (1 H), 1.50 (9 H). SFC: (S) Enantiomer tR: 1.89 min (100%) [Column: Chiralpak AD-3, 50 × 4.6 mm, ID, 3 μm, Mobile phase: A: CO2, B: MeOH (0.05% DEA), Gradient: 5% to 40%; Flow rate: 3 ml / min, Column temperature: 35°C]. Information: (R) Enantiomer tR: 1.17 min

[0286] I-02-1:5-[(3S)-isoxazolidine-3-yl]pyridine-3-carbonilicate [ka] 1.25 g of tert-butyl(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carboxylate was dissolved in 15 ml of dry DCM at room temperature with stirring. After adding 5.0 ml of TFA, the reaction mixture was stirred for 30 minutes. The solvent was then removed under vacuum. A saturated NaHCO3 solution was added to the residue, and the aqueous phase was extracted with DCM three times. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain 790 mg of the title compound, which was used directly in the next step without further purification. LC / MS: m / z = 176.2 [M+H] + ; tR: 0.71 min (LC / MS-method A). 1 H NMR (400.23 MHz, DMSO-d6) δ ppm 8.90 (1 H), 8.85 (1 H), 8.22 (1 H), 7.0-6.3 (1 H), 4.58 (1 H), 3.95 (1 H), 3.70 (1 H), 2.64 (1 H), 2.18 (1 H)

[0287] I-02-2:5-[(3S)-isoxazolidine-3-yl]pyridine-3-carbonitrili trifluoroacetate [ka] 250 mg of tert-butyl(S)-3-(5-cyanopyridine-3-yl)isoxazolidine-2-carboxylate (I-02g-2) was dissolved in 5 ml of DCM, and 1.5 ml of trifluoroacetic acid was added. After stirring for 0.75 hours, the solvent was removed under vacuum, the residue was dissolved in ACN / water, and freeze-dried overnight to obtain 248 mg of the title compound. LC / MS: m / z = 176.3 [M+H] + ; tR: 0.71 min (LC / MS-method A). 1 H NMR (400.23 MHz, DMSO-d6) δ ppm 8.93 (1 H), 8.87 (1 H), 8.26 (1 H), 4.70 (1 H), 4.07 (1 H), 3.80 (1 H), 2.69 (1 H), 2.28 (1 H)

[0288] I-02-2(R):5-[(3R)-isoxazolidine-3-yl]pyridine-3-carbonitrile TFA salt [ka] 100 mg of tert-butyl(R)-3-(5-cyanopyridine-3-yl)isoxazolidine-2-carboxylate (I-02g-1) was dissolved in 5 ml of DCM, and 0.27 ml of trifluoroacetic acid was added. After stirring under Ar for 2 hours, the solvent was removed under vacuum, and both solutions were evaporated twice with toluene to obtain 118 mg of the title compound. LC / MS: m / z = 176.3 [M + H] + ;tR: 0.27 min (LC / MS-Method D).

[0289] I-02-3: 5-[(3S)-isoxazolidine-3-yl]pyridine-3-carbonitrile (compound with 4-methylbenzenesulfonic acid) [ka] To a mixture of tert-butyl(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carboxylate (I-02g-2, 500 mg) and ethyl acetate (10 ml), 4-methylbenzenesulfonic acid (hydrate, maintained at 2.1 M in ethyl acetate at 35 °C, 2.6 ml) was added at 50 °C. After 3 hours at 55 °C, a white precipitate was formed, which was isolated by filtration at room temperature to obtain 1.1 g of the title compound. LC / MS: m / z = 175.9 [M + H] + ;tR:0.20 min (LC / MS-Method D)

[0290] I-03: 3-(1-methylpyrazole-3-yl)isoxazolidine TFA salt I-03a:(E)-3-(1-methylpyrazole-3-yl)prop-2-enal [ka] 1-Methyl-1H-pyrazole-3-carboaldehyde (1.0 g) was dissolved in DCM (15 ml), and (formylmethylene)triphenylphosphorane (3.0 g) was added while stirring. After stirring at 40°C for 96 hours, water was added. The aqueous phase was extracted with DCM (3 times), and the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (90 g; 0% to 20% EA in heptane for 40 minutes, 20% EA for 70 minutes). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 444.5 mg of the title compound. LC / MS: m / z = 137.2[M+H] + ;tR: 0.59 min (LC / MS-Method D).

[0291] I-03b: tert-butyl 5-hydroxy-3-(1-methylpyrazole-3-yl)isoxazolidine-2-carboxylate [ka] [Diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]trimethylsilane (219.1 mg) was dissolved in DCM (5 ml), and then benzoic acid (79.8 mg), (E)-3-(1-methylpyrazole-3-yl)prop-2-enal (444.5 mg) and tert-butyl N-hydroxycarbamate (532 mg) were added with stirring. After stirring for 4 hours, tert-butyl N-hydroxycarbamate (53 mg) was added, and the solution was stirred at room temperature for another hour. A mixture of DCM and saturated NH4Cl solution was added. The aqueous phase was extracted once with DCM, and the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (90 g; 0% to 50% EA in heptane for 30 minutes, 50% EA for 60 minutes). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 778.5 mg of the title compound. This compound contained tert-butyl 5-((tert-butoxycarbonyl)(hydroxy)amino)-3-(1-methyl-1H-pyrazole-3-yl)isoxazolidine-2-carboxylate as an impurity, but it was used in the next step without further purification. LC / MS: m / z = 254 [M-H2O] + ; tR: 0.87 min (LC / MS-method D). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.58 (1 H), 6.78 (1 H), 6.08 (1 H), 6.01 (1 H), 5.59 (1 H), 5.22 (1 H), 3.77 (3 H), 2.72 (1 H), 2.39 (1 H), 1.42 (9 H).

[0292] I-03c:tert-butyl N-hydroxy-N-[3-hydroxy-1-(1-methylpyrazole-3-yl)propyl]carbamate [ka] 778.5 mg of tert-butyl 5-hydroxy-3-(1-methylpyrazole-3-yl)isoxazolidine-2-carboxylate was dissolved in 12 ml of methanol, cooled to 0°C, and 109.4 mg of NaBH4 was added with stirring. After 24 hours, saturated NH4Cl solution was added. The aqueous phase was extracted by DCM (3 times), and the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was further purified by preparative RP HPLC (120 ml / min, 95% H2O + 0.1% TFA / 5% ACN to 5% H2O + 0.1% TFA / 95% ACN at 13 min; Waters Sunfire Prep C18 OBD-5 μm, 50 × 100 mm). The fractions containing the pure compound were combined, ACN was removed under vacuum, and the residue was freeze-dried overnight to obtain 240 mg of the title compound. LC / MS: m / z = 272.3[M+H] + ;tR:0.75 min (LC / MS-Method D)

[0293] I-03d: tert-butyl 3-(1-methylpyrazole-3-yl)isoxazolidine-2-carboxylate [ka] 240 mg of tert-butyl N-hydroxy-N-[3-hydroxy-1-(1-methylpyrazole-3-yl)propyl]carbamate was dissolved in 10 ml of THF, and triphenylphosphine (563 mg) and DIAD (355 μl) were added at 0°C while stirring under argon. After 4 hours, an additional amount of DIAD (88 μl) was added. After stirring for 2 days, triphenylphosphine (94.7 mg) and DIAD (53 μl) were added, and after 4 hours, another 53 μl of DIAD was added. After stirring for 3 days, triphenylphosphine (142 mg) and DIAD (106 μl) were added, and after stirring overnight, H2O was added. The aqueous phase was extracted by DCM (3 times), and the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was further purified by preparative RP HPLC (120 ml / min, 13 min from 95% H2O + 0.1% TFA / 5% ACN to 5% H2O + 0.1% TFA / 95% ACN; Waters Sunfire Prep C18 OBD-5 μm, 50 × 100 mm). The fractions containing the pure compound were combined, ACN was removed under vacuum, and the residue was freeze-dried overnight. 102.4 mg of the title compound was obtained as a 55 / 45 enantiomer mixture (Chiralpak AD-H / 148, 1 ml / min, 250 mm × 4.6 mm, heptane / EtOH / MeOH 1 / 1 / 1). LC / MS: m / z = 154 [M-CO2tBu+2H] + ; tR: 1.01 min (LC / MS-method D). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.58 (1 H), 6.10 (1 H), 5.15 (1 H), 4.09 (1 H), 3.78 (3 H), 3.71 (1 H), 2.58 (1 H), 2.42 (1 H), 1.41 (9 H).

[0294] I-03: 3-(1-methylpyrazole-3-yl)isoxazolidine TFA salt [ka] 102 mg of tert-butyl 3-(1-methylpyrazole-3-yl)isoxazolidine-2-carboxylate was dissolved in 3 ml of DCM, and 1.5 ml of TFA was added at room temperature while stirring. After 1.5 hours, the solvent was removed under vacuum, and the residue was evaporated twice with toluene to obtain 121 mg of the title compound. LC / MS: m / z = 154[M+H] + ;tR: 0.09 min (LC / MS-Method D).

[0295] I-04:3-Imidazol[1,2-a]pyridine-6-ylisoxazolidine TFA salt I-04a:(E)-3-imidazo[1,2-a]pyridine-6-ylpropa-2-enal [ka] Imidazo[1,2-a]pyridine-6-carbaldehyde (2.0 g) was dissolved in ACN (17 ml), and (formylmethylene)triphenylphosphorane (4.6 g) was added while stirring. After stirring at 80°C for 24 hours, water was added. The aqueous phase was extracted by DCM (3 times), and the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (120 g; 0% to 50% EA in heptane for 40 minutes, 50% EA for 230 minutes). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 1.63 g of the title compound (purity approximately 65%). LC / MS: m / z = 173.2[M+H] + ;tR: 0.09 min (LC / MS-Method D).

[0296] I-04b:tert-butyl5-hydroxy-3-imidazo[1,2-a]pyridine-6-yl-isoxazolidine-2-carboxylate [ka] [Diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]trimethylsilane (445.6 mg), benzoic acid (162.2 mg), and (E)-3-imidazo[1,2-a]pyridine-6-ylpropa-2-enal (1.63 g) were dissolved in DCM (15 ml) with stirring and cooled to 4°C. After 10 minutes, tert-butyl N-hydroxycarbamate (1.08 g) was added with stirring. After stirring at 4°C for 24 hours, a mixture of DCM and saturated NH4Cl solution was added. The aqueous phase was extracted once with DCM, and the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative RP HPLC (120 ml / min, 13 minutes from 95% H2O / 5% ACN to 5% H2O / 95% ACN; Waters Sunfire Prep C18 OBD-5 μm, 50 × 100 mm). The fractions containing the pure compound were combined, ACN was removed under vacuum, and the residue was freeze-dried overnight. 1.20 g of the title compound was obtained (enantiomer ratio not determined). LC / MS: m / z = 306.2[M+H] + ;tR: 0.62 min (LC / MS-Method D).

[0297] I-04c:tert-butylN-hydroxy-N-[3-hydroxy-1-imidazo[1,2-a]pyridine-6-yl-propyl]carbamate [ka] 1.20 g of tert-butyl 5-hydroxy-3-imidazo[1,2-a]pyridine-6-yl-isoxazolidine-2-carboxylate (the possible excess of the S enantiomer was not determined) was dissolved in 15 ml of methanol, cooled to 0°C, and 148.2 mg of NaBH4 was added with stirring. After 48 hours, saturated NH4Cl solution was added. The aqueous phase was extracted by DCM (3 times), the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum to obtain 1.05 g of the title compound, which was used in the next step without further purification. LC / MS: m / z = 308.3[M+H] + ;tR:0.54 min (LC / MS-Method D)

[0298] I-04d:tert-butyl3-imidazo[1,2-a]pyridine-6-ylisoxazolidine-2-carboxylate [ka] 1.045 g of tert-butyl N-hydroxy-N-[3-hydroxy-1-imidazo[1,2-a]pyridine-6-yl-propyl]carbamate was dissolved in 20 ml of THF, and triphenylphosphine (2.17 g) and DIAD (1.37 ml) were added at 0°C while stirring under argon. After 24 hours, H2O was added. The aqueous phase was extracted by DCM (3 times), and the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (180 g; 260 minutes in heptane from 0% to 90% EA). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 512.5 mg of the title compound. LC / MS: m / z = 290.3[M+H] + ;tR:0.69 min (LC / MS-Method D)

[0299] I-04:3-Imidazol[1,2-a]pyridine-6-ylisoxazolidine TFA salt [ka] 255 mg of tert-butyl 3-imidazo[1,2-a]pyridine-6-ylisoxazolidine-2-carboxylate was dissolved in 3 ml of DCM, and 3.4 ml of TFA was added at room temperature while stirring. After 1.5 hours, the solvent was removed under vacuum, and the resulting residue was evaporated twice with toluene to obtain 382 mg of the title compound. LC / MS: m / z = 190.1[M+H] + ;tR:0.10 min (LC / MS-Method D)

[0300] I-05: 5-(isoxazolidine-3-yl)pyridine-2-ol HCl salt I-05a:(E)-3-(6-chloro-3-pyridyl)propa-2-enal [ka] 6-Chloronicotinaldehyde (2 g) was dissolved in ACN (50 ml), and (formylmethylene)triphenylphosphorane (4.7 g) was added while stirring. After stirring at 80°C for 3 hours, the solution was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (100 g; 0% to 85% EA in heptane in 45 minutes). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 2.07 g of the title compound. LC / MS: m / z = 168.2 [M+H] + ; tR: 0.85 min (LC / MS-method D). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.71 (1 H), 8.77 (1 H), 8.29 (1 H), 7.79 (1 H), 7.65 (1 H), 7.03 (1 H).

[0301] I-05b: tert-butyl 3-(6-chloro-3-pyridyl)-5-hydroxyisoxazolidine-2-carboxylate [ka] [Diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]trimethylsilane (869.9 mg), benzoic acid (318.1 mg), and (E)-3-(6-chloro-3-pyridyl)prop-2-enal (2.17 g) were dissolved in DCM (20 ml) under stirring, and then tert-butyl N-hydroxycarbamate (2.11 g) was added. After stirring at room temperature for 3 hours, saturated NH4Cl solution was added, and the mixture was passed through an Agilent Chem Elut SLE cartridge for elution with DCM. The eluate was concentrated under vacuum, and the resulting residue was purified by flash chromatography on silica gel (100 g; 0% to 65% EA in 52 mins). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 3.64 g of the title compound (purity approximately 70%, enantiomer ratio not determined). LC / MS: m / z = 301.1[M+H] + ;tR: 1.14 min (LC / MS-Method D).

[0302] I-05c:tert-butyl N-[1-(6-chloro-3-pyridyl)-3-hydroxy-propyl]-N-hydroxy-carbamate [ka] 3.536 g of tert-butyl 3-(6-chloro-3-pyridyl)-5-hydroxy-isoxazolidine-2-carboxylate (the possible excess of the S enantiomer was not determined) was dissolved in methanol (10 ml), cooled to 0°C, and NaBH4 (444.8 mg) was added with stirring. After 2 hours at 0°C, saturated NH4Cl solution was added. The aqueous phase was extracted by DCM (3 times), and the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (50 g; 0% to 90% in 19 minutes). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 2.145 g of the title compound. LC / MS: m / z = 303.2[M+H] + ;tR:0.96 min (LC / MS-Method D)

[0303] I-05d: tert-butyl 3-(6-chloro-3-pyridyl)isoxazolidine-2-carboxylate [ka] 2.145 g of tert-butyl N-[1-(6-chloro-3-pyridyl)-3-hydroxy-propyl]-N-hydroxy-carbamate was dissolved in 100 ml of THF, and triphenylphosphine (4.51 g) and DIAD (2.85 ml) were added at 0°C while stirring under argon. After 24 hours, a mixture of DCM and H2O was added, and the phases were separated. The aqueous phase was extracted with DCM (3 times), and the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (100 g; 0% to 77% EA in heptane in 24 minutes). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 3.609 g of the title compound as a mixture with reduced DIAD (110 mol%).

[0304] A pure sample was analytically obtained by preparative HPLC (120 ml / min, 13 min from 95% H2O + 0.1% TFA / 5% ACN to 5% H2O + 0.1% TFA / 95% ACN; Waters Sunfire Prep C18 OBD-5 μm, 50 × 100 mm) to obtain 88 mg of a 60 / 40 enantiomer mixture (Chiralpak IC / 144, 250 × 4.6 mm, heptane / EtOH / MeOH 5 / 1 / 1). Preparative chiral HPLC (30 ml / min, heptane / EtOH / MeOH 5 / 1 / 1, Chiralpak IC, 250 × 30 mm, 5 μm) yielded 27 mg and 19 mg of the two enantiomers. LC / MS: m / z = 285.1 [M+H] + ; tR: 1.28 min (LC / MS-method D) 1H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (1 H), 7.79 (1H), 7.51 (1H), 5.24 (1 H), 4.17 (1H), 3.76 (1H), 2.82 (1H), 2.18 (1H), 1.39 (9 H).

[0305] I-05: 5-(isoxazolidine-3-yl)pyridine-2-ol HCl salt [ka] 325 mg of tert-butyl 3-(6-chloro-3-pyridyl)isoxazolidine-2-carboxylate was dissolved in HCl (12.5 ml, 6 M) and heated at 100°C with stirring. After 120 hours, the solvent was removed under vacuum, and the residue was evaporated three times with toluene. The resulting residue was dissolved in ACN / water and freeze-dried to obtain 226 mg of the title compound. LC / MS: m / z = 167.2[M+H] + ;tR:0.09 min (LC / MS-Method D)

[0306] I-06: 3-Tetrahydropyran-3-ylisoxazolidine TFA salt I-06a:(E)-3-tetrahydropyran-3-ylpropa-2-enal [ka] Tetrahydro-2H-pyran-3-carboaldehyde (539 mg) was dissolved in toluene (15 ml), and (formylmethylene)triphenylphosphoran (1.56 g) was added with stirring. After stirring at 120°C for 24 hours, the solution was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (25 g; 0% to 50% EA in heptane in 7 minutes). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 203 mg of the title compound as a mixture with approximately 50% (2E,4E)-5-(tetrahydro-2H-pyran-3-yl)penta-2,4-dienal. LC / MS: m / z = 141.2[M+H]+ ;tR: 0.69 min (LC / MS-Method D).

[0307] I-06b: tert-butyl 5-hydroxy-3-tetrahydropyran-3-yl isoxazolidine-2-carboxylate [ka] [Diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]trimethylsilane (85 mg), benzoic acid (25 mg), and tert-butyl N-hydroxycarbamate (206.6 mg) were dissolved in chloroform (1 ml) with stirring. (E)-3-tetrahydropyran-3-ylpropa-2-enal (203 mg) was dissolved in chloroform (1 ml) and added at 4°C with stirring. After stirring at 4°C for 24 hours, the solution was concentrated under vacuum. The residue was purified by preparative RP HPLC (120 ml / min, 95% H2O + 0.1% TFA / 5% ACN to 5% H2O + 0.1% TFA / 95% ACN at 13 min; Waters Sunfire Prep C18 OBD-5 μm, 50 × 100 mm). The fractions containing the pure compound were combined, the ACN was removed under vacuum, and the residue was freeze-dried overnight to obtain 112 mg of the title compound (enantiomer ratio not determined). LC / MS: m / z = 174.3 [M - CO2tBu + 2H] + ;tR: 0.81 min (LC / MS-Method D).

[0308] I-06c:tert-butylN-hydroxy-N-[3-hydroxy-1-tetrahydropyran-3-yl-propyl]carbamate [ka] 112 mg of tert-butyl 5-hydroxy-3-tetrahydropyran-3-yl isoxazolidine-2-carboxylate (the possible excess of the S enantiomer was not determined) was dissolved in methanol (5 ml), cooled to 0°C, and 15.5 mg of NaBH4 was added with stirring. After 45 minutes at 0°C, saturated NH4Cl solution was added, and the mixture was passed through an Agilent Chem Elut SLE cartridge for elution with DCM. The eluate was concentrated under vacuum to obtain 103 mg of the title compound, which was used in the next step without further purification. LC / MS: m / z = 176.2 [M - CO2tBu + 2H] + ;tR:0.96 min (LC / MS-Method D)

[0309] I-06d: tert-butyl 3-tetrahydropyran-3-ylisoxazolidine-2-carboxylate [ka] 103 mg of tert-butyl N-hydroxy-N-[3-hydroxy-1-tetrahydropyran-3-yl-propyl]carbamate was dissolved in 5 ml of THF, and triphenylphosphine (237.9 mg) and DIAD (150.3 μl) were added at 0°C while stirring under argon. After 24 hours, a mixture of DCM and H2O was added, and the phases were separated. The aqueous phase was extracted with DCM (3 times), and the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (10 g; 0% to 50% EA in heptane in 10 minutes). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 254 mg of the title compound as a mixture with reduced DIAD (200%). LC / MS: m / z = 158.3 [M - CO2tBu + 2H] + ;tR:1.19 min (LC / MS-Method D)

[0310] I-06: 3-Tetrahydropyran-3-ylisoxazolidine TFA salt [ka] 254 mg of tert-butyl 3-tetrahydropyran-3-ylisoxazolidine-2-carboxylate was dissolved in 5 ml of DCM, and 0.5 ml of TFA was added at room temperature while stirring. After 1.5 hours, the solvent was removed under vacuum, and the residue was evaporated twice with toluene to obtain 278 mg of the title compound. LC / MS: m / z = 158.2[M+H] + tR: 0.17 mins (LC / MS - Method D, retention time is based on MS trace)

[0311] I-07: (5-Isoxazolidine-3-yl-3-pyridyl)methanol TFA salt I-07a: Methyl 5-[(E)-3-oxopropa-1-enyl]pyridine-3-carboxylate [ka] Methyl-5-formylnicotinate (1.0 g) was dissolved in ACN (20 ml), and (formylmethylene)triphenylphosphorane (1.9 g) was added while stirring. After stirring at 80°C for 14 hours, the solution was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (90 g; 150 minutes in heptane from 10% to 35% EA). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 520 mg of the title compound. LC / MS: m / z = 192.2[M+H] + ;tR: 0.76 min (LC / MS-Method D).

[0312] I-07b:tert-butyl 5-hydroxy-3-(5-methoxycarbonyl-3-pyridyl)isoxazolidine-2-carboxylate [ka] Methyl 5-[(E)-3-oxopropa-1-enyl]pyridine-3-carboxylate (520 mg), [diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]trimethylsilane (182.6 mg), and benzoic acid (66.8 mg) were dissolved in DCM (10 ml) with stirring, and tert-butyl N-hydroxycarbamate (443.4 mg) was added with stirring at 4°C. After stirring at 4°C for 24 hours, a mixture of DCM and saturated NH4Cl solution was added, and the phases were separated. The aqueous phase was extracted with DCM, and the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (90 g; 140 minutes in heptane at 15% to 65% EA). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 750 mg of the title compound (enantiomer ratio not determined). LC / MS: m / z = 325.3[M+H] + ;tR: 0.95 min (LC / MS-Method D).

[0313] I-07c: Methyl 5-[1-[tert-butoxycarbonyl(hydroxy)amino]-3-hydroxy-propyl]pyridine-3-carboxylate [ka] 750 mg of tert-butyl 5-hydroxy-3-(5-methoxycarbonyl-3-pyridyl)isoxazolidine-2-carboxylate (the possible excess of the S enantiomer was not determined) was dissolved in 25 ml of methanol and cooled to 0°C. 87.5 mg of NaBH4 was added with stirring. After 45 minutes at 0°C, a mixture of saturated NH4Cl solution and DCM was added, and the phases were separated. The aqueous phase was extracted with DCM (twice), the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum to obtain 630 mg of the title compound, which was used in the next step without further purification. LC / MS: m / z = 327.3[M+H] + ;tR:0.80 min (LC / MS-Method D)

[0314] I-07d: tert-butyl 3-(5-methoxycarbonyl-3-pyridyl)isoxazolidine-2-carboxylate [ka] Methyl 5-[1-[tert-butoxycarbonyl(hydroxy)amino]-3-hydroxy-propyl]pyridine-3-carboxylate (630 mg) was dissolved in THF (30 ml), and triphenylphosphine (1.23 g) and DIAD (776 μl) were added at 0°C while stirring under argon. After 4.5 hours, a mixture of DCM and H2O was added, and the phases were separated. The aqueous phase was extracted with DCM (3 times), and the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (90 g; 120 minutes in heptane, 10% to 35% EA). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 310 mg of the title compound. A pure sample was obtained analytically by preparative HPLC (120 ml / min, 13 min from 95% H2O + 0.1% TFA / 5% ACN to 5% H2O + 0.1% TFA / 95% ACN; Waters Sunfire Prep C18 OBD-5 μm, 50 × 100 mm), and aliquots were purified. After lyophilization, 47 mg of the title compound was obtained. LC / MS: m / z = 309.3 [M+H] + ; tR: 1.07 min (LC / MS-method D) 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (1H), 8.79 (1H), 8.20 (1H), 5.35 (1H), 4.19 (1H), 3.77 (1H), 2.87 (1H), 2.23 (1H).

[0315] I-07e:tert-butyl3-[5-(hydroxymethyl)-3-pyridyl]isoxazolidine-2-carboxylate [ka] 100 mg of tert-butyl 3-(5-methoxycarbonyl-3-pyridyl)isoxazolidine-2-carboxylate was dissolved in 5 ml of THF, and lithium aluminum hydride (324 μl, 1 M in THF) was added at -78°C while stirring under argon, and the mixture was maintained at this temperature. After 3.5 hours, lithium aluminum hydride (20 μl, 1 M in THF) was added. After 30 minutes, aqueous potassium sodium tartrate (10 wt / wt%) was added at -78°C. The mixture was diluted with DCM, the phases were separated, the aqueous phase was extracted with DCM (3 times), the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum to obtain 119 mg of the title compound. LC / MS: m / z = 281.3 [M + H] + ;tR:0.61 min (LC / MS-Method D)

[0316] I-07: (5-Isoxazolidine-3-yl-3-pyridyl)methanol TFA salt [ka] 119 mg of tert-butyl 3-[5-(hydroxymethyl)-3-pyridyl]isoxazolidine-2-carboxylate was dissolved in 3 ml of DCM, and 1.6 ml of TFA was added at room temperature while stirring. After 1.5 hours, the solvent was removed under vacuum, and the residue was evaporated twice with toluene to obtain 140 mg of the title compound. LC / MS: m / z = 181.2[M+H] + ;tR:0.10 min (LC / MS-Method D)

[0317] I-08:5-(isoxazolidine-3-yl)pyridine-3-carboxamide TFA salt I-08a: tert-butyl 3-(5-carbamoyl-3-pyridyl)isoxazolidine-2-carboxylate [ka] 90 mg of tert-butyl 3-(5-methoxycarbonyl-3-pyridyl)isoxazolidine-2-carboxylate (I-07d) was dissolved in 1 ml of ammonia (7 M in methanol), and the mixture was stirred in an autoclave at 60°C for 6.5 hours. After this, 1 ml of ammonia (7 M in methanol) was added. The solution was further concentrated under vacuum at 60°C for 18 hours and at room temperature for 48 hours to obtain 89 mg of the title compound, which was used in the next step without further purification. LC / MS: m / z = 294.2[M+H] + ;tR:0.74 min (LC / MS-Method D)

[0318] I-08:5-(isoxazolidine-3-yl)pyridine-3-carboxamide TFA salt [ka] 89 mg of tert-butyl 3-(5-carbamoyl-3-pyridyl)isoxazolidine-2-carboxylate was dissolved in 3 ml of DCM, and 1.2 ml of TFA was added at room temperature while stirring. After 1.5 hours, the solvent was removed under vacuum, and the residue was evaporated twice with toluene to obtain 93 mg of the title compound. LC / MS: m / z = 194.2[M+H] + ;tR:0.092 min (LC / MS-Method D)

[0319] I-09: 5-(isoxazolidine-3-yl)pyridine-2-amine TFA salt I-09a: tert-butyl3-[6-(tert-butoxycarbonylamino)-3-pyridyl]isoxazolidine-2-carboxylate [ka] 90 mg of tert-butyl 3-(6-chloro-3-pyridyl)isoxazolidine-2-carboxylate (I-05d) was dissolved in 4 ml of THF, and Cs2CO3 (206 mg), tert-butylcarbamate (113.4 mg), Pd2(dba)3 (11.6 mg), and X-phos (6.2 mg) were added while stirring under argon. After stirring at 80°C for 24 hours, a mixture of H2O and DCM was added, and the phases were separated. The aqueous phase was extracted with DCM (3 times), and the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (5 g; 0% to 50% EA in heptane in 16 minutes). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 104 mg of the title compound. LC / MS: m / z = 366.5 [M+H] + ; tR: 2.13 min (LC / MS-method A) 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (1 H), 8.17 (1 H), 7.76 (1 H), 7.67 (1 H), 5.13 (1 H), 4.16 (1 H), 3.75 (1 H), 2.77 (1 H), 2.18 (1 H), 1.47 (9 H), 1.39 (9 H).

[0320] I-09: 5-(isoxazolidine-3-yl)pyridine-2-amine TFA salt [ka] 99 mg of tert-butyl(3S)-3-[6-(tert-butoxycarbonylamino)-3-pyridyl]isoxazolidine-2-carboxylate was dissolved in 2 ml of DCM, and 416 μl of TFA was added at room temperature while stirring. After 2 hours, the solvent was removed under vacuum, and the residue was evaporated twice with toluene to obtain 115 mg of the title compound. LC / MS: m / z = 166.3[M+H] + ;tR:0.09 min (LC / MS-Method D)

[0321] I-10:5-(isoxazolidine-3-yl)-N-methylpyridine-3-carboxamide TFA salt I-10a: tert-butyl 3-[5-(methylcarbamoyl)-3-pyridyl]isoxazolidine-2-carboxylate [ka] 90 mg of tert-butyl 3-(5-methoxycarbonyl-3-pyridyl)isoxazolidine-2-carboxylate (I-07d) was dissolved in methylamine (1.3 ml, 8 M in ethanol). After 1 hour at 100°C with stirring in a microwave oven, the solvent was removed under vacuum, and the residue was dried under high vacuum to obtain 84 mg of the title compound. LC / MS: m / z = 308.3[M+H] + ;tR:0.818 min (LC / MS-Method D)

[0322] I-10:5-(isoxazolidine-3-yl)-N-methylpyridine-3-carboxamide TFA salt [ka] 84 mg of tert-butyl 3-[5-(methylcarbamoyl)-3-pyridyl]isoxazolidine-2-carboxylate was dissolved in 3 ml of DCM, and 205 μl of TFA was added at room temperature with stirring. After 1.5 hours, the conversion was not complete, so 100 μl of TFA was added at room temperature with stirring. After 24 hours, the solvent was removed under vacuum, and the residue was evaporated twice with toluene to obtain 124 mg of the title compound. LC / MS: m / z = 208.2[M+H] + ;tR:0.096 min (LC / MS-Method D)

[0323] I-11: N-[5-[(3S)-isoxazolidine-3-yl]-3-pyridyl]acetamide TFA salt I-11a:(E)-3-(5-bromo-3-pyridyl)propa-2-enal [ka] 5-bromonicotinaldehyde (3.0 g) was dissolved in ACN (2 ml), and (formylmethylene)triphenylphosphorane (5.4 g) was added while stirring. After stirring at 80°C for 13 hours, the solution was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (190 g; 10% to 22% EA in heptane in 85 minutes). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 2.3 g of the title compound. LC / MS: m / z = 212.1 [M+H] + ; tR: 0.89 min (LC / MS-method D) 1 H NMR (400 MHz, DMSO-d6): δ ppm 9.70 (1H), 8.91 (1H), 8.81 (1H), 8.53 (1H), 7.75 (1H), 7.08 (1H).

[0324] I-11b: tert-butyl(3S)-3-(5-bromo-3-pyridyl)-5-hydroxyisoxazolidine-2-carboxylate [ka] (E)-3-(5-bromo-3-pyridyl)propa-2-enal (2.3 g), [diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]trimethylsilane (728 mg), and benzoic acid (359.3 mg) were dissolved in DCM (30 ml) with stirring, and tert-butyl N-hydroxycarbamate (1.71 g) was added with stirring at 4°C. After stirring at 4°C for 24 hours, a mixture of DCM and saturated NH4Cl solution was added, and the phases were separated. The aqueous phase was extracted with DCM, and the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (180 g; 12% to 35% EA in heptane at 70 mins). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 2.94 g of the title compound. LC / MS: m / z = 345.2 [M + H]+ ;tR: 1.12 min (LC / MS-Method D).

[0325] I-11c:tert-butylN-[(1S)-1-(5-bromo-3-pyridyl)-3-hydroxy-propyl]-N-hydroxy-carbamate [ka] 2.94 g of tert-butyl(3S)-3-(5-bromo-3-pyridyl)-5-hydroxyisoxazolidine-2-carboxylate was dissolved in 100 ml of methanol and cooled to 0°C. NaBH4 (322.2 mg) was added while stirring. After 90 minutes at 0°C, a mixture of saturated NH4Cl solution and DCM was added, and the phases were separated. The aqueous phase was extracted with DCM (twice), the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum to obtain 2.8 g of the title compound, which was used in the next step without further purification. LC / MS: m / z = 347.2[M+H] + ;tR:0.95 min (LC / MS-Method D)

[0326] I-11d: tert-butyl(3S)-3-(5-bromo-3-pyridyl)isoxazolidine-2-carboxylate [ka] 1.50 g of tert-butyl N-[(1S)-1-(5-bromo-3-pyridyl)-3-hydroxypropyl]-N-hydroxycarbamate was dissolved in 50 ml of THF, and triphenylphosphine (2.75 g) and DIAD (1.74 ml) were added at 0°C while stirring under argon. After 2 hours, a mixture of DCM and H2O was added, and the phases were separated. The aqueous phase was extracted with DCM (3 times), and the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (90 g; 10% to 25% EA in heptane at 75 mins). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 1.40 g of the title compound as a mixture with reduced DIAD. A pure sample was obtained analytically by preparative HPLC (120 ml / min, 13 min from 95% H2O + 0.1% TFA / 5% ACN to 5% H2O + 0.1% TFA / 95% ACN; Waters Sunfire Prep C18 OBD-5 μm, 50 × 100 mm), and aliquots were purified. After lyophilization, 22 mg was obtained. LC / MS: m / z = 329.1 [M+H] + ; tR: 1.26 min (LC / MS-method D) 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.63 (1 H), 8.54 (1 H), 7.95 (1 H), 5.24 (1 H), 4.18 (1 H), 3.77 (1 H), 2.82 (1 H), 2.23 (1 H), 1.39 (9 H). Chiral HPLC (Chiralpak AD-H / 148, 250×4.6mm, EtOH / MeOH 1 / 1, 1ml / min): 93 / 7er

[0327] I-11e:tert-butyl(3S)-3-(5-acetamido-3-pyridyl)isoxazolidine-2-carboxylate [ka] 100 mg of tert-butyl(3S)-3-(5-bromo-3-pyridyl)isoxazolidine-2-carboxylate was dissolved in 10 ml of dioxane, and 25.9 mg of acetamide (25.9 mg), cesium carbonate (141.4 mg), 5.6 mg of 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (5.6 mg), and tris(dibenzylideneacetone)dipalladium (0) (29.3 mg) were added under argon. After 9.5 hours at 100°C, H2O and EA were added, and the phases were separated. The aqueous phase was extracted with EA (3 times), washed with brine, and the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (25 g; 30 minutes over 0% to 5% MeOH in DCM). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 60 mg of the title compound. LC / MS: m / z = 308.37 [M+H] + ; tR: 1.13 min (LC / MS-method A) 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.16 (1 H), 8.64 (1 H), 8.21 (1 H), 7.98 (1 H), 5.20 (1 H), 4.16 (1 H), 3.74 (1 H), 2.83 (1 H), 2.14 (1 H), 2.06 (3 H), 1.39 (9 H).

[0328] I-11: N-[5-[(3S)-isoxazolidine-3-yl]-3-pyridyl]acetamide TFA salt [ka] 60 mg of tert-butyl(3S)-3-(5-acetamido-3-pyridyl)isoxazolidine-2-carboxylate was dissolved in 3 ml of DCM, and 147 μl of TFA was added at room temperature while stirring. After 1.5 hours, the solvent was removed under vacuum, and the residue was evaporated twice with toluene to obtain 20 mg of the title compound. LC / MS: m / z = 208.2[M+H] +;tR:0.15 min (LC / MS-Method D)

[0329] I-12: (3S)-3-(6-methylpyrazine-2-yl)isoxazolidine hydrochloride I-12a:2-[(E)-3,3-diethoxypropa-1-enyl]-6-methylpyrazine [ka] A mixture of 2-chloro-6-methylpyrazine (30 g), 3,3-diethoxypropa-1-ene (243.03 g), K2CO3 (64.50 g), tetrabutylammonium acetate (140.72 g), KCl (17.40 g), and Pd(OAc)2 (2.62 g) in DMF (300 ml) was stirred at 120°C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated. The residue was diluted with EA (500 ml), filtered, and the filtrate was diluted with water (500 ml) and extracted with EA (300 ml x 3). The combined organic layers were washed with brine (1 l), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 10:1 to 3:1) to obtain 21.1 g of the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 8.39 (1 H), 8.30 (1 H), 6.81 (2 H), 5.15 (1 H), 3.72 (2 H), 3.59 (2 H), 2.55 (3 H), 1.26 (6 H)

[0330] I-12b:(E)-3-(6-methylpyrazine-2-yl)prop-2-enal [ka] 37 g of 2-[(E)-3,3-diethoxypropa-1-enyl]-6-methylpyrazine was dissolved in 166 ml of acetone, to which 1 M HCl solution (166.45 ml) was added. The mixture was stirred at 25°C for 1 hour. The mixture was then adjusted to pH=7 with 50 ml of saturated NaHCO3 solution and extracted with EE (300 ml x 3). The combined organic layers were washed with brine (500 ml x 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 10:1 to 3:1) to obtain 22.4 g of the title compound.

[0331] I-12c:tert-butyl(3S)-5-hydroxy-3-(6-methylpyrazine-2-yl)isoxazolidine-2-carboxylate [ka] To a solution of [diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]trimethylsilane (9.84 g) in CHCl3 (230 ml), (E)-3-(6-methylpyrazine-2-yl)prop-2-enal (22.4 g) and tert-butyl N-hydroxycarbamate (24.16 g) were added at 0°C. The mixture was smoothly heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated. The residue was purified by RP-LC (flow rate: 100 ml / min; gradient: 22 minutes from 90% H2O (0.1% FA) / 10% ACN to 55% H2O (0.1% FA) / 45% ACN; 16 minutes from 55% H2O (0.1% FA) / 45% ACN; column: Agela C18, 20 μm, 100 Å, 60.6 mm × 187 mm) to obtain 23.5 g of the title compound.

[0332] I-12d:tert-butylN-hydroxy-N-[(1S)-3-hydroxy-1-(6-methylpyrazine-2-yl)propyl]carbamate [ka] To a solution of tert-butyl(3S)-5-hydroxy-3-(6-methylpyrazine-2-yl)isoxazolidine-2-carboxylate (23.5 g) in MeOH (235 ml), NaBH4 (3.79 g) was added. The mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched by adding saturated NH4Cl (50 ml) solution, then diluted with water (800 ml), and extracted with EA (1 l x 3). The combined organic layers were washed with brine (1 l), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by RP-LC (flow rate: 200 ml / min; gradient: 12 minutes from 90% H2O (0.1% FA) / 10% ACN to 70% H2O (0.1% FA) / 30% ACN; 10 minutes from 70% H2O (0.1% FA) / 30% ACN; column: Welch Ultimate XB C18, 20-40 μm, 120 Å, 95 mm × 365 mm) to obtain 21 g of the title compound.

[0333] I-12e:tert-butyl(3S)-3-(6-methylpyrazine-2-yl)isoxazolidine-2-carboxylate [ka] To a solution of tert-butyl N-hydroxy-N-[(1S)-3-hydroxy-1-(6-methylpyrazine-2-yl)propyl]carbamate (21 g) in THF (210 ml), tributylphosphan (23.99 g) and DIAD (19.48 g) were added at 0°C. The mixture was stirred at 0°C for 6 hours, then stirred at 25°C for 6 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by preparative HPLC (RP) (flow rate: 400 ml / min; gradient: 80% H2O (0.1% FA) / 20% ACN to 56% H2O (0.1% FA) / 44% ACN for 44 minutes; 56% H2O (0.1% FA) / 44% ACN for 19 minutes; column: Phenomenex Luna C18, 15 μm, 100 Å, 150 mm × 400 mm), followed by silica gel column chromatography (PE:EA = 10:1 to 0:1) to obtain three fractions: Fraction 1 (3 g, 90.8% ee), Fraction 2 (3.5 g, 90.4% ee), and Fraction 3 (1.5 g, 87.5% ee). Fractions 1 and 2 were combined to obtain 6.3 g (90.4% ee) of the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 8.58 (1H), 8.37 (1H), 5.34 (1H), 4.18 (1H), 3.95 (1H), 2.86 - 2.72 (1H), 2.67 - 2.57 (1H), 2.56 (3H), 1.50 (9H).

[0334] Chiral HPLC: (chiralpak IC-3, 50×4.6mm, 3μm; Phase A: CO2, B: MeOH (0.05%DEA); Gradient: MeOH (0.05%DEA) in CO2 from 5 to 40%; Flow rate 3ml / min; T35℃, p100bar) tert-butyl(3R)-3-(6-methylpyrazine-2-yl)isoxazolidine-2-carboxylate:tR 2.06 min, 4.8%, tert-butyl(3S)-3-(6-methylpyrazine-2-yl)isoxazolidine-2-carboxylate:tR 1.17 min, 95.2%

[0335] I-12: (3S)-3-(6-methylpyrazine-2-yl)isoxazolidine hydrochloride [ka] 500 mg of tert-butyl(S)-3-(6-methylpyrazine-2-yl)isoxazolidine-2-carboxylate was dissolved in 6 ml of dioxane, and 9.42 ml of HCl (4 M in dioxane) was added at room temperature while stirring. After standing overnight, the solvent was removed under vacuum, the residue was dissolved in ACN / water, and freeze-dried overnight to obtain 420 mg of the title compound. LC / MS: m / z = 166.2[M+H] + ;tR: 0.70 min (LC / MS-Method A).

[0336] I-13:3-(1-methylpyrazole-4-yl)isoxazolidine hydrochloride I-13a: tert-butyl-dimethyl-[(E)-3-(1-methylpyrazole-4-yl)allyloxy]silane [ka] 4-bromo-1-methyl-1H-pyrazole (1.05 g), (E)-3-(tert-butyldimethylsilyloxy)propene-1-ylboronic acid pinacol ester (2.24 ml), and cesium carbonate (4.12 g) were dissolved in a mixture of dioxane (42 ml) and water (10.5 ml). Ar was bubbling into the solution for 5 minutes. Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl]palladium(II) (249 mg) was then added, and Ar was bubbling into the solution again for 2 minutes. The mixture was refluxed under Ar with stirring for 1 hour. After cooling, water and EA were added. The aqueous phase was extracted with EA (twice). The combined organic phase was dehydrated with sodium sulfate, filtered, and concentrated under vacuum to obtain 1.97 g of the title compound, which was used directly in the next step.

[0337] I-13b:(E)-3-(1-methylpyrazole-4-yl)propa-2-en-1-ol [ka] 1.97 g of tert-butyl-dimethyl-[(E)-3-(1-methylpyrazole-4-yl)allyloxy]silane was dissolved in 40 ml of THF at 0°C, and 9.6 ml of tetrabutylammonium fluoride (1 M in THF) was added. After 5 hours, solid NaHCO3 was added with stirring. After 2 hours, the suspension was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (80 g SiO2, 100% DCM for 5 minutes; 10% ethanol from 100% DCM for 40 minutes; then 10% EtOH for 10 minutes). The fractions containing the pure product were combined, and the solvent was removed under vacuum to obtain 1.08 g of the title compound. LC / MS: m / z = 139.2[M+H] + ;tR:0.71 min (LC / MS-Method A)

[0338] I-13c:(E)-3-(1-methylpyrazole-4-yl)propa-2-enal [ka] (E)-3-(1-methyl-1H-pyrazole-4-yl)propa-2-en-1-ol (870 mg) was dissolved in DCM (42 ml), and MnO2 (10.95 g) was added while stirring. After 30 minutes, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain 666 mg of the title compound, which was used directly in the next step. LC / MS: m / z = 137.2[M+H] + ;tR:0.79 min (LC / MS-Method A)

[0339] I-13d: tert-butyl 5-hydroxy-3-(1-methylpyrazole-4-yl)isoxazolidine-2-carboxylate [ka] [Diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]trimethylsilane (410 mg) was dissolved in DCM (28 ml) at 0°C. (E)-3-(1-methyl-1H-pyrazole-4-yl)acrylaldehyde (0.66 g) and tert-butyl N-hydroxycarbamate (0.79 g) were added with stirring. After standing overnight in a refrigerator (4°C), silyl ether (0.1 equivalent) and carbamate (0.5 equivalent) were added, and the mixture was maintained in the refrigerator for 24 hours. Then saturated NH4Cl solution was added. The aqueous phase was extracted with DCM (3 times), and the combined organic phase was dehydrated with sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (flow rate 50 ml / min; 17.5 min from 90% H2O / 10% ACN to 10% H2O / 90% ACN; Agilent Prep C18-10 μm, 30 × 250 mm). The fractions containing the pure product were combined, ACN was removed under vacuum, and the aqueous phase was freeze-dried to obtain 267 mg of the title compound. LC / MS: m / z = 270.3 [M + H] + ;tR: 1.21 min (LC / MS-Method A).

[0340] I-13e:tert-butyl N-hydroxy-N-[3-hydroxy-1-(1-methylpyrazole-4-yl)propyl]carbamate [ka] 266 mg of tert-butyl 5-hydroxy-3-(1-methylpyrazole-4-yl)isoxazolidine-2-carboxylate was dissolved in 12 ml of methanol, cooled to 0°C, and 37 mg of NaBH4 was added with stirring. After 1 hour, saturated NH4Cl solution was added. The aqueous phase was extracted twice by DCM, and the combined organic phase was dehydrated with sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (flow rate 50 ml / min, 17.5 min from 90% H2O / 10% ACN to 10% H2O / 90% ACN; Agilent Prep C18-10 μm, 30 × 250 mm). The fractions containing the pure product were combined, ACN was removed under vacuum, and the aqueous phase was freeze-dried to obtain 73 mg of the title compound. LC / MS: m / z = 272.3[M+H] + ;tR:1.06 min (LC / MS-Method A)

[0341] I-13f:tert-butyl3-(1-methylpyrazole-4-yl)isoxazolidine-2-carboxylate [ka] 72 mg of tert-butyl N-hydroxy-N-[3-hydroxy-1-(1-methylpyrazole-4-yl)propyl]carbamate was dissolved in 3 ml of THF, and triphenylphosphine (101 mg) and DIAD (210 μl) were added while stirring. After standing overnight, triphenylphosphine (36 mg) and DIAD (25 μl) were added. After stirring for 5 hours, the temperature was raised to 50°C and stirring was continued for 1.5 hours. The solvent was then removed under vacuum, and the residue was directly separated by preparative HPLC (flow rate 50 ml / min, 97% H2O / 3% ACN to 10% H2O / 90% ACN in 15 minutes; Agilent Prep C18-10 μm, 21.2 × 250 mm). The fractions containing the pure product were combined, the ACN was removed under vacuum, and the aqueous phase was freeze-dried to obtain 30 mg of the title compound. We also recovered 50 mg of the starting material. LC / MS: m / z = 254.3 [M + H] + ;tR: 1.44 min (LC / MS-Method A).

[0342] I-13:3-(1-methylpyrazole-4-yl)isoxazolidine hydrochloride [ka] 77 mg of the title compound was obtained following the procedure described in I-12. LC / MS: m / z = 154.1 [M + H] + ;tR: 0.05 min (LC / MS-Method B).

[0343] I-14:3-(5-fluoro-3-pyridyl)isoxazolidine HCl / TFA salt I14-1a:(E)-3-(5-fluoro-3-pyridyl)propa-2-enal [ka] A mixture of 3-bromo-5-fluoropyridine (48 g), propa-2-enal (45.87 g), Pd(OAc)2 (3.06 g), benzyl(triethyl)ammonium chloride (62.12 g), and TEA (82.80 g) in DMF (400 ml) was stirred at 70°C for 12 hours under an N2 atmosphere. The mixture was concentrated, diluted with water (800 ml), extracted with ethyl acetate (500 ml x 3), washed with brine (1 l), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel column chromatography (PE:EA = 1:1) to obtain 26.7 g of the title compound. 1 1H NMR (400 MHz, CDCl3): δ ppm 9.77 (1 H), 8.62 (1 H), 8.55 (1 H), 7.60 (1 H), 7.50 (1 H), 6.78 (1 H).

[0344] I-14-1b:tert-butyl3-(5-fluoro-3-pyridyl)-5-hydroxyisoxazolidine-2-carboxylate [ka] (E)-3-(5-fluoro-3-pyridyl)prop-2-enal (2.5 g) was dissolved in toluene (30 ml) and cooled to 0°C. [Diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]trimethylsilane (1.03 ml) and benzoic acid (404 mg) were added, and the mixture was stirred for several minutes. Tert-butylhydroxycarbamate (2.64 g) was added. The suspension was stirred at 0°C for 2 hours and stored overnight at 5°C. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The starting material was purified by silica gel chromatography (330 g SiO2, n-heptane / acetone = 100 / 0 to 40 / 60 at 33 min). The combined fraction was evaporated under reduced pressure and purified six times by preparative RP-HPLC (column: YMC-Actus Triart Prep C18-S, 250×30, S-10μm, 12nm; flow rate: 70 ml / min; 2 min 95% H2O + 0.05% TFA, to 100% ACN within 12 min, 4 min 100% ACN). The combined fraction was freeze-dried to obtain 1.034 g of the title compound, and no chiral introduction at the 3-pyridyl-isoxazolidine position was observed.

[0345] I-14-1c:tert-butylN-[1-(5-fluoro-3-pyridyl)-3-hydroxy-propyl]-N-hydroxy-carbamate [ka] 1.034 g of tert-butyl 3-(5-fluoro-3-pyridyl)-5-hydroxy-isoxazolidine-2-carboxylate was dissolved in 15 ml of methanol and cooled to 0°C. 137.6 mg of sodium borohydride was added in two batches at 0°C with stirring (at 10-minute intervals). The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was evaporated under reduced pressure, quenched with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure to obtain 856 mg of the title compound.

[0346] I-14-1d:tert-butyl3-(5-fluoro-3-pyridyl)isoxazolidine-2-carboxylate [ka] 854 mg of tert-butyl N-[1-(5-fluoro-3-pyridyl)-3-hydroxypropyl]-N-hydroxycarbamate and 1.10 g of triphenylphosphine were dissolved in 20 ml of THF. The solution was cooled to 0°C, and 696 μl of diisopropylazodicarboxylic acid was added. The mixture was stirred at 0°C for 30 minutes and allowed to stand for 3 days. Then, 1.10 g of triphenylphosphine and 696 μl of diisopropylazodicarboxylic acid were added, and the mixture was stirred overnight. The reaction mixture was purified by preparative RP-HPLC (column: Water OBD Sunfire C18 250 × 50 mm 10 μm; flow rate: 150 ml / min; 90% H2O in 4 minutes, to 90% ACN in 25 minutes). The combined fraction was lyophilized to obtain 636 mg of the title compound.

[0347] I-14-1:3-(5-fluoro-3-pyridyl)isoxazolidine TFA salt [ka] 174.4 mg of tert-butyl 3-(5-fluoro-3-pyridyl)isoxazolidine-2-carboxylate was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (0.5 ml) and stirred overnight. The mixture was evaporated under reduced pressure and lyophilized twice to obtain 158 mg of the title compound. LC / MS: m / z = 169.2[M+H] + ;tR:0.69 min (LC / MS-Method A)

[0348] I-14-2:(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine HCl salt I-14-2a:tert-butyl(3S)-3-(5-fluoro-3-pyridyl)-5-hydroxy-isoxazolidine-2-carboxylate [ka] To a solution of [diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]trimethylsilane (11.50 g) in chloroform (260 ml), (E)-3-(5-fluoro-3-pyridyl)propa-2-enal (I-14-1a, 26.7 g) and tert-butyl N-hydroxycarbamate (28.23 g) were added at 0°C. The mixture was smoothly heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated. The residue was purified by RP-LC (flow rate: 400 ml / min; gradient: 90% H2O (0.1% FA) / 10% ACN to 60% H2O (0.1% FA) / 40% ACN over 50 minutes; 60% H2O (0.1% FA) / 40% ACN over 25 minutes; column: Phenomenex luna C18, 15 μm, 100 Å, ID 150 mm × H 400 mm) to obtain 25 g of the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 8.45 - 8.37 (2), 7.44 (1 H), 5.94 - 5.84 (1 H), 5.39 (1 H), 2.84 (1 H), 2.33 - 2.20 (1 H), 1.47 (9 H).

[0349] I-14-2b:tert-butylN-[(1S)-1-(5-fluoro-3-pyridyl)-3-hydroxypropyl]-N-hydroxycarbamate [ka] To a solution of tert-butyl 3-(5-fluoro-3-pyridyl)-5-hydroxy-isoxazolidine-2-carboxylate (25 g) in methanol (250 ml), NaBH4 (3.99 g) was added at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution (50 ml), then diluted with water (800 ml), and extracted with ethyl acetate (1 l x 3). The combined organic layers were washed with brine (1 l), dried over Na2SO4, filtered, and concentrated. The crude product was purified by RP-LC (flow rate: 200 ml / min; gradient: 15 minutes from 90% H2O (0.1% FA) / 10% ACN to 60% H2O (0.1% FA) / 40% ACN; 8 minutes from 60% H2O (0.1% FA) / 40% ACN; column: Welch Ultimate XB_C18, 20-40 μm, 120 Å, ID 95 mm × H 365 mm) to obtain 23.5 g of the title compound (enantiomer ratio: 94.7 (S): 5.3 (R)). 1 H NMR (400 MHz, CDCl3): δ ppm 8.49 - 8.30 (2 H), 7.66 - 7.51 (1 H), 5.33 (1 H), 3.89 - 3.71 (2 H), 2.41 (1 H), 2.05 (1 H), 1.47 (9 H).

[0350] Chiral HPLC: (Chiralpak AD-3, 50 x 4.6 mm, 3 μm; Phase A: CO2, Phase B: MeOH (0.05% DEA); Gradient: 5 to 40% MeOH (0.05% DEA) in CO2; Flow rate 3 ml / min; Temperature 35°C, pressure 100 bar) tert-butyl N-[(1S)-1-(5-fluoro-3-pyridyl)-3-hydroxy-propyl]-N-hydroxy-carbamate:tR 0.90 min, 94.7%, tert-butyl N-[(1R)-1-(5-fluoro-3-pyridyl)-3-hydroxypropyl]-N-hydroxycarbamate:tR 0.97 min, 5.3%

[0351] I-14-2c:tert-butyl(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-carboxylate [ka] To a solution of tert-butyl N-[1-(5-fluoro-3-pyridyl)-3-hydroxypropyl]-N-hydroxycarbamate (23.5 g) in THF (235 ml), tributylphosphan (26.57 g) and DIAD (21.58 g) were added at 0°C. The mixture was smoothly heated to 25°C and stirred under an N2 atmosphere for 12 hours. The reaction mixture was then concentrated. The residue was purified by RP HPLC (flow rate: 400 ml / min; gradient: 80% H2O (0.1% FA) / 20% ACN to 56% H2O (0.1% FA) / 44% ACN for 44 minutes; 56% H2O (0.1% FA) / 44% ACN for 19 minutes; column: Phenomenex luna C18, 15 μm, 100 Å, ID 150 mm × H 400 mm) and silica gel column chromatography (PE:EA = 10:1 to 0:1) to obtain 14.3 g of the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 8.42 (1 H), 8.38 (1 H), 7.46 (1 H), 5.28 (1 H), 4.21 (1 H), 3.90 (1 H), 2.85 (1 H), 2.29 (1 H), 1.48 (9 H).

[0352] Chiral HPLC: tR: 5.47 min, (R-enantiomer, 5.3%), 10.18 min (S-enantiomer, 94.7%), (Chiralcel AD-H, 4.6 mm x 250 mm, 5 μm; EtOH + 0.1% IPA; flow rate 0.75 ml / min; T30 °C)

[0353] I-14-2:(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine HCl salt [ka] Following the procedure described in I-12, 129 mg of the title compound was obtained. LC / MS: m / z = 169.2[M+H] + ;tR: 0.68 min (LC / MS-Method A).

[0354] I-15:1-[5-[(3S)-isoxazolidine-3-yl]-3-pyridyl]azetidine-2-one TFA salt I-15a: tert-butyl(3S)-3-[5-(2-oxoazetidine-1-yl)-3-pyridyl]isoxazolidine-2-carboxylate [ka] 100 mg of tert-butyl(3S)-3-(5-bromo-3-pyridyl)isoxazolidine-2-carboxylate (I-11d) was dissolved in 2 ml of dioxane, and 31.2 mg of 2-azetidinone, 141.4 mg of cesium carbonate, 5.6 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and 0 mg of tris(dibenzylideneacetone)dipalladium (29.3 mg) were added under argon. After 5 hours at 100°C, a mixture of EA and H2O was added, the phases were separated, and the aqueous phase was extracted with EA (3 times). The combined organic phases were washed with brine, dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (25 g; 37 minutes over 0% to 3% MeOH in DCM). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 81 mg of the title compound. LC / MS: m / z = 320.4 [M+H] + ; tR: 1.38 min (LC / MS-method A) 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (1H), 8.39 (1H), 7.70 (1H), 5.22 (1H), 4.18 (1H), 3.78 - 3.65 (3H), 3.14 (1H), 2,84 (1H), 2.17 (1H), 1.40 (9 H).

[0355] I-15:1-[5-[(3S)-isoxazolidine-3-yl]-3-pyridyl]azetidine-2-one TFA salt [ka] 80 mg of tert-butyl(3S)-3-[5-(2-oxoazetidine-1-yl)-3-pyridyl]isoxazolidine-2-carboxylate was dissolved in 3 ml of DCM, and 188 μl of TFA was added at room temperature while stirring. After 72 hours, the conversion was not complete, so another 50 μl of TFA was added at room temperature while stirring. After 1 hour, the solvent was removed under vacuum, and the residue was evaporated twice with toluene to obtain 80 mg of the title compound. LC / MS: m / z = 220.1[M+H] + ;tR:0.22 min (LC / MS-Method D)

[0356] I16:1-[5-[(3S)-isoxazolidine-3-yl]-3-pyridyl]pyrrolidine-2-one I-16a: tert-butyl(3S)-3-[5-(2-oxopyrrolidine-1-yl)-3-pyridyl]isoxazolidine-2-carboxylate [ka] 100 mg of tert-butyl(3S)-3-(5-bromo-3-pyridyl)isoxazolidine-2-carboxylate (I11d) was dissolved in 3 ml of dioxane, and 35 μl of 2-pyrrolidinene, 141.4 mg of cesium carbonate, 5.6 mg of 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene, and 0 mg of tris(dibenzylideneacetone)dipalladium (29.3 mg) were added under argon. After 5 hours at 100°C, a mixture of EA and H2O was added, the phases were separated, and the aqueous phase was extracted with EA (3 times). The combined organic phases were washed with brine, dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (25 g; 37 minutes over 0% to 3% MeOH in DCM). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 21 mg of the title compound. LC / MS: m / z = 334.4 [M+H] + ; tR: 1.34 min (LC / MS-method A) 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (1 H), 8.30 (1 H), 8.10 (1 H), 5.23 (1 H), 4.17 (t1 H), 3.87 (2 H), 3.75 (1 H), 2.84 (1 H), 2.50 (2H), 2.17 (1H), 2.09 (1H), 1.39 (9H).

[0357] I-16:1-[5-[(3S)-isoxazolidine-3-yl]-3-pyridyl]pyrrolidine-2-one TFA salt [ka] 20 mg of tert-butyl(3S)-3-[5-(2-oxopyrrolidine-1-yl)-3-pyridyl]isoxazolidine-2-carboxylate was dissolved in 3 ml of DCM, and 45 μl of TFA was added at room temperature while stirring. After 1.5 hours, the conversion was not complete, so another 30 μl of TFA was added at room temperature while stirring. After 1 hour, the solvent was removed under vacuum, and the residue was evaporated twice with toluene to obtain 20 mg of the title compound. LC / MS: m / z = 234.1[M+H] + ;tR:0.21 min (LC / MS-Method D)

[0358] I-17: (3S)-3-pyrazine-2-ylisoxazolidine hydrochloride I-17a: tert-butyl-dimethyl-[(E)-3-pyrazine-2-ylaryloxy]silane [ka] 2-bromopyrazine (2.5 g), (E)-3-(tert-butyldimethylsilyloxy)propene-1-ylboronic acid pinacol ester (5.3 ml), and cesium carbonate (9.73 g) were dissolved in a mixture of dioxane (42 ml) and water (10.5 ml). Ar was then bubbling into the solution for 5 minutes, and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl]palladium(II) (590 mg) was added. Ar was bubbling into the solution again for 5 minutes, and the mixture was refluxed under Ar with stirring for 1 hour. After cooling, water and EA were added. The aqueous phase was extracted with EA (twice). The combined organic phase was dehydrated with sodium sulfate, filtered, and concentrated under vacuum to obtain 6.36 g of the title compound, which was used directly in the next step.

[0359] I-17b:(E)-3-pyrazine-2-ilpropa-2-en-1-ol [ka] 6.36 g of tert-butyl-dimethyl-[(E)-3-pyrazine-2-ylallyloxy]silane was dissolved in 100 ml of THF, the mixture was cooled to 0°C, and 31.75 ml of tetrabutylammonium fluoride (1 M in THF) was added. After 2 hours, solid NaHCO3 was added with stirring. After 1.5 hours, the suspension was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (200 g SiO2, 100% DCM for 5 minutes; 10% ethanol from 100% DCM for 45 minutes; then 10% EtOH for 15 minutes). The fractions containing the pure product were combined, and the solvent was removed under vacuum to obtain 1.82 g of the title compound. LC / MS: m / z = 137.2[M+H] + ;tR:0.64 min (LC / MS-Method A)

[0360] I-17c:(E)-3-pyrazine-2-ilpropa-2-enal [ka] (E)-3-pyrazine-2-ylpropa-2-en-1-ol (1.82 mg) was dissolved in DCM (90 ml), and MnO2 (23.24 g) was added while stirring. After 30 minutes, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain 1.12 g of the title compound, which was used directly in the next step. LC / MS: m / z = 135.1[M+H] + ;tR:0.73 min (LC / MS-Method A)

[0361] I-17d: tert-butyl(3S)-5-hydroxy-3-pyrazine-2-ylisoxazolidine-2-carboxylate [ka] [Diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]trimethylsilane (700 mg) was dissolved in DCM (40 ml), and the mixture was cooled to 0°C. (E)-3-pyrazine-2-ylpropa-2-enal (1.12 g) and tert-butyl N-hydroxycarbamate (1.36 g), dissolved in DCM (10 ml), were added with stirring. After standing overnight in a refrigerator (4°C), silyl ether (0.1 equivalent) and carbamate (0.5 equivalent) were added, and the mixture was maintained in the refrigerator for 24 hours. Then saturated NH4Cl solution was added. The aqueous phase was extracted with DCM (twice), and the combined organic phase was dehydrated with sodium sulfate, filtered, and concentrated under vacuum. The residue was purified six times by preparative HPLC (flow rate 75 ml / min, 17.5 min from 90% H2O / 10% ACN to 10% H2O / 90% ACN; Agilent Prep C18-10 μm, 30 × 250 mm). The fractions containing the pure product were combined, ACN was removed under vacuum, and the aqueous phase was freeze-dried to obtain 358 mg of the title compound. LC / MS: m / z = 268.3[M+H] + ;tR: 1.19 min (LC / MS-Method A).

[0362] I-17e:tert-butylN-hydroxy-N-[(1S)-3-hydroxy-1-pyrazine-2-yl-propyl]carbamate [ka] 360 mg of tert-butyl(3S)-5-hydroxy-3-pyrazine-2-yl-isoxazolidine-2-carboxylate was dissolved in 20 ml of methanol, cooled to 0°C, and 50 mg of NaBH4 was added while stirring. After 1 hour, saturated NH4Cl solution was added. The aqueous phase was extracted by DCM (5 times), and the combined organic phase was dehydrated with sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (flow rate 75 ml / min, 17.5 min from 90% H2O / 10% ACN to 10% H2O / 90% ACN; Agilent Prep C18-10 μm, 30 × 250 mm). The fractions containing the pure product were combined, ACN was removed under vacuum, and the aqueous phase was freeze-dried to obtain 209 mg of the title compound. LC / MS: m / z = 270.3 [M + H] + ;tR:1.06 min (LC / MS-Method A)

[0363] I-17f:tert-butyl(3S)-3-pyrazine-2-ylisoxazolidine-2-carboxylate [ka] 205 mg of tert-butyl N-hydroxy-N-[(1S)-3-hydroxy-1-pyrazine-2-yl-propyl]carbamate was dissolved in 5 ml of THF, and triphenylphosphine (290 mg) and DIAD (210 μl) were added while stirring. After stirring for 1 hour, the solvent was removed under vacuum, and the residue was purified by preparative HPLC (flow rate 75 ml / min, 15 min from 90% H2O / 10% ACN to 10% H2O / 90% ACN; Agilent Prep C18-10 μm, 30 × 250 mm). The fractions containing the product were combined, ACN was removed under vacuum, and the aqueous phase was freeze-dried to obtain 275 mg of the title compound, which still contained approximately 50 mol% reduced DIAD. LC / MS: m / z = 252.3[M+H] + ;tR: 1.38 min (LC / MS-Method A).

[0364] I-17: (3S)-3-pyrazine-2-ylisoxazolidine hydrochloride [ka] Following the procedure described in I-12, the title compound (256 mg) was obtained, which still contained approximately 50 mol% of reduced DIAD from step I-35f as an impurity, but this did not interfere with the subsequent steps. LC / MS: m / z = 152.2[M+H] + ;tR: 0.46 min (LC / MS-Method A).

[0365] I-18:5-[(3S)-isoxazolidine-3-yl]-2-methylpyridine-3-carbonil HCl salt I-18a: 5-bromo-2-methylpyridine-3-carboxamide [ka] 5-bromo-2-methylpyridine-3-carboxylic acid (15 g), NH4Cl (11.14 g), and HATU (39.60 g) were dissolved in DMF (150 ml), to which DIPEA (26.92 g) was added. The mixture was stirred at 20°C for 12 hours. The reaction mixture was diluted with saturated NaHCO3 solution (300 ml), extracted with EA (200 ml x 3), washed with brine (200 ml), dried over Na2SO4, filtered, and concentrated to obtain 15 g of the title compound, which was used directly in the next step.

[0366] I-18b: 5-bromo-2-methylpyridine-3-carbonitrile [ka] To a solution of 5-bromo-2-methylpyridine-3-carboxamide (15 g) in dioxane (300 ml), pyridine (55.17 g) and TFAA (73.25 g) were added, and the reaction mixture was stirred at 20°C for 12 hours. The mixture was then quenched with ice / water (500 ml) and extracted with EA (200 ml x 3). The combined organic layer was washed with brine (200 ml), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 10:1) to obtain 10.2 g of the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 8.75 (1 H), 8.02 (1 H), 2.75 (3 H)

[0367] I-18d: 2-methyl-5-[(E)-3-oxopropa-1-enyl]pyridine-3-carbonitrile [ka] A mixture of 5-bromo-2-methylpyridine-3-carbonitrile (13.7 g), propa-2-enal (11.69 g), Pd(OAc)2 (780.53 mg), benzyl(triethyl)ammonium chloride (15.84 g), and TEA (21.11 g) in DMF (130 ml) was stirred at 80°C for 12 hours under an N2 atmosphere. The mixture was diluted with water (500 ml), extracted with EA (500 ml x 4), washed with brine (250 ml), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 10:1 to 2:1) to obtain 6.5 g of the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 9.78 (1 H), 8.87 (1 H), 8.09 (1 H), 7.47 (1 H), 6.81 (1 H), 2.86 (3 H)

[0368] I-18e:tert-butyl(3S)-3-(5-cyano-6-methyl-3-pyridyl)-5-hydroxy-isoxazolidine-2-carboxylate [ka] To a solution of [diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]trimethyl-silane (2.50 g) in CHCl3 (70 ml), 2-methyl-5-[(E)-3-oxopropa-1-enyl]pyridine-3-carbonitrile (6.6 g) and tert-butyl N-hydroxycarbamate (6.12 g) were added at 0°C. The mixture was smoothly heated to 25°C and stirred for 36 hours. The reaction mixture was concentrated. The residue was purified by RP preparative HPLC (0.1% FA conditions) to obtain 4.9 g of the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 8.65 (1 H), 7.91 (1 H), 5.87 (1 H), 5.36 (1 H), 4.61 - 4.33 (1 H), 2.86 - 2.74 (4 H), 2.23 (1 H), 1.46 (9 H)

[0369] I-18f:tert-butyl N-[(1S)-1-(5-cyano-6-methyl-3-pyridyl)-3-hydroxy-propyl]-N-hydroxy-carbamate [ka] To a solution of tert-butyl(3S)-3-(5-cyano-6-methyl-3-pyridyl)-5-hydroxyisoxazolidine-2-carboxylate (4.9 g) in MeOH (50 ml), NaBH4 (728.53 mg) was added at 0°C. The mixture was stirred at 0°C for 2 hours under an N2 atmosphere. The mixture was then quenched with saturated NH4Cl solution (10 ml), diluted with water (200 ml), extracted with EA (200 ml x 2), dried over Na2SO4, filtered, and concentrated. The residue was combined with the previous batch and purified by silica gel chromatography (PE:EA = 3:1 to 2:1) to obtain 3.1 g of the title compound. 1H NMR (400 MHz, CDCl3): δ ppm 8.69 (1 H), 8.03 (1 H), 6.72 (1 H), 5.31 (1 H), 3.92 - 3.75 (2 H), 2.77 (3 H), 2.41 (1 H), 2.04 - 1.97 (1 H), 1.49 (9H)

[0370] I-18g: tert-butyl(3S)-3-(5-cyano-6-methyl-3-pyridyl)isoxazolidine-2-carboxylate [ka] To a solution of tert-butyl N-[(1S)-1-(5-cyano-6-methyl-3-pyridyl)-3-hydroxypropyl]-N-hydroxycarbamate (3.1 g) in THF (31 ml), tributylphosphan (3.27 g) and DIAD (2.65 g) were added at 0°C. The mixture was smoothly warmed to 20°C and stirred under N2 for 16 hours. The mixture was concentrated. The residue was purified by preparative RP-LC (flow rate: 200 ml / min; gradient: 44 min from 85% H2O (0.1% FA) / 15% ACN to 55% H2O (0.1% FA) / 45% ACN; 24 min from 55% H2O (0.1% FA) / 45% ACN; column: Welch Ultimate XB C18, 20 / 40 μm, 100 Å, 95 mm × 365 mm), followed by flash silica gel chromatography (PE:EA = 1:4) to obtain 1.8 g of the title compound (enantiomer ratio 96 (S): 4 (R)). 1 H NMR (400 MHz, CDCl3): δ ppm 8.66 (1 H), 7.92 (1 H), 5.27 (1 H), 4.22 (1 H), 3.90 (1 H), 2.86 (1 H), 2.77 (3 H), 2.26 (1 H), 1.50 (9 H)

[0371] Chiral HPLC: (Chiralpak AD-3, 50 x 4.6 mm, 3 μm; Phase A: CO2, Phase B: MeOH (0.05% DEA); Gradient: 5 to 40% MeOH (0.05% DEA) in CO2; Flow rate 3 ml / min; Temperature 35°C, pressure 100 bar) tert-butyl(3R)-3-(5-cyano-6-methyl-3-pyridyl)isoxazolidine-2-carboxylate:tR 0.70 min, 4.3%, tert-butyl(3S)-3-(5-cyano-6-methyl-3-pyridyl)isoxazolidine-2-carboxylate:tR 1.91 min, 95.7%

[0372] I-18:5-[(3S)-isoxazolidine-3-yl]-2-methylpyridine-3-carbonil HCl salt [ka] Following the procedure described in I-12, 314 mg of the title compound was obtained. LC / MS: m / z = 190.2 [M+H] + ; tR: 0.88 min (LC / MS-method A). 1 H NMR (600.05 MHz, DMSO-d6) δ ppm 8.83 (1 H), 8.39 (1 H), 5.04 (1 H), 4.43 (1 H), 4.18 (1 H), 2.83 (1 H), 2.70 (3 H), 2.58 (1 H)

[0373] I-19: (3S)-3-(5-chloro-2-pyridyl)isoxazolidine TFA salt I-19a:(E)-3-(5-chloro-2-pyridyl)propa-2-enal [ka] 5-Chloropyridine-2-carbaldehyde (27g) and 2-(triphenyl-λ) 5A mixture of phosphanylidene acetaldehyde (58.05 g) in THF (250 ml) was stirred at 70°C for 12 hours. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 0:1) to obtain 5.3 g of the title compound. 1 H NMR (400MHz, CDCl3): δ ppm 9.81 (1 H), 8.66 (1 H), 7.75 (1 H), 7.55 - 7.44 (2 H), 7.07 (1 H).

[0374] I-19b: tert-butyl(3S)-3-(5-chloro-2-pyridyl)-5-hydroxyisoxazolidine-2-carboxylate [ka] To a solution of [diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]trimethylsilane (2.06 g) in CHCl3 (53 ml), (E)-3-(5-chloro-2-pyridyl)prop-2-enal (5.3 g) was added at 0°C. The mixture was stirred at 0°C for 15 minutes, and tert-butyl N-hydroxycarbamate (5.05 g) was added. The mixture was smoothly heated to 25°C and stirred for 12 hours. The reaction mixture was concentrated. The residue was purified by RP preparative HPLC (0.1% FA conditions) to obtain 4.93 g of the title compound.

[0375] I-19c:tert-butylN-[(1S)-1-(5-chloro-2-pyridyl)-3-hydroxy-propyl]-N-hydroxy-carbamate [ka] To a solution of tert-butyl(3S)-3-(5-chloro-2-pyridyl)-5-hydroxyisoxazolidine-2-carboxylate (4.9 g) in MeOH (49 ml), NaBH4 (308.21 mg) was added at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution (30 ml), diluted with water (200 ml), and extracted with EA (200 ml x 3). The combined organic layers were washed with brine (300 ml), dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (0.1% FA conditions) to obtain 3.7 g of the title compound. 1 H NMR (400MHz, CDCl3): δ ppm 8.45 (1 H), 7.69 (1 H), 7.29 (1 H), 5.44 (1 H), 3.87 - 3.77 (2 H), 2.33 (1 H), 2.18 - 2.07 (1 H), 1.43 (9 H)

[0376] I-19d: tert-butyl(3S)-3-(5-chloro-2-pyridyl)isoxazolidine-2-carboxylate [ka] To a solution of tert-butyl N-[(1S)-1-(5-chloro-2-pyridyl)-3-hydroxy-propyl]-N-hydroxy-carbamate (3.7 g) in THF (37 ml), tributylphosphan (3.96 g) and DIAD (3.21 g) were added at 0°C. The mixture was smoothly warmed to 25°C and stirred under N2 for 12 hours. Additional tributylphosphan (989 mg) and DIAD (988 mg) were added at 0°C. The reaction mixture was smoothly warmed to 25°C and stirred for 12 hours. The reaction mixture was concentrated. The residue was purified by RP preparative HPLC (0.1% FA conditions) and silica gel column chromatography (PE:EA = 10 / 1 to 0 / 1) to obtain 2.3 g of the title compound (enantiomer ratio 95(S):5(R)). 1H NMR (400 MHz, CDCl3): δ ppm 8.51 (1 H), 7.65 (1 H), 7.48 (1 H), 5.33 (1 H), 4.14 (1 H), 3.92 (1 H), 2.85 - 2.74 (1 H), 2.62 - 2.49 (1 H), 1.49 (9H)

[0377] Chiral HPLC: (Chiralpak AD-3, 50 x 4.6 mm, 3 μm; Phase A: CO2, Phase B: MeOH (0.05% DEA); Gradient: 5 to 40% MeOH (0.05% DEA) in CO2; Flow rate 3 ml / min; Temperature 35°C, pressure 100 bar) tert-butyl(3R)-3-(5-cyano-6-methyl-3-pyridyl)isoxazolidine-2-carboxylate:tR 0.68 min, 4.9%, tert-butyl(3S)-3-(5-cyano-6-methyl-3-pyridyl)isoxazolidine-2-carboxylate:tR 1.42 min, 95.1%

[0378] I-19: (3S)-3-(5-chloro-2-pyridyl)isoxazolidine TFA salt [ka] 60 mg of tert-butyl(3S)-3-(5-chloro-2-pyridyl)isoxazolidine-2-carboxylate was dissolved in 1.5 ml of DCM, and 1.0 ml of trifluoroacetic acid was added. After stirring for 2.5 hours, 0.2 ml of TFA was added. After standing overnight, the solvent was removed under vacuum. The residue was dissolved in ACN / water and lyophilized to obtain 60 mg of the title compound. LC / MS: m / z = 185.1[M+H] + ;tR: 1.00 min (LC / MS-Method A).

[0379] I-20: (3S)-3-(5-methylpyrazine-2-yl)isoxazolidine HCl salt I-20a: Methyl 5-methylpyrazine-2-carboxylate [ka] 5-methylpyrazine-2-carboxylic acid (24 g) was dissolved in MeOH (240 ml) and H2SO4 (852.09 mg) was added. The mixture was stirred at 80°C for 12 hours. The reaction mixture was adjusted to pH 7-8 with saturated NaHCO3 solution (300 ml) and extracted with EA (500 mL x 3). The combined organic layer was washed with brine (500 ml), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain 25.65 g of the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 9.20 (1 H), 8.58 (1 H), 4.04 (3 H), 2.68 (3 H)

[0380] I-20b: 5-Methylpyrazine-2-Carboaldehyde [ka] To a solution of methyl 5-methylpyrazine-2-carboxylate (41.3 g) in THF (600 ml), LiAlH4 (1 M, 135.72 ml) was added at -78°C. The mixture was stirred at -78°C for 0.3 hours. The reaction mixture was quenched with AcOH (40 ml) at -78°C. The resulting mixture was warmed to 25°C and concentrated. The residue was dissolved in HCl (1.5 M, 400 ml) and extracted with DCM (800 ml x 3). The organic layers were combined, washed with saturated NaHCO3 solution (200 ml), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (PE:EA=1 / 0~0 / 1) to obtain 21.5 g of the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 10.13 (1 H), 9.07 (1 H), 8.63 (1 H), 2.70 (3 H)

[0381] I-20c:(E)-3-(5-methylpyrazine-2-yl)prop-2-enal [ka] A mixture of 5-methylpyrazine-2-carboaldehyde (24.9 g) and (formylmethylene)triphenyl-phosphorane (62.05 g) in THF (250 ml) was stirred at 70°C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent, then ground with PE / EA (1:1, 1 l) and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (PE:EA = 1 / 0 to 0 / 1) to obtain 17.9 g of the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 9.82 (1 H), 8.65 (1 H), 8.55 (1 H), 7.52 (1 H), 7.17 (1 H), 2.64 (3 H).

[0382] I-20d: tert-butyl(3S)-5-hydroxy-3-(5-methylpyrazine-2-yl)isoxazolidine-2-carboxylate [ka] To a solution of [diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]trimethylsilane (3.95 g) in CHCl3 (89 ml), (E)-3-(5-methylpyrazine-2-yl)prop-2-enal (9 g) was added at 0°C. The mixture was stirred at 0°C for 15 minutes. Then tert-butyl N-hydroxycarbamate (9.71 g) was added. The mixture was stirred at 0°C for 2 hours, then heated, and then stirred at 25°C for 10 hours. The reaction mixture was concentrated under reduced pressure and the solvent was removed. The residue was purified by preparative RP-LC (flow rate: 400 mL / min; gradient: 45 minutes from 80% H2O (0.1% FA) / 20% ACN to 70% H2O (0.1% FA) / 30% ACN; 28 minutes from 70% H2O (0.1% FA) / 30% ACN; column: Phenomenex luna C18, 15 μm, 100 Å, 150 mm × 400 mm) to obtain 7.75 g of the title compound.

[0383] I-20e:tert-butylN-hydroxy-N-[(1S)-3-hydroxy-1-(5-methylpyrazine-2-yl)propyl]carbamate [ka] To a solution of tert-butyl(3S)-5-hydroxy-3-(5-methylpyrazine-2-yl)isoxazolidine-2-carboxylate (15.5 g) in MeOH (150 ml), NaBH4 (1.04 g) was added at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution (50 ml), diluted with water (800 ml), and extracted with EA (500 ml x 3). The combined organic layers were washed with brine (1000 ml), dehydrated with Na2SO4, filtered, and concentrated. The crude product was purified by preparative RP-LC (flow rate: 100 ml / min; gradient: 9 min from 90% H2O (0.1% FA) / 10% ACN to 71% H2O (0.1% FA) / 29% ACN; 12 min from 71% H2O (0.1% FA) / 29% ACN; column: Agela C18, 20 μm, 100 Å, 60.6 mm × 187 mm) to obtain 14.1 g of the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm = 8.54 (1 H), 8.34 (1 H), 7.62 (1 H), 5.50 (1 H), 3.83 (2 H), 2.57 (3 H), 2.47 (1 H), 2.37 (1 H), 2.16 (1 H), 1.48 (9 H)

[0384] I-20f:tert-butyl(3S)-3-(5-methylpyrazine-2-yl)isoxazolidine-2-carboxylate [ka] To a solution of tert-butyl N-hydroxy-N-[(1S)-3-hydroxy-1-(5-methylpyrazine-2-yl)propyl]carbamate (14.1 g) in THF (141 ml), tributylphosphan (16.11 g) and DIAD (13.08 g) were added at 0°C. The mixture was stirred at 0°C for 2 hours, then smoothly warmed to 25°C and stirred under N2 for 10 hours. The reaction mixture was concentrated under reduced pressure and the solvent was removed. The crude product was purified by preparative RP-LC (flow rate: 400 ml / min; gradient: 85% H2O (0.1% FA) / 15% ACN to 50% H2O (0.1% FA) / 50% ACN for 40 minutes; 50% H2O (0.1% FA) / 50% ACN for 19 minutes; column: Phenomenex Luna C18, 15 μm, 100 Å, 150 mm × 400 mm) and silica gel column chromatography (PE:EA = 10 / 1 to 0 / 1) to obtain 8 g of crude material (89% ee) as a yellow oily substance. This was ground with PE / EA (10:1, 50 ml) to obtain 5.8 g of the title compound as a filtration cake (99.0% ee). 1 H NMR (400 MHz, CDCl3): δ ppm 8.64 (1 H), 8.40 (1 H), 5.35 (1 H), 4.19 (1 H), 3.95 (1 H), 2.84 - 2.72 (1 H), 2.67 - 2.59 (1 H), 2.59 - 2.55 (3 H), 1.50 (9H)

[0385] Chiral HPLC: (Chiralpak AD-3, 50 x 4.6 mm, 3 μm; Phase A: CO2, Phase B: MeOH (0.05% DEA); Gradient: 5 to 40% MeOH (0.05% DEA) in CO2; Flow rate 3 ml / min; Temperature 35°C, pressure 100 bar) tert-butyl(3R)-3-(5-methylpyrazine-2-yl)isoxazolidine-2-carboxylate:tR 0.97 min, 0.5%, tert-butyl(3S)-3-(5-methylpyrazine-2-yl)isoxazolidine-2-carboxylate:tR 2.40 min, 99.5%

[0386] I-20: (3S)-3-(5-methylpyrazine-2-yl)isoxazolidine HCl salt [ka] 75 mg of tert-butyl(3S)-3-(5-methylpyrazine-2-yl)isoxazolidine-2-carboxylate was dissolved in 3 ml of dioxane. 1.4 ml of HCl solution (4N in dioxane) was added while stirring, followed by the addition of another 1.4 ml of HCl solution (4N in dioxane) after 24 hours. After 1 hour, the mixture was concentrated under vacuum, dissolved in ACN / water, and freeze-dried overnight to obtain 60 mg of the title compound. LC / MS: m / z = 166.2[M+H] + ;tR: 0.68 min (LC / MS-Method A).

[0387] I-21:3-(5-methyl-1,3,4-thiadiazole-2-yl)isoxazolidine TFA salt I-21a:(E)-3-(5-methyl-1,3,4-thiadiazole-2-yl)propa-2-enal [ka] 700 g of 5-methyl-1,3,4-thiadiazole-2-carboaldehyde was dissolved in 10 ml of ACN, and 1.8 g of (formylmethylene)triphenylphosphorane was added with stirring. After stirring at room temperature for 24 hours, the solution was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (25 g; 0% to 100% EA in heptane in 8 minutes). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 293 mg of the title compound, including some remaining triphenylphosphine oxide (13%). LC / MS: m / z = 155.1 [M+H] + ; tR: 0.52 min (LC / MS-method D). 1H N MR (600 MHz, DMSO-d6) δ ppm 9.77 (1 H), 8.05 (1 H), 6.9 2 (1 H), 2.80 (3 H).

[0388] I-21b: tert-butyl 5-hydroxy-3-(5-methyl-1,3,4-thiadiazole-2-yl)isoxazolidine-2-carboxylate [ka] (E)-3-(5-methyl-1,3,4-thiadiazole-2-yl)propa-2-enal (273 mg), [diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]trimethyl-silane (118.4 mg), benzoic acid (43.5 mg), and tert-butyl N-hydroxycarbamate (288.7 mg) were dissolved in DCM (10 ml) and stirred at -20°C. After stirring at this temperature for 48 hours, a mixture of DCM and saturated NH4Cl solution was added, and the phases were separated. The aqueous phase was extracted with DCM, and the combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative RP HPLC (120 ml / min, 13 minutes from 95% H2O + 0.1% TFA / 5% ACN to 5% H2O + 0.1% TFA / 95% ACN; Waters Sunfire Prep C18 OBD-5 μm, 50 × 100 mm). The fractions containing the pure compound were combined, ACN was removed under vacuum, and the residue was freeze-dried overnight to obtain 183 mg of the title compound (enantiomer ratio has not been determined). LC / MS: m / z = 288.1[M+H] + ;tR: 0.97 min (LC / MS-Method D).

[0389] I-21c:tert-butylN-hydroxy-N-[3-hydroxy-1-(5-methyl-1,3,4-thiadiazole-2-yl)propyl]carbamate [ka] 163 mg of tert-butyl 5-hydroxy-3-(5-methyl-1,3,4-thiadiazole-2-yl)isoxazolidine-2-carboxylate (the possible excess of the S enantiomer was not determined) was dissolved in methanol (1 ml), cooled to 0°C, and 21.5 mg of NaBH4 was added with stirring. After 45 minutes at 0°C, saturated NH4Cl solution was added, and the mixture was passed through an Agilent Chem Elut SLE cartridge for elution with DCM. The eluate was concentrated under vacuum to obtain 103 mg of the title compound, which was used in the next step without further purification. LC / MS: m / z = 290.1[M+H] + ;tR:0.77 min (LC / MS-Method D)

[0390] I-21d: tert-butyl3-(5-methyl-1,3,4-thiadiazole-2-yl)isoxazolidine-2-carboxylate [ka] 155 mg of tert-butyl N-hydroxy-N-[3-hydroxy-1-(5-methyl-1,3,4-thiadiazole-2-yl)propyl]carbamate was dissolved in 3 ml of THF, and triphenylphosphine (340.2 mg) and DIAD (215 μl) were added at 0°C while stirring under argon. After 24 hours, H2O was added, and the mixture was passed through an Agilent Chem Elut SLE cartridge for elution with DCM. The eluate was concentrated under vacuum, and the residue was purified by flash chromatography on silica gel (10 g; 0% to 100% EA in heptane in 12 minutes). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 34 mg of the title compound. LC / MS: m / z = 272.2 [M+H] + ; tR: 1.01 min (LC / MS-method D) 1H NMR (600 MHz, DMSO-d6) δ ppm 5.59 (1H), 4.16 (1H), 3.77 (1H), 2.83 (1H), 2.69 (3H), 2.59 (1H),1.44 (9H).

[0391] I-21:3-(5-methyl-1,3,4-thiadiazole-2-yl)isoxazolidine TFA salt [ka] 34 mg of tert-butyl 3-(5-methyl-1,3,4-thiadiazole-2-yl)isoxazolidine-2-carboxylate was dissolved in 5 ml of DCM, and 0.2 ml of TFA was added at room temperature while stirring. After 2 hours, the solvent was removed under vacuum, and the residue was evaporated twice with toluene to obtain 34 mg of the title compound. LC / MS: m / z = 172.2[M+H] + ;tR:0.21 min (LC / MS-Method D)

[0392] I-22: 1-(4-carbamoylpyrimidine-2-yl)piperidine-4-carboxylate hydrochloride I-22a: Methyl 1-(4-carbamoylpyrimidine-2-yl)piperidine-4-carboxylate [ka] Methylpiperidine-4-carboxylate (600 mg) and 2-chloropyrimidine-4-carboxamide (615 mg) were dissolved in dry ACN (10 ml) in a microwave vessel (10-20 ml). After adding DIPEA (2.59 ml), the mixture was heated in a microwave oven at 150°C for 1 hour. After cooling, the solvent was removed under vacuum. The residue was purified by silica gel chromatography (40 g SiO2, 100% n-heptane to 100% EA in 40 minutes). The fractions containing the pure compound were combined and concentrated under vacuum to obtain 834 mg of the title compound, which was used directly in the next step.

[0393] I-22: 1-(4-carbamoylpyrimidine-2-yl)piperidine-4-carboxylate hydrochloride [ka] Methyl 1-(4-carbamoylpyrimidine-2-yl)piperidine-4-carboxylate (834 mg) was dissolved in THF (15 ml). Lithium hydroxide (166 mg) was then added with stirring, followed by water (3 ml). After standing overnight, the solvent was removed under vacuum. HCl (1N), water, and ACN were added to the residue. The resulting precipitate was aspirated and dried in a vacuum oven to obtain 663 mg of the title compound. LC / MS: m / z = 251.3 [M + H] + ;tR:1.04 min (LC / MS-Method A)

[0394] I-22-1:1-(4-carbamoylpyrimidine-2-yl)piperidine-4-carboxylic acid I-22-1a:tert-butyl1-(4-carbamoylpyrimidine-2-yl)piperidine-4-carboxylate [ka] 1.000 g of tert-butylpiperidine-4-carboxylate hydrochloride was dissolved in 10 ml of dry ACN. 3.7 ml of DIPEA and 695.9 mg of 2-chloropyrimidine-4-carboxamide were added at room temperature, and the mixture was heated under argon at 120°C for 2.5 hours. After cooling, the solvent was removed under vacuum. The resulting residue was dissolved in a mixture of water and DCM, the phases were separated, and the aqueous phase was extracted with DCM (three times). The combined organic phases were dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (25 g; 0% to 50% EA in heptane at 12 mins). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 1.024 g of the title compound. LC / MS: m / z = 307.3[M+H] + ;tR:1.28 min (LC / MS-Method D)

[0395] I-22-1:1-(4-carbamoylpyrimidine-2-yl)piperidine-4-carboxylic acid [ka] 1.024 g of tert-butyl 1-(4-carbamoylpyrimidine-2-yl)piperidine-4-carboxylate was dissolved in 10 ml of DCM, and 6.6 ml of TFA was added at room temperature while stirring. After 2 hours, the solvent was removed under vacuum, and the residue was evaporated twice with toluene. The resulting residue was dissolved in ACN, the precipitate was filtered, washed with heptane, and dried under vacuum to obtain 780 mg of the title compound. LC / MS: m / z = 251.2[M+H] + ;tR:0.70 min (LC / MS-Method D)

[0396] I-22-2:1-(4-carbamoylpyrimidine-2-yl)piperidine-4-carboxylic acid TFA salt [ka] Crude tert-butyl 1-(4-carbamoylpyrimidine-2-yl)piperidine-4-carboxylate (I-22-1a, 425 mg) was dissolved in DCM (12 ml), and TFA (1.22 ml) was added at room temperature while stirring. After standing overnight, toluene (10 ml) was added, and then the solvent was removed under vacuum. The residue was freeze-dried to obtain 350 mg of the title compound. LC / MS: m / z = 251.3 [M + H] + ;tR:1.04 min (LC / MS-Method A)

[0397] I-23:1-(4-cyanopyrimidine-2-yl)piperidine-4-carboxylic acid I-23a: tert-butyl 1-(4-cyanopyrimidine-2-yl)piperidine-4-carboxylate [ka] 1,000 g of tert-butylpiperidine-4-carboxylate hydrochloride was dissolved in 10 ml of dry ACN. 3.7 ml of DIPEA and 629.4 mg of 2-chloropyrimidine-4-carbonitride were added at room temperature, and the mixture was heated under argon at 120°C for 2.5 hours. After cooling, the solvent was removed under vacuum. The resulting residue was dissolved in a mixture of water and DCM, and the aqueous phase was extracted with DCM (three times). The combined organic phase was dehydrated with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (25 g; 0% to 50% EA in heptane in 13 minutes). The fractions containing the compound were combined, and the solvent was removed under vacuum to obtain 879 mg of the title compound. LC / MS: m / z = 289.3[M+H] + ;tR:1.69 min (LC / MS-Method D)

[0398] I-23:1-(4-cyanopyrimidine-2-yl)piperidine-4-carboxylic acid [ka] 879 mg of tert-butyl 1-(4-cyanopyrimidine-2-yl)piperidine-4-carboxylate was dissolved in 10 ml of DCM, and 5 ml of TFA was added at room temperature with stirring. After 2 hours, the solvent was removed under vacuum, and the residue was evaporated twice with toluene. The residue was dissolved in ACN / heptane, the precipitate was filtered, washed with heptane, and dried under vacuum to obtain 790 mg of the title compound. LC / MS: m / z = 233.1[M+H] + ;tR:1.05 min (LC / MS-Method D)

[0399] I-23-1: 1-(4-cyanopyrimidine-2-yl)piperidine-4-carboxylic acid TFA salt [ka] Crude tert-butyl 1-(4-cyanopyrimidine-2-yl)piperidine-4-carboxylate (I-23a, 448 mg) was dissolved in DCM (12 ml), and TFA (1.22 ml) was added at room temperature while stirring. After standing overnight, toluene (10 ml) was added, and then the solvent was removed under vacuum. The residue was freeze-dried to obtain 380 mg of the title compound. LC / MS: m / z = 233.2[M+H] + ;tR:1.47 min (LC / MS-Method A)

[0400] I-24: 1-(4-cyano-2-pyridyl)piperidine-4-carboxylate trifluoroacetate I-24a: Methyl 1-(4-cyano-2-pyridyl)piperidine-4-carboxylate [ka] Methylpiperidine-4-carboxylate (800 mg) was dissolved in dry ACN (12 ml) in a microwave container (10-20 ml). After adding DIPEA (3.9 ml) and 4-cyano-2-fluoropyridine (790 mg), the mixture was heated in a microwave oven at 150°C for 1 hour. After cooling, the solvent was removed under vacuum. The residue was purified by silica gel chromatography (40 g SiO2, 100% n-heptane for 5 minutes, then 40% n-heptane / 60% EA from 100% heptane for 45 minutes). The fractions containing the pure compound were combined and concentrated under vacuum. The residue was dissolved in ACN / H2O and freeze-dried overnight to obtain 896 mg of the title compound. LC / MS: m / z = 246.4 [M + H] + ;tR:1.77 min (LC / MS-Method A)

[0401] I-24: 1-(4-cyano-2-pyridyl)piperidine-4-carboxylate trifluoroacetate [ka] Methyl 1-(4-cyanopyridine-2-yl)piperidine-4-carboxylate (225 mg) was dissolved in THF (10 ml). Then, LiOH (33 mg) and water (2 ml) were added with stirring. After standing overnight, LiOH (16 mg) and water (1 ml) were added with stirring. After stirring for 2.5 hours, the THF was removed under vacuum. Water was added to the residue, and the mixture was acidified with HCl (1N in water). After freeze-drying overnight, the residue was dissolved in ACN / water and purified by RP preparative HPLC (flow rate 25 ml / min; 95% H2O + 0.05% TFA / 5% ACN to 5% H2O + 0.05% TFA / 95% ACN in 45 minutes; column: Purosphere® STAR-RP18, 25 × 250 mm, 10 μm). The fractions containing the pure compound were combined, the ACN was removed under vacuum, and the residue was freeze-dried overnight to obtain 207 mg of the title compound. LC / MS: m / z = 232.3[M+H] + ;tR: 1.33 min (LC / MS-Method A).

[0402] I25:5-[(3S)-2-(4-methylpiperidine-4-carbonyl)isoxazolidine-3-yl]pyridine-3-carbonilicate trifluoroacetate I-25a: tert-butyl 4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-4-methyl-piperidine-1-carboxylate [ka] 1-tert-butoxycarbonyl-4-methylpiperidine-4-carboxylic acid (100 mg) was dissolved in dry DCM (4.5 ml) under Ar. A catalytic amount of dry DMF (approximately 2 drops) was added, and the mixture was cooled to 0°C. Then, thionyl chloride (60 μl) dissolved in dry DCM (0.5 ml) was added while stirring. After 1.5 hours, a further thionyl chloride (25 μl in dry DCM (0.3 ml)) was added. After 1 hour, the mixture was concentrated under vacuum, and the residue was dissolved in dry DCM (5 ml). This solution was added to a mixture of 5-[(3S)-isoxazolidine-3-yl]pyridine-3-carbonitride trifluoroacetate (I-02-2, 115 mg) dissolved in dry DCM (1.5 ml) and DIPEA (280 μl) at 0°C while stirring under Ar. After addition, the ice bath was removed, and stirring was continued for 1 hour. Next, a saturated NaHCO3 solution was added, and the aqueous phase was extracted by DCM (3 times). The combined organic phase was dehydrated with sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (12 g SiO2, 100% DCM to 80% DCM / 20% EtOH in 25 minutes). The fractions containing the pure compound were combined and concentrated under vacuum. The residue was dissolved in ACN / water and freeze-dried overnight to obtain 121 mg of the title compound. LC / MS: m / z = 301.4 [M - CO2tBu + 2H] + ;tR: 2.12 min (LC / MS-Method A).

[0403] I-25:5-[(3S)-2-(4-methylpiperidine-4-carbonyl)isoxazolidine-3-yl]pyridine-3-carbonilicate trifluoroacetate [ka] 0.5 ml of TFA was added to a solution of tert-butyl 4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-4-methylpiperidine-1-carboxylate (118 mg) in 2 ml of dry DCM while stirring under argon. After 1.5 hours, the mixture was concentrated under vacuum, and the residue was dissolved in water and then purified by preparative RP HPLC (flow rate 25 ml / min; 95% H2O + 0.05% TFA / 5% ACN to 5% H2O + 0.05% TFA / 95% ACN in 45 minutes; Purosphere® STAR-RP18, 25 × 250 mm, 10 μm). The fractions containing the pure product were combined, and ACN was removed under vacuum. The aqueous solution was lyophilized to obtain 82 mg of the title compound. LC / MS: m / z = 301.3[M+H] + ;tR:0.78 min (LC / MS-Method A)

[0404] I-26:2-(2-chloro-5-fluoropyrimidine-4-yl)oxyacetonitrile [ka] 2,4-Dichloro-5-fluoropyrimidine (1 g) was dissolved in ACN (80 ml). Glyconitrile (431 μl, 70% in water) and cesium carbonate (1.85 g) were added with stirring. After stirring for 2.5 hours, the mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (24 g SiO2, 100% n-heptane for 5 minutes, 100% n-heptane to 75% n-heptane / 25% EA for 45 minutes, then 75% n-heptane / 25% EA for 15 minutes). The fractions containing the pure compound were combined and concentrated under vacuum to obtain 995 mg of the title compound. LC / MS: m / z = 188.0 [M + H] + ;tR:1.16 min (LC / MS-Method A)

[0405] I-27: 1-(4-carbamoyl-2-pyridyl)piperidine-4-carboxylic acid TFA salt I-27a: Methyl 1-(4-carbamoyl-2-pyridyl)piperidine-4-carboxylate [ka] HBr solution (8 ml, 45 wt% in acetic acid) was added to methyl 1-(4-cyano-2-pyridyl)piperidine-4-carboxylate (I-24a, 665 mg), and the mixture was stirred for 2 hours. Then saturated NaHCO3 solution was added until the mixture reached a neutral pH. The aqueous mixture was extracted by DCM (3 times), the organic phases were combined, dehydrated with sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g SiO2, 100% DCM to 80% DCM / 20% EtOH in 45 minutes). The fractions containing the pure compound were combined and concentrated under vacuum, the residue was dissolved in ACN / water, and freeze-dried overnight to obtain 593 mg of the title compound. LC / MS: m / z = 264.3 [M + H] + ;tR:0.76 min (LC / MS-Method A)

[0406] I-27: 1-(4-carbamoyl-2-pyridyl)piperidine-4-carboxylic acid TFA salt [ka] Starting with 590 mg of methyl ester, 636 mg of the title compound was obtained by following the procedure described in I-24. LC / MS: m / z = 250.3[M+H] + ;tR:0.45 min (LC / MS-Method A)

[0407] I-28:5-[(3S)-2-(piperidine-4-carbonyl)isoxazolidine-3-yl]pyridine-3-carbonilicate trifluoroacetate I-28a: tert-butyl 4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]piperidine-1-carboxylate [ka] 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (740 mg) was dissolved in dry DMF (10 ml), and DIPEA (1.17 ml) and HATU (2.17 g) were added with stirring. After 15 minutes, (S)-5-(isoxazolidine-3-yl)nicotinonitrile (I02-1, 0.49 g) dissolved in dry DMF (8 ml) was added with stirring. After 1 hour, saturated sodium bicarbonate solution was added, and the aqueous phase was extracted with EA (3 times). The combined organic phase was washed with brine, dehydrated with sodium sulfate, filtered, and concentrated under vacuum to obtain 1.08 g of the title compound. LC / MS: m / z = 287.3 [M - CO2tBu + 2H] + ;tR: 1.91 min (LC / MS-Method A).

[0408] I-28:5-[(3S)-2-(piperidine-4-carbonyl)isoxazolidine-3-yl]pyridine-3-carbonilicate trifluoroacetate [ka] TFA (7 ml) was added to a solution of tert-butyl(S)-4-(3-(5-cyanopyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-carboxylate (1.08 g) in 25 ml of dry DCM while stirring under argon. After 15 minutes, the mixture was concentrated under vacuum, and the residue was dissolved in water + 0.05% TFA / ACN. The mixture was then purified by preparative RP HPLC (flow rate 25 ml / min; 95% H2O + 0.05% TFA / 5% ACN to 5% H2O + 0.05% TFA / 95% ACN in 45 minutes; Purosphere® STAR-RP18 25 × 250 mm, 10 μm). The fractions containing the pure product were combined, and the ACN was removed under vacuum. The aqueous solution was lyophilized to obtain 677 mg of the title compound. LC / MS: m / z = 287.2[M+H] + ;tR:0.58 min (LC / MS-Method A)

[0409] I-29: Ethyl 2-((2-chloro-5-fluoropyrimidine-4-yl)oxy)acetate [ka] Ethyl glycolate (0.91 ml) was dissolved in THF (60 ml) and cooled to 0°C. Sodium hydride (430 mg, 60% of the mineral oil) was added little by little while stirring, and then the cooling bath was removed. After 15 minutes, the mixture was cooled again to 0°C, and 2,4-dichloro-5-fluorpyrimidine (1.5 g) was added little by little. After removing the cooling bath, stirring was continued for 1 hour. Water (75 ml) was then added, followed by 1N HCl, to adjust the pH of the mixture to 1. The aqueous phase was extracted by DCM (twice). The combined organic phase was dehydrated with sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (24 g SiO2, 100% n-heptane for 5 minutes, 100% n-heptane to 50% n-heptane / 50% EA for 30 minutes, then 50% n-heptane / 50% EA for 10 minutes). The fractions containing the pure compound were combined and concentrated under vacuum to obtain 1.89 g of the title compound. LC / MS: m / z = 235.1[M+H] + ;tR:1.69 min (LC / MS-Method A)

[0410] I-30: Ethyl 6-chloro-5-fluoropyrimidine-4-carboxylate I-30a: 4-Chloro-6-(1-ethoxyvinyl)-5-fluoropyrimidine [ka] 4,6-Dichloro-5-fluoropyrimidine (2.5 g) and tributyl(1-ethoxyvinyl)tin were dissolved in dioxane, and argon was bubbling into the solution for 15 minutes. Then bis(triphenylphosphine)palladium(II) dichloride (1 g) was added, and argon was bubbling into the mixture for another 15 minutes. The mixture was heated under argon at 90°C for 3 hours, then cooled and concentrated under vacuum. Water and diethyl ether were added. The aqueous phase was extracted with diethyl ether (3 times). The combined organic phase was dehydrated with sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g SiO2, 100% n-heptane for 5 minutes, 100% n-heptane to 75% n-heptane / 25% EA for 60 minutes, then 75% n-heptane / 25% EA for 15 minutes). The fractions containing the pure compound were combined and concentrated under vacuum. The residue was dissolved in ACN / water and freeze-dried overnight to obtain 2.06 g of the title compound. LC / MS: m / z = 203.2[M+H] + ;tR:1.92 min (LC / MS-Method A)

[0411] I-30: Ethyl 6-chloro-5-fluoropyrimidine-4-carboxylate [ka] 4-Chloro-6-(1-ethoxyvinyl)-5-fluoropyrimidine (2.06 g) was dissolved in a mixture of 1,4-dioxane (90 ml) and water (24 ml) with stirring. Sodium periodate (5.44 g) was then added, and stirring was continued for 10 minutes. Potassium permanganate (0.96 g) was added, and the mixture was vigorously stirred for 2 hours. The mixture was then filtered through Celite®. The filtered cake was washed with a mixture of DCM (180 ml) and methanol (60 ml). The filtrate was added to a mixture of water and extracted with DCM (3 times). The combined DCM phase was dehydrated with sodium sulfate, filtered, and concentrated under vacuum to obtain 1.71 g of the title compound. 1H NMR (400.23 MHz, DMSO-d6) δ ppm 9.01 (1 H), 4.41 (2 H), 1.33 (3 H)

[0412] I-31:1-(4-carbamoyl-5-fluoropyrimidine-2-yl)-4-fluoropiperidine-4-carboxylic acid [ka]

[0413] I-31a: 2-Chloro-4-(1-ethoxyvinyl)-5-fluoropyrimidine [ka] To a solution of 2,4-dichloro-5-fluoropyrimidine (20 g) in DMF (170 ml), tributyl(1-ethoxyvinyl)tin (47.59 g) and Pd(PPh3)2Cl2 (1.67 g) were added. The mixture was stirred at 70°C under N2 for 1 hour. The reaction mixture was then quenched with 10% KF aqueous solution (50 ml), stirred at 25°C for 12 hours, diluted with EA (120 ml), and filtered. The organic phase was washed with brine (50 ml), dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 20:1) to obtain 23.7 g of the title compound. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.90 (1H), 5.20 (1H), 4.87 (1H), 3.94 (2H), 1.32 (3H)

[0414] I-31b: Methyl 1-[4-(1-ethoxyvinyl)-5-fluoropyrimidine-2-yl]-4-fluoropiperidine-4-carboxylate [ka] A mixture of 2-chloro-4-(1-ethoxyvinyl)-5-fluoropyrimidine (1.95 g), methyl 4-fluoropiperidine-4-carboxylate HCl (2 g), and DIPEA (3.74 g) in DMSO (20 ml) was stirred at 80°C for 2 hours. The reaction mixture was diluted with water (20 ml) and extracted with EA (30 ml x 3). The combined organic layer was washed with brine (50 ml), dehydrated with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 20:1) to obtain 1.8 g of the title compound.

[0415] I-31c: Ethyl 5-fluoro-2-(4-fluoro-4-methoxycarbonyl-1-piperidyl)pyrimidine-4-carboxylate [ka] To a solution of methyl 1-[4-(1-ethoxyvinyl)-5-fluoropyrimidine-2-yl]-4-fluoropiperidine-4-carboxylate (1.6 g) in dioxane (60 ml), a solution of NaIO4 (4.18 g) in water (30 ml) was added, followed by the addition of KMnO4 (772 mg). The mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered, and the filtrate was diluted with EA (50 ml), saturated NaHCO3 solution (50 ml), and brine (50 ml). The aqueous layer was extracted with EA (50 ml x 2), and the combined organic layers were dehydrated with NaSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 20:1 to 0:1) to obtain 980 mg of the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 8.35 (1 H), 4.68 - 4.59 (2 H), 4.45 (2 H), 3.81 (3 H), 3.41 - 3.26 (2 H), 2.15 - 2.00 (4 H), 1.42 (3 H)

[0416] I-31d: 5-Fluoro-2-(4-Fluoro-4-methoxycarbonyl-1-piperidyl)pyrimidine-4-carboxylic acid [ka] To a solution of Novozyme 435 (750 mg) in buffer (25 ml, 100 mmol / l, pH=7, phosphate buffer), a solution of ethyl 5-fluoro-2-(4-fluoro-4-methoxycarbonyl-1-piperidyl)pyrimidine-4-carboxylate (980 mg) in DMSO (10 ml) was added dropwise. The mixture was stirred at 37°C for 6 hours. The reaction mixture was adjusted to pH=2 with 1N HCl solution and extracted with EA (50 m × 3). The combined organic layers were washed with brine (100 ml), dehydrated with Na2SO4, filtered, and concentrated to obtain 1.1 g of the title compound, which was used in the next step without further purification.

[0417] I-31e: Methyl 1-(4-carbamoyl-5-fluoropyrimidine-2-yl)-4-fluoropiperidine-4-carboxylate [ka] A mixture of 5-fluoro-2-(4-fluoro-4-methoxycarbonyl-1-piperidyl)pyrimidine-4-carboxylic acid (1.1 g), HATU (2.78 g), DIPEA (2.36 g), and NH4Cl (976.60 ...

Claims

1. Compound of formula I: 【Chemistry 1】 (In the formula, R1 represents a 5-6 member heteroaryl group in which 1 to 3 ring atoms are independently selected from -N- or -S-, and R1 is halogen, - (C1-C4) alkyl, -O (C1-C4) alkyl, -S (C1-C4) alkyl, -S(O)(C1-C4) alkyl, -S(O) 2 (C1-C4) alkyl, -O(C1-C4)alkyl-R4, -(CO)OH, -CN, - (CO)O (C1-C4) alkyl, -NRaRb, - (CO)NRaRb, and -(CO)NRcRd It is substituted by one or two substituents independently selected from; Ra and Rb are H; Rc is H; Rd is -(CH 2 ) x - (C3-C7) cycloalkyl or - (CH 2 ) x - (C3-C7) heterocyclyl, where the cycloalkyl or heterocyclyl is optionally substituted with one substituent selected from (C1-C4) alkyl or (CO)O(C1-C4) alkyl; x is an integer of 0, 1, or 2; R2 is, A 5- to 10-membered heteroaryl or 5- to 6-membered heterocycle, where 1 to 3 ring atoms are independently selected from -N-, -O-, or -S-, and the heteroaryl or heterocycle is, The molecules are optionally substituted with one or two substituents selected from halogens, CN, -(C1-C4)alkyl, -(C1-C4)alkyl-OH, -(CO)NReRf and -NReRf, where Re and Rf are independently selected from H, (C1-C4)alkyl, or -CO(C1-C4)alkyl; or Re and Rf, together with the nitrogen atom to which they are bonded, form 4 to 6 membered rings that are optionally substituted with oxo; R3 is a halogen or (C1-C2) alkyl; m is an integer, either 0, 1, or 3; R4 is CN, -(CO)OH, -(CO)NRgRh, or -(CO)O(C1-C4) alkyl; Rg and Rh are H; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. A compound of formula I as described in claim 1, R1 represents a six-membered heteroaryl molecule in which one to three ring atoms are selected from -N-, and R1 is halogen - (C1-C4) alkyl, -O (C1-C4) alkyl, -S(O)(C1-C4) alkyl, -S(O) 2 (C1-C4) alkyl, -O(C1-C4)alkyl-R4, -CN, - (CO)O (C1-C4) alkyl, -NRaRb, - (CO)NRaRb, and -(CO)NRcRd; It is substituted by one or two substituents independently selected from; Ra and Rb are H; Rc is H; and Rd is -(CH 2 ) x -(C3-C7) cycloalkyl or -(CH 2 ) x -(C3-C7) heterocyclyl, and The cycloalkyl or heterocyclyl is optionally substituted with one substituent selected from (C1-C4)alkyl or (CO)O(C1-C4)alkyl; x is an integer of 0, 1, or 2; R2 is, A 5- to 6-membered monocyclic heteroaryl, where one or two ring atoms are independently selected from -N-, -O-, or -S-, and the heteroaryl is unsubstituted or has one or two substituents of halogen, CN, -(C1-C4)alkyl, -(CO)NReRf, and -NReRf. Substituting with substituents selected from, where Re and Rf are independently selected from H or -CO(C1-C4) alkyl groups; or Re and Rf, together with the nitrogen atom to which they are bonded, form a 4 or 5-membered ring which is optionally substituted with an oxo. R3 is a halogen or (C1-C2) alkyl; m is an integer, either 0, 1, or 3; R4 is CN, -(CO)NRgRh, or -(CO)O(C1-C4) alkyl. Here, Rg and Rh are H; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

3. The TPSA (Topological Polarity Surface Area) value is 90 Å. 2 The compound of formula I described in claim 1 is as described above; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

4. The TPSA (Topological Polarity Surface Area) value is 105 Å. 2 The compound of formula I described in claim 1 is as described above; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

5. R1 represents a 5-6 member heteroaryl group in which one or two ring atoms are -N- atoms, and R1 is halogen, - (C1-C4) alkyl, -O (C1-C4) alkyl, -S (C1-C4) alkyl, -S(O)(C1-C4) alkyl, -S(O) 2 (C1-C4) alkyl, -O(C1-C4)alkyl-R4, -(CO)OH, -CN, - (CO)O (C1-C4) alkyl, -NRaRb, - (CO)NRaRb, and -(CO)NRcRd It is substituted by one or two substituents independently selected from; Ra and Rb are H; Rc is H; Rd is -(CH 2 ) x - (C3-C7) cycloalkyl or - (CH 2 ) x - (C3-C7) heterocyclyl, where the cycloalkyl or heterocyclyl is optionally substituted with one substituent selected from (C1-C4) alkyl or COO(C1-C4) alkyl; x is an integer of 0, 1, or 2; R2 However, the heteroaryl or heterocycle is a 5- to 10-membered heteroaryl or a 5- to 6-membered heterocycle, where 1 to 3 ring atoms are independently selected from -N-, -O-, or -S-, and the heteroaryl or heterocycle is optionally substituted with 1 or 2 substituents selected from halogen, CN, -(C1-C4)alkyl, -(C1-C4)alkyl-OH, (CO)NReRf and -NReRf, where Re and Rf are independently selected from H, (C1-C4)alkyl, or -CO(C1-C4)alkyl; or Re and Rf are Together with the nitrogen atoms to which they are bonded, they form oxo-substituted, or possibly substituted, 4 to 6 membered rings; R3 is F, Cl, methyl, or ethyl; m is an integer of 0 or 1, R4 is CN, -(CO)OH, -(CO)NH 2 A compound of formula I according to any one of claims 1, 3, or 4, which is -(CO)O(C1-C4)alkyl; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

6. R1 is pyridyl, pyrazinyl, or pyrimidinyl, and R1 is halogen, - (C1-C4) alkyl, -O (C1-C4) alkyl, -S (C1-C4) alkyl, -S(O)(C1-C4) alkyl, -S(O) 2 (C1-C4) alkyl, -O(C1-C4)alkyl-R4, -(CO)OH, -CN, - (CO)O (C1-C4) alkyl, -NRaRb, - (CO)NRaRb, and -(CO)NRcRd It is substituted by one or two substituents independently selected from; Ra and Rb are H; Rc is H; Rd is -(CH 2 ) x - (C3-C7) cycloalkyl or - (CH 2 ) x - (C3-C7) heterocyclyl, where the cycloalkyl or heterocyclyl is optionally substituted with one substituent selected from (C1-C4) alkyl or (CO)O(C1-C4) alkyl; x is an integer of 0, 1, or 2; R2 However, the ring atoms are 5-10 member heteroaryls in which 1 to 3 ring atoms are independently selected from -N- or -S-, or 5-6 member heterocycles in which 1 or 2 ring atoms are independently selected from -N-, -O-, or -S-. Heteroaryl or heterocycles are They are optionally substituted with one or two substituents selected from halogens, CN, -(C1-C4)alkyl, -(C1-C4)alkyl-OH, (CO)NReRf and -NReRf, where Re and Rf are independently selected from H, (C1-C4)alkyl, or -CO(C1-C4)alkyl; or Re and Rf, together with the nitrogen atom to which they are bonded, form a 4 to 6-membered ring that is optionally substituted with an oxo at a position adjacent to the nitrogen atom; R3 is either F or methyl; m is an integer of 0 or 1; R4 is CN, -(CO)OH, -(CO)NH 2 A compound of formula I according to any one of claims 1, 3 to 5, which is -(CO)O(C-C4)alkyl; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

7. R1 is pyridyl, pyrazinyl, or pyrimidinyl, and R1 is F, Cl, Methyl, -O-methyl, -S-methyl, -S(O)methyl, -S(O) 2 Methyl, -O-CH 2 -R4、 -(CO)OH, -CN, -(CO)O-CH 3 、-(CO)O-CH 2 -CH 3 、 -NH 2 、 - (CO)NH 2 , and -(CO)NRcRd It is substituted by one or two substituents independently selected from; Rc is H; Rd is -(CH 2 )-(C3-C7) cycloalkyl or-(CH 2 )-(C3-C7) heterocyclyl, where the cycloalkyl or heterocyclyl is optionally substituted with methyl, ethyl, or (CO)O(C1-C4) alkyl; R2 However, a 5- to 10-membered heteroaryl having one or two ring atoms that are -N- and up to one more ring atom that is -S-; or It is a 5- to 6-membered heterocycle in which one or two ring atoms are -O-, Heteroaryl or heterocycles are They are optionally substituted with one or two substituents selected from halogens, CN, -(C1-C4)alkyl, -(C1-C4)alkyl-OH, (CO)NReRf and -NReRf, where Re and Rf are independently selected from H, (C1-C4)alkyl, or -CO(C1-C4)alkyl; or Re and Rf, together with the nitrogen atom to which they are bonded, form a 4 to 6-membered ring that is optionally substituted with an oxo at a position adjacent to the nitrogen atom; R3 is either F or methyl; m is an integer of 0 or 1; R4 is CN, -(CO)OH, -(CO)NH 2 A compound of formula I according to any one of claims 1, 3 to 6, which is -(CO)O(C1-C4)alkyl; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

8. R1 is pyridyl, pyrazinyl, or pyrimidinyl, and R1 -(CO)NRcRd is substituted; Rc is H; Rd is -(CH 2 )-(C3-C7) cycloalkyl or-(CH 2 ) - (C3-C7) heterocyclyl, Cycloalkyls are selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Heterocyclines are selected from azirine, azetidine, pyrrolidine, and piperidine. The compound of formula I according to any one of claims 1, 3 to 6, wherein the cycloalkyl or heterocyclyl is optionally substituted with methyl, ethyl, or (CO)O(C1-C4)alkyl; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

9. R1 is pyrimidinyl, and R1 is - (CO)NH 2 It is replaced by, and may be further replaced by F; R2 is selected from pyridyl and pyrazinyl, and may be methyl or CN. It has been replaced, A compound of formula I according to any one of claims 1, 3 to 7, wherein m is an integer of 0; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

10. R1 is pyridyl, pyrazinyl, or pyrimidinyl, and R1 -(CO)NRcRd It is replaced by, Rc is H; Rd is -(CH 2 )-Cyclopropyl,-(CH 2 )-Azetidine, or-(CH 2 ) - piperidine, The compound of formula I according to any one of claims 1, 3 to 7, wherein the cyclic group is optionally substituted with methyl, ethyl, or (CO)O(C1-C4) alkyl; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

11. R2 However, it is selected from pyrazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, imidazo[1,2a]pyridinyl, or tetrahydropyranil. F, Cl, Br, CN, -methyl, -(CH 2 )-OH, NH 2 NH(C1-C4) alkyl, NH(CO)-(C1-C4) alkyl, (CO)NH 2 , optionally substituted with one or two substituents selected from -(CO)NH(C1-C4)alkyl, -(CO)NH(CO)-(C1-C4)alkyl, 1-oxo-azilinyl, 1-oxo-azetidinyl, 1-oxo-pyrrolidinyl and 1-oxo-piperidinyl; R3 is either F or methyl; m is an integer of 0 or 1; R4 is CN, -(CO)OH, -(CO)NH 2 , -(CO)O-CH 3 , or -(CO)O-CH 2 -CH 3 A compound of formula I according to any one of claims 1, 3 to 10; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

12. The compound of formula I, 6-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-pyrimidine-5-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 6-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carbonitrile, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxylic acid, Methyl 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxylate, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carbonitrile, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyridine-4-carbonil, 5-[(3S)-2-[1-[4-(cyanomethoxy)-5-fluoro-2-pyridyl]-4-methyl-piperidine-4-carbonyl]isoxazolidine-3-yl]pyridin-3-carbonil, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2- [carbonyl]-4-methyl-1-piperidyl]pyrimidine-4-carboxamide, Methyl 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-4-methyl-1-piperidyl]pyrimidine-4-carboxylate, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-4-methyl-1-piperidyl]pyrimidine-4-carboxylic acid, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyridine-4-carboxamide, Ethyl 2-[2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-4-methyl-1-piperidyl]-5-fluoropyrimidine-4-yl]oxyacetate, 5-[(3S)-2-[1-[4-(cyanomethoxy)-5-fluoropyrimidine-2-yl]piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil, 2-[2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-yl]oxyacetic acid, 2-[2-[4-[(3S)-3-(5-carbamoyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-yl]oxyacetic acid, 2-[2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-yl]oxyacetamide, 5-[(3S)-2-[1-(4-amino-5-fluoropyrimidine-2-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonitrile, 2-[4-[(3S)-3-(5-acetamide-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(6-methylpyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(6-methylpyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carbonitrile, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-methylpyrimidine-4-carboxamide, 2-[4-[(3S)-3-[5-(2-oxoazetidine-1-yl)-3-pyridyl]isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-[5-(2-oxoazetidine-1-yl)-3-pyridyl]isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carbonil, Ethyl 6-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxylate, 6-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxylic acid, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-4-fluoro-1-piperidyl]-5-fluoropyrimidine-4-carboxamide, 2-[4-[(3S)-3-[5-(2-oxopyrrolidine-1-yl)-3-pyridyl]isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carb Xamide, 2-[4-methyl-4-[(3S)-3-pyrimidine-5-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[5-fluoro-2-[4-methyl-4-[(3S)-3-pyrimidine-5-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-yl]oxyacetonitrile, 2-[5-fluoro-2-[4-[(3S)-3-pyrimidine-5-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-yl]oxyacetonitrile, [1-(5-fluoro-4-methoxypyrimidine-2-yl)-4-piperidyl]-[(3S)-3-pyrimidine-5-ylisoxazolidine-2-yl]methanone, 2-[4-[(3S)-3-pyrimidine-5-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyridine-4-carbonil, 5-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrazine-2-carbonitrile, 6-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrazine-2-carbonitrile, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 6-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrazine-2-carboxamide, 5-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrazine-2-carboxamide, 6-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide, 2-[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 5-Fluoro-2-[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-N-(1-methylazetidine-3-yl)pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-N-[2-(1-methylcyclopropyl)ethyl]pyrimidine-4-carboxamide, Tert-butyl 3-[[2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carbonyl]amino]azetidine-1-carboxylate, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-N-[(1-ethyl-4-piperidyl)methyl]pyrimidine-4-carboxamide, 5-Fluoro-2-[4-[(3S)-3-(5-Fluoro-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-cyano-6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 5-Fluoro-2-[4-[(3S)-3-(6-methylpyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-chloro-2-pyridyl)isoxazolidine-2- [carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-chloro-2-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-cyano-6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide, N-(azetidine-3-yl)-2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-methylpyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, Ethyl 3-[[2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carbonyl]amino]azetidine-1-carboxylate, 5-Fluoro-2-[4-[(3S)-3-(5-methylpyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 6-[4-[(3S)-3-(5-methylpyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carbonil, 2-[(3R,4R)-4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-fluoro-1-piperidyl]pyrimidine-4-carboxamide, 2-[(3S,4S)-4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-fluoro-1-piperidyl]pyrimidine-4-carboxamide, 2-[(3R,4S)-4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-fluoro-1-piperidyl]pyrimidine-4-carboxamide, 2-[(3S,4R)-4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-fluoro-1-piperidyl]pyrimidine-4-carboxamide, 5-methyl-2-[4-[(3S)-3-(6-methylpyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-methylpyrimidine-4-carboxamide, 5-methyl-2-[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 5-[(3S)-2-[1-(5-fluoro-4-methylsulfanylpyrimidine-2-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil, 5-[(3S)-2-[1-(5-fluoro-4-methylsulfinylpyrimidine-2-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonitrile, 5-[(3S)-2-[1-(5-fluoro-4-methylsulfonylpyrimidine-2-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil, 2-[4-[(3S)-3-(5-cyano-2-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide, 6-[4-[(3S)-3-(5-cyano-2-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-cyano-2-pyridyl)isoxazolidine-2- [carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, (S)-6-(4-(3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide, (S)-2-(4-(3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carbonitrile, 2-[4-[(3S)-3-(5-cyano-2-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carbonitrile, 5-[(3S)-2-[1-(3-methyl-1,2,4-thiadiazole-5-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil, 5-[(3S)-2-[1-(5-fluoro-4-methoxypyrimidine-2-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonitrile, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3,3,4-trifluoro-1-piperidyl]pyrimidine-4-carboxamide, [1-(5-fluoro-4-methoxypyrimidine-2-yl)-4-piperidyl]-[(3S)-3-(6-methylpyrazine-2-yl)isoxazolidine-2-yl]methanone, 6-[(3S)-2-[1-(5-fluoro-4-methoxypyrimidine-2-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil, 2-[4-[(3S)-3-(6-cyanopyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 5-Fluoro-2-[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carbonitrile, 2-Chloro-5-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxylic acid, 2-[3,3,4-trifluoro-4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3,3,4-trifluoro-1-piperidyl]pyrimidine-4-carbonitrile, 2-[3,3,4-trifluoro-4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carbonitrile, (S)-5-fluoro-2-(4-fluoro-4-(3-(5-fluoropyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide, (S)-2-(4-(3-(6-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonitrile, (S)-6-(4-(3-(6-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonitrile, (S)-2-(4-(3-(6-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide, 5-[(3S)-2-[1-(2-chloro-5-fluoropyrimidine-4-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil, (S)-2-(4-(3-(5-methylpyridine-3-yl)isoxazolidine-2 -Carbonyl)piperidine-1-yl)pyrimidine-4-carbonitrile, (S)-2-(4-(3-(5-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide, (S)-6-(4-(3-(5-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonitrile, (S)-6-(4-(3-(5-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide, (S)-6-(4-(3-(6-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide, (S)-2-(4-(3-(5-fluoro-6-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonitrile, 2-[4-[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, (S)-6-(4-(3-(5-fluoro-6-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonitrile, 6-[4-[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, (S)-2-(4-(3-(5-fluoro-4-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonitrile, (S)-2-(4-(3-(5-fluoro-4-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide, (S)-6-(4-(3-(5-fluoro-4-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide, (S)-6-(4-(3-(5-fluoro-4-methylpyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonitrile, 5-[(3S)-2-[1-(2-methoxypyrimidine-4-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil, 4-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-2-carbonitrile, 5-[(3S)-2-[1-(2-methylsulfanylpyrimidine-4-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil, 5-[(3S)-2-[1-(2-chloropyrimidine-4-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil, 5-[(3S)-2-[1-(2-aminopyrimidine-4-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonitrile, Ethyl 4-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-2-carboxylate, (S)-2-(4-(3-(4-methylfuran-2-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonitrile, (S)-2-(4-(3-(4-methylfuran-2-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide, (S)-6-(4-(3-(4-methylfuran-2-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonitrile, (S)-6-(4-(3-(4-methylfuran-2-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carboxamide, 2-[(3R, 4R or 3S, 4S)-4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-fluoro-1-piperidyl]-5-fluoropyrimidine-4-carboxamide, 2-[(3S, 4S or 3R, 4R)-4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-fluoro-1-piperidyl]-5-fluoropyrimidine-4-carboxamide, 4-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-2-carboxamide, 5-[(3S)-2-[1-(2-bromopyrimidine-4-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil, 5-[(3S)-2-[1-(4-chloropyrimidine-2-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil, 5-[(3S)-2-[1-(6-chloropyrimidine-4-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil, 5-[(3S)-2-[1-(4-bromopyrimidine-2-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil, (S)-2-(4-(3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonitrile, (S)-6-(4-(3-(5-methylfuran-3-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-carbonitrile, 2-chloro-5-[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxylic acid, 5-[(3S)-2-[1-(6-bromopyrimidine-4-yl)piperidine-4-carbonyl]isoxazolidine-3-yl]pyridine-3-carbonil, 2-[4-[(3S)-3-(5-cyano-3-thienyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-cyano-3-furyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-cyano-3-thienyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, (S)-5-(2-(1-(6-fluoropyrimidine-4-yl)piperidine-4-carbonyl)isoxazolidine-3-yl)nicotinonitrile, 5-Fluoro-2-[4-[(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-cyano-3-furyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, [1-(4-chloro-1,3,5-triazine-2-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone, 5-Fluoro-2-[4-[(3S)-3-(2-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 6-[4-[(3S)-3-(5-methyl-2-thienyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(6-cyanopyridazine-4-yl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide, 2-[4-[(3S)-3-(6-cyanopyridazine-4-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, [1-(4-chloro-6-methyl-1,3,5-triazine-2-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone, [1-(4-chloro-6-methoxy-1,3,5-triazine-2-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone, 5-methyl-2-[4-[(3S)-3-(5-methyl-2-thienyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 5-Fluoro-2-[4-[(3S)-3-(5-methyl-2-thienyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, [1-(4-amino-6-chloro-1,3,5-triazine-2-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone, 2-[(3R,4R or 3S,4S)-3-fluoro-4-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-methyl-pyrimidine-4-carboxamide, 2-[(3S,4S or 3R,4R)-3-fluoro-4-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-methyl-pyrimidine-4-carboxamide, 5-Fluoro-6-[4-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide; trifluoroacetic acid, 2-[4-[(3S)-3-(2-cyanothiazole-4-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, and 2-[4-[(3S)-3-(2-cyanothiazole-4-yl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide, A compound of formula I according to any one of claims 1, 3, or 4, selected from: Or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

13. The compound of formula I, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide, 2-[4-[(3S)-3-(6-methylpyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide and 5-Fluoro-2-[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide; A compound of formula I according to claim 1, selected from: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

14. The compound of formula I, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide, 2-[4-[(3S)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-4-carboxamide, 2-[4-[(3S)-3-(6-methylpyrazine-2-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide and 5-Fluoro-2-[4-[(3S)-3-pyrazine-2-ylisoxazolidine- 2-carbonyl]-1-piperidyl]pyrimidine-4-carboxamide Selected from, TPSA (Topological Polarity Surface Area) value > 120 Å 2 The compound of formula I described in claim 1 is as described above; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

15. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in human pharmaceuticals.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable carrier.

17. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable carrier, and / or thrombolytic agents, tissue plasminogen activators, anticoagulants, platelet aggregation inhibitors, antimicrobial agents (antibiotics, broad-spectrum antibiotics, lactams, antimycobacterial agents, bactericidal antibiotics, anti-MRSA agents), beta-agonists, corticosteroids, leukotriene modulators, anti-IgE, methylxanthine bronchodilators, mast cell inhibitors, protein tyrosine kinase inhibitors, CRTH2 / D prostanoid receptor antagonists, epinephrine, phosphodiesterase inhibitors, phosphodiesterase-3 inhibitors, phosphodiesterase-4 inhibitors, anticholinergics, muscarinic antagonists, steroids, antithymocyte globulin, thalidomide, chlorambucil, calcium channel blockers, ACE inhibitors, serotonin A pharmaceutical composition comprising one or more selected from nin reuptake inhibitors, endothelin-I receptor inhibitors, antifibrotic agents, proton pump inhibitors, cystic fibrosis transmembrane conductance regulator enhancers, mucolytic agents, pancreatic enzymes, bronchodilators, antivascular endothelial growth factor inhibitors, ciliary neurotrophic growth factor agents, trivalent (IIV3) influenza inactivated vaccine, quadrivalent (IIV4) influenza inactivated vaccine, trivalent recombinant influenza vaccine, quadrivalent influenza attenuated live vaccine, antiviral agents, influenza inactivated vaccine, ciliary neurotrophic growth factor, gene transfer agents, immunomodulators, calcineurin inhibitors, interferon gamma, antihistamines, monoclonal antibodies, polyclonal anti-T cell antibodies, anti-thymocyte gamma globulin-equine antibodies, anti-thymocyte globulin-rabbit antibodies, anti-CD40 antagonists, JAK inhibitors, and anti-TCR mouse mAbs.

18. A drug for treating RIP kinase 1-mediated diseases or disorders comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

19. Necrotizing enterocolitis, tuberous sclerosis, Tangier disease, Wolmann syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis (e.g., acute pancreatitis), atopic dermatitis, rheumatoid arthritis (RA), spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune thrombotic tract infection A drug for treating P, transplant rejection, ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular disease, myocardial infarction, allergic disease, asthma, atopic dermatitis, type 1 diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converting enzyme-associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, periodontitis, bacterial infection, Staphylococcus infection, Mycobacterium infection, retinitis pigmentosa, influenza, transplant rejection, burns, or hypoxia, any one of claims 1 to 14 Compounds listed in the section, or their pharmaceutically acceptable salts, solvates, or stereoisomers.

20. A drug for treating rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease (IBD), Crohn's disease, or ulcerative colitis, comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition according to claim 16 or 17.

21. A pharmacopoeia for the treatment of cutaneous lupus erythematosus (CLE), lichen planus (LP), toxic epidermal necrolysis (TEN), or Stevens-Johnson syndrome (SJS), comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition according to claim 16 or 17.

22. A drug for treating acute respiratory distress syndrome (ARDS) or systemic inflammatory response syndrome (SIRS), comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition according to claim 16 or 17.

23. A drug for treating influenza (e.g., swine influenza, H7N9), severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), respiratory syncytial virus (RSV), or bronchiolitis, comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition according to claim 16 or 17.

24. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, or a stereoisomer thereof.

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