Isoxazolidines as RIPK1 inhibitors and their uses

Abstract

Isoxazolidines and their uses as RIPK1 inhibitors The present disclosure relates to isoxazolidines and their uses as receptor interacting protein kinase 1 inhibitors, for example in the treatment of diseases and disorders mediated by RIP kinase 1.

Description

[Background technology]

[0001] Although inflammation can be a protective mechanism in response to harmful stimuli such as pathogen invasion and tissue damage, chronic inflammation is an important underlying factor in many human diseases such as neurodegeneration, rheumatoid arthritis, autoimmune and inflammatory diseases, and cancer. Similarly, activation of cell death pathways such as necrosis and apoptosis, which are useful for eliminating infected or damaged cells, is also an important underlying mechanism of human diseases, including acute and chronic neurodegenerative diseases. Receptor-interacting protein kinase 1 (UniProtKB Q13546) is a key regulator of inflammation, apoptosis, and necroptosis. Receptor-interacting protein kinase 1 has an important role in regulating the inflammatory response mediated by nuclear factor kappa light-chain enhancer of activated B cells (NF-κB). More recent studies have shown that its kinase activity controls and characterizes a unique form of necroptosis, a form of necrotic cell death that was traditionally considered to be passive and unregulated. Furthermore, receptor-interacting protein kinase 1 is part of a proapoptotic complex that exhibits its activity in regulating apoptosis.

[0002] Receptor interacting protein kinase 1 undergoes a complex and intricate regulatory mechanism that includes ubiquitination, deubiquitination, and phosphorylation. These regulatory events collectively determine whether a cell will survive, activate an inflammatory response, or die by apoptosis or necroptosis. Dysregulation of receptor interacting protein kinase 1 signaling can lead to excessive inflammation or cell death, and conversely, studies have shown that inhibition of receptor interacting protein kinase 1 can be an effective treatment for diseases involving inflammation or cell death. RIPK1 inhibition has been identified as a promising principle for addressing various diseases such as rheumatoid arthritis (RA), psoriasis, multiple sclerosis, Alzheimer's disease, and inflammatory bowel diseases, such as Crohn's disease or ulcerative colitis (UC). To treat some of these diseases, such as multiple sclerosis (MS) and Alzheimer's disease, access to the central nervous system (CNS) is necessary, while for other diseases, such as rheumatoid arthritis, psoriasis, Crohn's disease, or inflammatory bowel diseases (IBD), such as UC, access to the CNS is not essentially required. The most advanced RIPK1 inhibitor, GSK2982772 (an oxazepinone derivative disclosed in WO 2014 / 125444), has been evaluated in Phase II clinical trials for RA, psoriasis, and UC.

[0003] Dihydropyrazoles and isoxazolidines as RIPK1 inhibitors are well known (GSK WO2018092089, WO2019130230). GSK has published dihydropyrazoles with phenyl substituents on the isoxazolidine and pyrimidine, which have shown good efficacy for inhibition of RIPK1 (Comparative Compound A, WO2018092089, Example 4, pIC50=8-9 (GSK data), IC50(U937)=8nM, proprietary data). The analogous isoxazolidine, Comparative Compound B, has the same efficacy (IC50(U937)=9nM, proprietary data). Replacement of the substituents on the pyrimidine ring to a heteroaryl ring results in a less effective dihydropyrazole (Comparative compound C, WO2018092089, Example 129, pIC50=7-9 (GSK data), pIC50(U937)=59 nM, proprietary data). With the same substitution pattern in the isoxazolidine series, the potency was further reduced compared to the phenyl substitution of Comparative compound B (Comparative compound D, IC50(U937)=92 nM, proprietary data). Replacement of the phenyl residue on the isoxazolidine with F, Cl, CH 3 Introducing substituents such as CN or CN reduces the efficacy of the compound (Comparative compound E, IC50(U937)=197 nM, own data). Surprisingly, replacement of 1,3,4-oxadiazole with optionally substituted imidazole, pyrazole and triazole heteroaromatic five-membered rings results in compounds with high efficacy for RIPK1 inhibition, such as Example 8, with IC50(U937)=1 nM (own data) (see Scheme A and Table 1). Scheme A: [ka] Summary of the Invention [Means for solving the problem]

[0004] A compound of formula I, [ka] During the ceremony, A represents a 5-membered heteroaryl ring in which 2 or 3 ring atoms are independently selected from nitrogen and optionally substituted with R3 and R4; R1 is H or CH 3 represents R2 represents Cl, F or CN; R3 is H or CH 3 represents R4 is H, CH 3 or cyclopropyl, R5 represents H or F; Disclosed herein are compounds, or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof.

[0005] In another aspect, methods for preparing compounds and intermediates thereof are provided.

[0006] In a related aspect, provided herein is a pharmaceutical composition comprising a compound of the present disclosure and a pharma- ceutically acceptable carrier.

[0007] In another aspect, provided herein is a method of inhibiting receptor interacting protein kinase 1. Further provided is a method of treating a receptor interacting protein kinase 1 mediated disease or disorder, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition described herein to a subject in need thereof. The present disclosure also provides for the use of a compound or composition thereof in the manufacture of a medicament for treating a disease, disorder, or condition mediated (or at least partially mediated) by receptor interacting protein kinase 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] definition As used herein, chemical nomenclature not otherwise defined shall have the meaning used in the art. As used herein, the term "5-membered heteroaryl ring in which 2-3 ring atoms are selected from nitrogen," alone or as part of another substituent, refers to a monocyclic aromatic ring assembly containing 5 atoms, where 2-3 ring atoms are nitrogen heteroatoms.

[0009] For example, the heteroaryl group can be a C5 heteroaryl with two carbon ring atoms replaced by a nitrogen heteroatom, or a C5 heteroaryl with three carbon ring atoms replaced by a nitrogen heteroatom. The heteroaryl group can include groups such as imidazole, pyrazole, and triazole. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be linked through any position on the ring. For example, imidazole includes 1-, 2-, 4-, and 5-imidazole, pyrazole includes 1-, 3-, 4-, and 5-pyrazole, and triazole includes 1-, 4-, and 5-triazole.

[0010] As used herein, the term "pharmaceutical acceptable excipient" refers to a substance that aids in the administration of an active agent to a subject. "Pharmaceutically acceptable" means that the excipient is compatible with the other components of the pharmaceutical composition and is not harmful to the recipient. Pharmaceutical excipients useful in the present disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, glidants, coatings, sweeteners, flavors, and colorants.

[0011] As used herein, the term "salt" refers to an acid or base salt of a compound disclosed herein. Illustrative examples of pharmaceutically acceptable salts are mineral acid salts, organic acid salts, and quaternary ammonium salts. It is understood that pharmaceutically acceptable salts are non-toxic.

[0012] Pharmaceutically acceptable salts of the acidic compounds disclosed herein are salts formed with bases, i.e. cationic salts such as alkali and alkaline earth metal salts. Similarly, when a basic group such as pyridyl forms part of the structure, acid addition salts with mineral acids, organic carboxylic acids and organic sulfonic acids, e.g. hydrochloric acid, methanesulfonic acid, maleic acid, and the like, are also possible. The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for purposes of this disclosure. In addition to salt forms, compounds are described herein that are in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Furthermore, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0013] "Treatment" or "treating" is an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition and / or reducing the severity of the disease or condition); b) delaying or halting the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition); and / or c) relieving the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of another drug, slowing the progression of the disease, improving quality of life, and / or prolonging survival).

[0014] "Prevention" or "preventing" refers to any treatment of a disease or condition that does not result in the development of clinical symptoms of the disease or condition. In some embodiments, the compounds may be administered to subjects at risk for the disease or condition or who have a family history of the disease or condition.

[0015] "Subject" refers to a human who has been or is the subject of treatment. The methods described herein may be useful for human treatment. The term "therapeutically effective amount" or "effective amount" of a compound of the present disclosure or a pharma- ceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof means an amount sufficient to effect treatment when administered to a subject to provide a therapeutic benefit, such as amelioration of symptoms or delay of disease progression. For example, a therapeutically effective amount may be an amount sufficient to reduce symptoms of a disease or condition described herein. A therapeutically effective amount may vary depending on the subject and the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the method of administration, which can be readily determined by one of ordinary skill in the art.

[0016] A compound of formula I, [ka] During the ceremony, A represents a 5-membered heteroaryl ring in which 2 or 3 ring atoms are independently selected from nitrogen and optionally substituted with R3 and R4; R1 is H or CH 3 represents R2 represents Cl, F or CN; R3 is H or CH 3 represents R4 is H, CH 3 or cyclopropyl, R5 represents H or F; Disclosed herein are compounds of Formula I, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof:

[0017] One embodiment is a compound of formula I, A is a heteroaryl selected from the group of imidazole, pyrazole, and triazole, optionally substituted with R3 and R4; A compound of formula I, or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof:

[0018] One embodiment is a compound of formula I, A is imidazole optionally substituted with R3 and R4; A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0019] One embodiment is a compound of formula I, A is pyrazole optionally substituted with R3 and R4; A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0020] One embodiment is a compound of formula I, A is a triazole optionally substituted with R3 and R4; A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0021] One embodiment is a compound of formula I, A is, 1-Imidazolyl, 2-Imidazolyl, 4-Imidazolyl, 5-Imidazolyl; 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, selected from 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl and 1,2,4-triazol-5-yl; R3 and R4 represent optionally substituted heteroaryl, A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0022] One embodiment is a compound of formula I, A is, [ka] [ka] [ka] wherein the dashed line indicates the bond to the pyrimidine ring of formula I; R3 is H or CH 3 represents R4 is H, CH 3 or cyclopropyl, A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0023] One embodiment is a compound of formula I, A is, 1-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl, and 1,2,4-triazol-1-yl; R3 and R4 represent optionally substituted heteroaryl, A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0024] One embodiment is a compound of formula I, A is, [ka] wherein the dashed line indicates the bond to the pyrimidine ring of formula I; R3 is H or CH 3 represents R4 is H, CH 3or cyclopropyl, A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0025] One embodiment is a compound of formula I, A is, selected from 1-imidazolyl and 3-pyrazolyl; R3 and R4 represent optionally substituted heteroaryl, A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0026] One embodiment is a compound of formula I, one of R3 or R4 does not represent H; A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0027] One embodiment is a compound of formula I, R3 represents H; R4 is CH 3 or cyclopropyl, A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0028] One embodiment is a compound of formula I, R3 is CH 3 represents R4 represents H; A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0029] One embodiment is a compound of formula I, R3 is CH 3 represents, and R4 is CH 3 Represents, A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0030] One embodiment is a compound of formula I, R3 is CH3 represents R4 is CH 3 or cyclopropyl, A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0031] One embodiment is a compound of formula I, A is, 2-methylpyrazol-3-yl, 3-methyl-1H-pyrazol-4-yl, 4-Methylpyrazol-1-yl 2,5-dimethylpyrazol-3-yl, 2-methylimidazol-1-yl, 4-cyclopropyl-2-methyl-imidazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-Methyl-1,2,4-triazol-1-yl and 3-methyltriazol-4-yl, A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0032] One embodiment is a compound of formula I, R1 is CH 3 represents R2 represents CN; A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0033] One embodiment is a compound of formula I, R1 represents H; R2 represents CN; A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0034] One embodiment is a compound of formula I, R1 represents H; R2 represents F; A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0035] One embodiment is a compound of formula I, R1 represents H; R2 represents Cl; A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0036] One embodiment is a compound of formula I, A represents imidazole or pyrazole; R1 represents H; R2 represents CN; R3 is CH 3 represents R4 represents H; R5 represents H or F; A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0037] One embodiment is a compound of formula I, A is, heteroaryl selected from 1-imidazolyl and 3-pyrazolyl; R1 represents H; R2 represents CN; R3 is CH 3 represents R4 represents H; R5 represents H or F; A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0038] One embodiment is a compound of formula I, R5 represents H; A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0039] One embodiment is a compound of formula I, R5 represents F. A compound of formula I or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0040] Another embodiment is 3-Fluoro-5-[(3S)-2-[1-[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; 3-Fluoro-2-methyl-5-[(3S)-2-[1-[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; 3-Fluoro-5-[(3S)-2-[1-[6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; [(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[1-[6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]-4-piperidyl]methanone; [(3S)-3-(3-chloro-5-fluoro-phenyl)isoxazolidin-2-yl]-[1-[6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]-4-piperidyl]methanone; 3-Fluoro-5-[(3S)-2-[1-[6-(3-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; 3-[(3S)-2-[1-[6-(4-cyclopropyl-2-methyl-imidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]-5-fluoro-benzonitrile; 5-[(3S)-2-[1-[6-(4-cyclopropyl-2-methyl-imidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]-3-fluoro-2-methyl-benzonitrile; 3-[(3S)-2-[1-[6-(2,5-dimethylpyrazol-3-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]-5-fluoro-benzonitrile; 3-Fluoro-5-[(3S)-2-[1-[6-(3-methyl-1,2,4-triazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; 3-Fluoro-5-[(3S)-2-[1-[6-(5-methyl-1,2,4-triazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; 3-Fluoro-5-[(3S)-2-[1-[6-(3-methyltriazol-4-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; 3-Fluoro-5-[(3S)-2-[1-[5-fluoro-6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; 3-Fluoro-5-[(3S)-2-[1-[5-fluoro-6-(4-methylpyrazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]-2-methyl-benzonitrile; and [(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[1-[5-fluoro-6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]-4-piperidyl]methanone; or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0041] Another embodiment is 3-Fluoro-5-[(3S)-2-[1-[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; 3-Fluoro-5-[(3S)-2-[1-[6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; and 3-Fluoro-5-[(3S)-2-[1-[5-fluoro-6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0042] Another embodiment is the compound 3-Fluoro-5-[(3S)-2-[1-[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; or a pharma-ceutically acceptable salt, solvate, or stereoisomer thereof.

[0043] Another embodiment is the compound 3-Fluoro-5-[(3S)-2-[1-[6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0044] Another embodiment is the compound 3-Fluoro-5-[(3S)-2-[1-[5-fluoro-6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0045] Compound synthesis Compounds of formula I can be prepared using the methods disclosed herein, and routine modifications thereof, which will be apparent in light of the disclosure herein and methods well known in the art.

[0046] Schemes 1-7 show the main reaction steps for obtaining the example compounds of formula I.

[0047] Scheme 1 refers to intermediates whose synthesis is described in detail in the Examples section. Intermediates I-01, I-02a, I-02b and I-03 are isoxalidine derivatives with R1 / R2 substituted phenyl. The central intermediate I-04 is coupled with R3 / R4 substituted A heteroaryl building blocks to give intermediates I-05, I-06, I-07, I-08, I-09 and I-10.

[0048] Schemes 2 to 7 show the main reaction steps for obtaining the example compounds.

[0049] Scheme 1 [ka]

[0050] Scheme 2 (Example from Intermediate-05) [ka]

[0051] Scheme 3 (Example from Intermediate-06) [ka]

[0052] Scheme 4 (Example from Intermediate-07) [ka]

[0053] Scheme 5 (Example from Intermediate-08) [ka]

[0054] Scheme 6 (Examples from Intermediate-09 and Intermediate-10) [ka]

[0055] Scheme 7 (Examples from Intermediate-11a and Intermediate-11b) [ka]

[0056] The synthesis of typical compounds described herein can be accomplished as described in the following examples. Where available, reagents can be purchased commercially, for example from Sigma Aldrich or other chemical suppliers. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise stated. Optimal reaction conditions may vary depending on the particular reactants or solvents used, but such conditions can be determined by one of ordinary skill in the art by routine optimization procedures.

[0057] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting certain 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 references cited therein.

[0058] Furthermore, the compounds of the present 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-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be 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, and the like.

[0059] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof. The terms "solvent", "inert organic solvent" or "inert solvent" refer to a solvent that is inert under the reaction conditions described therein, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane, "DCM"), diethyl ether, methanol, pyridine, and the like. Unless otherwise specified, the solvents used in the reactions of the present disclosure are inert organic solvents and the reactions are conducted under an inert gas, preferably argon.

[0060] Pharmaceutical Compositions The compounds of the present disclosure are usually administered in the form of pharmaceutical compositions.Therefore, also provided herein are pharmaceutical compositions containing one or more of the compounds of the present disclosure, or their pharma-ceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, and one or more pharma-ceutically acceptable carriers, adjuvants and excipients.Suitable pharma-ceutically acceptable carriers may include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers and adjuvants.Such compositions are prepared by methods well known in the pharmaceutical art.The pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for: Oral administration, e.g., as a drench (aqueous or non-aqueous solution or suspension), tablet, e.g., buccal, sublingual and those targeted for systemic absorption, bolus, powder, granule, paste for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous or epidural injection, e.g., as a sterile solution or suspension or sustained release pharmaceutical composition; topical application, e.g., as a cream, ointment or controlled release patch or spray applied to the skin; intravaginally or rectally, e.g., as a pessary, cream or foam; sublingually; ophthalmically; transdermally; or nasally to the lungs and other mucosal surfaces.

[0061] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio. The phrase "pharmacologically acceptable carrier" as used herein means a pharma- ceutically acceptable material, composition or carrier, such as a liquid or solid filler, diluent, excipient or solvent encapsulating material, involved in carrying or transporting a compound of interest from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not injurious to the subject. Some examples of materials which may function as pharma- ceutically acceptable carriers include sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; surfactants such as polysorbate 80 (i.e., Tween 80); powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide, aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; pH buffers; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances used in pharmaceutical compositions. Examples of such pharmaceutical compositions include, but are not limited to, DMSO, 10 mM DMSO, 8% hydroxypropyl-β-cyclodextrin in PBS, propylene glycol, etc. For example, in certain embodiments, the compounds of the present disclosure can be used as a 4 mM solution in 8% hydroxypropyl-β-cyclodextrin in PBS for parenteral administration.In another specific embodiment, the compounds of the present disclosure may be used as a suspension in 0.5% aqueous CMC containing 0.1% TWEEN80.

[0062] As described herein, certain embodiments of the compounds may contain basic functional groups, such as amino or methylamino (NCH3), and therefore may form pharma- ceutically acceptable salts with pharma-ceutically acceptable acids. In this regard, the term "pharma-ceutically acceptable salts" refers to relatively non-toxic inorganic and organic acid addition salts of the compounds of the present disclosure. These salts may be prepared in situ during the administration carrier or dosage form manufacturing process, or by separately reacting the purified compounds of the present disclosure in free base form with a suitable organic or inorganic acid and isolating the salt thus formed during subsequent purification.

[0063] Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition. Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid. Pharmaceutical compositions of the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The pharmaceutical compositions may be conveniently provided in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active compound that can be combined with carrier materials to produce a single dosage form varies depending on the host treated, the particular mode of administration. The amount of active compound that can be combined with carrier materials to produce a single dosage form is generally that amount of compound that produces a therapeutic effect. Generally, this amount ranges from about 1% to about 99% of the active compound, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%. In certain embodiments, the pharmaceutical composition of the present disclosure comprises one or more of cyclodextrins, liposomes, micelle forming agents, such as bile acids, and polymeric carriers, such as polyesters and polyanhydrides; and a compound of the present disclosure. In certain embodiments, the aforementioned pharmaceutical composition renders the compound of the present disclosure orally bioavailable. Methods of preparing these pharmaceutical compositions include the step of bringing the compound of the present disclosure into association with the carrier and, optionally, one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the compound of the present disclosure into association with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.Pharmaceutical compositions of the present disclosure suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavor base, usually sucrose and acacia or tragacanth), powder, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastille (using an inert base such as gelatin and glycerin or sucrose and acacia), and / or as a mouthwash, and the like, each containing a predetermined amount of a compound of the present disclosure as an active compound. The compounds of the present disclosure may also be administered as a bolus, electuary, or paste. In solid dosage forms of the present disclosure for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active compound is mixed with one or more pharma- ceutically acceptable carriers, e.g., fillers or extenders such as sodium citrate or dicalcium phosphate and / or starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; wetting agents such as glycerol; disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol monostearate, and nonionic surfactants; absorbents such as kaolin and bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical composition may also contain buffering agents.Solid compositions of a similar type may also be used as fillers in soft and hard shell gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.Tablets may be made by compression or molding, optionally with one or more accessory ingredients.Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants or dispersants. Molded tablets may be made in a suitable machine in which a mixture of powdered compounds is moistened with an inert liquid diluent. Tablets and other solid dosage forms of the pharmaceutical compositions of the present disclosure, such as dragees, capsules, pills and granules, may be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to provide sustained or controlled release of the active compound therein, for example, using hydroxypropylmethylcellulose, other polymer matrices, liposomes and / or microspheres in various proportions to provide the desired release profile. They may be formulated for rapid release, for example, lyophilization. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of a sterile solid composition that can be dissolved in sterile water or any other sterile injectable medium immediately prior to use. These compositions may also optionally contain opacifying agents and may be of a composition that releases the active compound(s) only or preferentially in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active compound may also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients. Liquid dosage forms for oral administration of the compounds of the present disclosure include pharma-ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, 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), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, coloring agents, aromatic agents and preservatives. Suspensions 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.

[0064] Pharmaceutical compositions of the disclosure for rectal or vaginal administration may be provided as suppositories, which can be prepared by mixing one or more compounds of the disclosure with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which are solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0065] Pharmaceutical compositions of the present disclosure suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or sprays containing such carriers as are known in the art to be appropriate. Dosage forms for topical or transdermal administration of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharma- ceutically acceptable carrier and any preservatives, buffers or propellants that may be required. The ointments, pastes, creams and gels may contain, in addition to the active compound of the present disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof. Powders and sprays may contain, in addition to the compounds of the present disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can further contain conventional propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.Transdermal patches have the added advantage of providing controlled delivery of the compounds of the present disclosure to the body.Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound across the skin.The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0066] Ophthalmic pharmaceutical compositions, eye ointments, powders, solutions, and the like are also contemplated to be within the scope of the present disclosure. Pharmaceutical compositions of the present disclosure suitable for parenteral administration comprise one or more compounds of the present disclosure in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions or sterile powders that can be reconstituted into a sterile injectable solution or dispersion immediately prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes that render the pharmaceutical composition isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0067] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0068] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms on the subject compounds can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenylsorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like, in the compositions. Furthermore, prolonged absorption of injectable pharmaceutical forms can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is desirable to delay absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug depends upon its rate of dissolution, which may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable pharmaceutical compositions are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

[0069] therapeutic use In other embodiments, provided herein are methods of treating a receptor interacting protein kinase 1 mediated disease or disorder. The method comprises administering a therapeutically effective amount of a compound or pharmaceutical composition described herein to a subject in need thereof. In some embodiments, the receptor interacting protein kinase 1 mediated disease or disorder is 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-associated dementia, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, non-infectious inflammatory skin disease (ncISD) such as psoriasis or atopic dermatitis, psoriatic arthritis, or inflammatory bowel disease.

[0070] The term "trauma" as used herein refers to any physical injury to the body caused by violence, accidents, fractures, and the like. The term "ischemia" refers to cardiovascular disorders characterized by a state of hypoxia, usually due to obstruction of the arterial blood supply or insufficient blood flow resulting in hypoxia in tissues. The term "stroke" refers to cardiovascular disorders caused by blood clots or bleeding in the brain, most commonly caused by interruption of blood flow in the brain, such as by a clot blocking a blood vessel, and in certain embodiments of the present disclosure, the term stroke refers to an ischemic stroke or a hemorrhagic stroke. The term "myocardial infarction" refers to a cardiovascular disorder characterized by focal necrosis due to obstruction of the blood supply. The methods described herein may be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. "Ex vivo" means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including bodily fluids or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this regard, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used ex vivo to determine optimal schedules and / or dosages of administration of the compounds of the present disclosure for a given indication, cell type, individual, and other parameters. Information gathered from such use can be used for experimental purposes or in the clinic to set up protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will become apparent to one of skill in the art. Selected compounds can be further characterized to determine safety or tolerated doses in human or non-human subjects. Such properties can be examined using methods commonly known to one of skill in the art.Experiments with 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-transmissible inflammatory skin diseases (ncISDs) such as psoriasis or atopic dermatitis, retinal detachment-induced photoreceptor necrosis, retinitis pigmentosa, caerulein-induced acute pancreatitis, and sepsis / systemic inflammatory response syndrome (SIRS), as well as in reducing ischemic brain injury, retinal ischemia / reperfusion injury, Huntington's disease, renal ischemia-reperfusion injury, cisplatin-induced renal injury, traumatic brain injury, hematological and solid organ malignancies, bacterial and viral infections (e.g., tuberculosis and influenza or SARS-coronavirus), and lysosomal storage diseases. Thus, the receptor interacting protein kinase 1 inhibitors of the present disclosure suggest that both RIPK1 kinase-driven inflammation and cell death are important contributors to systemic inflammatory response syndrome (SIRS). There is also a rationale that vascular permeability and endothelial dysfunction contribute to SIRS / shock and mortality. Thus, the receptor interacting protein kinase 1 inhibitors of the present disclosure are useful for treating diseases and conditions mediated by receptor interacting protein kinase 1, including, but not limited to, inflammatory diseases or disorders, necrotic cell diseases, neurodegenerative diseases, central nervous system (CNS) diseases, eye diseases, infectious diseases, and malignancies. In certain embodiments, the receptor interacting protein kinase 1 inhibitors described herein can inhibit inflammation, protect tissues or cells from damage or unwanted cell death (e.g., necrosis or apoptosis), ameliorate symptoms, and improve immune responses or neurological function in subjects suffering from any of the specified diseases or conditions. Furthermore, the compounds may be suitable for treating immune-mediated diseases, such as, but not limited to, allergic diseases, autoimmune diseases, and prevention of transplant rejection.

[0071] Provided herein are compounds and compositions for use in medicine. In certain embodiments, the compounds and compositions are for use in treating a receptor interacting protein kinase 1 mediated disease or disorder. Also provided are methods of treating a receptor interacting protein kinase 1 mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein. In certain embodiments, the disease or disorder is an inflammatory disease associated with A20SNP. Various specific diseases and disorders are described below. In certain embodiments, the disease or disorder is necrotizing enterocolitis, tuberous sclerosis, Tangier disease, Wolman syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, non-transmissible inflammatory skin diseases (ncISDs) such as psoriasis or atopic dermatitis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis (e.g., acute pancreatitis), interface dermatitis (e.g., cutaneous lupus erythematosus, lichen planus, lichen planus 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, Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune Infectious 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 disease, asthma, atopic dermatitis, multiple sclerosis, type I diabetes mellitus, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme-associated febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, periodontitis, bacterial infection, staphylococcal infection, mycobacterial infection, retinitis pigmentosa, influenza, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), acute respiratory response syndrome (ARDS), transplant rejection, burn, or hypoxia.In certain embodiments, the disease or disorder is trauma, ischemia, stroke, myocardial infarction, infection, lysosomal storage disease, 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-associated dementia, encephalopathy, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, non-infectious inflammatory skin disease (ncISD) such as psoriasis or atopic dermatitis, psoriatic arthritis or inflammatory bowel disease.

[0072] In certain embodiments, the disease is necrotizing enterocolitis, tuberous sclerosis, Tangier disease, Wolman 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, psoriatic arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic beta-lactamase inhibitors, and / or anti-inflammatory drugs. steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia, ischemia-reperfusion injury of solid organs, cerebral ischemia, sepsis, systemic inflammatory response syndrome, cerebrovascular disease, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, atopic dermatitis, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary ... coidosis, Behcet's disease, interleukin-1 converting enzyme-associated febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, periodontitis, infection, bacterial infection, staphylococcal infection, mycobacterial infection, influenza, transplant rejection, burns, hypoxia, trauma, stroke, myocardial infarction, lysosomal storage diseases, Niemann-Pick disease, Gaucher disease, Krabbe disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's disease), H IV-related dementia, encephalopathy, retinal degenerative disease, glaucoma, age-related macular degeneration, Friedreich's ataxia, Lewy body disease, diabetic neuropathy, polyglutamine (poly Q) disease, Fahr's disease, Menke disease, Wilson's disease, prion disorders, atherosclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, major depressive disorder, bipolar disorder, mental retardation, postoperative cognitive impairment, autism, schizophrenia, hidradenitis suppurativa, or incontinentia pigmenti.

[0073] 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, Fahr's disease, Menke's 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 a lysosomal storage disease. In certain embodiments, the disease is Parkinson's disease. In certain embodiments, the disorder is an ischemic disease of an organ, including but not limited to the brain, heart, kidney, and liver. In some different embodiments, the disorder is an ocular disorder, such as a retinal degenerative disease, glaucoma, or age-related macular degeneration. In some different embodiments, the disorder is a central nervous system (CNS) disorder.

[0074] In certain embodiments, methods are provided for treating rheumatoid arthritis (see Lawlor KE, et al., Nat Commun. 2015, 6282; Lee SH, et al., Sci Rep., 7, 2017, 10133), systemic juvenile idiopathic arthritis (SoJIA), spondyloarthritis, osteoarthritis, non-transmissible inflammatory skin disease (ncISD) 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, methods are provided for treating autoimmune hepatitis, atherosclerosis, neutrophilic skin disease, or rare diseases caused by A20, NEMO, and / or LUBAC mutations, comprising administering a therapeutically effective amount of a compound of the present disclosure to a subject in need thereof.

[0075] In certain embodiments, the compounds and compositions are useful for treating non-transmissible inflammatory skin diseases (ncISDs), such as psoriasis or atopic dermatitis. In certain embodiments, the disorder is an intestinal inflammatory disease, such as Crohn's disease or ulcerative colitis (both commonly known together as inflammatory bowel disease, IBD). Without wishing to be bound by theory, it is believed that inhibition of receptor interacting protein kinase 1 by the compounds of the present disclosure is at least partially responsible for their anti-inflammatory activity. Thus, embodiments of the present disclosure also include methods for inhibiting receptor interacting protein kinase 1 in vitro or in a subject in need thereof, the methods comprising contacting receptor interacting protein kinase 1 with a compound disclosed herein. In some of these embodiments, inhibiting receptor interacting protein kinase 1 is effective to block (partially or completely) the release of inflammatory mediators, such as TNF and / or IL6.

[0076] Dondelinger et al,Molecular Cell 60,1 October 2015,Pages 63-76 report that the molecular mechanisms regulating the contribution of RIPK1 to cell death are much less understood. The IKK complex, including NEMO / IKKy, has been shown to negatively regulate RIPK1 activation in TNFR1 complex I by phosphorylation, independently of its function in NF-κB activation, protecting cells from RIPK1 kinase-dependent death. Dirk A.Ridder et al,J Exp Med(2015)212(10):1529-1549 show that deletion of NEMO or TAK1 in mouse brain endothelial cells results in a phenotype reminiscent of the neurological symptoms associated with IP. Smahi A,et al. Genomic rearrangements in NEMO impair NF-κB activation and are responsible for incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature. 2000;405:466-72. Also, an overview of IP is given in Fusco et al. Orphanet Journal of Rare Diseases 2014,9:93. Incontinentia pigmenti (IP) is a genetic condition that affects the skin and other body systems. Skin symptoms change over time, beginning with a vesicular rash in infancy, followed by warty skin growths. The growths become whorl-shaped gray or brown spots in childhood, then whorl-shaped pale spots in adulthood. Other signs and symptoms may include hair loss, small or missing teeth, eye abnormalities that may lead to vision loss, and wrinkled or pitted nails. Most people with IP have normal intelligence, but some have developmental delays, intellectual disability, seizures, and / or other neurological problems. IP is caused by mutations in the IKBKG gene and is inherited in an X-linked dominant manner. In another embodiment, the compounds and compositions of Formula I are useful for treating incontinentia pigmenti.

[0077] Inflammatory diseases or disorders Receptor interacting protein kinase 1 inhibitors described herein can be used to treat inflammatory diseases and disorders. Inflammatory diseases and disorders typically show high levels of inflammation in connective tissues or degeneration of these tissues. Non-limiting examples of inflammatory diseases and disorders include Alzheimer's disease, ankylosing spondylitis, arthritis including osteoarthritis, rheumatoid arthritis (RA), non-infectious 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 the present disclosure are useful for treating autoimmune disorders such as rheumatoid arthritis, psoriasis, psoriatic arthritis, encephalitis, allograft rejection, autoimmune thyroid disease (such as Graves' disease and Hashimoto's thyroiditis), autoimmune uveitis, giant cell arteritis, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, and terminal ileitis), insulin-dependent diabetes mellitus, multiple sclerosis, pernicious anemia, sarcoidosis, scleroderma, and systemic lupus erythematosus. In one embodiment, the receptor-interacting 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-transmissible inflammatory skin diseases (ncISDs), such as psoriasis or atopic dermatitis.

[0078] In certain embodiments, the disorder is an intestinal inflammatory 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, canine or feline subject. In certain embodiments, the mammal is a human subject. Without wishing to be bound by theory, it is believed that inhibition of receptor interacting protein kinase 1 by the compounds of the present disclosure is at least in part responsible for their anti-inflammatory activity.

[0079] Accordingly, embodiments of the present disclosure also include methods for inhibiting receptor interacting protein kinase 1, in vitro or in a subject in need thereof, comprising contacting receptor interacting protein kinase 1 with a compound disclosed herein. In some of these embodiments, inhibiting receptor interacting protein kinase 1 is effective to block (partially or completely) the release of inflammatory mediators such as TNF and / or IL6.

[0080] 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, inflammatory bowel disease (IBD) such as Crohn's disease or ulcerative colitis.

[0081] In another embodiment, the receptor interacting protein kinase 1 inhibitors described herein can be used to treat interface dermatitis such as cutaneous lupus erythematosus (CLE), lichen planus (LP), toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS).

[0082] 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).

[0083] In another embodiment, the receptor interacting protein kinase 1 inhibitors described herein can be used to treat coronavirus disease 19 (COVID-19).

[0084] In another embodiment, the receptor interacting protein kinase 1 inhibitors described herein can be used to treat respiratory diseases such as influenza (e.g., swine flu, H7N9), severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), respiratory syncytial virus (RSV) or bronchiolitis.

[0085] Necrotic cell disease The compounds described herein may be used to treat diseases / disorders that cause or are otherwise associated with cell necrosis. In particular, the present disclosure provides a method for preventing or treating disorders associated with cell necrosis in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound or composition described herein. The term "necrotic cell disease" refers to diseases associated with or caused by cell necrosis, such as trauma, ischemia, stroke, myocardial infarction, infection, Gaucher's disease, Krabbe's disease, sepsis, systemic inflammatory response syndrome (SIRS), Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, HIV-associated dementia, retinal degenerative diseases, glaucoma, age-related macular degeneration, rheumatoid arthritis, non-infectious inflammatory skin diseases (ncISDs) such as psoriasis or atopic dermatitis, psoriatic arthritis, or inflammatory bowel disease. The necrotic cell disorder may be an acute disorder such as trauma, ischemia, stroke, myocardial infarction, anthrax lethal toxin-induced septic shock, sepsis, systemic respiratory response syndrome (SIRS), cell death induced by LPS, and HIV-induced T cell death leading to immune deficiency. In certain embodiments, the disorder is an ischemic disorder of an organ, including but not limited to the brain, heart, kidney, and liver. The necrotic cell disorder also includes a chronic neurodegenerative disorder, 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 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.

[0086] Neurodegenerative and CNS Disorders The receptor interacting protein kinase 1 inhibitors described herein may also be used to treat neurodegenerative diseases. Neurodegenerative diseases may affect many of the body's activities, such as balance, movement, speech, breathing, and heart function. Neurodegenerative diseases may be hereditary or may be caused by medical conditions, such as alcoholism, tumors, stroke, toxins, chemicals, and viruses. Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Lewy body disease, 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 disease, Parkinson's disease, and spinal muscular atrophy. In certain embodiments, the receptor interacting protein kinase 1 inhibitors described herein may be used to treat NPC1 by inhibiting necroptosis, which leads to neuronal loss. In certain embodiments, the compounds and compositions of the present disclosure are useful for treating Alzheimer's disease. In certain embodiments, the compounds and compositions of the present disclosure are useful for treating Parkinson's disease. In certain embodiments, the compounds and compositions of the present disclosure are useful for treating amyotrophic lateral sclerosis (ALS). More generally, the receptor interacting protein kinase 1 inhibitors described herein may be used to preserve neuronal viability and promote axonal growth and neuronal function in the central nervous system (CNS). Thus, the compounds may be used to reduce or even reverse loss of cognitive, motor, and sensory function associated with diseases or disorders of the CNS by maintaining neuronal viability and / or promoting axonal regeneration and / or neuronal function. The receptor interacting protein kinase 1 inhibitors described herein may be used in methods of promoting axonal regeneration in CNS neurons, such as CNS sensory neurons, motor neurons, cortical neurons, cerebellar neurons, hippocampal neurons, and midbrain neurons.The receptor interacting protein kinase 1 inhibitors described herein can be used in methods for promoting neuronal function or for preserving viability after injury to CNS neurons. In another embodiment, these compounds can be used to promote axonal regeneration in CNS neurons that have degenerated in a CNS disease or disorder. The RIP receptor interacting protein kinase 1 inhibitors can be administered by any conventional means, for example, locally to the neuron, or can be applied ex vivo prior to reimplantation. Thus, in one aspect, the present disclosure provides a method for treating a CNS disorder in a subject in need of treatment, where a symptom of the CNS disorder is axonal degeneration or injury in the CNS neuron. The method includes administering to the subject an effective amount of a compound or composition disclosed herein to promote axonal regeneration in the CNS neuron affected by the CNS disorder. After administration, neuronal function can be measured, for example, as an index of axonal regeneration. It is also contemplated that after administration of the compound or composition, the neuronal function of the CNS neuron is preserved or improved compared to the neuronal function before administration.

[0087] 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, Fahr's disease, Menke's disease, Wilson's disease, cerebral ischemia, and prion disorders. In an exemplary embodiment, the CNS disorder is brain injury or spinal cord injury.

[0088] Methods for promoting neuronal survival and axonal regeneration in the CNS are also provided herein. CNS disorders characterized by impaired or insufficient axonal growth or axonal degeneration can result from CNS neuron injury (e.g., trauma, surgery, nerve compression, nerve crush, nerve transection, neurotoxicity, or other physical injury to the brain or spinal cord) or neurodegenerative CNS diseases, where 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, Fahr's disease, Menke's disease, Wilson's disease, cerebral ischemia, prion disorders (e.g., Creutzfeldt-Jackson disease, and others). 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, the CNS disorder affects the subject's basic life functions, such as breathing, heart rate and blood pressure, e.g., brain stem injury or aneurysm. In certain embodiments, the CNS disease or disorder affects the subject's cognitive abilities. In certain embodiments, the CNS disease or disorder affects the subject's movement and / or strength. In certain embodiments, the CNS disease or disorder affects the subject's coordination.

[0089] In certain embodiments, the CNS disorder affects the cognitive abilities of a subject, 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. In certain embodiments, the CNS disorder affects the movement and / or strength of a subject, such as brain or spinal cord damage or neurodegenerative CNS disorders, such as Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration, progression of supranuclear palsy, Huntington's disease, multiple system atrophy, amyotrophic lateral sclerosis, and hereditary spastic paresis. In certain embodiments, the CNS disorder affects the coordination of a subject, such as brain damage to the cerebellum or neurodegenerative CNS disorders, such as spinocerebellar atrophy, Friedreich's ataxia, and prion disorders. In each of the aforementioned methods, the CNS disorder includes, but is 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) disease, stroke, Fahr's disease, Menke's 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 paresis, and spinocerebellar atrophy. Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, lysosomal storage diseases, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, and spinal muscular atrophy.

[0090] In certain embodiments, the compounds and compositions of the present disclosure are useful for treating Alzheimer's disease. In certain embodiments, the compounds and compositions of the present disclosure are useful for treating Parkinson's disease. In certain embodiments, the compounds and compositions of the present disclosure are useful for treating amyotrophic lateral sclerosis (ALS). In certain embodiments, the compounds and compositions of the present disclosure are useful for treating lysosomal storage diseases. In certain embodiments, the disorder is a brain disorder, such as, but not limited to, Alzheimer's disease, ALS, frontotemporal dementia, vascular dementia, Huntington's disease, Parkinson's disease, dementia with Lewy bodies, 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 depression, bipolar depression, schizophrenia, autism, Niemann-Pick disease, and neuro-Behcet's disease. In certain embodiments, a method of treating a CNS disease or disorder is provided, comprising administering a therapeutically effective amount of a 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).

[0091] Eye conditions The receptor interacting protein kinase 1 inhibitors described herein may also be used to treat ocular conditions, for example, to reduce or prevent loss of viability of photoreceptor and / or retinal pigment epithelial cells. In certain embodiments, the present disclosure provides a method of maintaining visual function of an eye of a subject having an ocular condition, where a symptom of the ocular condition is loss of photoreceptor cell viability in the retina of an eye having the condition. The method includes administering to the eye of the subject an effective amount of a compound or composition described herein, thereby maintaining viability of photoreceptor cells located within the retina of the eye. After administration, the visual function (e.g., visual acuity) of the eye may be preserved or improved compared to the visual function of the eye before administration. The ocular condition may be age-related macular degeneration (AMD), pigmentary retinopathy (RP), macular edema, diabetic retinopathy, central circular choroidal dystrophy, BEST disease, adult vitelliform disease, pattern dystrophy, myopic degeneration, central serous retinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis, or light-induced toxicity. The AMD may be neovascular or dry type of AMD. The retinal detachment may be keratogenic, serous, and tractional retinal detachment. In certain embodiments, the ocular condition may be geographic atrophy, glaucoma, or another ischemic ocular disease. In certain embodiments, the present disclosure provides a method of preserving the viability of retinal pigment epithelial (RPE) cells in the retina of a subject having an ocular condition by administering a compound of the present disclosure. The subject being treated may have a loss of retinal pigment epithelial cells in the retina of an eye having the condition, and the ocular condition may be age-related macular degeneration (AMD), BEST disease, myopic degeneration, Stargardt's disease, uveitis, adult foveal macular dystrophy, sickle fundus, multiple evanescent white dot syndrome, serpiginous choroidopathy, acute multifocal posterior plaque-like epitheliopathy (AMPPE), or another uveitis disorder. In certain embodiments, the method comprises administering to the eye of the subject an effective amount of a compound or composition described herein, thereby maintaining the viability of retinal pigment epithelial cells.In another embodiment, a method is provided for preserving the viability of photoreceptor cells located within the retina of a subject with age-related macular degeneration (AMD), pigmentary retinopathy (RP), macular edema, diabetic retinopathy, central circular choroidal dystrophy, BEST disease, adult vitelliform disease, pattern dystrophy, myopic degeneration, central serous retinopathy, Stargardt's disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis, or light-induced toxicity. Thus, in certain embodiments, the method comprises administering to the eye an effective amount of a compound or composition as described herein, thereby preserving the viability of photoreceptor cells located within the retina of a subject with a condition. In another embodiment, a method is provided for preserving the viability of photoreceptor cells located within the retina of a mammalian eye following retinal detachment. The retinal detachment can be rhegmatogenous retinal detachment, tractional retinal detachment, or serous retinal detachment. In other embodiments, retinal detachment may occur as a result of a retinal break, retinoblastoma, melanoma or other cancer, diabetic retinopathy, uveitis, choroidal neovascularization, retinal ischemia, pathological myopia, or trauma. In certain embodiments, the method comprises administering to an eye having a detached area of ​​retina a compound or composition as described herein in an amount sufficient to preserve the viability of photoreceptor cells located within the detached area of ​​retina. In another embodiment, a method of preserving visual function of an eye of a subject having age-related macular degeneration (AMD), pigmentary retinopathy (RP), macular edema, central circular choroidal dystrophy, retinal detachment, diabetic retinopathy, BEST disease, adult vitreous disease, pattern dystrophy, myopic degeneration, central serous retinopathy, Stargardt's disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis, or light-induced toxicity, wherein a symptom of the ocular condition is loss of photoreceptor cell viability in the retina of the eye, and the method comprises treating the subject with a compound or composition described herein. In another aspect, the disclosure provides a method of preserving visual function of an eye of a subject having an ocular condition, wherein a symptom of the ocular condition is 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.

[0092] In certain embodiments, a method of preserving visual function in an eye of a subject having an ocular condition is provided, wherein a symptom of the ocular condition is loss of retinal ganglion cell viability 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 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 may support axonal regeneration.

[0093] Non-limiting examples of symptoms related to ocular conditions include loss of retinal ganglion cell viability in the retina of the eye, glaucoma, optic nerve damage, optic neuritis, optic neuropathy, diabetic retinopathy, central retinal artery occlusion and central retinal vein occlusion. The compounds described herein can also be used to treat optic neuropathies, such as ischemic optic neuropathy (e.g., arteritic or non-arteritic anterior ischemic neuropathy 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, Behr's syndrome). Methods of maintaining visual function in the eye of a subject with glaucoma, optic nerve damage, optic neuropathy, diabetic retinopathy, central retinal artery occlusion or central retinal vein occlusion are also disclosed. The method includes administering an effective amount of a compound or composition described herein to the eye of a subject, thereby maintaining the viability of retinal ganglion cells located within the retina of the eye and the visual function of the eye. In another aspect, disclosed herein is a method of maintaining the viability of retinal ganglion cells located within the retina of a mammalian eye, for example, affected by glaucoma, optic nerve injury, optic neuritis, optic neuropathy, diabetic retinopathy, central retinal artery occlusion, and central retinal vein occlusion. The method includes administering a compound or composition described herein to an eye with an affected area of ​​the retina in an amount sufficient to preserve the viability of retinal ganglion cells located within the affected area of ​​the retina. The preserved retinal ganglion cells can support axonal regeneration, linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial and viral infections (e.g., tuberculosis and influenza or SARS-coronavirus), and lysosomal storage diseases.Non-limiting examples of lysosomal storage diseases include Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidase disease, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostat disease, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, and Wolman disease. In certain embodiments, compounds and compositions for use in medicine are provided. In certain embodiments, the compounds and compositions are for use in treating a receptor interacting protein kinase 1 mediated disease or disorder. Also provided is a method of treating a receptor interacting protein kinase 1 mediated disease or disorder, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein to a subject in need thereof. In another embodiment, the disclosure provides a method of inhibiting receptor interacting protein kinase 1. The method comprises contacting receptor interacting protein kinase 1 with an effective amount of a compound of the disclosure. Inhibiting receptor interacting protein kinase 1 generally comprises contacting receptor interacting protein kinase 1 with a compound of the disclosure in an amount sufficient to reduce the activity of receptor interacting protein kinase 1 compared to the receptor interacting protein kinase 1 activity in the absence of the compound. For example, contacting receptor interacting protein kinase 1 with a compound of the disclosure can result in about 1% to about 99% inhibition of receptor interacting protein kinase 1 (i.e., the activity of the inhibited enzyme ranges from 99% to 1% of the enzyme activity in the absence of a compound of the disclosure).The level of receptor interacting protein kinase 1 inhibition may range from about 1% to about 10%, or from about 10% to about 20%, or from about 20% to about 30%, or from about 30% to about 40%, or from about 40% to about 50%, or from about 50% to about 60%, or from about 60% to about 70%, or from about 70% to about 80%, or from about 80% to about 90%, or from about 90% to about 99%. The level of receptor interacting protein kinase 1 inhibition may range from about 5% to about 95%, or from about 10% to about 90%, or from about 20% to about 80%, or from about 30% to about 70%, or from about 40% to about 60%. In some embodiments, contacting receptor interacting protein kinase 1 with a compound of the present disclosure will result in complete (i.e., 100%) inhibition.

[0094] Combination therapy In certain embodiments, the compounds of the present disclosure may be administered in combination with at least one other therapeutically active agent. The two or more agents may be administered simultaneously, coformulated, or administered separately. In certain embodiments, the other therapeutically active agent is a thrombolytic agent, tissue plasminogen activator, an anticoagulant, a platelet aggregation inhibitor, an antimicrobial agent (antibiotics, broad spectrum antibiotics, lactams, antimycobacterial agents, bactericidal antibiotics, anti-MRSA treatments), a long-acting beta agonist, a combination of an inhaled corticosteroid and a long-acting beta agonist, a short-acting beta agonist, a leukotriene modifier, an anti-IgE, a methylxanthine bronchodilator, a mast cell inhibitor, a protein tyrosine kinase inhibitor, a CRTH2 / D prostanoid receptor antagonist, an epinephrine inhalation aerosol, a phosphodiesterase inhibitor, a combination of a phosphodiesterase-3 inhibitor and a phosphodiesterase-4 inhibitor, a long-acting inhaled anticholinergic, a muscarinic antagonist, a long-acting muscarinic antagonist, a low-dose steroid, an inhaled corticosteroid, an oral corticosteroid, a topical corticosteroid, an antithymocyte globulin, a thalidomastoid, a thyroiditis agent ... the medicament for treating the inflammatory bowel disease is selected from the group consisting of medicaments for treating inflammatory bowel disease, medicaments for treating inflammatory bowel disease, medicaments for treating inflammatory bowel disease, medicaments for treating inflammatory bowel disease, medicaments for treating inflammatory bowel disease, and medicaments for treating inflammatory bowel disease. Exemplary other therapeutically active agents include heparin, coumadin, clopidogrel, dipyridamole, ticlopidine HCL, eptifibatide, aspirin,Vacomycin, cefeprime, piperacillin and tazobactam combination, imipenem, meropenem, doripenem, ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, hydrocortisone, vedolizumab, alicaforsen, remestemcel-L, ixekizumab, tildrakizumab, secukinumab, chlorhexidine, doxycycline, minocycline, fluticasone (fluticasone propionate, fluticasone furoate), beclomethasone dipropionate, budesonide, tricinolone acetonide, flunisolide, mome Tazoneflate, ciclesonide, alloformoterol tartrate, formoterol fumarate, salmeterol xinafoate, albuterol (albuterol sulfate), levalbuterol tartrate, ipratropium bromide, montelukast sodium, zafirlukast, zileuton, omalizumab, theophylline, chromin sodium, nedocromil sodium, masitinib, AMG853, indacaterol, E004, reslizumab, salbutamol, tiotropium bromide, VR506, lebrikizumab, RPL554, afibercept, umecli dinium, inducterol maleate, aclidinium bromide, roflumilast, SCH527123, glycopronium bromide, olodaterol, fluticasone furoate in combination with vilanterol, fluticasone propionate in combination with salmeterol, fluticasone furoate in combination with fluticasone propionate, fluticasone propionate in combination with eformoterol fumarate dihydrate, formoterol in combination with budesonide, beclomethasone dipropionate in combination with formoterol, mometasone furoate in combination with formoterol fumarate dihydrate combinations with other drugs, combinations of umeclidinium and vilanterol, combinations of ipratropium bromide and albuterol sulfate, combinations of glycopyrronium bromide and indacaterol maleate, combinations of glycopyrrolate and formoterol fumarate, combinations of aclidinium and formoterol, isoniazid, ebutol, rifamine, pyrazinamide, rifabutin, rifapentine, capreomycin, levofloxacin, moxifloxicin, ofloxacin, ethionamide, cyclosporine, kanamycin, streptomycin, viomycin,Bedaquiline fumarate, PNU-100480, delamanid, imatinib, ARG201, tocilizumab, muromonab-CD3, basiliximab, daclizumab, rituximab, prednisolone, antithymocyte globulin, FK506 (tacrolimus), methotrexate, cyclosporine, sirolimus, everolimus, mycophenolate sodium, mycophenolate mofetil, cyclophosphamide, azathioprine, thalidomide, chlorambucil, nifedipine, nicardipine, nitroglycerin, lisinopril, dilutazem, 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, ivacaftor, dornase alfa, pancrelipase, tobramycin, aztreonam, colistimethate sodium, cefadroxil monohydrate, cefazolin, cephalexin , cefazolin, moxifloxacin, levofloxacin, gemifloxacin, azithromycin, gentamicin, ceftazidime, trimethoprim and sulfamethoxazole combination, chloramphenicol, ibacterium and lumacaftor combination, ataluren, NT-501-CNTF, gene transfer agent encoding myosin VIIA (MY07A), ranibizumab, pegaptanib sodium, NT501, humanized sphingomab, bevacizumab, oseltamivir, zanamivir, rimantadine, amantadine, nafcillin, sulfamethoxazolem , trimethoprim, sulfasalazine, acetylsulfisoxazole, vancomycin, muromonab-CD3, ASKP-1240, ASP015K, TOL101, pimecrolimus, hydrocortisone, betamethasone, flurantrenolide, triamcinolone, fluocinonide, clobetasol, hydrocortisone, methylprednisolone, prednisolone, recombinant synthetic type I interferon, interferon alpha-2a, interferon alpha-2b, hydroxyzine, diphenhydramine, flucloxacillin, dicloxacillin,and erythromycin.

[0095] The compounds of the disclosure may be administered in combination with other anti-inflammatory agents for any of the above indications, including oral or topical corticosteroids, anti-TNF agents, 5-aminoalicyclic acid and mesalamine preparations, hydroxychloroquine, thiopurines, methotrexate, cyclophosphamide, cyclosporine, calcineurin inhibitors, mycophenolic acid, mTOR inhibitors, JAK inhibitors, Syk inhibitors, anti-inflammatory biologics (including anti-IL6 biologics, anti-IL1 agents, anti-IL17 biologics, anti-CD22, anti-integrin agents, anti-IFNa, anti-CD20 or CD4 biologics, and other cytokine inhibitors or biologics), T cell or B cell receptor or interleukin.

[0096] For the treatment of ALS, compounds of the present disclosure may be administered in combination with riluzole.

[0097] In treating Parkinson's disease, the compounds of the present disclosure may be administered in combination with levodopa, carbodopa or a combination thereof, pramipexole, ropinirole, rotigotine, selegiline, rasagiline, entacapone, tolcapone, benztropine, trihexyphenidyl, or amantadine.

[0098] In the treatment of Alzheimer's disease, the compounds of the present disclosure 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 verubecestat, anti-tau therapies, such as AZD3293 (LY3314814), elenbecestat (E2609), LY2886721, PF-05297909, JNJ-54861911, TAK-070, VTP-37948, HPP854, CTS-21166, or LMTM (leuco-methylthionium-bis(hydromethanesulfonate®)).

[0099] In the treatment of rheumatoid arthritis, the compounds of the present disclosure may be administered in combination with ibuprofen, naproxen, prednisone, methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, tocilizumab, or tofacitinib.

[0100] In treating CVA, the compounds of the present disclosure may be administered in combination with thrombolytic agents (e.g., tissue plasminogen activator), anticoagulants (e.g., heparin, coumadin, clopidine gel, and platelet aggregation inhibitors (e.g., dipyridamole, ticlopidine HCL, eptifibatide, and / or aspirin, etc.).

[0101] In treating SIRS, the compounds of the present disclosure may be administered in combination with broad spectrum antibiotics (such as vancomycin) or other anti-MRSA therapies (cefeprime, piperacillin / tazobactam, carbapenems (imipenem, meropenem, doripenem), quinolones (ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, etc.), and low dose steroids such as hydrocortisone.

[0102] In the treatment of inflammatory bowel disease (particularly Crohn's disease and / or ulcerative colitis), a compound of any formula described herein may be administered in combination with vedolizumab, alicaforsen, or remestemcel-L. Specifically, in the treatment of inflammatory bowel disease (particularly Crohn's disease and / or ulcerative colitis), a compound of the present disclosure may be administered in combination with alicaforsen, or remestemcel-L.

[0103] In the treatment of non-transmissible inflammatory skin diseases (ncISDs), such as psoriasis or atopic dermatitis, compounds of the present disclosure may be administered in combination with ixekizumab, tildrakizumab (MK-3222), or secukinumab (AIN457).

[0104] Specifically, the compounds of the present disclosure may be administered in combination with ixekizumab or tildrakizumab (MK-3222) in the treatment of non-transmissible inflammatory skin diseases (ncISDs), such as psoriasis and atopic dermatitis. In the treatment of periodontitis, the compounds of any formula described herein may be administered in combination with an antibacterial agent (e.g., chlorhexidine) or an antibiotic (e.g., doxycycline or minocycline).

[0105] For the treatment of asthma, the compounds of any of the formulae described herein may be used in combination with inhaled corticosteroids (ICS) such as fluticasone propionate, beclomethasone dipropionate, budesonide (Pulmicort), triamcinolone acetonide, flunisolide, mometasone furoate or ciclesonide, long acting beta agonists (LABA) such as formoterol furamate, salmeterol xinafoate, combinations of ICS and LABA (e.g. fluticasone furoate and vilanterol, formoterol / budesonide inhalation, beclomethasone dipropionate / formoterol and fluticasone protease inhibitors). It may be administered in combination with pionate / salmerol, short-acting beta agonists ((SABA) such as albuterol sulfate, levalbuterol tartrate, ipratropium bromide / albuterol, ipratropium bromide, leukotriene modifiers (such as montelukast sodium, zafirlukast, or zileuton), and anti-IgE (such as omalizumab), methylxanthine bronchodilators (such as theophylline, mast cell inhibitors (such as sodium chromin and nedocromil sodium), long-acting muscarinic antagonists ((LAMA) such as mometasone furoate / formoterol fumarate dihydrate).

[0106] Other agents that may be suitable for use in combination therapy in 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 / eformoterol fumarate dihydrate, reslizumab, salbutamol dry powder inhalation, tiotropium bromide, formoterol / budesonide, fluticasone furoate, Vectura's VR506, lebrikizumab (RG3637), phosphodiesterase (PDE)-3 and (PDE)-4 inhibitors (RPL554).

[0107] In the treatment of COPD, the compounds of any of the formulas described herein may be used in combination with LABAs (e.g., salmeterol xinafoate, umeclidinium / vilanterol, umeclidinium, arformoterol tartrate, formoterol fumarate inhalation powder, inducterol maleate, or fluticasone propionate / eformoterol fumarate dihydrate), long-acting inhaled anticholinergics (or muscarinic antagonists such as tiotropium bromide, and aclidinium bromide, phosphodiesterase (PDE-r) inhibitors ( For example, roflumilast, darirep), ICS / LABA combinations (for example, fluticasone furoate and vilanterol, fluticasone propionate / salmeterol, budesonide / formoterol, mometasone / formoterol, ipratropium bromide / albuterol sulfate, albuterol / ipratropium, SABAs (such as ipratropium bromide and albuterol sulfate), and ICS (such as budesonide and fluticasone propionate, beclomethasone dipropionate, etc.).

[0108] Other agents that may be suitable for use in combination therapy in the treatment of COPD include SCH527123 (CXCR2 antagonist), glycopyrronium bromide (NVA237), glycopyrronium bromide and indacaterol maleate (QVA149), glycopyrrolate fumarate and formoterol fumarate (PT003), indacaterol maleate (QVA149), olodaterol, tiotropium / olodaterol, and aclidinium / formoterol inhalation.

[0109] For the treatment of mycobacterial infections (tuberculosis), the compounds of any of the formulas described herein may be administered in combination with antimycobacterial agents (e.g., isoniazid (INH), ehambutol, rifampin, and pyrazinamide), bactericidal antibiotics (e.g., rifabutin or rifapentine, aminoglycosides (capreomycin), fluoroquinolones (levofloxacin, moxifloxicin, ofloxacin), thioamides (ehionamide), cyclosporine, para-amino cycloaliphatic acids, cyclosporine, kanamycin, streptomycin, viomycin, capreomycin, betaquilin fumarate, oxazolidinones, or delamanid (OPC-67683).

[0110] Specifically, in the treatment of mycobacterial infections (tuberculosis), the compounds of the present disclosure may be administered in combination with antimycobacterial agents (e.g., isoniazid (INH), ehambutol, rifampin and pyrazinamide), bactericidal antibiotics (e.g., rifabutin or rifapentine, aminoglycosides (capreomycin), fluoroquinolones (levofloxacin, moxifloxicin, ofloxacin), thioamides (ehionamide), cycloserine, kanamycin, streptomycin, viomycin, capreomycin, betaquilin fumarate, oxazolidinones, or delamanid (OPC-67683).

[0111] In the treatment of systemic scleroderma, the compounds of any of the formulas described herein may be used in combination with oral corticosteroids (such as prednisolone, immunosuppressants (such as methotrexate, cyclosporine, antithymocyte globulin, mycophenolate mofetil, cyclophosphamide, FK506 (tacrolimus), thalidomide, chlorambucil, azathioprine, etc.), calcium channel blockers (such as nifedipine or nicardipine), topical emollients (such as nitroglycerin ointment), ACE inhibitors (such as lisinopril, etc.), serotonin reuptake inhibitors (such as serotonin reuptake inhibitors), and the like. In some cases, it may be administered in combination with inhibitors (such as fluoxetine), endothelin-I receptor inhibitors (such as bosentan or epoprostenol), antifibrotic agents (such as colchicine, para-aminobenzoic acid (PABA), dimethyl sulfoxide (DMSO), and D-penicillamine, interferon alpha and interferon gamma (INF-g)), proton pump inhibitors (such as omeprazole, metoclopramide, lansoprazole, esomeprazole, pantoprazole, rabeprazole or imatinib, ARG201 (arGentis Pharmaceutical), belimumab, tocilizumab, etc.).

[0112] Specifically, in the treatment of systemic sclerosis, the compounds of any of the formulas described herein may be used in combination with oral corticosteroids (such as prednisolone), antithymocyte globulin, FK506 (tacrolimus), thalidomide, chlorambucil, calcium channel blockers (such as nifedipine or nicardipine), topical emollients (nitroglycerin ointment), ACE inhibitors (such as lisinopril), dilutizem, serotonin reuptake inhibitors (such as fluoxetine), endothelin-I receptor antagonists (such as cyclosporine), and the like. It may be administered in combination with inhibitors (such as bosentan or epoprostenol), antifibrotic agents (such as colchicine (Colcrys), para-aminobenzoic acid (PABA), dimethylsulfoxide (DMSO), and D-penicillamine, interferon alpha and interferon gamma (INF-g)), proton pump inhibitors (such as omeprazole, metoclopramide, lansoprazole, esomeprazole, pantoprazole, rabeprazole or imatinib, ARG201 (arGentis Pharmaceutical) or tocilizumab).

[0113] In the treatment of cystic fibrosis, the compounds of the disclosure may be used in combination with cystic fibrosis transmembrane conductance regulator (CFTR) enhancers (e.g., ivacaftor, mucolytics (e.g., dornase alfa), pancreatic enzymes (e.g., pancrelipase), bronchodilators (e.g., albuterol), antibiotics (inhalation, oral or parenteral, e.g., tobramycin solution for inhalation, aztreonam inhalation, colistimethate sodium, cephalosporins (cefadroxil monohydrate, cefazolin, It may be administered in combination with cephalexin, cefazolin, fluoroquinolones (such as moxifloxacin, levofloxacin, gemifloxacin), azithromycin, gentamicin, piperacillin / tazobacam, cephalexin, ceftazidime, ciprofloxin, trimethoprim / sulfamethoxazole, or ivacufutor / lumacaftor (VX-809), ataluren, or thiopropium bromide as an addition to standard treatment.

[0114] For the treatment of retinitis pigmentosa, compounds of the present disclosure may be administered in combination with ciliary neurotrophic growth factor (NT-501-CNTF) or the gene transfer agent UshStat.

[0115] In the treatment of macular degeneration, the compound of any formula described herein may be administered in combination with an ophthalmic intravitreal injection (afibercept) or an anti-vascular endothelial growth factor (VEGF) inhibitor (such as ranibizumab or pegaptanib sodium, ciliary neurotrophic growth factor agent (NT501), iSONEP or bevacizumab).

[0116] For the treatment of influenza, the compounds of the present disclosure may be administered in combination with a trivalent (IIV3) inactivated influenza vaccine (e.g., Afluria, Fluarix, Flucelvax, FluLaval, Fluvirin, Fluzone), a quadrivalent (IIV4) inactivated influenza vaccine (such as Fluarix Quadrivalent, Flulaval Quadrivalent, Fluzone Quadrivalent), a trivalent recombinant influenza vaccine (such as FluBlok), a quadrivalent live attenuated influenza vaccine (such as FluMist Quadrivalent), an antiviral agent (such as oseltamivir, zanamivir, rimantadine or amantadine), or Fluad, Fludase, FluNhance, Preflucel, or VaxiGrip.

[0117] For the treatment of staphylococcal infections, the compounds of any of the formulas described herein may be administered in combination with antibiotics (a-lactam cephalosporins, nafcillin, sulfonamides (sulfamethoxazole and trimethoprim, sulfasalazine, acetylsulfisoxazole), or vancomycin.

[0118] In the treatment of transplant rejection, a compound of any of the formulas described herein may be administered in combination with high dose corticosteroids (prednisone, methylprednisolone, calcineurin inhibitors (such as cyclosporine), tacrolimus, mTor inhibitors (such as sirolimus or everolimus), antiproliferative agents (such as azathioprine, mycophenolate mofetil or mycophenolate sodium), monoclonal antibodies (such as muromonab-CD3, interleukin-2 receptor antagonists, daclizumab or rituximab), polyclonal anti-T cell antibodies (such as anti-thymocyte gamma globulin-horse or anti-thymocyte globulin-rabbit), anti-CD40 antagonists (ASKP-1240), JAK inhibitors (ASP015K) or anti-TCR mouse mAb (TOL101).

[0119] Specifically, in the treatment of transplant rejection, a compound of any formula 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-horse or anti-thymocyte globulin-rabbit), an anti-CD40 antagonist (ASKP-1240), a JAK inhibitor (ASP015K) or an anti-TCR mouse mAb (TOL101).

[0120] In the treatment of atopic dermatitis, the compounds of any formula described herein may be administered in combination with topical immunomodulators or calcineurin inhibitors (such as pimecrolimus or tacrolimus ointment), topical corticosteroids (such as hydrocortisone, betamethasone, flurandrenolide, fluticasone, triamcinolone, fluocinonide and clobetasol), oral corticosteroids (such as hydrocortisone, methylprednisolone or prednisolone), immunosuppressants (such as cyclosporine or interferon gamma) (Alferon N, Infergen, Intron A, Roferon-A®), antihistamines (for itch such as Atarax, Vistaril, Benadryl), antibiotics (such as penicillin derivatives flucloxacillin or dicloxacillin, erythromycin, nonsteroidal immunosuppressants (such as azathioprine), methotrexate, cyclosporine or mycophenolate mofetil.

[0121] Specifically, in the treatment of atopic dermatitis, a 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 itch such as Atarax, Vistaril, Benadryl) or antibiotics (e.g., penicillin derivatives flucloxacillin or dicloxacillin, erythromycin).

[0122] In the treatment of burns, such as burn injury or burn shock, the compound of any formula described herein can be administered alone or in combination with antibacterial agents, typically topical antibiotics (mafenide acetate cream, silver sulfadiazine cream) and / or analgesics (opioid analgesics, such as morphine, oxycodone).Other therapeutic agents that may be useful in the treatment of burns include retinoids and pirfenidone.

[0123] In certain embodiments, the at least one other therapeutically active agent is selected from a thrombolytic agent, a tissue plasminogen activator, an anticoagulant, and a platelet aggregation inhibitor.

[0124] In certain embodiments, the at least one other therapeutically active agent is selected from heparin, coumadin, clopidogrel, dipyridamole, ticlopidine HCL, eptifibatide, and aspirin, hi certain embodiments, the kinase-mediated disease or disorder treated with these agents is a cerebrovascular disorder.

[0125] In certain embodiments, the at least one other therapeutically active agent is selected from broad spectrum antibiotics, anti-MRSA therapy, and low-dose steroids. In certain embodiments, the 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 systemic inflammatory response syndrome.

[0126] In certain embodiments, the at least one other therapeutically active agent is alicaforsen or remostemcel-L. In certain embodiments, the disease or disorder treated with these agents is Crohn's disease or ulcerative colitis.

[0127] In certain embodiments, the 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-transmissible inflammatory skin disease (ncISD), such as psoriasis or atopic dermatitis.

[0128] In certain embodiments, the at least one other therapeutically active agent is an antibacterial agent or antibiotic. In certain embodiments, the 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 interdental inflammation.

[0129] In certain embodiments, the at least one other therapeutically active agent is selected from an inhaled corticosteroid, a long-acting beta agonist, a combination of an inhaled corticosteroid and a long-acting beta agonist, a short-acting beta agonist, a leukotriene modifier, an anti-IgE, a methylxanthine bronchodilator, a mast cell inhibitor, and a long-acting muscarinic antagonist. In certain embodiments, the at least one other therapeutically active agent is selected from fluticasone propionate, beclomethasone dipropionate, budesonide, trimcinolone acetonide, flunisolide, mometasone furoate, or ciclesonide, formoterol fumarate, salmeterol xinafoate, a combination of fluticasone furoate and vilanterol, a combination of formoterol and inhaled budesonide, a combination of beclomethasone dipropionate and formoterol, a combination of fluticasone propionate and salmeterol, albuterol sulfate, rubuterol tartrate, a combination of ipratropium bromide and albuterol, ipratropium bromide, montelukast sodium, zaulkast, zileuton, omalizumab theophylline, chromin sodium, nedocromil sodium, and a combination of mometasone furoate and formoterol fumarate dihydrate. In certain embodiments, the at least one other therapeutically active agent is selected from protein tyrosine kinase inhibitors, CRTH2 / D-prostanoid receptor antagonists, epinephrine inhalation aerosol, and a combination of a phosphodiesterase-3 inhibitor and a phosphodiesterase-4 inhibitor. In certain embodiments, the at least one other therapeutically active agent is selected from masitinib, AMG853, indacaterol, E004, a combination of fluticasone furoate and fluticasone propionate, a combination of binanterol furoate, a combination of fluticasone propionate and eformoterol fumarate dihydrate, reslizumab, salbutamol, tiotropium bromide, a combination 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.

[0130] In certain embodiments, the at least one other therapeutically active agent is selected from a combination of a long-acting beta agonist, a long-acting inhaled anticholinergic or muscarinic antagonist, a phosphodiesterase inhibitor, an inhaled corticosteroid long-acting beta agonist, a short-acting beta agonist, and an inhaled corticosteroid. In certain embodiments, the at least one other therapeutically active agent is selected from salmeterol xinafoate, a combination of umeclidinium and vilanterol, umeclidinium, arformoterol tartrate, formoterol fumarate, industerol maleate, a combination of fluticasone propionate and eformoterol 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 albuterium and ipratropiterol, ipratropium bromide, albuterol sulfate, budesonide, fluticasone propionate, and beclomethasone dipropionate. In certain embodiments, the at least one other therapeutically active agent is selected from SCH527123, glycopronium 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 aclidinium and formoterol. In certain embodiments, the disease or disorder treated with these agents is COPD.

[0131] In certain embodiments, the at least one other therapeutically active agent is an antimycobacterial agent or a bactericidal antibiotic. In certain embodiments, the at least one other therapeutically active agent is selected from isoniazid, ehambutol, rifampin, pyrazinamide, rifabutin, rifapentine, capreomycin, levofloxacin, moxifloxicin, ofloxacin, ehionamide, cycloserine, kanamycin, streptomycin, viomycin, bedaquiline fumarate, PNU-100480, and delamanid. In certain embodiments, the kinase-mediated disease or disorder treated with these agents is a mycobacterial infection.

[0132] In certain embodiments, the at least one other therapeutically active agent is selected from oral corticosteroids, antithymocyte globulin, 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, the at least one active agent is selected from prednisolone, antithymocyte globulin, FK506 (tacrolimus), thalidomide, chlorambucil, nifedipine, nicardipine, nitroglycerin ointment, lisinopril, dilutyzem, fluoxetine, bosentan, epoprostenol, colchicine, paraaminobenzoic acid, dimethylsulfoxide, 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.

[0133] In certain embodiments, the at least one other therapeutically active agent is selected from cystic fibrosis transmembrane conductance regulator enhancers, mucolytic agents, pancreatic enzymes, bronchodilators, antibiotics, or ivacaftor / lumacaftor, ataluren, and thiopropium bromide. In certain embodiments, the at least one other therapeutically active agent is selected from ivacaftor, dornase alfa, pancrelipase, albuterol, tobramycin, aztreonam, colistimethate sodium, cefadroxil monohydrate, cefazolin, cephalexin, cefazolin, moxifloxacin, levofloxacin, gemifloxacin, azithromycin, gentamicin, piperacillin / tazobacam, ceftazidime, ciprofloxine, trimethoprim / sulfamethoxazole, chloramphenicol, or ivacaftor / lumacaftor, ataluren, and thiopropium bromide. In certain embodiments, the disease or disorder treated with these agents is cystic fibrosis.

[0134] In certain embodiments, the at least one other therapeutically active agent is a ciliary neurotrophic growth factor or a gene transfer agent. In certain embodiments, the at least one other therapeutically active agent is a gene transfer agent encoding NT-501-CNTF or myosin VIIA (MY07A). In certain embodiments, the disease or disorder treated with these agents is retinitis pigmentosa.

[0135] In certain embodiments, at least one other therapeutically active agent is selected from ophthalmic intravitreal 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 afibercept, ranibizumab, pegaptanib sodium, NT501, humanized sphingomab, and bevacizumab.In certain embodiments, the disease or disorder treated with these agents is macular degeneration.

[0136] In certain embodiments, the at least one other therapeutically active agent is selected from a trivalent (IIV3) inactivated influenza vaccine, a quadrivalent (IIV4) inactivated influenza vaccine, a trivalent recombinant influenza vaccine, a quadrivalent live attenuated influenza vaccine, an antiviral agent, or an inactivated influenza vaccine. In certain embodiments, the 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.

[0137] In certain embodiments, the at least one other therapeutically active agent is selected from β-lactams, nafcillin, sulfamethoxazolam, trimethoprim, sulfasalazine, acetylsulfisoxazole, and vancomycin, hi certain embodiments, the disease or disorder treated with these agents is a staphylococcal infection.

[0138] In certain embodiments, the at least one other therapeutically active agent is selected from a monoclonal antibody, a polyclonal anti-T cell antibody, an anti-thymocyte gamma globulin-horse antibody, an anti-thymocyte globulin-rabbit antibody, an anti-CD40 antagonist, a JAK inhibitor, and an anti-TCR mouse mAb.

[0139] In certain embodiments, the at least one other therapeutically active agent is selected from muromonab-CD3, ASKP-1240, ASP015K, and TOL 101. In certain embodiments, the disease or disorder treated by these agents is transplant rejection.

[0140] In certain embodiments, the at least one other therapeutically active agent is selected from a topical immunomodulator or calcineurin inhibitor, a topical corticosteroid, an oral corticosteroid, interferon gamma, an antihistamine, or an antibiotic. In certain embodiments, the 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.

[0141] Administration The phrases "parenteral administration" and "administered parenterally" as used herein refer to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0142] As used herein, the phrases "systemic administration," "systemically administered," "peripheral administration," and "administered peripherally" refer to administration of a compound, drug, or other substance other than directly into the central nervous system, e.g., subcutaneous administration, so that the compound, drug, or other substance enters the subject's system and is thus subjected to metabolism and other similar processes. These compounds may be administered to humans and other animals for treatment by any suitable route of administration, including orally, nasally, e.g., sprays, rectally, intravaginally, parenterally, intracisternally, and topically, by powders, ointments, or drops (including buccal and sublingual).

[0143] Regardless of the route of administration selected, the compounds of the present disclosure, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present disclosure, are formulated into pharma- ceutical acceptable dosage forms by conventional methods known to those of skill in the art.

[0144] Actual dosage levels of the active compounds in the pharmaceutical compositions of the present disclosure may be varied to obtain an amount of the active compound that is not toxic to the subject and is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration.

[0145] The dosage level selected will depend on a variety of factors, including the activity of the particular compound of the disclosure or its esters, salts, or amides being used, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being used, the duration of treatment, other drugs, compounds and / or substances being used in combination with the particular compound being used, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and similar factors well known in the medical arts. Daily, weekly or monthly dosages (or other time intervals) can be used.

[0146] A person skilled in the art can easily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start a 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.

[0147] In general, a suitable daily dose of a compound of the present disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect (e.g., inhibit necrosis). Such an effective dose will generally depend upon the factors described above.

[0148] In general, the dosage of the compounds of the present disclosure to a subject, when used for the indicated effects, ranges from about 0.0001 to about 100 mg / kg body weight / day. Preferably, the daily dosage ranges from 0.001 to 50 mg of compound per kg body weight, and even more preferably, from 0.01 to 10 mg of compound per kg body weight.

[0149] If desired, the effective daily dose of the active compound can be administered as 2, 3, 4, 5, 6 or more subdoses administered separately at appropriate intervals throughout the day, optionally in unit dosage form. In certain embodiments, the present disclosure relates to a compound for inhibiting cell death, wherein the compound is represented by structure (I). In certain embodiments, the compounds of the present disclosure are inhibitors of cell death. In any case, the compounds of the present disclosure preferably exert their effect on inhibiting cell death at a concentration of less than about 50 micromolar, more preferably less than about 10 micromolar, and most preferably less than 1 micromolar. The compounds of the present disclosure can be tested in standard animal models of stroke and standard protocols such as those described by Hara, H., et al. Proc. Natl. Acad. Sci. USA, 1997. 94(5):2007-12.

[0150] When the compounds of the present disclosure are administered to humans and animals as pharmaceuticals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active compound in combination with a pharma- ceutically acceptable carrier.

[0151] The compounds of the present application or compositions thereof may be administered once, twice, three or four times a day using any suitable mode as described above. Administration or treatment with the compound may also continue for several days, for example, treatment will generally continue for at least 7 days, 14 days or 28 days during one cycle of treatment. Treatment cycles are well known and frequently alternate with rest periods of about 1 to 28 days, generally about 7 days or about 14 days, between cycles. In certain embodiments, treatment cycles may be continuous.

[0152] When administered orally, the total daily dosage for a human subject can be 1 mg to 1,000 mg, about 1,000 to 2,000 mg / day, about 10 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 100 to 150 mg / day.

[0153] Daily dosage may also be described as the total amount of the compound of the present disclosure administered per dose or per day. The daily dosage 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 includes administering to the subject an initial daily dose of about 1 to 800 mg of the compound of the present disclosure, and increasing the dose in increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg may be used to increase the dose. The dosage may be increased daily, every other day, twice a week, or once a week.

[0154] In certain embodiments, the compound or pharmaceutical formulation is administered orally. In certain embodiments, the compound or pharmaceutical formulation is administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

[0155] The preparations of the present disclosure can be administered orally, parenterally, topically or rectally. They are naturally given in a form suitable for each administration route. For example, they are administered in the form of tablets or capsules, by injection, inhalation, eye drops, ointments, suppositories, etc., by injection, infusion or inhalation; topically by lotion or ointment; and rectally by suppositories. In certain embodiments, administration is oral. EXAMPLES

[0156] Abbreviation:

[0157] [Table 1]

[0158] [Table 2]

[0159] Silica gel chromatography Silica gel chromatography was performed using a CombiFlash® Rf (Teledyne ISCO), a Biotage Isolera One automated flash purification system or two Büchi systems equipped with pre-packed cartridges (a combination of C-660, C-605, C-620, C-635 and a combination of C-660, C-605, C-615, C-630).

[0160] Preparative reversed-phase HPLC For preparative reversed phase HPLC, an Agilent 1200 preparative HPLC system, a Gilson system (GX-271 liquid handler, 331 / 332 pumps, UV / VIS-155) or a Waters autopurification LC preparative system were used.

[0161] Preparative RP-LC Reversed phase liquid chromatography was performed using a Biotage instrument using a C18 column and a water (0.1% formic acid) / acetonitrile gradient.

[0162] NMR 400 MHz: NMR spectra were recorded on a Bruker AVANCE II 400 spectrometer operating at a proton frequency of 400.23 MHz. The instrument was equipped with a 5 mm BBI room temperature probehead. Alternatively, a Bruker AVANCE III HD 400 MHz or a Bruker AVANCE NEO 400 MHz was used.

[0163] 600 MHz: NMR spectra were recorded on a Bruker AVANCE III 600 spectrometer operating at a proton frequency of 600.05 MHz. The instrument was equipped with a 5 mm BBI room temperature probehead. Analytical LC / MS setup for Method A

[0164] Analytical LC / MS Instrument for Method A Retention time and mass detection was performed on a Waters Acquity UHPLC system coupled with a Waters SQD mass detector. The injection volume was 1.0 μl. Molecular weights are given in grams per mole [g / mol] and detected masses are given in mass / charge [m / z].

[0165] LC / MS equipment for analysis of methods B, C, and D For retention time and mass detection, an LC / MS system manufactured by Agilent (LC1200 series / MS6120 quadrupole LC / MS, LC1260 infinity / MS6120 quadrupole LC / MS or LC1260 Infinity II / MSD Infinity Lab) was used. Molecular weights are given in grams / mole [g / mol], and detected masses are given in mass / charge [m / z].

[0166] LC / MS-Method A Gradient: 98%H 2 HO (0.05% formic acid) / 2% acetonitrile (0.035% formic acid) for 0.2 min, then 98% HO 2 O (0.05% formic acid) to 98% acetonitrile (0.035% formic acid) for 3.6 min, then 98% acetonitrile (0.035% formic acid) for 0.5 min, flow rate: 1.0 ml / min, column: 2.1 × 50 mm Waters ACQUITY UPLC BEH C18, 1.7 μm, 55 °C. UV data: retention times ad λ = 220 nm (given in minutes) MS data: ES+ ionization, [M+H] unless otherwise stated + m / z given as

[0167] LC / MS-Method B Gradient: 93% H in 1.0 min 2 O(0.05% TFA) / 7% acetonitrile to 95% acetonitrile, then 95% acetonitrile in 0.45 min, flow rate: 1.1 ml / min, column: 2.0 x 10 mm Luna C18, 3 μm, 30°C, injection volume 0.2 μl UV data: retention times ad λ220nm given in minutes MS data: ES+ ionization, [M+H] unless otherwise stated + m / z given as

[0168] LC / MS-Method C Gradient: 95% H in 0.8 min 2 O (0.0375% TFA) / 5% acetonitrile (0.01875% TFA) to 5% H 2 O (0.0375% TFA) / 95% acetonitrile (0.01875% TFA), flow rate: 1.5 ml / min, column: Kinetex EVO C18 2.1 x 30 mm, 5 μm, 50 °C UV data: retention times ad λ220nm given in minutes MS data: ES+ ionization, [M+H] unless otherwise stated + m / z given as

[0169] LC / MS-Method D Gradient: 100% H in 0.8 min 2 O (0.0375% TFA) / 0% acetonitrile (0.01875% TFA) to 40% H 2 HO (0.0375% TFA) / 60% acetonitrile (0.01875% TFA), then 40% HO for 0.4 min 2 O (0.0375% TFA) / 60% acetonitrile (0.01875% TFA), flow rate: 1.5 ml / min, column: Kinetex EVO C18 2.1 x 30 mm, 5 μm, 50 °C UV data: retention times ad λ220nm given in minutes MS data: ES+ ionization, [M+H] unless otherwise stated + m / z given as

[0170] Analytical Chiral HPLC SFC: Shimadzu LC-30AD sf system LC: Agilent 1100 series system

[0171] salt For compounds described as HCl-, TFA-, or other salts, the exact amount of each salt is not usually determined, and therefore the amount of salt may range from as low as 0.01 equivalents to as high as 5.0 equivalents depending on the chemical structure (e.g., number of basic centers).

[0172] Chiral Purity If the enantiomeric ratio is greater than 90:10, the compound is removed and named as a single enantiomer. If the enantiomeric ratio is less than 90:10, the racemate is used.

[0173] Synthesis method: Synthesis of comparative compounds:

[0174] Comparative Example A (GSK WO 2018092089, Example 4): (3-phenyl-3,4-dihydropyrazol-2-yl)-[1-(4-phenylpyrimidin-2-yl)-4-piperidyl]methanone [ka] Step 1: tert-Butyl 4-(3-phenyl-3,4-dihydropyrazole-2-carbonyl)piperidine-1-carboxylate [ka] 5-phenyl-4,5-dihydro-1H-pyrazole (500 mg, 3.42 mmol, 1.0 equiv.), To a mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (862.58 mg, 0.74 ml, 3.76 mmol, 1.1 eq.) and HATU (1950.7 mg, 5.13 mmol, 1.5 eq.) in DMF (5 ml, 64.6 mmol), DIPEA (1105.1 mg, 1.49 ml, 8.5 mmol, 2.5 eq.) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure, diluted with ethyl acetate, and washed with 0.1 N aqueous HCl and water. The organic layer was extracted with Na 2SO 4 Dry at 40° C., filter, evaporate, and chromatograph on silica gel (40 g SiO 2 , eluent: heptane and ethyl acetate, gradient: 0% to 50% ethyl acetate, flow rate: 40 ml / min) to give the title compound (1.22 g, 94% yield). LC / MS: m / z = [M-56+H] + ;tR:0.89 min (LC / MS-Method B).

[0175] Step 2: (3-phenyl-3,4-dihydropyrazol-2-yl)-(4-piperidyl)methanone [ka] A solution of tert-butyl 4-(3-phenyl-3,4-dihydropyrazole-2-carbonyl)piperidine-1-carboxylate (1.145 g, 3.204 mmol, 1.0 equiv), DCM (25 mg, 0.2944 mmol, 0.1 equiv) and TFA (3.653 g, 2.47 ml, 32.04 mmol, 10.00 equiv) was stirred at room temperature for 24 h. The reaction mixture was diluted with toluene (10 ml) and evaporated. The crude product was diluted with water and acetonitrile and lyophilized. The crude material was purified by filtration with saturated NaHCO 3 The solution was diluted with DCM and extracted twice. The combined organic layers were washed with Na 2 SO 4 Drying at 40° C., filtering and evaporating afforded the title compound (824 mg, 76% yield). LC / MS: m / z = 258.1 [M+H] + ;tR:0.87 min (LC / MS-Method A). 1 H NMR (400.23MHz, DMSO-d 6):δppm 7.27(m,4H),7.10(m,2H),5.29(dd,J=11.92,4.58Hz,1H),3.48(m,1H),3.23(m,1H) ,3.10(m,1H),3.00(m,1H),2.69(m,2H),1.91(m,1H),1.81(m,1H),1.47-1.75(m,4H)

[0176] Step 3: (3-phenyl-3,4-dihydropyrazol-2-yl)-[1-(4-phenylpyrimidin-2-yl)-4-piperidyl]methanone [ka] To a solution of (3-phenyl-3,4-dihydropyrazol-2-yl)-(4-piperidyl)methanone (77.2 mg, 0.300 mmol, 1.00 equiv.) and 2-chloro-4-phenyl-pyrimidine (62.9 mg, 0.330 mmol, 1.10 equiv.) in acetonitrile (4 ml), DIPEA (96.9 mg, 0.131 ml, 0.750 mmol, 2.50 equiv.) was added. The reaction mixture was heated to 100° C. under microwave irradiation for 30 min. DIPEA (96.9 mg, 0.131 ml, 0.750 mmol, 2.50 equiv.) was added again and the reaction mixture was heated to 100° C. under microwave irradiation for 30 min. A catalytic amount of K 2 CO 3 After adding 1,2-dichlorophenyl ether (0.5 ml) and DMF (0.5 ml), the reaction mixture was heated to 100° C. for 30 min under microwave irradiation. The reaction mixture was filtered, washed with acetonitrile, and the filtrate was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Luna(r) 5 μm C18(2) 100 Å 100×30 mm, AXIAL; eluent: water and acetonitrile; gradient: 5% to 100% acetonitrile in 20 min, flow rate: 50 ml / min) to give the title compound (55 mg, 45% yield). LC / MS: m / z=412.2 [M+H] + ;tR:2.51 min(LC / MS-Method A). 1 H NMR (400.23MHz, DMSO-d 6):δ ppm 8.42(d,J=5.14Hz,1H),8.11(m,2H),7.51(m,3H),7.31(m,2H),7.18(m,5H),5.31(dd,J=11.86,4.65Hz,1H),4.80(br d,J=13.08Hz,2H),3.48(m,2H),3.05(m,2H),2.68(m,1H),1.92(br d,J=11.00Hz,1H),1.80(br d,J=11.49Hz,1H),1.51(m,2H)

[0177] Comparative Example B (Isoxazolidine of Comparative Example A): [(3S)-3-Phenylisoxazolidin-2-yl]-[1-(4-phenylpyrimidin-2-yl)-4-piperidyl]methanone [ka] Step 1: tert-Butyl 4-[(3S)-3-phenylisoxazolidine-2-carbonyl]piperidine-1-carboxylate [ka] To a mixture of (S)-3-phenylisoxazolidine (500 mg, 3.35 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (922 mg, 4.02 mmol) and HATU (1.91 g, 5.03 mmol) in DMF (10 ml) was added DIPEA (1.46 ml, 8.38 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with half-saturated NH 4 The mixture was diluted with Cl solution and ethyl acetate, and the organic layer was washed with water and Na 2 SO 4 Dry at 40° C., filter, evaporate, and chromatograph on silica gel (40 g SiO 2 , eluent: DCM and DCM / methanol=9 / 1, gradient: 0% to 50% DCM / methanol=9 / 1, flow rate: 40 ml / min) to give the title compound (920 mg, yield 76%). LC / MS: m / z=381.3 [M+H] + ;tR:2.28 min(LC / MS-Method A).

[0178] Step 2: [(3S)-3-Phenylisoxazolidin-2-yl]-(4-piperidyl)methanone [ka] tert-Butyl 4-[(3S)-3-phenylisoxazolidine-2-carbonyl]piperidine-1-carboxylate A solution of (920 mg, 2.55 mmol), DCM (20 ml) and TFA (2.9 g, 1.96 ml, 25.47 mmol) was stirred at room temperature for 16 h. The reaction mixture was diluted with toluene (5 ml), evaporated and lyophilized twice to give the title compound (850 mg, 84% yield). LC / MS: m / z=261.2 [M+H] + ;tR:0.90 min(LC / MS-Method A). 1 H NMR (400.23MHz, DMSO-d 6 ):δ ppm 8.50(br s,1H),8.24(br s,1H),7.34(m,2H),7.27(m,3H),5.31(m,1H),4.27(td,J=7.64,7.64,3.06Hz, 1H),3.91(m,1H),3.25(m,1H),2.93(m,3H),2.55(m,1H),2.20(m,1H),1.98(br t,J=9.66,9.66Hz,2H),1.80(br s,1H),1.71(m,2H)

[0179] Step 3: [(3S)-3-Phenylisoxazolidin-2-yl]-[1-(4-phenylpyrimidin-2-yl)-4-piperidyl]methanone [ka] To a solution of [(3S)-3-phenylisoxazolidin-2-yl]-(4-piperidyl)methanone trifluoroacetate (116 mg, 0.300 mmol, 1.00 equiv.) and 2-chloro-4-phenyl-pyrimidine (62.9 mg, 0.330 mmol, 1.10 equiv.) in acetonitrile (4 ml), DIPEA (136 mg, 0.183 ml, 1.05 mmol, 3.50 equiv.) was added and heated to 100° C. under microwave irradiation for 30 min. DIPEA (96.9 mg, 0.131 ml, 0.750 mmol, 2.50 equiv.) was added again and the reaction mixture was heated to 100° C. under microwave irradiation for 30 min. A catalytic amount of K 2 CO 3 After adding 1,2-dichlorophenyl ether (0.5 ml) and DMF (0.5 ml), the reaction mixture was heated to 100° C. for 30 min under microwave irradiation. The reaction mixture was filtered, washed with acetonitrile, and the filtrate was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Luna(r) 5 μm C18(2) 100 Å 100×30 mm, AXIAL; eluent: water and acetonitrile; gradient: 5% to 100% acetonitrile in 20 min, flow rate: 50 ml / min) to give the title compound (73 mg, 59% yield). LC / MS: m / z=415.2 [M+H] + ;tR:2.58 min(LC / MS-Method A). 1 H NMR (400.23MHz, DMSO-d 6 ):δ ppm 8.43(d,J=5.14Hz,1H),8.12(m,2H),7.51(m,3H),7.30(m,5H),7.18(d,J=5.14Hz,1H),5.33(br t,J=7.46,7.46Hz,1H),4.78(br dd,J=8.99,3.97Hz,2H),4.29(td,J=7.73,7.73,3.00Hz,1H),3.92(m,1H),3.08(br t,J=11.43,11.43Hz,3H),2.89(m,1H),2.20(m,1H),1.94(br d,J=11.49Hz,1H),1.75(br s,1H),1.53(m,2H)

[0180] Comparative Example C (GSK WO 2018092089, Example 129): [1-[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]-4-piperidyl]-[(3S)-3-phenyl-3,4-dihydropyrazol-2-yl]methanone [ka] Process 1 N'-Acetyl-6-chloro-pyrimidine-4-carbohydrazide [ka] To a solution of 6-chloropyrimidine-4-carboxylic acid (500 mg, 3.00 mmol, 1.00 equiv) in THF (30 ml) was added DMF (4.38 mg, 4.6 μl, 59.9 μmol, 0.02 equiv) under argon atmosphere and the reaction mixture was cooled to 0° C. Oxalyl chloride (2M in DCM) (2.25 ml, 4.49 mmol, 1.5 equiv) was added dropwise. The reaction was then allowed to warm to room temperature and stirred for 1 h. The mixture was evaporated under reduced pressure and the residue was dissolved in 1,4-dioxane (30 ml) and cooled to 0° C. Acetydrazide (444 mg, 5.99 mmol, 2.00 equiv) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was evaporated under reduced pressure and used in the next step without purification.

[0181] Step 2: 2-(6-chloropyrimidin-4-yl)-5-methyl-1,3,4-oxadiazole [ka] A solution of N'-acetyl-6-chloro-pyrimidine-4-carbohydrazide (step 1, crude) in acetonitrile (30 ml) was cooled to 0°C and DIPEA (774 mg, 1.04 ml, 5.99 mmol, 2.0 equiv) was added dropwise. p-Toluenesulfonyl chloride (1.713 g, 8.99 mmol, 3.0 equiv) was added and the reaction mixture was allowed to warm to room temperature and stirred for 20 min. The reaction mixture was evaporated under reduced pressure and purified by silica gel chromatography (80 g SiO 2 , eluent: n-heptane and ethyl acetate, gradient: 0% to 100% ethyl acetate, flow rate: 60 ml / min) to give the title compound (83 mg, 14% yield for both steps). The unreacted reagent N'-acetyl-6-chloro-pyrimidine-4-carbohydrazide (355 mg, 55% yield) was isolated. The reisolated reagent was converted to the title compound above to give 254 mg (79% yield). LC / MS: m / z=197 [M+H] + ;tR:0.99 min(LC / MS-Method A). 1 H NMR (400.23MHz, DMSO-d 6 ):δ ppm 9.26(d,J=0.98Hz,1H),8.33(d, J=0.98Hz,1H),2.66(s,3H)

[0182] Process 3 [1-[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]-4-piperidyl]-[(3S)-3-phenyl-3,4-dihydropyrazol-2-yl]methanone [ka] To a mixture of (3-phenyl-3,4-dihydropyrazol-2-yl)-(4-piperidyl)methanone (Comparative Example A, Step 2, 154.4 mg, 0.600 mmol, 1.00 equiv) and 2-(6-chloropyrimidin-4-yl)-5-methyl-1,3,4-oxadiazole (123.85 mg, 0.63 mmol, 1.05 equiv) in acetonitrile (20 ml) was added DIPEA (193.86 mg, 0.261 ml, 1.5 mmol, 2.5 equiv). The reaction mixture was heated to 100° C. under microwave irradiation for 30 min, evaporated under reduced pressure and purified by preparative HPLC (column: Luna(r) 5 μm C18(2) 100 Å 100×30 mm, AXIAL; eluent: water and acetonitrile; gradient: 10% to 100% acetonitrile in 12 min, flow rate: 50 ml / min) to give the racemic title compound (153 mg, 61% yield). The isomers were purified by chiral HPLC (column: Chiralpak IB / 83, 250×4.6 mm; eluent: heptane:EtOH:MeOH 2:1:1; isocratic gradient) to give the title compound (67 mg, 27% yield). LC / MS: m / z=418.2 [M+H] + ;tR:1.68 min(LC / MS-Method A). 1 H NMR (400.23MHz, DMSO-d 6 ):δ ppm 8.61(d,J=0.98Hz,1H),7.42(d, J=0.98Hz,1H),7.27(m,4H),7.11(d,J=7.49Hz,2H),5.31(dd,J=11.86,4.65Hz,1H),4.49(br s,2H),3.48(m,2H),3.13(m,2H),2.68(m,1H),2.60(s,3H),1.94(br d,J=11.62Hz,1H),1.82(br d,J=10.88Hz,1H),1.51(m,2H)

[0183] Comparative Example D (Isoxazolidine of Comparative Example C): [1-[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]-4-piperidyl]-[(3S)-3-phenylisoxazolidin-2-yl]methanone [ka] To a solution of [(3S)-3-phenylisoxazolidin-2-yl]-(4-piperidyl)methanone trifluoroacetate (Comparative Example B, Step 2, 116 mg, 0.300 mmol, 1.00 equiv) and 2-(6-chloropyrimidin-4-yl)-5-methyl-1,3,4-oxadiazole (61.9 mg, 0.315 mmol, 1.05 equiv) in acetonitrile (10 ml) was added DIPEA (136 mg, 0.183 ml, 1.05 mmol, 3.50 equiv). The reaction mixture was heated to 100 °C under microwave irradiation for 30 min and purified by preparative HPLC (column: Luna(r) 5 μm C18(2) 100 Å 100 × 30 mm, AXIAL; eluent: water and acetonitrile; gradient: 10% to 100% acetonitrile in 12 min, flow rate: 50 ml / min) to give the title compound (89 mg, 71% yield). LC / MS: m / z=421.2 [M+H] + ;tR:1.75 min(LC / MS-Method A). 1 H NMR (400.23MHz, DMSO-d 6 ):δ ppm 8.62(s,1H),7.43(s,1H),7.30(m,5H),5.33(m,1H),4.47(br s,2H),4.28(m,1H),3.92(m,1H),3.19(br s,1H),3.14(m,2H),2.89(m,1H),2.61(s,3H),2.20(m,1H),1.96(br d,J=12.96Hz,1H),1.77(br s,1H),1.54(m,2H)

[0184] Comparative Example E (Substituted Phenyl-isoxazolidine of Comparative Example C): 3-Fluoro-5-[(3S)-2-[1-[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile [ka] Comparative Example E was synthesized similarly to Comparative Example D using 3-fluoro-5-[(3S)-2-(piperidine-4-carbonyl)isoxazolidin-3-yl]benzonitrile (synthesized from Intermediate-1 as described for Comparative Example B) instead of [(3S)-3-phenylisoxazolidin-2-yl]-(4-piperidyl)methanone as the coupling reagent and HBTU instead of HATU to give 14.8 mg (31.9 μmol, 32% yield). LC / MS: m / z=464.3 [M+H] + ;tR:1.77 min(LC / MS-Method A). 1 H NMR (400.23MHz, DMSO-d 6 ):δ ppm 8.62(d,J=0.86Hz,1H),7.77(d,J=8.62Hz,1H),7.62(s,1H),7.49(br d,J=9.66Hz,1H),7.43(s,1H),5.40(m,1H),4.46(m,2H),4.30(td,J=7.70,7.70,2. 93Hz,1H),3.95(m,1H),3.14(m,3H),2.91(m,1H),2.61(s,3H),2.27(m,1H),1.99(br d,J=11.62Hz,1H),1.80(br d,J=11.62Hz,1H),1.54(m,2H),1.24(s,1H)

[0185] Synthesis of intermediates: Intermediate-01 3-Fluoro-5-[(3S)-isoxazolidin-3-yl]benzonitrile [ka] Process 1 3-Fluoro-5-[(E)-3-oxoprop-1-enyl]benzonitrile [ka] To a solution of 3-fluoro-5-formyl-benzonitrile (90 g, 603.53 mmol, 1 equiv.) in THF (900 ml) was added 2-(triphenyllambda-5-phosphanylidene)acetaldehyde (183.67 g, 603.53 mmol, 1 equiv.). The mixture was stirred at 70° C. for 12 h and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=1:0 to 3:1) to give the title compound (72 g, 68% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ):δ ppm 9.76(d,J=7.3Hz,1H),7.67-7.63(m,1H),7.52(td,J=1.8,9.0Hz,1H),7.46-7.39(m,2H),6.74(dd,J=7.4,16.1Hz,1H)

[0186] Process 2 tert-Butyl (3S)-3-(3-cyano-5-fluoro-phenyl)-5-hydroxy-isoxazolidine-2-carboxylate [ka] [Diphenyl-[(2S)-pyrrolidin-2-yl]methoxy]-trimethyl-silane (26.02 g, 79.93 mmol, 0.2 equiv.) in CHCl 3To the solution in (300 ml) was added 3-fluoro-5-[(E)-3-oxoprop-1-enyl]benzonitrile (70 g, 399.64 mmol, 1 equiv.) at 0° C., the mixture was stirred at 0° C. for 0.5 h, and tert-butyl N-hydroxycarbamate (58.53 g, 439.60 mmol, 1.1 equiv.) was added. The mixture was smoothly warmed to 20° C. and stirred for 12 h. The residue was purified by preparative reverse phase HPLC (column: Phenomenex luna C18, 15 μm, 100 Å, ID 150×H 400 mm, eluent: water (0.1% formic acid) and acetonitrile, gradient: 60% to 47% acetonitrile in 53 min and 47% acetonitrile in 32 min, flow rate: 600 ml / min) to give the title compound (77.5 g, 63% yield) as a yellow solid. LC / MS: m / z=191.1 [M-100-18+H] + ;tR:0.900 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3 ):δppm 7.46(s,1H),7.34(td,J=1.7,9.2Hz,1H),7.31-7.28(m,1H),5.90(d,J=4.4Hz,1H),5.34(t,J= 8.3Hz,1H),2.83(dd,J=8.5,12.5Hz,1H),2.21(ddd,J=4.4,8.1,12.5Hz,1H),1.51-1.41(m,9H)

[0187] Process 3 tert-Butyl N-[(1S)-1-(3-cyano-5-fluoro-phenyl)-3-hydroxy-propyl]-N-hydroxycarbamate [ka] To a solution of tert-butyl (3S)-3-(3-cyano-5-fluoro-phenyl)-5-hydroxy-isoxazolidine-2-carboxylate (77.5 g, 251.38 mmol, 1 equiv.) in MeOH (750 ml) was added NaBH 4 (10.46 g, 276.51 mmol, 1.1 equiv.) was added at 0° C. The mixture was diluted with N2 The mixture was stirred at 0° C. for 3 h under reduced pressure. 4 Quench with Cl solution (100 ml), dilute with water (800 ml), extract with ethyl acetate (1 L x 3), and add Na 2 SO 4 The residue was purified by preparative reverse phase HPLC (column: Phenomenex luna C18, 15μm, 100Å, ID150×H400mm, eluent: water (0.1% formic acid) and acetonitrile, gradient: 70%-50% acetonitrile in 50min, 50% acetonitrile in 26min, flow rate: 400ml / min) and silica gel column chromatography (petroleum ether / ethyl acetate=1:0-1:1) to obtain the title compound (59.5g) as a red-brown solid, which was triturated with petroleum ether / ethyl acetate (4:1, 500ml) to obtain the title compound (41g filter cake as a white solid and 18g filtrate as a red solid). LC / MS: m / z=211.1 [M-100+H] + ;tR:0.850 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3 ):δppm 7.52(s,1H),7.43(td,J=1.9,9.3Hz,1H),7.30-7.27(m,1H),5.25(dd,J=5.0,10 .8Hz,1H),3.93-3.73(m,2H),2.45-2.33(m,1H),2.05-1.97(m,1H),1.46(s,9H)

[0188] Process 4 tert-Butyl (3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carboxylate [ka] To a solution of tert-butyl N-[(1S)-1-(3-cyano-5-fluoro-phenyl)-3-hydroxy-propyl]-N-hydroxycarbamate (41 g, 132.12 mmol, 1 equiv.) in THF (410 ml) was added tributylphosphane (42.77 g, 211.39 mmol, 52.16 ml, 1.6 equiv.) and DIAD (34.73 g, 171.76 mmol, 33.40 ml, 1.3 equiv.) at 0° C. The mixture was allowed to warm smoothly to 20° C. and N 2 The mixture was stirred under atmospheric pressure for 12 hours. The residue was purified by preparative reversed-phase HPLC (column: Phenomenex luna C18, 15 μm, 100 Å, ID 150 × H 400 mm, eluent: water (0.1% formic acid) and acetonitrile, gradient: 70% to 50% acetonitrile in 50 min, 50% acetonitrile in 26 min, flow rate: 400 ml / min) and triturated with petroleum ether / ethyl acetate (10:1, 500 mL) to give the title compound (filter cake 29.6 g, yield 77%, >99.9% ee) as a white solid. LC / MS: m / z=193.2 [M-100+H] + ;tR:0.901 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3 ):δppm 7.47(s,1H),7.36(td,J=1.8,9.3Hz,1H),7.27-7.24(m,1H),5.25(dd,J=5.6,8.9Hz,1H),4.20(dt,J=3.2,8.0Hz,1H ),3.95-3.83(m,1H),2.85(dddd,J=3.3,7.0,8.9,12.3Hz,1H),2.24(dddd,J=5.6,7.8,9.2,12.3Hz,1H),1.50(s,9H) SFC (column: Chiralcel AD-3 50 × 4.6 mm I.D., 3 μm, gradient: CO 2 In 5%-40% MeOH (0.05% DEA), flow rate: 3 ml / min, column temperature: 35 °C, 100 bar: tR = 0.97 min (100%); tR (R-enantiomer) = 0.72 min (0%)

[0189] Process 5 3-Fluoro-5-[(3S)-isoxazolidin-3-yl]benzonitrile [ka] To a solution of tert-butyl (3S)-3-(3-cyano-5-fluoro-phenyl)isoxazolidine-2-carboxylate (5.00 g, 17.11 mmol) in DCM (100 ml) was added TFA (14.8 g, 10.0 ml, 129.8 mmol). After 16 h at room temperature, toluene (10 ml) was added and the reaction mixture was evaporated and washed with saturated NaHCO 3 The solution was stirred for 10 min. The aqueous phase was extracted twice with ethyl acetate. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered, evaporated and purified by silica gel chromatography (column: 220 g SiO 2 , eluent: n-heptane and ethyl acetate, gradient: 0% to 100% ethyl acetate in 23 min) to give the title compound (2.64 g, 13.7 mmol, 84% yield). LC / MS: m / z=193.1 [M+H] + ;tR:1.19 min (LC / MS method A). 1 H NMR (400.23MHz, DMSO-d 6 ):δ ppm 7.71(m,1H),7.68(s,1H),7.58(br d,J=10.03Hz,1H),6.62(br s,1H),4.53(br s,1H),3.92(m,1H),3.66(m,1H),2.63(m,1H),2.11(m,1H).

[0190] Intermediate 02a (3S)-3-(3,5-difluorophenyl)isoxazolidine [ka] Process 1 tert-Butyl (3S)-3-(3,5-difluorophenyl)isoxazolidine-2-carboxylate [ka] The title compound was synthesized similarly to Intermediate-01 steps 1-4 using 3,5-di-fluoro-benzaldehyde as starting material to give 17 g (59.6 mmol, 79% yield) of the title compound. LC / MS: m / z=230.1 [M-56+H] + ;tR:0.936 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3 ):δppm 6.90(dd,J=1.9,8.0Hz,2H),6.70(tt,J=2.3,8.9Hz,1H),5.19(dd,J=5.5,8.8Hz,1H),4.18( dt,J=3.6,7.9Hz,1H),3.94-3.82(m,1H),2.85-2.73(m,1H),2.33-2.19(m,1H),1.49(s,9H) SFC (column: Chiralcel AD-3 50 × 4.6 mm I.D., 3 μm, gradient: CO 2 Medium 5%~40%MeOH (0.05%DEA), flow rate: 3ml / min, column temperature: 35℃, 100bar): tR=0.66min (100%)

[0191] Process 2 (3S)-3-(3,5-difluorophenyl)isoxazolidine [ka] To a solution of tert-butyl (3S)-3-(3,5-difluorophenyl)isoxazolidine-2-carboxylate (5.00 g, 17.53 mmol, 1.0 equiv.) in DCM (100 ml) was added TFA (19.64 g, 15.7 ml, 175.30 mmol, 10.0 equiv.). After 16 h at room temperature, toluene (10 ml) was added and the reaction mixture was evaporated and washed with saturated NaHCO 3 The solution was stirred for 10 min. The aqueous phase was extracted twice with DCM and the organic layer was washed with Na 2 SO 4Drying at 40° C., filtration and evaporation gave the title compound (3.24 g, 17.50 mmol, quant.). LC / MS: m / z=186.0 [M+H] + ;tR:1.32 min (LC / MS method A). 1 H NMR (400.23MHz, DMSO-d 6 ):δ ppm 7.07(m,3H),6.54(br s,1H),4.45(br s,1H),3.90(m,1H),3.66(m,1H),2.61(m,1H),2.08(m,1H)

[0192] Intermediate 02b (3S)-3-(3-chloro-5-fluorophenyl)isoxazolidine [ka] The title compound was synthesized using the method described for Intermediate-02a and 3-chloro-5-fluoro-benzaldehyde to give a mixture of enantiomers, which was purified by SFC (column: REGIS(s,s)WHELK-O1, 250×50 mm, 10 μm, eluent: CO 2 Medium 15%EtOH(0.1%NH 3 H 2 O), a single batch cycle process using a 3.8 min delay time between two successive injections, total duration of 120 min) to afford the title compound (3.9 g, 86% yield) as a yellow oil and 78 mg (1.6% yield) of the R-enantiomer as a yellow oil. LC / MS: m / z=246.3 [M-56+H] + ,tR:0.900 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3):δ ppm 7.16(s,1H),6.95-7.03(m,2H),5.18(dd,J=5.6,8.7Hz,1H),4.18(dt,J=3.5,8.0Hz,1H),3.87( dt,J=7.2,8.6Hz,1H),2.79(dddd,J=3.5,7.0,8.8,12.3Hz,1H),2.19-2.30(m,1H),1.49(s,9H) SFC(カラム:Kromasil(S,S)Whelk-O1 50×4.6mmI.D., 3.5μm, blend:CO 2 5%~40% EtOH (0.05% DEA), flow rate: 3ml / min, temperature: 35℃, 100bar): tR=1.069min (100%)

[0193] R-エナンチオマー: LC / MS m / z 246.3 [M-56+H] + ,tR:0.890 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3 ):δ ppm 7.16(s,1H),6.96-7.03(m,2H),5.18(dd,J=5.6,8.8Hz,1H),4.18(dt,J=3.6,7 .9Hz,1H),3.83-3.92(m,1H),2.74-2.84(m,1H),2.20-2.31(m,1H),1.49(s,9H) SFC(カラム:Kromasil(S,S)Whelk-O1 50×4.6mmI.D., 3.5μm, blend:CO 2 5%~40% EtOH (0.05% DEA), flow rate: 3ml / min, temperature: 35℃, 100bar): tR=0.890min (100%)

[0194] Intermediate-03 3-フルオロ-5-[(3S)-イソオキサゾリジン-3-イル]-2-メチル-ベンゾニトリル

change

[0195] Process 2 5-Bromo-3-fluoro-2-methyl-benzonitrile [ka] A solution of 5-bromo-3-fluoro-2-methyl-benzaldehyde (9.5 g, 43.77 mmol, 1 equiv.) in EtOH (95 ml) was added with TBHP (5 M in decane, 9.63 ml, 1.1 equiv.), I 2 (277.74mg, 1.09mmol, 0.025eq), NH 4 OAc (5.06 g, 65.66 mmol, 1.5 equiv.) and Na 2 CO 3(4.64 g, 43.77 mmol, 1 equiv.) was added and the mixture was then stirred at 50° C. for 12 h. The reaction mixture was diluted with saturated Na 2 SO 3 The mixture was quenched with ethyl acetate (20 ml), diluted with water (100 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine (200 ml) and diluted with Na 2 SO 4 The extract was dried at 40° C., filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate=1:0 to 10:1) to give the title compound (8 g, 85% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ):δ ppm 7.59-7.55(m,1H),7.44(dd,J=1.9,8.6Hz,1H),2.44(d,J=2.1Hz,3H)

[0196] Process 3 5-[(E)-3,3-diethoxyprop-1-enyl]-3-fluoro-2-methyl-benzonitrile [ka] 5-Bromo-3-fluoro-2-methyl-benzonitrile (10.1 g, 47.19 mmol, 1 equiv.), 3,3-diethoxyprop-1-ene (18.43 g, 141.57 mmol, 21.58 ml, 3 equiv.), Pd(t-Bu 3 P) 2 A mixture of (1.21 g, 2.36 mmol, 0.05 equiv.) and triethylamine (14.32 g, 141.57 mmol, 19.70 ml, 3 equiv.) in DMF (100 ml) was diluted with N 2 The mixture was stirred at 80° C. under atmospheric pressure for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×3). The combined organic layer was washed with brine (100 ml×3) and diluted with Na 2 SO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave the title compound (13 g, crude).

[0197] Step 4: 3-Fluoro-2-methyl-5-[(E)-3-oxoprop-1-enyl]benzonitrile [ka] A mixture of 5-[(E)-3,3-diethoxyprop-1-enyl]-3-fluoro-2-methyl-benzonitrile (13 g, crude) in HCl (1 M, 94.38 ml, 2 eq.) and acetone (80 ml) was stirred at 25° C. for 0.5 h. The mixture was diluted with saturated NaHCO 3 The pH was adjusted to 7-8 with ethyl acetate (100 ml x 3), and the mixture was extracted with ethyl acetate (100 ml x 3). The combined organic layer was washed with brine (100 ml) and then diluted with Na 2 SO 4 The extract was dried at 40° C., filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate=1:0 to 3:1) to give the title compound (5.5 g, 62% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ ppm 9.74(d,J=7.5Hz,1H),7.60(s,1H),7.46(dd,J=1.5,9.7Hz,1H),7.38(d,J=16.0Hz,1H),6.70(dd,J=7.4,16.1Hz,1H),2.53(d,J=2.1Hz,3H)

[0198] Step 5: tert-Butyl (3S)-3-(3-cyano-5-fluoro-4-methyl-phenyl)-5-hydroxy-isoxazolidine-2-carboxylate [ka] [Diphenyl-[(2S)-pyrrolidin-2-yl]methoxy]-trimethyl-silane (1.82 g, 5.60 mmol, 0.2 equiv.) in CHCl 3To a solution in (53 ml) was added 3-fluoro-2-methyl-5-[(E)-3-oxoprop-1-enyl]benzonitrile (5.3 g, 28.01 mmol, 1 equiv) at 0° C., the mixture was stirred at 0° C. for 30 min, and tert-butyl N-hydroxycarbamate (4.48 g, 33.62 mmol, 1.2 equiv) was added at 0° C. The mixture was allowed to warm smoothly to 20° C. and stirred for 12 h. The reaction mixture was concentrated under reduced pressure and purified by preparative reverse phase HPLC (column: Welch Ultimate XB_C18, 20-40 μm; 120 Å, ID 95×H 365 mm, eluent: water (0.1% formic acid) and acetonitrile, gradient: 20%-50% acetonitrile in 30 min and 50% acetonitrile in 20 min, flow rate: 200 ml / min) to give the title compound (5.8 g, 64% yield) as a yellow solid. LC / MS: m / z=205.2 [M-100-18+H] + ;tR:0.896 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3 ):δppm 7.40(s,1H),7.27(s,1H),5.86(d,J=4.3Hz,1H),5.28(t,J=8.2Hz,1H),2.80(dd,J=8.5, 12.5Hz,1H),2.46(d,J=2.0Hz,3H),2.19(ddd,J=4.3,8.1,12.5Hz,1H),1.51-1.42(m,9H)

[0199] Process 6 tert-Butyl N-[(1S)-1-(3-cyano-5-fluoro-4-methyl-phenyl)-3-hydroxypropyl]-N-hydroxycarbamate [ka] To a solution of tert-butyl (3S)-3-(3-cyano-5-fluoro-4-methyl-phenyl)-5-hydroxy-isoxazolidine-2-carboxylate (4.8 g, 14.89 mmol, 1 equiv.) in MeOH (48 ml), NaBH 4 (619.68 mg, 16.38 mmol, 1.1 equiv) was added at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH 4 The mixture was quenched with Cl solution (20 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine (200 ml) and diluted with Na 2 SO 4 The residue was dried at 40° C., filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate=1:0 to 0:1) to give the title compound (3.6 g, 73% yield) as a white solid, which was triturated with petroleum ether / ethyl acetate (3:1, 50 ml) to give 2.7 g of filter cake as a white solid and 1.1 g of filtrate as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ):δ ppm 7.46(s,1H),7.40-7.33(m,1H),6.75(br s,1H),5.22(dd,J=5.1,10.8Hz,1H),3.93-3.73(m,2H),2.46(d,J=2.0Hz,3H),2.37(dddd,J=3.4,7.5,10.9,14.6Hz,1H),2.12(br s,1H),1.48(s,9H)

[0200] Process 7 tert-Butyl (3S)-3-(3-cyano-5-fluoro-4-methyl-phenyl)isoxazolidine-2-carboxylate [ka] To a solution of tert-butyl N-[(1S)-1-(3-cyano-5-fluoro-4-methyl-phenyl)-3-hydroxy-propyl]-N-hydroxycarbamate (2.7 g, 8.32 mmol, 1 equiv.) in THF (27 ml), was added n-Bu 3P (2.69 g, 13.32 mmol, 3.29 ml, 1.6 equiv) and DIAD (2.19 g, 10.82 mmol, 2.10 ml, 1.3 equiv) were added at 0° C. The mixture was allowed to warm smoothly to 25° C. and N 2 The mixture was stirred under ambient atmosphere for 12 hours. The reaction was concentrated under reduced pressure and purified by preparative reversed-phase HPLC (column: Welch Ultimate XB_C18 20-40 μm; 120 Å, ID 75×H 348 mm, eluent: water (0.1% formic acid) and acetonitrile, gradient: 10%-65% acetonitrile in 28 min, 65% acetonitrile in 5 min, flow rate: 200 ml / min) and silica gel column chromatography (petroleum ether / ethyl acetate=1:0-0:1) to give the title compound (2 g, 78% yield, 94.1% ee) as a white solid. The product was purified by SFC (column: DAICEL CHIRALPAK AD, 250×30 mm, 10 μm; mobile phase: CO 2 In 25% methanol (0.1% NH 3 H 2 O), a single batch cycle process with a 3.0 min delay between two successive injections, total duration of 75 min) to afford the title compound (1.7 g, 85% yield, >99.9% ee) as an off-white solid. LC / MS: m / z=251.1 [M-56+H] + ;tR:0.949 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3 ):δppm 7.41(s,1H),7.29(dd,J=1.4,10.0Hz,1H),5.20(dd,J=5.6,8.8Hz,1H),4.18(dt,J=3.4,8.0Hz,1H),3.88(dt,J=7.2,8.7Hz ,1H),2.81(dddd,J=3.4,7.0,8.8,12.3Hz,1H),2.45(d,J=2.0Hz,3H),2.23(dddd,J=5.5,7.8,9.1,12.3Hz,1H),1.49(s,9H) SFC (column: Chiralcel AD-3 50 × 4.6 mm I.D., 3 μm, gradient: CO 2In 5%-40% MeOH (0.05% DEA), flow rate: 3 ml / min, column temperature: 35°C, 100 bar: tR = 1.22 min (100%); tR (R-enantiomer) = 0.86 min (0%)

[0201] Process 8 3-Fluoro-5-[(3S)-isoxazolidin-3-yl]-2-methyl-benzonitrile [ka] To a solution of tert-butyl (3S)-3-(3-cyano-5-fluoro-4-methyl-phenyl)isoxazolidine-2-carboxylate (1.36 g, 4.44 mmol, 1.0 equiv.) in DCM (40 ml) was added TFA (4.975 g, 3.974 ml, 44.40 mmol, 10.0 equiv.). After 16 h at room temperature, toluene (5 ml) was added and the reaction mixture was evaporated and washed with saturated NaHCO 3 The solution was stirred for 10 minutes. The aqueous phase was extracted with DCM (10 ml x 2), and the organic layer was washed with Na 2 SO 4 Drying at rt, filtration and evaporation gave the title compound (860 mg, 4.17 mmol, 94% yield). 1 H NMR (400.23MHz, DMSO-d 6 ):δ ppm 7.62(s,1H),7.52(br d,J=10.64Hz,1H),6.55(br s,1H),4.47(br s,1H),3.90(td,J=7.95,7.95,5.14Hz,1H),3.67(br s,1H),2.60(m,1H),2.36(d,J=1.83Hz,3H),2.09(m,1H)

[0202] Intermediate-04 Methyl 1-(6-chloropyrimidin-4-yl)piperidine-4-carboxylate [ka] A mixture of 4,6-dichloropyrimidine (80 g, 536.99 mmol, 1 equiv.), methyl piperidine-4-carboxylate (96.47 g, 536.99 mmol, 1 equiv., HCl), and DIEA (208.21 g, 1.61 mol, 280.60 ml, 3 equiv.) in n-BuOH (700 ml) was degassed and diluted with N 2 The mixture was then purged with N 2 The mixture was stirred at 80° C. under atmospheric pressure for 2 hours. The reaction mixture was concentrated under reduced pressure to remove n-BuOH. Then, H 2 The mixture was diluted with 200 mL of 1H2O (100 ml) and EA (200 ml), adjusted to pH 6 with 1N HCl solution, and extracted with ethyl acetate (200 ml x 3). The combined organic layers were diluted with NaHCO 3 Wash with aqueous solution (500 ml) and brine (500 ml) and add Na 2 SO 4 Drying at 40° C., filtering and concentrating afforded the title compound (crude 135.4 g, 529.53 mmol, 97% yield) as a yellow solid. LC / MS: m / z=256.1 [M+H] + ;tR:0.737 min(LC / MS method C). 1 H NMR (400MHz, DMSO-d 6 ):δppm 8.32(s,1H),6.97(s,1H),4.38-4.19(m,2H),3.62(s,3H),3.16-3.02(m ,2H),2.71(tt,J=4.0,10.8Hz,1H),1.96-1.84(m,2H),1.60-1.44(m,2H)

[0203] Intermediate-05 1-[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylic acid [ka] Process 1 Methyl 1-[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylate [ka] Intermediate-04 (3.97 g, 15.53 mmol, 1 equiv.), 2-methyl-1H-imidazole (2.55 g, 31.05 mmol, 2 equiv.), K 2 CO 3 A mixture of (8.58 g, 62.10 mmol, 4 equiv.) and CuI (1.48 g, 7.76 mmol, 0.5 equiv.) in DMSO (40 ml) was degassed and diluted with N 2 The mixture was purged with N 2 The mixture was stirred at 120° C. under atmospheric pressure for 12 hours. The reaction mixture was filtered, diluted with water (400 ml) and extracted with ethyl acetate (200 ml×3). The combined organic layer was washed with brine (300 ml) and diluted with Na 2 SO 4 It was dried at rt, filtered, concentrated and purified by flash silica gel chromatography (eluent: petroleum ether and ethyl acetate, gradient: 35% to 70% ethyl acetate and eluent: MeOH and DCM, gradient, 5% to 15% MeOH) to give the title compound (2.3 g, 7.63 mmol, 49% yield) as a yellow oil. LC / MS: m / z=302.1 [M+H] + ;tR:0.615 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3 ):δ ppm 8.54(s,1H),7.30(s,1H),7.04(s,1H),6.41(s,1H),4.32(br d,J=13.1Hz,2H),3.73(s,3H),3.18(ddd,J=3.0,11.0,13.7Hz,2H),2.67(s,3H),2.08-2.03(m,2H),1.84-1.74(m,3H)

[0204] Process 2 1-[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylic acid [ka] A solution of methyl 1-[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylate (4.46 g, 14.80 mmol, 1 equiv.) in THF (50 ml) was added with LiOH H 2 0 (1M, 29.60 ml, 2 equiv.) was added. The mixture was stirred at 20° C. for 1 h. The reaction mixture was adjusted to pH 3 with 4N aqueous HCl, the mixture was concentrated in vacuo and purified by reverse phase HPLC (column: Welch Ultimate XB_C18, 20-40 μm, 120 Å; eluent: water (0.1% formic acid) and acetonitrile, gradient: 100%-10% acetonitrile in 20 min, 10% acetonitrile in 20 min, flow rate: 100 ml / min) to give the title compound (3.5 g, 10.81 mmol, 73% yield, HCl) as a yellow solid. LC / MS: m / z=288.2 [M+H] + ;tR:0.700 min(LC / MS method D). 1 H NMR (400MHz, D 2 O):δ ppm 8.50(s,1H),7.70(d,J=2.3Hz,1H),7.47(d,J=2.2Hz,1H),7.08(s,1H),4.3 4-4.17(m,2H),3.34-3.26(m,2H),2.83-2.76(m,1H),2.73(s,3H),2.06(br dd,J=3.4,13.5Hz,2H),1.75-1.65(m,2H)

[0205] Intermediate-06 1-[6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]piperidine-4-carboxylic acid [ka] Process 1 Methyl 1-[6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]piperidine-4-carboxylate [ka] Intermediate-04 (25 g, 97.77 mmol, 1 equiv.) in dioxane (200 ml) and H 2 To a solution in 20 (40 ml), 2 CO 3 (27.03 g, 195.54 mmol, 2 equiv.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (20.34 g, 97.77 mmol, 1 equiv.) and Pd(dppf)Cl 2 (7.15 g, 9.78 mmol, 0.1 equiv.) was added. The mixture was diluted with N 2 The mixture was stirred at 120°C under atmospheric pressure for 2 hours. 2 The mixture was diluted with O (200 ml) and extracted with ethyl acetate (300 ml x 2). The combined organic layer was diluted with Na 2 SO 4 It was dried at rt, filtered, concentrated under reduced pressure and purified by flash silica gel chromatography (column: 220 g SepaFlash® silica flash, eluent: petroleum ether and ethyl acetate, gradient: 0% to 20% ethyl acetate, flow rate: 100 ml / min) to give the title compound (29.3 g, 86.44 mmol, 88% yield) as a yellow oil. LC / MS: m / z=302.1 [M+H] + ;tR:0.644 min(LC / MS method C).

[0206] Process 2 1-[6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]piperidine-4-carboxylic acid [ka] Methyl 1-[6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]piperidine-4-carboxylate (29.3 g, 97.23 mmol, 1 equiv.) in THF (250 ml) and H 2 A solution of LiOH H 2 2H2O (12.24 g, 291.69 mmol, 3 equiv.) was added. The mixture was stirred at 25° C. for 12 h, adjusted to pH 5 with 1N HCl solution, concentrated under reduced pressure, and filtered. The filter cake was purified by H2 O (50 ml) and triturated with ethyl acetate at 20° C. for 1 h to give the title compound (19.4 g, 64.89 mmol, 67% yield) as a grey solid. LC / MS: m / z=288.4 [M+H] + ;tR:0.295 min(LC / MS method C). 1 H NMR (400MHz, DMSO-d 6 ):δppm 12.30(s,1H),8.57(d,J=0.9Hz,1H),7.48(d,J=2.0Hz,1H),7.13(d,J=0.9Hz,1H),6.95(d,J=2.0Hz,1H),4.3 7(d,J=12.6Hz,2H),4.14(s,3H),3.17-3.02(m,2H),2.64-2.54(m,1H),1.97-1.83(m,2H),1.58-1.41(m,2H)

[0207] Intermediate-07 1-[6-(4-cyclopropyl-2-methyl-imidazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylic acid [ka] Process 1 4-Cyclopropyl-2-methyl-1H-imidazole [ka] To a solution of acetamidine (10.3 g, 108.94 mmol, 5 equiv., HCl) in MeOH (100 ml) was added NaOH (4.36 g, 108.94 mmol, 5 equiv.) at 0° C. The mixture was stirred at 25° C. for 3 h. The reaction mixture was filtered, the filtrate was concentrated in vacuo, and the residue was dissolved in acetonitrile (60 ml). 2 CO 3 (6.02g, 43.58mmol, 2eq) of H 2A solution of 30 ml of 2-bromo-1-cyclopropyl-ethanone (3.55 g, 21.79 mmol, 1 eq) in acetonitrile (10 ml) was added and stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure and filtered. The filter cake was washed with water to give the title compound as a crude product (1.5 g, 12.28 mmol, 56% yield) as a white solid, which was used directly in the next step. 1 H NMR: (400MHz, CDCl 3 ):δ ppm 9.43-8.77(m,1H),6.52(s,1H),2.28(s,3H),1.79-1.66(m,1H),0.79-0.69(m,2H),0.63-0.55(m,2H)

[0208] Process 2 Methyl 1-[6-(4-cyclopropyl-2-methyl-imidazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylate [ka] A solution of 4-cyclopropyl-2-methyl-1H-imidazole (573.33 mg, 4.69 mmol, 1.2 equiv.) in DMF (10 ml) was added to the solution of Cs 2 CO 3 (2.55 g, 7.82 mmol, 2 equiv.) and Intermediate-04 (1 g, 3.91 mmol, 1 equiv.) were added to N 2 The reaction mixture was stirred at 120° C. for 12 h and cooled to 25° C. MeI (275 mg, 19.5 mmol, 5 equiv.) was added and the reaction mixture was immersed in N 2 Incubate at 25°C for 2 hours in saturated NaHCO 3 The mixture was poured into aqueous solution (100 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layer was washed with brine (50 ml) and then diluted with Na 2 SO 4 It was dried at 40° C., filtered, concentrated and purified by silica gel column chromatography (eluent: petroleum ether and ethyl acetate, gradient: 10 / 1 to 0 / 1) to give the title compound (1 g, crude) as a yellow oil. LC / MS: m / z=342.3 [M+H] + ;tR:0.739 min(LC / MS method C).

[0209] Process 3 1-[6-(4-cyclopropyl-2-methyl-imidazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylic acid [ka] Methyl 1-[6-(4-cyclopropyl-2-methyl-imidazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylate (900 mg, 2.64 mmol, 1 equiv.) in THF (4 ml) and H 2 A solution of LiOH H 2 O (331.87 mg, 7.91 mmol, 3 equiv.) 2 The reaction mixture was stirred at 25° C. for 12 hours, adjusted to pH 4 with 1N HCl solution, and extracted with ethyl acetate (50 ml×3). The combined organic layers were washed with brine (100 ml) and diluted with Na 2 SO 4 The residue was purified by reverse phase HPLC (column: 330 g flash column Welch Ultimate XB_C18 20-40 μm, 120 Å, eluent: water (0.1% HCl) and acetonitrile, gradient: 0%-20% acetonitrile in 20 min, 20% acetonitrile in 10 min, flow rate: 100 ml / min) and triturated with petroleum ether / ethyl acetate (1:1, 7 ml) at 25° C. to give the title compound (540 mg, 1.62 mmol, 53% yield) as a white solid. LC / MS: m / z=328.2 [M+H] + ;tR:0.685 min(LC / MS method C). 1 H NMR (400MHz, DMSO-d 6):δppm 8.54(s,1H),7.94(s,1H),7.13(s,1H),4.45-4.35(m,2H),3.24-3.11(m,2H),2.81(s,3H),2 .70-2.60(m,1H),2.07-1.84(m,3H),1.62-1.41(m,2H),1.09-0.98(m,2H),0.93-0.83(m,2H)

[0210] Intermediate-08 3-[(3S)-2-[1-(6-chloropyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]-5-fluoro-benzonitrile [ka] Step 1: 1-(6-chloropyrimidin-4-yl)piperidine-4-carboxylic acid [ka] THF (10 ml) and H 2 A mixture of intermediate-04 (3 g, 11.73 mmol, 1 equiv.) in 2H2O (10 ml) was added with LiOH H 2 0 (1M, 23.46 ml, 2 equiv.) was added and the reaction mixture was stirred for 1 h at 25° C. The reaction mixture was adjusted to pH 3-4 with 1M HCl, filtered and concentrated under reduced pressure to give the title compound (2.43 g, 86% yield), which was used directly in the next step. LC / MS: m / z=242.0 [M+H] + ;tR:0.835 min(LC / MS method D). 1 H NMR (400MHz, DMSO-d 6 ):δ ppm 12.43 -12.20(m,1H),8.32(s,1H),6.97(s,1H),4.37 -4.14(m,2H),3.16 -3.05(m,2H),2.62 -2.55(m,1H),1.88(br dd,J=13.5,3.5Hz,2H),1.55 -1.42(m,2H)

[0211] Step 2: 3-[(3S)-2-[1-(6-chloropyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-yl]-5-fluoro-benzonitrile [ka] To a solution of 1-(6-chloropyrimidin-4-yl)piperidine-4-carboxylic acid (4 g, 16.55 mmol, 1 equiv.), 3-fluoro-5-[(3S)-isoxazolidin-3-yl]benzonitrile (3.97 g, 17.38 mmol, 1.05 equiv., HCl) in DMF (40 ml), HATU (12.59 g, 33.10 mmol, 2 equiv.) and DIEA (10.70 g, 82.76 mmol, 14.41 ml, 5 equiv.) were added. The reaction mixture was stirred at 25° C. for 12 h. The reaction mixture was filtered, concentrated under reduced pressure and purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=4 / 1 to 3 / 1) to give the title compound (4 g, yield 58%) as a brown solid. LC / MS: m / z=214.0 [M+H] + ;tR:0.637 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3 ):δ ppm 8.39(s,1H),7.42(s,1H),7.31 -7.29(m,1H),7.27(br d,J=1.6Hz,1H),6.55(s,1H),5.42(dd,J=8.8,6.4Hz,1H),4.35(td,J=7.9,3.0Hz,3H),4.01 -3.89(m,1H),3.21 -3.08(m,4H),2.99 -2.90(m,1H),2.41 -2.30(m,1H),2.14 -2.07(m,1H),1.89 -1.76(m,3H) SFC (column: Chiralcel OJ-3 50 × 4.6 mm I.D., 3 μm, gradient: CO 2Medium 5%~40%MeOH (0.05%DEA), flow rate: 3ml / min, column temperature: 35℃, 100bar): tR=1.42min (100%)

[0212] Intermediate-09 1-[6-(5-methyl-1,2,4-triazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylic acid [ka] Process 1 Methyl 1-(6-hydrazinopyrimidin-4-yl)piperidine-4-carboxylate [ka] A solution of Intermediate-04 (1 g, 3.91 mmol, 1 equiv.) in i-PrOH (10 ml) was added with DIEA (1.01 g, 7.82 mmol, 1.36 ml, 2 equiv.) and N 2 H 4 H 2 O (253.36 mg, 4.30 mmol, 245.98 μl, 85% purity, 1.1 equiv.) was added. The mixture was stirred at 80° C. for 12 h, diluted with water (50 ml) and extracted with ethyl acetate (30 ml×3). The combined organic layers were washed with brine (50 ml×2) and diluted with Na 2 SO 4 Drying at rt, filtering and concentrating afforded the title compound (980 mg, crude) as a white solid. LC / MS: m / z=252.3 [M+H] + ;tR:0.703 min(LC / MS method D).

[0213] Process 2 Methyl 1-[6-(5-methyl-1,2,4-triazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylate [ka] To a solution of methyl 1-(6-hydrazinopyrimidin-4-yl)piperidine-4-carboxylate (980 mg, 3.90 mmol, 1 equiv.) and p-toluenesulfonic acid (671.57 mg, 3.90 mmol, 1 equiv.) in EtOH (10 ml) was added N-(dimethylaminomethylene)acetamide (890.33 mg, 7.80 mmol, 2 equiv.) at 25° C. The reaction mixture was stirred at 80° C. for 2 h and concentrated to remove most of the solvent. NaHCO 3 Saturated aqueous solution (30 ml) was added and the aqueous layer was extracted with ethyl acetate (20 ml x 2). The organic layer was washed with brine (50 ml) and then with Na 2 SO 4 The residue was dried at rt, filtered, concentrated and purified by flash silica gel chromatography (column: 20 g SepaFlash® silica flash column, eluent: petroleum ether and ethyl acetate, gradient: 10% to 40% ethyl acetate, flow rate: 60 ml / min) to give the title compound (475 mg, 1.56 mmol, 40% yield) as a white solid. LC / MS: m / z=303.2 [M+H] + ;tR:0.799 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3 ):δ ppm 8.51(s,1H),7.90(s,1H),7.07(s,1H),4.45-4.31(m,2H),3.72(s,3H),3.17(br t,J=11.9Hz,2H),2.92(s,3H),2.70-2.61(m,1H),2.03(br s,1H),1.77(q,J=10.4Hz,2H)

[0214] Process 3 1-[6-(5-methyl-1,2,4-triazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylic acid [ka] A solution of methyl 1-[6-(5-methyl-1,2,4-triazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylate (475 mg, 1.57 mmol, 1 equiv.) in THF (5 ml) was added with LiOH H 2 0 (1M, 3.14 ml, 2 eq.) was added. The mixture was stirred at 25° C. for 1 h, adjusted to pH 3 with 1N aqueous HCl, concentrated to remove most of the solvent, and filtered. The filter cake was collected and dried to give the title compound (470 mg, crude) as a white solid. LC / MS: m / z=289.0 [M+H] + ;tR:0.729 min(LC / MS method C). 1 H NMR (400MHz, DMSO-d 6 ):δ ppm 12.31(br s,1H),8.51(s,1H),8.09(s,1H),7.08(s,1H),4.31(br d,J=2.3Hz,2H),3.15(br t,J=11.1Hz,2H),2.77(s,3H),2.60(ddd,J=4.1,6.8,10.7Hz,1H),1.91(br dd,J=3.2,13.2Hz,2H),1.57-1.47(m,2H)

[0215] Intermediate-10 1-[6-(3-methyl-1,2,4-triazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylic acid [ka] Process 1 Methyl 1-[6-(3-methyl-1,2,4-triazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylate [ka] A solution of 5-methyl-1H-1,2,4-triazole (1.17 g, 14.08 mmol, 1.2 equiv.) in DMF (30 mL) was added to the solution of Cs 2 CO 3(7.65 g, 23.46 mmol, 2 equiv.), Intermediate-04 (3 g, 11.73 mmol, 1 equiv.) and molecular sieves 4 Å (3 g, 11.73 mmol, 1 equiv.) were reacted with N 2 The reaction mixture was stirred at 120° C. for 12 h and cooled to 25° C. MeI (833 mg, 58.6 mmol, 5 equiv.) was added and the reaction mixture was immersed in N 2 The mixture was kept at 25° C. under atmospheric pressure for 2 hours. The reaction mixture was filtered, diluted with water (300 ml) and extracted with ethyl acetate (200 ml×3). The combined organic layer was washed with brine (300 ml×2) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated and purified by preparative HPLC (column: Welch Ultimate XB-CN250×50 mm, 10 μm, eluent: 2% EtOH in hexanes (0.1% formic acid), 18 min) to give the title compound as a white solid in a mixture with the second product methyl 1-[6-(5-methyl-1,2,4-triazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylate (Intermediate-09, Step 2) (5 g, 15.05 mmol, 87% yield). 1 H NMR (400 MHz, CDCl 3 ):δppm 9.05(s,1H),8.52(s,1H),7.93(s,1H),7.08(s,1H),4.42-4.32(m,2H), 3.72(s,3H),3.22-3.15(m,2H),2.94(s,3H),2.70-2.64(m,1H),2.05(br dd,J=2.8,13.8Hz,2H),1.82-1.78(m,2H)

[0216] Process 2 1-[6-(3-methyl-1,2,4-triazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylic acid [ka] A solution of methyl 1-[6-(3-methyl-1,2,4-triazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylate and the by-product methyl 1-[6-(5-methyl-1,2,4-triazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylate (4.9 g, 16.21 mmol, 1 equiv.) in THF (50 ml) was treated with LiOH H 2 0 (1M, 32.41 ml, 2 equiv.) was added. The mixture was stirred at 25° C. for 1 h, adjusted to pH 3 with 1N aqueous HCl, concentrated to remove most of the solvent, and filtered. The filter cake was recrystallized from DMF (50 ml) at 80° C. for 1 h and filtered to give the title compound (4 g, 13.87 mmol, 86% yield) as a white solid. LC / MS: m / z=289 [M+H] + ;tR:0.649 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3 ):δ ppm 12.35(br s,1H),9.20(s,1H),8.45(s,1H),6.99(s,1H),4.33(br dd,J=4.6,2.1Hz,2H),3.15(br t,J=11.5Hz,2H),2.66 -2.56(m,1H),2.39(s,3H),1.98 -1.87(m,2H),1.60 -1.46(m,2H)

[0217] Intermediate 11a Methyl 1-(6-chloro-5-fluoro-pyrimidin-4-yl)piperidine-4-carboxylate [ka] A mixture of 4,6-dichloro-5-fluoro-pyrimidine (1 g, 5.99 mmol, 1 equiv.), methyl piperidine-4-carboxylate (806.21 mg, 5.63 mmol, 0.94 equiv.), DIEA (2.32 g, 17.97 mmol, 3.13 ml, 3 equiv.) in dioxane (10 ml) was degassed and purified with N 2 The mixture was then purged with N 2The mixture was stirred at 80°C under atmospheric pressure for 2 hours. 2 The mixture was diluted with 200 ml of O (30 ml) and extracted with ethyl acetate (30 ml x 2). The combined organic layers were washed with Na 2 SO 4 The residue was dried at rt, filtered, concentrated under reduced pressure and purified by flash silica gel chromatography (column: 20 g SepaFlash® silica flash column, eluent: petroleum ether and ethyl acetate, gradient: 0% to 50% ethyl acetate, flow rate: 50 ml / min) to give the title compound (1.45 g, 5.30 mmol, 88% yield) as a yellow oil. LC / MS: m / z=374.1 [M+H] + ;tR:0.894 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3 ):δ ppm 8.20-8.12(m,1H),4.51-4.34(m,2H),3.75-3.69(m,3H),3.31-3.15(m,2H),2.72-2.57(m,1H),2.09-1.98(m,2H),1.89-1.75(m,2H)

[0218] Intermediate 11b Ethyl 1-(6-chloro-5-fluoro-pyrimidin-4-yl)piperidine-4-carboxylate [ka] A mixture of 4,6-dichloro-5-fluoro-pyrimidine (1.06 g, 6.36 mmol, 1 equiv.), ethyl piperidine-4-carboxylate (1.00 g, 6.36 mmol, 1.0 equiv.), DIEA (3.29 g, 25.44 mmol, 4.43 ml, 4 equiv.) in acetonitrile (20 ml) was stirred at room temperature for 1 h. The residue was purified by H 2 The reaction mixture was diluted with ethyl acetate (30 ml) and extracted with ethyl acetate (30 ml x 2). The reaction mixture was diluted with ethyl acetate and washed twice with 0.1 N HCl. The combined organic layers were washed with water and then with Na 2 SO 4Drying at rt, filtering and concentrating under reduced pressure gave the title compound (1.65 g, 5.73 mmol, 90% yield). LC / MS: m / z=288.1 [M+H] + ;tR:2.14 min (LC / MS method A). 1 H NMR (400.23MHz, DMSO-d 6 ):δ ppm 8.19(d,J=1.34Hz,1H),4.29(m,2H),4.08(q,J=7.09Hz,2H),3.24(m,2H),2.71(m,1H),1.93(m,2H),1.62(m,2H),1.19(t,J=7.09Hz,3H)

[0219] Example Synthesis: Example 1 3-Fluoro-5-[(3S)-2-[1-[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile [ka] A mixture of Intermediate-05 (300 mg, 926.56 μmol, 1 eq, HCl), Intermediate-01 (222.45 mg, 972.89 μmol, 1.05 eq, HCl), HATU (528.46 mg, 1.39 mmol, 1.5 eq) and DIEA (838.24 mg, 6.49 mmol, 1.13 ml, 7 eq) in DMF (3 ml) was stirred at 20° C. for 12 h. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (10 ml×3). The combined organic layer was washed with brine (15 ml×2) and diluted with Na 2 SO 4The residue was dried at rt, filtered, concentrated and purified by flash silica gel chromatography (eluent: DCM and MeOH, gradient: 0% to 10% MeOH) followed by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30 mm, 3 μm, eluent: water (0.225% formic acid) and acetonitrile, gradient: 12% to 42% acetonitrile in 5 min) to give the title compound (229 mg, 491.16 μmol, 53% yield) as a yellow solid. LC / MS: m / z=462.1 [M+H] + ;tR:0.501 min(LC / MS method C). 1 H NMR (400MHz, DMSO-d 6 ):δ ppm 8.48(s,1H),7.78(br d,J=8.4Hz,1H),7.66-7.60(m,2H),7.49(br d,J=9.7Hz,1H),6.90(s,2H),5.39(br t,J=7.5Hz,1H),4.48(br d,J=3.9Hz,2H),4.30(dt,J=2.8,7.6Hz,1H),3.97-3.90(m,1H),3.16-3.06(m,3H) ),2.95-2.87(m,1H),2.55(s,3H),2.28-2.19(m,1H),2.00-1.94(m,1H),1.77(br d,J=10.8Hz,1H),1.58-1.48(m,2H) SFC (Column: Chiralpak AD-3 50×4.6mmI.D., 3μm, Eluent: CO 2 Medium 40% MeOH (0.05% DEA), flow rate: 3 ml / min, column temperature: 35°C, 100 bar): tR: 1.05 min (100%)

[0220] Example 2 3-Fluoro-2-methyl-5-[(3S)-2-[1-[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile [ka] The title compound was synthesized using HATU coupling conditions described in Example 1 using Intermediate-05 and Intermediate-03 as reagents to give 10 mg (0.021 mmol, 21% yield). LC / MS: m / z=476.3 [M+H] + ;tR:1.57 min (LC / MS method A). 1 H NMR (600.05MHz, DMSO-d 6 ):δ ppm 8.48(d,J=0.92Hz,1H),7.64(d,J=1.47Hz,1H),7.55(s,1H),7.43(d,J=10.27Hz,1H),6.90(dd,J=5.78,1.19Hz,2H),5.35(m,1H),4.48(br s,1H),4.29(td,J=7.70,7.70,2.93Hz,1H),3.93(m,1H),3.28(m,1H),3.11(m ,3H),2.89(m,1H),2.54(s,3H),2.37(d,J=1.83Hz,3H),2.23(m,1H),1.96(br d,J=11.19Hz,1H),1.77(br d,J=12.65Hz,1H),1.53(m,2H)

[0221] Example 3 3-Fluoro-5-[(3S)-2-[1-[6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile [ka] The title compound was synthesized using HATU coupling conditions described in Example 1 using Intermediate-06 and Intermediate-01 as reagents to give 240 mg (0.52 mmol, 77% yield). LC / MS: m / z=463.2 [M+H] + ;tR:0.66 min(LC / MS method B). 1 H NMR (400.23MHz, DMSO-d 6):δppm 8.57(d,J=0.98Hz,1H),7.77(d,J=8.62Hz,1H),7.62(s,1H),7.50(s,1H),7.4 8(d,J=1.96Hz,1H),7.13(s,1H),6.94(d,J=1.96Hz,1H),5.40(m,1H),4.49(br s,2H),4.30(td,J=7.67,7.67,3.00Hz,1H),4.14(s,3H),3.94(m,1H),3.09(m,3 H),2.91(dddd,J=12.18,9.15,6.42,3.06Hz,1H),2.50(u),2.25(m,1H),1.97(br d,J=10.51Hz,1H),1.77(br d,J=12.84Hz,1H),1.53(m,2H)

[0222] Example 4 [(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[1-[6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]-4-piperidyl]methanone [ka] The title compound was synthesized using HATU coupling conditions described in Example 1 using Intermediate-06 and Intermediate-02a as reagents to give 180 mg (0.40 mmol, 57% yield). LC / MS: m / z=455.1 [M+H] + ;tR:0.55 min (LC / MS method C). 1 H NMR (400 MHz, CDCl 3):δppm 8.66(s,1H),7.50(d,J=2.0Hz,1H),6.86-6.79(m,2H),6.74-6.68(m,2H),6.59(d,J=2.0Hz,1H),5.38(dd,J=6.1,8.7Hz,1H),4.51-4.3 9(m,2H),4.30(dt,J=3.2,7.7Hz,1H),4.22(s,3H),3.97-3.89(m,1H),3.17-3.08(m,3H),2.94-2.80(m,1H),2.42-2.27(m,1H),2.09(br dd,J=2.4,13.4Hz,1H),1.87-1.79(m,3H) SFC (Column: Chiralpak OJ-3 50×4.6mmI.D., 3μm, Eluent: CO 2 Medium 5~40% MeOH (0.05% DEA), flow rate: 3 ml / min, column temperature: 35°C, 100 bar): tR: 1.389 min (100%)

[0223] Example 5 [(3S)-3-(3-chloro-5-fluoro-phenyl)isoxazolidin-2-yl]-[1-[6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]-4-piperidyl]methanone [ka] The title compound was synthesized using HATU coupling conditions described in Example 1 using Intermediate-06 and Intermediate-02b as reagents to give 37 mg (0.08 mmol, 78% yield). LC / MS: m / z=471.2 [M+H] + ;tR:2.00 min(LC / MS method A). 1 H NMR (400.23MHz, DMSO-d 6):δ ppm 8.59(s,1H),7.50(d,J=1.96Hz,1H),7.34(dt,J=8.68Hz,J=2.08Hz,1H),7.20(s,1H),7.15(s,1H),7.11(br d,J=9.41Hz,1H),6.93(d,J=1.96Hz,1H),5.35(m,1H),4.49(br s,2H),4.29(m,1H),4.13(s,3H),3.92(m,1H),3.11(m,3H),2.90(m,1H),2.22(m,1H),1.97(br d,J=11.13Hz,1H),1.77(br d, J = 12.23 Hz, 1H), 1.53 (m, 2H)

[0224] Example 6 3-Fluoro-5-[(3S)-2-[1-[6-(3-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile [ka] A mixture of Intermediate-08 (41.58 mg, 0.10 mmol, 1.0 equiv), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (38.22 mg, 0.18 mmol, 1.8 equiv), sodium carbonate (40.28 mg, 0.38 mmol, 3.8 equiv) and 1,1'-bis(diphenylphosphino)-ferrocene-palladium(II) dichloride dichloromethane complex (16.33 mg, 0.02 mmol, 0.2 equiv) in DME (3.0 ml) and water (1 ml) was heated to 100° C. under microwave irradiation for 30 min. The reaction mixture was filtered and purified by preparative HPLC (column: Luna(r) 5 μm C18(2) 100 Å 100×30 mm, AXIAL, eluent: water and acetonitrile, gradient: 10% to 100% acetonitrile in 12 min, flow rate: 50 ml / min) to give the title compound (18 mg, 39% yield). LC / MS: m / z=462.2 [M+H] + ;tR:1.34 min (LC / MS method A). 1 H NMR (400.23MHz, DMSO-d 6 ):δ ppm 8.45(s,1H),8.14(s,1H),7.77(br d,J=7.98Hz,1H),7.62(s,1H),7.49(br d,J=9.41Hz,1H),6.93(s,1H),5.40(m,1H),4.45(br d,J=9.90Hz,2H),4.30(td,J=7.58,2.81Hz,1H),3.94(m,1H),3.09(br d,J=7.09Hz,1H),3.03(m,2H),2.91(m,1H),2.27(m,2H),1.95(br d,J=11.37Hz,1H),1.76(br d,J=11.74Hz,1H),1.52(m,2H),1.24(s,3H)

[0225] Example 7 3-[(3S)-2-[1-[6-(4-cyclopropyl-2-methyl-imidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]-5-fluoro-benzonitrile [ka] The title compound was synthesized using HATU coupling conditions described in Example 1 using Intermediate-07 and Intermediate-02a as reagents to give 77 mg (0.23 mmol, 36% yield). LC / MS: m / z=502.2 [M+H] + ;tR:0.81 min (LC / MS method C). 1 H NMR (400MHz, DMSO-d 6):δ ppm 8.45(s,1H),8.13(s,1H),7.80-7.74(m,1H),7.62(s,1H),7.49(br d,J=9.5Hz,1H),7.43(s,1H),6.84(s,1H),5.42-5.36(m,1H),4.54-4.39 (m,2H),4.30(dt,J=2.8,7.7Hz,1H),3.96-3.90(m,1H),3.14-3.05(m,3H) ,2.95-2.88(m,1H),2.52(s,3H),2.27-2.21(m,1H),1.99-1.94(m,1H),1 .80-1.73(m,2H),1.56-1.48(m,2H),0.80-0.76(m,2H),0.68-0.64(m,2H) SFC (Column: Chiralpak OJ-3 50×4.6mmI.D., 3μm, Eluent: CO 2 Medium 5~40% MeOH (0.05% DEA), flow rate: 3 ml / min, column temperature: 35°C, 100 bar): tR: 1.73 min (98.8%)

[0226] Example 8 5-[(3S)-2-[1-[6-(4-cyclopropyl-2-methyl-imidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]-3-fluoro-2-methyl-benzonitrile [ka] The title compound was synthesized using HATU coupling conditions described in Example 1 using Intermediate-07 and Intermediate-03 as reagents to give 28 mg (0.08 mmol, 81% yield). LC / MS: m / z=516.3 [M+H] + ;tR:1.67 min (LC / MS method A). 1 H NMR (400.23MHz, DMSO-d 6 ):δ ppm 8.45(s,1H),7.55(s,1H),7.44 (m,2H),6.83(s,1H),5.35(m,1H),4.47(br s,2H),4.29(td,J=7.64, 7.64,3.18Hz,1H),3.93(m,1H),3.10(m,3H),2.89(m,1H),2.50(s,3H,in DMSO peak),2.37(d,J=1.71Hz,3H),2.24(m,1H),1.96(br d,J=12.84Hz,1H),1.77(m,2H),1.52(m,2H),0.78(m,2H),0.67(m,2H)

[0227] Example 9 3-[(3S)-2-[1-[6-(2,5-dimethylpyrazol-3-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]-5-fluoro-benzonitrile [ka] Intermediate-08 (100 mg, 240.47 μmol, 1 equiv.), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (58.75 mg, 264.52 μmol, 1.1 equiv.), K 2 CO 3 (66.47 mg, 480.95 μmol, 2 equiv.) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (19.64 mg, 24.05 μmol, 0.1 equiv.) in dioxane (0.8 ml) and H 2 The mixture was degassed in O (0.2 ml) and purified with N 2 The reaction mixture was purged with N 2 The mixture was stirred at 80° C. under atmospheric pressure for 2 hours. The reaction mixture was diluted with water (5 ml) and extracted with ethyl acetate (3 ml×3). The combined organic layer was washed with brine (8 ml) and diluted with Na 2 SO 4The mixture was dried at 40° C., filtered, concentrated and purified by preparative HPLC (column: Phenomenex C18 75×30 mm, 3 μm, eluent: water (0.1% formic acid) and acetonitrile, gradient: 25% to 55% acetonitrile in 7 min) to afford the title compound (62 mg, 130.38 μmol, 54% yield) as a yellow solid. LC / MS: m / z=476.3 [M+H] + ;tR:0.822 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3 ):δ ppm 8.69(s,1H),7.40(s,1H),7.30-7.27(m,1H),7.26(br d,J=1.4Hz,1H),6.67(s,1H),6.54(br s,1H),5.41(dd,J=6.4,8.6Hz,1H),4.58-4.27(m,3H),4.14(s,3H),3.95(dt,J=6.8,8.7Hz,1H),3.32-3.10(m,3H) ),2.93(dddd,J=3.1,6.6,9.2,12.2Hz,1H),2.40-2.32(m,1H),2.30(s,3H),2.16-2.08(m,1H),1.91-1.82(m,3H) SFC (column: Chiralcel OJ-3 50 × 4.6 mm I.D., 3 μm, gradient: CO 2 Medium 5%~40%MeOH (0.05%DEA), flow rate: 3ml / min, column temperature: 35℃, 100bar): tR: 1.54 min (100%)

[0228] Example 10 3-Fluoro-5-[(3S)-2-[1-[6-(3-methyl-1,2,4-triazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile [ka] The title compound was synthesized using HATU coupling conditions described in Example 1 using Intermediate-07 and Intermediate-03 as reagents to give 62 mg (0.13 mmol, 38% yield). LC / MS: m / z=463.3 [M+H] + ;tR:0.820 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3 ):δ ppm 9.20(s,1H),8.43(s,1H),7.32(s,1H),7.21(br d,J=1.1Hz,1H),7.18(br d,J=1.6Hz,1H),6.96(s,1H),5.34(dd,J=8.7,6.3Hz,1H),5.20 -5.09(m,1H),4.47 -4.34(m,1H),4.27(td,J=7.8,2.9Hz,1H),3.93 -3.85(m,1H),3.26 -3.14(m,2H),3.13 -3.04(m,1H),2.86(dddd,J=12.3,9.2,6.4,2.9Hz,1H),2.48(s,3H),2.33 -2.21(m,1H),2.05(br dd,J=13.5,3.3Hz,1H),1.88 -1.72(m,3H) SFC (column: Chiralcel OJ-3 50 × 4.6 mm I.D., 3 μm, gradient: CO 2 Medium 5%~40%MeOH (0.05%DEA), flow rate: 3ml / min, column temperature: 35℃, 100bar): tR: 1.418 min (100%)

[0229] Example 11 3-Fluoro-5-[(3S)-2-[1-[6-(5-methyl-1,2,4-triazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile [ka] The title compound was synthesized using HATU coupling conditions described in Example 1 using Intermediate-09 and Intermediate-01 as reagents to give 38 mg (0.12 mmol, 24% yield). LC / MS: m / z 463.1 [M+H] + ;tR:0.874 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3 ):δ ppm 8.52(s,1H),7.92(s,1H),7.40(s,1H),7.28(br d,J=2.1Hz,1H),7.26(br d,J=1.5Hz,1H),7.09(s,1H),5.41(dd,J=6.4,8.8Hz,1H),4.50(br d,J=2.1Hz,2H),4.34(dt,J=2.9,7.9Hz,1H),3.94(dt,J=6.7,8.8Hz,1H),3. 24-3.10(m,3H),2.94(s,3H),2.93-2.87(m,1H),2.39-2.29(m,1H),2.09(br dd,J=2.7,13.1Hz,1H),1.87-1.80(m,3H) SFC (column: Chiralcel OD-3 50 × 4.6 mm I.D., 3 μm, gradient: CO 2 Medium 5%~40%MeOH (0.05%DEA), flow rate: 3ml / min, column temperature: 35℃, 100bar): tR: 1.926 min (100%)

[0230] Example 12 3-Fluoro-5-[(3S)-2-[1-[6-(3-methyltriazol-4-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile [ka] Process 1 Tributyl-(3-methyltriazol-4-yl)stannane [ka] To a solution of n-BuLi (2.5 M, 2.41 ml, 1 equiv.) in THF (5 ml), 5-methylcyclohexa-1,3-diene (566.57 mg, 6.02 mmol, 5 ml, 1 equiv.) was added dropwise at -70°C, followed by a solution of 1-methyltriazole (500 mg, 6.02 mmol, 1 equiv.) in THF (2 ml) with N 2 Dropwise addition under atmospheric pressure. The reaction mixture was stirred for 1 h and tributyl(chloro)stannane (1.96 g, 6.02 mmol, 1.62 ml, 1 equiv) was added. The reaction mixture was allowed to warm smoothly to 25° C. After 10 h, the reaction mixture was filtered, concentrated under reduced pressure, and purified by flash silica gel chromatography (column: 20 g SepaFlash® silica flash column, eluent: petroleum ether and ethyl acetate, gradient: 0% to 20% ethyl acetate, flow rate: 50 ml / min) to give the title compound (1.3 g, 3.49 mmol, 58% yield) as a colorless oil. LC / MS: m / z 374.1 [M+H] + ;tR:0.831 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3 ):δ ppm 7.61(s,1H),4.10(s,3H),1.57-1.49(m,6H),1.37-1.31(m,6H),1.21-1.16(m,6H),0.90(t,J=7.3Hz,9H)

[0231] Process 2 3-Fluoro-5-[(3S)-2-[1-[6-(3-methyltriazol-4-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile [ka] Intermediate-08 (100 mg, 240.47 μmol, 1 eq.), tributyl-(3-methyltriazol-4-yl)stannane (178.98 mg, 480.95 μmol, 2 eq.), triethylamine (48.67 mg, 480.95 μmol, 66.94 μl, 2 eq.), CuI (4.58 mg, 24.05 μmol, 0.1 eq.) and Pd(PPh 3 ) 4 A mixture of (27.79 mg, 24.05 μmol, 0.1 equiv.) in dioxane (1 ml) was degassed and diluted with N 2 The reaction mixture was purged with N 2 The mixture was stirred at 100° C. under atmospheric pressure for 12 hours, quenched by the addition of saturated aqueous KF solution (3 ml), diluted with water (5 ml), and extracted with ethyl acetate (5 ml×3). The combined organic layers were washed with Na 2 SO 4 The extract was dried at rt, filtered, concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex C18 75×30 mm, 3 μm, eluent: water (0.1% formic acid) and acetonitrile, gradient: 28% to 58% acetonitrile in 7 min) to give the title compound (26 mg, 56.22 μmol, 23% yield) as a yellow solid. LC / MS: m / z 463.1 [M+H] + ;tR:0.626 min(LC / MS method C). 1 H NMR (400MHz, DMSO-d 6 ):δ ppm 8.60(d,J=1.0Hz,1H),8.39(s,1H),7.80-7.75(m,1H),7.62(s,1H),7.49(br d,J=9.2Hz,1H),7.28(d,J=0.9Hz,1H),5.39(br dd,J=6.5,8.1Hz,1H),4.58-4.42(m,2H),4.32(s,3H),4.31-4.27(m,1H),3.98-3.89(m,1H),3.16-3.08(m,3H),2.91( tdd,J=3.1,5.8,8.8Hz,1H),2.24(dtd,J=2.0,4.6,9.3Hz,1H),2.01-1.94(m,1H),1.82-1.74(m,1H),1.56-1.47(m,2H) SFC (column: Chiralcel OD-3 50 × 4.6 mm I.D., 3 μm, gradient: CO 2 Medium 5%~40% MeOH (0.05% DEA), flow rate: 3ml / min, column temperature: 35℃, 100bar): tR: 2.380 min (100%)

[0232] Example 13 3-Fluoro-5-[(3S)-2-[1-[5-fluoro-6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile [ka] Process 1 Methyl 1-[5-fluoro-6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylate [ka] Intermediate-11a (5.38 g, 19.66 mmol, 1 equiv.), 2-methyl-1H-imidazole (2.10 g, 25.55 mmol, 1.3 equiv.), K 2 CO 3 A mixture of (10.87 g, 78.63 mmol, 4 equiv.), CuI (1.87 g, 9.83 mmol, 0.5 equiv.) in DMSO (50 ml) was degassed and diluted with N 2 The reaction mixture was stirred at 120° C. for 16 h and then purged with H 2 The mixture was diluted with 200 ml of O (60 ml) and extracted with ethyl acetate (60 ml x 2). The combined organic layer was washed with anhydrous Na 2 SO 4 It was dried at rt, filtered, concentrated under reduced pressure and purified by flash silica gel chromatography (column: 8 g SepaFlash® silica flash column, eluent: petroleum ether and ethyl acetate, gradient: 0% to 80% ethyl acetate, flow rate: 40 ml / min) to give the title compound (6 g, 17.85 mmol, 91% yield) as a white solid. 1H NMR (400 MHz, CDCl 3 ):δppm 8.30(d,J=1.3Hz,1H),7.18-7.10(m,1H),7.02(s,1H),4.52-4.40(m,2H),3. 75-3.65(m,3H),3.32-3.17(m,2H),2.71-2.64(m,2H),2.49(s,3H),2.05(br d,J=3.5Hz,1H),1.89-1.77(m,2H)

[0233] Process 2 1-[5-Fluoro-6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylic acid [ka] A solution of methyl 1-[5-fluoro-6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylate (3 g, 9.39 mmol, 1 equiv.) in THF (24 ml) was added with LiOH H 2 O (1.58 g, 37.58 mmol, 4 equiv.) and H 2 O (6 ml) was added. The reaction mixture was stirred at 25° C. for 2 h and then H 2 The mixture was diluted with 200 ml of O (60 ml) and extracted with ethyl acetate (60 ml x 2). The combined organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried at rt, filtered, concentrated under reduced pressure and purified by reverse phase HPLC (Column: 330 g flash column Welch Ultimate XB_C18 20-40 μm, 120 Å, eluent: water (0.1% formic acid) and acetonitrile, gradient: 0%-25% acetonitrile in 15 min, 25% acetonitrile in 10 min, flow rate: 100 mL / min) to give the title compound (1.4 g, 4.58 mmol, 49% yield) as a white solid. LC / MS: m / z 306.2 [M+H] + ;tR:0.226 min(LC / MS method C). 1 H NMR (400MHz, DMSO-d 6):δ ppm 12.49-12.14(m,1H),8.36(d,J=1.4Hz,1H),7.47(dd,J=1.6,2.4Hz,1H),7.04(d,J=1.5Hz,1H),4.34(br d,J=13.4Hz,2H),3.27-3.21(m,2H),2.64-2.61(m,1H),2.40(s,3H),1.97-1.91(m,2H),1.69-1.61(m,2H)

[0234] Process 3 3-Fluoro-5-[(3S)-2-[1-[5-fluoro-6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile [ka] The title compound was synthesized using the HATU coupling conditions described in Example 1 using 1-[5-fluoro-6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylic acid (Step 2) and Intermediate-01 as reagents to give 112 mg (228.7 μmol, 78% yield) as a yellow solid. LC / MS: m / z 480.1 [M+H] + ;tR:0.512 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3 ): δ ppm 8.33(d,J=1.5Hz,1H),7.40(s,1H),7.34(s,1H),7.28(br s,2H),7.26(br s,1H),5.42(dd,J=6.4,8.7Hz,1H),4.62(br d,J=13.3Hz,2H),4.34(dt,J=2.9,7.8Hz,1H),4.02-3.91(m,1H),3.34-3.28(m,2H),3.22-3. 13(m,1H),2.95(dddd,J=3.0,6.4,9.2,12.3Hz,1H),2.68(s,3H),2.40-2.28(m,1H),2.13(br dd,J=3.2,13.6Hz,1H),1.93-1.85(m,3H) SFC (column: Chiralcel OJ-3 50 × 4.6 mm I.D., 3 μm, gradient: CO 2 Medium 5%~40%MeOH (0.05%DEA), flow rate: 3ml / min, column temperature: 35℃, 100bar): tR: 1.294 min (100%)

[0235] Example 14 3-Fluoro-5-[(3S)-2-[1-[5-fluoro-6-(4-methylpyrazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]-2-methyl-benzonitrile [ka] Process 1 Ethyl 1-[5-fluoro-6-(4-methylpyrazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylate [ka] A mixture of intermediate-11b (300 mg, 1.04 mmol, 1 eq), 4-methyl-1H-pyrazole (171.22 mg, 0.168 ml, 2.085 mmol, 2.0 eq), potassium carbonate (576.42 mg, 4.171 mmol, 4.0 eq) and copper(I) iodide (99.3 mg, 0.521 mmol, 0.5 eq) in DMSO (1.5 ml) was stirred at 120° C. for 4 h under microwave irradiation. The reaction mixture was diluted with water and ethyl acetate and filtered. The filtrate was evaporated under reduced pressure to give the title compound (294 mg, 0.75 mmol, 72% yield), which was used directly in the next step.

[0236] Process 2 1-[5-fluoro-6-(4-methylpyrazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylic acid [ka] A solution of the crude product from step 1 (294 mg, 0.75 mmol, 1 equiv.) in NaOH (2N in water / THF / MeOH=1 / 1 / 1, 5.7 ml, 3.75 mmol, 5 equiv.) was stirred at room temperature for 16 h. The reaction mixture was diluted with 1N H 2 SO 4 The mixture was acidified with ethyl acetate and extracted three times with ethyl acetate. The combined organic layers were washed with Na 2 SO 4 The residue was dried at 40° C., filtered, evaporated and purified by preparative HPLC (column: YMC-Actus Triart Prep C18-S 250×30 mm, 5-10 μm, eluent: water (0.05% TFA) and acetonitrile, gradient: 5% to 100% acetonitrile in 24 min, flow rate: 70 ml / min) to give the title compound (156 mg, 68% yield). LC / MS: m / z=306.1 [M+H] + ;tR:1.61 min (LC / MS method A). 1 H NMR (400.23MHz, DMSO-d 6):δ ppm 12.28(br s,1H),8.26(d,J=1.47Hz,1H),8.23(s,1H),7.71(s,1H),4.29(br d,J=13.45Hz,2H),3.25(m,2H),2.61(m,1H),2.10(s,3H),1.93(br dd,J=13.20,3.30Hz,2H),1.63(m,2H)

[0237] Process 3 3-Fluoro-5-[(3S)-2-[1-[5-fluoro-6-(4-methylpyrazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]-2-methyl-benzonitrile [ka] The title compound was synthesized using HATU coupling conditions described in Example 1 using the compound from step 2 and Intermediate-03 as reagents to give 36 mg (0.072 mmol, 72% yield). LC / MS: m / z=494.2 [M+H] + ;tR:2.40 min (LC / MS method A). 1 H NMR (400.23MHz, DMSO-d 6 ):δppm 8.26(d,J=1.47Hz,1H),8.23(s,1H),7.70(s,1H),7.56(s,1H),7.43(d,J=10.27H z,1H),5.35(m,1H),4.40(m,2H),4.29(m,1H),3.93(m,1H),3.24(m,2H),3.13(br s,1H),2.88(m,1H),2.37(d,J=1.83Hz,3H),2.23(m,1H),2.10(s,3H),1.98(br d,J=11.74Hz,1H),1.80(m,1H),1.64(m,2H)

[0238] Example 15 [(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[1-[5-fluoro-6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]-4-piperidyl]methanone [ka] Process 1 Methyl 1-[5-fluoro-6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]piperidine-4-carboxylate [ka] Intermediate-11a (1.4 g, 5.12 mmol, 1 equiv.) in dioxane (16 ml) and H 2 A solution of K 2 CO 3 (1.41g, 10.23mmol, 2eq), Pd(dppf)Cl 2 (374.29 mg, 511.53 μmol, 0.1 equiv.) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.17 g, 5.63 mmol, 1.1 equiv.). The mixture was stirred at 80° C. for 12 h and then cooled to 5° C. with H 2 The mixture was diluted with 200 ml of O (30 ml) and extracted with ethyl acetate (30 ml x 2). The combined organic layers were washed with Na 2 SO 4 The residue was dried at rt, filtered, concentrated under reduced pressure and purified by flash silica gel chromatography (column: 4 g SepaFlash® silica flash column, eluent: petroleum ether and ethyl acetate, gradient: 0% to 30% ethyl acetate, flow rate: 50 ml / min) to give the title compound (1.66 g, 4.05 mmol, 79% yield) as a white solid. LC / MS: m / z 320.12 [M+H] + ;tR:0.875 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3):δppm 8.44(d,J=2.3Hz,1H),7.56(d,J=2.0Hz,1H),6.73(dd,J=2.1,3.9Hz,1H),4.46(td,J=3.4,13.7Hz,2H),4. 19(s,3H),3.83(s,1H),3.72(s,3H),3.32-3.18(m,2H),2.67(s,1H),2.03-2.01(m,1H),1.86-1.79(m,2H)

[0239] Process 2 1-[5-Fluoro-6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]piperidine-4-carboxylic acid [ka] Methyl 1-[5-fluoro-6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]piperidine-4-carboxylate (1.16 g, 2.83 mmol, 1 equiv.) in THF (8 ml) and H 2 A solution of LiOH H 2 O (237.80 mg, 5.67 mmol, 2 equiv.) was added. The reaction mixture was stirred at 25° C. for 2 h, adjusted to pH 3 with 1N HCl solution, and THF was removed under reduced pressure. The mixture was filtered and the filter cake was washed with 1N HCl solution to give the title compound (380 mg, 1.24 mmol, 44% yield) as a white solid. LC / MS: m / z 306.1 [M+H] + ;tR:0.899 min(LC / MS method C). 1 H NMR (400MHz, DMSO-d 6 ):δppm 8.44(d,J=2.5Hz,1H),7.56(d,J=2.0Hz,1H),6.72(dd,J=2.0,3.8Hz,1H),4. 44-4.21(m,2H),4.05(s,3H),3.21-3.16(m,2H),2.64-2.54(m,2H),1.93(br dd,J=3.3,13.3Hz,2H),1.68-1.57(m,2H)

[0240] Process 3 [(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[1-[5-fluoro-6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]-4-piperidyl]methanone [ka] The title compound was synthesized using HATU coupling conditions described in Example 1 using Intermediate-11a and Intermediate-01 as reagents to give 120 mg (0.25 mmol, 78% yield). LC / MS: m / z=473.1 [M+H] + ;tR:0.942 min(LC / MS method C). 1 H NMR (400 MHz, CDCl 3 ):δppm 8.43(s,1H),7.57(d,J=1.7Hz,1H),6.87-6.79(m,2H),6.77-6.67(m,2H), 5.38(dd,J=6.3,8.7Hz,1H),4.70-4.47(m,2H),4.30(dt,J=3.2,7.7Hz,1H ),4.17(s,3H),4.01-3.87(m,1H),3.35-3.21(m,2H),3.19-3.07(m,1H),2 .93-2.81(m,1H),2.40-2.29(m,1H),2.17-2.06(m,1H),2.00-1.88(m,3H) SFC: (Column: Chiralcel OD50 x 4.6 mm ID, 3 μm, Gradient: CO 2 Medium 5%~40%MeOH (0.05%DEA), flow rate: 3ml / min, column temperature: 35℃, 100bar): tR: 1.581 min (100%)

[0241] Assessment of receptor-interacting protein kinase 1 inhibition. The catalytic activity of RIPK1 was measured by monitoring the conversion of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) by autophosphorylation using ADP-Glo ​​Kinase Kit (Promega, Cat. No. V9104). In particular, 2 μl of recombinantly produced hRIPK1 (aa1-375) fusion protein (final concentration 3.6 μg / ml) and 2 μl of compound (final concentration 33300-1.69 nM; DMSO final concentration 1%) were incubated at room temperature for 30 min, and then 2 μl of ATP (ADP Glo Kit, final concentration 50 μM) was added. After further incubation at room temperature for 240 min, 5 μl of Promega ADP-Glo ​​Reagent I was added to quench the reaction and deplete unconsumed ATP. After a 30 min incubation period, 10 μl of Promega ADP-Glo ​​detection reagent II was added, which converts ADP to ATP and generates a light reaction between luciferase and luciferin. After 30 min, luminescence was quantified using a Pherastar FS (BMG LABTECH, Ortenberg). For dose-response experiments, IC values ​​with 95% confidence intervals were calculated. 50 Values ​​were calculated using a four-parameter logistic model according to Ratkowsky and Reedy, with constraints for lower and upper asymptotic values ​​of 0% and 100%. Adjustments were obtained by nonlinear regression using the Levenberg Marquardt algorithm.

[0242] Cellular assay in U937 cells to measure the activity of RIPK1 inhibitors on cell death (necroptosis). Upon TNF-receptor I ligation, the Ser / Thr kinase RIPK1 is recruited to the transient receptor complex I. Upon modification of RIPK1 that promotes RIPK1 activation, complex IIb can be formed, which is involved in the recruitment of RIPK3 and MLKL (mixed lineage kinase domain-like protein), which then translocates from the cytosol to the plasma membrane to execute cell death (Cai, Z. et al, Nat. Cell Biol. (2014) 16:55-65). Cell death was quantified in 96-well plates by determining the amount of live cells using CellTiter 96 AQueous reagent (Promega), a calorimetric method that measures the amount of live cells by reducing the tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; MTS] to formazan. The absorbance of the formazan was read at 490 nm. The inhibitory activity of the test compounds was determined by concentration-response curve (CRC) experiments. Compounds were obtained as 10 mM stock solutions and diluted 1 to 10 volumes with DMSO to obtain a 1 mM solution. From this solution, 2 μl was diluted in 998 μl growth medium. 100 μl of the 2 μM compound solution was serially further diluted with a dilution factor of 2.5 by adding 150 μl growth medium. A total of 10 concentrations ranging from 10 μM to 0.26 nM or 1 μM to 0.07 nM were tested. U937 cells were cultured in RPMI 1640 Glutamax and 10% heat-inactivated FBS. 50 μl of cell suspension containing 1 × 106 cells / ml supplemented with 50 μM zVAD.fmk (benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone) and 100 ng / ml recombinant human TNFα was dispensed into each well of a 96-well plate. 50 μl of compound dilution (see above) was added and the cell suspension was incubated at 37 °C in a humidified atmosphere (95% rH2O) at 5% CO2. 2The plates were incubated overnight (18-24 hours) at 37°C (5% CO). High controls (no compound) and low controls (no TNFα, no zVAD.fmk) were tested in seven replicates, and all compound concentrations were tested in duplicate on each experimental plate. CellTiter96 aqueous reagent was mixed (100 μl PMS (phenazine methosulfate) solution / 2 ml MTS (3-(4,5-dimethyldiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) solution) and 20 μl was added per well. The plates were incubated at 37°C (5% CO). 2 After 4 h of incubation in 95% rHO, optical density was measured at 490 nm in a microplate reader (Tecan Infinite M1000). % inhibition is expressed as a percentage of the maximum inhibition value obtained in the absence of TNFα / zVAD.fmc. For each dose-response experiment, IC values ​​with 95% confidence intervals were calculated. 50 Values ​​were calculated using a four-parameter logistic model according to Ratkowsky and Reedy without constraints using an internal application (Biost@t-Speed ​​LTS V2.3). The biological activity results are shown in Table 1 (ADP-Glo ​​IC50 (μM) and U937 IC50 (μM)).

[0243] [Table 3]

Claims

1. A compound of formula I, 【Chemical 1】 During the ceremony, A represents a 5-membered heteroaryl ring in which 2 or 3 ring atoms are independently selected from nitrogen and optionally substituted with R3 and R4; R1 is H or CH ３ represents R2 represents Cl, F or CN; R3 is H or CH ３ represents R4 is H, CH ３ or cyclopropyl, R5 represents H or F; A compound of formula I or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

2. A is selected from imidazole, pyrazole and triazole optionally substituted with R3 and R4; 2. A compound of formula I according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

3. A is, 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 wherein the dashed line indicates the bond to the pyrimidine ring of formula I; R3 is H or CH ３ represents R4 is H, CH ３ or cyclopropyl, 2. A compound of formula I according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

4. A is, represents heteroaryl selected from 1-imidazolyl and 3-pyrazolyl, optionally substituted by R3 and R4; 2. A compound of formula I according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

5. A represents a heteroaryl selected from 1-imidazolyl and 3-pyrazolyl; R1 represents H, R2 represents CN; R3 is CH ３ represents R4 represents H; R5 represents H or F; 2. A compound of formula I according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

6. The compound of formula I is 3-fluoro-5-[(3S)-2-[1-[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; 3-fluoro-2-methyl-5-[(3S)-2-[1-[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; 3-fluoro-5-[(3S)-2-[1-[6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; [(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[1-[6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]-4-piperidyl]methanone; [(3S)-3-(3-chloro-5-fluoro-phenyl)isoxazolidin-2-yl]-[1-[6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]-4-piperidyl]methanone; 3-fluoro-5-[(3S)-2-[1-[6-(3-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; 3-[(3S)-2-[1-[6-(4-cyclopropyl-2-methyl-imidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]-5-fluoro-benzonitrile; 5-[(3S)-2-[1-[6-(4-cyclopropyl-2-methyl-imidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]-3-fluoro-2-methyl-benzonitrile; 3-[(3S)-2-[1-[6-(2,5-dimethylpyrazol-3-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]-5-fluoro-benzonitrile; 3-fluoro-5-[(3S)-2-[1-[6-(3-methyl-1,2,4-triazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; 3-fluoro-5-[(3S)-2-[1-[6-(5-methyl-1,2,4-triazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; 3-fluoro-5-[(3S)-2-[1-[6-(3-methyltriazol-4-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; 3-fluoro-5-[(3S)-2-[1-[5-fluoro-6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile; 3-fluoro-5-[(3S)-2-[1-[5-fluoro-6-(4-methylpyrazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]-2-methyl-benzonitrile; and [(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-yl]-[1-[5-fluoro-6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]-4-piperidyl]methanone; 2. The compound of formula I according to claim 1, selected from: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

7. 2. The compound of formula I according to claim 1, wherein the compound of formula I is 3-fluoro-5-[(3S)-2-[1-[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

8. 2. The compound of formula I according to claim 1, wherein the compound of formula I is 3-fluoro-5-[(3S)-2-[1-[6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

9. 2. The compound of formula I according to claim 1, wherein the compound of formula I is 3-fluoro-5-[(3S)-2-[1-[5-fluoro-6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in human medicine.

11. A pharmaceutical composition comprising the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

12. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable carrier, and a thrombolytic agent, tissue plasminogen activator, anticoagulant, platelet aggregation inhibitor, antibacterial agent (antibiotic, broad-spectrum antibiotic, lactam, antimycobacterial agent, bactericidal antibiotic, anti-MRSA treatment), long-acting beta agonist, combination of inhaled corticosteroid and long-acting beta agonist, short-acting beta agonist, leukotriene modifier, anti-IgE , methylxanthine bronchodilators, mast cell inhibitors, protein tyrosine kinase inhibitors, CRTH2 / D prostanoid receptor antagonists, epinephrine inhalation aerosol, phosphodiesterase inhibitors, combination 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 loid, antithymocyte globulin, thalidomide, chlorambucil, 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, intravitreal injections, anti-vascular endothelial growth factor inhibitors, ciliary neurotrophic growth factor agents, trivalent (IIV3) inactivated influenza vaccine, quadrivalent (IIV4) inactivated influenza vaccine, trivalent recombinant influenza vaccine and one or more additional active pharmaceutical agents selected from influenza vaccines, tetravalent live attenuated influenza vaccines, antiviral agents, inactivated influenza vaccines, ciliary neurotrophic growth factor, gene transfer agents, local immunomodulators, calcineurin inhibitors, interferon gamma, antihistamines, monoclonal antibodies, polyclonal anti-T cell antibodies, anti-thymocyte gamma globulin-horse antibodies, anti-thymocyte globulin-rabbit antibodies, anti-CD40 antagonists, JAK inhibitors, and anti-TCR mouse mAbs.

13. 10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP kinase 1 mediated disease or disorder.

14. Necrotizing enterocolitis, tuberous sclerosis, Tangier disease, Wolman 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, psoriatic arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune diseases Infectious hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia, ischemia-reperfusion injury of solid organs, cerebral ischemia, sepsis, systemic inflammatory response syndrome, 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, Behcet's disease, interleukin-1 converting enzyme activity Multi-fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, periodontitis, infection, bacterial infection, staphylococcal infection, mycobacterial infection, influenza, transplant rejection, burns, hypoxia, trauma, stroke, myocardial infarction, lysosomal storage disease, Niemann-Pick disease, Gaucher disease, Krabbe disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's disease), HIV-associated dementia, encephalopathy, retinal degenerative disease, glaucoma, age-related macular degeneration, Friedreich's disease 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in the treatment of ataxia, Lewy body disease, diabetic neuropathy, polyglutamine (polyQ) disease, Fahr's disease, Menke's disease, Wilson's disease, prion disorders, atherosclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, major depressive disorder, bipolar disorder, mental retardation, postoperative cognitive impairment, autism, schizophrenia, hidradenitis suppurativa, and incontinentia pigmenti.

15. 10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for use in the treatment of Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and incontinentia pigmenti.

16. 10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in the treatment of Alzheimer's disease.

17. 10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in the treatment of multiple sclerosis.

18. 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in the treatment of amyotrophic lateral sclerosis (ALS).

19. 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in the treatment of incontinentia pigmenti.

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